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Sociedade Brasileira de Cardiologia • ISSN-0066-782X • Volume 105, Nº 4, October 2015
Figure 1 – Thematic maps of the mean mortality rate from cardiovascular diseases (MMRCD) per
thousand inhabitants in each Brazilian state and gender in the periods from 1996 to 2000 and from
2006 to 2010. Natal (RN), Brazil, 2015. Source: Department of Informatics the Unified Health System
(DATASUS)/ Ministry of Health, 2015. Page 375
Editorial
Development and Validation of Predictive Models of Cardiac Mortality
Cardiovascular Risk Factors: From Consolidated Knowledge to a Call
and Transplantation in Resynchronization Therapy
for Action
Special Article
Executive Summary of the Guidelines on Stable Coronary Disease
Changes in Medical Management after Coronary CT Angiography
Review Article
A Systematic Review on Sleep Duration and Dyslipidemia in
Original Articles
Adolescents: Understanding Inconsistencies
Acute Coronary Syndrome Treatment Costs from the Perspective of the
Viewpoint
Supplementary Health System
Patient Management with Metallic Valve Prosthesis during Pregnancy
The Benefits of Prone SPECT Myocardial Perfusion Imaging in
and Postpartum Period
Reducing Both Artifact Defects and Patient Radiation Exposure
Anatomopathological Session
Palliative Senning in the Treatment of Congenital Heart Disease with
Case 4 – A 79-Year-Old Man with Congestive Heart Failure Due to
Severe Pulmonary Hypertension
Restrictive Cardiomyopathy
Anxiety, Depression, and General Psychological Distress in Patients
Case Report
with Coronary Slow Flow
Percutaneous Treatment of Mitral Paraprosthetic Regurgitation: an
Mortality from Cardiovascular Diseases in the Elderly: Comparative
Analysis of Two Five-year Periods
Sex-Specific Equations to Estimate Maximum Oxygen Uptake in
Cycle Ergometry
A Novel Algorithm to Quantify Coronary Remodeling Using Inferred
Normal Dimensions
Alternative to Surgery
Image
Persistent Left Superior Vena Cava in Permanent Pacemaker
Implantation
Erratum
A JOURNAL OF SOCIEDADE BRASILEIRA DE CARDIOLOGIA - Published since 1948
Contents
Editorial
Cardiovascular Risk Factors: From Consolidated Knowledge to a Call for Action
Guilherme Brasil Grezzana e Lucia Campos Pellanda
.....................................................................................................................................................................page 325
Special Article
Executive Summary of the Guidelines on Stable Coronary Disease
Luiz Antonio Machado César, Antonio de Pádua Mansur, João Fernando Monteiro Ferreira
.....................................................................................................................................................................page 328
Original Articles
Coronary Angioplasty with and without Stent
Acute Coronary Syndrome Treatment Costs from the Perspective of the Supplementary Health System
Vanessa Teich, Tony Piha, Lucas Fahham, Haline Bianca Squiassi, Everton de Matos Paloni, Denizar Vianna
Araújo, Paulo Miranda
.....................................................................................................................................................................page 339
Nuclear Cardiology and PET
The Benefits of Prone SPECT Myocardial Perfusion Imaging in Reducing Both Artifact Defects
and Patient Radiation Exposure
Maria Stathaki, Sophia Koukouraki, Emmanouela Papadaki, Angeliki Tsaroucha, Nikolaos Karkavitsas
.....................................................................................................................................................................page 345
Cardiac Surgery – Adults
Palliative Senning in the Treatment of Congenital Heart Disease with Severe Pulmonary Hypertension
Juliano Gomes Penha, Leina Zorzanelli, Antonio Augusto Barbosa-Lopes, Edimar Atik, Leonardo Augusto Miana,
Carla Tanamati, Luiz Fernando Caneo, Nana Miura, Vera Demarchi Aiello, Marcelo Biscegli Jatene
.....................................................................................................................................................................page 353
Chronic Acute Coronary Syndrome
Anxiety, Depression, and General Psychological Distress in Patients with Coronary Slow Flow
Mehmet Baran Karataş, Ebru Şahan, Kazım Serhan Özcan, Yiğit Çanga, Barış Güngör, Tolga Onuk, Göktürk İpek,
Yasin Çakıllı, Emre Arugaslan, Osman Bolca
.....................................................................................................................................................................page 362
Arquivos Brasileiros de Cardiologia - Volume 105, Nº 4, October 2015
Epidemiology
Mortality from Cardiovascular Diseases in the Elderly: Comparative Analysis of Two Five-year Periods
Grasiela Piuvezam, Wilton Rodrigues Medeiros, Andressa Vellasco Costa, Felipe Fonseca Emerenciano, Renata
Cristina Santos, Danilo Silveira Seabra
.....................................................................................................................................................................page 371
Ergospirometry
Sex-Specific Equations to Estimate Maximum Oxygen Uptake in Cycle Ergometry
Christina G. de Souza e Silva e Claudio Gil S. Araújo
.....................................................................................................................................................................page 381
Hemodynamics - Adults
A Novel Algorithm to Quantify Coronary Remodeling Using Inferred Normal Dimensions
Breno A. A. Falcão, João Luiz A. A. Falcão, Gustavo R. Morais, Rafael C. Silva, Augusto C. Lopes, Paulo R.
Soares, José Mariani Jr, Roberto Kalil-Filho, Elazer R. Edelman, Pedro A. Lemos
.....................................................................................................................................................................page 390
Resynchronization
Development and Validation of Predictive Models of Cardiac Mortality and Transplantation in
Resynchronization Therapy
Eduardo Arrais Rocha, Francisca Tatiana Moreira Pereira, José Sebastião Abreu, José Wellington O. Lima,
Marcelo de Paula Martins Monteiro, Almino Cavalcante Rocha Neto, Camilla Viana Arrais Goés, Ana Gardênia
P. Farias, Carlos Roberto Martins Rodrigues Sobrinho, Ana Rosa Pinto Quidute, Maurício Ibrahim Scanavacca
.....................................................................................................................................................................page 399
Cardiovascular Computed Tomography
Changes in Medical Management after Coronary CT Angiography
Vânia Mairi Naue, Gabriel Camargo, Letícia Roberto Sabioni, Ronaldo de Souza Leão Lima, Maria Eduarda
Derenne, Andréa Rocha de Lorenzo, Monica Di Calafiori Freire, Clério Francisco Azevedo Filho, Elmiro Santos
Resende, Ilan Gottlieb
.....................................................................................................................................................................page 410
Review Article
A Systematic Review on Sleep Duration and Dyslipidemia in Adolescents: Understanding
Inconsistencies
Gabriela de Azevedo Abreu, Laura Augusta Barufaldi, Katia Vergetti Bloch, Moyses Szklo
.....................................................................................................................................................................page 418
Viewpoint
Patient Management with Metallic Valve Prosthesis during Pregnancy and Postpartum Period
Juliane Dantas Seabra Garcez, Vitor Emer Egypto Rosa, Antonio Sergio de Santis Andrade Lopes, Tarso Augusto Duenhas
Accorsi, João Ricardo Cordeiro Fernandes, Pablo Maria Pomerantzeff, Walkiria Samuel Avila, Flavio Tarasoutchi
.....................................................................................................................................................................page 426
Anatomopathological Session
Case 4 – A 79-Year-Old Man with Congestive Heart Failure Due to Restrictive Cardiomyopathy
Sumaia Mustafa, Alice Tatsuko Yamada, Fabio Mitsuo Lima, Valdemir Melechco Carvalho,Vera Demarchi Aiello
e Jussara Bianchi Castelli
.....................................................................................................................................................................page 430
Arquivos Brasileiros de Cardiologia - Volume 105, Nº 4, October 20X15
Case Report
Percutaneous Treatment of Mitral Paraprosthetic Regurgitation: an Alternative to Surgery
Roney Orismar Sampaio, Alessandra Gomes de Oliveira, George Barreto Miranda, Pedro Alves Lemos Neto,
Marcelo Luiz Campos Vieira, Flávio Tarasoutchi
.....................................................................................................................................................................page 440
Image
Persistent Left Superior Vena Cava in Permanent Pacemaker Implantation
Jerson Hernando Quitián, José Julian Carvajal, Mariana Soto, Guillermo Mora
.....................................................................................................................................................................page 443
Erratum
.....................................................................................................................................................................page 445
Arquivos Brasileiros de Cardiologia - Volume 105, Nº 4, October 2015
www.arquivosonline.com.br
A JOURNAL OF SOCIEDADE BRASILEIRA DE CARDIOLOGIA - Published since 1948
Scientific Director
Maria da Consolação V. Moreira
Interventionist Cardiology
Pedro A. Lemos
Chief Editor
Luiz Felipe P. Moreira
Pediatric/Congenital Cardiology
Antonio Augusto Lopes
Associated Editors
Arrhythmias/Pacemaker
Mauricio Scanavacca
Clinical Cardiology
José Augusto Barreto-Filho
Non-Invasive Diagnostic Methods
Carlos E. Rochitte
Surgical Cardiology
Paulo Roberto B. Evora
Basic or Experimental Research
Leonardo A. M. Zornoff
Epidemiology/Statistics
Lucia Campos Pellanda
Arterial Hypertension
Paulo Cesar B. V. Jardim
Ergometrics, Exercise and
Cardiac Rehabilitation
Ricardo Stein
First Editor (1948-1953)
† Jairo Ramos
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Exterior
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Sociedade Brasileira de Cardiologia
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Arquivos Brasileiros de Cardiologia
Volume 105, Nº 4, October 2015
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SUPPORT
Back to the Cover
Editorial
Cardiovascular Risk Factors: From Consolidated Knowledge to a Call
for Action
Guilherme Brasil Grezzana1 and Lucia Campos Pellanda1,2
Fundação Universitária de Cardiologia do Rio Grande do Sul1 – ICFUC; Universidade Federal de Ciências da saúde de Porto Alegre2 – UFCSPA,
Porto Alegre, RS – Brazil
Since the decade of 1950, the most prominent journal
in cardiology in Brazil, Arquivos Brasileiros de Cardiologia
(ABC), has been indexed in Medline1. A total of 7,102
articles have been published since then, on various subjects
related to clinical, invasive, surgical cardiology, as well as
diagnostic methods.
We performed a systematic review of articles published
in ABC during the period from January 2001 to June 2015
containing the MeSH term “cardiovascular risk factors”.
Of the 3,087 titles of articles published in the period, 116
articles were identified. The abstracts of these articles
were reviewed, and 107 articles, in which assessment of
cardiovascular risk factors was the main topic, were included.
The sample was composed by 102 original articles, 3 letters
and 2 editorials. When specific topics were assessed,
“cardiovascular factor or cardiovascular risk” was generally
described in 88 articles, 6 articles focused on quality of life and
cardiovascular risk factor, 4 articles described epidemiological
factors and risk factors, 5 articles specifically explored systemic
arterial hypertension and risk factors, 3 were guidelines on
risk factors and 1 articles related risk factor with public health.
However, when we focused only on isolated risk factors, there
has been a clear preponderance of articles involving arterial
hypertension (18% between 2010 and 2013) and a trend of
increase in the number of articles on diabetes (approximately
10%) published on ABC in the last years.
The average annual number of articles focused on
cardiovascular risk factors published on ABC has been
Keywords
Risk Factors; Cardiovascular Diseases; Prevention;
Epidemiologic Studies; Data Interpretation Statistical;
Journals Articles.
Mailing Address: Lucia Campos Pellanda •
Av. Princesa Isabel, 370, Santana Postal Code 90620-000. Porto Alegre,
RS – Brazil
E-mail: [email protected]
DOI: 10.5935/abc.20150128
325
consistent in the last 15 years, with a mean of 3.47% of total
publications per year, and no significant differences between
years (p = 0.195) (Table 1). Considering SciELO database
and the number of accesses to the articles selected between
January 2014 and June 2015, the 2 most accessed articles were
cross-sectional studies on metabolic syndrome and systemic
arterial hypertension (Table 2)2,3.
In 2005, an ABC editorial discussed the cardiovascular
risk factors in Brazil and the perspective of cardiovascular
epidemiology in the next 50 years4. National data published
at that time (one study conducted in São Paulo metropolitan
region and the AFIRMAR study)5,6, and a study with students
about life style and cardiovascular disease7 revealed that
predictive factors of atherosclerosis in Brazil were not different
from those in Europe and North America8. In addition,
there is a relationship between early mortality caused by
cardiovascular disease and social inequality9. However, ten
years after publication of this editorial, which clarified the
definitions of cardiovascular risks in Brazil, most studies about
this topic published on ABC have had an observational design.
This trend may be found in a review of articles published on
ABC in the last 60 years10. Therefore, the current scenario is
of consolidation and confirmation of traditional risk factors
for cardiovascular events, associated with results of mortality
rates for ischemic and cerebrovascular disease in different
regions of the country.
Therefore, the challenge of cardiovascular epidemiology
and of academic publishing in the next years is to promote
the development of interventional studies. This approach, in
line with primary and secondary prevention measures, may
contribute to changes in the epidemiology of cardiovascular
risks in Brazil in the coming years. Thus, the role of the leading
journal in cardiology in Brazil is to support solid evidence that
serve as the basis for practices in our society.
Grezzana & Pellanda
Cardiovascular risk factors: from consolidated knowledge to call to action
Editorial
Table 1 – Total of publications on cardiovascular risk factors between 2001 and 2015 identified by search of MeSH term and revision of the
articles’ title and abstract
Year
N
N-Reviewed
% N-Reviewed/N
2001
134
4
2.98%
2002
168
3
1.78%
2003
160
5
3.12%
2004
184
2
1.08%
2005
224
8
3.57%
2006
274
11
4.05%
2007
244
9
3.68%
2008
172
5
2.9%
2009
259
11
4.24%
2010
331
18
5.43%
2011
235
5
2.12%
2012
209
4
1.91%
2013
236
10
4.23%
2014
227
9
3.96%
2015
30
3
10%
Total
3087
107
3.47%
N: Number of articles published; N-Reviewed: Articles selected from the review of abstracts; % N-Reviewed/N: % of articles on cardiovascular risk factors in relation
to total number of articles published.
Table 2 – List of articles selected in 2014 and 2015 and the number of accesses accroding to SciELO database (date of access 06/23/15)
Access
Year
Vol/N/Pags
Article title
Design
Country
Study City
100
2014
V 102, n 4, p 345-354
Dietary interventions and blood pressure
In Latin America: systematic review and
meta-analysis
SR
Curitiba
Brazil
280
2014
V 102,n 4, p 374-382
Alimentary habits, physical activity,
and Framingham global risk score in
metabolic syndrome
CSS
Porto Alegre
Brazil
119
2014
V 103,n 21; p 1-31
South American gruidelines for
cardiovascular disease prevention
and rehabilitation
G
–
Brazil
168
2014
V 103,n 6, p 493-501
Comparison of cardiovascular risk
factors in different areas of health care
over a 20-year period
CS
Goiânia
Brazil
107
2014
V 102,n 5, p 473-480
Prevalence of cardiovascular risk
factors in hemodialysis patients – The
CORDIAL study
CSS
Porto Alegre
Brazil
235
2014
V 102,n 6, p 571-578
Blood pressure control In hypertensive
patients in the “Hiperdia Program”: a
territory-based study
CSS
Porto Alegre
Brazil
151
2014
V 102,n 5, p 420-431
l cardiovascular prevention guideline of
the BSC – executive summary
D
–
Brazil
CSS: Cross-sectional study; G: Guidelines; CS: cohort study; SR: Systematic review; BSC: Brazilian Society of Cardiology
Arq Bras Cardiol. 2015; 105(4):325-327
326
Grezzana & Pellanda
Cardiovascular risk factors: from consolidated knowledge to call to action
Editorial
References
1.
Stein R, Araújo CG. Heart, exercise and the Brazilian Archives of Cardiology.
Arq Bras Cardiol. 2011;97(6):446-8.
2.
Soares TS, Piovesan CH, Gustavo Ada S, Macagnan FE, Bodanese LC, Feoli
AM. Alimentary habits, physical activity, and Framingham global risk score
in metabolic syndrome. Arq Bras Cardiol. 2014;102(4):374-82.
3. Souza CS, Stein AT, Bastos GA, Pellanda LC. Blood pressure control in
hypertensive patients in the “Hiperdia Program”: a territory-based study.
Arq Bras Cardiol. 2014;102(6):571-8.
4. Polanczyk CA. [Cardiovascular risk factors in Brazil: the next 50 years!].
Arq Bras Cardiol. 2005;84(3):199-201.
5. Avezum A, Piegas LS, Pereira JC. [Risk factors associated with
acute myocardial infarction in the São Paulo metropolitan region:
a developed region in a developing country]. Arq Bras Cardiol.
2005;84(3):206-13.
327
Arq Bras Cardiol. 2015; 105(4):325-327
6. Piegas LS, Avezum A, Pereira JC, Neto JM, Hoepfner C, Farran JA, et al;
AFIRMAR Study Investigators. Risk factors for myocardial infarction in Brazil.
Am Heart J. 2003;146(2):331-8.
7.
Lancarotte I, Nobre MR, Zanetta R, Polydoro M. Lifestyle and cardiovascular
health in school adolescents from São Paulo. Arq Bras Cardiol. 2010;95(1):61-9.
8. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, et al;
INTERHEART Study Investigators. Effect of potentially modifiable risk factors
associated with myocardial infarction in 52 countries (the INTERHEART
study): case-control study. Lancet. 2004;364(9438):937-52.
9. Bassanesi SL, Azambuja MI, Achutti A. Premature mortality due to
cardiovascular disease and social inequalities in Porto Alegre: from evidence
to action. Arq Bras Cardiol. 2008;90(6):370-9.
10. Evora PR, Nather JC, Rodrigues AJ. Prevalence of heart disease demonstrated
in 60 years of the Arquivos Brasileiros de Cardiologia. Arq Bras Cardiol.
2014;102(1):3-9.
Back to the Cover
Special Article
Executive Summary of the Guidelines on Stable Coronary Disease
Luiz Antonio Machado César, Antonio de Pádua Mansur, João Fernando Monteiro Ferreira
Instituto do Coração (InCor) HC-FMUSP, São Paulo, SP – Brasil
Part I – Diagnosis and risk stratification
Diagnosis
Introduction
Diagnosis of subclinical coronary artery disease
The risk of atherosclerotic disease may be measured by
the sum of individual risks and by the synergism between the
known risk factors for cardiovascular disease. Due to these
complex interactions, an intuitive approach of risk attribution
frequently lead to underestimation or overestimation of cases
with higher or low risk, respectively.
These guidelines aim to assist physicians, particularly
cardiologists, to identify adults at high risk of coronary disease as
early as possible, and to highlight its most common symptoms,
especially coronary arery disease (CAD) symptoms.
According to Brazilian’s Unified Health System database
(DATASUS), cardiovascular causes represent nearly 30% of all
causes of death in Brazil1.
Recommendation levels:
• Class I: conditions for which there is conclusive
evidence or general agreement that the procedure is
useful/effective;
• Class II: conditions for which there is conflicting
evidence and/or divergence of opinion about the
usefulness/efficacy of the procedure;
• Class IIa: weight of evidence/opinion in favor of
usefulness/efficacy. Approved by the majority of
the professionals;
• Class IIb: safety and usefulness/efficacy is less well
established, with no predominance of opinion in favor
of the procedure;
• Class III: conditions for which there is evidence and/or
general agreement that the procedure is not useful or
effective and in some cases may be harmful;
Evidence level:
• Level A: data derived from multiple consistent, large
randomized clinical trials and/or robust systematic
meta‑analysis of randomized clinical trials.
• Level of evidence B: data derived from a less
robust meta-analysis, a single randomized trial or
nonrandomized (observational) studies.
• Level of evidence C: data derived from consensus
opinion of experts.
Keywords
Coronary Artery Disease; Diagnosis; Risk Factors; Physical
Examination; Atherosclerosis.
Mailing Address: Luiz Antonio Machado César •
Av. Dr. Enéas de Carvalho Aguiar, 44. Cerqueira Cesar, Postal Code 05403-000.
São Paulo, SP – Brazil
Email: [email protected]
Manuscript received September 23, 2015; revised manuscript September
23, 2015; accepted September 23, 2015.
DOI: 10.5935/abc.20150136
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Diagnosis of symptomatic patients
The approach proposed by Diamond and Forrester2,3
(Table 1): Level of recommendation I, evidence level B was
considered for diagnosis.
For the assessment of cardiovascular risk, the Brazilian
Guidelines for Atherosclerosis Prevention and the V
Brazilian Guidelines on Dyslipidemia and Atherosclerosis
Prevention were used4,5. (Level of recommendation IIa,
evidence level B).
Diagnosis of manifest coronary artery disease
History, physical examination, differential diagnosis
Definition of angina
Angina is a clinical syndrome characterized by pain or
discomfort in any of the following regions: chest, epigastrium,
mandible, shoulder, dorsum, or upper limbs. It is triggered
or aggravated by physical activity or emotional stress and
attenuated by nitroglycerin and its derivatives.
Clinical assessment of patients with chest pain
a) Clinical history: Detailed clinical history. Some
characteristics should be carefully investigated to determine
the probability of the presence of angina:
quality: constriction, tightness, heaviness, distress,
suffocation, discomfort, burning, and stabbing; location:
precordium, retrosternal area, shoulder, epigastrium, neck,
hemithorax and dorsum; irradiation: upper limbs (right, left,
or both), shoulder, mandible, neck, dorsum, and epigastrium;
duration: seconds, minutes, hours, or days; triggering factors:
exertion, sexual activity, position, eating habits, breathing,
emotional component , and spontaneous; relieving factors:
rest, sublingual nitrates, analgesic, food, antacids, position,
and apnea; associated symptoms: sweating, nausea, vomiting,
pallor, dyspnea, hemoptysis, cough, presyncope, and syncope.
An episode of angina lasts for a few minutes. It is generally
triggered by exertion of emotional stress, and relieved by rest.
The use of nitroglycerin, such as sublingual nitrate, relieves
César et al
Summary of the guidelines on stable coronary disease
Special Article
Table 1 – Pre-test probability of coronary artery disease in symptomatic patients by age and sex (Diamond/Forrester e CASS Data)
Age (years)
Nonanginal chest pain
Male
Female
35
3-35
45
9-47
55
65
Atypical angina
Typical angina
Male
Female
Male
Female
1-19
8-59
2-39
30-88
10-78
2-22
21-70
5-43
51-92
20-79
23-59
4-25
25-79
10-47
80-95
38-82
49-69
9-29
71-86
20-51
93-97
56-84
angina within approximately 1 min. Pain in the chondrosternal
joints is rarely of cardiac origin.
The Canadian Cardiovascular Society (CCS) grading of
angina pectoris6 is the most widely used classification of
angina (Chart 1).
b) Physical examination: Physical examination is usually
normal in patients with stable angina. However, during
an episode of angina, it may provide important evidence
about the presence of absence of CAD. When physical
examination is performed during an episode of pain, third
heart sound (S3), fourth heart sound (S4) or gallop, mitral
regurgitation, paradoxical splitting of the second heart sound
(S2), and bibasilar crackles are suggestive and predictive
indicators of DAC7. The occurrence of atherosclerosis in
other regions, including decreased pulse in lower limbs,
arterial hardening, and abdominal aneurysm, increase the
likelihood of CAD.
Differential diagnosis of chest pain: associated conditions,
and provoking and relieving factors of angina
In all patients, especially in those with typical angina,
associated (simultaneous) diseases that can precipitate
“functional” angina, i.e. myocardial ischemia in the
absence of significant anatomic coronary obstruction,
should be considered. These diseases generally cause
myocardial ischemia either by increasing myocardial oxygen
consumption or by decreasing the oxygen supply. An increase
in oxygen consumption may be caused by hyperthermia,
hyperthyroidism, and cocaine use. Obstructive sleep apnea
should be seriously considered in patients with significant
nocturnal symptoms.
Electrocardiogram
The test is indicated when a cardiac cause of chest pain
is suspected (level of recommendation I, evidence level B).
Chest radiography
Chest radiography is indicated for patients with CAD
and signs or symptoms of congestive heart failure (level of
recommendation I, evidence level B), and patients with signs
and symptoms of pulmonary disease (level of recommendation
IIa, evidence level B).
Exercise treadmill test
The most predictive variables in the diagnosis of coronary
obstruction are ST-segment depression ≥ 1 mm (measured at
0.80 seconds from the J-point), with a horizontal or descending
pattern, and presence of anginal pain.
Exercise treadmill test for the diagnosis of coronary obstruction
Level of recommendation I, evidence level B
1. Intermediate probability
Level of recommendation IIa, evidence level B
1. Suspected vasospastic angina.
2.Coronary angiography for assessment of intermediate
lesions.
3. Asymptomatic individuals with more than two risk factors.
Level of recommendation IIb, evidence level B
1. A high or low pretest probability of coronary obstruction,
based on age, sex and symptoms.
2.Risk assessment for noncardiac surgery (in low
cardiovascular risk).
Noninvasive tests
Additional tests in stable angina are based on the probability
of CAD. After estimating the probability, it is categorized as low,
intermediate, or high according to established values: 10%–90%
in intermediate probability, < 10% in low probability, and
> 90% in high probability cases.
Level of recommendation III: abnormalities: preexcitation syndrome or Wolff-Parkinson-White syndrome,
pacemaker rhythm, ST-segment depression >1 mm at rest,
and complete left bundle-branch block.
Since overall mortality of patients with stable angina
varies from 1.2% to 2.4% per year8, a diagnostic method
that leads to a higher incidence of complications and death
would be inappropriate.
Echocardiography
Echocardiography may help in the diagnosis9, by showing
reversible and irreversible abnormalities in segmental motion
in patients with clinical features of CAD.
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Chart 1 – Canadian Cardiovascular Society grading of angina pectoris
Class I
Habitual physical activity, such as walking and climbing sairs, does not cause angina. Angina occurs during prolonged or strenuous physical activity.
Class II
Slight limitation for habitual activities. Angina during walking or climbing stairs rapidly, walking uphill, walking or climbing stairs after meals or in
the cold, in the wind or under emotional stress, or within a few hours after waking up. Angina occurs after walking two blocks or climbing more
than 1 flight of stairs in normal conditions.
Class III
Limitation of habitual activities. Angina occurs after walking one block or climbing 1 flight of stairs.
Class IV
Unable to carry on any habitual physical without discomfort. Angina symptoms may be present at rest.
a) Stress echocardiography in chronic coronary
atherosclerotic disease: the test is used in diagnosis and
prognosis, to assess the impact of revascularization therapies
and myocardial viability, and to support therapeutic decisions.
The test has good accuracy for induced myocardial ischemia
in patients with intermediate or high pretest probability, with
higher diagnostic sensitivity and specificity as compared with
the exercise treadmill test10.
Level of recommendation IIa, evidence level B
Asymptomatic individuals at low risk using the overall risk
score and family history of early CAD.
Level of recommendation IIIa, evidence level B
1.Asymptomatic patients at high risk of CAD or with
known CAD.
2. Follow-up of coronary calcification progression.
b) Preoperative evaluation: according to recommendations
of the American College of Cardiology/American Heart
Association (ACC/AHA) and the European Association
of Cardiovascular Imaging (EACVI), dobutamine stress
echocardiography has been valuable in preoperative risk
stratification in patients with CAD11.
Radioisotopes
Aspects of myocardial perfusion, cellular integrity, myocardial
metabolism, myocardial contractility, and global or segmental
ventricular function are evaluated 12. The radioisotope
thallium-201 is less frequently used because of its association
with higher radiation, and is indicated for the detection of
ischemia concomitant with viable myocardium.
Coronary angiography
Coronary lesions are significant when one or more
epicardial arteries are obstructed, with at least 70% stenosis
and/or stenosis greater than 50% of the left main coronary
artery. Assessment and measurement of obstructions are
performed using coronary angiography (Chart 2).
3. Symptomatic patients.
b) Coronary computed tomography angiography
Coronary computed tomography angiography enables the
noninvasive evaluation of the lumen of coronary arteries14.
The test is clinically indicated for symptomatic patients
with conflicting results between ischemia and clinical tests.
Level of recommendation IIa, evidence level A
Suspected chronic CAD using:
a) Previous conflicting or inconclusive ischemia tests;
b) Continuous symptoms and ischemia tests with normal
or inconclusive results.
Level of recommendation IIa, evidence level B
1.To assess the patency of grafts for myocardial
revascularization in symptomatic individuals with
pretest probability.
Level of recommendation IIb, evidence level B
Cardiac computed tomography
There are two main modes of examinations using cardiac
computed tomography that use different techniques and
provide different information: the calcium score and coronary
computed tomography angiography.
1. Symptomatic individuals with intermediate probability
of CAD and positive ischemia tests.
2. Symptomatic individuals with low probability of CAD
and negative ischemia tests.
3.Assessment of in-stent restenosis in symptomatic
individuals with intermediate pretest probability.
a) Calcium score
Quantification of coronary artery calcification using calcium
score correlates with the atheroscleroctic load13.
Level of recommendation I, evidence level A
Asymptomatic individuals at intermediate risk using the
overall risk score.
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Level of recommendation III, evidence level B
1. Symptomatic individuals with high probability of CAD.
2. Initial evaluation of CAD in asymptomatic individuals,
able to exercise and with interpretable electrocardiogram.
3.Follow-up of coronary atheroscleroctic lesions in
asymptomatic individuals.
César et al
Summary of the guidelines on stable coronary disease
Special Article
Chart 2 – Recommendations for coronary angiography in patients with coronary artery disease
Stable angina (CCS III or IV) despite clinical treatment (B)
Class I
High risk in noninvasive tests, regardless of angina (B)
Angina and cardiac arrest or severe ventricular arrhythmia survivors (B)
Angina and symptoms/signs of congestive heart failure (C)
Patients with uncertain diagnosis after noninvasive tests, when the benefits of an accurate diagnosis outweigh the risks and costs of coronary
angiography (C)
Class IIa
Unable to undergo noninvasive tests due to physical disability, illness, or obesity (C)
High-risk jobs that require an accurate diagnosis (C)
Patients with uncertain prognostic information after noninvasive tests (C)
Class IIb
Multiple hospitalizations for chest pain, when a definitive diagnosis is considered necessary (C)
Significant comorbidities, when the risks of angiography outweigh the benefits of the procedure (C)
Class III
Stable angina (CCS I or II) that responds to drug treatment and no evidence of ischemia in noninvasive tests (C)
Preference to avoid revascularization (C)
CCS: Canadian Cardiovascular Society.
Cardiovascular magnetic resonance imaging
Magnetic resonance imaging is an excellent diagnostic method;
it allows the assessment of cardiac and vascular anatomy, ventricular
function, myocardial perfusion, and tissue characterization in an
accurate, reproducible manner, in a single test15.
a) Myocardial ischemia
The protocols for the investigation of ischemia by magnetic
resonance with myocardial perfusion are similar to those used
in scintigraphy.
b) Delayed enhancement
The diagnosis and characterization of areas of myocardial
infarction/necrosis/fibrosis using CMR is based on the delayed
enhancement technique16-18.
c) Coronary magnetic resonance angiography
The clinical use of the test has been focused on the
assessment of congenital anomalies and the origin and course
of the coronary arteries19.
Recommendations for magnetic resonance imaging
Level of recommendation I, evidence level A
Evaluation of the global (left and right) ventricular function,
volume, and mass
Detection of ischemia:
• Assessment of myocardial perfusion under stress using
vasodilators.
• Assessment of ventricular contractility using dobutamine
stress magnetic resonance.
• Detection and quantification of myocardial fibrosis
and infarction.
• Assessment of myocardial viability.
Level of recommendation I, evidence level B
Differentiation between ischemic and nonischemic cardiopahty
• Coronary magnetic resonance angiography:
• Assessment of congenital anomalies.
Cardiovascular risk stratification in CAD
The strategies and methods used in the diagnosis of CAD
also provide information on disease severity, with implications
for complementary invasive methods, including coronary
angiography, and therapeutic decision-making.
Exercise treadmill test for the prognosis of coronary
atherosclerosis
Level of recommendation I, evidence level B
Patients with intermediate or high probability of CAD after
initial evaluation; patients showing changes in symptoms.
Level of recommendation IIb, evidence level B
Patients with pre-excitation, ST-segment depression
> 1 mm in echocardiogram at rest, pacemaker rhythm, and
complete left bundle-branch block.
Level of recommendation IIa, evidence level C
Revascularized patients with symptoms suggestive
of ischemia.
Level of recommendation III, evidence level C
Patients with severe comorbidities.
In patients with CAD who are able to reach stage 3 of the
Bruce protocol, the annual mortality rate is approximately
1%, whereas in those unable to exceed 5 METs, the annual
mortality rate is approximately 5%20.
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Other high-risk variables include ST-segment depression in
multiple leads, persistent ST-segment depression in recovery
phase > 5 min, inadequate chronotropic response, fall in
systolic blood pressure during physical exertion or a flat curve,
and severe ventricular arrhythmia at low level of exercise in
the presence of ST-segment depression or anginal pain.
Stress echocardiography
Echocardiography for CAD prognosis takes into account
mainly the left ventricle function, and the presence or absence
of myocardial ischemia induced by physical or pharmacological
stress on echocardiography. In asymptomatic patients who have
successfully undergone coronary artery bypass graft surgery
(CABG), routine evaluation using stress echocardiography is
not indicated. Other important variables for risk stratification
include pulmonary uptake of thallium in myocardial perfusion
scintigraphy, and the transient increase in the left ventricle.
Strategies for the diagnosis and stratification of coronary
artery disease
The prognosis of CAD may also be based on the direct
anatomical visualization of the coronary lesion by coronary
angiography. Normal functional testing, performed with
appropriate stress protocol yields the same prognosis as
compared with the standard coronary angiography test.
For specific situations and after implantation of antiproliferative
drugs-coated stent, follow the Brazilian Guidelines of
Antiplatelet Agents and Anticoagulants in Cardiology.
Secondary prevention: Hypolipidemic agent
Lifestyle change (LC) is recommended for all patients with
CAD (Chart 3).
Blockade of the renin–angiotensin system
a) ACE inhibitors: the benefits of ACE inhibitors in the
treatment of CAD have been shown in clinical trials involving
asymptomatic patients with reduced ejection fraction21 and
patients with ventricular dysfunction after acute myocardial
infarction21,22. They should be used routinely for ventricular
dysfunction, and/or heart failure, and/or diabetes mellitus
management23,24. Level of recommendation I, evidence level A.
It should be used routinely in all patients with CAD: Level
of recommendation IIa, evidence level A.
Part II – Drug Treatment
b) Angiotensin receptor blockers: alternative therapy for
patients intolerant to ACE inhibitors, since no study has been
conducted on the use of this group of drugs in stable coronary
disease. In other situations, angiotensin receptor blockers have
provided no additional benefits over those of ACE inhibitors,
which can decrease the incidence of infarction.
The main objectives of the treatment of CAD are to
prevent myocardial infarction and decrease mortality, and to
reduce symptoms and the incidence of myocardial ischemia,
providing a better quality of life.
Treatment to reduce symptoms and
myocardial ischemia
Drug treatments to reduce the risk of
myocardial infarction and mortality
Antiplatelet drugs
a) Acetylsalicylic acid (ASA): Level of recommendation I,
evidence level A.
b) Thienopyridine derivatives:
Clopidogrel: Level of recommendation I, evidence level B.
Indicated when aspirin is absolutely contraindicated, and
associated with aspirin after stent implant for at least 30 days.
Ticlopidine: Level of recommendation IIa, evidence level B.
Indicated when aspirin is absolutely contraindicated, and
associated with aspirin after stent implant for at least 30 days.
c) Dipyridamole: Level of recommendation III, evidence
level B.
d) Anticoagulants: should be used in combination
with aspirin in case of high risk of thrombosis, especially
after myocardial infarction. Level of recommendation I,
evidence level A.
332
As an alternative to aspirin intolerance: Level of
recommendation IIa, evidence level A.
Arq Bras Cardiol. 2015; 105(4):328-338
a) Beta-blockers: beta-blockers are drugs of choice, to be
administered alone or in combination with other antianginal
drugs. Indicated as first-line agents in patients with stable angina
without previous myocardial infarction and/or left ventricle
dysfunction25. Level of recommendation I, evidence level B.
– First-line agents in patients with stable angina within
2 years of myocardial infarction and/or left ventricle.
Level of recommendation III, evidence level C.
– For symptomatic relief in patients with vasospastic angina:
Level of recommendation III, evidence level C.
b) Calcium-channel blockers: heterogeneous group of
drugs with pharmacological effects that include smooth muscle
relaxation, afterload reduction, and negative inotropic effects
(some formulations). On the other hand, they are contraindicated
in case of ventricular dysfunction (verapamil and diltiazem)26.
– First-line agents for symptomatic relief in patients with
vasospastic angina. Level of recommendation IIa,
evidence level B.
– In symptomatic patients with stable angina on betablockers (dihydropyridines). Level of recommendation
I, evidence level B.
– In symptomatic patients with stable angina on
beta-blockers (verapamil or diltiazem). Level of
recommendation III, evidence level B.
César et al
Summary of the guidelines on stable coronary disease
Special Article
Chart 3 – Recommendations for drug therapy in dyslipidemias
Indications
Class-level of evidence
Statins are first choice treatment in primary and secondary prevention
I-A
Fibrate monotherapy or in combination with statins to prevent microvascular diseases in type 2 diabetes patients
I-A
Associations of ezetimibe or resins with statins when LDL-C target levels are not achieved
IIa-C
Association of niacin with statins
III-A
Omega-3 fatty acids for cardiovascular prevention
IIII-A
Source: Brazilian guidelines for cardiovascular disease prevention10.
– In patients with stable angina and contraindications to
beta-blockers (preferably verapamil or diltiazem). Level
of recommendation I, evidence level B.
– In symptomatic patients with stable angina (fastacting ihydropyridines). Level of recommendation
III, evidence level B.
c) Nitrates:
– Fast-acting nitrates: for symptomatic relief of acute
angina. Level of recommendation I, evidence level B.
– Long-acting nitrates: continuous use of long-acting
nitrates leads to drug tolerance.
– First-line agents in patients with stable angina. Level of
recommendation III, evidence level C.
– Third-line agents in stable angina patients who still
have symptoms even after using other antianginal
agents associated. Level of recommendation IIa,
evidence level B.
– For symptomatic relief in patients with vasospastic
angina after using calcium-channel blockers. Level of
recommendation IIa, evidence level B.
d) Trimetazidine: drug with metabolic and anti-ischemic
effects and no effect on cardiovascular hemodynamics27.
– In symptomatic patients with stable angina on
beta-blockers alone or in combination with other
antianginal agents. Level of recommendation IIa,
evidence level B.
– In patients with stable angina and left ventricle
dysfunction associated with optimized medical therapy.
Level of recommendation IIa, evidence level B.
– In patients with stable angina during myocardial
revascularization procedures (percutaneous or surgical).
Level of recommendation IIa, evidence level B.
– In symptomatic patients with stable angina who
are intolerant to beta-blockers alone or with other
antianginal agents. Level of recommendation IIb,
evidence level B.
– In patients with stable angina, left ventricle dysfunction
(LVEF < 40%) and heart rate ≥ 70 bpm under
optimized medical therapy. Level of recommendation
IIa, evidence level B.
f) Ranolazine: piperazine derivative. Similar to trimetazidine,
it protects patients from ischemia by increasing glucose
metabolism and decreasing fatty acids oxidation. However, its
major effect appears to be the inhibition of late sodium current29.
Figures 1 and 2 depict algorithms that facilitate understanding
of drug therapy options in stable CAD.
Part III – Treatment with invasive measures
Treatment with invasive measures
Direct surgical revascularization
The Guidelines on Myocardial Revascularization30 cover
the procedure techniques, alternatives, and current practices.
They also briefly review classic studies, comparing surgical
treatment strategies with clinical treatment and percutaneous
coronary intervention.
Main indications for direct revascularization
Level of recommendation I
Left main coronary artery stenosis ≥ 50% or equivalent
conditions (left descending anterior and circumflex arteries in the
ostium, or before the exit of important branches). Evidence level A.
e) Ivabradine: a specific sinus node If current i inhibitor,
which specifically decreases the heart rate28.
Proximal stenosis (> 70%) in the three main arteries with
or without involvement of proximal left anterior descending
artery, especially in patients with ejection fraction < 50%
or functional evidence of moderate to severe ischemia.
Evidence level B.
– In symptomatic patients with stable angina on betablockers alone or with other antianginal agents, and
heart rate > 70 bpm. Level of recommendation IIa,
evidence level B.
Stenosis in two main vessels, with proximal left anterior
descending artery lesion in patients with ejection fraction
< 50% or functional evidence of moderate to severe ischemia.
Evidence level B.
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Figure 1 – Algorithm for drug treatment of stable angina with antianginal drugs to relieve symptoms and improve quality of life. Details, levels of recommendation and
evidence level: see the corresponding text.
Level of recommendation IIa
Left internal mammary artery graft in patients with
significant stenosis (> 70%) in proximal left anterior
descending artery and evidence of extensive ischemia, aiming
to improve survival. Evidence level B.
Coronary artery by-pass surgery instead of percutaneous
coronary intervention in patients with multivessel CAD and
diabetes mellitus, particularly in those who underwent internal
mammary artery grafting with revascularization to the left
anterior descending artery. Evidence level B.
functional lesions (e.g., fractional flow reserve > 0.8 or mild
ischemia in noninvasive tests). Evidence level C.
Involvement of one or two arteries, except for the proximal
left anterior descending artery, with no evidence of relevant
ischemia in functional tests, and presence of perfusion in small
areas of viable myocardium. Evidence level B.
Moderate lesions (between 50% and 60%) except in left main
coronary artery, without moderate ischemia in functional tests.
Insignificant lesions (< 50%).
The “Heart Team” concept for myocardial revascularization
Level of recommendation III
Asymptomatic patients with normal ventricular function,
without extensive areas of ischemia or involvement of the left
anterior descending artery. Evidence level C.
Asymptomatic patients without significant anatomical
lesions (< 70%, or < 50% of the left main coronary artery) or
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Class I
A team made up of clinical cardiologists, cardiac
surgeons and interventional cardiologists is recommended
to individualize the indication for the treatment of left main
coronary artery lesions or complex CAD. Evidence level C31.
César et al
Summary of the guidelines on stable coronary disease
Special Article
Figure 2 – Algorithm for reduction of cardiovascular events in the presence of left ventricular dysfunction. Details, levels of recommendation and evidence level: see the
corresponding text. ASA: Acetylsalicylic acid; AH: Arterial hypertension; ACE inhibitors: Angiotensin-converting enzyme inhibitors; ARB: Angiotensin receptor blocker I;
AP: Arterial pressure; HR: Heart rate.
Catheter-based revascularization: clinical indications
Indications for myocardial revascularization
Revascularization vs. drug treatment (Figure 3)
Comparison of revascularization strategies in diabetic
patients with multi-vessel CAD
Percutaneous coronary intervention vs. clinical treatment
Sensitivity analysis showed that the superiority of
coronary artery bypass surgery was more evident in
individuals with high Syntax score (> 33), with no significant
difference between the low score and intermediate
score groups33.
To date, no study has demonstrated that percutaneous coronary
intervention in patients with CAD improves survival rates32.
Appropriate use of revascularization
Patients with three-vessel disease
The coronary artery bypass surgery is the preferred
strategy for three-vessel disease patients with increased age,
low ejection fraction, renal dysfunction, peripheral vascular
disease, diabetes mellitus, or Syntax score > 22.
Special situations
Aspects of percutaneous coronary intervention in
diabetes mellitus patients
Drug-eluting stents are recommended to reduce restenosis
and the need of a new target vessel revascularization34,35.
The dual antiplatelet therapy with aspirin and a P2Y12
receptor blocker is an essential component of drug regiments
for perioperative and postoperative periods. Patients who
receive drug-eluting stents should use the therapy for
12 months, and those who receive non-drug-eluting stents
should use it for 1 month.
Patients with diabetes mellitus
Diabetes mellitus is an increasingly prevalent condition
associated with increased risk of cardiovascular complications,
especially late mortality.
Patients with previous revascularization
The main indications for revascularization are persistence of
symptoms, despite optimized medical therapy and/or prognosis.
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Figure 3 – Percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) in stable coronary atheroscleroctic disease without involvement of left
main coronary artery. a≥ 50% stenosis and confirmation of ischemia, lesion > 90% confirmed by two physicians or fractional flow reserve of 0.80; bCABG is the preferred
option in most patients, unless in case of comorbidities or other particularities that require discussion with the Heart Team. Adapted from: 2010 Guidelines on myocardial
revascularization of the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery.
Author contributions
Writing of the manuscript and Critical revision of the
manuscript for intellectual content: César LAM, Mansur AP,
Ferreira JFM.
advisory board member or director of a Servier e Astra-Zeneca;
Committees participated in completion of research sponsored
by Servier e Astra-Zeneca; Personal or institutional aid received
from Servier e Astra-Zeneca; Produced scientific papers in
journals sponsored by Servier e Astra-Zeneca.
Potencial conflito de interesse
Sources of Funding
Drs. Luiz Antonio Machado César and João Fernando
Monteiro Ferreira participated in clinical studies and / or
experimental trials supported by Servier e Astra-Zeneca.
There were no external funding sources for this study.
Study Association
Dr. Luiz Antonio Machado César has spoken at events
or activities sponsored by Servier e Astra-Zeneca; It was (is)
This study is not associated with any thesis or dissertation work.
References
1.
Mansur AP, Favarato D. Mortality due to cardiovascular diseases in Brazil and
in the metropolitan region of São Paulo: a 2011 update. Arq Bras Cardiol.
2012;99(2):755-61.
2. Diamond GA, Forrester JS. Analysis of probability as an aid the clinical
diagnosis of coronary-artery disease. N Engl J Med. 1979;300(24):1350-8.
6.
3. Chaitman BR, Bourassa MG, Davis K, Rogers WJ, Tyras DH, Berger R, et
al. Angiographic prevalence of high-risk coronary artery disease in patient
subsets (CASS). Circulation. 1981;64(2):360-7.
7. Levine HJ. Difficult problems in the diagnosis of chest pain. Am Heart J.
1980;100(1):108-18.
4. Simão AF, Précoma DB, Andrade JP, Correa Filho H, Saraiva JF, Oliveira
GM, et al; Sociedade Brasileira de Cardiologia. [I Brazilian Guidelines for
cardiovascular prevention]. Arq Bras Cardiol. 2013;101(6 Suppl. 2):1-63.
336
5. Xavier HT, Izar MC, Faria Neto JR, Assad MH, Rocha VZ, Sposito AC, et al;
Sociedade Brasileira de Cardiologia. V Diretriz brasileira de dislipidemias e
prevenção da aterosclerose. Arq Bras Cardiol. 2013;101(4 supl. 1):1-36.
Arq Bras Cardiol. 2015; 105(4):328-338
Campeau L. The Canadian Cardiovascular Society grading of angina pectoris
revisited 30 years later. Can J Cardiol. 2002;18(4):371-9.
8. Steg PG, Greenlaw N, Tardif JC, Tendera M, Ford I, Kaab S, et al. Women
and men with stable coronary artery disease have similar clinical outcomes:
insights from the international prospective CLARIFY registry. Eur Heart J.
2012;33(22):2831-40.
César et al
Summary of the guidelines on stable coronary disease
Special Article
9. Barbosa MM, Nunes MC, Campos Filho O, Camarozano A, Rabischoffsky A,
Maciel BC, et al; Sociedade Brasileira de Cardiologia. Diretrizes das indicações
da ecocardiografia. Arq Bras Cardiol. 2009;93(6 supl.3):e265-302.
10. Mathias W Jr, Arruda AL, Andrade JL, Campos O, Porter TR. Endocardial
border delineation during dobutamine infusion through use of contrast
echocardiography. Echocardiography. 2002;19(2):109-14.
11. Sicari R, Nihoyannopoulos P, Evangelista A, Kasprzak J, Lancellotti P,
Poldermans D, et al; European Association of Echocardiography. Stress
echocardiography expert consensus statement. European Association of
Echocardiography (EAE). Eur J Echocardiogr. 2008;9(4):415-37.
12. Marcassa C, Bax JJ, Bengel F, Hesse B, Petersen CL, Reyes E, et al. Clinical
value, cost effectiveness, and safety of myocardial perfusion scintigraphy: a
position statement. Eur Heart J. 2008;29(4):557-63.
13. Detrano R, Guerci AD, Carr JJ, Bild DE, Burke G, Folsom AR, et al. Coronary
calcium as a predictor of coronary events in four racial or ethnic groups. N
Engl J Med. 2008;358(13):1336-45.
14. Budoff MJ, Dowe D, Jollis JG, Gitter M, Sutherland J, Halamert E, et al.
Diagnostic performance of 64-multidetector row coronary computed
tomographic angiography for evaluation of coronary artery stenosis in
individuals without known coronary artery disease: results from the
prospective multicenter ACCURACY (Assessment by Coronary Computed
Tomographic Angiography of Individuals Undergoing Invasive Coronary
Angiography) trial. J Am Coll Cardiol. 2008;52(21):1724-32.
15. Hundley WG, Bluemke DA, Finn JP, Flamm SD, Fogel MA, Friedrich MG,
et al; American College of Cardiology Foundation Task Force on Expert
Consensus Documents.ACCF/ACR/AHA/NASCI/SCMR 2010 expert
consensus document on cardiovascular magnetic resonance: a report of the
American College of Cardiology Foundation Task Force on Expert Consensus
Documents. Circulation. 2010;121(22):2462-508.
16. Kim RJ, Fieno DS, Parrish TB, Harris K, Chen EL, Simonetti O, et al.
Relationship of MRI delayed contrast enhancement to irreversible injury,
infarct age, and contractile function. Circulation. 1999;100(19):1992-2002.
17. Simonetti OP, Kim RJ, Fieno DS, Hillenbrand HB, Wu E, Bundy JM, et al.
An improved MR imaging technique for the visualization of myocardial
infarction. Radiology. 2001;218(1):215-23.
18. Lima JA, Judd RM, Bazille A, Schulman SP, Atalar E, Zerhouni EA. Regional
heterogeneity of human myocardial infarcts demonstrated by contrastenhanced MRI. Potential mechanisms. Circulation. 1995;92(5):1117-25.
19. McConnell MV, Ganz P, Selwyn AP, Li W, Edelman RR, Manning WJ.
Identification of anomalous coronary arteries and their anatomic course by
magnetic resonance coronary angiography. Circulation. 1995;92(11):3158-62.
20. Weiner DA, Ryan TJ, McCabe CH, Chaitman BR, Sheffield LT, Ferguson JC, et al.
Prognostic importance of a clinical profile and exercise test in medically treated
patients with coronary artery disease. J Am Coll Cardiol. 1984;3(3):772-9.
21. Effect of enalapril on mortality and the development of the heart failure in
asymptomatic patients with reduced left ventricular ejection tractions. The
SOLVD Investigators. N Engl J Med. 1992;327(10):685-91. Erratum in N
Engl J Med. 1992;327(24):1768.
22. Pfeffer MA, Braunwald E, Moyé LA, Basta L, Brown EJ Jr, Cuddy TE, et al.
Effect of captopril on mortality and morbidity in patients with left ventricular
dysfunction after myocardial infarction. Results on the Survival and
Ventricular Enlargement (SAVE) Trial. N Engl J Med. 1992;327(10):669-77.
23. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk
patients. The Heart Outcomes Prevention Evaluation Study Investigators. N
Engl J Med. 2000;342(3):147-53. Erratum in N Engl J Med. 2000;342(10):748.
24. Fox KM. EURopean trial On reduction of cardiac events with Perindopril
instable coronary Artery disease Investigators. Efficacy of perindopril in
reduction of cardiovascular events among patients with stable coronary
artery disease randomised, double-blind, placebo-controlled, multicentre
trial (the EUROPA study). Lancet. 2003;362(9386):782-8.
25. Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R, et al; COMMIT
(ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative
group. Addition of clopidogrel to aspirin in 45 852 patients with acute
myocardial infarction: randomised placebo-controlled trial. Lancet.
2005;366(9497):1607-21.
26. Stone PH, Gibson RS, Glasson SP, DeWood MA, Parker JD, Kawanishi
DT, et al. Comparison of Propranolol, Diltiazem, and Nifedipine
in the treatment of ambulatory ischemia in patients with stable
angina. Diferencial effects on ambulatory ischaemia exercise
performance and angina symptoms. The ASIS Study Group. Circulation.
1990;82(6):1962-72.
27. Marzilli M, Klein WW. Efficacy and tolerability of trimetazidine in stable
angina: a meta-analysis of randomized, double-blind, controlled trials.
Coron Artery Dis. 2003;14(2):171-9.
28. Tardif JC, Ponikowski P, Kahan T. Efficacy of the I f current inhibitor
ivabradine in patients with chronic stable angina receiving beta-blocker
therapy a 4-month, randomized, placebo-controlled trial. Eur Heart J.
2009;30(5):540-8.
29. Kloner RA, Hines ME, Geunes-Boyer S. Efficacy and safety of ranolazine in
patients with chronic stable angina. Postgrad Med. 2013;125(6):43-52.
30. Sociedade Brasileira de Cardiologia. Diretrizes da cirurgia de
revascularização miocárdica, valvopatias e doenças da aorta. Arq Bras
Cardiol. 2004;82(supl. 5):1-21.
31. Serryus PW, Morice MC, Kappetein P, Colombo A,Holmes DR, Mack
MJ,et al;SYNTAX Investigators.Percutaneous coronary intervention
versus coronary-artery bypass grafting for severe coronary artery disease.
TRIAL.N Engl J Med. 2009;360(10):961-72. Erratum in N Engl J Med.
2013;368(6):584.
32. Hlatky MA, Boothroyd DB, Bravata DM, Boersma E, Booth J, Brooks
MM, et al. Coronary artery bypass surgery compared with percutaneous
coronary interventions for multivessel disease: a collaborative
analysis of individual patient data from ten randomised trials. Lancet.
2009;373(9670):1190-7.
33. Hakeem A, Garg N, Bhatti S, Rajpurohit N, Ahmed Z, Uretsky BF.
Effectiveness of percutaneous coronary intervention with drug-eluting stents
compared with bypass surgery in diabetics with multivessel coronary disease:
comprehensive systematic review and meta-analysis of randomized clinical
data. J Am Heart Assoc. 2013;2(4):e000354.
34. Stettler C, Allemann S, Wandel S, Kastrati A, Morice MC, Schömig A, et al.
Drug eluting and bare metal stents in people with and without diabetes:
collaborative network meta-analysis. BMJ. 2008;337:a1331.
35. Grines CL, Bonow RO, Casey DE Jr, Gardner TJ, Lockhart PB, Moliterno
DJ, et al; American Heart Association; American College of Cardiology;
Society for Cardiovascular Angiography and Interventions; American
College of Surgeons; American Dental Association; American College
of Physicians. Prevention of premature discontinuation of dual
antiplatelet therapy in patients with coronary artery stents: a science
advisory from the American Heart Association, American College of
Cardiology, Society for Cardiovascular Angiography and Interventions,
American College of Surgeons, and American Dental Association, with
representation from the American College of Physicians. J Am Coll
Cardiol. 2007;49(6):734-9.
Arq Bras Cardiol. 2015; 105(4):328-338
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Back to the Cover
Original Article
Acute Coronary Syndrome Treatment Costs from the Perspective of
the Supplementary Health System
Vanessa Teich1, Tony Piha2, Lucas Fahham1, Haline Bianca Squiassi1, Everton de Matos Paloni3, Paulo Miranda2,
Denizar Vianna Araújo4
MedInsight1, São Paulo, SP; AstraZeneca Brasil2, Cotia, SP; Orizon3, São Paulo, SP; Departamento de Clínica Médica da Universidade do Estado
do Rio de Janeiro4, Rio de Janeiro, RJ – Brazil
Abstract
Background: Acute coronary syndrome (ACS) is defined as a “group of clinical symptoms compatible with acute
myocardial ischemia”, representing the leading cause of death worldwide, with a high clinical and financial
impact. In this sense, the development of economic studies assessing the costs related to the treatment of ACS
should be considered.
Objective: To evaluate costs and length of hospital stay between groups of patients treated for ACS undergoing
angioplasty with or without stent implantation (stent+ / stent-), coronary artery bypass surgery (CABG) and treated only
clinically (Clinical) from the perspective of the Brazilian Supplementary Health System (SHS).
Methods: A retrospective analysis of medical claims of beneficiaries of health plans was performed considering
hospitalization costs and length of hospital stay for management of patients undergoing different types of treatment for
ACS, between Jan/2010 and Jun/2012.
Results: The average costs per patient were R$ 18,261.77, R$ 30,611.07, R$ 37,454.94 and R$ 40,883.37 in the following
groups: Clinical, stent-, stent+ and CABG, respectively. The average costs per day of hospitalization were R$ 1,987.03,
R$ 4,024.72, R$ 6,033.40 and R$ 2,663.82, respectively. The average results for length of stay were 9.19 days, 7.61 days,
6.19 days and 15.20 days in these same groups. The differences were significant between all groups except Clinical and
stent- and between stent + and CABG groups for cost analysis.
Conclusion: Hospitalization costs of SCA are high in the Brazilian SHS, being significantly higher when interventional
procedures are required. (Arq Bras Cardiol. 2015; 105(4):339-344)
Keywords: Acute Coronary Syndrome / economy; Health Care Costs; Health Expenditures; Data Interpretation,
Statistical; Prepaid Health Plans.
Introduction
Acute coronary syndrome (ACS) is defined by the American
Heart Association as a “group of clinical symptoms compatible
with acute myocardial ischemia”. Its clinical spectrum includes
unstable angina and acute myocardial infarction (AMI) with
or without ST-segment elevation.
According to Polanczyk and Ribeiro1, prevalence data in Brazil
estimate that 5% to 8% of adults older than 40 years old have
ACS1. The disease is the leading cause of mortality in Brazil2 and
developed countries3. It is estimated that for every 5 to 7 cases of
myocardial infarction there is one death4,5. Thus, coronary heart
disease is the leading cause of death worldwide, making it one
of the diseases with the highest clinical and financial impact4.
Mailing Address: Vanessa Teich •
Rua Ministro Jesuíno Cardoso, 454. Postal Code 04544-051, São Paulo,
SP – Brazil
E-mail: [email protected], [email protected]
Manuscript received February 20, 2015; revised manuscript April 26, 2015;
accepted April 30, 2015.
DOI: 10.5935/abc.20150129
339
Several types of interventions have been shown to be
beneficial for the management of ACS, including the use of
medications such as antiplatelet agents, beta-blockers, heparin,
glycoprotein IIb/IIIa inhibitors and the use of procedures such
as catheterization and thrombolytic therapy such as coronary
angioplasty and revascularization6.
Currently in Brazil there are no studies comparing the costs
of different types of treatment for ACS in SHS. Studies such as
this are needed to make it possible to evaluate the economic
impact a disease such as ACS has on society.
Thus, the objective of this article is to evaluate the costs
and the length of hospital stay between groups of patients
that were treated for ACS, submitted to angioplasty with or
without stenting (stent + / stent-), revascularization (CABG)
and treated only clinically (Clinical), from the perspective of
the Brazilian Supplementary Health System (SHS).
Methods
A retrospective analysis was carried out of medical
claims from beneficiaries of health care provided by private
institutions in all Brazilian regions (excluding the states of
Tocantins, Roraima and Mato Grosso do Sul), through a
Teich et al.
Economic evaluation of acute coronary syndrome
Original Article
database obtained from Orizon, a health care company
responsible for the management of information processes
from 110 health insurance companies, representing more
than 18 million beneficiaries in Brazil. This database included
data from patients undergoing hospital treatment for ACS and
costs related to hospitalization by type of procedure (food,
exams, medical gases, hygiene/cosmetics, fees, materials,
drugs, procedures and taxes) and length of hospital stay.
The period considered for the analysis was between January
2010 and June 2012.
Orizon carried out the preliminary analysis of the
data and MedInsight performed the statistical analysis.
The treatments included in the analysis for the ACS episode
management were: medical treatment, angioplasty with
stenting, angioplasty without stenting (balloon angioplasty)
and coronary artery bypass grafting (CABG).
Quantitative variables such as cost and length of stay were
described by the mean, median and mode. An exploratory
analysis through Q-Q Plots method was performed to define
the normality of the extracted data, and the Shapiro-Wilk
normality test was applied to determine the adherence of
the sample to a normal distribution. In cases of non-normal
distributions, the nonparametric Kruskal-Wallis test was
applied, used to determine equality between groups, and
the Nemenyi-Damico-Wolfe-Dunn post-hoc Test, to test
the difference between groups after the Kruskal-Wallis test.
Analyses were performed using the R Statistical Software,
version 3.1.17. A significance level of 5% was used.
Results
A total of 2,876 patients were identified in the period between
1/2010 and 6/2012, being divided into four groups: patients
treated by angioplasty with stenting (stent+) patients treated
by angioplasty without stenting (stent-) patients undergoing
revascularization (CABG) and patients treated clinically (Clinical),
all of them using antiplatelet agents. The mean age of patients
in each group ranged between 55 and 65 years (55 years in the
Clinical group, 59 years in the CABG group, 62 years in the stent+
group and 65 years in the stent- group), whereas the percentage
of female patients ranged from 18% to 24% (22% in the Clinical
group, 20% in the CABG group, 24% in the stent+ group and
18% in the stent- group; p = 0.51).
Patient characteristics were similar between groups, with
significant difference in the mean age between the Clinical
group and patients from groups submitted to angioplasty with
or without stent (Clinical vs stent-, p = 0.003; Clinical vs stent+,
p = 0.016).
After the sample selection, total hospital costs for the same
period (between 1/2010 and 6/2012) were extracted and
divided by procedure, as shown in Table 1.
The analysis of total costs showed that the highest costs in
the Clinical group were related to medications, followed by
fees, materials and exams. In the stent- group, higher costs
were associated with the use of materials, followed by fees,
procedures and use of medications. In the stent+ group, the
higher costs were related to the use of materials, followed by
procedures, fees and medications. Finally, in the CABG group,
the higher costs were associated with the use of materials,
followed by procedures, fees and medications. The results of the
analysis of the mean costs per procedure, segmented by group,
are shown in Table 2.
The median costs among the four groups were compared
using the Kruskal-Wallis method, which showed a
p-value < 0.001, rejecting the hypothesis of equality between
the costs. A post‑hoc test was used to perform the pairwise
comparison, as shown in Table 3.
The comparison analysis of the median costs of treatment,
in the period between 1/2010 and 6/2012, indicated that the
difference was not significant when comparing the Clinical
group with stent- group and in the comparison between the
stent+ group and CABG group. All other comparisons showed
statistically significant differences.
The representativeness of the types of cost in the four analyzed
groups is shown in Figure 1.
The chart analysis shows that the stent-, stent+ and
CABG groups had higher cost with materials and procedures
(representing > 50% of the total cost of each group), while in the
Clinical group this cost is only 18%. The Clinical group showed
that most of the costs are related to medications and fees (58%),
which was expected, as the cost is basically restricted to the use
of medications and consultations.
The results of the analysis of hospital stay of the four groups
and the mean cost per day of hospitalization are shown in Table 4.
Patients in the Clinical group showed a minimum hospital stay
of two days and a maximum of 35 days. In the stent+ patients
group, the hospital stay varied from one day to a maximum of
515 days. Patients in the stent- group had a maximum length
of stay of 80 days, while in the CABG group patients showed a
variation in hospital stay from four to 50 days.
To test the normality of the data related to the length of stay,
exploratory analysis was performed through a QQ Plot graphic,
and non-adherence to a normal distribution was confirmed by
the Shapiro-Wilk test (p < 0.001). Therefore, it was decided
to analyze the data by non-parametric methods. Thus, when
comparing the mean length of hospital stay, the mean costs
among the four groups were compared using the Kruskal‑Wallis
method, which showed a p-value < 0.001, rejecting the
hypothesis of equality between lengths of hospitalization.
A post-hoc test was used to perform the pairwise comparison,
as shown in Table 5.
Regarding the median hospitalization time, only the
comparison of the Clinical group versus the stent- group was
not significant. All other comparisons showed significant results.
These results can be confirmed graphically in Figure 2, where the
confidence interval of the difference between mean lengths of
hospitalization crosses the vertical axis of the graph only for the
comparison between Clinical and stent- groups.
Discussion
An analysis was performed of the data related to medical
claims of Supplementary Health System patients with ACS,
clinically treated without intervention, patients undergoing
angioplasty with or without stenting and patients undergoing
CABG. The patients that were only clinically treated were
considered the control group in this analysis.
Arq Bras Cardiol. 2015; 105(4):339-344
340
Teich et al.
Economic evaluation of acute coronary syndrome
Original Article
Table 1 – Total cost of hospital treatment by type of cost
Type of cost
Clinical
Food
stent-
stent+
CABG
R$ 8,735.28
R$ 62,470.20
R$ 205,822.95
R$ 39,885.35
Examination
R$ 122,649.76
R$ 559,699.66
R$ 4,374,932.76
R$ 574,814.36
Medical Gases
R$ 72,369.09
R$ 198,039.56
R$ 848,664.42
R$ 217,487.94
R$ 897,14
R$ 1,125.15
R$ 10,062.67
R$ 1,823.80
Hygiene/Cosmetics
Fees
R$ 62,786.31
R$ 131,953.21
R$ 1,425,054.16
R$ 276,275.32
Materials
R$ 196,965.06
R$ 2,139,035.25
R$ 55,820,543.70
R$ 2,629,796.09
Medications
R$ 357,560.41
R$ 961,490.33
R$ 4,855,775.35
R$ 971,924.45
Procedures
R$ 16,969.35
R$ 1,101,482.66
R$ 13,435,554.79
R$ 2,219,036.26
Taxes
R$ 311,558.95
R$ 1,210,965.32
R$ 8,724,484.12
R$ 1,654,359.39
Others
Total
R$ 0,00
R$ 841,11
R$ 3.696,23
R$ 104,40
R$ 1,150,491.35
R$ 6,367,102.45
R$89,704,591.15
R$ 8,585,507.36
stent-
stent+
CABG
CABG: Coronary artery bypass surgery.
Table 2 – Mean cost per procedure by type of cost
Type of cost
Food
Clinical
R$ 138.66
R$ 300.34
R$ 85.69
R$ 188.14
Examination
R$ 1,946.82
R$ 2,690.86
R$ 1,821.37
R$ 2,711.39
Medical Gases
R$ 1,148.72
R$ 952.11
R$ 353.32
R$ 1,025.89
R$ 14.24
R$ 5.41
R$ 4.19
R$ 8.60
Hygiene/Cosmetics
R$ 996.61
R$ 634.39
R$ 593.28
R$ 1,303.19
Materials
Fees
R$ 3,126.43
R$ 10,283.82
R$ 23,239.19
R$ 12,404.70
Medications
R$ 5,675.56
R$ 4,622.55
R$ 2,021.56
R$ 4,584.55
Procedures
R$ 269.35
R$ 5,295.59
R$ 5,593.49
R$ 10,467.15
Taxes
R$ 4,945.38
R$ 5,821.95
R$ 3,632.17
R$ 7,803.58
Others
R$ 0.00
R$ 4.05
R$ 1.53
R$ 0.49
R$ 18,261.77
R$ 30,611.07
R$ 37,345.79
R$ 40,497.68
stent+
stent-
CABG
S
NS
S
S
NS
Total
CABG: Coronary artery bypass surgery.
Table 3 – Cost comparison between groups
Clinical
Clinical
stent+
stentCABG
S: Significant; NS: Non-significant; CABG: Coronary artery bypass surgery.
341
Arq Bras Cardiol. 2015; 105(4):339-344
S
Teich et al.
Economic evaluation of acute coronary syndrome
Original Article
100%
90%
Food
80%
Examination
Cytopathological analysis
70%
Exame Genética
60%
Medical gases
50%
Hygiene/Cosmetics
40%
Fees
30%
Materials
20%
Medicamentos
10%
Procedures
0%
Taxes
Clinical
Stent-
Stent+
CABG
Figure 1 – Percentage of average costs by type of cost and analyzed group; CABG: Coronary artery bypass surgery.
Table 4 – Mean length of stay and mean cost of hospitalization
Admission
Clinical
stent-
stent+
CABG
Mean (DP)
9.19 days (6,7)
7.61 days (8.1)
619 days* (12)
15.20 days* (7.3)
8 days
6 days
5 days
14 days
Median
Mode
Mean cost - Admission day
5 days
2 days
2 days
14 days
R$ 1,987.03
R$ 4,024.72
R$ 6,033.40
R$ 2,663.82
stent+
stent-
CABG
S
NS
S
S
S
* Significant difference compared to the Clinical group; CABG: Coronary artery bypass surgery.
Table 5 – Length of stay comparison between groups
Clinical
Clinical
stent+
stentCABG
S
S: significant; NS: non-significant; CABG: Coronary artery bypass surgery.
An important finding of this analysis is related to the
fact that the mean cost results did not show a statistically
significant difference between the clinically treated group
and the group submitted to angioplasty without stenting,
as well as between the group treated by CABG and the
group submitted to angioplasty with stenting. This finding
suggests that patients treated with angioplasty without
stenting and those submitted only to clinical treatment
have similar treatment costs, which can be explained by
the lower complexity of angioplasty, often performed on
an outpatient basis and with shorter hospital length of stay.
Patients undergoing CABG and those submitted to
angioplasty with stent implantation showed similar costs
between them and higher costs when compared to less
complex procedures (angioplasty without stent and clinical
treatment), representing significant expenditures for the
treatment of patients with ACS.
Arq Bras Cardiol. 2015; 105(4):339-344
342
Teich et al.
Economic evaluation of acute coronary syndrome
Original Article
CABG - Clinical
Stent- - Clinical
Stent+ - Clinical
Stent- - CABG
Stent+ - CABG
Stent+ - Stent-
-10
-5
0
5
Figure 2 – Mean length of stay difference and 95%CI; CABG: coronary artery bypass surgery.
A retrospective study carried out in France, involving
154 patients with ACS and submitted to angioplasty with
stent implantation in 2005, concluded that the costs
involved in performing this procedure have a financial
impact for hospitals8.
Another study carried out in Brazil measured direct
and indirect costs related to the treatment of ACS, from
the perspectives of the Unified Health System (SUS) and
Supplementary Health System. The study considered the
historical series of hospitalizations in SUS between 1999
and 2010 and the expected number of hospitalizations for
2011 projected by a linear extrapolation of the historical
series and concluded that the estimated direct cost
associated with ACS in 2011, from the SUS perspective,
is approximately 0.77% of the total SUS budget, and
from the SHS perspective, this estimate would come to
R$ 515.138.6179.
Studies like this demonstrate the importance of
following these patients, the pharmacological treatment
and lifestyle changes that can contribute to preserving the
health of patients and prevention of complications, in order
to prevent patients from undergoing complex treatments
that may excessively burden the health care system.
A limitation of the present study is the lack of a reliable
national registry of cases of cardiovascular diseases and
343
Arq Bras Cardiol. 2015; 105(4):339-344
hence, the scarcity of supplementary medical data and
other health care providers, as this study used data from
health insurance companies linked to the Orizon© company.
Conclusions
In the present study it was observed that the clinical
treatment and angioplasty without stenting procedure,
associated with the use of antiplatelet agents, are less
onerous for the SHS compared to major procedures such
as angioplasty with stenting and CABG, as, due to the
high degree of complexity, these procedures had higher
associated costs and therefore should be considered as
relevant costs to the health system.
Author contributions
Conception and design of the research:Teich V, Piha T,
Fahham L, Squiassi HB, Paloni EM, Araújo DV, Miranda
P. Acquisition of data:Piha T, Paloni EM. Analysis and
interpretation of the data: Teich V, Piha T, Fahham L, Squiassi
HB, Araújo DV, Miranda P. Statistical analysis: Fahham L.
Obtaining financing: Teich V, Piha T, Miranda P. Writing of the
manuscript:Squiassi HB. Critical revision of the manuscript for
intellectual content: Teich V, Piha T, Fahham L, Paloni EM,
Araújo DV, Miranda P.
Teich et al.
Economic evaluation of acute coronary syndrome
Original Article
Potential Conflict of Interest
Sources of Funding
Drs. Tony Piha and Paulo Miranda are employees of
AstraZeneca Brazil. Vanessa Teich, Lucas Fahham, Haline Bianca
Squiassi are employees of Medinsight, company that received
funding from AstraZeneca to perform the analysis and preparation
of the article.
This study was funded by Astrazeneca do Brasil.
Study Association
This study is not associated with any thesis or dissertation work.
References
1. Polanczyk CA, Ribeiro JP. Coronary artery disease in Brazil: contemporary
management and future perspectives. Heart. 2009;95(11):870-6.
2.
Souza e Silva NA. Saúde cardiovascular na era tecnológica. Arq Bras Cardiol.
2004;83(6):453-5.
3. Grech ED, Ramsdale DR. Acute coronary syndrome: unstable
angina and non-ST segment elevation myocardial infarction. BMJ.
2003;326(7401):1259-61.
4. Ministério da Saúde. Protocolo Clínico Síndromes Coronarianas Agudas.
Brasília; 2011. [Acesso em 2013 jn 21]. Disponível em: http://portal.saude.
gov.br/portal/arquivos/pdf/protocolo_clinico_sindromes_coronarianas_
agudas.pdf
5.
6. Pesaro AE, Campos PC, Katz M, Corrêa TD, Knobel E. Síndromes
coronarianas agudas: tratamento e estratificação de risco. Rev Bras Ter
Intensiva. 2008;20(2):197-204.
7. R Core Team (2014). R: a language and environment for statistical computing.
R Foundation for Statistical Computing, Vienna, Austria. URL http://www.Rproject.org/.
8.
Nidegger D, Metz D, Vacter C, Tassan-Mangina S, Deschildre A, Gawron M,
et al. Financial impact of coronary stenting in emergency for acute coronary
syndromes. Arch Cardiovasc Dis. 2009;102(5):409-18.
9. Teich V, Araujo DV. Estimativa de custo da síndrome coronariana aguda no
Brasil. Rev Bras Cardiol. 2011;24(2):85-94.
Polanczyk CA, Prado K, Borges MS, Ribeiro JP. Acute myocardial infarction
in the thrombolytic era: high mortality in elderly patients. Rev Assoc Med
Bras. 1993;39(2):65-72.
Arq Bras Cardiol. 2015; 105(4):339-344
344
Back to the Cover
Original Article
The Benefits of Prone SPECT Myocardial Perfusion Imaging in
Reducing Both Artifact Defects and Patient Radiation Exposure
Maria Stathaki, Sophia Koukouraki, Emmanouela Papadaki, Angeliki Tsaroucha, Nikolaos Karkavitsas
Department of Nuclear Medicine, University Hospital of Heraklion, Crete – Greece
Abstract
Background: Prone imaging has been demonstrated to minimize diaphragmatic and breast tissue attenuation.
Objectives: To determine the role of prone imaging on the reduction of unnecessary rest perfusion studies and coronary
angiographies performed, thus decreasing investigation time and radiation exposure.
Methods: We examined 139 patients, 120 with an inferior wall and 19 with an anterior wall perfusion defect that might
represented attenuation artifact. Post-stress images were acquired in both the supine and prone position. Coronary angiography
was used as the “gold standard” for evaluating coronary artery patency. The study was terminated and rest imaging was obviated
in the presence of complete improvement of the defect in the prone position. Quantitative interpretation was performed.
Results were compared with clinical data and coronary angiographic findings.
Results: Prone acquisition correctly revealed defect improvement in 89 patients (89/120) with inferior wall and 12 patients
(12/19) with anterior wall attenuation artifact. Quantitative analysis demonstrated statistically significant difference in
the mean summed stress scores (SSS) of supine and mean SSS of prone studies in patients with disappearing inferior
wall defect in the prone position and patent right coronary artery (true negative results). The mean difference between
SSS in supine and in prone position was higher with disappearing than with remaining defects.
Conclusion: Technetium-99m (Tc-99m) tetrofosmin myocardial perfusion imaging with the patient in the prone position
overcomes soft tissue attenuation; moreover it provides an inexpensive, accurate approach to limit the number of
unnecessary rest perfusion studies and coronary angiographies performed. (Arq Bras Cardiol. 2015; 105(4):345-352)
Keywords: Prone Position; Myocardial Perfusion; Radioactive Emission; Technetium (Tc-99m) Tetrofosmin; SPECT
instead of Tomography emission-computed single-photon.
Introduction
Myocardial perfusion imaging has become an effective
clinical tool for diagnosing coronary artery disease (CAD), risk
stratifying of patients after infarction, assessing myocardial
viability and planning therapy1,2 and is usually performed with
the patient in the supine position3,4. It is, however, recognized
that the diaphragmatic attenuation of the inferior wall and the
breast attenuation of the anterior wall in females, has an impact
on the test specificity1,3-5. Planar acquisition, prone imaging,
ECG gating and image quantitation constitute commonly used
approaches to overcome soft tissue attenuation. Although direct
approaches for attenuation correction have been commercially
available, they are quite expensive and possibly not provided
to all nuclear medicine departments1,6.
Mailing Address: Maria Stathaki •
University Hospital of Heraklion, Stavrakia, Voutes. Postal Code 71306,
Heraklion Crete – Greece
E-mail: [email protected]
Manuscript received July 20, 2014; revised manuscript January 15, 2015;
accepted January 19, 2015.
DOI: 10.5935/abc.20150122
345
Prone imaging has been reported to improve inferior wall
attenuation artifact by producing an anterior shifting of the
heart and lowering of the diaphragm and subdiaphragmatic
organs 4,5. Normal prone scans in patients with inferior
wall defects in the supine images are associated with low
cardiac event rates, similar to that of patients with normal
supine‑only studies4,7,8. The main pitfall of this imaging
approach is that sternal and rib attenuation may create
an anterior or anteroseptal wall defect1,4. In addition, the
technique seems to be less suitable for reducing attenuation
from the breast tissue9,10.
Although stress studies have traditionally been
followed by several hour-rest delayed images, the normal
stress-only approach is recently preferred8, as it is less
time-consuming , reduces radiation exposure and has
an excellent short-term prognosis 4,6,8. In the presence
of an inferior wall perfusion defect in the stress-supine
study, positional change (prone imaging) is a low cost,
effective and clinically validated technique to overcome
diaphragmatic attenuation artifacts 5,7.
The purpose of this study was initially to confirm the
impact of the supine and prone approaches on attenuation
artifacts. Additionally, we investigated its role in reducing
subsequent rest imaging and unnecessary referrals to
Stathaki et al.
Prone imaging in myocardial perfusion SPECT
Original Article
coronary arteriography, aiming to decrease investigation
and hospital waiting time, patient discomfort and also
radiation exposure.
Methods
Study population
We examined 139 patients, 120 with an inferior wall
and 19 with an anterior wall perfusion defect. The clinical
characteristics of the patients are shown in Table 1.
Post‑stress images were acquired in both the supine and
prone position. Coronary angiography was used as the “gold
standard” for identifying coronary vessels patency. In many
instances, scintigraphy was performed within 6 months
of coronary angiography so as to evaluate the success of
revascularization and/or to determine the hemodynamic
significance of coronary stenosis, the adequacy of collateral
circulation and the risk stratification of known CAD.
In some cases myocardial perfusion imaging was followed
by coronary angiography, in order to determine coronary
artery narrowing of a scintigraphically-demonstrated
ischemia and/or to evaluate patients with inexplicable
chest pain. In all cases, the time interval between coronary
angiography and scintigraphy was limited to no more than
6 months. The aforementioned criteria defined the size
of our sample. The clinical indications for myocardial
perfusion imaging are shown in Table 2. There was no case
of dominant left circumflex artery (LCx), which could also
be relevant to inferior wall defects.
Scintigraphic imaging
Technetium-99m 1,2-bis [di-(2-ethoxyethyl) phosphino]
ethane ([Tc-99m] tetrofosmin) one day stress-rest protocol
was used. All patients had fasted for at least 4 hours
and were previously advised to discontinue b-blockers,
calcium-channel blockers, nitrates and avoid taking
caffeine‑containing products for 24 hours before the
radionuclide study. Exercise stress testing was preferred,
using a modified Bruce protocol. In the presence of
exercise limitations or contraindications, pharmacological
stress with adenosine was used. Tc-99m tetrofosmin
(370‑555 MBq) was administrated intravenously 1 min
prior to peak exercise or 3 min into the adenosine infusion.
Stress images were acquired first in the supine and second
in the prone position, starting 15-30 min after exercise and
30-45 min after adenosine. A dual-headed, large-field-of
view gamma camera (Philips, Forte Jetstream AZ) with a
low-energy, high resolution collimator was used. The same
acquisition settings and reconstruction parameters were
used for both the supine and prone image acquisitions.
In the presence of a disappearing defect in the prone
position, rest imaging was omitted. Otherwise, 2 hours
after the stress test, Tc-99m tetrofosmin (740-925 MBq)
was infused intravenously and rest acquisition in the
supine position was initiated 45‑60 min after the injection.
Attenuation or scatter correction was not available and
cine testing was not applied.
Table 1 – Patients’ Characteristics
Parameter
Value
Number of patients
139
Age (years)
Sex (male : female)
65.8 ± 11.6
114 (82%):25 (18%)
Perfusion defect location
Inferior wall
120 (86.4%)
Anterior wall
19 (13.6%)
Hypertension
72 (51.7%)
Diabetes
33 (23.7%)
Hypercholesterolemia
58 (41.7%)
Smoking
68 (48.9%)
Family history of CAD
51 (36.6%)
History of MI
8 (5.7%)
History of revascularization
60 (43.1%)
Adenosine stress
17 (12.2%)
Data are shown as mean ± SD or number (%).
CAD: Coronary artery disease, MI: Myocardial infarction
Image analysis
The supine defects were classified as remaining or
disappearing in the prone position. The wall defect improvement
with positional change had to be complete to be considered
as disappearing. New apparent anterior-anteroseptal defects in
the prone position were attributed to sternal or rib attenuation
artifact and did not alter the classification.
Processing and quantitative visual interpretation was
performed using a 20-segment model 4,11. Scintigrams
were evaluated by observers with more than 15 years’
experience in nuclear cardiology. In case of difference in
observers’ scores, there was agreement following discussion.
The 5-point scoring system was used: 0 = normal;
1 = equivocal; 2 = moderate reduction of uptake;
3 = severe reduction of uptake; and 4 = no detectable
tracer uptake. Based on the number and severity of segments
with scores ≥ 2, the observers defined the study results as
normal, probably normal, equivocal, probably abnormal or
definitely abnormal4,11. To further define the results as normal
or abnormal, the summed stress score (SSS) was calculated
by adding the scores of the 20 segments of the stress Tc-99m
tetrofosmin images4,11. SSS < 4 were considered normal, 4 to
8 mildly abnormal and >8 moderate to severely abnormal.
The SSS had to be < 4 and the final scan interpretation had
to be normal or probably normal, as any other case was
considered abnormal4. Moreover, the SSS difference (SSS
in supine image minus SSS in prone image) was calculated
for each patient. Then the mean value of SSS difference for
each defect group (disappearing or remaining defect group)
was calculated. When rest imaging was done, segments were
scored as well. Results were compared with clinical data and
coronary angiography findings.
Arq Bras Cardiol. 2015; 105(4):345-352
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Stathaki et al.
Prone imaging in myocardial perfusion SPECT
Original Article
Table 2 – Clinical indications for myocardial perfusion imaging
Inferior wall defect
Anterior wall defect
Diagnosis
41
8
Prognosis
24
4
Therapeutic control
45
3
Preoperative evaluation
10
4
Statistical analysis
The paired sample t-test was used to assess the statistical
significance between the mean SSS derived from supine
and prone studies. The mean SSS difference between the
disappearing and remaining defect groups were compared
using the independent samples t-test. The software program
used for the statistical analysis was the SPSS statistics 19.0.
A significance level of 0.01 was used.
The normality of the data was tested by using the
Shapiro-Wilk test, which showed the data followed a
normal distribution.
Results
Inferior wall artifacts were seen in 114 male and in
6 female patients. In the present study, 94 of 120 patients
with an inferior defect in the supine position (78.3%)
showed normal prone interpretation (disappearing
defect) and no further scintigraphy study was performed.
The finding was attributed to diaphragmatic attenuation
(Figure 1). Coronary angiography showed a patent right
coronary artery (RCA) in 89 (74.2%) of 94 patients (true
negative) and significant stenosis of the RCA in 5 (4.2%) of
94 patients (false negative). Among the study population,
26 of 120 patients (21.6%) showed abnormal prone
interpretation (remaining defect) and the rest study was
performed. In 19 (15.8%) of 26 patients, RCA stenosis
was angiographically confirmed and the rest study
disclosed evidence of transient ischemia or prior infarction
(true positive). Of the remaining 7 patients (5.8%),
the angiography showed normal RCA (false positive).
The rest study demonstrated reversible defect in 4 of
them, resulting in insufficient differentiation between
ischemia and attenuation artifact. A fixed inferior wall
defect was shown in the remaining 3 patients. Based on the
patient’s clinical data and our experience, these findings
were finally attributed to diaphragmatic attenuation.
Among all 120 patients studied, an apparently new
anterior-anteroseptal defect was observed in 8 patients
(6.7%) in the prone position. This was attributed to
sternal or rib attenuation, considering the angiographically
confirmed normal patency of the corresponding coronary
artery. Moreover, prone imaging tended to improve the
specificity (92.7%) of detecting CAD in the inferior wall,
without a significant reduction in sensitivity (79.2%).
Considering our data, 6 of 120 patients with an inferior
wall defect in the supine position had prior infarction.
Scintigraphy showed a “remaining” defect in the prone
347
Arq Bras Cardiol. 2015; 105(4):345-352
position in 4 of them (true positive). This finding was expected
due to history of inferior wall infarction. In one female patient
with prior inferior infarction, an unexpected prone normal
interpretation was observed (false negative). Finally, one
patient with anterior wall infarction showed perfusion defect
improvement with positional change (true negative).
In patients with normal prone interpretation (disappearing
defect) and angiographically confirmed patent RCA, the
mean SSS of supine and prone studies were 9.35 ± 2.32 and
2.07 ± 1.28, respectively with the difference between them
being statistically significant (p: 0.00). The mean SSS in patients
with abnormal prone interpretation (remaining defect) and
severely stenotic RCA were 11.74 ± 3.05 for the supine versus
10.95 ± 2.65 for the prone studies and the difference was
marginally non-significant (p: 0.012). The statistical analysis is
shown in Table 3. The mean SSS difference of the abnormal
supine - normal prone and abnormal supine - abnormal prone
scans was 7.28 ± 2.65 and 0.85 ± 1.19 respectively, with
a significant difference (p: 0.00). Patients with inferior wall
perfusion defect that had supine and prone acquisitions were
more frequently males. Quantitative analysis did not change
the scintigraphic results of visual interpretation and provided
more accuracy.
Performing the statistical analysis in women with an anterior
wall defect was not feasible, due to the limited number of
patients. Prone acquisition showed normal anterior wall
activity in 12 of 19 patients (63.1%) and rest imaging was
not performed. The finding was correctly attributed to breast
attenuation (Figure 2). The normal patency of coronary vessels
was angiographically confirmed. Two patients (10.5%) showed
a defect that persisted despite positional change and the rest
study was performed. Both had a history of anterior wall
infarction. In spite of normal coronary angiograms and no
history of CAD, 4 patients (21%) showed remaining defects
(false positive). Moreover, one patient (5.2%) with total
occlusion of the first diagonal branch showed prone normal
tracer uptake (false negative).
Exercise on a treadmill was performed in 122 out of the
139 patients and achieved at least 85% of the maximum
predicted heart rate (52 maximal and 70 sub-maximal stress
tests). Pharmacological stress was performed with adenosine
infusion in 17 patients. Positive exercise stress test suggestive
of ischemia was observed in 29 patients. Scintigraphy showed
reversible and fixed perfusion defects in 19 and in 2 patients
respectively. In the remaining 8, normal perfusion imaging
was detected. Fifteen patients with reversible perfusion
defects had angiographically confirmed coronary artery
stenosis, while 4 patients had a history of revascularization.
Both cases with fixed defects had prior infarction, while
angiography revealed borderline stenosis. Four patients
with normal perfusion imaging had coronary artery stenosis,
3 had history of revascularization and one patient was
highly suspected of cardiac syndrome X. Negative exercise
stress test was observed in 93 patients. Myocardial imaging
showed normal perfusion in 86 and abnormal in 7 cases.
Observers diagnosed reversible and fixed defects in 3 and
4 cases respectively. One patient with reversible defect had
angiographically confirmed stenosis, while the angiography
showed normal vessel patency in the remaining 2; therefore,
Stathaki et al.
Prone imaging in myocardial perfusion SPECT
Original Article
Figure 1 – A 65-year old man with normal findings on coronary arteriography: an inferior wall defect in the supine position (arrow) that disappears with positional change
(arrowhead), attributed to diaphragmatic attenuation artifact.
Table 3 – Data of the statistical analysis in the comparison of supine versus prone study
Summed Stress Score
Supine
Prone
p Value
Disappearing defect by prone SPECT
9.35 ± 2.32
2.07 ± 1.28
0.00
Remaining defect by prone SPECT
11.77 ± 3.05
10.95 ± 2.65
0.012
Figure 2 – A 75-year old woman with no obstructive coronary artery disease: an anterior wall perfusion defect (arrow) that improves completely when changing from
supine to prone (arrowhead). The defect was considered breast tissue attenuation artifact.
the finding was most likely attributed to attenuation artifact.
Two patients with fixed defects had prior myocardial
infarction, 1 had a history of revascularization and 1 was
scheduled for angioplasty because of severe stenosis of the
left anterior descending artery (LAD).
Discussion
The present study confirms that prone imaging enhances
the specificity and reduces artifact inferior wall abnormalities
associated with supine-only study 3-5,9, leading to more
appropriate clinical decisions and shortening the hospital
waiting period and patient discomfort5,7,12. Most importantly,
rest myocardial perfusion study can be safely excluded in
patients with an inferior wall “disappearing” defect by prone
SPECT. This provides an excellent approach to limit radiation
exposure by avoiding additional radiotracer infusion.
Soft tissue attenuation artifacts constitute a major shortcoming
of myocardial perfusion imaging. Various techniques to improve
specificity have been evaluated1, but to date there has been
no clear definition of which is the best one13,14. It is generally
accepted that attenuation artifacts are less frequent with
Tc‑99m tracers than with thallium-201 (Tl-201)15. Prone imaging
yields more accurate scintigraphic interpretations without any
additional cost, it is inexpensive and it does not deliver any
extra radiation to the patient6. It is associated with increased
inferior and septal wall counts, less patient motion, patient
discomfort and cardiac drift12,16-18. However, it is less suitable
for females with large breasts and obese patients2,19. ECG-gating
Arq Bras Cardiol. 2015; 105(4):345-352
348
Stathaki et al.
Prone imaging in myocardial perfusion SPECT
Original Article
improves specificity of inferior wall disease detection and it
additionally provides functional information6,16. The presence
of normal wall motion in a fixed perfusion defect is usually
consistent with attenuation artifact; however, small scars or
nontransmural injuries may display this same imaging pattern1.
Nevertheless, some authors believe that ECG-gating is the most
practical method in routine investigations20. Direct attenuation
correction systems are commercially available1. Although these
systems tend to decrease the rate of equivocal interpretations
to a greater extent than prone imaging, they require high-cost
hardware and software products1,5,6,21.
The routine change of supine to prone imaging is a
controversial matter, given the occasionally seen artifactual
anterior‑anteroseptal wall prone defect19,22,23. This finding
is presumably attributed to sternal and/or rib attenuation1,4
In the present study, this pitfall was observed in 8 out of the
120 patients (6.7%) The majority feels that prone should be
considered only when imaging in the supine position raises
the question of true inferior wall perfusion defect or artifact
abnormality4,19,22.
The use of combined supine and prone quantitative
imaging in overcoming diaphragmatic and/or breast
attenuation artifacts has been evaluated before.
Data from several researchers have shown significantly
increased specificity without compromising sensitivity
for the diagnosis of CAD 3,4,24. This is in agreement with
the results of our study, where a sensitivity of 79.2% and
a specificity of 92.7% were shown. Katayama et al. have
similarly demonstrated that prone stress Tl-201 study tends
to improve the specificity of detecting coronary disease
in the inferior wall. On the other hand, they showed
that sensitivity is reduced when compared to stress-rest
supine images25.
In our study population, rest acquisition was omitted in
patients with defects on supine SPECT that disappear on
prone imaging. However, few research groups performed
stress and rest scans in all cases4,9,10,18.19. They all pointed
out the excellent usefulness of combined supine and prone
acquisitions on attenuation artifacts, which was also seen in
our study. Segall and Davis have demonstrated that specificity
for RCA was dramatically better (90% versus 66%) when
patients were submitted to prone image acquisition compared
to supine. Furthermore, the overall effect on the detection
of CAD was an improved accuracy and higher specificity
(82% versus 59%) without significant loss of sensitivity (75%
versus 79%)9. In addition, Hayer et al concluded that patients
with inferior wall defect in the supine position that was not
present in the prone image had similar low risk of cardiac
events, when compared with those that had normal supine
only studies4. Recently Nishiyama et al, assessed the feasibility
of combined imaging using a novel ultrafast cadmium zinc
telluride (CZT) camera. They concluded that the combined
supine and prone CZT SPECT yields significant gains in
specificity and accuracy, whereas acquisition time is reduced
by up to one fifth26.
False negative and false positive results of prone imaging
were seen in 4.2% and 5.8% of our study population,
respectively. The development of coronary collateral
349
Arq Bras Cardiol. 2015; 105(4):345-352
circulation could be a possible explanation for the false
negative results. Thus, positional change may not always be
sufficient to differentiate attenuation artifacts from CAD6.
Although some authors believe that prone imaging is
associated with increased camera-to-chest wall distance
and lower total myocardial counts when compared to
supine position2,19, in this work prone image quality was
very satisfactory. This is in agreement with a recent study by
Gutstein et al. which showed that prone and supine imaging
is associated with comparable good image quality in the
non-obese population, even though half-time acquisition
has been used27.
Anterior wall defects are most common in women.
Although some believe that positional change mainly
contributes to the disappearance rate of diaphragmatic
attenuation9,10, it is a confirmed knowledge that combined
supine and prone approach improve specificity and
normalcy rates in women24. Although our study was limited
to 19 patients only, 63.1% of the anterior wall defects
disappeared in the prone image and subsequently, the rest
perfusion study was properly obviated. Anterior wall defects
in the supine acquisition that were absent with positional
change tended to represent breast attenuation artifacts.
A number of strategies have been used to minimize
dose in cardiac nuclear imaging. According to the “ALARA”
philosophy, one should strive to keep radiation exposure
As Low As Reasonably Achievable28. One enticing strategy
is the use of Tc-99m agents and stress-first or stress-only
protocols 28. It seems that prone imaging provides an
alternative imaging approach to reduce patient’s radiation
exposure. Based on our study, prone acquisition correctly
disclosed disappearing defects in 89 out of 120 patients
with reduced uptake in the inferior wall and in 12 out
of 19 women with reduced uptake in the anterior wall.
The findings were considered to be diaphragmatic and
breast tissue attenuation artifacts, respectively. Hence, prone
SPECT imaging offers the possibility of avoiding the additional
radiotracer infusion in an unnecessary rest study. This tends
to reduce radiation dose by a factor of 429,30, whilst providing
similar prognostic information to normal rest-stress perfusion
study8,29. Moreover, it saves time for both patients and busy
departments, thus allowing additional nuclear medicine
studies to be performed29.
Recently, a research group compared the inter-observer
agreement between two experienced readers using supine
alone versus combined supine/prone imaging. They showed
improved inter-observer correlation and diagnostic agreement,
by eliminating common artifacts, such as inferior wall
attenuation, patient’s motion and interfering external activity.
This will likely result in more uniform and standard care, which
in addition to improvement in accuracy, will lead to fewer
unnecessary additional tests30.
Ceylan Gunay et al have recently reported that
an unnecessary rest Tc-99m methoxyisobutylisonitrile
myocardial perfusion scintigraphy could be prevented in
patients with complete disappearing inferior wall defect at
stress prone imaging7. Similar to our results, they indicated
that in patients with true defects, perfusion quantification
Stathaki et al.
Prone imaging in myocardial perfusion SPECT
Original Article
was irrelevant to imaging position, as SSS of supine and prone
stress studies were not different. This is of utmost importance,
regarding the improvement of specificity, true positive rate
and reliability of scintigraphic study.
Considering our data, there were 7 patients with an inferior
wall and one patient with an anterior wall disappearing prone
defect that underwent coronary angiography within a month
after perfusion scintigraphy. They were highly suspected of
having coronary artery stenosis because of their symptoms
and risk factors. Angiograms showed no stenotic CAD.
It seems that prone imaging might have an additional role in
preventing unnecessary coronary angiograms and furthermore
minimize radiation exposure, especially in low-risk patients.
Recently, Worden et al. showed that patients with perfusion
abnormalities during stress supine imaging that resolved during
prone imaging are at low risk for cardiac death or myocardial
infarction at medium-term follow up. Given that they seldom
require invasive coronary angiography, broader application of
prone imaging could lead to reduced exposure to the risks and
expenses of unnecessary invasive procedures31.
Limitations of the study
There are some limitations to the present study.
The analysis is limited to the stress images of 120 patients
only. Although rest imaging was performed in the presence of
a remaining defect in the prone position and segments were
scored as well, this was acquired only in the supine position.
The study population was selected from a single center.
Our results were related to supine and prone quantitative
imaging without using gated assessment of wall motion or
wall thickening. We investigated a mixed gender population
regarding inferior wall perfusion defects, without performing
any feasibility investigation. Although our data regarding
female patients with an anterior wall defect are encouraging,
the study sample is quite small and further trials are required
on this issue. Here, we only present the preliminary results
of an ongoing study.
Conclusion
The addition of prone position to stress supine myocardial
scintigraphy decreases the false positive rates and leads to
more accurate results. Furthermore, it increases specificity
without compromising sensitivity for the diagnosis of CAD.
It has a key benefit of reducing the number of unnecessary
rest studies performed, whilst minimizing radiation exposure,
investigation time and costs. Moreover, it could possibly be a
useful and practical method of obviating unnecessary referrals
to coronary angiograms, especially in low-risk patients.
There were no external funding sources for this study.
Acknowledgments
We thank Dr. Panagiotis Stratakis for statistical assistance.
Author contributions
Conception and design of the research: Stathaki M,
Karkavitsas N. Acquisition of data: Stathaki M, Koukouraki S,
Papadaki E, Tsaroucha A. Analysis and interpretation of the data:
Stathaki M, Koukouraki S, Papadaki E, Tsaroucha A. Statistical
analysis: Stathaki M. Writing of the manuscript: Stathaki M,
Papadaki E. Critical revision of the manuscript for intellectual
content: Stathaki M, Koukouraki S. Supervision / as the major
investigador: Stathaki M, Koukouraki S, Karkavitsas N.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This study is not associated with any thesis or dissertation work.
References
1. Bateman TM, Cullom SJ. Attenuation correction single-photon emission
computed tomography myocardial perfusion imaging. Semin Nucl Med.
2005;35(1):37-51.
2.
Heiba SI, Hayat NJ, Salman HS, Higazy E, Sayed ME, Saleh Z, et al. Technetium99m-MIBI myocardial SPECT: supine versus right lateral imaging and
comparison with coronary arteriography. J Nucl Med. 1997;38(10):1510-4.
3. Nishina H, Slomka PJ, Abidov A, Yoda S, Akincioglu C, Kang X, et al.
Combined supine and prone quantitative myocardial perfusion SPECT:
method development and clinical validation in patients with no known
coronary artery disease. J Nucl Med. 2006;47(1):51-8.
4. Hayes SW, De Lorenzo A, Hachamovitch R, Dhar SC, Hsu P, Cohen I, et
al. Prognostic implications of combined prone and supine acquisitions in
patients with equivocal or abnormal supine myocardial perfusion SPECT. J
Nucl Med. 2003;44(10):1633-40.
5.
Stowers SA, Umfrid R. Supine-prone SPECT myocardial perfusion imaging:
the poor man’s attenuation compensation. J Nucl Cardiol. 2003;10(3):338.
6. Hedén B, Persson E, Carlsson M, Pahlm O, Arheden H. Disappearance
of myocardial perfusion defects on prone SPECT imaging: comparison
with cardiac magnetic resonance imaging in patients without established
coronary artery disease. BMC Med Imaging. 2009;9:16.
7. Ceylan Gunay E, Erdogan A, Yalcin H, Ozcan Kara P. Prone imaging allows
efficient radiopharmaceutical usage by obviating the necessity of a rest study
in Tc-99m-methoxyisobutylisonitrile myocardial perfusion scintigraphy. Nucl
Med Commun. 2011;32(4):284-8.
8.
Duvall WL, Wijetunga MN, Klein TM, Razzouk L, Godbold J, Croft LB, et al.
The prognosis of a normal stress-only Tc-99m myocardial perfusion imaging
study. J Nucl Cardiol. 2010;17(3):370-7.
9.
Segall GM, Davis MJ. Prone versus supine thallium myocardial SPECT: a method
to decrease artifactual inferior wall defects. J Nucl Med. 1989;30(4):548-55.
10. Perault C, Loboguerrero A, Liehn JC, Wampach H, Gibold C, Ouzan J, et
al. Quantitative comparison of prone and supine myocardial SPECT MIBI
images. Clin Nucl Med. 1995;20(8):678-84.
Arq Bras Cardiol. 2015; 105(4):345-352
350
Stathaki et al.
Prone imaging in myocardial perfusion SPECT
Original Article
11. Berman DS, Hachamovitch R, Kiat H, Cohen I, Cabico JA, Wang FP, et al.
Incremental value of prognostic testing in patients with known or suspected
ischemic heart disease: a basis for optimal utilization of exercise technetium99m sestamibi myocardial perfusion single-photon emission computed
tomography. J Am Coll Cardiol. 1995;26(3):639-47.
22. Berman D, Germano G, Lewin H, Kang X, Kavanagh PB, Tapnio P, et al.
Comparison of post-stress ejection fraction and relative left ventricular
volumes by automatic analysis of gated myocardial perfusion single-photon
emission computed tomography acquired in the supine and prone positions.
J Nucl Cardiol. 1998;5(1):40-7.
12. Esquerré JP, Coca FJ, Martinez SJ, Guiraud RF. Prone decubitus: a solution
to inferior wall attenuation in thallium-201 myocardial tomography. J Nucl
Med. 1989;30(3):398-401.
23. Shin JH, Pokharna HK, Williams KA, Mehta R, Ward RP. SPECT myocardial
perfusion imaging with prone-only acquisitions: correlation with coronary
angiography. J Nucl Cardiol. 2009;16(4):590-6.
13. Garcia EV. SPECT attenuation correction: an essential tool to realize nuclear
cardiology’s manifest destiny. J Nucl Cardiol. 2007;14(1):16-24.
24. Slomka PJ, Nishina H, Abidov A, Hayes SW, Friedman JD, Berman DS, et al.
Combined quantitative supine-prone myocardial perfusion SPECT improves
detection of coronary artery disease and normalcy rates in women. J Nucl
Cardiol. 2007;14(1):44-52.
14. Germano G, Slomka PJ, Berman DS. Attenuation correction in cardiac
SPECT: the boy who cried wolf? J Nucl Cardiol. 2007;14(1):25-35.
15. DePuey EG 3rd. How to detect and avoid myocardial perfusion SPECT
artifacts. J Nucl Med. 1994;35(4):699-702.
16. Berman DS, Kang X, Nishina H, Slomka PJ, Shaw LJ, Hayes SW, et al. Diagnostic
accuracy of gated Tc-99m sestamibi stress myocardial perfusion SPECT with
combined supine and prone acquisitions to detect coronary artery disease in
obese and nonobese patients. J Nucl Cardiol. 2006;13(2):191-201.
17. Peterson PN, Parker JA, Tepper MR, Hauser TH, English J, Danias PG. Prone
SPECT myocardial perfusion imaging is associated with less cardiac drift
during the acquisition duration than imaging in the supine position. Nucl
Med Commun. 2005;26(2):115-7.
18. Lisbona R, Dinh L, Derbekyan V, Novales-Diaz JA. Supine and prone SPECT
Tc-99m MIBI myocardial perfusion imaging for dipyridamole studies. Clin
Nucl Med. 1995;20(8):674-7.
19. Kiat H, Van Train KF, Friedman JD, Germano G, Silagan G, Wang FP, et al.
Quantitative stress-redistribution thallium-201 SPECT using prone imaging:
methodologic development and validation. J Nucl Med. 1992;33(8):1509-15.
20. Doğruca Z, Kabasakal L, Yapar F, Nisil C, Vural VA, Onsel Q. A comparison of
Tl-201 stress-reinjection-prone SPECT and Tc-99m-sestamibi gated SPECT in
the differentiation of inferior wall defects from artifacts. Nucl Med Commun.
2000;21(8):719-27.
21. Malkerneker D, Brenner R, Martin WH, Sampson UK, Feurer ID, Kronenberg
MW, et al. CT-based attenuation correction versus prone imaging to decrease
equivocal interpretations of rest/stress Tc-99m tetrofosmin SPECT MPI. J Nucl
Cardiol. 2007;14(3):314-23.
351
Arq Bras Cardiol. 2015; 105(4):345-352
25. Katayama T, Ogata N, Tsuruya Y. Diagnostic accuracy of supine and prone
thallium-201 stress myocardial perfusion single-photon emission computed
tomography to detect coronary artery disease in inferior wall of left ventricle.
Ann Nucl Med. 2008;22(4):317-21.
26. Nishiyama Y, Miyagawa M, Kawaguchi N, Nakamura M, Kido T, Kurata A,
et al. Combined supine and prone myocardial perfusion single-photon
emission computed tomography with a cadmium zinc telluride camera for
detection of coronary artery disease. Circ J. 2014;78(5):1169-75.
27. Gutstein A, Solodky A, Mats I, Nevzorov R, Belzer D, Hasid Y, et al. Feasibility
of myocardial perfusion SPECT with prone and half-time imaging. Nucl Med
Commun. 2011;32(5):386-91.
28. Einstein AJ, Moser KW, Thompson RC, Cerqueira MD, Henzlova MJ.
Radiation dose to patients from cardiac diagnostic imaging.Circulation.
2007;116(11):1290-305.
29. Cheetham AM, Naylor V, McGhie J, Ghiotto F, Al-Housni MB, Kelion AD.
Is stress-only imaging practical when a 1-day stress-rest 99mTc-tetrofosmin
protocol is used? Nucl Med Commun. 2006;27(2):113-7.
30. Arsanjani R, Hayes SW, Fish M, Shalev A, Nakanishi R, Thomson LE, et al. Twoposition supine/prone myocardial perfusion SPEC (MPS) imaging improves visual
inter-observer correlation and agreement. J Nucl Cardiol. 2014;21(4):703-11.
31. Worden NE, Lindower PD, Burns TL, Chatterjee K, Weiss RM. A second
look with prone SPECT myocardial perfusion imaging reduces the need for
angiography in patients at low risk for cardiac death or MI. J Nucl Cardiol.
2015;22(1):115-22.
Stathaki et al.
Prone imaging in myocardial perfusion SPECT
Original Article
Arq Bras Cardiol. 2015; 105(4):345-352
352
Back to the Cover
Original Article
Palliative Senning in the Treatment of Congenital Heart Disease with
Severe Pulmonary Hypertension
Juliano Gomes Penha, Leina Zorzanelli, Antonio Augusto Barbosa-Lopes, Edimar Atik, Leonardo Augusto Miana,
Carla Tanamati, Luiz Fernando Caneo, Nana Miura, Vera Demarchi Aiello, Marcelo Biscegli Jatene
Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da USP, São Paulo, SP – Brazil
Abstract
Background: Transposition of the great arteries (TGA) is the most common cyanotic cardiopathy, with an incidence ranging
between 0.2 and 0.4 per 1000 live births. Many patients not treated in the first few months of life may progress with severe
pulmonary vascular disease. Treatment of these patients may include palliative surgery to redirect the flow at the atrial level.
Objective: Report our institutional experience with the palliative Senning procedure in children diagnosed with TGA
and double outlet right ventricle with severe pulmonary vascular disease, and to evaluate the early and late clinical
progression of the palliative Senning procedure.
Method: Retrospective study based on the evaluation of medical records in the period of 1991 to 2014. Only patients
without an indication for definitive surgical treatment of the cardiopathy due to elevated pulmonary pressure were included.
Results: After one year of follow-up there was a mean increase in arterial oxygen saturation from 62.1% to 92.5% and a
mean decrease in hematocrit from 49.4% to 36.3%. Lung histological analysis was feasible in 16 patients. In 8 patients,
pulmonary biopsy grades 3 and 4 were evidenced.
Conclusion: The palliative Senning procedure improved arterial oxygen saturation, reduced polycythemia, and provided
a better quality of life for patients with TGA with ventricular septal defect, severe pulmonary hypertension, and poor
prognosis. (Arq Bras Cardiol. 2015; 105(4):353-361)
Keywords: Heart Defects, Congenital; Pulmonary Hypertension; Child; Transposition of the Great Vessels/surgery.
Introduction
Congenital cardiopathies are the most frequent inborn
defects in newborns, representing about 1% of the cases.
The transposition of the great arteries (TGA) is the most
common cyanotic cardiopathy, with an incidence ranging
from 0.2 to 0.4 per 1000 live births1,2.
The first proposal for physiologic correction of TGA at
the atrial level was described by Albert in 1954. In 1958,
Ake Senning performed with success the proposal suggested
by Albert, performing the correction at the atrial level using
autogenous atrial tissue to construct intracardiac baffles. The use
of flaps made of a prosthetic material for intra-atrial correction
was first proposed and performed by Mustard in 1964.
However, the occurrence of systemic ventricular dysfunction
and a high prevalence of arrhythmias as late morbidity factors
placed this technique out of use and replaced it with a more
physiologic technique, the Jatene procedure3.
Mailing address: Juliano Gomes Penha •
Av. Dr. Enéas de Carvalho Aguiar 44, bloco 2, sala 5, Jardim Paulista.
Postal Code 05403-900, São Paulo, SP – Brazil
E-mail: [email protected]
Manuscript received December 09, 2014; revised manuscript May 14, 2015;
accepted May 18, 2015.
DOI: 10.5935/abc.20150097
353
In 1972, Lindesmith et al4 reported for the first time a
series of patients with TGA and ventricular septal defect
(VSD) with severe pulmonary vascular obstructive disease
who underwent a palliative surgery to redirect the flow
at the atrial level. The Mustard surgery was the proposed
procedure to redirect the pulmonary and systemic venous
drainage, maintaining the VSD open. The VSD is maintained
open in these patients because its closure is associated with
early and late prohibitive mortality, as previously described4.
From then on, the indications for palliative surgery were
widened to include other complex congenital lesions with
VSD and pulmonary hypertension (PH)5.
The present study aims to report the results of palliative
surgical treatment in patients with complex congenital
heart disease with PH due to an important intracardiac
shunt which was not surgically treated within the period
considered safe. It also aims at evaluating the early and late
clinical progression with the palliative Senning procedure in
this group of patients with contraindication to total surgical
correction of the cardiopathy.
Methods
The study included patients with a diagnosis of TGA with
VSD and Taussig-Bing double-outlet right ventricle (DORV),
aged up to 11 years, seen by the Pediatric Cardiology and
Pediatric Cardiac Surgery teams at Instituto do Coração,
Penha et al.
Palliative Senning in severe PH
Original Article
Hospital das Clínicas of the School of Medicine at USP
(InCor-HCFMUSP). This was a retrospective study based
on the evaluation of medical records between 1991
to 2014. Only patients without indication of definitive
surgical treatment of the cardiopathy due to suprasystemic
pulmonary pressure were part of the analysis. Patients with
a diagnosis of TGA and Taussig-Bing DORV with favorable
pulmonary pressure were not included in this study.
The data collected included age and weight at the time of the
surgery, preoperative diagnosis, preoperative functional status,
palliative procedures prior to the main surgical procedure, type
of surgical procedure performed, preoperative hemodynamic
status, early and late morbidity including any cardiovascular
or pulmonary event and reoperations, late functional status,
analysis of lung biopsies, and survival. The statistical analysis was
descriptive. (A software was not required since the calculations
were performed manually.)
As for the surgical procedure, all patients underwent
median sternotomy and opening of the pericardium.
The anatomy was verified with careful initial inspection.
Following that, an extensive dissection and release of the
superior and inferior venae cavae was performed, with the
dissection also including the groove between the left and
right atria. Pockets were created in the aorta and venae
cavae with prolene suture, heparin was infused, and direct
cannulation of the aorta and venae cavae was performed.
Care was taken to cannulate the venae cavae as distal as
possible to facilitate the surgical maneuvers inside the
atria. Before full heparinization, a fragment of the lung
was removed for histological analysis. This was generally
performed with wedge resection of the right upper lobe with
the lung inflated. The biopsy was feasible in 16 patients.
We used the studies of Heath and Edwards6 and Rabinovitch
et al7 as the criteria for the histological classification of the
lung fragments (Table 1).
After full heparinization and cannulation, cardiopulmonary
bypass (CPB) was initiated. The ascending aorta was clamped,
and the St. Thomas' solution was used for cardioplegia.
The cardioplegic solution was initially infused at a rate of
20 mL/kg, and then maintained at 10 mL/kg every 20 to
30 minutes. The target temperature was 28oC in patients
not undergoing total circulatory arrest (TCA) and 20°C in
those undergoing TCA. The right atrium was opened with
an incision parallel to the interatrial groove, positioned at a
distance of about 0.5 to 1 cm from the caval drainage into
the right atrium. The atrial septal defect (ASD), the anatomical
relations of the tricuspid and mitral valves, and the caval
drainage were analyzed. A wide enlargement of the ASD
towards the superior and inferior venae cavae was performed
and a bovine pericardium patch was sutured covering and
isolating the pulmonary veins, leaving the two atrioventricular
valves and venae cavae in the same cavity. After that, a cava
baffle was constructed by suturing the edge of the lateral wall
of the right atriotomy, directing the flow from the venae cavae
to the mitral valve. This procedure allows the caval drainage
to be directed to the left ventricle which is connected to the
pulmonary trunk. An incision was then performed in the left
atrium anteriorly to the right pulmonary veins, exposing the
left atrium along with the pulmonary veins. After that, the
right edge of the left atriotomy was sutured to the left edge
of the right atriotomy. With this procedure, the left atrium
and pulmonary veins were connected to the tricuspid valve
and right ventricle, which is related to the aorta. The VSD
was maintained open (Figures 1, 2, 3 and 4).
After redirecting the flow from the atria, the patient
was warmed up. Maneuvers were carried out to remove
the air from the cavities and for weaning from CPB.
The use of modified ultrafiltration became routine after
2011, and intraoperative transesophageal echocardiography
was only feasible in children weighing more than 3 kg due
to an incompatibility of the probe used in our institution
for children weighing less than that. Death in the initial
postoperative period was defined as any death occurring
within the first 30 days after the surgical procedure or during
the same hospitalization.
Results
From November 1991 to April 2011, a total of 21 patients
with a diagnosis of TGA with VSD or Taussig-Bing DORV and
severe pulmonary vascular disease were referred to palliative
surgical treatment after other types of treatment were precluded.
(The last surgery was performed in 2011, but patients were
followed up until 2014. This fact results in two different dates
in the Results and in the Methods sections). The age of the
patients at the time of the surgery ranged from 1 to 130 months
(mean 24.6 months and median 16 months), and 30% were
aged 12 months or less. Among the 21 patients, 11 were male.
The weight of the patients ranged from 2.8 to 30 kg (mean
8.3 kg and median 7.1 kg).
Preoperative functional evaluation according to the New
York Heart Association (NYHA) was feasible in 18 patients,
and most (83%) were classified as functional class III or
IV. The main anatomic diagnoses were TGA with VSD in
17 patients (81%), and Taussig-Bing DORV in 4 patients
(19%). Smaller associated defects are shown in Table 2.
Table 1 – Lung biopsy histological classification
Classification of Rabinovitch et al.
Classification of Heath and Edwards
Grade A: early muscularization of the distal arteries;
Grade B: hypertrophy of the arterial wall;
Grade C: grade B changes associated with increased proportion of the number
of alveoli and arteries.
Grade 1: isolated hypertrophy of the media;
Grade 2: fibrointimal proliferation;
Grade 3: total occlusion of the lumen by fibrosis;
Grade 4: plexiform lesions;
Grade 5: hypertrophy of muscular arteries, cavernous lesions,angiomatoid lesions;
Grade 6: necrotizing arteritis.
Arq Bras Cardiol. 2015; 105(4):353-361
354
Penha et al.
Palliative Senning in severe PH
Original Article
Figure 1 – Place of the incision in the right atrium, maintaining a safety margin between the venae cavae and the pulmonary veins.
Figure 2 – Atrial septal sutures or bovine pericardium and isolation of the pulmonary veins which will be directed to the tricuspid valve and to the aorta.
The Rashkind procedure was performed in 13 of the
21 patients before the surgery, 11 of which had TGA with VSD.
One patient in the DORV group who had aortic coarctation
had previously undergone isthmoplasty and pulmonary artery
banding at the age of 20 days.
Cardiac catheterization was performed prior to the surgery
in all cases. Pulmonary vascular resistance (PVR) with inhaled
100% oxygen ranged from 3.2 to 14 U.m2 (mean 8.1 U.m2
and median 7.7 U.m2). The PVR of 3.2 U.m2 was found in
a patient with systolic pulmonary artery pressure (SPAP) of
94 mmHg and no response to the oxygen test. Preoperative
355
Arq Bras Cardiol. 2015; 105(4):353-361
SPAPs ranged from 41 to 130 mmHg (mean 77.8 mmHg
and median 75 mmHg). Oxygen saturation and hematocrit
ranged from 40% to 80% (mean 62.1% and median 67%) and
40% to 65% (mean 49.2% and median 50%), respectively.
Length of circulatory assistance ranged between 65 and
170 minutes (mean 113.6 minutes and median 108 minutes).
Length of aortic clamping ranged between 50 and 95 minutes
(mean 72.5 minutes and median 78.5 minutes). In three
patients, TCA with selective cerebral perfusion through the
brachiocephalic trunk and deep hypothermia (20°C) were
performed, with a mean duration of 52 minutes.
Penha et al.
Palliative Senning in severe PH
Original Article
Figure 3 – Cava baffle and direction of the venous blood flow to the mitral valve. Opening of the left atrium above the right pulmonary veins.
Figure 4 – Suture of the edge of the right atrium in place of the opening of the left atrium with redirection of the arterial blood flow to the tricuspid valve.
The initial mortality rate was 47% (10 patients). The causes
of death were low output in 6 patients, sepsis in 2 patients,
and pulmonary hypertensive crisis in the 2 remaining
patients. The mean total duration of hospitalization was
15 days (range 1 to 43 days), with a mean duration of
hospitalization of 19.1 days in patients discharged from
the hospital. Postoperative comorbidities not resulting in
death were pulmonary hypertensive crisis (which improved
with nitric oxide), pneumonia, acute renal failure (ARF),
chylothorax with ligation of the thoracic duct, pulmonary
congestion, total atrioventricular block (TAVB), and junctional
rhythm (Table 3). Assessments performed 1 year after
hospital discharge showed a mean increase in arterial oxygen
saturation from 62.1% to 92.5%, and a mean reduction in
hematocrit from 49.4% to 36.3%.
Lung histological analysis was feasible in 16 patients
and was performed with the classifications of Heath and
Edwards6, and Rabinovitch et al7. In 8 patients, grades 3
and 4 pulmonary biopsies were evidenced. Of 10 biopsies
in which the classification of Rabinovitch et al7 was used, 4
Arq Bras Cardiol. 2015; 105(4):353-361
356
Penha et al.
Palliative Senning in severe PH
Original Article
Table 2 – Associated defects
TGA with VSD
17
Taussig-Bing DORV
4
Coronary anomaly
6
Coronary anomaly
2
Single left coronary ostium
5
Single left coronary ostium
1
Right coronary artery arising from the circumflex artery
1
Right coronary artery arising from the circumflex artery
1
Situs inversus totalis
1
VSD > 5mm
4
Patent ductus arteriosus
2
Aortic coarctation
1
VSD > 5 mm
10
Pulmonary valve infundibular stenosis
3
Patent ductus arteriosus
5
TGA: Transposition of the great arteries; VSD: Ventricular septal defect; DORV: Double-outlet right ventricle.
were grade B and 6 were grade C (Table 4). All patients with
grades 3 and 4 biopsies were older than 16 months and had
a mean pulmonary artery pressure above 45 mmHg.
Mean follow-up of the 11 survivors was 6.4 years with
a maximum of 19 years. Five patients continue to follow
up at our institution while 5 other patients are currently
following up in other centers closer to their homes (Manaus,
Fortaleza, Brasília, and Salvador). There was 1 case of
sudden death at home due to an unknown cause 18 months
after hospital discharge.
Functional assessment according to the NYHA was feasible
in 10 of the 11 survivors. Functional class improved in all
patients (5 class I and 5 class II). Ten had a sinus rhythm, and
1 had a junctional rhythm. None of the patients required
definitive pacemaker implantation during follow-up.
PH crisis
6
Pulmonary congestion
4
ARF
2
Chylothorax
2
Pneumonia
1
TAVB
1
Junctional rhythm
1
PH: Pulmonary hypertension; ARF: Acute renal failure; TAVB: Total
atrioventricular block
However, we unfortunately still see complex congenital
cardiopathies diagnosed late, often when signs and symptoms
of severe PH are already manifesting, hindering the total
correction of the anomaly. With a lack of reference centers
in congenital cardiopathies in Brazil for establishment of
early diagnosis and treatment, there are still patients with PH
without access to an ideal and definitive surgical treatment.
These patients present clinically with cyanosis, and most
are NYHA functional class IV and unable to undergo definitive
correction due to elevated levels of pulmonary pressure
and vascular resistance. Some centers are trying and testing
pharmacological treatment with sildenafil in these patients.
However, the high cost of this treatment, lack of standardization
by the Unified Health System (Sistema Único de Saúde, SUS)
and use by only a few institutions provide no scientific evidence
to justify its widespread use in this type of patient. (Regarding
pharmacological treatment, sildenafil was only approved by
the FDA for the treatment of PH patients in 2005, and even
then, only for adult patients. Only 1 patient underwent surgery
after this date, in 2011. This patient was on sildenafil on his last
follow-up in 2014. There was no preoperative pharmacological
preparation or postoperative pharmacological treatment intended
for PH patients operated on with this technique in the 1990s,
the period in which 17 of the 21 surgeries were performed.
Only tests with nitric oxide and 100% oxygen during diagnostic
catheterization and inhaled nitric oxide after surgery were
available. The technique was proposed due to lack of other forms
of preoperative care and postoperative treatment.)
Progression of PH occurs particularly in patients with large
left-right shunts. It is worth noting that the structural changes
in the pulmonary circulation are histologically similar to those
seen in other forms of primary PH1. The presence of large
intracardiac communication and ductus arteriosus accelerate
the progression of the pulmonary vascular disease8.
Considering that there is no current evidence of treatment
for patients in the pediatric age group with severe PH and
the fact that the guidelines are empirically based on experts
recommendations1, the palliative Senning procedure should
be considered in patients with late diagnosis, when severe
pulmonary vascular disease is already established.
Echocardiographic evaluations were performed during
follow-up. The ventricular function remained preserved in
all patients. One patient presented cava baffle stenosis and
5 presented tricuspid valve insufficiency (3 of moderate
degree and 2 of severe degree).
Discussion
Most patients currently diagnosed with TGA with VSD and
Taussig-Bing DORV do not progress to pulmonary vascular
disease because total surgical correction is performed early,
soon after establishment of the diagnosis, which often occurs
before birth due to the increasingly frequent use of fetal
echocardiography.
357
Table 3 – Non-fatal postoperative comorbidities
Arq Bras Cardiol. 2015; 105(4):353-361
Penha et al.
Palliative Senning in severe PH
Original Article
Table 4 – Correlation between histology, hemodynamics, and age
Patient
Age (months)
SPAP (mmHg)
Classification of Heath and Edwards
Classification of Rabinovitch et al.
1
16
80
4
C
2
18
88
1
B
C
3
3
94
2
4
73
130
3
5
23
75
2
C
6
8
107
2
C
7
130
89
3
8
11
41
2
9
21
53
4
10
33
67
11
1
12
14
PVR (U.m2)
C
5
3
C
9.6
90
1
B
48
2
B
C
6.6
13
11
59
2
14
23
55
4
6.8
15
8
66
3
8.6
16
38
45
4
SPAP: Systolic pulmonary artery pressure; PVR: Pulmonary vascular resistance.
Historically, operations at the atrial level were the first
truly effective surgical procedures in the treatment of TGA9.
The technique proposed by Mustard was the procedure of
choice for correction of simple TGA from 1965 to 19823.
However, a 1982 survey conducted in several institutions
showed a high incidence of complications caused by the
synthetic flaps used in the procedure10,11. Since the Senning
procedure is only performed with autogenous tissues, it has
allowed most patients to reach adulthood, with a survival
rate of 88% after 20 years and with a late mortality of 9.4%
according to Roubertie et al12.
It should be noted that arterial correction is still the
treatment of choice in the neonatal period in patients with
a diagnosis of TGA with or without VSD. These patients are
operated on with the technique successfully performed for the
first time by Jatene in 197513. After the decade of 1980, this
became the surgery of choice by most centers specialized in
congenital cardiopathies11.
Patients with an intracardiac shunt with increased PVR are
unable to be promptly referred to surgical correction of the
anomaly, and in many centers are treated with pulmonary
vasodilators prior to the surgery. It was previously believed that
the early correction of the heart defect would result in regression
of the pulmonary vascular abnormalities6, regardless of the degree
of arterial remodeling14. However, wait for the regression of
pulmonary lesions only with surgical repair is not recommended,
wherein the combination of pharmacological treatment (sildenafil
and/or bosentan) has been used in the management of these
patients, even in the absence of widespread evidence-based
recommendation for this type of approach1,15.
Cardiac catheterization is essential to define treatment
in patients with PH. Tests with inhaled 100% oxygen
and/or nitric oxide are important in defining management.
The definition of severe PH is often arbitrary. A PVR of
10 to 12 U.m2 or greater is generally considered severe.
The presence of advanced grades in the Heath and Edwards
histological classification is often considered irreversible 6.
In patients aged 1 to 2 years presenting reduced PVR with
inhaled 100% oxygen, the Senning procedure with VSD
closure may be considered. However, in patients with an
inadequate response to inhaled 100% oxygen, the procedure
of choice would be the palliative Senning procedure5.
Hemodynamic studies have shown that almost all patients
above the age of 1 year with a diagnosis of TGA and large VSD
have a significant increase in PVR. Fourteen of the 21 patients
operated on at InCor-HCFMUSP were older than 1 year.
In contrast, the increase in PVR was a rare finding in older
children with TGA and intact ventricular septum8.
Newfeld et al8 have shown that patients with pulmonary
pressure of 50 mmHg or greater and pulmonary biopsies
grade 4 or greater were older than 1 year. In contrast, all
patients with pulmonary pressure of 50 mmHg or greater
with a pulmonary biopsy grade below 4 were younger than
1 year of age8. In this study, all patients with a grade 4 biopsy
were older than 1 year, and of the 6 patients younger than
1 year at the time of the surgery, 4 presented a grade 2, 1 a
grade 1, and 1 a grade 3 biopsy. For the decision of treatment
type, age is an important factor in view of the complications
associated with longer exposure of the pulmonary parenchyma
in cardiopathies with hyperflow.
The development of severe pulmonary vascular disease
remains one of the major concerns in patients with TGA,
and its occurrence is often considered a contraindication for
surgical correction. Histological studies have shown that a
Arq Bras Cardiol. 2015; 105(4):353-361
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Penha et al.
Palliative Senning in severe PH
Original Article
rapid progression of the pulmonary vascular disease may occur
in TGA patients, particularly in those with non-restrictive VSD8.
Ferencz16 reported early and severe hypertensive changes in
biopsies of pulmonary arteries in 106 TGA patients. He noted
that the lung lesions increased in severity with the increase in
VSD size16. Many patients older than 1 year with a diagnosis
of TGA with VSD and mean pulmonary pressure of 50 mmHg
or greater have established pulmonary vascular disease grade 4
on Heath and Edwards' classification8. Of the patients operated
on at InCor, 66% had a non-restrictive VSD, and 6 had patent
ductus arteriosus causing hemodynamic repercussion.
According to the classic work of Heath et al17, when specific
histological changes emerge on the pulmonary vasculature
of patients with TGA with large communications, PH will
not regress until the defect is corrected. These authors also
reported that a pulmonary biopsy grade 4 or greater is usually
indicative of irreversible pulmonary vascular disease and that
the pulmonary pressure levels were unlikely to decrease unless
surgical treatment was performed. Pulmonary vascular disease
of advanced grade (above 3) also increased significantly the risk
associated with surgery and death due to low output, which
occurred in the immediate postoperative period17. Even after
surgical correction, PH may still progress along with the disease.
Microscopic studies of these patients' lungs showed biopsies
grade 4 or greater in the majority of the cases18.
In an attempt to contain the advance of the PH or improve
the arterial oxygen saturation, palliative procedures are a
therapeutic option. In 1950, Blalock and Hanlon published
a procedure that allowed mixing of the pulmonary and
systemic circulations with the establishment of an interatrial
communication. This was the first palliative procedure to
allow survival of patients with TGA and restrictive intracardiac
communications. The Rashkind technique has now replaced
the previous procedure with enlargement of the foramen ovale
with a balloon catheter11. Pulmonary artery banding has also
been advocated to protect the lungs against the development
of pulmonary vascular disease in patients with TGA and VSD,
particularly in those younger than 6 months. A persistent large
ductus arteriosus should also be treated. In patients with large
septal defects, treatment of the ductus arteriosus, pulmonary
artery banding, or corrective surgery with closure of the VSD
should be performed up to the age of 6 months to prevent
progressive pulmonary vascular disease8.
There are currently four indications for the Senning
procedure. The first is in children with isolated TGA presenting
after the neonatal period, in which the left ventricle would
already be misadjusted and unable to support the systemic
circulation with the Jatene procedure. The second is as a
palliative method in patients with a pulmonary vascular disease
associated with VSD. The third indication is for patients with
corrected TGA. In this case, both the venous and arterial switch
are required to create a concordant ventricle (double switch).
The fourth is in the presence of rare isolated ventricular
inversion. In this situation, there is an atrioventricular
discordance with a ventriculoarterial concordance11.
Burkhart et al5 have shown in a study with 28 patients,
operated on at the Mayo Clinic in Rochester and at the
Hospital for Sick Children in Toronto, that there was a 23%
increase in oxygen saturation, a significant decrease in
359
Arq Bras Cardiol. 2015; 105(4):353-361
hematocrit, and improvement in NYHA functional class III and
IV to I and II after atrial palliative surgery in patients with severe
PH. The Mustard procedure was performed in 25 patients and
the Senning procedure in 35. These improvements were also
found in all patients operated on with the Senning procedure
in our study, with a mean 12.9 points decrease in hematocrit,
30.4 points increase in pulse oximetry, and improvement in
functional class. Humes et al19 also found a significant decrease
in hemoglobin levels and increase in mean oxygen saturation
from 64% to 85% after 9 years of follow-up19.
In a series of 132 Senning cases with 20 years of follow‑up,
Roubertie et al12 showed a 5.3% mortality within the first
30 thirty days and a 9.6% late mortality. Senning reported that
6% of the patients died due to systemic ventricular failure after
10 years of progression, and Cochrane et al20 reported this
occurrence in 10% of the patients after 7 years. Right ventricular
dysfunction is a well-known late complication of the Senning
procedure and is described in almost all studies. The rate of
right ventricular dysfunction may be as high as 48% in simple
TGAs and 61% in complex TGAs at 15 years of follow-up12.
It is worth noting that in previous studies the patients had
normal pulmonary pressures. Mortality due to ventricular failure
occurred within 30 days of follow-up in our series, accounting
for 6 of the 10 deaths. Of the 21 patients who were operated
on, 11 were discharged from the hospital, and 1 died at home
due to an unknown cause after 18 months. Greater rates of
sudden death have been reported in patients undergoing the
Mustard procedure when compared with those undergoing
the Senning procedure9.
Rhythm disturbances are the most common causes of
morbidity in the first few days after surgery. Junctional rhythm
is present in 56% and TAVB in 6% of the operated patients.
The late follow-up showed that 65% progressed with brief
episodes of junctional rhythm and 38% with sinus bradycardia3.
Rhythm abnormalities occurred in only 2 patients in our series.
One patient presented transient TAVB that soon improved
and returned to sinus rhythm, and another patient presented
junctional rhythm. Arrhythmias may be explained by reentrant
mechanisms caused by suture lines in the atrium, whereas
sinus node dysfunction may occur due to direct injury of the
node or its artery8.
Some late complications may be observed, many related to
technical aspects of the surgical correction such as obstruction
of the superior vena cava in 10% of the cases, obstruction of
the inferior vena cava in 2%, interatrial leaks, obstruction of the
pulmonary veins, atrial arrhythmias (sinus node dysfunction),
right ventricular dysfunction, and tricuspid insufficiency21,
this last probably due to annular dilatation as a consequence
of right ventricular dysfunction9. Baffle stenosis or leak was
the main complication in 5% of the patients operated on in
Toronto, and also the most frequent reason for reoperation22.
During follow‑up in our study, we found 1 case of cava
baffle stenosis and 5 cases of tricuspid valve dysfunction.
Reoperations are related to systemic venous or pulmonary
venous obstruction3. Sarkar et al23 found a lower incidence
of reoperation for intra-atrial baffle abnormalities in patients
operated with the Senning procedure. They occurred in 12%
of the 226 survivors undergoing the Mustard procedure and in
2% of the 132 survivors undergoing the Senning procedure23.
Penha et al.
Palliative Senning in severe PH
Original Article
The palliative Senning procedure aims at improving the
quality of life in critical patients unable to undergo another
surgical treatment or improve with pharmacological therapy,
since high levels of pulmonary pressure increase the risk of
premature mortality and worsen the quality of life of the few
survivors. The group of patients included in this study had
elevated early mortality with low output as the main cause.
The hypoxemia in these patients, who survive in a regimen
of overload both in the systemic right ventricle as well as in
the pulmonary left ventricle, aggravate the function of the
ventricles. This has also been reported by Burkhart et al5 who
found low output as the main cause of early mortality in 5 of
the 6 deaths within the first 30 days5. Low output was also the
leading cause in our series, accounting for 6 of the 10 initial
deaths. However, the survival rate found in our study after
19 years of follow-up was superior: 52.3% versus 46.4%.
The fact that 7 of the 10 deaths occurred more than 20 years
ago may be associated with the few therapeutic resources
existing at that time. The use of nitric oxide as postoperative
treatment was not feasible in all patients in the initial series
due to the absence of this resource in our institution in
the early 1990s. Lack of improved postoperative support,
which contrasts to the support currently available, may have
influenced the early mortality in the first operated patients.
Conclusion
The palliative Senning procedure improved arterial
oxygen saturation, reduced polycythemia, and provided
a better quality of life to patients with TGA and VSD or
Taussig-Bing DORV who had severe PH, were considered
inoperable, and had a poor prognosis. Our study also
showed that pulmonary lesions of more advanced grades
are predominant in patients who were operated on after
the age of 12 months. This confirms the need for surgical
treatment as early as possible.
Author contributions
Conception and design of the research: Penha JG,
Zorzanelli L, Aiello VD; Acquisition of data: Penha JG,
Zorzanelli L; Analysis and interpretation of the data: Penha
JG, Zorzanelli L, Barbosa-Lopes AA, Atik E, Tanamati C, Miana
LA, Caneo LF, Aiello VD, Jatene MB; Statistical analysis: Penha
JG; Writing of the manuscript: Penha JG, Zorzanelli L, Atik
E, Tanamati C, Miura N, Jatene MB; Critical revision of the
manuscript for intellectual content: Zorzanelli L, BarbosaLopes AA, Miana LA, Caneo LF, Aiello VD, Miura N, Jatene MB.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This study is not associated with any thesis or dissertation work.
References
1.
Galié N, Beghetti M, Gatzoulis MA, Granton J, Berger RM, Lauer A, et al.
Bonsetan therapy in patients with Eisenmenger syndrome. A multicenter, double
blind, randomized, placebo-controlled study. Circulation. 2006;114(1):48-54.
9. Hörer J, Karl E, Theodoratou G, Scheiber C, Cleuziou J, Prodan Z, et al. Incidence
and results of reoperations following the Senning operation: 27 years of follow-up
in 314 patients at a single center. Eur J Cardiothorac Surg. 2008;33(6):1061-7.
2. Wa r n e s C A . Tr a n s p o s i t i o n o f t h e g r e a t a r t e r i e s . C i r c u l a t i o n .
2006;114(24):2699-709.
10. Cobanoglu A, Abbruzzese PA, Freimanis I, Garcia CE, Grunkemeier G,
Starr A. Pericardial baffle complications following the Mustard operation:
age-related incidence and ease of management. J Thorac Cardiovasc Surg.
1984;87(3):371-8.
3. Reddy V, Sharma S, Cobanoglu A. Atrial switch (Senning procedure) in the
era of the arterial switch operation: current indications and results. Eur J
Cardiothorac Surg. 1996;10(7):546-50.
4.
5.
Lindesmith GG, Stiles QR, Turcker BL, Gallaher ME, Stanton RE, Meyer BW.
The Mustard operation as a palliative procedure. J Thorac Cardiovasc Surg.
1972;63(1):75-8.
Burkhart HM, Dearani JA, Williams WG, Puga FJ, Mair DD, Ashburn DA, et al.
Late results of palliative atrial switch for transposition, ventricular septal defect, and
pulmonary vascular obstructive disease. Ann Thorac Surg. 2004;77(2):464-9.
6. Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular
disease: a description of six grades of structural changes in the pulmonary
arteries with special reference to congenital cardiac septal defects.
Circulation. 1958;18(4 Part1):533-47.
7. Rabinovitch M, Haworth SG, Cataneda AR, Nadas AS, Reid LM. Lung biopsy
in congenital heart disease: a morphometric approach to pulmonary vascular
disease. Circulation. 1978;58(6):1107-22.
8. Newfeld EA, Paul MH, Muster AJ, Idriss FS. Pulmonary vascular disease in
complete transposition of the great arteries: a study of 200 patients. Am J
Cardiol. 1974;34(1):75-82.
11. Konstantinov IE, Meskishvili VV, Williams WG, Freedom RM, Van Praagh
R. Atrial switch operation: past, present, and future. Ann Thorac Surg.
2004;77(6):2250-8.
12. Roubertie F, Thambo JB, Bretonneau A, Iriart X, Laborde N, Baudet E, et al.
Late outcome of 132 Senning procedures after 20 years of follow-up. Ann
Thorac Surg. 2011;92(6):2206-13.
13. Jatene AD, Fontes VF, Paulista PP, Souza LC, Neger F, Galantier M, et
al. Anatomic correction of transposition of the great vessels. J. Thorac
Cardiovasc Surg. 1976;72(3):364-70.
14. Rabinovitch M, Keane JF, Norwood WI, Castaneda AR, Reid L. Vascular structure
in lung tissue obtained at biopsy correlated with pulmonary hemodynamic
findings after repair of congenital heart defects. Circulation. 1984;69(4):655-67.
15. Haworth SG, Hislop AA. Treatment and survival in children with pulmonary
arterial hypertension: the UK pulmonary hypertension service for children
2001-2006. Heart. 2009;95(4):312-7.
16. Ferencz C. Transposition of the great vessels: pathophysiologic considerations
based upon a study of the lungs. Circulation. 1966;33(2):232-41.
Arq Bras Cardiol. 2015; 105(4):353-361
360
Penha et al.
Palliative Senning in severe PH
Original Article
17. Heath D, Helmhoz HF Jr, Burchell HB, Dushane JW, Kirklin JW, Edwards
JE. Relation between structural changes in the small pulmonary arteries and
the immediate reversibility of pulmonary hypertension following closure of
ventricular and atrial septal defects. Circulation. 1958;18(6):1167-74.
18. Cartmill TB, DuShane JW, McGoon DC, Kirklin JW. Results of repair of
ventricular septal defect. J Thorac Cardiovasc Surg. 1966;52(4):486-501.
19. Humes RA, Driscoll DJ, Mair DD, Danielson GK, McGoon DC. Palliative
transposition of venous return: long-term follow-up. J Thorac Cardiovasc
Surg. 1988;96(3):364-7.
20. Cochrane AD, Karl TR, Mee RB. Staged conversion to arterial switch for late
failure of the systemic right ventricle. Ann Thorac Surg. 1993;56(4):854-62.
361
Arq Bras Cardiol. 2015; 105(4):353-361
21. Jatene IB, Jatene MB. Transposição das Grandes Artérias. In: Croti U, Mattos
SS, Pinto VC, Aiello VD. Cardiologia e cirurgia cardiovascular pediátrica. São
Paulo: Ed. Roca; 2008. p. 355-76.
22. Wells WJ, Blackstone E. Intermediate outcome after Mustard and Senning
procedures: a study by the Congenital Heart Surgeons Society. Semin Thorac
Cardiovasc Surg Pediatr Card Surg Annu. 2000;3:186-97.
23. Sarkar D, Bull C, Yates R, Wright D, Cullen S, Gewillig M, et al.
Comparison of long-term outcomes of atrial repair of simple transposition
with implications for a late arterial switch strategy. Circulation.
1999;100(19 Suppl):II176-81.
Back to the Cover
Original Article
Anxiety, Depression, and General Psychological Distress in Patients
with Coronary Slow Flow
Mehmet Baran Karataş1, Ebru Şahan2, Kazım Serhan Özcan3, Yiğit Çanga4, Barış Güngör1, Tolga Onuk1, Göktürk
İpek1, Yasin Çakıllı1, Emre Arugaslan1, Osman Bolca1
Siyami Ersek Thoracic and Cardiovascular Surgery Center, Training and Research Hospital Department of Cardiology1, Haydarpaşa Numune
Training and Research Hospital Department of Psychiatry2, Derince Training and Research Hospital Department of Cardiology3, Kartal Yavuz
Selim Hospital Department of Cardiology4
Abstract
Background: The relationship between psychiatric illness and heart disease has been frequently discussed in the
literature. The aim of the present study was to investigate the relationship between anxiety, depression and overall
psychological distress, and coronary slow flow (CSF).
Methods: In total, 44 patients with CSF and a control group of 50 patients with normal coronary arteries (NCA) were
prospectively recruited. Clinical data, admission laboratory parameters, and echocardiographic and angiographic
characteristics were recorded. Symptom Checklist 90 Revised (SCL-90-R), Beck Depression Inventory (BDI), and Beck
Anxiety Inventory (BAI) scales were administered to each patient.
Results: The groups were comparable with respect to age, sex, and atherosclerotic risk factors. In the CSF group, BAI
score, BDI score, and general symptom index were significantly higher than controls (13 [18.7] vs. 7.5 [7], p = 0.01;
11 [14.7] vs. 6.5 [7], p = 0.01; 1.76 [0.81] vs. 1.1[0.24], p = 0.01; respectively). Patients with CSF in more than one
vessel had the highest test scores. In univariate correlation analysis, mean thrombolysis in myocardial infarction (TIMI)
frame counts were positively correlated with BAI (r = 0.56, p = 0.01), BDI (r = 0.47, p = 0.01), and general symptom
index (r = 0.65, p = 0.01). The psychiatric tests were not correlated with risk factors for atherosclerosis.
Conclusion: Our study revealed higher rates of depression, anxiety, and overall psychological distress in patients with
CSF. This conclusion warrants further studies. (Arq Bras Cardiol. 2015; 105(4):362-370)
Keywords: Coronary Circulation; Depression; Anxiety Disorders; Stress, Psychological; Coronary Artery Disease / psychology.
Introduction
The effect of psychiatric disorders on the incidence and
progression of cardiovascular diseases has been investigated
in previous studies1. Concomitant depression is associated
with an increased risk of cardiac morbidity and mortality
after an acute myocardial infarction (MI) and coronary
revascularization procedures2,3.
Coronary slow flow (CSF) is a relatively common
angiographic phenomenon that is characterized by slow
progression of a contrast agent through the coronary
arteries in the absence of any stenosis 4. Functional and
morphological abnormalities in the microvasculature,
endothelial dysfunction, raised inflammatory markers,
occult atherosclerosis, and anatomical factors of epicardial
Mailing Address: Barış Güngör •
Siyami Ersek Training and Research Hospital, Tibbiye Caddesi, N° 13,
Postal Code 34668, Kadiköy/Istanbul, Turkey.
E-mail: [email protected]
Manuscript received January 24, 2015; manuscript revised May 28, 2015;
accepted June 01, 2015.
DOI: 10.5935/abc.20150092
362
arteries have all been implicated in the pathogenesis of CSF5.
However, little is known about the relationship between CSF
and psychiatric disorders. Thus, in this study, we aimed to
investigate the correlation of CSF with anxiety, depression,
and general psychiatric status.
Methods
Study Protocol
We prospectively enrolled 44 consecutive patients with
CSF who had undergone diagnostic coronary angiography
(CAG) between January 2014 and March 2014 in Siyami
Ersek Training and Research Hospital. The control group
consisted of 50 consecutive patients with normal coronary
arteries who had undergone CAG between January 2014
and March 2014. Indications of coronary angiographies
were determined with positive results of myocardial
ischemia in non­invasive myocardial imaging and typical
angina pectoris. All patients were assessed for demographic
features, cardiovascular risk factors, laboratory parameters,
and medications. The local ethics committee approved the
study protocol and written informed consent was obtained
from the study participants according to the Declaration
of Helsinki.
Karataş et al.
Psychiatric scales and coronary slow flow
Original Article
Exclusion criteria included the following: refusal to
participate in the study, known coronary artery disease (CAD),
acute coronary syndrome, left ventricular (LV) dysfunction
(defined as LV ejection fraction [LVEF] < 50%), severe valvular
heart disease, rhythm other than sinus, end-stage renal or
hepatic dysfunction, severe chronic obstructive pulmonary
disease, systemic diseases, subjects receiving medical
treatment for any type of psychiatric disorder, insufficient
cooperation, presence of coronary artery stenosis > 20%,
or any type of congenital coronary abnormality (such as
myocardial bridging and coronary fistulas).
Hypertension (HT) was defined as the use of antihypertensive
drugs or initial blood pressure over 140/90 mmHg .
Diabetes mellitus (DM) was defined as the use of antidiabetic
drugs or fasting plasma glucose levels of > 126 mg/dL.
Hyperlipidemia was defined as total serum cholesterol levels
> 240 mg/dL. Smoking status was defined as current tobacco
use. Body mass index (BMI) was calculated by dividing weight
into the square of height.
Venous blood samples were taken from the antecubital vein
and collected in calcium EDTA tubes, and were then studied
by an auto-analyser (Cell-dyn 3700 Abbott, USA) on the day
of CAG. Transthoracic echocardiography (Vivid 3 system,
General Electric, made in Norway) was performed prior to
CAG to detect LV functions and valvular heart disease. LVEF
was measured using the modified Simpson method.
Coronary angiography and documentation of coronary
slow flow
Selective CAG was performed by the femoral approach
using the Judkins technique. Angiographic images were
obtained by the Simens Axiom 792 Axa Angiographic
System. Multiple views were obtained with visualization
of the left anterior descending (LAD) and left circumflex
coronary arteries in at least four projections, and the right
coronary artery in at least two projections. CAGs were
recorded at 15 frames per second and recorded on compact
discs in DICOM format. Angiograms were interpreted by
two cardiologists and thrombolysis in myocardial infarction
(TIMI) frame counts (TFC) were calculated for each coronary
artery6. TFC were defined as the number of cine frames
required for the contrast agent to reach standardized distal
coronary landmarks as described by Gibson et al6. TFC for
the left anterior descending artery were divided by 1.7 to
obtain the corrected TFC (cTFC). Since the most frequently
standardized filming rate is 30 frames per second, the TFCs
were multiplied by 2. The subjects with a TFC greater than
two standard deviations (SD) above the normal range were
considered to have CSF6. Total TFC was defined as the sum
of TFC in three major epicardial vessels. Mean TFC was
calculated by dividing the total TFC by 3.
Beck Anxiety Inventory (BAI). The SCL-90-R is a revised
version of the original SCL-90 (Derogatis et al.) scale, which
is a psychiatric self-report inventory screening for general
psychiatric symptomatology. This inventory focuses on nine
dimensions: somatization, anxiety, obsessive-compulsive,
depression, interpersonal sensitivity, psychoticism, paranoid
ideation, hostility, and phobic anxiety7. Each of 90 items
is scored on a five-point Likert scale from 0 (not at all) to
4 (extremely) according to the rate of occurence of each
symptom over the last week. Global Severity Index (GSI)
is a quantitative indicator concerning the respondent’s
current level of psychological distress and is calculated
by summing the scores of nine dimensions and additional
items, then dividing by the total number of responses.
The realibility and validity of the Turkish version of SCL-90
has been analyzed by Dağ et al8.
The severity of depression was assessed using BDI, which
is a 21 item self-report scale developed by Beck et al9.
Items in the scale are rated from 0 to 3 in increasing order of
severity. Item scores are totaled and can range from 0 to 63.
Higher scores correlate with more severe depression.
The pathologic cut-off value for the BDI score was determined
to be 17 in the Turkish population, which reflects moderate
and severe depressive states10,11. The validity and accuracy of
the BDI in the Turkish population have been studied by Hisli
et al12. Anxiety is measured using the 21-item self-reported
BAI13. Each item is scored from 0 to 3 according to severity.
Item scores are totaled and higher scores indicate higher
anxiety levels. The pathologic cut-off value for the BAI score
was determined to be 16 in the Turkish population; scores
above this value reflect moderate to severe anxiety states10,11.
The validity and realibility of the Turkish version of the BAI
have been studied by Ulusoy et al14.
Statistical Analyses
All data is presented as a mean ± SD for variables with normal
distribution or a median [interquantile range] for variables with
non-normal distribution. Categorical variables are reported as
numbers and percentages. Continuous variables were checked
for the normal distribution assumption using Kolmogorov‑Smirnov
statistics. Categorical variables were tested by Pearson’s χ2 test
and Fisher’s Exact Test. Differences between patients and control
subjects were evaluated using the Mann–Whitney U test or
the Student t-test, when appropriate. The relation between
numerical variables was identified using Pearson or Spearman’s
rho test. Multivariate linear regression analysis was performed to
investigate the independent correlates of mean TFC. p-values
were two sided and values < 0.05 were considered statistically
significant. All statistical studies were carried out using Statistical
Package for Social Sciences software (SPSS 16.0 for Windows,
SPSS Inc., Chicago, Illinois).
Psychological tests
Results
Psychological interviews were performed by a psychiatrist
blinded to the CAG results. Subjects who met the
inclusion criteria for the study completed the following
psychological symptoms scales: Symptom Checklist 90
Revised (SCL‑90-R), Beck Depression Inventory (BDI), and
Demographic, clinical, laboratory, echocardiographic,
and angiographic characteristics of the 44 patients with
CSF and 50 control subjects were summarized in Table 1.
The two groups were similar in terms of age, sex, DM,
HT, hyperlipidemia, alcohol consumption, smoking status,
Arq Bras Cardiol. 2015; 105(4):362-370
363
Karataş et al.
Psychiatric scales and coronary slow flow
Original Article
Table 1 – Demographic, clinical, echocardiographic, laboratory, and demographic characteristics of the study population
Characteristics
Control Group (n = 50)
Slow flow group (n = 44)
p value
Age, years
53.8 ± 7.8
53.1 ± 10.4
0.73
Male, n (%)
27 (54)
29 (66)
0.24
HT, n (%)
24 (48)
20 (45)
0.80
Hyperlipiemia, n (%)
19 (38)
16 (36)
0.87
Diabetes, n (%)
9 (18)
8 (18)
0.98
Smoking, n (%)
27 (54)
20 (45)
0.41
Alcohol, n (%)
7 (14)
5 (11)
0.70
3 (6)
4 (9)
0.57
Medications
ASA, n (%)
Beta Blocker, n (%)
3 (6)
2 (5)
0.76
ACEI, n (%)
6 (12)
5 (11)
0.92
ARB, n (%)
9 (18)
5 (11)
0.37
Calcium Channel Blocker, n (%)
7 (14)
6 (14)
0.95
Statin, n (%)
17 (34)
13 (30)
0.66
OAD, n (%)
6 (12)
5 (11)
0.92
Insulin, n (%)
5 (10)
6 (14)
0.58
Diuretic, n (%)
12 (24)
8 (18)
0.49
Education level
Primary school, n(%)
23 (46)
25 (57)
High school, n(%)
20 (40)
13 (29)
University, n(%)
7 (14)
6 (14)
0.55
Montly income
Low, n(%)
27 (54)
25 (57)
Intermediate, n(%)
20 (40)
17 (39)
High, n(%)
BMI
Heart rate (bpm)
3 (6)
2 (4)
25.6 ± 2.2
30.1 ± 6.4
0.93
0.01
78 ± 8
76 ± 7
0.11
Systolic BP (mmHg)
117 ± 12
119 ± 13
0.85
LDL cholesterol (mg/dL)
108 ± 27
110 ± 31
0.87
Fasting plasma glucose (mg/dL)
100 ± 32
103 ± 35
0.71
60 ± 9
59 ± 8
0.61
1 vessel , n(%)
-
24 (54)
-
> 1 vessel , n(%)
-
20 (45)
-
LAD
18.9 ± 1.1
27.7 ± 8.2
0.01
LCx
19.1 ± 1.7
24.5 ± 6.3
0.01
RCA
18.5 ± 1.3
24.9 ± 7.2
0.01
LV ejection fraction (%)
Total number of vessels with CSF
TIMI frame counts
HT: Hypertension; ACEI: Angiotensin converting enzyme inhibitor; ARB: Angiotensin receptor blocker; ASA: Acetylsalicylic acid; BMI: Body mass index; CSF: Coronary
slow flow; BP: Blood pressure; LAD: Left anterior descending; LCx: Left circumflex; LDL: Low-density lipoprotein; LV: Left ventricular; n: Number; OAD: Oral
antidiabetic; RCA: Right coronary artery; TIMI: Thrombolysis in myocardial infarction.
364
Arq Bras Cardiol. 2015; 105(4):362-370
Karataş et al.
Psychiatric scales and coronary slow flow
Original Article
medications, heart rate, systolic blood pressure, low-density
lipoprotein (LDL) cholesterol, and fasting plasma glucose
levels. In addition, there was no significant difference in
terms of monthly income and educational levels between
the two groups (p = 0.93 and p = 0.55, respectively).
TIMI frame counts were significantly higher in patients with
CSF than those in controls (p = 0.01). In 24 (54%) of the
cases, CSF was observed in one vessel, and in 20 (46%) of
the cases, more than one vessel had CSF.
A comparison of psychiatric test results between the two
groups is summarized in Table 2. In the CSF group, the BAI
score was significantly higher than in controls (13 [18.7] vs
7.5 [7], p = 0.01). Twenty patients in the CSF group had
a BAI score ≥ 16, which was significantly higher than the
control group (8 cases) (p = 0.01). When the BDI test scores
were compared between the two groups, subjects in the CSF
group had significantly higher scores than those in control
group (11 [14.7] vs. 6.5 [7], p = 0.01). The frequency of
subjects with a BDI score ≥ 17 was higher in the CSF group
(32% vs. 2%, p = 0.01). In addition, the median general
symptoms index score was significantly higher in the CSF
group (1.76 [0.81] vs 1.1[0.24], p = 0.01).
In univariate correlation analysis, mean TIMI scores were
positively correlated with BAI (r = 0.56, p = 0.01), as were
BDI scores (r = 0.47, p = 0.01) and the general symptom
index (r = 0.65, p = 0.01); however, they were not correlated
with age, educational level, monthly income, glucose, or LDL
levels (Table 3). In addition, BMI was significantly correlated
with mean TFC (r = 0.28, p = 0.01) but was not correlated
with BAI (r = 0.16, p = 0.11), BDI (r = 0.08, p = 0.78), or
GSI (r = 0.15, p = 0.18).
To investigate the independent determinants of mean TFC,
we performed a multivariate linear regression analysis using a
model adjusted for age, gender, and BMI. Results indicated
that BMI (standardized β coefficient = 0.221; p = 0.01),
BAI (standardized β coefficient = 0.546; p = 0.01), BDI
(standardized β coefficient = 0.444; p = 0.01), and GSI
(standardized β coefficient = 0.607; p = 0.01) were
independently correlated with mean TFC. No correlation
with age or gender was observed.
Correlation and subgroup analyses were performed
to investigate the correlation of BAI, BDI, and GSI with
atherosclerosis risk factors. In these analyses, BAI was not
significantly correlated with age (r=0.09, p = 0.54), fasting
glucose levels (r = −0.05, p = 0.64), LDL (r = −0.14,
p = 0.19), or systolic blood pressure (r = 0.07, p = 0.72).
BDI was not significantly correlated with age (r = 0.08, p = 0.41),
fasting glucose levels (r = −0.11, p = 0.31), LDL (r = −0.14,
p = 0.11), or systolic blood pressure (r = 0.17, p = 0.09). GSI
was not significantly correlated with age (r = 0.03, p = 0.79),
fasting glucose levels (r = −0.06, p = 0.65), LDL (r = −0.12,
p = 0.26) or systolic blood pressure (r = 0.12, p = 0.24).
In subgroup analysis, BAI, BDI, and GSI were not significantly
different when compared between females and males (10 [14.9]
vs. 8 [9.7], p = 0.26; 9 [13] vs. 8.5 [9.5], p = 0.18; 1.12 [0.92]
vs. 1.38 [0.67], p = 0.46, respectively). In addition, BAI, BDI,
and GSI were not significantly different between smokers and
non-smokers (8 [10] vs. 10 [12], p = 0.21; 9 [8] vs. 9 [12],
p = 0.49; 1.35 [0.57] vs. 1.21 [0.89], p = 0.57, respectively).
In total, 28 study participants (30%) had BAI scores ≥ 16
(Table 4). In these patients, total TFC and mean TFC were
significantly higher (75.2 ± 17.5 vs. 62.4 ± 9.6, p = 0.01
and 25.1 ± 5.8 vs. 20.8 ± 3.2, p = 0.01, respectively).
Age, gender, HT, DM, hyperlipidemia, smoking, alcohol
consumption, educational status, monthly income, BMI,
systolic blood pressure, fasting glucose, LDL cholesterol, and
LVEF were similar among patients with BAI score < 16 and
BAI score ≥ 16.
A comparison of study parameters in subgroups of patients
classified as BDI score < 17 and ≥ 17 is depicted in Table 5.
Overall, 76 patients (81%) had a BDI score < 17, whereas
18 patients (19%) had BDI scores ≥ 17. In both groups, age,
gender, HT, DM, hyperlipidemia, smoking, alcohol, educational
status, monthly income, BMI, systolic blood pressure, fasting
glucose, LDL cholesterol, and LVEF were similar. Total TFC
and mean TFC were significantly higher in subjects with a BDI
score ≥ 17 than in those with a BDI score < 17. (78 ± 19 vs
63 ± 10; 25.9 ± 6.5 vs 21.1 ± 3.4, p = 0.01, respectively).
In a subgroup analysis of the 44 patients with CSF patients,
those with CSF in more than one vessel had significantly higher
BAI, BDI, and GSI scores than those with CSF restricted to
one vessel (26 [16] vs. 8 [7.2], p = 0.01; 17 [14] vs 6 [1.1],
p = 0.01; 2.1 [0.7] vs 1.4 [0.6], p = 0.01, respectively).
In univariate correlation analysis, the number of vessels with
CSF was positively correlated with BAI (r = 0.66, p = 0.01),
BDI (r = 0.61, p = 0.01), and GSI (r = 0.59, p = 0.01).
Table 2 – Comparison of psychiatric tests results between CNF and CSF patients
Characteristics
CNF (n = 50)
CSF (n = 44)
p value
7.5 [7]
13 [18.7]
0.01
< 16, n (%)
42 (84)
24 (55)
0.01
≥ 16, n (%)
8 (16)
20 (45)
0.01
6.5 [7]
11 [14.7]
0.03
< 17, n (%)
46 (92)
30 (68)
0.01
4 (8)
14 (32)
0.01
1.1 [0.24]
1.76 [0.81]
0.01
BAI
BDI
≥ 17, n (%)
General Symptoms Index
BAI: Beck Anxiety Inventory; BDI: Beck Depression Inventory; CNF: Coronary normal flow; CSF: Coronary slow flow.
Arq Bras Cardiol. 2015; 105(4):362-370
365
Karataş et al.
Psychiatric scales and coronary slow flow
Original Article
Table 3 – Univariate correlation analysis of mean TIMI frame counts with study parameters
Characteristics
Mean TIMI frame count
BAI
r = 0.56; p = 0.01
BDI
r = 0.47; p = 0.01
General Symptoms Index
r = 0.65; p = 0.01
Age
r = 0.09; p = 0.36
BMI
r = 0.28; p = 0.01
Education level
r = −0.15; p = 0.15
Montly income
r = 0.08; p = 0.44
LDL
r = 0.02; p = 0.88
Glucose
r = 0.05; p = 0.67
EF
r = 0.09; p = 0.92
BAI: Beck Anxiety Inventory; BDI: Beck Depression Inventory; BMI: Body mass index; LDL: Low-density lipoprotein; EF: Ejection fraction; TIMI: Thrombolysis in
myocardial infarction.
Table 4 – Comparison of study parameters in patients with BAI score < 16 and ≥ 16
Characteristics
BAI < 16 (n = 66)
BAI ≥ 16 (n = 28)
p value
Age
53 ± 8.7
54.7 ± 9.8
0.42
Female Gender, n (%)
23 (35)
15 (53)
0.06
HT, n (%)
32 (48)
12 (43)
0.82
Hyperlipiemia, n (%)
23 (35)
12 (43)
0.48
Diabetes, n (%)
14 (21)
3 (11)
0.38
Smoking, n (%)
36 (54)
11 (39)
0.36
Alcohol, n (%)
10 (15)
3 (11)
0.75
Primary school, n(%)
31 (52)
19 (68)
High school, n(%)
27 (41)
6 (21)
University, n(%)
8 (12)
3 (11)
< 1500 TL, n (%)
36 (54)
16 (57)
1500-3000 TL, n (%)
26 (39)
11 (39)
4 (6)
1 (3)
BMI
27 ± 3.4
29.3 ± 7.7
0.07
Systolic BP (mmHg)
116 ± 10
118 ± 12
0.46
LDL cholesterol (mg/dL)
110 ± 28
113 ± 30
0.35
Glucose (mg/dL)
95 ± 33
103 ± 34
0.33
Education level
0.11
Montly income
>3000 TL, n (%)
EF (%)
0.88
62 ± 4
59 ± 6
0.15
Mean TIMI FC
20.8 ± 3.2
25.1 ± 5.8
0.01
Total TIMI FC
62.4 ± 9.6
75.2 ± 17.5
0.01
BAI: Beck Anxiety Inventory; HT: Hypertension; BMI: Body mass index; BP: Blood pressure; EF: Ejection fraction; LDL: Low-density lipoprotein; TIMI FC: Thrombolysis
in miyocardial infarction frame count; TL: Turkish Liras.
366
Arq Bras Cardiol. 2015; 105(4):362-370
Karataş et al.
Psychiatric scales and coronary slow flow
Original Article
Table 5 – Comparison of study parameters in patients with BDI score < 17 and ≥ 17
Characteristics
BDI < 17 (n = 76)
BDI ≥ 17 (n = 18)
p value
Age, years
53 ± 9.3
55.3 ± 8.2
0.36
Female gender, n (%)
28 (37)
10 (55)
0.15
HT, n (%)
37 (49)
7 (39)
0.60
Hyperlipiemia, n (%)
29 (38)
6 (33)
0.79
Diabetes, n (%)
13 (17)
4 (22)
0.73
Smoking, n (%)
41 (54)
6 (33)
0.19
Alcohol, n (%)
11 (14)
2 (11)
0.71
Primary school, n (%)
40 (53)
10 (55)
High school, n (%)
27 (35)
6 (33)
University, n (%)
9 (12)
2 (11)
< 1500 TL, n (%)
41 (54)
11 (61)
1500-3000 TL, n (%)
31 (41)
6 (33)
Education level
0.97
Montly income
> 3000 TL, n (%)
BMI
0.84
4 (5)
1 (5)
27 ± 5.4
28.7 ± 4.1
0.36
Systolic BP (mmHg)
116 ± 12
120 ± 11
0.21
LDL cholesterol (mg/dL)
110 ± 29
101 ± 27
0.23
Glucose (mg/dL)
100 ± 32
106 ± 42
0.47
62 ± 4
59 ± 5
0.14
Mean TIMI
21.1 ± 3.4
25.9 ± 6.5
0.01
Total TIMI
63 ± 10
78 ± 19
0.01
EF (%)
BDI: Beck Depression Inventory; HT: Hypertension; BP: Blood pressure; LDL: Low-density lipoprotein; TIMI: Trombolysis in myocardial infarction; TL:Turkish Liras;
BMI: Body mass index; EF: Ejection fraction.
Discussion
Results of the present study indicate that patients with
CSF had significantly increased levels of depression, anxiety,
and overall psychological distress compared with patients
having CNF.
The INTERHEART study is the largest trial conducted to date
to investigate the correlation between stress and heart disease.
This trial included 11,119 patients with MI from 52 countries.
In this study, perceived stress and depression were shown to be
important risk factors, which together accounted for 32.5% of
the population with attributable risk for CAD. These findings
suggest that these variables together were as important as
smoking and more important than DM15. In a previous study,
every 5-point increase in BDI score was associated with a
25%–30% increase in the risk of abnormal CAG findings or
definitive CAD10. Furthermore, Shiozaki et al. demonstrated
that depression emerging during the year after experiencing
a MI is significantly associated with subsequent cardiovascular
events in a 2.9-year follow-up for male patients16.
The prevalence of depression in the Turkish population
is estimated to beabout 10%–20% 17. Prior studies have
estimated the prevalence of depression ranging from 20% to
40% in patients with CAD and have found that the presence
of depression is associated with increased risk for adverse
events18. In our study, 32% of patients with CSF were found
to have major depressive disorder documented with a BDI
score ≥ 17. Consistent with our results, Durmaz et al. have
reported higher depression rates among patients with CSF
(50% vs. 8%)19. Their study examined 90 patients and used
the Hamilton Rating Scale (HAMD) to measure depression19.
A total of 94 patients were included in our study but a
different scale for depression (BDI) was used.
The pathophysiological mechanism between
psychological distress and cardiovascular events has not
been fully elucidated. Some of the proposed mechanisms
are as follows: high sympathetic tone; increased cortisol
and catecholamine; endothelial dysfunction; abnormal
platelet activation, including enhanced platelet reactivity
and release of platelet products (such as platelet factor 4 and
b-thromboglobulin); augmented release of inflammatory
markers; decreased heart rate variability; accelerated
atherogenesis; and poor adherence10,11. We did not observe
any correlation between level of anxiety or depression
and atherosclerotic risk factors, which is similar to a prior
report by Zafar et al20 Furthermore, no relationship between
educational or monthly income (socioeconomic) status and
depression or anxiety have been established.
Arq Bras Cardiol. 2015; 105(4):362-370
367
Karataş et al.
Psychiatric scales and coronary slow flow
Original Article
Compared with the extensive literature on depression
in patients with CAD, relatively few studies have examined
the role of anxiety. Some studies have reported anxiety
symptoms to be predictive of subsequent cardiac events,
mortality, and in-hospital complications in patients with CAD,
whereas others have found no association21-23. Martens et
al24 have found that participants with baseline generalized
anxiety disorder (GAD) had a greater rate of subsequent
cardiovascular events than did participants without GAD.
Vural et al10 found significant correlation between CAD and
BAI scores. Todaro et al25 reported the lifetime prevalence
of anxiety disorders to be 45.3% in patients with CAD.
In addition, Durmaz et al19 investigated the relationship
between anxiety and CSF. Unlike the other studies in the
literature, their study utilized State-Trait Anxiety Inventory
(STAI) for anxiety. They found that STAI scores were
significantly higher in the CSF group. However, their study
did not include a known cut-off value for anxiety; therefore,
whether a difference was observed between the two groups
in terms of the number of people with anxiety is unknown.
As a result, no percentage was provided for anxiety19.
Our present study utilized the BAI scale to identify
anxious people according to the cut-off value and found
that 45.4% of patients with CSF had anxiety disorder; this
was significantly higher than the control group. Previous
studies have shown that obese and overweight people are
more likely to experience anxiety and depression than
those who are of normal weight26. However, comparison of
the frequency of psychiatric disorders between overweight
and obese people are controversial in the literature. In our
study population, CNF patients were overweight, whereas
patients with CSF were obese according to the mean BMI
levels. As we did not intend to investigate correlation of
obesity with psychiatric tests, our data may not be suitable
to draw conclusions regarding obesity and psychiatric
disorders; however, in our study, BMI was not correlated
with BAI, BDI, and GSI scores.
GSI, which can be used as a summary of the SCL-90-R
test, is designed to measure overall psychological distress. In
our study, the GSI of patients CSF was 1.76, whereas the GSI
of those subjects in the control group was 1.1 (p = 0.01),
indicating that patients with CSF exhibit more psychological
distress than those with normal coronary blood flow.
Therefore, our study is the first study in the literature to use
the SCL-90-R scale in patients with CSF.
368
Arq Bras Cardiol. 2015; 105(4):362-370
Our study also found that patients with CSF in more than
one coronary vessel had higher BAI, BDI, and GSI scores,
which indicates the positive correlation between these scores
and the extent and severity of CSF. Our study is the first study
in the literature to report this correlation.
Limitations
This study has several limitations that deserve mention.
This is a single center, cross-sectional prospective study
with relatively small sample size. In addition, we could not
report the correlation of the study parameters with long-term
outcomes in the study population.
Conclusions
Although we could not draw a causal relationship, we
observed higher levels of depression, anxiety, and overall
psychological distress in patients with CSF. Further studies are
needed to confirm our results and the importance of these
findings in long-term outcomes and prognosis of patients
with CSF.
Author contributions
Conception and design of the research: Karataş MB,
Bolca O; Acquisition of data: Şahan E, Çakıllı Y, Arugaslan E;
Analysis and interpretation of the data: Karataş MB, Şahan
E, Güngör B, İpek G, Çakıllı Y, Bolca O; Statistical analysis:
Güngör B, İpek G; Writing of the manuscript: Özcan KS,
Çanga Y, Arugaslan E; Critical revision of the manuscript
for intellectual content: Karataş MB, Özcan KS, Çanga Y,
Güngör B.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This study is not associated with any thesis or dissertation work.
Karataş et al.
Psychiatric scales and coronary slow flow
Original Article
References
1. Bunker SJ, Colquhoun DM, Esler MD, Hickie IB, Hunt D, Jelinek VM, et al.
“Stress” and coronary heart disease:psychosocial risk factors. Med J Aust.
2003;178(6):272­6.
2. Barth J, Schumacher M, Herrmann­Linger C. Depression as a risk factor for
mortality in patients with coronary heart disease: a meta­analysis. Psychosom
Med. 2004;66(6):802-13.
3. Lampert R, Joska T, Burg MM, Batsford WP, McPherson CA, Jain D.
Emotional and physical precipitants of ventricular arrhythmia. Circulation.
2002;106(14):1800-5.
4. Erden I, Cakcak Erden E, Durmuş H, Tıbıllı H, Tabakçı M, Kalkan ME, et al.
Association between restless leg syndrom and slow coronary flow. Anadolu
Kardiyol Derg. 2014;14(7):612-6.
5.
Beltrame JF, Limaye SB, Horowitz JD. The coronary slow flow phenomenon
- a new coronary microvascular disorder. Cardiology. 2002;97(4):197-202.
6. Gibson CM, Cannon CP, Daley WL, Dodge JT Jr, Alexander B Jr, Marble SJ,
et al. TIMI frame count: a quantitative method of assessing coronary artery
flow. Circulation. 1996;93(5):879-88.
7. Derogatis LR. SCL-90-R, administration, scoring & procedures manual I.
Baltimore: John Hopkins University School of Medicine; 1977.
8.
Dag I. Reliability and validity of the Symptom Checklist – 90 Revised among
university students. Türk J Psychiatry. 1991;2:5-12.
9. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for
measuring depression. Arch Gen Psychiatry. 1961;4:561-71.
10. Vural M, Satiroglu O, Akbas B, Goksel I, Karabay O. Coronary artery disease
in association with depression or anxiety among patients undergoing
angiography to investigate chest pain. Tex Heart Inst J. 2009;36(1):17-23.
11. Ünal FE, Determining the frequency of depression and anxiety and
investigating the sociodemographic factors in Bakirköy Dr. Sadi Konuk
Training and Research Hospital intern doctors. Speciality Thesis, Bakirköy
Dr. Sadi Konuk Training and Research Hospital, İstanbul; 2008
12. Hisli N. Validity and accuracy of Beck depression inventory among university
students (İn Turkish). Psikoloji Dergis. 1989;7(23):3-13.
13. Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical
anxiety: psychometric properties. J Consult Clin Psychol. 1988;56(6):893-7.
14. Ulusoy M, Sahin NH, Erkmen H. Turkish version of the Beck Anxiety Inventory:
psychometric properties. J Cogn Psycother Int Q. 1998;12(2):163-72.
15. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, et al;
INTERHEART Study Investigators. Effect of potentially modifiable risk factors
associated with myocardial infarction in 52 countries (the INTERHEART
study): case­control study. Lancet. 2004;364(9438):937­52.
16. Shiozaki M, Iso H, Ohira T, Nakatani D, Shimizu M, Sakata Y, et al.
Longitudinal risk of cardiovascular events in relation to depression
symptoms after discharge among survivors of myocardial infarction:Osaka
Acute Coronary Insufficiency Study (OACIS). Circ J. 2011;75(12):2878-84.
17. Yildiz B, Turan MT, Besirli A. Metabolic syndrome in bipolar affective
disorder. Erciyes Tip Dergisi (Erciyes Medical Journal). 2011;33(3):197-204.
18. Nicholson A, Kuper H, Hemingway H. Depression as an aetiologic and
prognostic factor in coronary heart disease: a meta­analysis of 6362 events
among 146 538 participants in 54 observational studies. Eur Heart J.
2006;27(23):2763-74.
19. Durmaz T, Keles T, Erdogan KE, Ayhan H, Bilen E, Bayram NA, et al. Coronary
slow flow is associated with depression and anxiety. Acta Cardiol Sin.
2014;30:197-203.
20. Zafar MU, Paz-Yepes M, Shimbo D, Vilahur G, Burg MM, Chaplin W, et al.
Anxiety is a better predictor of platelet reactivity in coronary artery disease
patients than depression. Eur Heart J. 2010;31(13):1573-82.
21. Grace SL, Abbey SE, Irvine J, Shnek ZM, Stewart DE. Prospective examination
of anxiety persistence and its relationship to cardiac symptoms and recurrent
cardiac events. Psychother Psychosom. 2004;73(6):344­52.
22. Mayou RA, Gill D, Thompson DR, Day A, Hicks N, Volmink J, et al.
Depression and anxiety as predictors of outcome after myocardial infarction.
Psychosom Med. 2000;62(2):212­9.
23. Herrmann C, Brand­Driehorst S, Buss U, Rüger U. Effects of anxiety and
depression on 5­year mortality in 5057 patients referred for exercise testing.
J Psychosom Res. 2000;48(4­5):455­62.
24. Martens EJ, De Jonge P, Na B, Cohen BE, Lett H, Whooley MA. Scared to
death? Generalized anxiety disorder and cardiovascular events in patients
with stable coronary heartdisease: The Heart and Soul Study. Arch Gen
Psychiatry. 2010;67(7):750­8.
25. Todaro JF, Shen BJ, Raffa SD, Tilkemeier PL, Niaura R. Prevalence of anxiety
disorders in men and women with established coronary heart disease. J
Cardiopulm Rehabil Prev. 2007;27(2):86-91.
26. Martínez Hernández F, Tovilla Zárate CA, López Narváez L, Juárez Rojop
IE, Jiménez Santos MA, González Gutiérrez CP, et al. Prevalence and
gravity of depression and anxiety in patients with obesity and type 2
diabetes: a study in the population of Tabasco, Mexico. Gac Med Mex.
2014;150(1):101-6.
Arq Bras Cardiol. 2015; 105(4):362-370
369
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Back to the Cover
Original Article
Mortality from Cardiovascular Diseases in the Elderly: Comparative
Analysis of Two Five-year Periods
Grasiela Piuvezam, Wilton Rodrigues Medeiros, Andressa Vellasco Costa, Felipe Fonseca Emerenciano, Renata
Cristina Santos, Danilo Silveira Seabra
Universidade Federal do Rio Grande do Norte, Natal, RN – Brazil
Abstract
Background: Cardiovascular diseases are the leading cause of death in Brazil. The better understanding of the spatial
and temporal distribution of mortality from cardiovascular diseases in the Brazilian elderly population is essential to
support more appropriate health actions for each region of the country.
Objective: To describe and to compare geospatially the rates of mortality from cardiovascular disease in elderly
individuals living in Brazil by gender in two 5-year periods: 1996 to 2000 and 2006 to 2010.
Methods: This is an ecological study, for which rates of mortality were obtained from DATASUS and the population rates
from the Brazilian Institute of Geography and Statistics (Instituto Brasileiro de Geografia e Estatística). An average mortality
rate for cardiovascular disease in elderly by gender was calculated for each period. The spatial autocorrelation was
evaluated by TerraView 4.2.0 through global Moran index and the formation of clusters by the index of local Moran-LISA.
Results: There was an increase, in the second 5-year period, in the mortality rates in the Northeast and North regions,
parallel to a decrease in the South, South-East and Midwest regions. Moreover, there was the formation of clusters
with high mortality rates in the second period in Roraima among females, and in Ceará, Pernambuco and Roraima
among males.
Conclusion: The increase in mortality rates in the North and Northeast regions is probably related to the changing
profile of mortality and improvement in the quality of information, a result of the increase in surveillance and health
care measures in these regions. (Arq Bras Cardiol. 2015; 105(4):371-380)
Keywords: Cardiovascular Diseases / mortality; Cardiovascular Diseases / epidemiology; Comparative Study; Aged.
Introduction
Noncommunicable diseases (NCD), according to the
worldwide trend of recent decades, currently determine the
majority of causes of death in Brazil, changing the profile
of diseases that occur in the population, being higher than
mortality rates from infectious and parasitic diseases1.
In the country, the NCD in 2007 accounted for 72% of
causes of death and affected more individuals that belong
to vulnerable groups, such as the elderly2. Over the past
decade, cardiovascular diseases (CVD) accounted for 50%
of the mortality of all the NCD3. According to data from the
Ministry of Health, NCD corresponded to the first cause of
death in Brazil and accounted in 2008 for 40.8% of deaths
of individuals aged 60 or older4.
Mailing Address: Andressa Vellasco Brito Costa •
Universidade Federal do Rio Grande do Norte. Rua Joana D’Arc, 1.780,
Candelária. Postal Code 59065-620, Natal, RN – Brazil
E-mail: [email protected]
Manuscript received December 22, 2014; revised manuscript May 04, 2015;
accepted May 06, 2015
DOI: 10.5935/abc.20150096
371
Although CVD are the leading cause of death in Brazil,
few studies have addressed the spatial and temporal
distribution of mortality caused by them, especially
regarding the elderly age group. Mortality from CVD
is a phenomenon that has different risk factors, from
behavioral and social factors to genetic ones and,
therefore, one can infer that their distribution can be
shown in different ways, as the context in which different
population groups are inserted is variable. In this sense, it
can be observed that the territory configurations, as well
as the process of urbanization, have a direct impact on
the way several population groups deal with this group
of diseases5.
From this perspective, this study aimed to describe the
geographical distribution of mortality from CVD in the elderly
population in Brazil by gender, in the five-year period of
1996 to 2000 and from 2006 to 2010, and compare them
in both periods. The search for a better understanding of
the spatial and temporal distribution of these rates is critical
for planning evidence-based sustainable public policies.
This set of information can contribute to a better control and
prevention of CVD, as it supports the achievement of more
targeted actions for each country region, aiming thereby to
reduce health inequalities.
Piuvezam et al.
Mortality from Cardiovascular Diseases in the Elderly
Original Article
Methods
This was an ecological study, of which the area analysis units
were the Brazilian states, which constitute 27 elements in the
total sample. Data considered in the study are covered by the
five-year periods of 1996-2000 and 2006-2010.
The study population was a group of elderly residents
in Brazil who died from CVD in the analyzed period.
For inclusion in the study, it was considered an elderly any
individual aged ≥ 60 years6.
Data were obtained from the Data Processing Department
of the Unified Health System (DATASUS), from the mortality
information system (SIM). These data are grouped by SIM
through the records of its legal instrument collection,
the death certificate (DC). This information is available
on the Internet for free consultation as data amassed by
municipalities, that is, they were not individually and
nominally collected. In this sense, there is no possibility
of physical or moral damage from the individual's and
community’s perspective, as the principles contained in
Resolution 466 of 12 December 2012 were followed.
Therefore, this article did not require approval by the
Ethics Committee of Universidade Federal do Rio Grande
do Norte (CEP-UFRN).
The outcome variables were the adjusted mortality rate
from cardiovascular diseases (MRCD) in female elderly
(MRCDf) and male (MRCDm) for each state. MRCD is
calculated by the ratio of the number of elderly deaths from
CVD by gender in Brazil in the assessed period and the
elderly population in Brazil in the same period, by gender
and per thousand inhabitants.
It is appropriate to clarify that the present investigation
was based on the rate adjusted by the year 2003
population (corresponding to half of the study period five-year periods of 1996-2000 and 2006-2010), as well as
by age groups detailed by five-year intervals, from 60 years
to 80 years and older, according to the standardization
established by DATASUS.
We chose to perform, simultaneously, the comparison of
mortality rates from III-defined causes (IDC) in both periods,
to better demonstrate the information qualification process
during the assessed period. Thus, a similar methodology was
used to obtain adjusted rates of mortality from IDC in male
and female elderly individuals.
Therefore, for comparative analysis, data were selected for
two five-year periods, the first from 1996 to 2000, and the
second from 2006 to 2010. The necessary population data
to calculate the MRCD for each municipality were obtained
from the Brazilian Institute of Geography and Statistics
(Instituto Brasileiro de Geografia e Estatística - IBGE), available
in DATASUS site. The TabWin software was used for data
tabulation and calculation of mortality rates. The analysis of
this coefficient in two different five-year periods allowed this
study to assess changes in the epidemiology of mortality from
CVD in Brazil, focusing on their geospatial characteristics.
This rate was calculated for each year of the two
assessed five-year periods. Then, for each five-year period,
using arithmetic mean, we obtained the mean mortality
rate from cardiovascular diseases (MMRCD) per thousand
individuals for each state of Brazil. This MMRCD was
then distributed spatially to carry out exploratory and
geostatistical analysis.
The IBGE cartographic shape was used in the study, which
was obtained from its site. Initially, thematic maps were
built for the two five-year periods, a phase that consisted
in the exploratory analysis of spatial data. Their production
was carried out using the SIG TerraView 4.2.0. program, in
which the distribution amount was divided into five ranges
for the legend, through the "equal step" division for the
second five-year period, which was the basis for the first
period distribution. At this point, the gray scale was chosen
for visual comparison. At the time when the legend was
created, which was carried out using a color gradient, the
darker color represented the group of municipalities with
the worse situations.
The spatial autocorrelation was calculated using the
free Software TerraView 4.2.0 through the global Moran
index for the MMRCD distribution in both analyzed
periods. The value of the global Moran index ranges
from -1 to 1. Values close to zero indicate lack of spatial
autocorrelation; positive values indicate positive spatial
autocorrelation; and negative values indicate negative
autocorrelation. Subsequently, the standard analysis of the
spatial distribution and the possible cluster formation was
performed. For this, we used the local index of Moran‑LISA,
in order to map the intensity of clusters, considering a
p value < 0.05 as statistically significant. The representative
map of this situation is the Moran Map.
Results
The overall population of elderly individuals in Brazil
varied by 17.24% in the first analyzed five-year period,
totaling 14,536,029 in 2000. Regarding the period
between 2006 and 2010, there was a 30.57% increase
in the elderly population, i.e., in the end of the last year
of the second five-year period, there were 20,590,599
Brazilians aged 60 and older in absolute numbers.
In relative terms, 7.86% of the population of the country
was elderly in 1996 and, after 15 years, this number
increased to 10.79%. Regarding the elderly population
divided by gender, there was an increase between 1996
and 2010 of 38.22% for males and 41.03% for females.
In the period of 1996-2000, there were 4,629,638
deaths in Brazil, of which 53.8% occurred in individuals
aged 60 and older. In the years 2006-2010, 5,396,557
records of deaths were released by SIM, with 60.5% being
related to elderly individuals. Converting this analysis to the
causes related to Chapter IX - Circulatory Disorders of the
International Classification of Diseases and Health-Related
Problems (ICD-10)7, it is possible to see that such diseases
accounted for 27.51% of deaths in the general population
and 37.42% among the elderly, in the first five-year period.
For the second period, these numbers were respectively
29.19% and 37.17%.
Arq Bras Cardiol. 2015; 105(4):371-380
372
Piuvezam et al.
Mortality from Cardiovascular Diseases in the Elderly
Original Article
Regarding the eight leading causes of death, Graph 1
shows the proportional mortality of the elderly, by
gender, in both studied periods. In both genders, in the
first five‑year period, the three main causes of death
corresponded to diseases of the circulatory system in
the first place, IDC in the second, and neoplasms in
the third; in the second five‑year period, the top three
were: diseases of the circulatory system, cancer and
respiratory diseases.
Regarding the categories of most prevalent cause of
CVD in Brazil, it can be observed that in the first five years,
more than 50% were caused by the following conditions:
acute myocardial infarction (21.18%), CVA (19.50 %), heart
failure (13.43%) and chronic ischemic heart disease (6.09%).
In the second five-year period, it was observed that the most
prevalent were: acute myocardial infarction, with 22.05%;
hemorrhagic or ischemic CVA, with 15.86%; heart failure,
with 9.64% and primary hypertension, with 6.64%.
A
XX
XVIII
XI
X
IX
IV
II
I
5
0
10
15
20
Proportional Mortality Causes (%) 2006-2010
25
30
35
40
45
Proportional Mortality Causes (%) 1996-2000
B
XX
XVIII
XI
X
IX
IV
II
I
0
5
10
15
Proportional Mortality Causes (%) 2006-2010
20
25
30
35
40
Proportional Mortality Causes (%) 1996-2000
Graph 1 – (A) Proportional mortality among female elderly in Brazil, divided by cause of death in five-year periods, from 1996 to 2000 and 2006 to 2010. (B) Proportional
mortality among male elderly in Brazil, divided by cause of death in five-year periods, from 1996 to 2000 and 2006 2010.
Chapter I: infectious and parasitic diseases; Chapter II: neoplasms; Chapter IV: endocrine, nutritional and metabolic diseases; Chapter IX: circulatory system diseases;
Chapter X: respiratory diseases; Chapter XI: digestive diseases; Chapter XVIII: poorly-defined causes; Chapter XX: External causes. Source: Department of Informatics
of the Unified Health System (DATASUS) / Ministry of Health.
373
Arq Bras Cardiol. 2015; 105(4):371-380
Piuvezam et al.
Mortality from Cardiovascular Diseases in the Elderly
Original Article
Table 1 shows the distribution of MMRCD in the elderly,
per thousand inhabitants, by gender, in the Brazilian
states in the period from 1996 to 2000 and from 2006 to
2010. The highest rates in the first five year period was
concentrated in the South and Southeast states. The lowest
value found in Brazil was observed in the state of Maranhão
(4.24% for females and 5.32% for males), in the Northeast,
and the highest in the state of Paraná (19.78% for females
and 23.07% for males), in the South.
In the period 2006-2010, the lowest rate was found in the
state of Amapá (6.02% for females and 8.72% for men) and
the highest in the state of Santa Catarina, for elderly women
(21,92%) and Mato Grosso do Sul, for males (16.47%).
A significant decrease was observed regarding results found
in the South, Southeast and Midwest regions. In contrast,
the North and Northeast regions showed significant increase
in their rates, with emphasis on the states of Piauí, Paraíba,
Maranhão and Tocantins, for both genders.
The analysis concerning the distribution of MMRCDf
and MMRCDm in the Brazilian states is shown in Figure 1.
The results were obtained from the mean rate of deaths
from cardiovascular diseases in the elderly, in the periods
1996‑2000 and 2006-2010, and the significance test for the
global Moran's index, under the null hypothesis of absence
of spatial autocorrelation.
It was observed that the global Moran’s index for the
first five years was 0.225048 for females and 0.209145 for
males, with p = 0.09 and 0.16, respectively. In the second
five-year period, the value was 0.0887927, with p = 0.21
for elderly women and 0.0842536 and p = 0.21 for men
older than 60 years.
In order to support the results obtained by the
aforementioned analysis, the characterization of deaths
in the elderly was performed using an analogous
methodology, by gender and Brazilian Federation unit,
Table 1 – Distribution by gender of the mean mortality rate from cardiovascular disease (MMRCD) in the elderly, per thousand inhabitants, in
the Brazilian states in the periods 1996-2000 and 2006-2010
Federation Unit
First 5-year period (A)
Second 5-year period (B)
Delta (B-A)
Female
Male
Female
Male
Female
Male
Rondônia
13.56
14.15
11.75
13.12
-1.81
-1.03
Acre
8.31
9.32
9.58
11.96
1.27
2.64
Amazonas
8.02
8.94
7.90
9.86
-0.12
0.92
Roraima
11.03
15.87
9.49
12.72
-1.54
-3.15
Pará
8.69
9.46
8.74
10.72
0.04
1.26
Amapá
9.76
12.97
6.02
8.72
-3.73
-4.25
Tocantins
8.33
9.56
13.04
14.54
4.71
4.98
Maranhão
4.24
5.32
9.84
13.54
5.60
8.22
Piauí
6.59
8.43
14.68
17.83
8.09
9.39
Ceará
8.19
9.31
11.04
13.61
2.85
4.30
Rio Grande do Norte
7.44
8.69
9.99
12.67
2.55
3.98
Paraíba
5.43
6.00
11.99
14.00
6.56
8.00
Pernambuco
12.67
14.42
13.51
15.35
0.84
0.93
Alagoas
9.04
10.47
12.71
15.32
3.68
4.85
Sergipe
7.96
8.58
11.96
13.32
4.01
4.74
Bahia
8.10
9.01
8.73
10.03
0.63
1.02
Minas Gerais
13.76
16.25
9.84
12.03
-3.93
-4.21
Espírito Santo
13.63
17.46
12.50
15.89
-1.13
-1.58
Rio de Janeiro
17.14
22.27
11.36
15.77
-5.78
-6.50
São Paulo
18.00
22.00
11.51
14.96
-6.49
-7.04
Paraná
19.78
23.07
12.46
15.45
-7.32
-7.61
Santa Catarina
16.36
19.41
21.92
13.50
5.57
-5.91
Rio Grande do Sul
17.56
19.45
11.88
14.64
-5.69
-4.81
Mato Grosso do Sul
16.19
19.26
12.67
16.47
-3.52
-2.79
Mato Grosso
14.80
16.44
11.66
14.30
-3.14
-2.14
Goiás
14.41
15.54
11.31
12.99
-3.10
-2.55
Distrito Federal
17.25
21.35
9.63
14.29
-7.62
-7.05
Source: Mortality Information System (SIM). Department of Informatics of the Brazilian Unified Health System (DATASUS)/Ministry of Health, 2015.
Arq Bras Cardiol. 2015; 105(4):371-380
374
Piuvezam et al.
Mortality from Cardiovascular Diseases in the Elderly
Back to the Cover
Original Article
Figure 1 – Thematic maps of the mean mortality rate from cardiovascular diseases (MMRCD) per thousand inhabitants in each Brazilian state and gender in the periods
from 1996 to 2000 and from 2006 to 2010. Natal (RN), Brazil, 2015. Source: Department of Informatics the Unified Health System (DATASUS)/ Ministry of Health, 2015.
375
classified as ill‑defined causes (IDC) (Chapter XVIII of
ICD 10). The global Moran’s index values found for
elderly women and men, in the first five-year period were,
respectively: 0.388822 (p = 0.01) and 0.335994 (p = 0.04).
For the second five-year period, the values were 0.06128
(p = 0.38) and -0.00415266 (p = 44). Distribution of
deaths from IDC can be seen in Figure 2.
Therefore, in the first five-year period, in relation to the
outcome variables, clusters were formed in the states of Ceará
and Pernambuco for the female gender and in Rio Grande
do Norte, Ceará and Pernambuco for the male gender. In the
second five-year period, the autocorrelation was observed in
the states of Roraima, for the group of elderly women, and
Roraima, Ceará and Pernambuco, in relation to males.
To create the maps depicted in Figure 3, we used
the interpretation capabilities of the Moran Map, which
allows the visualization of the statistically significant
spatial autocorrelation areas 8 and identify the location
of homogeneous regions consisting of states with spatial
association, regarding MMRCDf and MMRCDm. Thus, the
Federation units were classified according to their location in
relation to the Moran scatter plot quadrants: the quadrants 1
(high-high) and 2 (low-low) indicate areas with positive spatial
association, i.e., the values were similar to those shown for
neighboring states; quadrant 3 (high-low) and 4 (low-high)
showed that the results did not follow the global trend and
therefore had a negative spatial association, as there were
neighbors that had discordant values8.
It is noteworthy the fact that for the spatial autocorrelation
analysis performed for deaths classified as IDC, as seen
in Figure 4, the methods described for the MMRCDf and
MMRCDm variables were used. Therefore, clusters were
formed, in the first five-year period, in Ceará and Pernambuco
for both genders. In the second five-year period, the
autocorrelation was observed in the states of Roraima, Acre,
Rondonia, Goias and Minas Gerais for the elderly females, and
Roraima, Acre, Goias and Minas Gerais for males.
Arq Bras Cardiol. 2015; 105(4):371-380
Discussion
Based on the results, it was observed that in the first
five‑year period, the highest MRCD were mainly concentrated
Piuvezam et al.
Mortality from Cardiovascular Diseases in the Elderly
Original Article
Figure 2 – Thematic maps of the mean rate of mortality from ill-defined causes (IDC) per thousand inhabitants for each Brazilian state and by gender in the periods from
1996 to 2000 and from 2006 to 2010. Natal (RN), Brazil, 2015. Source: Department of Informatics of the Unified Health System (DATASUS) / Ministry of Health, 2015.
in the South and Southeast regions. In the second five-year
period, there was a considerable increase in the rates observed
in the Northeast, as well as a decrease in the rates in the
South and Southeast regions. There was also a slight increase
in mortality rates in the North region.
The emergence of a cluster in the states of Rio Grande
do Norte, Ceará and Pernambuco, as seen in the Moran
Map for both genders, in the period 1996-2000, allowed the
identification of a positive spatial association of MMRCD,
indicating the similarity of this rate between those states and
their neighbors. Thus, a homogeneous area in the Northeast
was observed, characterized by high levels of MMRCD that
appeared in the second five-year period.
The literature shows that mortality statistics, as shown in
this study, are the most often used to obtain health status
information of a population and to plan necessary actions
for health promotion. However, it is of utmost importance
to also discuss the proportion of deaths attributed to IDC,
as it constitutes one of the indicators used to assess the
quality of that information and the correct trend of the
mortality analysis9.
At the stratification of deaths in the elderly population in
Brazil for the period of 1996-2000, the causes identified as
ill-defined encompassed the second overall position, with
a total of 17.64% of notifications. For the second five-year
period, there was substantial improvement, relocating
mortality from undetermined causes to the fourth position
(8.10%). Therefore, the lowest proportion of notifications
from Chapter XVIII of ICD-10 (CMD) indicates more
accurate statistics on mortality10.
In the country, the highest number deaths from ill-defined
causes concentrated in the age group older than 60 years;
that is, regarding the data for 2005, 67.2% of deaths from
IDC corresponded to this population group. One explanation
for the high proportion of deaths from IDC is the difficulty
in establishing the underlying cause of death in the elderly.
This is probably due to the presence of multiple diseases in
the elderly and the influence of age on the clinical expression
of signs and symptoms for the correct diagnosis of the
underlying cause of death11. In this sense, the data obtained
in the first five years for the analysis carried out on deaths
from IDC in the elderly corroborate the above statements,
as they show statistically significant results (p < 0.05).
Arq Bras Cardiol. 2015; 105(4):371-380
376
Piuvezam et al.
Mortality from Cardiovascular Diseases in the Elderly
Original Article
Figure 3 – Moran Map (significant) of spatial autocorrelation of the variable mean mortality rate from cardiovascular disease by gender, per thousand individuals for each
state in Brazil, in the periods 1996-2000, and 2006 to 2010. Natal (RN), Brazil, 2015. CVD: cardiovascular disease; Source: Department of Informatics of the Unified
Health System (DATASUS) / Ministry of Health, 2015.
One question to be assessed is the increased prevalence of
CVD in the North and Northeast states during the study period.
This fact was possibly related to the information production
qualification, both regarding the collection and sending of
data to the health management central level. Studies have
shown that over the past three decades, advances in health
information systems used in Brazil were supported by the
development of computer technology and the training of
Health Secretariat employees12,13.
The mortality information is compiled from SIM of the
Ministry of Health, which was designed in 1975 and initially
covered only some Brazilian states, which already held the
collection of this information12. Another milestone related
to the development of the mentioned information system
was the creation of the current design of the DO, along the
development of a new computerized application, which was
first used in 199914.
The information on mortality is obtained from the SIM of
the Ministry of Health, designed in 1975 and that initially
covered only a few Brazilian states, which already performed
this information collection12. Another milestone related to
377
Arq Bras Cardiol. 2015; 105(4):371-380
the development of the aforementioned information system
was the creation of the current design of the DC, along with
the development of a new computer application, which was
first used in 199914.
In 2004, the Health Surveillance Secretariat of the
Ministry of Health included the program Percentage
Reduction of Death from Ill-defined Causes in the Multi‑Year
Plan 2004-2008 and the "Investigation of the cause of
death” form was standardized. This program included
the data provided by medical or health professionals, or
those obtained from medical records and the results of
additional tests, to also ensure a more accurate recording
of information on the causes of death15.
In addition to this investigation, in March 2008, the
Ministry of Health launched a project to implement the
verbal autopsy in the country as a method to investigate
deaths from IDC, so that its analysis would allow the
physician to identify the sequence of events that led to the
death. Several international studies using verbal autopsy
methodology also observed changes in the structure of causes
of death, decrease in IDC and identification of external
Piuvezam et al.
Mortality from Cardiovascular Diseases in the Elderly
Original Article
Figure 4 – Moran Map (significant) of spatial autocorrelation of the mean mortality rate from ill-defined causes (IDC) by gender, per thousand individuals for each state
in Brazil, in the periods 1996-2000, and 2006 to 2010. Natal (RN), Brazil, 2015. Source: Department of Informatics of the Unified Health System (DATASUS) / Ministry
of Health, 2015.
causes, with the most frequent diseases being allocated in the
chapter of circulatory diseases and external causes - results
that are similar to those observed in this study16.
This phenomenon is called the "paradox of information",
which is characterized by the relocation of deaths from
IDC to other chapters of ICD-10. That is, the variation in
the proportion of death notifications from IDC can modify
the temporal series of mortality rates for certain groups of
causes17. In this regard, the absolute increase in the number
of deaths from diseases of the circulatory system is closely
associated to the decrease in notifications originating from
Chapter XVIII.
Another factor to be considered is the significant increase
in mortality from CVD among the elderly in the North and
Northeast states of the country, a trend less intense in the
South, Southeast and Midwest regions, where the increases
were discreet. Such regional variation is influenced by the
fact that primary and secondary prevention would be more
appropriate in more developed regions, with better control of
risk factors for CVD, such as smoking, dyslipidemia, diabetes
and systemic hypertension9.
In a study carried out between 2000 and 2009 in Brazil,
it was clear that the coverage provided by the family
health strategy was associated with a reduction in MRCD
(acute myocardial infarction and CVA). However, it is
noteworthy that this study evaluated 1,662 of the 5,507
Brazilian municipalities and used as an exclusion criterion
the municipalities with high mortality rates from IDC.
Therefore, their results are valid for municipalities where
the quality of information is better18,19.
Another relevant aspect is related to the distribution of
medical professionals registered in the Regional Councils of
Medicine in their physician per thousand inhabitant ratio.
In this regard, the North and Northeast regions have the
lowest proportions, 0.98% and 1.19%, respectively, below
the national average, which is 1.95%20. That is, the North
and Northeast regions have higher limitation regarding
health services provided to the population, a fact that also
corroborates the increase in MRCD in the study.
Regarding the aspects related to the epidemiological
transition, it is possible to estimate that, in general, it
occurs together with socioeconomic transformations and,
therefore, it shows major demographic differences 21.
Arq Bras Cardiol. 2015; 105(4):371-380
378
Piuvezam et al.
Mortality from Cardiovascular Diseases in the Elderly
Original Article
Hence, the majority of published studies provide evidence
of the association between social inequalities and
morbimortality. Brazil is the tenth most unequal country
in the world in terms of income distribution; even though
changes in the economy have resulted in improvements in
this regard, they do not seem to have been able to reduce
mortality inequalities. Hence, important differences persist
in the distribution of morbidity and mortality, both between
different Brazilian states and within the same state22.
It is worth mentioning that this study has as limiting
factor the use of data collected by a Federation state, which
can conceal the heterogeneous distribution of deaths and,
therefore, mask relevant intrastate differences. Furthermore,
the use of secondary data record is subject to several data
recording errors and underreporting.
Another limitation is due to the "ecological fallacy" in which,
due to the effects of data aggregation and scale, the results
found for a population cannot be repeated at the individual
level. In this study, the mortality analysis was based only on the
cause of death and there was no analysis of multiple causes;
thus, there may be an underestimation of cardiovascular
mortality, especially among the elderly, which may have
several comorbidities.
Conclusion
Based on the analyses, it was observed that the proportion
of mortality from circulatory system diseases in the elderly, in
the 2006-2010 period, decreased significantly in the South,
Southeast and Midwest states, and showed a considerable
increase in the North and Northeast regions. These results
are consistent with geographical clusters obtained in the
aforementioned period, during which spatial autocorrelation
was observed between the states of Rio Grande do Norte,
Ceará, Pernambuco and Roraima.
These findings can be explained by the information
qualification, reallocation of deaths from ill-defined causes
and improved health care. Added to these, other issues
were also evaluated, such as changes in the socioeconomic
situation of the country, mainly regarding the phase of
epidemiological transition in which Brazil currently is, with
decreased morbidity and mortality from infectious and
parasitic diseases, and increase in the number of deaths due
to chronic non-communicable diseases and external injuries.
Effective planning of health promotion actions originates
from the knowledge of a population’s health status, based
on mortality statistics. The quality of information on the
causes of death is, therefore, essential. The search for a
better understanding of the spatial and temporal distribution
of these rates is critical for the planning of evidence-based
sustainable public policies. Therefore, the study may
contribute to better control and prevention of cardiovascular
disease, as it supports the achievement of more targeted
actions for the different regions of the country, thus aiming
to reduce health inequalities.
The study was carried out with the authors’ own resources
and also received a scientific initiation research grant (PIBIC)
from Pró-Reitoria de Pesquisa da Universidade Federal do Rio
Grande do Norte (PROPESQ-UFRN).
Author contributions
Conception and design of the research and Critical revision
of the manuscript for intellectual content: Piuvezam G,
Medeiros WR; Acquisition of data, Analysis and interpretation
of the data and Statistical analysis: Costa AV, Emerenciano
FF, Seabra DS; Obtaining financing: Piuvezam G; Writing
of the manuscript: Piuvezam G, Medeiros WR, Costa AV,
Emerenciano FF, Seabra DS.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
This study was partially funded by Bolsa de pesquisa de
Iniciação Científica (PIBIC) da Pró-reitoria de Pesquisa da
Universidade Federal do Rio Grande do Norte (PROPESQ-UFRN).
Study Association
This study is not associated with any thesis or dissertation work.
References
1. Malta DC, Cezario AC, Moura L. A construção da vigilância e prevenção
das doenças crônicas não transmissíveis no contexto do Sistema Único de
Saúde. Epidemiol Serv Saúde. 2006;15(3):47-65.
5.
Mansur AP, Favarato D. Mortalidade por doenças cardiovasculares no Brasil
e na região metropolitana de São Paulo: atualização 2011. Arq Bras Cardiol.
2012;99(2):755-61.
2. Schmidt MI, Duncan BB, Azevedo e Silva G, Menezes AM, Monteiro CA,
Barreto SM, et al. Chronic non-communicable diseases in Brazil: burden
and current challenges. Lancet. 2011;377(9781):1949-61.
6.
Brasil. Senado Federal. Lei nº 10.741 de 1 de outubro de 2003. Dispõe sobre
o Estatuto do Idoso e dá outras providências. Brasília; 2003.
3.
Goulart FA. Doenças crônicas não transmissíveis: estratégias de controle e
desafios para os sistemas de saúde. Brasília: Ministério da Saúde / OMS; 2011.
4. Muller EV, Aranha SR, Roza WS, Gimeno SG. Distribuição espacial da
mortalidade por doenças cardiovasculares no Estado do Paraná, Brasil:
1989-1991 e 2006-2008. Cad Saúde Pública. 2012;28(6):1067-77.
379
Arq Bras Cardiol. 2015; 105(4):371-380
7. Organização Mundial da Saúde. Classificação estatística internacional de
doenças e problemas relacionados à saúde. CID-10, EDUSP, São Paulo:
EDUSP; 1997.
8.
Ministério da Saúde. Introdução à estatística espacial para a saúde pública.
Brasília; 2007.
Piuvezam et al.
Mortality from Cardiovascular Diseases in the Elderly
Original Article
9. Gaui EN, Oliveira GM, Klein CH. Mortalidade por insuficiência cardíaca e
doença isquêmica do coração no Brasil de 1996 a 2011. Arq Bras Cardiol.
2014;102(6):557-65.
10. Laurenti R, Jorge MH, Gotlieb SL. A confiabilidade dos dados de mortalidade
e morbidade por doenças crônicas não-transmissíveis. Ciênc Saúde Colet.
2004;9(4):909-20.
11. Jorge MH, Laurenti R, Lima-Costa MF, Gotlieb SL, Chiavegatto Filho AD.
A mortalidade de idosos no Brasil: a questão das causas mal definidas.
Epidemiol Serv Saúde. 2008;17(4):271-81.
12. Jorge MH, Laurenti R, Gotlieb SL. Análise da qualidade das estatísticas vitais
brasileiras: a experiência de implantação do SIM e do SINASC. Ciênc Saúde
Colet. 2007;12(3):643-54.
13. Justino JR, Freire FH, Lucio OS. Estimação de sub-registros de óbitos em
pequenas áreas com os métodos bayesiano empírico e algoritmo EM. Rev
bras estud popul. 2012;29(1):87-100.
14. Ministério da Saúde. Manual de procedimento do sistema de informações
sobre mortalidade. Brasília: Fundação Nacional da Saúde; 2001.
15. Ministério da Saúde. Manual para investigação do óbito com causa mal
definida. Brasília: Secretaria de vigilância em saúde; 2008.
16. Campo D, França E, Loschi RH, Souza MF. Uso da autópsia verbal na
investigação de óbitos com causa mal definida em Minas Gerais, Brasil. Cad
Saúde Pública. 2010;26(6):1221-33.
17. Teixeira CL, Klein CH, Bloch KV, Coeli CM. Reclassificação dos grupos
de causas prováveis dos óbitos de causas mal definidas, com base nas
Autorizações de Internação Hospitalar no Sistema Único de Saúde, Estado
do Rio de Janeiro, Brasil. Cad Saúde Pública. 2006;22(6):1315‑24.
18. Rasella D, Harhay MO, Pamponet ML, Aquino R, Barreto ML. Impact
of primary health care on mortality from heart and cerebrovascular
diseases in Brazil: a nationwide analysis of longitudinal data. BMJ.
2014;349:g4014.
19. Rasella D, Aquino R, Barreto Ml. Impact of the Family Health Program
on the quality of vital information and reduction of child unattended
deaths in Brazil: an ecological longitudinal study. BMC Public Health.
2010;10:380.
20. São Paulo. Conselho Regional de Medicina do Estado de São Paulo
(CREMESP). Conselho Federal de Medicina. Demografia médica no Brasil:
dados gerais e descrições de desigualdades. São Paulo; 2011.
21. Schramm JM, Oliveira AF, Leite IC, Valente JG, Gadelha AM, Portela MC, et
al. Transição epidemiológica e o estudo de carga de doença no Brasil. Ciênc
Saúde Colet. 2004;9(4):897-908.
22. Cruz AS, Vieira-da-Silva SM, Costa MC, Paim JS. Evolution of inequalities in
mortality in Salvador, Bahia State, Brazil, 1991/2006. Cad Saúde Pública.
2011; 27 (2):S176-84.
Arq Bras Cardiol. 2015; 105(4):371-380
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Back to the Cover
Original Article
Sex-Specific Equations to Estimate Maximum Oxygen Uptake in
Cycle Ergometry
Christina G. de Souza e Silva e Claudio Gil S. Araújo
Programa de Pós-Graduação em Cardiologia - Universidade Federal do Rio de Janeiro; Instituto do Coração Edson Saad - Universidade Federal
do Rio de Janeiro; Clínica de Medicina do Exercício - CLINIMEX, Rio de Janeiro, RJ – Brazil
Abstract
Background: Aerobic fitness, assessed by measuring VO2max in maximum cardiopulmonary exercise testing (CPX) or
by estimating VO2max through the use of equations in exercise testing, is a predictor of mortality. However, the error
resulting from this estimate in a given individual can be high, affecting clinical decisions.
Objective: To determine the error of estimate of VO2max in cycle ergometry in a population attending clinical exercise
testing laboratories, and to propose sex-specific equations to minimize that error.
Methods: This study assessed 1715 adults (18 to 91 years, 68% men) undertaking maximum CPX in a lower limbs cycle
ergometer (LLCE) with ramp protocol. The percentage error (E%) between measured VO2max and that estimated from
the modified ACSM equation (Lang et al. MSSE, 1992) was calculated. Then, estimation equations were developed: 1)
for all the population tested (C-GENERAL); and 2) separately by sex (C-MEN and C-WOMEN).
Results: Measured VO2max was higher in men than in WOMEN: -29.4 ± 10.5 and 24.2 ± 9.2 mL.(kg.min)-1 (p < 0.01).
The equations for estimating VO2max [in mL.(kg.min)-1] were: C-GENERAL = [final workload (W)/body weight (kg)] x 10.483 + 7;
C-MEN = [final workload (W)/body weight (kg)] x 10.791 + 7; and C-WOMEN = [final workload (W)/body weight (kg)] x
9.820 + 7. The E% for MEN was: -3.4 ± 13.4% (modified ACSM); 1.2 ± 13.2% (C-GENERAL); and -0.9 ± 13.4% (C-MEN)
(p < 0.01). For WOMEN: -14.7 ± 17.4% (modified ACSM); -6.3 ± 16.5% (C-GENERAL); and -1.7 ± 16.2% (C-WOMEN) (p < 0.01).
Conclusion: The error of estimate of VO2max by use of sex-specific equations was reduced, but not eliminated, in
exercise tests on LLCE. (Arq Bras Cardiol. 2015; 105(4):381-389)
Keywords: Breathing Exercise / utilization; Physical Exertion; Oxygen Consumption; Cardiopulmonary Exercise Testing;
Demographic Data; Ergometry.
Introduction
Aerobic fitness is an independent predictor of mortality1-3
and provides relevant diagnostic and prognostic information4-8.
It is non-invasively assessed by measuring maximum oxygen
uptake (VO2max) during exercise testing, in which expired gases
are collected and analyzed. This procedure is called maximum
cardiopulmonary exercise testing (CPX)9,10.
Although available at several clinical exercise testing
laboratories, VO2max measurement requires professional
training11 and specific equipment, and increases the time for
test performance, hindering the wider use of CPX.
When CPX cannot be performed, VO 2max can be
estimated by use of equations based on duration12 or intensity
Mailing Address: Claudio Gil Soares de Araújo •
Clínica de Medicina do Exercício – CLINIMEX. Rua Siqueira Campos,
93/101, Copacabana. Postal Code 22071-030, Rio de Janeiro, RJ – Brazil
E-mail: [email protected], [email protected]
Manuscript received January 29, 2015; revised manuscript May 04, 2015;
accepted May 06, 2015.
DOI: 10.5935/abc.20150089
381
at peak exertion13,14. By applying these equations to groups of
individuals, the association between estimated and measured
VO2max values tends to be good. However, the margin of error
of estimate (EE) for a given subject can be large, greater than
15%15. Errors of such magnitude are rarely accepted in other
biological variables, and exceed those observed in laboratory
tests or in clinical and anthropometric measurements (height
and weight). Considering that small variations in VO2max can
lead to important differences in clinical management or sports
training guidance16, such errors can be challenging, requiring
some effort to minimize them.
Theoretically, the mechanical efficiency in performing
a certain motor gesture is expressed by the ratio between
the work generated and the oxygen consumed in its
performance17. That efficiency varies between individuals
and depends on age, sex, clinical condition and physical
fitness. Most equations available for estimating VO2max,
however, do not consider those possible relationships,
which might contribute to errors in VO 2max estimate.
For example, considering anthropometric, physiological and
biomechanical differences, as well as sports performance,
the influence of sex on the EE of VO2max is worth assessing.
The objectives of this study were: a) to determine the EE
of VO2max in cycle ergometry for a population undergoing
de Souza e Silva and Araújo
Estimation of VO2max in cycle ergometry
Original Article
CPX at a clinical exercise testing laboratory; and b) to propose
sex-specific equations aimed at reducing the EE of aerobic
capacity in cycle ergometry.
Body weight was measured with a Cardiomed scale, Welmy
model, with 0.1-kg resolution. Height was measured with a
Sanny stadiometer with 0.1-cm resolution.
Methods
Maximum cardiopulmonary exercise testing
Sample
This study reviewed data of patients voluntarily submitted
to CPX between January 2008 and June 2014 at a private
clinical exercise testing laboratory. Patients simultaneously
meeting the following inclusion criteria were selected:
a) no previous assessment at the private clinical exercise
testing laboratory; b) age ≥ 18 years; and c) maximum
CPX performed on a lower limbs cycle ergometer (LLCE)
(Inbrasport CG-04, Inbrasport, Brazil).
During that period, 3874 assessments were performed and,
after applying the inclusion criteria, 1715 individuals (1172
men) were included (Figure 1). In addition, 200 individuals
subsequently undergoing CPX and meeting the inclusion
criteria were used to validate the equations developed.
Ethical considerations
All patients provided written informed consent before
undergoing CPX. The retrospective analysis of data was
approved by the Committee on Ethics and Research of
the institution.
Clinical assessment and body weight and height
measurements
Before performing CPX, clinical history was taken, with
emphasis on regularly used medications and cardiovascular risk
factors, and physical examination was undertaken. Body weight
and height of all individuals were measured. The prescribed
medications were not suspended before CPX.
The CPX was conducted in a specific room, with
temperature ranging from 21°C to 24°C, and relative air
humidity between 40% and 60%. The test was performed
according to an individualized ramp protocol, aimed
at 8-12-minute duration, on an LLCE, according to the
Brazilian Society of Cardiology guidelines18, in the presence
of a qualified physician, at a laboratory properly equipped
to manage occasional clinical events. Only four physicians
performed all the tests, following a routine of well-defined
procedures, especially regarding the stimulus to reach
truly maximum exertion. The height of the saddle was
individually adjusted to provide both an almost complete
knee extension at the lowest pedal position, and a
lower‑hip 90-degree flexion at the highest pedal position.
The pedaling frequency was kept between 65 and
75 rotations per minute.
During CPX, the individuals were monitored with a digital
electrocardiograph (ErgoPC Elite, versions 3.2.1.5 or 3.3.4.3
or 3.3.6.2, Micromed, Brazil), and heart rate (HR) was
measured on the ECG recording (leads CC5 or CM5) at the
end of each minute. Expired gases were collected by use of a
Prevent pneumotacograph (MedGraphics, USA) coupled to a
mouthpiece, with concomitant nasal occlusion. The expired
gases were measured and analyzed by using a VO2000 metabolic
analyzer (MedGraphics, USA), daily calibrated before the first
assessment and whenever necessary. The mean results of the
expired gases were read every 10 seconds, and consolidated
at every minute. The highest VO2 value obtained at a certain
point of the CPX was considered the VO2max. Blood pressure
was measured every minute on the right arm by using a
manual sphygmomanometer.
Figure 1 – Flowchart of study sample selection.
Arq Bras Cardiol. 2015; 105(4):381-389
382
de Souza e Silva and Araújo
Estimation of VO2max in cycle ergometry
Original Article
The maximum intensity of the exercise, which is more easily
assessed by using CPX – presence of anaerobic threshold and
U-pattern curves of ventilatory equivalents -, was confirmed
by maximum voluntary exhaustion (score 10 in the Borg
scale ranging from 0 to 1019) represented by the incapacity
to continue pedaling at the previously established frequency
despite strong verbal encouragement. As already reported in a
previous study20, the characterization of CPX as maximum was
also confirmed by the impression of the physician in charge,
and recorded on the CPX description. It is worth noting that
CPX was neither interrupted nor considered maximum based
exclusively on HR.
Equations to predict VO2max and maximum HR
The predicted values of VO2max for each patient, as a mere
reference for comparison with the actually measured VO2max
values, were obtained based on specific equations for men
[60 – 0.55 x age (years)] and women [48 – 0.37 x age (years)]21.
The predicted values of maximum HR were obtained from
the equation 208 – 0.7 x age22, for patients of both sexes.
Equations to estimate VO2max
To assess the EE of VO2max, VO2max was initially estimated
based on the modified American College of Sports Medicine
(ACSM) equation14, in which VO2max is adjusted for body
weight [mL.(kg.min)-1] as follows: (W x 11.4 + 260 + body
weight x 3.5)/weight. In that equation, W is the maximum
workload in watts, body weight is expressed in kg, and the
constant 260 mL.min-1 represents the oxygen volume in mL
and corresponds to the necessary energetic expenditure
to pedal without any additional resistance [approximately
3.5 mL.(kg.min)-1 x mean body weight of the individuals
studied by Lang et al.]14. In addition, the last term in that
equation corresponds to the energetic expenditure at rest.
Following that line of thought, and in accordance with
that adopted by the ACSM23, in our study, we subtracted
7 mL.(kg .min) -1 from the VO 2 max value measured
[corresponding to 3.5 mL.(kg.min) -1 of VO2 at rest and
3.5 mL.(kg.min)-1 of VO2 expended to pedal without any
load]. The result obtained was divided by the ratio between
workloads (watts) and body weight (kg), originating the
constant “k” for each participant. From the mean value of
the constant “k”, we obtained the multiplying factor values of
the workloads (watts)/body weight (kg) ratio for the equations
for the general sample, men and women, respectively: a)
general equation to estimate VO2max (equation C-GENERAL);
b) specific equation to estimate VO2max in the male sex
(equation C-MEN); and c) specific equation to estimate
VO2max in the female sex (equation C-WOMEN).
Error of estimate of VO2max
The magnitude of the EE of VO 2max expressed as
a function of body weight was assessed based on the
calculation of: 1) the difference between the measured and
estimated values: (measured VO2max – estimated VO2max)
in mL.(kg.min)-1; and the percentage error (E%): [(measured
VO2max - estimated VO2max)/measured VO2max] x 100.
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Arq Bras Cardiol. 2015; 105(4):381-389
The measured VO2max was obtained by collecting and
analyzing expired gases, as previously detailed. A negative
EE or E% value thus means that the estimated VO2max
was higher than the measured VO2max, that is, the value
calculated by using the equation overestimated the
value measured.
Statistical analysis
The results were expressed as mean and standard
deviation or as percentage, depending on the nature of
the variable. The demographic characteristics and CPX
results were compared between men and women by using
non-paired t test or chi-square test. The ER and E% of the
equations, when appropriate, were compared by using
paired t test or ANOVA, when the comparison was performed
between three or more groups. The measured VO2max value
and that estimated based on the three equations of the study
– C-GENERAL, C-MEN and C-WOMEN – were compared
and analyzed by using linear regression and intraclass
correlation. The statistical analyses were performed with
the programs Prism 6 (GraphPad, USA) and SPSS 16 (SPSS,
USA), adopting 5% as the significance level.
Results
Demographic and clinical characteristics of the sample
The sample was mostly formed by men (68.3%), with
age ranging from 18 to 91 years, and 23.2% had a body
mass index (BMI) ≥ 30 kg.m-2. Tables 1 and 2 show other
demographic and clinical data, as well as the prevalence
of some risk factors for coronary artery disease, major
morbidities and medications regularly used.
CPX data
The mean duration of CPX was 10 ± 2 minutes. The mean
maximum HR for the set of individuals was 159 ± 25 bpm,
corresponding to 92% of that predicted, being higher in
patients not on beta-blockers (166 ± 20 bpm) (p < 0.01).
Men achieved final workloads higher than women (172 ± 70
vs 111 ± 45 watts; p < 0.01), as well as greater VO2max
values [29.4 ± 10.5 vs 24.2 ± 9.2 mL.(kg.min)-1; p < 0.01].
In the sample studied, the measured VO2max tended to be
slightly lower than that predicted based on age and sex,
corresponding to 96% and 82% of the value predicted by
using the equations of Jones et al.21 for men and women,
respectively. Table 3 shows the major CPX results.
Estimated VO2max values
Regarding estimated VO2max, the values obtained by
using the modified ACSM equation were 29.8 ± 9.8 and
26.9 ± 8.9 mL.(kg.min)-1 for men and women, respectively,
showing that the equation tends to overestimate VO2max.
Both ER and E% differed between sexes (p < 0.01), with
values of -0.4 ± 3.2 mL.(kg.min)-1 and -3.4 ± 13.4% for
men, and -2.7 ± 3.5 mL.(kg.min)-1 and -14.7 ± 17.4% for
women, respectively.
de Souza e Silva and Araújo
Estimation of VO2max in cycle ergometry
Original Article
Table 1 – Major demographic and morphofunctional characteristics of the sample (n = 1715)*
Demographic characteristics
Men 1172 (68.3%)
Women 543 (31.7%)
Age (years)
53 ± 15
51 ± 15
BMI (kg.m-2)
27.9 ± 4.2
25.3 ± 4.9
Weight (kg)
85.9 ± 14.8
66.9 ± 12.8
Height (cm)
175.3 ± 6.9
162.6 ± 6.5
Predicted VO2max [mL.(kg.min) )]
-1
Predicted maximum HR (bpm)
30.7 ± 8.1
29.3 ± 5.5
170.7 ± 10.3
172.6 ± 10.5
BMI: Body mass index; HR: Heart rate. *Values expressed as mean ± standard deviation.
Table 2 – Major clinical characteristics of the sample and regularly used medications (n = 1715)*
Men (n = 1172)
Women (n = 543)
Morbidities
Systemic arterial hypertension
428 (36.5%)
114 (21.0%)
Dyslipidemia
496 (42.6%)
140 (25.8%)
Obesity
193 (16.5%)
61 (11.2%)
Diabetes mellitus
113 (9.6%)
29 (5.3%)
Coronary artery disease
249 (21.2%)
39 (7.2%)
Acute myocardial infarction
125 (10.7%)
18 (3.3%)
Myocardial revascularization
96 (8.2%)
10 (1.8%)
302 (25.8%)
91 (16.8%)
Calcium channel blocker
109 (9.3%)
37 (6.8%)
ACEI
125 (10.7%)
19 (3.5%)
ARB
340 (29.0%)
113 (20.8%)
Diuretic
186 (15.9%)
68 (12.5%)
Use of medications
Beta-blocker
Vasodilator
82 (7.0%)
14 (2.6%)
Lipid-lowering
531 (45.3%)
151 (27.8%)
Antiplatelet
387 (33.0%)
82 (15.1%)
71 (6.1%)
25 (4.6%)
Antiarrhythmic
ARB: Angiotensin-receptor blocker; ACEI: Angiotensin-converting-enzyme inhibitor. * Values expressed as N(%).
Table 3 – Major results of cardiopulmonary exercise test (n = 1715)*
Variable
Duration (min)
Maximum HR (bpm)
Men (n = 1172)
Women (n = 543)
10 ± 2
9±3
158 ± 26
161 ± 24
- with beta-blocker
135 ± 25
133 ± 24
- without beta-blocker
166 ± 21
167 ± 20
172 ± 70
111 ± 45
29.4 ± 10.5
24.2 ± 9.2
Maximum workload (watts)
Measured VO2max [mL.(kg.min) )]
-1
HR: Heart rate. *Values expressed as mean ± standard deviation.
Arq Bras Cardiol. 2015; 105(4):381-389
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C-GENERAL equation
Determining the specific equation for the sample studied,
with no distinction between sexes and with the same variables
of the modified ACSM equation, the following C-GENERAL
equation was obtained: (final workload/body weight x
10.483 + 7, where 7, as previously explained, corresponds
to a simplification of the last two terms of that equation
[the addition of oxygen uptake at rest (3.5 mL.(kg.min)-1
and an identical oxygen uptake value to pedal with no
resistance]. Applying the C-GENERAL equation, the estimated
VO2max values obtained were 28.3 ± 8.9 mL.(kg.min)-1
and 24.9 ± 7.9 mL.(kg .min) -1 for men and women,
respectively. Although EE and E% values remained similar
in men [1.1 ± 3.3 mL.(kg .min) -1 and 1.2 ± 13.2%,
respectively], a significant reduction in the EE of VO2max
was observed in women [-0.7 ± 3.5 mL.(kg.min)-1], and
E% was -6.3 ± 16.5% (p < 0.01).
C-MEN and C-WOMEN equations
Then the following sex-specific equations, C-MEN and
C-WOMEN were obtained: (final workload/body weight) x
10.791 + 7 and (final workload/body weight) x 9.820 + 7,
respectively. Using these equations, the estimated VO2max values
were 28.9 ± 9.2 mL.(kg.min)-1 and 23.7 ± 7.4 mL.(kg.min)-1
for men and women, respectively. Errors of estimate were
reduced in both sexes, but more expressively for women.
For men, EE and E% were 0.5 ± 3.2 mL.(kg.min)-1 and
-0.9 ± 13.4% (p < 0.01), respectively, while for women,
they were reduced to 0.5 ± 3.6 mL.(kg.min)-1 and only
-1.7 ± 16.2% (p < 0.01), respectively (Figure 2).
Figure 3 shows the standard EE and the association
between the estimated and measured VO2max values for
the general sample and for men and women, analyzed
separately. It is worth noting the high intraclass correlation
coefficients, with their respective confidence intervals (CI)
obtained: C-GENERAL, 0.9703 (95%CI: 0.9674 - 0.9730);
C-MEN, 0.9725 (95%CI: 0.9691 - 0.9755), and C-WOMEN,
0.9680 (95%CI: 0.9621 - 0.9729). The visual inspection of
the distributions allowed characterizing the linear regressions
as homoscedastic.
Based on the application of the equations developed in the
present study, the following EE and E% were obtained in the
validation sample: C-GENERAL (n = 200) 0.5 ± 2.5 mL.(kg.min)-1
and 0.7 ± 9.1%; C-MEN (n = 135) 0.5 ± 2.5 mL.(kg.min)-1
and 1.0 ± 8.6%; and C-WOMEN (n = 65) 0.5 ± 2.0 mL.(kg.min)-1
and 0.5 ± 8.5%, respectively.
Discussion
The CPX is the most appropriate test to assess aerobic
capacity. However, the use of the exercise test with neither
collection nor analysis of expired gases is very common
among us, even though accompanied by a significant margin
of error15. Therefore, it is important to develop specific
equations to reduce that EE in exercise tests performed at
hospitals and clinics.
Although previous studies with that same objective have
been conducted24-27, the use of small samples hinders the
extrapolation of the results found. For example, Lang et al.14
and Latin et al.28 have used the ACSM equation to estimate
VO2max13 for 60 men and 60 women, respectively, and have
Figure 2 – Percentage errors obtained from the comparison between measured VO2max and estimated VO2max by using the modified ACSM equations, and the
C-GENERAL, C-MEN e C-WOMEN equations.
385
Arq Bras Cardiol. 2015; 105(4):381-389
de Souza e Silva and Araújo
Estimation of VO2max in cycle ergometry
Original Article
Figure 3 – Correlation between measured VO2max values and those estimated by using the equations: a) C-GENERAL, b) C-MEN and c) C-WOMEN. SEE: Standard
error of estimate; ric: Intraclass correlation coefficient.
Arq Bras Cardiol. 2015; 105(4):381-389
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de Souza e Silva and Araújo
Estimation of VO2max in cycle ergometry
Original Article
found lower estimated VO2max values than the measured
ones, for both sexes. On the other hand, Greiwe et al.29,
applying that same equation to 15 men and 15 women
with similar clinical profiles, have obtained overestimated
VO2max values. In addition, the introduction by Lang et
al. 14 of the factor 260 mL.min -1, which corresponds to
the energetic expenditure of pedaling without additional
resistance, has produced estimated results more similar
to measured VO 2 max results in their sample. In our
study, however, the use of that modified ACSM equation
maintained significant errors in the comparison between
estimated and measured values. The discrepancy in the
results described suggests significant errors when the
equations are developed based on small samples.
In addition, the difference in EE between men and
women using the same equation suggests that sex‑specific
equations should be developed. Storer et al. 30 have
developed three equations of to estimate VO2max using
the variables workload, body weight and age: one general
for both sexes; one specific for men; and one specific
for women. Those authors have reported a significant
increase in the coefficient of determination when the
variable ‘sex’ was added to the linear regression model
used to create the equations. However, when applied
to 77 men and 30 women of the Brazilian population31,
a trend to overestimate VO2max was observed in men,
evidencing the need to develop specific equations for
each population.
Recently, Almeida et al. have conducted an important
study with a large sample of Brazilians (3119 individuals),
aimed at developing an equation to predict VO2max for
treadmill exercise tests, based on age, sex, BMI and physical
activity level. However, it is worth noting that, despite
the importance of having VO2max reference data from
equations developed for the Brazilian population, this does
not contemplate the EE of VO2max when expired gases
are not collected and analyzed during exercise testing.
While the predicted VO2max is obtained based on pre‑test
clinical variables, such as age and sex, the estimated
VO2max is calculated based on variables obtained during
exercise testing, such as workload and test duration. To the
best of our knowledge, there is no study on the Brazilian
population with a large sample (more than 1000 cases)
developing specific equations to estimate VO 2max in
exercise tests performed on a LLCE.
32
In reality, sample size and representability are extremely
relevant. Neder et al. 33 have observed that individuals
typically selected to participate in studies did not represent
those most commonly referred for exercise testing, which
could lead to selection biases. Thus, in our study, we
chose not to exclude obese patients, individuals with
cardiovascular or pulmonary diseases and/or individuals
on regular use of medications that could influence the
physiological responses to exercise, to guarantee a sample
representing the individuals most commonly referred to
clinical exercise testing laboratories. It is worth noting that
despite that varied clinical profile, the VO2max predicted for
age was relatively close to that actually measured, especially
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Arq Bras Cardiol. 2015; 105(4):381-389
in men. Comparing the data obtained in our study with
those reported by Herdy and Uhlendorf34 in the Brazilian
Southern region, the VO2max values measured in men were
similar to the reference values for sedentary individuals
aged 55 to 64 years [30.0 ± 6.3 mL.(kg.min)-1] or active
individuals aged 65 to 74 years [30.0 ± 6.1 mL.(kg.min)-1].
The VO 2max values found for women were similar to
the reference values of sedentary individuals aged 55 to
64 years [23.9 ± 4.2 mL.(kg.min)-1]34. The most probable
reason for that slight discrepancy is due to the fact that the
study by Herdy and Uhlendorf34 used CPX on a treadmill,
which might explain the tendency towards higher values
for the same age group.
The strong points of our study are as follows: 1) to our
knowledge, no other Brazilian study assessing equations
for VO2max estimation was based on such a large number
of individuals (over 1000); 2) the cycle ergometers and
gas analyzers were periodically calibrated according to the
specifications of their manufacturers; and 3) all original
information of test reports was available in the digital
format (data bank) and carefully reviewed to exclude
those incomplete.
This study has limitations. All tests were performed
following the ramp protocol. Thus, one cannot know if the
equations for VO2max estimate here presented can be applied
to exercise tests performed following other protocols.
Other factors, such as age, adiposity level, recent pattern
or history of regular physical training, and use of certain
medications, might contribute to the EE by influencing
mechanical efficiency. This was a preliminary study to assess
the influence of sex on the EE of VO2max. Other variables
are being assessed, as already reported. Subsequent statistical
analyses, such as multivariate regression, using the variables
that evidenced influence on EE of VO2max can lead to the
development of one single equation for VO2max estimate
capable of effectively reducing EE.
Briefly, the present study contributed to current knowledge
by proposing equations derived from a large sample of
Brazilian adults, with clinical characteristics and profiles
similar to those usually observed at clinical exercise testing
laboratories. The equations are specific to the male and
female sexes, thus contributing to reduce EE when VO2max
measurement is not available.
Conclusion
Our study identified that the use of foreign equations
(modified ACSM) induced an important EE when applied to
a typical population of clinical exercise testing laboratories
in Brazil. Thus, an equation was developed – C-GENERAL –,
partially reducing EE. However, an analysis separated by sex
identified the need to develop specific equations – C-MEN
and C-WOMEN – that could further reduce, but not
eliminate, EE. Thus, more accurate alternatives to VO2max
estimate in exercise tests of lower limbs are presented to
places with no condition to effectively perform CPX to
measure VO2max.
de Souza e Silva and Araújo
Estimation of VO2max in cycle ergometry
Original Article
Author contributions
Sources of Funding
Conception and design of the research, Analysis and
interpretation of the data, Statistical analysis, Writing of the
manuscript and Critical revision of the manuscript for intellectual
content: de Souza e Silva CG, Araújo CGS; Acquisition of data:
Araújo CGS.
This study was partially funded by CNPq and FAPERJ.
Potential Conflict of Interest
Study Association
This article is part of the MSc thesis submitted by Christina
G. de Souza e Silva, from Instituto do Coração Edson Saad Universidade Federal do Rio de Janeiro.
No potential conflict of interest relevant to this article
was reported.
References
1.
Barry VW, Baruth M, Beets MW, Durstine JL, Liu J, Blair SN. Fitness vs. fatness on
all-cause mortality: a meta-analysis. Prog Cardiovasc Dis. 2014;56(4):382-90.
14. Lang PB, Latin RW, Berg KE, Mellion MB. The accuracy of the ACSM cycle
ergometry equation. Med Sci Sports Exerc. 1992;24(2):272-6.
2. Kodama S, Saito K, Tanaka S, Maki M, Yachi Y, Asumi M, et al.
Cardiorespiratory fitness as a quantitative predictor of all-cause mortality
and cardiovascular events in healthy men and women: a meta-analysis.
JAMA. 2009;301(19):2024-35.
15. Araújo CG, Herdy AH, Stein R. Maximum oxygen consumption
measurement: valuable biological marker in health and in sickness. Arq
Bras Cardiol. 2013;100(4):e51-3.
3. Laukkanen JA, Rauramaa R, Salonen JT, Kurl S. The predictive value
of cardiorespiratory fitness combined with coronary risk evaluation
and the risk of cardiovascular and all-cause death. J Intern Med.
2007;262(2):263-72.
4. Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE. Exercise
capacity and mortality among men referred for exercise testing. N Engl J
Med. 2002;346(11):793-801.
5. Chang JA, Froelicher VF. Clinical and exercise test markers of prognosis
in patients with stable coronary artery disease. Curr Probl Cardiol.
1994;19(9):533-87.
6. Pate RR, Pratt M, Blair SN, Haskell WL, Macera CA, Bouchard C, et al.
Physical activity and public health. A recommendation from the Centers
for Disease Control and Prevention and the American College of Sports
Medicine. JAMA. 1995;273(5):402-7.
7. Kavanagh T, Mertens DJ, Hamm LF, Beyene J, Kennedy J, Corey P, et al.
Peak oxygen intake and cardiac mortality in women referred for cardiac
rehabilitation. J Am Coll Cardiol. 2003;42(12):2139-43.
16. Kavanagh T, Mertens DJ, Hamm LF, Beyene J, Kennedy J, Corey P, et al.
Prediction of long-term prognosis in 12 169 men referred for cardiac
rehabilitation. Circulation. 2002;106(6):666-71.
17. Jobson AS, Hopker JG, Korff T, Passfield L. Gross efficiency and cycling
performance: a brief review. J Sci Cycling. 2012;1(1):3-8.
18. Meneghelo RS, Araújo CG, Stein R, Mastrocolla LE, Albuquerque PF, Serra
SM, et al; Sociedade Brasileira de Cardiologia. III Guidelines of Sociedade
Brasileira de Cardiologia on the exercise test. Arq Bras Cardiol. 2010;95(5
supl 1):1-26.
19. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports Exerc.
1982;14(5):377-81.
20. Balassiano DH, Araújo CG. Maximal heart rate: influence of sport practice
during childhood and adolescence. Arq Bras Cardiol. 2013;100(4):333-8.
21. Jones NL, Campbell EK, Edwards RH, Robertson DG. Clinical exercise
testing. Philadelphia: WB Saunders; 1975.
22. Duarte CV. Araujo CG. Cardiac vagal index does not explain ageindependent maximal heart rate. Int J Sports Med. 2013;34(6):502-6.
8. Mitchell JH, Sproule BJ, Chapman CB. The physiological meaning of the
maximal oxygen intake test. J Clin Invest. 1958;37(4):538-47.
23. American College of Sports Medicine. ACSM’s guidelines for exercise testing
and prescription. 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2006.
9. Albouaini K, Egred M, Alahmar A, Wright DJ. Cardiopulmonary exercise
testing and its application. Heart. 2007;93(10):1285-92.
24. Artero EG, Jackson AS, Sui X, Lee DC, O’Connor DP, Lavie CJ, et al.
Longitudinal algorithms to estimate cardiorespiratory fitness: associations
with nonfatal cardiovascular disease and disease-specific mortality. J Am Coll
Cardiol. 2014;63(21):2289-96.
10. Haskell WL, Lee IM, Pate RR, Powell KE, Blair SN, Franklin BA, et al. Physical
activity and public health: updated recommendation for adults from the
American College of Sports Medicine and the American Heart Association.
Med Sci Sports Exerc. 2007;39(8):1423-34.
11. Guazzi M, Adams V, Conraads V, Halle M, Mezzani A, Vanhees L, et al.
EACPR/AHA Joint Scientific Statement. Clinical recommendations for
cardiopulmonary exercise testing data assessment in specific patient
populations. Eur Heart J. 2012;33(23):2917-27.
12. Bruce RA, Kusumi F, Hosmer D. Maximal oxygen intake and nomographic
assessment of functional aerobic impairment in cardiovascular disease. Am
Heart J. 1973;85(4):546-62.
13. American College of Sports Medicine. (ACSM). Guidelines for graded
exercise testing and training. 3rd ed. Philadelphia: Lea & Febiger; 1986.
p. 162-3.
25. Grant S, Corbett K, Amjad AM, Wilson J, Aitchison T. A comparison of methods
of predicting maximum oxygen uptake. Br J Sports Med. 1995;29(3):147-52.
26. Harrison MH, Bruce DL, Brown GA, Cochrane LA. A comparison of some
indirect methods for predicting maximal oxygen uptake. Aviat Space Environ
Med. 1980;51(10):1128-33.
27. Peterson MJ, Pieper CF, Morey MC. Accuracy of VO2(max) prediction
equations in older adults. Med Sci Sports Exerc. 2003;35(1):145-9.
28. Latin RW, Berg KE. The accuracy of the ACSM and a new cycle ergometry
equation for young women. Med Sci Sports Exerc. 1994;26(5):642-6.
29. Greiwe JS, Kaminsky LA, Whaley MH, Dwyer GB. Evaluation of the ACSM
submaximal ergometer test for estimating VO2max. Med Sci Sports Exerc.
1995;27(9):1315-20.
Arq Bras Cardiol. 2015; 105(4):381-389
388
de Souza e Silva and Araújo
Estimation of VO2max in cycle ergometry
Original Article
30. Storer TW, Davis JA, Caiozzo VJ. Accurate prediction of VO2max in cycle
ergometry. Med Sci Sports Exerc. 1990;22(5):704-12.
31. Magrani P, Pompeu FA. Equations for predicting aerobic power (VO2) of
young Brazilian adults. Arq Bras Cardiol. 2010;94(6):763-70.
32. Almeida AE, Stefani CM, Nascimento JA, Almeida NM, Santos AC, Ribeiro
JP, et al. An equation for the prediction of oxygen consumption in a Brazilian
population. Arq Bras Cardiol. 2014;103(4):299-307.
389
Arq Bras Cardiol. 2015; 105(4):381-389
33. Neder JA, Nery LE, Castelo A, Andreoni S, Lerario MC, Sachs A, et al.
Prediction of metabolic and cardiopulmonary responses to maximum cycle
ergometry: a randomised study. Eur Respir J. 1999;14(6):1304-13.
34. Herdy AH, Uhlendorf D. Reference values for cardiopulmonary exercise
testing for sedentary and active men and women. Arq Bras Cardiol.
2011;96(1):54-9.
Back to the Cover
Original Article
A Novel Algorithm to Quantify Coronary Remodeling Using Inferred
Normal Dimensions
Breno A. A. Falcão1, João Luiz A. A. Falcão1, Gustavo R. Morais1, Rafael C. Silva1, Augusto C. Lopes2, Paulo R.
Soares1, José Mariani Jr1, Roberto Kalil-Filho1, Elazer R. Edelman2,3, Pedro A. Lemos1
Departamento de Cardiologia Intervencionista, Instituto do Coração (InCor), Faculdade de Medicina da Universidade de São Paulo1, São
Paulo, SP - Brazil; Institute of Medical Engineering and Science, Massachusetts Institute of Technology2, Cambridge; Divisão Cardiovascular,
Departamento de Medicina, Brigham and Womens Hospital, Harvard Medical School3, Boston, MA - USA
Abstract
Background: Vascular remodeling, the dynamic dimensional change in face of stress, can assume different directions
as well as magnitudes in atherosclerotic disease. Classical measurements rely on reference to segments at a distance,
risking inappropriate comparison between dislike vessel portions.
Objective: to explore a new method for quantifying vessel remodeling, based on the comparison between a given target
segment and its inferred normal dimensions.
Methods: Geometric parameters and plaque composition were determined in 67 patients using three-vessel intravascular
ultrasound with virtual histology (IVUS-VH). Coronary vessel remodeling at cross-section (n = 27.639) and lesion (n = 618)
levels was assessed using classical metrics and a novel analytic algorithm based on the fractional vessel remodeling index
(FVRI), which quantifies the total change in arterial wall dimensions related to the estimated normal dimension of the
vessel. A prediction model was built to estimate the normal dimension of the vessel for calculation of FVRI.
Results: According to the new algorithm, “Ectatic” remodeling pattern was least common, “Complete compensatory”
remodeling was present in approximately half of the instances, and “Negative” and “Incomplete compensatory”
remodeling types were detected in the remaining. Compared to a traditional diagnostic scheme, FVRI-based classification
seemed to better discriminate plaque composition by IVUS-VH.
Conclusions: Quantitative assessment of coronary remodeling using target segment dimensions offers a promising approach
to evaluate the vessel response to plaque growth/regression. (Arq Bras Cardiol. 2015; 105(4):390-398)
Keywords: Coronary Artery Diseases; Vascular Remodeling; Atherosclerosis / physiopathology; Neovascularization,
Pathologic; Ultrasonography.
Introduction
Coronary artery remodeling, the geometric change in
artery dimensions, evolves with the ebb and flow of the
atherosclerotic process. Arterial remodeling encompasses
a wide spectrum of presentations, ranging from expansive
to constrictive remodeling 1,2. In the former, coronary
vessel dimensions increase as plaque accumulates, while
in the latter there is relative contraction of the vessel
wall and impingement on the lumen. There might be a
limit to expansive effects, which eventually stabilize or
decompensate to luminal encroachment1. It is therefore
evident that the pattern and extent of arterial remodeling
Mailing Address: Breno de Alencar Araripe Falcão •
Rua Oscar Freire, 1753 Apt. 41b, Pinheiros. Postal Code 05409-011,
São Paulo, SP – Brazil
E-mail: [email protected]; [email protected]
Manuscript received January 17, 2014; revised manuscript April 10, 2015;
accepted April 13, 2015.
DOI: 10.5935/abc.20150098
390
play an important role in ultimately determining the effect of
the atherosclerotic disease on luminal dimensions3-5.
Several methods have been described to characterize
and quantify vessel remodeling in patients with coronary
artery disease, mostly using intravascular ultrasound
(IVUS) imaging. In cross-sectional studies, the evaluation
of coronary remodeling is frequently described as a
simple comparison between the most diseased portion
and nearby reference segments 6,7. However, reference
vessel segments are not perfect surrogates for normality8.
In sequential studies a region of interest is examined at
baseline and compared with the same matched portion
during follow‑up9. This approach, however, only captures
the changes in plaque and vessel dimensions over time,
regardless of the degree of atherosclerosis and remodeling
at baseline, which may have a marked influence on the
outcomes thereafter.
The classification of remodeling varies substantially as a
function of definition10, and no consensus exists for a universal
definition of remodeling11. In theory, the ideal method to
measure vessel remodeling would evaluate the diseased
coronary segment compared to the same region before the
Falcão et al.
Novel algorithm for vessel remodeling
Original Article
existence of the atherosclerotic plaque. Obviously, such a
normality comparator cannot be directly assessed in practice.
We hypothesized, however, that the native normal vessel size
could be inferred for any given coronary segment to create a
more appropriate baseline for determination of remodeling.
The present study explored a new method to quantify vessel
remodeling, based on the comparison between any target
segment with its assumed normal dimensions.
Methods
FVRI =
EEM areaACTUAL
EEM areaPREDICTED + plaque area
Where,
EEM areaACTUAL is the real EEM area measured in the
cross‑section,
EEM areaPREDICTED is the hypothetical dimension of the vessel
before the formation of the atherosclerotic plaque (estimated
according to the methodology described below), and
Plaque area is the current plaque plus media area measured.
Study Design and Patient Population
This prospective, single-arm survey enrolled 67 patients
scheduled to undergo coronary angioplasty. During the
procedure, before any coronary intervention, all patients
were examined with three-vessel coronary IVUS to evaluate
coronary geometric parameters. The study was approved by
the institutional review board and signed written informed
consent was obtained from every patient.
IVUS Procedure and Image Segmentation
Intracoronary nitroglycerin (100-200 µg) was injected
before imaging acquisition. Intravascular ultrasound imaging
of the left main trunk and of the proximal portions (40-80 mm)
of the three coronary arteries was obtained using a 20 MHz
electronic solid-state catheter (Eagle Eye Gold catheter and
Vision Gold System console, Volcano Corporation, Rancho
Cordova-CA, USA) during automatic pullback at 0.5 mm/s
(R100 pullback device, Volcano Corporation, Rancho
Cordova-CA, USA).
Two experienced analysts, blinded to clinical data,
performed all offline analyses using dedicated software
(pcVH 2.2, Volcano Corporation, Rancho Cordova-CA,
USA). The external elastic lamina and lumen contours were
traced semi-automatically in every acquired IVUS frame to
obtain the following grey-scale IVUS parameters: lumen
area, elastic external membrane area (EEM area), plaque
+ media area (EEM area minus lumen area) and plaque
burden (plaque + media area divided by the EEM area,
multiplied by 100). In addition to the geometric vessel
information, radiofrequency analysis of the IVUS signal
backscatter, the so-called virtual histology (IVUS‑VH),
was used to characterize plaque composition into four
components: fibrous, fibrolipidic, necrotic core, and dense
calcium. The absolute area and percent contribution of each
component were computed for all frames.
To verify data accuracy, interobserver reproducibility
analyses were performed in 1,000 randomly selected coronary
frames of ten patients. The Pearson correlation coefficient for
EEM area, lumen area, and plaque + media area were 0.98,
0.95, and 0.93, respectively.
For the calculation of the EEM area PREDICTED , we
hypothesized that the original coronary lumen is maintained
in the initial phases of the atherosclerotic process.
Therefore, all cross-sections with an IVUS plaque burden
< 20% were assumed to have normal lumen dimensions.
As EEM and lumen areas are coincident on IVUS in the
absence of plaque, the estimation of the EEM areaPREDICTED was
based on the lumen size of cross-sections with absent or trivial
plaque (i.e. plaque burden < 20%)12. Those cross-sections
were analyzed to derive a predictive model for the normal
luminal area (i.e. the EEM areaORIGINAL) using the following
arbitrarily chosen constitutional and anatomical parameters:
body surface area, coronary dominance, coronary territory,
and the distance in millimeters from the coronary ostium.
A final multivariable linear model was built using a
bootstrap technique with 5000 replicated samples, with a
final prediction equation obtained from the bootstrapped
B-coefficients13. For the sake of keeping the prediction within
the limits of clinically relevant coronary vessels, and because
of the sample size, the analysis was restricted to frames with
luminal areas between 3.1 mm2 and 19.6 mm2 (i.e. average
vessel diameter between 2.0 mm and 5.0 mm).
Interpretation of FVRI
An FVRI close to a unit, in face of significant plaque,
indicates compensatory vessel enlargement resulting in
complete accommodation for plaque growth (Figure 1).
The cutoff of one standard deviation of FVRI at plaque level
was arbitrarily chosen for the FVRI range (between 0.83
and 1.17) to signal “complete compensatory” remodeling.
Conversely, an FVRI > 1.17 indicates a disproportionally
larger vessel increase compared to the plaque load, denoting
"ectatic” remodeling. Finally, an FVRI < 0.83 implies that
plaque accumulation was not totally compensated, and
there is absolute shrinkage of the vessel (i.e. current EEM is
smaller than the hypothetical vessel size) or insufficient vessel
enlargement to counterbalance plaque growth.
Per Cross-Section & Lesion Remodeling Analysis
Calculation of the Novel Fractional Vessel Remodeling
Index
The FVRI was calculated at the cross-sectional frame level,
together with the classification of the remodeling pattern
according to the FVRI-based algorithm.
The fractional vessel remodeling index (FVRI) was conceived
to quantify the total change in arterial wall dimensions related
to the atherosclerotic plaque load, and was calculated as:
For the lesion level, a coronary lesion was defined as any
sequence of three consecutive frames with a plaque burden
> 40%14. Within each lesion, the frame with the minimal
Arq Bras Cardiol. 2015; 105(4):390-398
391
Falcão et al.
Novel algorithm for vessel remodeling
Original Article
“Negative” remodeling
FVRI = 0.72
Luminal area = 9 mm2 2
Plaque area = 4 mm
2
EEM area = 13 mm
↓ EEM
FVRI < 0.83
“Incomplete compensatory” remodeling
FVRI = 0.71
2
Luminal area = 8 mm2
Plaque area = 7 mm
2
EEM area = 15 mm
↑ EEM
NORMAL VESSEL
Luminal area = 14 mm2
EEM area = 14 mm2
“Complete compensatory” remodeling
FVRI = 1.00
2
Luminal area = 14 mm
2
Plaque area = 7 mm
EEM area = 21 mm2
0.83 ≤ FVRI ≤ 1.17
FVRI > 1.17
“Ectatic” remodeling
FVRI = 1.19
2
Luminal area = 18 mm
2
Plaque area = 7 mm
EEM area = 25 mm2
Figure 1 – Possible remodeling outcomes of a normal coronary vessel after the occurrence of atherosclerotic plaque. The figure shows the remodeling patterns classified
according to the algorithm based on the fractional vessel remodeling index (FVRI). The numeric values are only illustrative. EEM: External elastic membrane.
lumen area was chosen as the representative cross-section
for the assessment of the lesion remodeling pattern, which
was classified according to two methods: the FVRI-based
algorithm and the classical remodeling index, calculated
as the ratio of EEM area of plaque and reference vessel.
In this classic case, EEM plaque area was measured at the
in-plaque cross-section with the smallest lumen area, and
the reference EEM area was the average EEM area of the
proximal and distal references.
ANOVA one‑way testing. Univariable association between
continuous variables was assessed by the Pearson correlation
method. Categorical variables were expressed by their count
and proportions. Statistical significance was set at p < 0.05
and all tests were bicaudal. The regression modelling to
estimate the normal vessel size and the calculation of the
derived parameters were detailed above. Statistical analyses
were performed using SPSS version 21.0 (IBM Corporation).
The proximal and distal references were specified as the
frames with a plaque burden ≤40% adjacent to the respective
plaque edges. Only lesions for which both distal and proximal
references were available were considered for analysis.
Results
As recently proposed14, the plaques were categorized
based on the classical remodeling index into "negative
remodeling” (classical index < 0.88), "intermediate
remodeling" (classical index 0.88 – 1.00) or "positive
remodeling" (classical index > 1.00).
Statistical Considerations
This is an exploratory study for which no formal sample
size calculation was performed. A total study population
of approximately 65 patients was arbitrarily set to permit,
for illustrative purposes, demonstrating a significant
linear correlation with an r-coefficient of 0.4 between
two continuous variables, considering a two-tailed
alpha value of 0.05 and a one-tailed beta value of 0.115.
Continuous variables were expressed as mean ± standard
deviation and median (interquartile range) and compared by
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Arq Bras Cardiol. 2015; 105(4):390-398
Baseline clinical characteristics of the 67 patients (Table 1)
display classic demographics of patients presenting for cardiac
catheterization and coronary angioplasty. On average,
3.8 ± 1.0 arteries were imaged per patient (total number of
coronary arteries = 255): 25% left main, 26% left anterior
descending artery, 24% circumflex artery, 22% right coronary
artery, 3% others.
Overall, 31,159 IVUS cross-sections along a total length of
9,579.8 mm (142.9 ± 22.3 mm per patient) were analyzed.
For all frames, lumen area was 8.2 ± 4.0 mm2, EEM area
was 14.2 ± 5.7 mm2, plaque area was 6.0 ± 3.5 mm2, and
percent plaque burden was 41.6 ± 16.5% of the arterial
section. A total of 3,520 cross-sections (11.3%) had no or
only mild atherosclerotic plaques (i.e. percent plaque burden
< 20%), which were computed for the calculation of the
EEM areaPREDICTED.
The overall characteristics of the bootstrapped
prediction model to estimate the EEM areaPREDICTED (Table 2)
Falcão et al.
Novel algorithm for vessel remodeling
Original Article
demonstrated that all preselected variables remained
significant in the final multivariable model. The estimated
and the actual vessel areas in cross-sections with absent
or trivial plaques (plaque burden < 20%) correlated well
(p < 0.001; adjusted R2 = 0.46) (Figure 2).
Vessel Remodeling at Cross-Section Level
For cross-sections with established plaques (i.e. plaque
burden ≥ 20%), the average FVRI was 0.86 ± 0.21 (median
0.84; interquartile range 0.71 – 0.98). Overall, 43% of frames
had FVRI between 0.83 and 1.17 ("complete compensatory"
remodeling). For the remaining cross‑sections, 8.6% had FVRI
> 1.17 ("ectatic" remodeling) and, in 48.4%, the FVRI was
< 0.83. From these, 38.7% (18.7% of the total) exhibited
reduction in EEM area ("negative" remodeling), while 61.3%
(29.6% of the total) had insufficient increment in EEM area
("incomplete compensatory" remodeling) (Figure 3).
The level of FVRI was influenced by the degree of the
atherosclerotic load. FVRI was negatively related to increasing
plaque burden (Figure 4); cross-sections with a percent
Table 1 – Baseline Characteristics
plaque burden < 20% had an average FVRI of 0.99, which
progressively decreased to a mean FVRI of 0.71 in frames with
plaque burden > 60%.
Vessel Remodeling at Lesion Level
The analysis included 618 lesions (mean length
7.7 ± 11.2 mm). In-lesion, lumen area was 6.0 ± 3.1 mm2,
EEM area was 13.4 ± 5.4 mm2, and percent plaque burden
was 55.0 ± 11.3%. For the mean reference segments, lumen
area was 8.9 ± 3.5 mm2, EEM area was 14.0 ± 5.4 mm2, and
percent plaque burden was 36.2 ± 3.2%.
Overall, the in-lesion FVRI was 0.77 ± 0.17 (median 0.77;
interquartile range 0.64 – 0.88). When classified according to
the FVRI-based algorithm, lesions had complete compensatory
remodeling in 35.1%, ectatic remodeling in 1.3%, negative
remodeling in 22.3%, and incomplete compensatory
remodeling in 41.3% (Figure 3).
The classical remodeling index for the lesions was
0.96 ± 0.16 (median 0.99; interquartile range 0.90 – 1.04).
The remodeling categories according to the classical index
were: negative remodeling 22%, intermediate remodeling
34.6%, and positive remodeling 43.4%.
The FVRI-based algorithm and the classical remodeling
index had a low agreement for the remodeling classification
of the lesions, with an overall concordance of only 38.1%:
negative/negative in 8.3%, complete compensatory/positive
in 17%, and incomplete compensatory/intermediate in
12.8% (Table 3). Nevertheless, there was a significant trend
towards increasing FVRI values from negative to positive
remodeling categories according to the classical index
groups (Table 3).
Age, years
58.9 ± 9.2
Male gender
44 (66%)
Weight, kg
72.0 ± 11.6
Height, cm
161.6 ± 7.9
Body mass index, cm/kg2
27.6 ± 4.0
Waist circumference, cm
97.4 + 11.1
Acute coronary syndrome
30 (45%)
Multivessel coronary disease
46 (69%)
Diabetes mellitus
28 (42%)
Hypertension
56 (84%)
Current smoking
14 (21%)
Metabolic syndrome
30 (45%)
Total cholesterol
165.0 ± 39.8
LDL cholesterol
99.9 ± 35.4
HDL cholesterol
36.5 ± 10.3
Triglycerides
143.2 ± 72.1
Impact of Vessel Remodeling on Plaque Composition
Numbers are counts (percentages) or mean ± standard deviation.
The two diagnostic schemes of remodeling classification
at plaque level (FVRI or classical remodeling index) were
further analyzed for their diagnostic ability in identifying
plaque tissue composition. The FVRI-based classification
seemed to better discriminate plaque composition: FVRI
remodeling classes significantly differed in their plaque
composition profile, for all tissue types (fibrous, fibrolipidic,
necrolipidic, and calcific) (Figure 5). Conversely, remodeling
types by classical remodeling index were not significantly
different in relation to their fibrous and necrolipidic
components (Figure 5).
Table 2 – Final prediction model* to estimate the original external elastic membrane area (EEM areaPREDICTED)
Variable
Β-coefficient (95% confidence interval)
p-value
Constant
12.20 (11.07 – 13.33)
< 0.001
Dominance pattern
-1.14 (-1.46 – -0.82)
< 0.001
Coronary vessel
-1.73 (-1.80 – -1.66)
< 0.001
Distance from the coronary ostium (in mm) †
-1.28 (-1.39 – -1.18)
< 0.001
2.60 (1.99 – 3.20)
< 0.001
Body surface area (in m2)
*Adjusted R2 = 0.46; † Logarithmic transformation.
Arq Bras Cardiol. 2015; 105(4):390-398
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Falcão et al.
Novel algorithm for vessel remodeling
Original Article
Figure 2 – Scatter correlation graph between estimated normal external elastic membrane area (EEM areaPREDICTED) and the actual lumen area in cross-sections with
absent or trivial plaque (plaque burden < 20%).
Discussion
Classic quantitative techniques to evaluate coronary
remodeling compare vessel size to "normal" adjacent
segments, but do so with no standard for distance from the
predicate site or precision in "normality". We now describe
a new method of assessing coronary vessel remodeling
that replaces arbitrary reference vessels with a quantitative
approach derived from the estimation of the original normal
vessel size. The proposed analytic algorithm, based on the
novel FVRI, compares the current vessel to its inferred
native state, allowing to measure and classify the remodeling
pattern in any point of the coronary tree, providing a
numeric assessment of arterial expansion or shrinkage
related to coronary atherosclerosis. The proposed method
permitted a frame-by-frame, as well as a per-lesion, analysis
of the remodeling pattern. To the best of our knowledge, this
is the first description of an approach to assess remodeling
at individual cross-section level.
The FVRI adds precision and physiologic insight to the
remodeling classification, distinguishing vascular responses
where plaque is associated with absolute vessel shrinkage
from those where plaque growth leads to different
degrees of vessel accommodation. In our test population,
complete vessel adaptation to plaque accumulation
occurred in approximately half of the instances, at both the
cross‑section and plaque levels. Moreover, partial vessel
394
Arq Bras Cardiol. 2015; 105(4):390-398
adaptation to atherosclerosis or negative vessel remodeling
(i.e. vessel shrinkage) was often detected, although vessel
ectasia was infrequent.
In line with previous studies12,16, the present findings
indicate that the adaptive vessel enlargement to plaque
growth is progressively lost as plaque load increases,
beginning as early as plaque burden ~20%, but with
a more marked failure in the accommodation in larger
plaque burdens. Similar results were seen in a recent
cross-sectional substudy from the PROSPECT trial, where
compensatory remodeling was also shown to decrease
with increasing plaque loads12. These results challenge the
common concept that lumen dimensions are maintained
intact until 40-50% plaque burden occurs9.
A number of different approaches have been proposed
to measure coronary remodeling in the lesion level10,14.
Commonly, vessel remodeling is assessed by comparing
the vessel size at target segment with the dimensions of
adjacent “normal” references7. In sequential studies, current
guidelines propose the simple change in target vessel size to
assess remodeling17. Other sequential studies have suggested
a classification of remodeling based on the ratio between
vessel size and plaque variation18. This method, however,
is unable to provide quantitative information regarding the
magnitude of the remodeling response and is not applicable
to segments with minimal or no plaque change (due to
Falcão et al.
Novel algorithm for vessel remodeling
Original Article
Cross-section (n = 27,639)
Negative
18.7%
Incomplete
compensatory
29.6%
Ectatic
8.6%
Complete
compensatory
43%
Lesion (n = 618)
Incomplete
compensatory
41.4%
Negative
22.3%
Ectatic
1.3%
Complete
compensatory
35.1%
Figure 3 – Per cross-section (frames with plaque burden ≥ 20%) and per lesion types of vascular remodeling classified according to the algorithm based on fractional
vessel remodeling index (FVRI).
division by a null or very low denominator). Use of FVRI
reduces some of the caveats of previous methods and may be
a viable alternative to quantify remodeling in cross-sectional
as well as sequential studies.
A recent study, using alternative cutoff values for the
classical remodeling index, showed that "positive" and
"negative" remodeling were associated with similar outcomes,
and both were worse than "intermediate remodeling"14.
One could hypothesize that the similarly poorer outcomes
for the two opposite types of remodeling, to some extent,
might have been related to limitations in measurement
and categorization of the remodeling pattern. Indeed, the
classical definitions of remodeling as positive, negative, or
intermediate are adequate descriptors in only ~40% of cases,
as compared to the FVRI-based algorithm. The authors of
the previous work reasoned that the impact of remodeling
on outcomes could be explained by differences in plaque
composition14. In line with that, in our series, plaques with
classical positive remodeling had more fibrolipidic tissue,
while classical negative remodeling was associated with an
increase in the calcific component. However, there were
no significant differences among the classical remodeling
categories in terms of their fibrous and necrotic components.
Conversely, the FVRI-based assessment seemed to be
more discriminative for the composition of the underlying
plaque than the classical approach, with FVRI remodeling
types significantly associated with varying profiles for all
IVUS-VH plaque components. Altogether, FRVI appears
to stratify coronary remodeling into four, instead of three,
physiologically meaningful patterns with markedly different
plaque composition. Whether these findings will be
translated to the addition of clinical value by FVRI assessment
remains open for future investigations.
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Fractional vessel remodeling index
1.0
p < 0.001
0.8
0.6
0.99
0.4
0.96
0.94
0.87
0.80
0.71
0.2
0
< 20
20-30
30-40
40-50
50-60
Percent plaque burden
> 60
Figure 4 – Average fractional vessel remodeling index in relation to percent plaque burden (error bars are one standard error of the mean).
Table 3 – Comparative classification of the lesion remodeling patterns according to FVRI-based algorithm or classical remodeling index
(n = 618 lesions)
Classical remodeling
Mean FVRI*
Mean classical remodeling index*
Negative
Intermediate
Positive
0.70 ± 0.16
0.79 ± 0.18
0.80 ± 0.16
51 (8.3)
49 (7.9)
38 (6.1)
0.90 ± 0.16
FVRI-based remodeling class
Negative
Incomplete compensatory
57 (9.2)
79 (12.8)
119 (19.3)
0.97 ± 0.18
Complete compensatory
28 (4.5)
84 (13.6)
105 (17.0)
0.99 ± 0.11
Ectatic
0 (0.0)
2 (0.3)
6 (1.0)
1.09 ± 0.15
Numbers are mean ± standard deviation or counts (percentages relative to total number of lesions); FVRI: Fractional vessel remodeling index; *p < 0.001 for all.
Our analyses suggest that the estimation of the original
normal lumen and vessel size in any point of the coronary
tree - a crucial step to calculate FVRI - is feasible and easily
obtained. Nevertheless, due to the relatively small sample
size of the present study and the intrinsic statistical limitations
of any prediction modeling of multiple interdependent
parameters, future studies are warranted to further refine
and validate the estimation of normal vessel dimensions.
It must be highlighted, however, that our study does
not aim at validating the proposed method, but has the
main objective of describing the theoretical concept of
the FVRI‑based algorithm for remodeling assessment and
providing initial exploratory results of the new score.
Conclusion
The FVRI provides a quantitative assessment of coronary
vessel remodeling, independent of nearby references, and
396
Arq Bras Cardiol. 2015; 105(4):390-398
offers a promising approach to evaluate the vessel response
to plaque growth/regression.
Author contributions
Conception and design of the research: Falcão BAA,
Falcão JLAA, Morais GR, Edelman ER, Lemos PA; Acquisition
of data: Falcão BAA, Falcão JLAA, Morais GR, Silva RC,
Lopes AC, Soares PR, Mariani Jr J, Lemos PA; Analysis
and interpretation of the data and Critical revision of the
manuscript for intellectual content: Falcão BAA, Falcão
JLAA, Morais GR, Silva RC, Lopes AC, Soares PR, Mariani Jr
J, Kalil-Filho R, Edelman ER, Lemos PA; Statistical analysis:
Falcão BAA, Falcão JLAA, Morais GR, Silva RC, Lemos PA;
Obtaining financing: Falcão BAA, Falcão JLAA, Lemos PA;
Writing of the manuscript: Falcão BAA, Lopes AC, Edelman
ER, Lemos PA.
Falcão et al.
Novel algorithm for vessel remodeling
Original Article
Classical remodeling index
60
FVRI algorithm
p = 0.2
60
Fibrous
component 40
(%)
20
61.2
63.5
63.0
p = 0.019
61.6
62.4
70.1
p < 0.001
20
15
12.1
15.0
14.8
10
5
12.9
11.8
17.3
16.6
0
0
p = 0.13
15
Necro-lipidic
component 10
(%)
5
p = 0.019
20
15
17.7
15.3
16.0
0
12
10
Calcific
8
component 6
(%)
4
2
0
65.0
0
15
Fibro-lipidic
component 10
(%)
5
20
40
20
0
20
p = 0.024
80
10
5
17.4
16.4
14.7
10.3
0
p = 0.001
p = 0.004
10
8
10.7
Negative
6
7.7
Intermediate
7.3
Positive
4
9.2
9.1
2
0
Negative
6.6
Incomplete
Complete
compensatory compensatory
4.0
Ectatic
Figure 5 – Plaque composition in vascular remodeling types according to fractional vessel remodeling index or classical remodeling index (FVRI) (n = 618 plaques).
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Study Association
This article is part of the thesis of Doctoral submitted by
Breno de Alencar Araripe Falcão, from Instituto do Coração
da Faculdade de Medicina da Universidade de São Paulo.
Sources of Funding
This study was partially funded by FAPESP.
References
1. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ.
Compensatory enlargement of human atherosclerotic coronary arteries. N
Engl J Med. 1987;316(22):1371-5.
2.
Nishioka T, Luo H, Eigler NL, Berglund H, Kim CJ, Siegel RJ. Contribution of
inadequate compensatory enlargement to development of human coronary
artery stenosis: an in vivo intravascular ultrasound study. J Am Coll Cardiol.
1996;27(7):1571-6.
3. Berry C, Noble S, Ibrahim R, Gregoire J, Levesque S, L’Allier PL, et
al. Remodeling is a more important determinant of lumen size than
atheroma burden in left main coronary artery disease. Am Heart J.
2010;160(1):188-194.
4. Puri R, Wolski K, Uno K, Kataoka Y, King KL, Crowe TD, et al. Left main
coronary atherosclerosis progression, constrictive remodeling, and clinical
events. JACC Cardiovasc Interv. 2013;6:29-35.
Arq Bras Cardiol. 2015; 105(4):390-398
397
Falcão et al.
Novel algorithm for vessel remodeling
Original Article
5. Kang SJ, Kim WJ, Yun SC, Park DW, Lee SW, Kim YH, et al. Vascular remodeling
at both branch ostia in bifurcation disease assessed by intravascular ultrasound.
Catheter Cardiovasc Interv. 2013;81(7):1150-5.
12. Inaba S, Mintz GS, Shimizu T, Weisz G, Mehran R, Marso SP, et al.
Compensatory enlargement of the left main coronary artery: insights from
the PROSPECT study. Coron Artery Dis. 2014;25(2):98-103.
6.
Mintz GS, Kent KM, Pichard AD, Satler LF, Popma JJ, Leon MB. Contribution
of inadequate arterial remodeling to the development of focal coronary artery
stenoses: an intravascular ultrasound study. Circulation. 1997;95(7):1791-8.
13. Harrell FE Jr, Lee KL, Mark DB. Multivariable prognostic models: issues in
developing models, evaluating assumptions and adequacy, and measuring
and reducing errors. Stat Med. 1996;15(4):361-87.
7.
Schoenhagen P, Ziada KM, Kapadia SR, Crowe TD, Nissen SE, Tuzcu EM.
Extent and direction of arterial remodeling in stable versus unstable coronary
syndromes : an intravascular ultrasound study. Circulation. 2000;101(6):598603.
14. Inaba S, Mintz GS, Farhat NZ, Fajadet J, Dudek D, Marzocchi A, et al. Impact
of positive and negative lesion site remodeling on clinical outcomes: insights
from PROSPECT. JACC Cardiovasc Imaging. 2014;7(1):70-8.
8.
Mintz GS, Painter JA, Pichard AD, Kent KM, Satler LF, Popma JJ, et al.
Atherosclerosis in angiographically “normal” coronary artery reference
segments: an intravascular ultrasound study with clinical correlations. J Am Coll
Cardiol. 1995;25(7):1479-85.
9.
Schoenhagen P, Ziada KM, Vince DG, Nissen SE, Tuzcu EM. Arterial remodeling
and coronary artery disease: the concept of “dilated” versus “obstructive”
coronary atherosclerosis. J Am Coll Cardiol. 2001;38(2):297-306.
10. Hibi K, Ward MR, Honda Y, Suzuki T, Jeremias A, Okura H, et al. Impact of
different definitions on the interpretation of coronary remodeling determined
by intravascular ultrasound. Catheter Cardiovasc Interv. 2005;65(2):233-9.
11. von Birgelen C, Hartmann M, Mintz GS, Bose D, Eggebrecht H, Neumann T, et
al. Remodeling index compared to actual vascular remodeling in atherosclerotic
left main coronary arteries as assessed with long-term (> or =12 months) serial
intravascular ultrasound. J Am Coll Cardiol. 2006;47(7):1363-8.
398
Arq Bras Cardiol. 2015; 105(4):390-398
15. Hsieh FY, Bloch DA, Larsen MD. A simple method of sample size calculation
for linear and logistic regression. Stat Med. 1998;17(14):1623-34.
16. von Birgelen C, Airiian SG, Mintz GS, van der Giessen WJ, Foley DP,
Roelandt JR, et al. Variations of remodeling in response to left main
atherosclerosis assessed with intravascular ultrasound in vivo. Am J Cardiol.
1997;80(11):1408-13.
17. Mintz GS, Garcia-Garcia HM, Nicholls SJ, Weissman NJ, Bruining N, Crowe
T, et al. Clinical expert consensus document on standards for acquisition,
measurement and reporting of intravascular ultrasound regression/
progression studies. EuroIntervention. 2011;6(9):1123-30, 9.
18. Sipahi I, Tuzcu EM, Schoenhagen P, Nicholls SJ, Crowe T, Kapadia S,
et al. Static and serial assessments of coronary arterial remodeling are
discordant: an intravascular ultrasound análise from the Reversal of
Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial. Am Heart
J. 2006;152(3):544-50.
Back to the Cover
Original Article
Development and Validation of Predictive Models of Cardiac
Mortality and Transplantation in Resynchronization Therapy
Eduardo Arrais Rocha1, Francisca Tatiana Moreira Pereira2, José Sebastião Abreu2, José Wellington O. Lima3,
Marcelo de Paula Martins Monteiro2, Almino Cavalcante Rocha Neto2, Camilla Viana Arrais Goés1, Ana Gardênia
P. Farias2, Carlos Roberto Martins Rodrigues Sobrinho2, Ana Rosa Pinto Quidute2, Maurício Ibrahim Scanavacca1
Instituto do Coração (InCor) – Universidade de São Paulo1, São Paulo, SP; Hospital Universitário – Universidade Federal do Ceará2, CE;
Departamento de Saúde Pública – Universidade Estadual do Ceará3, Fortaleza CE – Brazil
Abstract
Background: 30-40% of cardiac resynchronization therapy cases do not achieve favorable outcomes.
Objective: This study aimed to develop predictive models for the combined endpoint of cardiac death and transplantation
(Tx) at different stages of cardiac resynchronization therapy (CRT).
Methods: Prospective observational study of 116 patients aged 64.8 ± 11.1 years, 68.1% of whom had functional
class (FC) III and 31.9% had ambulatory class IV. Clinical, electrocardiographic and echocardiographic variables were
assessed by using Cox regression and Kaplan–Meier curves.
Results: The cardiac mortality/Tx rate was 16.3% during the follow-up period of 34.0 ± 17.9 months. Prior to
implantation, right ventricular dysfunction (RVD), ejection fraction < 25% and use of high doses of diuretics (HDD)
increased the risk of cardiac death and Tx by 3.9-, 4.8-, and 5.9-fold, respectively. In the first year after CRT, RVD,
HDD and hospitalization due to congestive heart failure increased the risk of death at hazard ratios of 3.5, 5.3, and
12.5, respectively. In the second year after CRT, RVD and FC III/IV were significant risk factors of mortality in the
multivariate Cox model. The accuracy rates of the models were 84.6% at preimplantation, 93% in the first year after
CRT, and 90.5% in the second year after CRT. The models were validated by bootstrapping.
Conclusion: We developed predictive models of cardiac death and Tx at different stages of CRT based on the analysis
of simple and easily obtainable clinical and echocardiographic variables. The models showed good accuracy and
adjustment, were validated internally, and are useful in the selection, monitoring and counseling of patients indicated
for CRT. (Arq Bras Cardiol. 2015; 105(4):399-409)
Keywords: Heart Transplantation / mortality; Heart Failure / physiopathology; Cardiac Resynchronization Therapy;
Follow-Up Studies; Pacemaker, Artificial.
Introduction
The main international guidelines strongly recommend
(class I) cardiac resynchronization therapy (CRT) for
patients with congestive heart failure (CHF) and New
York Heart Association (NYHA) functional class (FC) II or
III or ambulatory class IV when they have intraventricular
conduction disturbances and ejection fraction (EF) ≤ 35%
while undergoing optimal medical therapy1.
However, 30%–40% of CRT cases do not achieve favorable
outcomes, which means that these patients undergo surgery
with high risks and costs but with no clinical, hemodynamic,
or survival benefits2. Thus, multifactorial indexes or scores
Mailing Address: Eduardo Arrais Rocha •
Universidade Federal do Ceará. Av. Padre Antônio Tomás, 3535 / 1301,
Cocó. Postal Code 60192-120, Fortaleza, CE – Brazil
E-mail: [email protected], [email protected]
Manuscript received March 15, 2015; reviewed manuscript May 05, 2015;
accepted May 06, 2015.
DOI: 10.5935/abc.20150093
399
need to be developed to more accurately identify survival
predictors and treatment responders3,4. Such indexes should
involve variables related to mortality reduction, with high rates
of sensitivity and specificity.
This work aimed to develop predictive models for the
combined endpoint of cardiac death and transplantation (Tx)
at different stages of CRT.
Methods
This prospective observational study evaluated 116 patients
with multisite pacemakers implanted consecutively in a
tertiary university hospital between January 2008 and March
2013 (Table 1), who had NYHA FC III or ambulatory FC IV
(ambulatory outpatients who were taking oral medications),
EF ≤ 35%, QRS ≥ 120 ms (left bundle branch block [LBBB]
and right bundle branch block [RBBB] with divisional block or
pacemaker rhythm), and optimized treatment. The exclusion
criteria were severe comorbidities, previous indication for
pacemaker implantation, hospitalization for NYHA FC IV
heart failure, primary valvular disease, and incomplete data.
Rocha et al.
Development of predictive models in CRT
Original Article
Table 1 – Baseline characteristics and comparison of the results of some variables during the assessment periods
Variables
Patients
Age (years)
Sex (male)
Time 1
Time 2
P Value
Time 3
p Value*
116
114
-
92
-
64.8 ± 11.1
-
-
-
-
69.8%
-
-
-
-
25.8 ± 4.1
-
-
-
-
Beta-blockers
88.7%
89.2%
-
91.8%
ACE-inhibitors
97.4%
96%
Furosemide ≥ 80mg/day
31.9%
17%
-
-
-
Dilated cardiomyopathy
59.4%
-
-
-
-
Ischemic cardiomyopathy
29.3%
-
-
-
-
Chagas disease
11.2%
-
-
-
-
BMI
Atrial fibrillation
95.9%
12%
-
-
-
-
CRT-D
54.2%
-
-
-
-
LBBB
71.55%
-
-
-
-
140
< 0.001
-
-
RBBB with divisional block
12%
Pacemaker
16.3%
Posterolateral vein
45.4%
Anterolateral veins
52.5%
Prior QRS width (ms)
160
Number of hospitalizations due to CHF
108
24
< 0.001
16
0.79*
Ejection fraction (median)
29%
33%
< 0.001
35%
0.03*
LVDD (mm)
70
66
< 0.001
65
0.73*
Systolic BP (mm Hg)
115
119.6
< 0.001
121.8
0.84*
Diastolic BP (mm Hg)
70
80
0.07
70
0.34*
FC IIl (NYHA)
68.1%
8.7%
< 0.001
12%
0.07*
FC IV (NYHA)
31.9%
6.1%
DD
< 0.001
7.6%
0.07*
< 0.001
-
0.06*
DD Grade I
34.6%
59.2%
-
63.2%
-
DD Grade II
23.7%
27.1%
-
13.9%
-
DD Grade III
29.7%
8.7%
-
16.4%
-
DD Grade IV
11.8%
4.8%
-
5.0%
0.009*
-
-
0.008
-
No MR
MR
3.4%
5.3%
-
15.3%
Mild MR
50.4%
66.0%
-
56.0%
-
Moderate MR
30.4%
18.7%
-
18.6%
-
Severe MR
15.6%
9.8%
-
9.8%
-
RV dysfunction
20.9%
17%
0.62
12%
0.5*
1.1
1.1
-
1.2
-
Creatinine (mg/dL)
Time 1, preimplantation; time 2, 1 year; time 3, 2 years.
*Analysis of time 3 in relation to time 2; QRS width, ejection fraction, left ventricular diastolic diameter and blood pressure were variables without normal distribution
(median values); BMI: Body mass index; ACE: Angiotensin-converting enzyme; CRT-D: Cardioverter-defibrillator with biventricular pacing; LBBB: Left bundle branch
block; RBBB: Right bundle branch block; CHF: Congestive heart failure; LVDD: Left ventricular diastolic diameter; BP: Blood pressure; FC: Functional class (NYHA);
DD: Diastolic dysfunction; MR: Mitral regurgitation; RV: Right ventricle.
Arq Bras Cardiol. 2015; 105(4):399-409
400
Rocha et al.
Development of predictive models in CRT
Original Article
Of the 147 patients who underwent implantation during
the study period, only 116 were included in the study
for the following reasons: 4 had an EF >35%, 3 had total
atrioventricular block, 2 had primary valvular heart disease, 2
had pacemaker infection, 7 had incomplete data, 4 had loss
of capture in the left ventricle electrode, 2 did not undergo
complete follow-up, 1 had severe comorbidity, 5 were
hospitalized for class IV CHF at the time of inclusion, and 1
died of premature respiratory infection.
The electrodes of the right ventricle were positioned
preferentially in the apical region (84%). The models used in 92,
12, 10, and 2 patients were from St. Jude Medical, Biotronik,
Medtronic, and Guidant, respectively. Patients with concomitant
indication for an implantable cardioverter-defibrillator (CRT-D
group) (54% of the 116 patients) were also included in this study.
This indication was for primary prevention in 47 patients and
for secondary prevention in 16 patients.
Assessments were performed in the preimplantation
period (first analysis), at 1 year after implantation (second
analysis), and at 2 years after implantation (third analysis)
according to a fixed protocol. We analyzed 12 clinical,
8 electrocardiographic, and 7 echocardiographic variables.
The clinical variables were age, sex, body mass index,
cardiac cachexia, FC, etiology of cardiomyopathy, cardiac
vein where the electrode was positioned in the left
ventricle, serum creatinine level, systolic and diastolic blood
pressures, use of high-dose loop diuretics (≥ 80 mg/day
of furosemide), and hospitalization due to heart failure.
The electrocardiographic variables were: atrial fibrillation;
LBBB or RBBB; previous cardiac pacemaker; 1st-degree
atrioventricular block; QRS duration; QRS narrowing
after implantation; R wave in the V1 lead in patients with
LBBB; and QRS axis in the frontal plane after implantation.
The echocardiographic variables were: left ventricular
(LV) diastolic and systolic diameters; EF computed using
Simpson’s method; degree of diastolic dysfunction (DD)
from I to IV; degree of mitral regurgitation from I to III; right
ventricular dysfunction (RVD); and dyssynchrony.
A 12-lead surface electrocardiogram was recorded at the
speed of 25 mm/s and amplitude of 10 mm/mV. The longest
duration of the QRS measured in one of the leads of the frontal
or horizontal plane, which was the lead with the highest value
and thus allowed for better evaluation, was taken into account.
Cardiac mortality was defined for deaths of end-stage CHF
or for sudden death.
Echocardiographic parameters
The echocardiographic guidelines for the analysis of
various echocardiographic parameters were followed, as
well as the guidelines for dyssynchrony for the analysis of
such parameters5, 6. Three experienced physicians performed
the echocardiographic examinations, 72% of which were
performed by the same specialist. The examinations were
performed using the GE Vivid 7 Ultrasound System (GE
Healthcare, Fairfield, CT, USA).
The systolic function analysis of the cardiac chambers was
performed using Simpson’s method in the two-dimensional
mode. Ventricular diameters were obtained on M-mode
401
Arq Bras Cardiol. 2015; 105(4):399-409
echocardiography, according to the standard guideline5.
Right ventricular function was analyzed qualitatively,
differentiated between the presence and absence of any
degree of dysfunction5.
Diastolic dysfunction analysis was conducted by assessing
mitral flow (at rest and after a Valsalva maneuver), tissue
Doppler images, and flow propagation speed on color
M-mode. Results were used to classify DD into four grades
(0, absent; I, mild; II, moderate; III, accentuated or with
restrictive dysfunction; and IV, severe or with irreversible
restrictive dysfunction)7.
The degree of mitral regurgitation was assessed as the
percentage of the left atrium filling using color Doppler
echocardiography. The percentage was less than 20% in
mild reflux, and between 20% and 40% in moderate reflux;
values above these percentages indicated severe reflux5.
In this practical context, the Coanda effect was interpreted
as a moderate reflux when restricted to the atrial sidewall
and accentuated when it stretched through the upper pole
of the left atrium.
All patients provided informed consent, and the ethics
committee of the hospital approved the study, whose
protocol conforms to the ethical guidelines of the declaration
of Helsinki.
Statistical analysis
The categorical variables were presented as frequencies
and percentages, whereas the continuous variables were
presented as means and standard deviations, or medians.
The categorical variables were compared using the McNemar,
Stuart–Maxwell, or chi-square test. The Student t test was
used to compare the distribution of approximately normal,
continuous variables, and the Wilcoxon/Mann–Whitney U
test was used for the comparisons of continuous variables
without normal distribution. Distributions were considered
significantly different if p < 0.05.
The univariate relationship between the clinical,
electrocardiographic, and echocardiographic variables and
the combined endpoint of cardiac mortality and Tx was
evaluated by using the Kaplan–Meier survival curve, log-rank
test, and Cox regression analysis. Some continuous variables
were assessed to determine a cutoff value.
Cox multiple regression models were developed in
the following analysis times to assess the independent
contribution of each of the significant variables in the Cox
univariate model: preimplantation (time 1), first year after CRT
(time 2), and second year after CRT (time 3). Variables with
p < 10% were considered potential confounders. Each of the
variables was included in the multivariate model according to
hazard descending order and was excluded when p ≥ 5%.
After obtaining the final model, the previously excluded
variables were included again in the model and tested
individually using the same criteria.
We conducted logistic regression analyses by using hazard8
as an independent variable to measure risk, and cardiac death/
Tx as the dependent variable. The accuracy of the models was
tested with the receiver-operating characteristic (ROC) curve,
along with its sensitivity and specificity. Models were prepared
Rocha et al.
Development of predictive models in CRT
Original Article
by dividing the hazard scores into risk categories according
to the number of variables present and classified as low (class
A), medium (class B), and high risk (class C).
Kaplan–Meier survival curves were elaborated individually
for the independent variables and risk classes, and compared
using the log-rank test.
For the proposed models, all the variables were tested
for compliance with the proportional hazards assumptions
by performing the Schoenfeld test and a visual analysis
of the Schoenfeld residuals against the time of deaths or
censorship. For each model, the effect of each observation
on the estimated parameters was analyzed. To achieve this,
after the deletion of an observation, the model was estimated
again and the new estimates were compared to the previous
ones. Values should not change much or the model may be
too sensitive to a particular observation.
To obtain the bootstrap confidence intervals, the
original data were sampled 10,000 times to obtain 10,000
pseudo-samples of size 60. Then, for each pseudo-sample,
the hazard ratios of the three models were estimated.
These estimated hazard rates were sorted, and the 95%
confidence interval was reported.
The data were analyzed by using Stata/SE version
12.1 (StataCorp LP, College Station, TX, USA) and the
“R” software (2014 –“R”: A language and environment
for statistical computing . R Foundation for Statistical
Computing, Vienna, Austria).
Results
During the study, 29 deaths were recorded, representing
a total mortality rate of 25% during the follow-up period of
34.09 ± 17.9 months. Cardiac mortality/Tx accounted for
16.3% (19 patients) of the cases. Six patients underwent
Tx during the study period, 5 for refractory CHF and 1
for recurrent arrhythmic storm. Three Tx patients died
prematurely due to disease severity at the time of Tx.
No sudden death occurred in the CRT-D group, but sudden
death occurred in 3 patients in the CRT-P (pacemaker
without defibrillator) group. In the CRT-D group, 6 patients
with fast ventricular tachycardia or fibrillation were treated
with effective shock. The baseline characteristics of the
patients and the comparison of the results of the variables
during the assessment period are shown in Table 1.
No significant statistical evidence showed that the
assumption of proportional hazards was violated. The effect
of each observation on the estimated parameters for each
model was analyzed. The data obtained do not suggest
influential observations. Bootstrapping confidence intervals
for a 95% level of significance were obtained and confirmed
the statistical significance of the estimated hazard ratios.
These results did not reject the adjustment of the model with
the proposed variables (Table 2).
Analysis of the variables at time 1 (preimplantation)
Of the 27 variables analyzed during the first study period
(preimplantation), 13 were significant in the Cox univariate
regression model. In the Cox multivariate model, RVD,
Table 2 – Bootstrap 95% confidence intervals and formal test for the
proportional hazards assumption
Model 1
Covariate
CI
EF
(1.7142; 14.2053)
RVD
(1.8754; 16.6939)
HDD
(2.2563; 18.7021)
Model 2
CHF
(2.1747; 11.4814)
RVD
(3.0642; 10.6684)
HDD
(4.0963; 18.3712)
Model 3
FC
(3.5177; 37.5661)
RVD
(6.0592; 46.8405)
Model 1
Covariate
ρ
χ2
p value
EF
0,073
0,08099
0,776
RVD
0,124
0,28512
0,593
HDD
-0,012
0,00259
0,939
0,33714
0,953
Global
Model 2
ICC
0,3713
1,785
0,182
RVD
0,1089
0,223
0,637
HDD
-0,0934
0,167
0,683
1,905
0,592
Global
Model 3
FC
-0,110
0,118
0,732
RVD
0,125
0,162
0,687
0,254
0,881
Global
CI: Confidence interval; EF: Ejection fraction; RVD: Right ventricular
dysfunction; CHF: Hospitalization due to congestive heart failure;
HDD: High doses of diuretic (furosemide ≥ 80 mg/day); FC: Functional
class (NYHA) III/IV compared with I/II.
EF <25%, and use of high-dose diuretics (HDD) were
independently associated with increased cardiac mortality/Tx,
with hazard ratios of 3.9, 4.8, and 5.9, respectively (Table 3).
Significant variables in the multivariate model were also
significant in the Kaplan–Meier model when compared using
the log-rank test. The analysis of the model by using the ROC
curve showed an area under the curve (AUC) of 0.81, with a
sensitivity of 61.1%, a specificity of 89.5%, and an accuracy
of 84.6% (Figure 1).
From the combinations of these variables, we developed
a model with three classes as follows: class A (low risk for
cardiac death/Tx) was the absence of the variables or the
presence of only one of the significant variables in the
Arq Bras Cardiol. 2015; 105(4):399-409
402
Rocha et al.
Development of predictive models in CRT
Original Article
Table 3 – Analysis by the Cox model with respect to cardiac mortality/Tx at time 1 (preimplantation)
Variable
HR
95% CI
p
HR
Univariate
95% CI
p
Multivariate
Hospitalization ≥ 1
9.23
1.23-69.21
0.031
RV dysfunction
5.01
1.97-12.76
0.001
FC III / IV
4.87
1.85-12.83
0.001
Chagas Disease
4.73
1.77-12.63
0.002
EF < 25 %
4.43
1.77-11.05
Diuretic ↑
3.89
1.56-9.72
SBP < 100 mmHg
3.38
1.35-8.46
0.009
Creatinine > 1.1
2.85
1.06-7.67
0.038
LVDD > 80 mm
2.68
1.00-7.15
0.048
DBP < 60 mmHg
2.63
1.02-6.75
0.044
ACE inhibitors
4.34
0.98-19.17
0.052
MR grade II
2.50
0.89-7.41
0.08
MR grade III
2.80
0.87-9.43
0.08
3.95
1.45-10.74
0.007
0.001
4.85
1.71-13.73
0.003
0.004
5.97
2.15-16.53
0.001
HR: Hazard ratio (hazard ratio in the Cox model); CI: Confidence interval, P: Level of statistical significance; Diuretic ↑: ≥ 80mg of furosemide; SBP: Systolic blood
pressure; DBP: Diastolic blood pressure; FC III / IV: Percentage of functional class (FC) III over FC IV; Hospitalization ≥ 1: one or more hospitalizations due to congestive
heart failure (CHF); RV: Right ventricular; EF: Ejection fraction; LVDD: Left ventricular diastolic diameter; ACE: Angiotensin-converting enzyme; MR: Mitral regurgitation.
multivariate analysis, implying a 30-month cardiac event‑free
rate of 93%. The combination of two (class B) and three
variables (class C) resulted in 30-month cardiac event-free
rates of 61% and 0%, respectively.
Analysis of the variables at time 2 (first year after CRT)
During time 2 (first year after CTR), 13 variables
were significant in the Cox univariate regression model.
In the Cox multivariate model, RVD, use of HDD, and
hospitalization due to CHF were independently related to
increased cardiac mortality/Tx rate, with hazard ratios of
3.5, 5.3, and 12.5, respectively.
The significant variables in the multivariate model were also
significant in the Kaplan–Meier model, when compared by using
the log-rank test. The analysis of the model by using the ROC
curve showed an AUC of 0.910, with a sensitivity of 76.4%, a
specificity of 96.3%, and an accuracy of 93% (Figure 2).
From the combinations of these variables, we were able to
construct a model with three classes (Table 4). Class A means low
risk of cardiac death/Tx, composed by the absence or presence
of only one of the significant variables in the multivariate
analysis, resulting in a 30-month cardiac event‑free rate of 98%.
The combination of two (class B) and three variables (class C)
resulted in 30-month cardiac event-free rates of 65% and 0%,
respectively (Figure 2).
Analysis of the variables at time 3 (second year after CRT)
Hospitalizations due to CHF, use of HDD, FC, DD, RVD,
EF < 30%, Chagas disease, and systolic blood pressure < 110
mmHg were significant in the univariate Cox regression model
in the second year after CRT.
403
Arq Bras Cardiol. 2015; 105(4):399-409
In the multivariate Cox model, RVD and FC III/IV were
independently related to increased cardiac mortality/
Tx rate, with hazard ratios of 7.7 and 12.0, respectively.
The significant variables in the multivariate model were
also separately significant in the Kaplan–Meier model when
compared using the log-rank test (p < 0.001). The analysis
of the model using the ROC curve showed an AUC of 0.789,
with a sensitivity of 40%, a specificity of 98.4%, and an
accuracy of 90.5% (Figure 3).
From the combination of these variables, we were able to
construct a model with three classes. Class A means low risk
of cardiac death/Tx, composed by the absence of the two
significant variables in the multivariate analysis, implying a
30-month cardiac event-free rate of 97.5%. The presence of
the combination of two (class B) and three variables (class
C) resulted in 30-month cardiac event-free rates of 83.1%
and 38.5%, respectively.
Discussion
In the present study, we developed three predictive models
for the risk of cardiac death and Tx at different stages of
CRT. To our knowledge, this is the first study to sequentially
and prospectively analyze predictive variables in the same
population and at different stages of development (at
preimplantation, in the first year after CRT, and in the second
year after CRT) and to develop risk models for cardiac death/
Tx. The models identified simple variables that, when present,
were associated with a high risk for cardiac death/Tx.
The total mortality rate was 25% (29/116) at 34 ± 17 months.
In the CARE-HF study9, the mortality was 30% in the group
without intervention, compared with 20% in the group with
Rocha et al.
Development of predictive models in CRT
Original Article
Figure 1 – Kaplan-Meier survival curve of the variables with independent value in the multivariate Cox analysis, compared by using the log-rank test, with the construction
of the ROC curve, an area under the curve (AUC) of 0.81, sensitivity of 61%, specificity of 89%, and accuracy of 84%. At the bottom right, risk model, being a low risk of
cardiac mortality/Tx the absence of the three variables, furosemide> 80 mg/day, right ventricular dysfunction, and ejection fraction (EF) < 25% or presence of one of them.
Arq Bras Cardiol. 2015; 105(4):399-409
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Rocha et al.
Development of predictive models in CRT
Original Article
Figure 2 – Kaplan-Meier curve of the variable hospitalization due to congestive heart failure (CHF), which, associated with right ventricular dysfunction and use of high
doses of diuretics, formed the predictive model of cardiac death/Tx at time 2 (1st year). The absence of the three variables or the presence of only one (low risk) indicates an
event‑free rate in 30 months of 98%. At the top right, the ROC curve with an area under the curve (AUC) of 0.91, sensitivity of 76.4%, specificity of 96.3%, and accuracy of 93%.
CRT, during a 29.4-month follow-up. In the COMPANION
study10, the mortality rate was 21% (131/617) in the CRT
group, compared with 25% (77/308) in the control group,
during a 24-month follow-up. Therefore, our total mortality
data are within the range described by large-scale studies.
In our study, we analyzed the combined endpoints of cardiac
mortality and Tx, aiming at identifying more-specific variables
related to CRT results11.
405
right ventricle as an independent predictor of mortality.
Therefore, patients with RVD should not be excluded from
the indication for CRT, although they represent a subgroup at
higher risk of cardiac death or Tx after CRT22. The importance
of the right ventricle in CRT has been demonstrated in other
recent studies, but not in the elaboration of risk models for
different evolution stages23,24.
Several studies have evaluated predictors of response or
death in different populations and with different response
criteria, and the results were inconsistent. However, several
publications identified the following predictors of response:
dilated cardiomyopathy12, QRS width13, QRS narrowing14,
presence of dyssynchrony15, female sex16, type of bundle
branch block 17, LV diameter 18, the aortic velocity time
integral13, and DD19.
Thirteen patients (11.2%) had Chagas disease, 5 of whom
had RVD. Chagas cardiomyopathy was related to increased
mortality in the survival curve, similar to another study that
related it with worse outcome25. In the multivariate analysis,
Chagas disease did not remain as an independent variable,
probably because 41% of the patients had RVD, a variable
that was significant at all the analysis times. Therefore, the
relevance of RVD was not exclusively related to Chagas disease,
as 19 patients had RVD due to other etiologies.
The patients with RVD (20.9% of the group) had worse
evolution in all the analysis times. However, we noticed
that 6 patients with good outcomes had regression of the
alterations in the right ventricle. The study by Praus et al20
showed that the regression of the right ventricle occurred
later (15 months), whereas Leong et al 21 identified the
A preimplantation EF < 25% identified a subgroup with
the highest risk for cardiac death. Linde et al26, in a subanalysis
of the REVERSE study, have shown that a basal EF < 30%,
compared with values between 30% and 40%, was positively
related to survival. Meanwhile, Kronborg et al27 showed that a
basal EF < 22.5% determined an increased mortality after CRT.
Arq Bras Cardiol. 2015; 105(4):399-409
Rocha et al.
Development of predictive models in CRT
Original Article
Table 4 – Predictive scores of cardiac mortality and transplantation in cardiac resynchronization therapy
Score at time 1 (preimplantation)
Variable
Hazard
N
Scores
Class
Risk
None
1.0
45
0
A1
Low
RVD
3.9
8
3
A2
Low
EF
4.8
14
4
A2
Low
Diuretic ↑
5.9
17
5
A2
Low
RVD + EF
19.1
5
7
B
Intermediate
RVD + Diuretic ↑
23.6
4
8
B
Intermediate
EF + Diuretic ↑
29.0
6
9
B
Intermediate
RVD + EF + Diuretic ↑
114.0
5
12
C
High
Hazard
N
Scores
Class
Risk
None
1.0
62
0
A
Low
RVD
3.5
7
2
A
Low
Diuretic ↑
5.3
12
3
A
Low
Hospitalization
12.5
3
5
A
Low
RVD + Diuretic ↑
18.7
2
6*
B
Intermediate
RVD + Hospitalization
44.0
2
7
B
Intermediate
Diuretic ↑ + Hospitalization
66.3
6
8
B
Intermediate
RVD + Hospitalization + Diuretic ↑
234.0
6
10
C
High
Hazard
N
Scores
Class
Risk
None
1.0
55
0
A
Low
FC III/IV
7.7
10
8
B
Intermediate
RVD
12.1
4
13
B
Intermediate
RVD + FC III/IV
94.5
5
21
C
High
Score at time 2 (1st year)
Variable
Score at time 3 (2nd year)
Variable
RVD: Right ventricular dysfunction; EF: Ejection fraction lower than 25%; diuretic ↑: use of ≥ 80 mg of furosemide; FC: Functional class (NYHA); Hospitalization: ≥ 1
hospitalization due to congestive heart failure. Class A: Low risk category, Class B: Intermediate risk and Class C: High risk. The hazard was used as an independent
variable in the logistic regression model for the preparation of the score. The score was obtained by the hazard ratio of the variable divided by the highest value. * one
unit was added to maintain the hazard proportion. N: Number of patients.
The hospitalizations for heart failure proved to be an
independent variable in relation to the prediction of cardiac
mortality/Tx in the first year after CRT. The study represents,
to our knowledge, the first time this variable was included as
independent in the analysis of mortality risk in the first year
after CRT and not as part of the outcome combined with
death. Hospitalization due to CHF is a well-defined risk factor
for cardiomyopathy, with a reduction in the incidence of these
events after CRT demonstrated in several studies9,10.
Another easily obtainable clinical variable that showed
significant value in the preimplantation period and first year
after CRT was the use of high-dose loop diuretics (furosemide
≥ 80 mg/day). Van Boven et al28 reported an association
between chronic non-use of diuretics and response to CRT.
Meanwhile, Cleland et al29 observed that the use of HDD
was related to a worse prognosis only in the univariate
analysis. We believe that the description of this variable as
an independent value of cardiac death in two periods of the
CRT analysis in our study is an original observation.
A clinical prediction rule to identify patients at heightened
risk for early demise after CRT has been recently elaborated30,
including the following four independent variables:
LV end‑diastolic diameter (LVEDD) > 65 mm, non-LBBB
morphology, creatinine level > 1.5, and non-use of
beta‑blockers. In our study, LVEDD and creatinine level were
significant only in the univariate analyses. Hospitalization due
to CHF, use of HDD, and RVD, some independent variables
in our work, were not included in the previous study.
Arq Bras Cardiol. 2015; 105(4):399-409
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Rocha et al.
Development of predictive models in CRT
Original Article
Figure 3 – A: ROC curve of the model at time 3 (2nd year), with the variables right ventricle (RV) dysfunction and functional class (FC) III and IV compared with I and
II, with an area under the curve (AUC) of 0.789, sensitivity of 40%, specificity of 98.4% and accuracy of 90.5%. B: Kaplan-Meier curve showing that the absence of the
variables RV dysfunction and FC III / IV (Class A - low risk) indicates an event-free rate of 97.5% at 30 months.
We achieved a significant improvement in the specificity
of the predictive models of mortality or response after CRT,
reaching 96% in the first year after CTR and 98% in the second
year after CRT, when compared with the specificity of 22%–70%
of previously described models in relation to total and cardiac
mortality. These results are in accordance with the target
outcomes of CRT in the treatment of patients with severe illnesses,
with high costs and risks in the procedure31. The models used in
this study showed good accuracy, ranging from 84.6% to 93%,
and can be used in three different stages of CRT, which is another
original contribution of our work. At the usual significance levels,
the model was validated internally and did not reveal lack of
adjustment or exaggerated sensitivity to the data.
We believe that the study contributes to and advances the
search for better criteria for prognostic evaluation, with the
composition of simple multifactorial indexes and with the
inclusion of easily obtainable variables that are used in clinical
practice. The models will be useful in the selection, monitoring,
and counseling of patients indicated for CRT.
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Arq Bras Cardiol. 2015; 105(4):399-409
Study limitations
Analyses of intraobserver and interobserver variabilities
of echocardiographic and electrocardiographic parameters
were not performed. The patients did not undergo
optimization of the atrioventricular interval after surgery.
The models created were not validated externally, although
they were validated internally. This study is also limited by
the small number of patients, the large number of excluded
patients, and the fact that it was conducted at a single
center. The RV function was analyzed qualitatively due to
the absence of correlation between the RV measures and
the prognosis at the beginning of the study. These results
must be considered within the study population, who
had 59.4% of dilated cardiomyopathy, 11.2% of Chagas
cardiomyopathy, 12% of patients with RBBB and 16.3%
of patients with prior cardiac pacemaker. Future larger
prospective studies will help validate the important variables
related to cardiac death or Tx after CRT.
Rocha et al.
Development of predictive models in CRT
Original Article
Conclusion
We developed predictive models of cardiac death or Tx
at different stages of CRT based on the analysis of simple and
easily obtainable clinical and echocardiographic variables.
The models showed good accuracy and adjustment, were
validated internally, and are useful in the selection, monitoring,
and counseling of patients indicated for CRT.
Acknowledgments
We are grateful to Professor José Wellington O. Lima, Luis
Gustavo Bastos Pinho, and Juvêncio Santos Nobre for the statistical
advice and Dr. Italo Martins by the local coordination of Ph.D.
Author contributions
Conception and design of the research: Rocha EA, Pereira
FTM, Abreu JS, Lima JWO, Rocha Neto AC, Farias AGP, Sobrinho
CRMR, Scanavacca MI; Acquisition of data: Rocha EA, Pereira
FTM, Abreu JS, Monteiro MPM, Goés CVA, Farias AGP; Analysis
and interpretation of the data: Rocha EA, Pereira FTM, Abreu JS,
Lima JWO, Monteiro MPM, Rocha Neto AC; Statistical analysis:
Rocha EA, Lima JWO, Quidute ARP; Obtaining financing: Rocha
EA; Writing of the manuscript: Rocha EA, Abreu JS, Rocha Neto
AC, Quidute ARP, Sobrinho CRMR, Scanavacca MI.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
This study was funded by CAPES and FUNCAP.
Study Association
This article is part of the thesis of Doctoral submitted by
Eduardo Arrais Rocha, from Universidade de São Paulo e
Universidade Federal do Ceará.
References
1.
Tracy CM, Epstein AE, Darbar D, Dimarco JP, Dunbar SB, Estes NA 3rd, et al.
ACCF/AHA/HRS focused update of the 2008 guidelines for device-based
therapy of cardiac rhythm abnormalities: a report of the American College of
Cardiology Foundation/American Heart Association Task Force on Practice
Guidelines. J Am Coll Cardiol. 2012;60(14):1297-313.
10. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, et al;
Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure
(COMPANION) Investigators. Cardiac-resynchronization therapy with or
without an implantable defibrillator in advanced chronic heart failure. N
Engl J Med. 2004;350(21):2140-50.
2. Saxon LA, Ellenbogen KA. Resynchronization therapy for the treatment of
heart failure. Circulation. 2003;108(9):1044-8.
11. Carson P, Anand I, O’Connor C, Jaski B, Steinberg J, Lwin A, et al. Mode
of death in advanced heart failure: the Comparison of Medical, Pacing,
and Defibrillation Therapies in Heart Failure (COMPANION) Trial. J
Am Coll Cardiol. 2005;46(12):2329-34. Erratum in: J Am Coll Cardiol.
2008;51(22):2197.
3. Achilli A, Peraldo C, Sassara M, Orazi S, Bianchi S, Laurenzi F, et al; SCART
Study Investigators. Prediction of response to cardiac resynchronization
therapy: the selection of candidates for CRT (SCART) study. Pacing Clin
Electrophysiol. 2006;29 Suppl 2:S11-9.
4. Foley PW, Leyva F, Frenneaux MP. What is treatment success in cardiac
resynchronization therapy? Europace 2009;11 Suppl 5:v58-65.
12. Mangiavacchi M, Gasparini M, Faletra F, Klersy C, Morenghi E, Galimberti
P, et al. Clinical predictors of marked improvement in left ventricular
performance after cardiac resynchronization therapy in patients with chronic
heart failure. Am Heart J. 2006;151(2):477.e1-477.
5. Gottdiener JS, Bednarz J, Devereux R, Gardin J, Klein A, Manning WJ,
et al; American Society of Echocardiography. American Society of
Echocardiography recommendations for use of echocardiography in clinical
trials. J Am Soc Echocardiogr. 2004;17(10):1086-119.
13. Bonakdar HR, Jorat MV, Fazelifar AF, Alizadeh A, Givtaj N, Sameie N,
et al. Prediction of response to cardiac resynchronization therapy using
simple electrocardiographic and echocardiographic tools. Europace.
2009;11(10):1330-7.
6. Gorcsan J 3rd, Abraham T, Agler DA, Bax JJ, Derumeaux G, Grimm RA, et
al; American Society of Echocardiography Dyssynchrony Writing Group.
Echocardiography for cardiac resynchronization therapy: recommendations
for performance and reporting - a report from the American Society of
Echocardiography Dyssynchrony Writing Group endorsed by the Heart
Rhythm Society. J Am Soc Echocardiogr. 2008;21(3):191-213.
14. Yeim S, Bordachar P, Reuter S, Laborderie J, O’Neill MD, Lafitte S, et
al. Predictors of a positive response to biventricular pacing in patients
with severe heart failure and ventricular conduction delay. Pacing Clin
Electrophysiol. 2007;30(8):970-5.
7. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA, et al.
Recommendations for the evaluation of left ventricular diastolic function by
echocardiography. Eur J Echocardiogr. 2009;10(2):165-93.
8. Boidol J, Średniawa B, Kowalski O, Szulik M, Mazurek M, Sokal A, et al;
Triple-Site Versus Standard Cardiac Resynchronisation Trial (TRUST CRT)
Investigators. Many response criteria are poor predictors of outcomes
after cardiac resynchronization therapy: validation using data from the
randomized trial. Europace. 2013;15(6):835-44.
9. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger
L, et al; Cardiac Resynchronization-Heart Failure (CARE-HF) Study
Investigators. The effect of cardiac resynchronization on morbidity and
mortality in heart failure. N Engl J Med. 2005;352(15):1539-49.
15. Shen X, Nair CK, Aronow WS, Holmberg MJ, Reddy M, Anand K, et al.
A new baseline scoring system may help to predict response to cardiac
resynchronization therapy. Arch Med Sci. 2011;7(4):627-33.
16. Verhaert D, Grimm RA, Puntawangkoon C, Wolski K, De S, Wilkoff BL, et
al. Long-term reverse remodeling with cardiac resynchronization therapy:
results of extended echocardiographic follow-up. J Am Coll Cardiol.
2010;55(17):1788-95.
17. Martinelli Filho M, Baggio Júnior JM, Nishioka SA, Pedrosa A, Torres GG,
Escarião A, et al. Cardiac resynchronization in long-term follow up: analysis
of clinical response predictors. Relampa. 2006;19(1):45-52.
18. Gradaus R, Stuckenborg V, Loher A, Kobe J, Reinke F, Gunia S, et
al. Diastolic filling pattern and left ventricular diameter predict
response and prognosis after cardiac resynchronisation therapy. Heart.
2008;94(8):1026-31.
Arq Bras Cardiol. 2015; 105(4):399-409
408
Rocha et al.
Development of predictive models in CRT
Original Article
19. Kandala J, Altman RK, Park MY, Singh JP. Clinical, laboratory, and pacing
predictors of CRT response. J Cardiovasc Transl Res. 2012;5(2):196-212.
20. Pr aus R , H am an L , Tauchm an M, Pud i l R , B laha V, Par i zek P.
Echocardiographic changes after cardiac resynchronisation therapy. Kardiol
Pol. 2012;70(12):1250-7.
21. Leong DP, Hoke U, Delgado V, Auger D, Witkowski T, Thijssen J, et al. Right
ventricular function and survival following cardiac resynchronisation therapy.
Heart. 2013;99(10):722-8.
22. Nunes Mdo C, Rocha MO, Ribeiro AL, Colosimo EA, Rezende RA, Carmo
GA, et al. Right ventricular dysfunction is an independent predictor of
survival in patients with dilated chronic Chagas’ cardiomyopathy. Int J
Cardiol. 2008;127(3):372-9.
23. Ogunyankin KO, Puthumana JJ. Effect of cardiac resynchronization therapy
on right ventricular function. Curr Opin Cardiol. 2010;25(5):464-8.
24. Aksoy H, Okutucu S, Aytemir K, Kaya EB, Tulumen E, Evranos B, et
al. Improvement in right ventricular systolic function after cardiac
resynchronization therapy correlates with left ventricular reverse
remodeling. Pacing Clin Electrophysiol. 2011;34(2):200-7.
25. Freitas HF, Chizzola PR, Paes AT, Lima AC, Mansur AJ. Risk stratification in a
Brazilian hospital-based cohort of 1220 outpatients with heart failure: role
of Chagas’ heart disease. Int J Cardiol. 2005;102(2):239-47.
26. Linde C, Daubert C, Abraham WT, St John Sutton M, Ghio S, Hassager C,
et al; REsynchronization reVErses Remodeling in Systolic left vEntricular
409
Arq Bras Cardiol. 2015; 105(4):399-409
dysfunction (REVERSE) Study Group. Impact of ejection fraction on the
clinical response to cardiac resynchronization therapy in mil heart failure.
Circ Heart Fail. 2013;6(6):1180-9.
27. Kronborg MB, Mortensen PT, Kirkfeldt RE, Nielsen JC. Very long term followup of cardiac resynchronization therapy: clinical outcome and predictors of
mortality. Eur J Heart Fail. 2008;10(8):796-801.
28. Van Boven N, Bogaard K, Ruiter J, Kimman G, Theuns D, Kardys I, et al.
Functional response to cardiac resynchronization therapy is associated with
improved clinical outcome and absence of appropriate shocks. J Cardiovasc
Electrophysiol. 2013;24(3):316-22.
29. Cleland J, Freemantle N, Ghio S, Fruhwald F, Shankar A, Marijanowski M, et
al. Predicting the long-term effects of cardiac resynchronization therapy on
mortality from baseline variables and the early response a report from the
CARE-HF (Cardiac Resynchronization in Heart Failure) Trial. J Am Coll Cardiol.
2008;52(6):438-45.
30. Rickard J, Cheng A, Spragg D, Cantillon D, Baranowski B, Varma N, et al. A
clinical prediction rule to identify patients at heightened risk for early demise
following cardiac resynchronization therapy. J Cardiovasc Electrophysiol.
2014;25(3):278-82.
31. Van Rees JB, de Bie MK, Thijssen J, Borleffs CJ, Schalij MJ, van Erven
L. Implantation-related complications of implantable cardioverterdefibrillators and cardiac resynchronization therapy devices: a
systematic review of randomized clinical trials. J Am Coll Cardiol.
2011;58(10):995-1000.
Back to the Cover
Original Article
Changes in Medical Management after Coronary CT Angiography
Vânia Mairi Naue, Gabriel Camargo, Letícia Roberto Sabioni, Ronaldo de Souza Leão Lima, Maria Eduarda
Derenne, Andréa Rocha de Lorenzo, Monica Di Calafiori Freire, Clério Francisco Azevedo Filho, Elmiro Santos
Resende, Ilan Gottlieb
CDPI - Clínica de Diagnóstico por Imagem
Abstract
Introduction: Coronary computed tomography angiography (CCTA) allows for non-invasive coronary artery disease (CAD)
phenotyping. There are still some uncertainties regarding the impact this knowledge has on the clinical care of patients.
Objective: To determine whether CAD phenotyping by CCTA influences clinical decision making by the prescription of
cardiovascular drugs and their impact on non-LDL cholesterol (NLDLC) levels.
Methods: We analysed consecutive patients from 2008 to 2011 submitted to CCTA without previous diagnosis of CAD
that had two serial measures of NLDLC, one up to 3 months before CCTA and the second from 3 to 6 months after.
Results: A total of 97 patients were included, of which 69% were men, mean age 64 ± 12 years. CCTA revealed that
18 (18%) patients had no CAD, 38 (39%) had non-obstructive (< 50%) lesions and 41 (42%) had at least one obstructive
≥ 50% lesion. NLDLC was similar at baseline between the grups (138 ± 52 mg/dL vs. 135 ± 42 mg/dL vs. 131 ± 44 mg/dL,
respectively, p = 0.32). We found significative reduction in NLDLC among patients with obstrctive lesions (-18%,
p = 0.001). We also found a positive relationship between clinical treatment intensification with aspirin and cholesterol
reducing drugs and the severity of CAD.
Conclusions: Our data suggest that CCTA results were used for cardiovascular clinical treatment titration, with especial
intensification seen in patients with obstructive ≥50% CAD. (Arq Bras Cardiol. 2015; 105(4):410-417)
Keywords: Coronary Artery Disease; Diagnostic Imaging; Atherosclerosis/physiopathology; Therapeutics.
Introduction
Cardiovascular clinical treatment titration in patients
without prior diagnosis of coronary artery disease (CAD) is
based on patient cardiovascular risk estimated by clinical
variables, being generally indicated in patients classified as
high risk1.
Coronary computed tomography angiography (CCTA)
is generally used with high accuracy2 for obstructive CAD
diagnosis and, as it allows three-dimensional evaluation of the
wall vessel, it also provides non-obstructive CAD visualization,
showing good correlation with intravascular ultrasound3.
The main therapeutic intervention used in patients with
atherosclerosis, as a means of primary prevention of ischemic
events, are cholesterol-lowering drugs (CLD)4. However, the
number needed to treat (NNT) varies according to the studied
population and low cardiovascular risk patients benefit less than
those at high cardiovascular risk. However, the potential for
adverse effects remains similar1,5,6. According to the variation
Mailing Address: Vania Mairi Naue •
Rua H, 53, Parque Dez. Postal Code 69050-230, Manaus, AM – Brasil
E-mail: [email protected], [email protected]
Manuscript received August 23, 2014; revised manuscript May 06, 2015;
accepted May 06, 2015.
DOI: 10.5935/abc.20150088
410
of baseline risk, the NNT may vary from 24 to 549 treated
patients, for the reduction of an event5.
Studies show that approximately 20% to 30% of
asymptomatic patients considered at low cardiovascular risk
(event rate less than 10% in ten years) have atherosclerosis
in the coronary computed tomography angiography
(CCTA)7,8 and it is known that these findings are associated
with increased incidence of cardiovascular events,
independently from and in addition to the clinical risk
factors9,10. However, it is still uncertain how doctors use
the results of CCTA in the clinical treatment titration of
their patients.
This study aimed to evaluate the changes in both the
prescription and plasma cholesterol levels in the short
term, after a CCTA assessment in patients with no prior
diagnosis of CAD, according to the severity of CAD found
at the examination.
Methods
A retrospective and analytical cohort was analyzed,
and the project was approved by the Research Ethics
Committee of HUCFF/FM/UFRJ, under protocol number
27341114.7.0000.5257.
All patients (123) submitted to CCTA between the years
2008 and 2011 in a cardiac imaging laboratory in Rio
de Janeiro, with no prior diagnosis of CAD (i.e. without
Naue et al.
Impact of Coronary CT angiography on clinical treatment
Original Article
myocardial revascularization history or AMI and no previous
CCTA) and had cholesterol measurement recorded at
two different times: one up to three months before the
CCTA (index measurement), followed by a second sample
taken from three to six months after the CCTA (follow-up
measurement) were included in this analysis. This period
was chosen due to the homogeneity of image acquisition
protocols used at that time.
In this institution, a physician from the team performs an
interview with the patient prior to the examination, in which
information such as anthropometric data, indication for the
examination, risk factors, current medications and previous
examinations is recorded. Access to the existing clinic database
was requested for this study.
The analyzed items were: gender, age, CCTA indication
(asymptomatic, typical pain, atypical pain or dyspnea), risk
factors (hypertension, diabetes, dyslipidemia, sedentary
lifestyle, smoking and family history), medications being used
in the index consultation and at the second consultation, such
as antiplatelet drugs and CLD and the cholesterol levels both
at the index and the second consultations. CLD were defined
as any drug of the statins or fibrates classes.
Patients whose medical records did not provide the
necessary data for this analysis, such as current medication
or present risk factors were excluded from the analysis.
Additionally patients whose imaging tests had inadequate
quality for analysis in three or more coronary segments were
also excluded.
The primary outcome of this study was non-LDL
cholesterol (NLDLC) reduction after assessment by
CCTA in the pre-specified period (three to six months).
The NLDLC was considered as the sum of VLDL cholesterol
and LDL cholesterol. It was decided to restrict the follow‑up
to such short period in order to minimize the influence
of factors rather than the CCTA outcome on therapeutic
decision‑making.
As a secondary outcome, the change in medications
prescription after the CCTA outcome. was assessed.
CCTA images were acquired using 256-channel devices
(BrillianceTIC, Philips Healthcare®, Cleveland, Ohio) or
one of the two 64-channel scanners (Brilliance64, Philips
Healthcare®, Cleveland, Ohio, SomatomSensation 64,
Siemens Healthcare®, Erlangen). For CCTA acquisition,
venous and oral beta-blockers were used aiming to reduce HR
to less than 60 bpm. Isosorbide dinitrate, 0.4 mg, sublingually
was also administered to all patients without contraindications,
3 to 5 minutes prior to image acquisition.
Image analysis was performed by a single expert that had
broad experience with the method. The coronary plaques
were defined as the presence of image with soft tissue
density ≥ 1 mm2 compatible with coronary atheromatosis,
whereas the degree of luminal stenosis was defined as the
ratio between the smallest luminal diameter at the lesion and
the reference diameter closest to the lesion.
Patients were classified according to the highest degree
of coronary stenosis found, considering: I - no plaque;
II - non‑obstructive plaques only (< 50% in stenosis); III - at
least one obstructive plaque (≥ 50% in stenosis). To measure
the cholesterol-lowering effects, a positive CCTA was considered
the one with any evidence of coronary atherosclerosis.
Statistical analysis
The following software programs were used for data
processing: SPSS version 19.0 and Microsoft Excel 2000©
(9.0.2812).
To calculate sample size, we considered a difference
of 30% in LDL cholesterol between patients with positive
(estimated at 30% of the sample) and negative CCTA (70%
of the sample). The estimated “n” was 90 patients for an
alpha error of 0.05 and beta of 0.25.
Quantitative data showed normal distribution through
the Kolmogorov-Smirnov test with a significance level of 5%.
Continuous variables were expressed as mean ± standard
deviation and were compared using paired and unpaired
Student’s t test, as appropriate. Categorical variables were
expressed as amounts and proportions and were compared
using the Chi-square and Fisher tests, when appropriate.
p values < 0.05 were considered significant.
Patients were divided into three groups: without CAD,
non-obstructive CAD (< 50% in stenosis) and obstructive
CAD (≥ 50% in stenosis). Statistical analysis was carried out
for each group separately and the two periods were compared
by paired-t test.
Results
Of a total of 123 patients that had two cholesterol
measurements recorded in the proposed time period, 24 were
excluded due to incomplete filling out of medical records and
two due to poor quality of the images, resulting in 97 patients
included in the analysis, of which 67 (69%) were men.
The mean age was 64 ± 12 years. Nineteen percent had no
risk factor; 15% had only one risk factor; 35% had two or three
risk factors; and 31% had four or more risk factors for CAD.
CCTA was performed to assess pain with angina
characteristics in 10% of patients; atypical pain in 16%;
dyspnea or decreased functional capacity of 23%; and 51%
of patients were asymptomatic. The clinical characteristics are
described in Table 1. CCTA was normal in 18 (18%) patients,
showed no obstructive CAD < 50% in 38 (39%) patients and
obstructive CAD ≥ 50% in 42 (43%) patients.
Cholesterol levels
NLDLC significantly decreased from 136 ± 44 mg/dL in the
first to 117 ± 38 mg/dL in the follow-up visit (p = 0.007), a 14%
decrease in the average of the general population (Chart 1).
Between the index and the follow-up visit, the variation
in NLDLC in the group with negative CCTA was 4%
(137 ± 53 mg/dL to 132 ± 39 mg/dL, p = 0.7), in the group
with non‑obstructive CCTA was 10% (135 ± 42 mg/dL
to 121 ± 39 mg/dL, p = 0.07) and the in group in which
CCTA showed obstructive lesions was 18% (130 ± 44 mg/dL
to 107 ± 36 mg/dL, p = 0.001). There was no significant
difference in NLDLC values between the different groups of
CCTA in the index visit (p = 0.3).
Arq Bras Cardiol. 2015; 105(4):410-417
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Impact of Coronary CT angiography on clinical treatment
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Table 1 – Population characteristics of individuals submitted to CCTA
Variables
Age (years)
64.2 ± 12
Gender
Male
67(69)
Female
30(31)
Hypertension
57(58)
Risk Factors
DM
23(24)
DLP
57(58)
Family history
35(36)
Smoking
13(13)
Sedentary life style
17(17)
Without pain
50 (51)
Indications of CCTA
Typical angina
10(10)
Atypical angina
16(16)
Dyspnea and exercise intolerance
11(11)
DM: Diabetes mellitus; DLP: Dyslipidemia; CCTA: Coronary computed tomography angiography.
Chart 1 – Difference of NLDLC levels pre and post-CCTA when divided into categories according to CAD severity (without CAD, lesions < 50% and lesions ≥ 50%).
CAD: Coronary artery disease; NLDLC: Non-LDL cholesterol.
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Of the 42 individuals that had lesions ≥ 50% in stenosis,
32 (76%) showed LDL values < 100 mg/dL at the second
visit (Chart 2).
This study allowed to evaluate, in the real world and in
the short term, the impact of CCTA results on drug therapy,
evaluating trends in cholesterol levels and the use of
medications shortly after the CCTA results.
Medication use
The analysis of this impact on clinical therapy is
relevant, as the benefit of antiplatelet agents and CLD
is directly associated with the patient’s cardiovascular
risk. It has been demonstrated that in an asymptomatic
population with zero calcium score, the NNT with aspirin
is approximately two thousand individuals to prevent one
major cardiovascular event, while the number needed to
harm (NNH) is 442 individuals, demonstrating a much
greater risk in the prescription of aspirin than its benefits15.
A cost-effectiveness analysis showed that the aspirin is
only cost-effective in men with clinical risk in ten years
greater than 10% and in women when the risk is > 15%16.
In our study, aspirin was started in 5% of patients after a
completely normal CCTA result, which probably would not
be indicated, considering that the annual risk is < 0.1% of
combined coronary events9,16,17. Conversely, we observed
that 22% of patients with positive CCTA (obstructive or not)
in our study started aspirin therapy.
Considering only the 64 (65%) patients that did not use
the CLD in the index visit, 28 (43%) started using them after
CCTA, when the latter showed at least one coronary segment
with lesion (obstructive or not) versus 2 (3%) patients with
normal CCTA (p < 0.05). Considering only the 34 patients
that used CLD in the index visit, 8 (23%) had negative CCTA
(of which 3 discontinued use of CLD) and 5 had at least
one coronary segment with lesion (obstructive or not) and
discontinued these drugs. Chart 3 illustrates the dynamics
between treatment with CLD and CCTA results.
Aspirin use was started after the normal CCTA result in 2
(11%) patients and in 17 (21%) patients with positive CCTA
(Chart 4). Importantly, 15 (36%) patients with obstructive lesions
were not using any antiplatelet agents on the second visit.
The combined use of aspirin and CLD was started at 0%, 2%
and 19% of patients with negative CCTA, with non-obstructive
lesions and lesions ≥ 50%, respectively (p = 0.004), and only
one of the two drugs alone in 18%, 24% and 38% respectively
(p = 0.006).
Discussion
CAD phenotyping by CCTA has a relevant prognostic
impact and improves risk classification for cardiovascular
events when compared to the classic risk factors11-14.
The proportion of patients that initiated therapy with CLD
has increased significantly as the severity of CAD increased
(normal CCTA = 12%; non-obstructive CAD = 24%;
CAD ≥ 50% = 43%), demonstrating that in the real world
there is an agreement between therapy intensity and the
severity of CAD lesions. There was no reduction in NLDLC in
patients with normal CCTA, which occurred in patients with
obstructive lesions ≥ 50%. There was a NLDLC decrease trend
Chart 2 – Changes in the decrease of total cholesterol levels, its fractions and triglycerides, pre and post-CCTA. NLDLC: Non-LDL cholesterol; HDL: High-density
lipoprotein; NHDL: Non-high-density lipoprotein; LDL: Low-density lipoprotein; VLDL: Very low-density lipoprotein.
Arq Bras Cardiol. 2015; 105(4):410-417
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Chart 3 – Changes in therapy with cholesterol-lowering drugs, according to CAD severity, demonstrated by CCTA (without CAD, lesions < 50% and lesions ≥ 50%).
CAD: Coronary artery disease; CLD: Chodesterol lowering drugs.
Chart 4 – Aspirin prescription as primary preventive therapy, pre and post-CCTA. CAD: Coronary artery disease; ASA: Aspirim.
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in patients with non-obstructive lesions, and these data are
corroborated by other studies 9,15,18,19. Among the 42 patients
with obstructive CAD ≥ 50%, 12 (29%) maintained the
prescription of statin and/or aspirin and 24 (57%) started the
use of the two drugs or added one of the two to previous
therapy, after the CCTA result, corroborating the results of
other published studies19-23.
A meta-analysis24 involving 170,000 patients showed that
a 1-mmol/L decrease in LDL cholesterol was able to reduce
the risk of cardiovascular events by 20%. We observed in
this study that 28 (29%) showed LDL decrease > 1 mmol/L,
which implies a reduction of cardiovascular risk in this group.
The reduction in all lipid fractions, except HDL,
demonstrates not only the potent LDL-lowering effect of the
CLD, as well as reductions more related to changes in dietary
habits, as demonstrated by the reduction in triglycerides 1,4,19.
Of all patients considered at high risk by CCTA
(lesion ≥ 50%), 32 (76%) reached the LDL target < 100 mg/dL.
This result contrasts with the data collected by Vacanti et
al.25in a Brazilian population, in which it was found that only
30% of patients had LDL values within the Guideline’s targets.
The stratification of cardiovascular risk made by visualization
of coronary atherosclerosis has previously demonstrated to
have greater impact on medication adherence and change
in clinical management than the risk stratification by clinical
scores20,21,26-29. The results of this study indirectly corroborate
that, showing patients with higher atherosclerotic disease
severity have higher reduction in cholesterol levels.
Hulten et al.26 recently addressed the impact of CCTA
findings on drug therapy in a study that evaluated 2,839 patients
with a mean follow-up of 3.6 years, and found that after the
CCTA examination there was an increase in the prescription
of aspirin even in the group without CAD (10‑46% vs.
17%-72% vs. 25%-89%, p = 0.001). This study also found
statin prescription intensification after the CCTA results.
After the CCTA results, 36% of patients without CAD were using
CLD and 18% had been prescribed therapy intensification;
in patients with non-obstructive lesions < 50%, 72% were
using CLD and in 42%, prescription intensified occurred; in
patients with lesions > 50% in stenosis, of the total 90% in
use of statin, there was an intensification of 63%.
Among the assessed patients, two of them are especially
illustrative for the analysis of the results. The first one, aged
54, had fatigue on moderate exertion, hypertension and
did not use statins or aspirin. He had NLDLC of 201 mg/dL
in the index visit. The CCTA disclosed 50% -70% lesion in
the middle third of the Anterior Descending Artery (ADA).
In the follow-up assessment, the patient was using aspirin
and CLD and the NLDLC had decreased to 140 mg/dL.
The second patient, aged 66 years, had atypical chest pain,
diabetes, dyslipidemia, was hypertensive and sedentary,
was using aspirin and CLD in the index visit had a NLDLC
of 120 mg/dL. The CCTA disclosed a 50% -70% lesion in
the proximal third of the ADA. At the second assessment,
the NLDLC had decreased to 100 mg/dL with medication
maintenance. The two patients were at high risk for
cardiovascular events, but in the second case, there
was not so marked decrease in NLDLC values, probably
because the patient was already undergoing medical
treatment and the medication was only optimized after
CCTA the result.
Study limitations
Some limitations should be considered in our study,
which was observational and retrospective, performed at a
single diagnostic imaging center, with two CTs of different
manufacturers, with a relatively small sample. Because we
selected patients with two sequential cholesterol measurements,
there may have been some selection bias, preferably excluding
patients that had not started treatment with CLD and therefore
had no clinical need to collect a new blood sample for lipid
level measurement. Therefore, the results are more relevant for
the analysis of factors involved in the prescription of antiplatelet
agents and CLD than for the lack of their indication.
Conclusions
The severity of CAD positively correlated with the decrease
in cholesterol levels and more frequent prescription of
antiplatelet agents and CLD. These data suggest that the CCTA
result can influence drug treatment approach in the short term
in the real world.
Author contributions
Conception and design of the research: Camargo
G, Derenne MR, Resende ES, Gottlieb I; Acquisition of
data: Naue VM, Freire MDC, Sabioni LR; Analysis and
interpretation of the data: Naue VM, Camargo G, de Lorenzo
AR, Lima RSL, Gottlieb I; Statistical analysis: Azevedo
Filho CF, Gottlieb I; Writing of the manuscript: Naue VM,
Camargo G, Gottlieb I; Critical revision of the manuscript
for intellectual content: Gottlieb I.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This article is part of the thesis of master submitted by
Vânia Mairi Naue, from Universidade Federal de Uberlândia.
Arq Bras Cardiol. 2015; 105(4):410-417
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References
1. Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. Executive Summary of the Third Report of the
National Cholesterol Education Program (NCEP) expert panel on detection,
evaluation, and treatment of high blood cholesterol in adults (Adult
Treatment Panel III). JAMA. 2001;285(19):2486-97.
2.
3.
4.
Dewey M, Vavere AL, Arbab-Zadeh A, Miller JM, Sara L, Cox C, et al. Patient
characteristics as predictors of image quality and diagnostic accuracy of
MDCT compared with conventional coronary angiography for detecting
coronary artery stenoses: CORE-64 Multicenter International Trial. AJR Am
J Roentgenol. 2010;194(1):93-102.
Leber AW, Knez A, von Ziegler F, Becker A, Nikolaou K, Paul S, et al. Quantification
of obstructive and nonobstructive coronary lesions by 64-slice computed
tomography: a comparative study with quantitative coronary angiography and
intravascular ultrasound. J Am Coll Cardiol. 2005;46(1):147-54.
Stone NJ, Robinson J, Lichtenstein AH, Merz CNB, Blum CB, Eckel RH, et al;
American College of Cardiology/American Heart Association Task Force on
Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood
cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of
the American College of Cardiology/American Heart Association Task Force
on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S1-45. Erratum
in: Circulation. 2014;129(25 Suppl 2):S46-8.
5. Blaha MJ, Budoff MJ, DeFilippis AP, Blankstein R, Rivera JJ, Agatston A, et
al. Associations between C-reactive protein, coronary artery calcium, and
cardiovascular events: implications for the JUPITER population from MESA,
a population-based cohort study. Lancet. 2011;378(9792):684-92.
6. National Institute for Health and Care Excellence (NICE). Statins for the
prevention of cardiovascular events. London; 2015. [Accessed in 2014 May
10]. Available from: http://www.publications.nice.org.UK/statins-for-theprevention-of-cardiovascular-events-7a94
7. Choi EK, Choi SI, Rivera JJ, Nasir K, Chang SA, Chun EJ, et al. Coronary
computed tomography angiography as a screening tool for the detection
of occult coronary artery disease in asymptomatic individuals. J Am Coll
Cardiol. 2008;52(5):357-65.
8. Greenland P, Smith SC Jr, Grundy SM. Improving coronary heart disease
risk assessment in asymptomatic people: role of traditional risk factors and
noninvasive cardiovascular tests. Circulation. 2001;104(15):1863-7.
9. Min JK, Shaw LJ, Devereux RB, Okin PM, Weinsaft JW, Russo DJ, et al.
Prognostic value of multidetector coronary computed tomographic
angiography for prediction of all-cause mortality. J Am Coll Cardiol.
2007;50(12):1161-70.
10. Min JK, Dunning A, Lin FY, Achenbach S, Al-Mallah M, Budoff MJ, et al;
CONFIRM Investigators. Age-and sex-related differences in all-cause
mortality risk based on coronary computed tomography angiography
findings: results from the International Multicenter CONFIRM (Coronary CT
Angiography Evaluation for Clinical Outcomes: an international multicenter
registry) of 23,854 patients without known coronary artery disease. J Am Coll
Cardiol. 2011;58(8):849-60.
11. Gottlieb I, Mansur Filho J, Costa Lima JA. Estratificação de risco cardiovascular
no paciente assintomático por tomografia computadorizada cardíaca de
múltiplos detectores. Rev SOCERJ. 2006;19(4):339-46.
12. Schlett CL, Banerji D, Siegel E, Bamberg F, Lehman SJ, Ferencik M, et al.
Prognostic value of CT angiography for major adverse cardiac events in patients
with acute chest pain from the emergency department: 2-year outcomes of
the ROMICAT trial. JACC Cardiovasc Imaging. 2011;4(5):481-91.
13. Prazeres CE, Cury RC, Carneiro AC, Rochitte CE. Angiotomografia de
coronárias na avaliação da dor torácica aguda na sala de emergência. Arq
Bras Cardiol. 2013;101(6):562-9.
14. Shareghi S, Ahmadi N, Young E, Gopal A, Liu ST, Budoff MJ. Prognostic
significance of zero coronary calcium scores on cardiac computed
tomography. J Cardiovasc Comput Tomogr. 2007;1(3):155-9.
416
Arq Bras Cardiol. 2015; 105(4):410-417
15. Miedema MD, Duprez DA, Misialek JR, Blaha MJ, Nasir K, Silverman MG,
et al. Use of coronary artery calcium testing to guide aspirin utilization for
primary prevention: estimates from the multi-ethnic study of atherosclerosis.
Circ Cardiovasc Qual Outcomes. 2014;7(3):453-60.
16. Greving JP, Buskens E, Koffijberg H, Algra A. Cost-effectiveness of Aspirin
treatment in the primary prevention of cardiovascular disease events in
subgroups based on age, gender, and varying cardiovascular risk. Circulation.
2008;117(22):2875-83.
17. Sarwar A, Shaw LJ, Shapiro MD, Blankstein R, Hoffmann U, Cury RC, et al.
Diagnostic and prognostic value of absence of coronary artery calcification.
JACC Cardiovasc Imaging. 2009;2(6):675-88.
18. Schwartz J, Allison MA, Rifkin DE, Wright CM. Influence of patients’ coronary
artery calcium on subsequent medication use patterns. Am J Health Behav.
2012;36(5):628-38.
19. Nasir K, McClelland RL, Blumenthal RS, Goff DC Jr, Hoffmann U,
Psaty BM, et al. Coronary artery calcium in relation to initiation and
continuation of cardiovascular preventive medications. The Multi-Ethnic
Study of Atherosclerosis (MESA). Circ Cardiovasc Qual Outcomes.
2010;3(3):228-35.
20. Xavier HT, Izar MC, Faria Neto JR, Assad MH, Rocha VZ, Sposito AC;
Sociedade Brasileira de Cardiologia. V Diretriz brasileira de dislipidemias e
prevenção da aterosclerose. Arq Bras Cardiol. 2013;101(4 Supl.1):1-22.
21. McEvoy JW, Blaha MJ, Nasir K, Yoon YE, Choi EK, Cho IS, et al. Impact
of coronary computed tomographic angiography results on patient
and physician behavior in a low-risk population. Arch Intern Med.
2011;171(14):1260-8.
22. LaBounty TM, Devereux RB, Lin FY, Weinsaft JW, Min JK. Impact of coronary
computed tomographic angiography findings on the medical treatment
and control of coronary artery disease and its risk factors. Am J Cardiol.
2009;104(7):873-7.
23. Blankstein R, Murphy MK, Nasir K, Gazelle GS, Batlle JC, Al-Mallah M, et
al. Perceived usefulness of cardiac computed tomography as assessed by
referring physicians and its effect on patient management. Am J Cardiol.
2010;105(9):1246-53.
24. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al;
Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more
intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000
participants in 26 randomised trials. Lancet. 2010;376(9753):1670-81.
25. Vacanti LJ, Santos SC, Fujita AM, Lima DS, Lopes AF, Vetorazi R, et al. A baixa
taxa de obtenção da meta do LDL- colesterol numa população de baixa
renda. Arq Bras Cardiol. 2005;85(3):162-5. Erratum in: Arq Bras Cardiol.
2005;85(4):302.
26. Hulten E, Bittencourt MS, Singh A, O’Leary D, Christman MP, Osmani W, et
al. Coronary artery disease detected by coronary computed tomographic
angiography is associated with intensification of preventive medical therapy
and lower low-density lipoprotein cholesterol. Circ Cardiovasc Imaging.
2014;7(4):629-38.
27. Cheezum MK, Hulten EA, Smith RM, Taylor AJ, Kircher J, Surry L, et al.
Changes in preventive medical therapies and CV risk factors after CT
angiography. JACC Cardiovasc Imaging. 2013;6(5):574-81.
28. Rozanski A, Gransar H, Shaw LJ, Kim J, Miranda-Peats L, Wong ND, et
al. Impact of coronary artery calcium scanning on coronary risk factors
and downstream testing the EISNER (Early Identification of Subclinical
Atherosclerosis by Noninvasive Imaging Research) prospective randomized
trial. J Am Coll Cardiol. 2011;57(15):1622-32.
29. Taylor AJ, Bindeman J, Feuerstein I, Le T, Bauer K, Byrd C, et al. Communitybased provision of statin and aspirin after the detection of coronary artery
calcium within a community-based screening cohort. J Am Coll Cardiol.
2008;51(14):1337-41.
Naue et al.
Impact of Coronary CT angiography on clinical treatment
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Back to the Cover
Review Article
A Systematic Review on Sleep Duration and Dyslipidemia in
Adolescents: Understanding Inconsistencies
Gabriela de Azevedo Abreu, Laura Augusta Barufaldi, Katia Vergetti Bloch, Moyses Szklo
Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ – Brazil
Introduction
Although many questions about the role of sleep remain
unanswered, it is known that sleep is not only a physiological
function, but also performs an important role in promoting
growth, maturation and general health of children and
adolescents1, contributing significantly to cognitive, emotional
functions and school performance2. Currently, there is a
tendency for the young population to have irregular sleeping
hours, with differences in bed and wake-up times between
weekdays and weekends, especially as they get older2-4.
There is a growing interest about the impact of sleep and
its disorders on regulation of inflammatory processes and
morbidities, particularly in the context of metabolic and
cardiovascular diseases (CVD) and their complications1.
In children and adolescents, cross-sectional 5-7 and
prospective8,9 studies have shown an association between
overweight or obesity and few hours of sleep. In adults,
there is evidence supporting this association, as well
as correlations with insulin resistance, diabetes and
cardiovascular diseases10-15.
Few hours of sleep can also play a role in the etiology of
a key risk factor to CVD, dyslipidemia12,14,15. Physiologically,
sleep reduction is associated with hormonal alterations
that may promote the development of an atherogenic
lipid profile, including increase of cortisol and ghrelin and
reduction of leptin levels, in addition to sympathovagal
responses16-18. In order to obtain more information about the
association between lipid metabolism alterations and sleep
duration specifically in adolescents, we have performed a
systematic review of the literature.
Methods
This systematic review was based on the guidelines of
the Preferred Reporting Items for Systematic Reviews and
Meta‑analyses (PRISMA) statement19.
The search was performed in the electronic databases
Medline via Pubmed20 Lilacs21, Web of Science22, Scopus23
and Adolec 24.
Keywords
Sleep; Dyslipidemias; Adolescent; Review.
Mailing Address: Gabriela de Azevedo Abreu •
Universidade Federal do Rio de Janeiro
Avenida Horácio Macedo, S/N – Cidade Universitária. Postal Code 21941-598,
Rio de Janeiro, RJ, Brasil, Rio de Janeiro, RJ – Brazil
E-mail: [email protected]
Manuscript received January 18, 2015; revised manuscript June 29, 2015;
accepted July 01, 2015.
DOI: 10.5935/abc.20150121
418
Selection of the descriptors used in the review process was
made through MeSH (Pubmed’s Medical Subject Headings).
The search was performed in English, using three concept
blocks: the first with terms related to sleep (sleep); the second
with terms related to adolescence (adoles*, teen*, student*,
youth, young); and the third with terms related to lipids (lipid*,
lipemia*, cholesterol, HDL, LDL, triglyceride*, lipoprotein*,
hypercholesterolemia*, hypercholesteremia*, dyslipidemia*,
dyslipoproteinemia*, hyperlipidemia*, hyperlipemia*, “high
density lipoprotein cholesterol”, “low density lipoprotein
cholesterol”). The Boolean operator “OR” was used for the
combination of the descriptors within each block and the
Boolean operator “AND” was used to combine the blocks
amongst themselves. The truncation of terms was applied
when necessary. No search limits were used for date, language,
study design or sample size. The search was carried out in
August 2014, contemplating articles published up to that
date. Table 1 shows the search strategy used in each database.
Criteria for article inclusion in the systematic review were
as follows: (a) studies on adolescents older than 10 years
old; (b) studies that evaluated the association between sleep
duration in hours and any lipid marker; (c) original research
article. Articles evaluating any kind of sleep-related disorder,
review studies, and experimental studies with animals were
excluded. It was decided not to include theses, dissertations,
and monographs. We reviewed the bibliographic references
of reviews, systematic reviews, and meta-analyses that were
found in the databases.
The articles were selected by two epidemiologists (GAA
and LAB), initially based on title reading and then on
abstract reading. Of the selected abstracts, the full articles
were reviewed. In case of disagreement between the two
reviewers with regard to the inclusion criteria, the title,
and the abstract or the full article was maintained to be
further evaluated. In case of disagreement with regard to
the inclusion criteria, a third person was consulted.
Data from included articles were extracted independently, in
duplicate (GAA and LAB), using a standard form. After extraction,
data were compared and discussed. We extracted information
about authorship, publication date, study place, population
study, type of study, methods of sleep duration measurement and
lipid profile assessment, sleep duration in hours, lipid markers,
measure of association used to evaluate the correlation between
hours of sleep and lipid profile, and variables used for adjustment
of regression models.
We used an adaptation of the Newcastle-Ottawa (NOS)
Quality Assessment Scale for Case-Control and Cohort
Studies25, from the Ottawa Hospital Research Institute, to
assess the quality of the longitudinal study included in this
review. We also used the same scale adapted by Flynn et al26
to assess the quality of cross-sectional studies.
Abreu et al.
Sleep hours and lipid profile in adolescents
Review Article
Table 1 – Search strategy used for each database
Pubmed
(sleep*[Title/Abstract] AND (adoles* OR teen* OR student* OR youth OR young[Title/Abstract]) AND (lipid* OR lipemia* OR
cholesterol OR HDL OR LDL OR VLDL OR triglyceride* OR lipoprotein* OR hypercholesterolemia* OR hypercholesteremia* OR
dyslipidemia* OR dyslipoproteinemia* OR hyperlipidemia* OR hyperlipemia* OR "high density lipoprotein cholesterol" OR "low
density lipoprotein cholesterol"[Title/Abstract]))
Lilacs
sleep$ and (adoles$ OR teen$ OR student$ OR youth OR young) and (lipid$ OR lipemia$ OR cholesterol OR HDL OR LDL OR VLDL
OR triglyceride$ OR lipoprotein$ OR hypercholesterolemia$ OR hypercholesteremia$ OR dyslipidemia$ OR dyslipoproteinemia$ OR
hyperlipidemia$ OR hyperlipemia$ OR "high density lipoprotein cholesterol" OR "low density lipoprotein cholesterol")
Adolec
sleep$ [Words] and adoles$ OR teen$ OR student$ OR youth OR young [Words] and lipid$ OR lipemia$ OR cholesterol OR HDL
OR LDL OR VLDL OR triglyceride$ OR lipoprotein$ OR hypercholesterolemia$ OR hypercholesteremia$ OR dyslipidemia$ OR
dyslipoproteinemia$ OR hyperlipidemia$ OR hyperlipemia$ OR "high density lipoprotein cholesterol" OR "low density lipoprotein
cholesterol" [Words]
Web of Science
(Topic(sleep*) AND Topic(adoles* OR teen* OR student* OR youth OR young) AND Topic(lipid* OR lipemia* OR cholesterol
OR hdl OR ldl OR vldl OR triglyceride* OR lipoprotein* OR hypercholesterolemia* OR hypercholesteremia* OR dyslipidemia*
OR dyslipoproteinemia* OR hyperlipidemia* OR hyperlipemia* OR "high density lipoprotein cholesterol" OR "low density
lipoprotein cholesterol"))
Scopus
(TITLE-ABS-KEY(sleep*) AND TITLE-ABS-KEY(adoles* OR teen* OR student* OR youth OR young) AND TITLE-ABS-KEY(lipid*
OR lipemia* OR cholesterol OR HDL OR LDL OR VLDL OR triglyceride* OR lipoprotein* OR hypercholesterolemia* OR
hypercholesteremia* OR dyslipidemia* OR dyslipoproteinemia* OR hyperlipidemia* OR hyperlipemia* OR "high density lipoprotein
cholesterol" OR "low density lipoprotein cholesterol"))
Due to the great amount of methodological heterogeneity
observed between the assessed studies, a narrative approach
to synthesize the results of studies included in the present
systematic review was considered a better strategy.
Results
The flowchart showing the selection process is shown
in Figure 1. By the end of the evaluation process, of the
859 articles chosen after the removal of duplicates, 25 were
submitted to full evaluation. Seven articles met the inclusion
criteria at the end of the process.
Table 2 shows the relevant characteristics of the selected
studies. Of the seven studies included, only one27 is longitudinal.
The other six studies are cross-sectional. Five of the 7 studies27-31
included students. Sample sizes varied considerably, from 699
in the study by Rey-López et al30 to 14,267 adolescents in the
study by Gangwisch et al27.
All studies used questionnaires to obtain hours of sleep.
The variable “sleep duration” was used as continuous in
three studies27,29,30; whereas the other studies used different
categories to classify sleep duration.
To obtain the lipid profiles, five studies collected venous
blood28,30-33, one collected capillary blood29, and another
used self-reported information27. Five studies measured total
cholesterol28-32 and HDL-cholesterol28-30,32,33, four measured
triglycerides28,30,31,33, and two evaluated LDL-cholesterol28,31.
Almost all studies controlled for gender27,28,30,33 and age27,28,30-33;
waist perimeter was adjusted for in two28,29, physical activity
in four27,30,31,33, Tanner stage in two28,32, maternal level of
education in two31,32, socioeconomic status in two30,31, body
mass index (BMI) in one28, and caloric intake in one33.
The methodological quality assessment of the seven included
studies is shown in Table 3. Only two cross-sectional studies28,31
obtained four points out of six in the bias risk evaluation.
The longitudinal study showed a moderate risk of bias27.
Table 4 shows the main results of the associations found
and the control variables each study used. Considering the
seven studies included, only in three an association was found
between hours of sleep and lipid profile27,28,33. Two studies
found that shorter sleep duration was associated with a worse
lipid profile (total cholesterol and LDL-cholesterol)27,28, and
the results of the third one33 showed that long sleep duration
was associated with high triglyceride levels. The other four
studies29-32 did not find any association.
In four studies 27,29,31,33 the odds ratio was reported,
whereas the other studies reported28,30,32 β coefficients from
regression analysis.
Discussion
The present systematic review showed lack of consistent
evidence regarding the association between sleep duration
and lipid profile in adolescents. Few studies were found
and some had methodological limitations. There was great
heterogeneity regarding the classification and type of
analysis of sleep duration and lipid metabolism markers,
which probably contributed to the inconsistency of the
observed results.
Concerning heterogeneity between studies, this
systematic review included studies that evaluated the
outcome using different methods (self-reported27, capillary
blood sample29, venous blood sample28,30-33) or with different
interval duration between the measure of exposition and
the outcome32.
Gangwisch et al 27 did not exclude adolescents with
dyslipidemia at baseline, thus, the incidence of dyslipidemia
in adolescents could not be ascertained. Moreover, as the
outcome established was self-reported, and the diagnosis of
dyslipidemia depends on access to medical care, a bias may
have occurred if adolescents from different socioeconomic
status have different sleep habits.
Arq Bras Cardiol. 2015; 105(4):418-425
419
Abreu et al.
Sleep hours and lipid profile in adolescents
Review Article
Figure 1 – Flowchart of article selection.
All studies included in this systematic review obtained
information about sleep duration based on questionnaires,
a method frequently used in sleep research because of its
easy application and low cost. However, the validity of the
information obtained through questionnaires is of concern,
particularly when the tools have not been submitted to a
validation process. Adolescents may report only socially
desirable sleeping and waking up hours 34. Although all
studies used questionnaires, sleep duration evaluation was
also heterogeneous: one study asked the parents about the
adolescent´s sleep duration31, one used pre-defined categories
of bedtime and waking-up time32, while the others asked about
sleep duration in an open question27-30,33.
Actigraphy – based on monitoring of activities – has
been established as a valid and reliable method to evaluate
sleep-wake patterns in children, adolescents and adults35,36.
Objective methods for hours of sleep quantification in a
population-based study are difficult to use, particularly
in studies with relatively large samples. Kong et al28 used
actigraphy in only about 7% of their study sample (138 out of
2,053) and demonstrated a reasonable agreement between
actigraphy and adolescents’ self-reports (intra-class correlation
coefficient = 0.72, CI 95%: 0.61-0.80).
In the studies included in this review, duration of sleep
was measured in two different ways, as a continuous27,29,30 or
categorical variable28,31-33. The lack of consensus about the best
420
Arq Bras Cardiol. 2015; 105(4):418-425
cut-off point to define short sleep duration makes it difficult
to compare different studies, which would become easier if
sleep duration were used as a continuous variable.
The present systematic review included a longitudinal
study with important limitations and the cross-sectional
studies showed associations in different directions. It was not
possible to evaluate publication bias, due to the small number
of studies identified. In summary, it is still uncertain whether
there is an association between hours of sleep and lipid profile
in adolescents. Heterogeneity regarding the way sleep hours
were classified and analyzed, as well as the use of different
lipids analytes may have contributed for the inconsistency of
findings. More studies should be conducted on this issue to
clarify the nature of this association and the involved biological
mechanisms. These future studies must be longitudinal, use
sleep duration as a continuous variable and consider the role
of potential confounders or effect modifiers. Care must be
taken to avoid over-adjustment, including variables that can
be intermediary in the association between sleep duration and
dyslipidemia such as BMI and food consumption.
Because of its strong association with cardiovascular disease
in adults, it is important to identify and modify factors that
are associated with lipid profile15 in adolescents. If short
sleep duration is responsible for an unfavorable lipid profile,
interventions that improve the quality and duration of sleep
may contribute to decrease long-term cardiovascular risk.
Abreu et al.
Sleep hours and lipid profile in adolescents
Review Article
Table 2 – Main characteristics of the selected studies
Reference/
Country
Gangwisch
et al.27, 2010/
United States
Study design/
Collection date
Study population
Longitudinal
Students,
with national
representativeness
n = 14,257
Wave I: 1994-95
Wave II: 1996
Wave III
2001-02
48.7% male
Age
11-21 years
boys ≅ 15.8
years old
girls ≅ 15.9
years old
Method for
obtaining hours
of sleep
Questionnaire
Exposure
classification
(hours of sleep)
Method for lipid
profile evaluation
Outcome
(alterations of lipids)
Continuous
Questionnaire/
“Has any doctor
ever (between
the 1st and the
3rd wave) said
you have high
cholesterol?”
Dichotomous variable
Yes/No
Blood collection
(TC, TG, HDL, LDL
cholesterol)
Hypercholesterolemia
Comparison of
extreme quintiles
TC ≥ 5.2 mmol/L
LDL ≥ 2.6 mmol/L
HDL <1.0 mmol/L
TG ≥ 1.7 mmol/L
Questionnaire7
Kong et al28, 2011/
Hong Kong
Cross-sectional/
February 2007 –
April 2008
Students*
n = 1,274
12-20 years
old†
Actigraphy in
sub-sample
(n = 138)
Student
n = 3,372
Narang et al , 2012/
Canada
29
Cross-sectional/
2009-2010
Continuous
≅ 14.6 years
old‡
Questionnaire37,38
48.9% male
Azadbakht et al31,
2013/
Iran
Cross-sectional
Data from
CASPIAN III//
Students
n = 5,528
General population
n = 1,481
Berentzen et al32,
2014/
Netherlands
Cross-sectional
49% male
Rey-López et al30,
2014/ Greece,
Germany, Belgium,
France, Hungary,
Italy, Sweden,
Austria, Spain
Cross-sectional/
2006-2007
Lee et al, 2014/
Republic of Korea33
Cross-sectional/
2007-2008
Students
n = 699
52% male
General population
n = 1,187
53% male
<6.5h: 20%
6.5-8h: 40%
>8h: 20%
Quartiles
≅ 14.69
(2.45) years
old boys
Capillary blood
collection without
fasting
(TC and HDL
cholesterol)
TC
Borderline: 4.4-5.1
mmol/L:
High: ≥ 5.2 mmol/L
Non-HDL-cholesterol§
Borderline: > 3.10 to
3.75 mmol/L
High: > 3.75 mmol/L
Questionnaire
< 5h
5 to 8h
> 8h
Blood collection
(TC, TG and LDL)
Abnormal serum lipids
were defined as TC,
LDL-C and or TG
higher than the
level corresponding
to the age and
gender-specific 95th
percentile39
Mean age at
completion
of the
questionnaire
11.4
(± 0.3) years
Mean age at
the moment
of medical
examination
12.7
(± 0.4) years
Questionnaire
7.5–9.5 h
10–10.5 h
(ref. cat.)
11–12.5 h
Blood collection
(TC and HDL
cholesterol)
Continuous variable
(mM)
≅ 14.8 years
old
Questionnaire
Continuous
variable
Blood collection
(TG, TC and HDL
cholesterol)
Continuous variable
(mg/dL)
≅ 15 years
old
Questionnaire
≤ 5h
6-7h
8-9h (ref. cat.)
≥ 10h
Blood collection
(TG and HDL
cholesterol)
Continuous variable
(mg/dL)
≅ 14.7 (2.38)
years old
girls
LDL: Low-density lipoprotein; HDL: High-density lipoprotein; TC: Total cholesterol; TG: Triglycerides; BMI: Body mass index.
number of adolescents evaluated; total number of individuals evaluated in the study is 2,053, including children and adolescents; † does not provide average age
data or distribution by gender only for the adolescents’ group; ‡ does not provide age group;
§
non-HDL cholesterol corresponds to total cholesterol minus HDL cholesterol; //CASPIAN III – Childhood and Adolescence Surveillance and Prevention of Adult
Non-communicable disease.
*
Arq Bras Cardiol. 2015; 105(4):418-425
421
Abreu et al.
Sleep hours and lipid profile in adolescents
Review Article
Table 3 – Evaluation of the risk of bias of the studies included
Kong et al ,
2011/ Hong
Kong
Narang et al29,
2012/ Canada
Azadbakht et
al31, 2013/ Iran
Berentzen
et al32, 2014/
Netherlands
Rey-López et al30,
2014/ Greece,
Germany, Belgium,
France, Hungary,
Italy, Sweden,
Austria, Spain
Sample
representativeness
0
0
1
0
0
1
0
Definition of
presenting condition
1
1
1
1
1
1
0
Evaluation of
exposure
1
0
0
0
0
0
0
Evaluation of
outcome
2
1
2
2
2
2
0
Nonresponse rate
0
0
0
0
0
0
0
Representativeness
of the exposed
cohort
0
0
0
0
0
0
1
Demonstration that
outcome of interest
was not present at
start of study
0
0
0
0
0
0
0
Comparability of
cohorts
0
0
0
0
0
0
1
Assessment of
outcome
0
0
0
0
0
0
0
Was follow-up
long enough for
outcomes to occur
0
0
0
0
0
0
1
Adequacy of follow
up of cohorts
0
0
0
0
0
0
1
4/6
2/6
4/6
3/6
3/6
3/6
4/9
28
Study
Total
Lee et al33, 2014/
Republic of
Korea
Gangwisch et
al27, 2010/ United
States
Cross-sectional studies (maximum 6 points)
Sample representativeness: yes (1); no (0); not informed (0)
Definition of presenting condition: classification based on two or more lipid markers (1); on only one lipid marker (0)
Evaluation of Exposure (hours of sleep): combination of questionnaire with another evaluation method (1); only questionnaire (0)
Evaluation of Outcome (lipid profile): venous blood (2); capillary blood (1); self-referred (0)
Nonresponse rate: non-respondents described (1); non-described (0)
Cohort studies (maximum 9 points)
Evaluation of Exposure (hours of sleep): combination of questionnaire with another evaluation method (1); only questionnaire (0)
Evaluation of Outcome (lipid profile): venous blood (2); capillary blood (1); self-reported (0)
Representativeness of the exposed cohort (representative of the average): adequately addressed (1); not adequately addressed ⁄ not reported (0)
Demonstration that outcome of interest was not present at start of study: adequately addressed (1); not adequately addressed ⁄ not reported (0)
Comparability of cohorts on the basis of the design or analysis: adequately addressed (1); not adequately addressed ⁄ not reported (0)
Assessment of outcome (independent blind assessment or record linkage): adequately addressed (1); not adequately addressed ⁄ not reported (0)
Was follow-up long enough for outcomes to occur: adequately addressed (1); not adequately addressed ⁄ not reported (0)
Adequacy of follow up of cohorts (complete follow up or subjects lost to follow up unlikely to introduce bias): adequately addressed (1); not adequately addressed ⁄ not reported (0)
422
Arq Bras Cardiol. 2015; 105(4):418-425
Abreu et al.
Sleep hours and lipid profile in adolescents
Review Article
Table 4 – Main results of the studies included in the review
Total
Male
Female
Control variables investigated
OR (CI 95%)
Each hour: 0.87 (0.79-0.96)
OR (CI 95%)
Each hour: 0.91
(0.79‑1.05)
OR (CI 95%)
Each hour: 0.85
(0.75‑0.96)
Age/ gender/ race/ ethnic group/ alcohol/ smoke/
physical activity/ inactivity/ stress/ body weight
β* = -0.160
(p-value = 0.023)
---
---
Age/ sex/ BMI/ waist perimeter/ Tanner stages
(2-3 and 4-5)
---
OR (CI 95%)
<5h = 1
5–8h = 4.00 (0.54–29.94)
> 8h = 5.63 (0.76–41.56)
OR (CI 95%)
< 5h = 1
5–8h = 1.07 (0.31–3.73)
>8h = 1.14 (0.33–3.85)
Age/ socioeconomic status/ parents’ level of
education/ family
history of chronic disease/ sedentary lifestyle/ BMI
---
β (CI 95%)
7.5–9.5 h = -0.15
(-0.35; 0.04)
10–10.5 h = 1
11–12.5 h = -0.06
(-0.17; 0.05)
β (CI 95%)
7.5–9.5 h = -0.01
(-0.22; 0.21)
10–10.5 h = 1
11–12.5 h = -0.06
(-0.16; 0.05)
Age at completion of the questionnaire/ age at
medical examination/ height/ maternal level of
education/ puberty and screen time
β* = -0.122
(p-value = 0.042)
---
---
---
OR (95%CI)
<5h=1
5–8 h = 1.04 (0.30-3.61)
>8 h = 0.97 (0.28–3.30)
OR (95%CI)
<5h=1
5–8 h = 1.36 (0.26–5.05)
>8 h = 0.76 (0.20–2.89)
β* = -0.056
(p-value = 0.061)
---
---
---
β (95% CI)
7.5–9.5 h = 0.03
(-0.07; 0.12)
10–10.5 h = 1
11–12.5 h = 0.02
(-0.04; 0.07)
β(95% CI)
7.5–9.5 h = 0.07
(-0.03; 0.17)
10–10.5 h = 1
11–12.5 h = <0.01
(-0.05; 0.05)
OR (95%CI)
≤ 5 h = 0.79 (0.40 - 1.53)
6-7 h = 0.86 (0.50 - 1.49)
8-9 h = 1
≥ 10 h = 1.03 (0.44 - 2.40)
---
---
β* = 0.060
(p = 0.115)
---
---
Azadbakht et al31, 2013
---
OR (95%CI)
<5h=1
5–8 h = 1.09 (0.41–2.92)
> 8 h = 1.16 (0.44–3.09)
OR (95%CI)
<5h=1
5–8 h = 0.53 (0.22–1.30)
> 8 h = 0.53 (0.22–1.30)
Rey-López et al30, 2014
β (95%CI)
School days: 0.26
(-2.57; 3.09)
Weekends: 0.69
(-1.50; 2.88)
---
---
Age/ gender/ socioeconomic status/
physical activity
OR (95%CI)
≤ 5 h= 1.05 (0.55 - 2.00)
6-7 h= 1.20 (0.79 - 1.83)
8-9 h= 1
≥ 10 h = 2.17 (1.14 - 4.13)
---
---
Age/ gender/ household income/ caloric intake/
physical activity
Total cholesterol
Gangwisch et al27, 2010
Kong et al28, 2011
Azadbakht et al31, 2013
Berentzen et al32, 2014
LDL cholesterol
Kong et al28, 2011
Azadbakht et al , 2013
31
HDL cholesterol
Kong et al28, 201
Berentzen et al31, 2014
Lee et al33, 2014
TG
Kong et al28, 2011
Lee et al , 2014
33
Arq Bras Cardiol. 2015; 105(4):418-425
423
Abreu et al.
Sleep hours and lipid profile in adolescents
Review Article
Continuation
Non-HDL†
Narang et al29, 2012
OR (95%CI)
Each hour
1.03 (0.93-1.13)
First quartile (reference) x
last quartile
0.92 (0.70-1.22)
---
---
β (95%CI)
School days: -0.001 (-0.05;
0.05)
Weekends: 0.009 (-0.03;
0.05)
---
---
---
β(95% CI)
7.5–9.5 h = -0.22 (-0.51;
0.08)
10–10.5 h = 1
11–12.5 h = -0.14 (-0.31;
0.02)
β(95% CI)
7.5–9.5 h = -0.18 (-0.44;
0.08)
10–10.5 h = 1
11–12.5 h = -0.04 (-0.17;
0.09)
Waist perimeter/nutrition/physical activity/sex/
family history of premature cardiovascular
disease in first degree relatives/sleep
disturbance score
TC/HDL-c
Rey-López et al30, 2014
Berentzen et al31, 2014
OR: OPdds ratio; CI: Confidence interval; SD: Standard deviation; LDL: Low-density lipoprotein; HDL: Gigh-density lipoprotein; TC: Total cholesterol; TG: Triglycerides;
BMI: Body mass index; PR: Prevalence ratio.
* β regression coefficient of the multiple regression model to compare groups with the largest and smallest (reference) quintile of the lipid variables in relation to hours
of sleep (group with 20% of individual with shorter sleep duration vs. group with 20% of individual with longer sleep duration.); † non-HDL cholesterol corresponds to
total cholesterol minus HDL cholesterol.
Acknowledgments
We would like to thank Fundação de Amparo à Pesquisa
do Estado do Rio de Janeiro (FAPERJ) for providing a
doctoral fellowship to GAA (process nº E26/100.332/2013).
KVB (process nº 303594/2009-8) and MS process nº
302877/2009-6) were partially supported by CNPq.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
There were no external funding sources for this study.
Author contributions
Conception and design of the research, Analysis and
interpretation of the data and Critical revision of the
manuscript for intellectual content: Abreu GA, Barufaldi LA,
Bloch KV, Szklo M; Acquisition of data: Abreu GA, Barufaldi
LA; Writing of the manuscript: Abreu GA.
Study Association
This article is part of the thesis of Doctoral submitted by
Gabriela de Azevedo Abreu, from Universidade Federal do
Rio de Janeiro.
References
1. Kim J, Hakim F, Kheirandish-Gozal L, Gozal D. Inflammatory pathways in
children with insufficient or disordered sleep. Respir Physiol Neurobiol.
2011;178(3):465-74.
National Sleep Foundation. Adolescente sleep needs and patterns: research
report. Washington, DC; 2000.
Chaput JP, Brunet M, Tremblay A. Relationship between short sleeping hours
and childhood overweight/obesity: results from the ‘Quebec en Forme’
Project. Int J Obes. 2006;30(7):1080-5.
3. Dahl R, Carskadon M. Sleep and its disorders in adolescence. In: Ferber R,
Kryger MH (eds.). Principles and practices of sleep medicine in the child.
Philadelphia: Saunders; 1995. p. 19-27.
7. Chen MY, Wang EK, Jeng YJ. Adequate sleep among adolescents is positively
associated with health status and health-related behaviors. BMC Public
Health. 2006;6:59-66.
4. Iglowstein I, Jenni OG, Molinari L, Largo RH. Sleep duration from infancy
to adolescence: reference values and generational trends. Pediatrics.
2003;111(2):302-7.
8. Agras WS, Hammer LD, McNicholas F, Kraemer HC. Risk factors for
childhood overweight: a prospective study from birth to 9.5 years. J Pediatr.
2004;145(1):20-5.
2.
424
5. Gupta NK, Mueller WH, Chan W, Meininger JC. Is obesity associated with
poor sleep quality in adolescents? Am J Hum Biol. 2002;14(6):762-8.
Arq Bras Cardiol. 2015; 105(4):418-425
6.
Abreu et al.
Sleep hours and lipid profile in adolescents
Review Article
9.
Reilly JJ, Armstrong J, Dorosty AR, Emmett PM, Ness A, Rogers I, et al. Early life
risk factors for obesity in childhood: cohort study. BMJ. 2005;330(7504):1357.
10. Van Cauter E, Holmback U, Knutson K, Leproult R, Miller A, Nedeltcheva
A, et al. Impact of sleep and sleep loss on neuroendocrine and metabolic
function. Horm Res. 2007;67 Suppl 1:2-9.
11. Taheri S. The link between short sleep duration and obesity: we should
recommend more sleep to prevent obesity. Arch Child. 2006;91(11):881-4.
12. Bjorvatn B, Sagen IM, Oyane N, Waage S, Fetveit A, Pallesen S, et al. The
association between sleep duration, body mass index and metabolic
measures in the Hordaland Health Study. J Sleep Res. 2007;16(1):66-76.
13. Choi KM, Lee JS, Park HS, Baik SH, Choi DS, Kim SM. Relationship between
sleep duration and the metabolic syndrome: Korean National Health and
Nutrition Survey 2001. Int J Obes. 2008;32(7):1091-7.
14. Williams CJ, Hu FB, Patel SR, Mantzoros CS. Sleep duration and snoring in
relation to biomarkers of cardiovascular disease risk among women with
type 2 diabetes. Diabetes Care. 2007;30(5):1233-40.
15. Kaneita Y, Uchiyama M, Yoshiike N, Ohida T. Associations of usual sleep
duration with serum lipid and lipoprotein levels. Sleep. 2008;31(5):645-52.
26. Flynn D, Knoedler MA, Hess EP, Murad MH, Erwin PJ, Montori VM, et al.
Engaging patients in health care decisions in the emergency department
through shared decision-making: a systematic review. Acad Emerg Med.
2015;19(8):959-67.
27. Gangwisch JE, Malaspina D, Babiss LA, Opler MG, Posner K, Shen S,
et al. Short sleep duration as a risk factor for hypercholesterolemia:
analyses of the National Longitudinal Study of Adolescent Health. Sleep.
2010;33(7):956-61.
28. Kong AP, Wing YK, Choi KC, Li AM, Ko GT, Ma RC, et al. Associations of sleep
duration with obesity and serum lipid profile in children and adolescents.
Sleep Med. 2011;12(7):659-65.
29. Narang I, Manlhiot C, Davies-Shaw J, Gibson D, Chahal N, Stearne K,
et al. Sleep disturbance and cardiovascular risk in adolescents. CMAJ.
2012;184(17):E913-20.
30. Rey-Lopez JP, de Carvalho HB, de Moraes AC, Ruiz JR, Sjostrom M, Marcos A,
et al. Sleep time and cardiovascular risk factors in adolescents: The HELENA
(Healthy Lifestyle in Europe by Nutrition in Adolescence) study. Sleep Med.
2014;15(1):104-10.
16. Taheri S, Lin L, Austin D, Young T, Mignot E. Short sleep duration is associated
with reduced leptin, elevated ghrelin, and increased body mass index. PLoS
Med. 2004;1(3):e62.
31. Azadbakht L, Kelishadi R, Khodarahmi M, Qorbani M, Heshmat R, Motlagh
ME, et al. The association of sleep duration and cardiometabolic risk factors
in a national sample of children and adolescents: The CASPIAN III Study.
Nutrition. 2013;29(9):1133-41.
17. Spiegel K, Leproult R, L’hermite-Balériaux M, Copinschi G, Penev PD, Van
Cauter E. Leptin levels are dependent on sleep duration: relationships with
sympathovagal balance, carbohydrate regulation, cortisol, and thyrotropin.
J Clin Endocrinol Metab. 2004;89(11):5762-71.
32. Berentzen NE, Smit HA, Bekkers MB, Brunekreef B, Koppelman GH,
De Jongste JC, et al. Time in bed, sleep quality and associations with
cardiometabolic markers in children: the Prevention and Incidence of
Asthma and Mite Allergy birth cohort study. J Sleep Res. 2014;23(1):3-12.
18. Mullington JM, Chan JL, Van Dongen HP, Szuba MP, Samaras J, Price NJ, et
al. Sleep loss reduces diurnal rhythm amplitude of leptin in healthy men. J
Neuroendocrinol. 2003;15(9):851-4.
33. Lee JA, Park HS. Relation between sleep duration, overweight, and
metabolic syndrome in Korean adolescents. Nutr Metab Cardiovasc Dis.
2014;24(1):65-71.
19. Moher D, Liberati A, Tetzlaff J, Altman DG, Altman D, Antes G, et al; PRISMA
Group. Preferred reporting items for systematic reviews and meta-analyses:
the PRISMA statement. Ann Intern Med. 2015;151(4):264-9.
34. Wolfson AR, Carskadon MA, Acebo C, Seifer R, Fallone G, Labyak SE, et
al. Evidence for the validity of a sleep habits survey for adolescents. Sleep.
2003;26(2):213-6.
20. U.S. National Library of Medicine. Home Pubmed. [Internet]. [Acessed in
2015 Jan 8]. Available from: http://www.ncbi.nlm.nih.gov/pubmed
35. Sadeh A, Sharkey KM, Carskadon MA. Activity-based sleep-wake identification:
an empirical test of methodological issues. Sleep. 1994;17(3):201-7.
21. BIREME. Biblioteca Virtual em Saúde (BVS). Lilacs. [Internet]. [Acesso em
2015 Maio 10]. Disponível em: http://www.lilacs.bvsalud.org.
36. Acebo C, Sadeh A, Seifer R, Tzischinsky O, Wolfson AR, Hafer A, et
al. Estimating sleep patterns with activity monitoring in children and
adolescents: how many nights are necessary for reliable measures? Sleep.
1999;22(1):95-103.
22. Thomson Reuters. Web of Science.[Internet]. [Accessed in 2015 Jun 12].
Available from: http://www.apps.webofknowledge.ez67.periodicos.capes.
gov.br/wos.
23. ELSEVIER. Scopus. [Internet]. [Accessed in 2015 Jun 10]. Available from:
http://www.scopus.com.ez67.periodicos.capes.gov.br
24. BIREME. Biblioteca Virtual em Saúde (BVS). Adolec. [Internet]. [Acesso em
2015 maio 10]. Disponível em http://www.adolec.org.br
25. Wells G, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The
Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized
studies in meta-analyses: Ottawa Hospital Research Institute. [Accessed
in 2010 Jun 20]. Available from: http://www.ohri.ca/programs/clinical_
epidemiology/oxford.asp.
37. Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh
Sleep Quality Index: a new instrument for psychiatric practice and research.
Psychiatry Res. 1989;28(2):193-213.
38. Perry CL, Sellers DE, Johnson C, Pedersen S, Bachman KJ, Parcel GS, et al. The
Child and Adolescent Trial for Cardiovascular Health (CATCH): intervention,
implementation, and feasibility for elementary schools in the United States.
Health Educ Behav. 1997;24(6):716-35.
39. Lipid Research Clinics. Population studies data book. Volume 1. NIH
Publication No.80-1527. Washington, DC; US Department of Health and
Human Services; 1980.
Arq Bras Cardiol. 2015; 105(4):418-425
425
Back to the Cover
Viewpoint
Patient Management with Metallic Valve Prosthesis during
Pregnancy and Postpartum Period
Juliane Dantas Seabra Garcez, Vitor Emer Egypto Rosa, Antonio Sergio de Santis Andrade Lopes, Tarso Augusto
Duenhas Accorsi, João Ricardo Cordeiro Fernandes, Pablo Maria Pomerantzeff, Walkiria Samuel Avila, Flavio Tarasoutchi
Instituto do Coração – Hospital das Clínicas – Faculdade de Medicina – Universidade de São Paulo – USP, São Paulo, SP – Brazil
Abstract
Prosthetic thrombosis is a rare complication, but it has
high mortality and morbidity. Young women of childbearing
age that have prosthetic heart valves are at increased risk of
thrombosis during pregnancy due to changes in coagulation
factors. Anticoagulation with adequate control and frequent
follow-up if pregnancy occurs must be performed in order
to prevent complications related to anticoagulant use.
Surgery remains the treatment of choice for prosthetic heart
valve thrombosis in most clinical conditions.
Patients with metallic prosthetic valves have an estimated
5% risk of thrombosis during pregnancy and maternal mortality
of 1.5% related to the event. Anticoagulation with vitamin K
antagonists during pregnancy is related to varying degrees of
complications at each stage of the pregnancy and postpartum
periods. Warfarin sodium crosses the placental barrier and when
used in the first trimester of pregnancy is a teratogenic agent,
causing 1-3% of malformations characterized by fetal warfarin
syndrome and also constitutes a major cause of miscarriage in
10-30% of cases. In the third trimester and at delivery, the use
of warfarin is associated with maternal and neonatal bleeding
in approximately 5 to 15% of cases, respectively. On the other
hand, inadequate anticoagulation, including the suspension
of the oral anticoagulants aiming at fetal protection, carries a
maternal risk of about 25% of metallic prosthesis thrombosis,
particularly in the mitral valve. This fact is also due to the state
of maternal hypercoagulability with activation of coagulation
factors V, VI, VII, IX, X, platelet activity and fibrinogen synthesis,
and decrease in protein S levels.
The Registry of Pregnancy and Cardiac Disease (ROPAC),
assessing 212 pregnant women with metal prosthesis,
showed that prosthesis thrombosis occurred in 10 (4.7%)
patients and maternal hemorrhage in 23.1%, concluding
that only 58% of patients with metallic prosthesis had a
complication-free pregnancy1-7.
Keywords
Heart Valve Prosthesis; Thrombosis; Anticoagulants /
therapeutic use; Pregnancy; Mortality; Abortion, Spontaneous.
Mailing Address: Flavio Tarasoutchi •
Instituto do Coração do Hospital das Clínicas da FMUSP. Avenida Doutor
Enéas de Carvalho Aguiar, 44, Cerqueira Cesar. Postal Code 05403-900, São
Paulo, SP – Brazil
E-mail: [email protected]
Manuscript received March 24, 2015; revised manuscript August 19, 2015;
accepted August 27, 2015.
DOI: 10.5935/abc.20150130
426
There are controversies about the best anticoagulation
regimen during pregnancy, childbirth and postpartum
of women with metallic valve prosthesis. There are no
guidelines about the best single or combined treatment
option considering the presumed risk of thrombosis,
because there is no evidence regarding maternal
effectiveness while taking fetal protection into account.
Current recommendations, based on the literature, have
been the replacement of warfarin sodium in the first
trimester of pregnancy by low-molecular weight heparin
(LMWH) until the 12 th week of pregnancy. After this
gestational age, warfarin is reintroduced until the 36th week
of gestation and then replaced again by LMWH 24 hours
before delivery8. The target INR (International Normalized
Ratio) during pregnancy should be 2.5 to 3.5 (mean 3.0)
when it is mitral prosthesis, and 2.0 to 3.0 when it is aortic
prosthesis, values that give the highest maternal protection
rates (5.7% risk of death or thromboembolism) compared
with heparine8. Published review of pregnant women with
prosthetic outcomes showed that warfarin provides better
protection than heparin as prophylaxis of thromboembolic
events in women with metal prostheses, but with greater risk
of embryopathy9. However, a retrospective, observational
study with 3 anticoagulation regimens: enoxaparin before
6 weeks of pregnancy, between 6‑12 weeks or oral
anticoagulants throughout the pregnancy, showed that
with the use of enoxaparin, thromboembolic complications
were seen in 14.9% and most of them were related to
subtherapeutic doses, verified through the measurement
of anti-factor Xa 10 . The anticoagulation regimen at
subtherapeutic levels is the main cause of valve thrombosis,
being found in up to 93% of cases, regardless of the regimen
used11,12. The risk of thrombosis is probably lower if the
anticoagulant dose is appropriate and varies according to
the type and position of the metal valve, also taking into
consideration the patient’s risk factors.
Data from the literature1,8,9, warn about the inefficiency
of using subcutaneous unfractionated heparin (UFH)
in preventing metal prosthetic valve thrombosis during
pregnancy, due to difficulties in attaining effective
anticoagulation, its control and patient adherence to the
drug. However, in services that choose this alternative,
it is recommended that UFH be initiated at high doses
(17,500-20,000 IU 2xday/subcutaneously) and controlled
by activated partial prothrombin time (aPTT), which should
be twice the control value, remembering that response to
heparin is modified by the physiological state of maternal
hypercoagulability. When the LMWH is selected, the dose
Seabra Garcez et al.
Metal prosthesis during pregnancy and postpartum period
Viewpoint
should be administered every 12 hours, subcutaneously,
based on the control of the anti-factor Xa between
0.8‑1.2 U/ml, which should be determined after 4-6h of use.
Factors that should be taken into account in deciding the best
anticoagulant therapy include: patient preferences, expertise
of the attending physician and availability of medication level
monitoring11-14 (Table 1).
The European Society of Cardiology contraindicates the use
of ASA in addition to anticoagulation in patients with prosthetic
valves, as there is no data in the literature demonstrating its
benefit and safety13. On the other hand, the latest guideline of
American Heart Association/American College of Cardiology
suggests adding 75-110 mg/day of ASA to the anticoagulation
regimen to all patients with metal valves and in patients with
biological valves, anticoagulation should be prescribed in
the first 3 months and after that maintain ASA at a dose of
75-100 mg/day indefinitely. The addition of aspirin reduces
the incidence of embolic phenomena, cardiovascular death
and stroke and the Brazilian Society of Cardiology suggests
its association in patients with high thromboembolic risk (old
prosthesis model in the mitral position, atrial fibrillation, more
than one metal prosthesis)6,15.
The use of new anticoagulants (direct thrombin inhibitors
and Factor Xa oral inhibitors) is formally contraindicated in
patients with metallic prosthetic valve.
In the postpartum period, LMWH should be used with
Anti‑factor Xa control and subsequent interruption after
reaching 3.0 INR with warfarin. During this period, valve
thrombosis should be suspected when patients develop
progressive dyspnea, pulmonary edema, syncope, symptoms
of low cardiac output or hemodynamic instability, after
excluding tachyarrhythmias as the cause, especially in patients
with inadequate anticoagulation. Additionally, an auscultatory
finding that suggests valve thrombosis is the cessation or
muffling of the clicking sound when the prosthesis closes.
Transesophageal echocardiography seems to be the most
sensitive method to confirm the diagnosis16.
The treatment of thrombosis during the puerperal period
should be the one proposed for patients with prosthetic
valve out of the pregnancy and postpartum period, taking
into consideration their clinical condition, thrombus size
and location of the affected prosthesis. Surgery is the
treatment of choice and should preferably be indicated
in patients with NYHA functional class III and IV dyspnea,
with no surgical contraindication, left prosthesis thrombosis,
thrombus ≥ 10 mm or thrombus area > 0.8 cm 2 6,17.
The disadvantage of surgery is due to high perioperative
mortality (between 5%-18%) closely associated with
functional class, which is the main predictor. Patients in
functional classes I to III (NYHA) have 4-7% mortality, while
those in FC IV have 17.5% and 31.3%. However, compared
to thrombolysis, surgery has the highest success rates (81%
vs. 70.9%)18,19.
The use of thrombolytic should be considered in: critical
patients at high risk of death if submitted to surgery in places
where there is no surgical team available or tricuspid or
pulmonary valve thrombosis20. Thrombolysis has a systemic
embolization risk of 5-19 %, major bleeding 5-8%, recurrence
15-31% and mortality from 6 to 12.5%. Success rates vary from 64
to 89%, with a high chance of being effective if the thrombus has
presumably existed for less than 14 days12,19,21,22. In case of partial
success, or residual thrombus, the patient should be referred to
surgery after 24 hours of thrombolytic infusion withdrawal. In this
scenario, surgery should be considered an urgency or emergency
case, depending on the patient’s clinical condition, with high
mortality rates. This reinforces the importance of choosing the
initial therapy for patients with valve thrombosis, to minimize
risks of re-interventions and increase the full resolution rate19.
Patient monitoring with transesophageal echocardiography
should be performed during the procedure. The recommended
doses of thrombolytic agents are: streptokinase 1,500,000 IU in
60 min without UFH and Alteplase (rtPA) 10mg in bolus + 90 mg
in 90 minutes with UFH20. Recently, a thrombolytic protocol with
low-dose and slow infusion (rtPA 25 mg intravenous infusion in
6 hours, repeating at 24 h and, if necessary, up to 6x reaching the
maximum dose of 150 mg, without bolus or use of concomitant
heparin) in pregnant women with prosthetic thrombosis, showed
effective thrombolysis with no maternal deaths and fetal mortality
around 20%, a better result than the commonly used strategies11.
However, the author compares it with old studies, and perhaps
this difference could be less with the improvement in surgical
techniques. Therefore, we can not infer that thrombolysis is better
than the surgical strategy in pregnant women.
Table 1 – Anticoagulation in pregnant patient
Time
Up to 6-12th week
12th up to 36th week
After 36th week up to delivery
Puerperium
Medication
Control
LMWH 1.0 mg/kg SC 12/12h
UFH 17.500 to 20.000 IU SC 2x/day
Anti-factor Xa: 0.8-1.2 U/mL
aPTT 2x higher than control
Warfarin 5 mg 1x/day orally
LMWH 1.0 mg/kg SC 12/12h
INR between 2.0 and 3.0 if aortic prosthesis and
between 2.5 and 3.5 if mitral valve prosthesis
Anti-factor Xa: 0.8-1.2 U/mL
LMWH 1.0 mg/kg SC 12/12h
UFH 17,500 to 20,000 IU SC 2x/day
Anti-factor Xa: 0.8-1.2 U/mL
aPTT 2x higher than control
LMWH 1.0 mg/kg SC 12/12h
Reach target INR after introduction of warfarin 5 mg 1x/day orally
Anti-factor Xa: 0.8-1.2 U/mL
INR between 2.0 and 3.0 if aortic prosthesis and
between 2.5 and 3.5 if mitral valve prosthesis
LMWH: Low molecular weight heparin; SC: Subcutaneous; UFH: Unfractionated heparin; IU: International units. INR: International normalized ratio.
Arq Bras Cardiol. 2015; 105(4):426-429
427
Seabra Garcez et al.
Metal prosthesis during pregnancy and postpartum period
Viewpoint
After surgery or thrombolysis, the patients should be
anticoagulated. The US Guidelines advises INR: 3-4 for
prostheses in the aortic position and INR: 3.5-4.5 with
the addition of aspirin in the mitral position. On the other
hand, the European guideline recommends anticoagulation
according to the prosthesis thrombogenicity and risk factors for
thromboembolic events of the patient (mitral or tricuspid valve,
previous thromboembolism, atrial fibrillation, mitral stenosis,
ventricular dysfunction EF < 35%), with INR ranging from:
2.5 - 3.5 for low-risk, INR: 3.0 - 4.0 for high risk regardless of
prosthesis position6,20.
Considering the abovementioned facts, we highlight the
importance of warning women of childbearing age that
have prosthetic heart valves of the risks during pregnancy,
establishing anticoagulation with adequate control and
frequent monitoring if pregnancy occurs, preferably at
centers of excellence in valvular heart disease, in order to
prevent complications related to the use of anticoagulants
such as embryopathies, miscarriage, bleeding and prosthesis
thrombosis 23. The treatment should be individualized
depending on the patient’s clinical condition, according to
the our algorithm proposed by our team (Figure 1).
Author contributions
Conception and design of the research: Seabra Garcez
JDS, Rosa VEE, Lopes ASSA, Accorsi TAD, Fernandes JRC,
Pomerantzeff PM, Avila WS, Tarasoutchi F; Writing of the
manuscript: Seabra Garcez JDS, Rosa VEE, Lopes ASSA, Accorsi
TAD, Fernandes JRC, Pomerantzeff PM, Avila WS, Tarasoutchi
F; Critical revision of the manuscript for intellectual content:
Seabra Garcez JDS, Rosa VEE, Lopes ASSA, Accorsi TAD,
Fernandes JRC, Pomerantzeff PM, Avila WS, Tarasoutchi F.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This study is not associated with any thesis or dissertation work.
Figure 1 – Algorithm proposed for the treatment of prosthetic heart valve thrombosis in pregnant and postpartum women. FC: Functional class the New York Heart
Association (NYHA)
428
Arq Bras Cardiol. 2015; 105(4):426-429
Seabra Garcez et al.
Metal prosthesis during pregnancy and postpartum period
Viewpoint
References
1. Whitlock RP, Sun JC, Fremes SE, Rubens FD, Teoh KH; American College
of Chest Physicians. Antithrombotic and thrombolytic therapy for valvular
disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed:
American College of Chest Physicians Evidence-Based Clinical Practice
Guidelines. Chest. 2012;141(2 Suppl):e576S-600S.
2. Sbarouni E, Oakley CM. Outcome of pregnancy in women with valve
prostheses. Br Heart J. 1994;71:196-201.
3. Casais P, Rolandi F. Prosthetic valve thrombosis in pregnancy: a promising
treatment for a rare and mostly preventable complication. Circulation.
2013;128(5):481-2.
4.
Elkayam U, Bitar F. Valvular heart disease and pregnancy: part II: prosthetic
valves. J Am Coll Cardiol. 2005;46(3):403-10.
5.
Katz M, Tarasoutchi F, Grinberg M. [Thrombolytic therapy in prosthetic valve
thrombosis]. Arq Bras Cardiol. 2005;85(1):76-8.
6. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP 3rd, Guyton
RA, et al; American College of Cardiology/American Heart Association Task
Force on Practice Guidelines. 2014 AHA/ACC guideline for the management
of patients with valvular heart disease: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines.
J Am Coll Cardiol. 2014;63(22):e57-185. Erratum in: J Am Coll Cardiol.
2014;63(22):2489.
7. Van Hagen IM, Roos-Hesselink JW, Ruys TP, Merz WM, Goland S, Gabriel H,
et al; ROPAC Investigators and the EURObservational Research Programme
(EORP) Team. Pregnancy in women with a mechanical heart valve: data
of the European Society of Cardiology Registry of Pregnancy and Cardiac
Disease (ROPAC). Circulation. 2015;132(2):132-42.
8. Tarasoutchi F, Montera MW, Grinberg M, Piñeiro DJ, Sánchez CR, Bacelar
AC, et al. [Brazilian Guidelines for Valve Disease - SBC 2011 / I Guideline
Inter-American Valve Disease - 2011 SIAC]. Arq Bras Cardiol. 2011;97(5
Suppl 1):1-67.
9. Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with
mechanical heart valves: a systematic review of the literature. Arch Intern
Med. 2000;160(2):191-6.
10. McLintock C, McCowan LM, North RA. Maternal complications and
pregnancy outcome in women with mechanical prosthetic heart valve
treated with enoxaparin. BJOG. 2009;116(12):1585-92.
11. Özkan M, Çakal B, Karakoyun S, Gürsoy OM, Çevik C, Kalçık M, et al.
Thrombolytic therapy for the treatment of prosthetic heart valve thrombosis
in pregnancy with low-dose, slow infusion of tissue-type plasminogen
activator. Circulation. 2013;128(5):532-40.
12. Ramos AI, Ramos RF, Togna DJ, Arnoni AS, Staico R, Galo MM, et al.
Fibrinolytic therapy for thrombosis in cardiac valvular prosthesis short and
long term results. Arq Bras Cardiol. 2003;81(4):393-8, 387-92.
13. Regitz-Zagrosek V, Blomstrom Lundqvist C, Borghi C, Cifkova R, Ferreira
R, Foidart JM, et al; European Society of Gynecology (ESG); Association
for European Paediatric Cardiology (AEPC); German Society for Gender
Medicine (DGesGM); ESC Committee for Practice Guidelines. ESC
Guidelines on the management of cardiovascular diseases during
pregnancy: the Task Force on the Management of Cardiovascular Diseases
during Pregnancy of the European Society of Cardiology (ESC). Eur Heart J.
2011;32(24):3147-97.
14. McLintock C. Anticoagulant choices in pregnant women with mechanical
heart valves: balancing maternal and fetal risks – the difference the dose
makes. Thromb Res. 2013;131 Suppl 1:S8-10.
15. Sociedade Brasileira de Cardiologia. [Guidelines for pregnancy in the woman
with heart disease]. Arq Bras Cardiol. 2009;93(6 supl.1):e110-e78.
16. Parro A Jr, Carramona ML, Amaral CA, Jacob JL, Nicolau JC. Bioprosthetic
mitral valve thrombosis. Importance of transesophageal echocardiography
in the diagnosis and follow-up after treatment. Arq Bras Cardiol.
2004;82(4):346-59.
17. Tong AT, Roudaut R, Ozkan M, Sagie A, Shahid MS, Pontes Júnior
SC, et al; Prosthetic Valve Thrombolysis-Role of Transesophageal
Echocardiography (PRO-TEE) Registry Investigators. Transesophageal
echocardiography improves risk assessment of thrombolysis of prosthetic
valve thrombosis: results of the International PRO-TEE registry. J Am Coll
Cardiol. 2004;43(1):77-84.
18. Roudaut R, Lafitte S, Roudaut MF, Reant P, Pillois X, Durrieu-Jaïs C, et al.
Management of prosthetic heart valve obstruction: fibrinolysis versus surgery.
Early results and long-term follow-up in a single-centre study of 263 cases.
Arch Cardiovasc Dis. 2009;102(4):269-77.
19. Huang G, Schaff HV, Sundt TM, Rahimtoola SH. Treatment of obstructive
thrombosed prosthetic heart valve. J Am Coll Cardiol. 2013;62(19):1731-6.
20. Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Barón-Esquivias G,
Baumgartner H, et al; Joint Task Force on the Management of Valvular Heart
Disease of the European Society of Cardiology (ESC); European Association
for Cardio-Thoracic Surgery (EACTS). Guidelines on the management of
valvular heart disease (version 2012). Eur Heart J. 2012;33(19):2451-96.
21. Cáceres-Lóriga FM, Pérez-López H, Morlans-Hernández K, FacundoSánchez H, Santos-Gracia J, Valiente-Mustelier J, et al. Thrombolysis as first
choice therapy in prosthetic heart valve thrombosis: a study of 68 patients.
J Thromb Thrombolysis. 2006;21(2):185-90.
22. Bonou M, Lampropoulos K, Barbetseas J. Prosthetic heart valve obstruction:
thrombolysis or surgical treatment? Eur Heart J Acute Cardiovasc Care.
2012;1(2):122-7.
23. Avila WS, Grinberg M. [Anticoagulation, pregnancy and cardiopathy. A triad,
three dominions and five moments]. Arq Bras Cardiol. 2005;84(1):44-8.
Arq Bras Cardiol. 2015; 105(4):426-429
429
Back to the Cover
Anatomopathological Session
Case 4 – A 79-Year-Old Man with Congestive Heart Failure Due to
Restrictive Cardiomyopathy
Sumaia Mustafa1, Alice Tatsuko Yamada1, Fabio Mitsuo Lima2, Valdemir Melechco Carvalho2, Vera Demarchi
Aiello1, Jussara Bianchi Castelli1
Instituto do Coração (InCor) HC-FMUSP1; Grupo Fleury Medicina e Saúde2, São Paulo, SP – Brasil
JAP, a 79-year-old male and retired metalworker, born
in Várzea Alegre (Ceará, Brazil) and residing in São Paulo
was admitted to the hospital in October 2013 due to
decompensated heart failure.
The patient was referred 1 year before to InCor with
a history of progressive dyspnea triggered by less than
ordinary activities, lower-extremity edema, and abdominal
enlargement. He sought medical care due to the abdominal
enlargement, which was diagnosed as an ascites. He denied
chest pain, hospitalization due to myocardial infarction or
stroke, hypertension, dyslipidemia, and diabetes.
The patient was a previous smoker and had stopped
smoking at the age of 37 years. He was also an alcoholic and
reported drinking alcohol for the last time 1 year before.
He was referred to InCor for treatment of heart failure.
An echocardiogram revealed an increased thickness in the
septum (17 mm) and free left ventricular wall (15 mm), and a
left ventricular ejection fraction of 26%.
The patient reported daily use of enalapril 10 mg,
spironolactone 25 mg, furosemide 80 mg, omeprazole 40 mg,
and ferrous sulfate (40 mg Fe) three tablets.
On March 12, 2013, his physical examination showed
a weight of 55 kg, height of 1.75 m, body mass index
(BMI) of 18 kg/m², heart rate of 60 bpm, blood pressure
of 90 X 50 mm Hg, and the presence of a hepatojugular
reflux. There were no signs of jugular venous hypertension,
and the pulmonary and cardiac auscultations were normal.
He had ascites, and his liver was palpable 5 cm below the
right costal margin. Peripheral pulses were palpable, and a
++/4+ edema was observed.
An ECG (February 23, 2012) had shown a sinus rhythm,
heart rate of 52 bpm, PR interval of 192 ms, QRS duration
of 106 ms, indirect signs of right atrial overload (wide
variability in QRS amplitude between V1 and V2), and left
A chest x-ray showed cardiomegaly.
Laboratory tests performed on April 20, 2012, had shown
the following results: hemoglobin 13.1 g/dL, hematocrit
40%, mean corpuscular volume (MCV) 87 fL, leukocytes
9,230/mm³ (banded neutrophils 1%, segmented neutrophils
35%, eosinophils 20%, basophils 1%, lymphocytes 33%, and
monocytes 10%), platelets 222,000 /mm³, cholesterol 207 mg/dL,
HDL-cholesterol 54 mg/dL, LDL‑cholesterol 138 mg/dL,
triglycerides 77 mg/dL, creatine phosphokinase (CPK) 77 U/L,
blood glucose 88 mg/dL, urea 80 mg/dL, creatinine 1.2 mg/dL
(glomerular filtration rate ≥ 60 mL/min/1.73 m²), sodium
131 mEq/L, potassium 6.3 mEq/L, aspartate aminotransferase
(AST) 22 U/L, alanine aminotransferase (ALT) 34 U/L, uric
acid 6.3 mg/dL, TSH 1.24 µUI/mL, free T4 1.36 ng/dL,
prostate‑specific antigen (PSA) 1.24 ng/mL. On urinalysis,
urine specific gravity was 1.007, pH 5.5, the sediment was
normal, and there were no abnormal elements.
A new echocardiographic assessment on April 20, 2012,
had shown an aortic diameter of 32 mm, left atrium of 52 mm,
septal and posterior left ventricular wall thickness of 15 mm,
diastolic/systolic left ventricular diameters of 46/40 mm, and
left ventricular ejection fraction of 28%. Both ventricles had
diffuse and marked hypokinesia. The valves were normal
and the pulmonary artery systolic pressure was estimated at
32 mmHg (Figure 2).
A 24-hour electrocardiographic (Holter) monitoring on April
19, 2012, showed a baseline sinus rhythm with a lowest rate of
46 bpm and greatest rate of 97 bpm; 48 isolated, polymorphic,
and paired ventricular extrasystoles; 137 atrial extrasystoles; and
an episode of atrial tachycardia over three beats with a frequency
of 98 bpm. There were no atrioventricular or intraventricular
blocks interfering with the conduction of the stimulus.
The patient was transferred from the pacemaker clinic to
the general cardiopathy clinic.
Keywords
Heart Failure; Cardiomyopathy, Restrictive; Ascites;
Cardiomegaly; Heart Arrest.
Editor da Seção: Alfredo José Mansur ([email protected])
Editores Associados: Desidério Favarato ([email protected])
Vera Demarchi Aiello ([email protected])
Mailing Address: Vera Demarchi Aiello •
Avenida Dr. Enéas de Carvalho Aguiar, 44, subsolo, bloco I, Cerqueira César.
Postal Code 05403-000, São Paulo, SP – Brazil
E-mail: [email protected], [email protected]
DOI: 10.5935/abc.20150135
430
atrial overload (prolonged and notched P waves), low QRS
voltage in the frontal plane with an indeterminate axis, an
electrically inactive area in the anteroseptal region and
secondary changes in ventricular repolarization (Figure 1).
During a clinic appointment on January 22, 2013, the
patient was asymptomatic and reported the use of enalapril
10 mg, spironolactone 25 mg, furosemide 60 mg, and
carvedilol 12.5 mg. His physical examination was normal.
The main diagnostic hypotheses were hypertrophic or
restrictive cardiomyopathy.
A testicular ultrasound (September 09, 2013) was normal,
except for cystic formations in the right inguinal canal.
An abdominal ultrasonography (September 10, 2013) showed
substantial ascites and hepatic cysts with internal septations,
and no signs of portal hypertension.
Mustafa et al
Congestive heart failure due to restrictive cardiomyopathy
Anatomopathological Session
Figure 1 – ECG: sinus bradycardia, low-voltage QRS complexes in the frontal plane, indirect signs of right atrial overload (small QRS complexes in V1 and wide QRS
complexes in V2), left atrial overload, electrically inactive area in the anteroseptal region.
Figure 2 – Echocardiogram - a) Four-chamber view: marked enlargement of the left and right atria; b) parasternal long-axis view: enlarged left atrium, left ventricular
wall thickening, normal cavity.
After presenting an increase in dyspnea with the
development of paroxysmal nocturnal dyspnea, worsening
ascites and lower-extremity edema, and paresthesia on hands
and feet, the patient was admitted to the hospital.
On physical examination (October 19, 2013) he was oriented
and eupneic, with a heart rate of 69 bpm, blood pressure of
80 X 60 mmHg, a normal pulmonary auscultation, cardiac
auscultation with arrhythmia and no murmurs, substantial
ascites, and edema and hyperemia of the lower extremities.
A chest x-ray (October 21, 2013) showed cardiomegaly
and interstitial lung infiltrates; the lateral incidence showed
the right ventricle markedly enlarged (Figures 3 and 4).
On ECG, the patient presented atrial flutter with variable
atrioventricular block, indirect signs of right atrial overload
(Peñaloza-Tranchesi sign), heart rate of 61 bpm, low QRS
voltage in the frontal plane, intraventricular conduction
impairment, left ventricular overload, and secondary changes
in ventricular repolarization (Figure 5).
Laboratory tests on October 19, 2013, showed the
following results: hemoglobin 13.5 g/dL, hematocrit 42%,
leukocytes 7,230/mm³ (neutrophils 66%, eosinophils 12%,
lymphocytes 13%, monocytes 9%), platelets 232,000 /mm³,
urea 193 mg/dL, creatinine 2.03 m/dL (glomerular filtration
rate of 34 mL/min/1,73 m²), sodium 133 mEq/L, potassium
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Congestive heart failure due to restrictive cardiomyopathy
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Figure 3 – Chest x-ray (October 21, 2013), posteroanterior (PA) view: pulmonary interstitial infiltrates and cardiomegaly.
Figure 4 – Chest x-ray (October 21, 2013) in lateral view: right ventricle markedly enlarged.
3.9 mEq/L, C-reactive protein (CRP) 18.1 mg/L, vitamin B12
360 pg/mL, folic acid 8.35 ng/mL, total bilirubin 0.75 mg/dL,
direct bilirubin 0.37 mg/dL, AST 24 U/L, ALT 16 U/L, gammaglutamyl transferase (gamma GT) 241 U/L, alkaline phosphatase
166 U/L, iron 71 µg/dL, ferritin 62.9 ng/mL, prothrombin time
(PT, INR) 0.95, activated partial thromboplastin time (aPTT,
rel) 0.95, ionic calcium 1.09 mmol/L, chloride 89 mEq/L, and
arterial lactate 15 mg/dL. Urinalysis showed urine specific
gravity of 1.020, pH 5.5, proteinuria 0.25 g/L, epithelial cells
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Arq Bras Cardiol. 2015; 105(4):430-439
4,000/mL, leukocytes 2,000/mL, erythrocytes 3,000/mL, and
hyaline casts 27,250/mL.
Another echocardiogram performed on October 21, 2013,
showed a left atrial diameter of 56 mm, septal thickness of
18 mm, posterior wall thickness of 13 mm, left ventricle
(diastole/systole) with 46/40 mm, left ventricular ejection
fraction of 28%, pulmonary artery systolic pressure estimated
at 45 mmHg, marked left ventricular and moderate right
ventricular dysfunction, and moderate tricuspid insufficiency.
Mustafa et al
Congestive heart failure due to restrictive cardiomyopathy
Anatomopathological Session
Figure 5 – ECG: Atrial flutter, impaired intraventricular conduction, left ventricular overload.
An ultrasound of the kidneys and urinary tract (October
24, 2013) showed that the left kidney measured 9.6 cm, and
the right kidney measured 9 cm and had simple cortical cysts.
Serum protein electrophoresis was normal, and a urinary
electrophoresis did not detect proteins. Measurement of serum
beta 2-microglobulin was 7 mg/mL (limit for individuals above
the age of 60 years = 2.6 mg/mL).
A biopsy of the cheek mucosa (October 23, 2013) showed
deposits of amyloid substance in the deep chorion and in the
adjacent adipose tissue.
Stool microscopy (October 25, 2013) was positive for
Blastocystis hominis and Entamoeba coli.
A paracentesis drained 3,500 mL of a yellowish fluid with
normal cellularity.
During hospitalization, the patient received daily intravenous
furosemide 60 mg, carvedilol 25 mg, hydrochlorothiazide
100 mg, hydralazine 75 mg, isosorbide 80 mg, aspirin 100 mg,
spironolactone 25 mg, and enoxaparin 40 mg. The patient also
received oxacillin 2 g/day for 7 days initially, and later vancomycin,
meropenem and teicoplanin, and piperacillin/tazobactam.
A new chest x-ray (November 08, 2013) showed
cardiomegaly and an interstitial pulmonary infiltrate suggestive
of pulmonary congestion (Figure 6).
During a new paracentesis (November 11, 2013), the
aspirated fluid was bloody, and the patient presented
hypotension and decreased consciousness, progressing to
cardiac arrest with pulseless electrical activity, which was
reverted. This was followed by ventricular tachycardia,
cardioverted with 200 J.
New tests (November 11, 2013 - morning) showed the
following results: hemoglobin 11.9 g/dL, hematocrit 36%,
leukocytes 7,780/mm³ (neutrophils 83%, eosinophils 2%,
lymphocytes 9%, and monocytes 6%), platelets 188,000 /mm³,
urea 301 mg/dL, creatinine 4.14 mg/dL, sodium 125 mEq/L,
potassium 4.4 mEq/L, CRP 97.06 mg/L. On venous blood gas
analysis, pH was 7.33, bicarbonate 19.9 mmol/L, and base
excess (-) 5.4 mmol/L. Additional tests performed on the same
day (November 11, 2013 – 5:44 pm) showed hemoglobin of
6.3 g/dL, sodium of 123 mEq/L, potassium of 5.4 mEq/L, venous
lactate of 93 mg/dL, PT (INR) of 3.2 and aPTT (rel) of 1.98.
Later during the day, the patient progressed with shock
refractory to high doses of dobutamine (20 µg/kg/min ) and
norepinephrine (1.2 µg/kg/min), followed by cardiac arrest
with pulseless electrical activity that recovered but was
followed by a new irreversible cardiac arrest with pulseless
electrical activity during intra-aortic balloon placement
(November 11, 2013 – 6:30 pm).
Clinical Aspects
The patient JAB, a 79-year-old previous smoker and alcoholic
man residing in São Paulo, attended an outpatient clinic at InCor
due to heart failure which worsened progressively since 2012,
requiring hospitalization for treatment.
Heart failure is a systemic and complex clinical syndrome,
defined as a cardiac dysfunction that causes the blood supply
to be insufficient to meet tissular metabolic demands, in the
presence of a normal venous return, or which only meets the
demands with high filling pressure1.
Prevalence studies estimate that 23 million individuals
worldwide have heart failure and that 2 million new cases
are diagnosed annually. According to DATASUS information,
Brazil has about 2 million individuals with heart failure and
240,000 new cases diagnosed annually2.
The main causes of heart failure are hypertension,
coronary artery disease, Chagas disease, cardiomyopathies,
endocrinopathies, toxins, and drugs, among others 1 .
The cardinal manifestations of heart failure are dyspnea and
fatigue, and may include exercise intolerance, fluid retention,
and pulmonary and systemic congestion3. The patient in this
case presented with progressive dyspnea triggered by less than
Arq Bras Cardiol. 2015; 105(4):430-439
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Congestive heart failure due to restrictive cardiomyopathy
Anatomopathological Session
Figure 6 – Chest x-ray (November 08, 2013): pulmonary interstitial infiltrates suggestive of pulmonary congestion and cardiomegaly.
ordinary activities, lower-extremity edema, and ascites, which
characterized him as class III according to the New York Heart
Association (NYHA) classification.
On complementary tests, the echocardiogram showed
marked left ventricular hypertrophy with some degree
of asymmetry, and reduced ejection fraction. Cardiac
hypertrophy is often associated with hypertension or
hypertrophic cardiomyopathy, but both present with normal
or increased ECG voltage. Therefore, the findings of ventricular
hypertrophy associated with decreased ECG voltage in the
absence of pericardial effusion are exclusive of infiltrative
cardiomyopathies, a group of cardiac disorders within the
restrictive cardiomyopathies4.
Restrictive cardiomyopathy may occur with a wide variety
of systemic diseases. Some restrictive cardiomyopathies are
rare in clinical practice and may present initially with heart
failure. This type of cardiomyopathy is characterized by filling
restriction, with reduced diastolic volume in one or both
ventricles, normal or close to normal systolic function, and
ventricular wall thickening. It may be idiopathic or associated
with other diseases, such as amyloidosis, endomyocardial
disease with or without eosinophilia, sarcoidosis, and
hemochromatosis, among others5. In this case, the presence
of amyloid deposits in the cheek mucosa biopsy indicated a
diagnosis of amyloidosis, and the increase in serum beta-2
microglobulin reflected a worse prognosis5.
Amyloidosis is characterized by deposits of amyloid
protein in different organs and tissues. These deposits may
be responsible for different types of clinical presentation, with
a spectrum that ranges from lack of symptoms to sequential
organic dysfunction culminating with death6.
Cardiac amyloidosis is caused by amyloid deposits around
cardiac fibers, and can be identified by a left ventricular wall
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Arq Bras Cardiol. 2015; 105(4):430-439
thickening exceeding 12 mm in the absence of hypertension
with at least one of the following characteristics: conduction
disorder and low voltage complexes on the ECG, restrictive
cardiomyopathy, low cardiac output, isolate atrial involvement
(as commonly seen in elderly individuals) or diffuse
involvement affecting the ventricles. In the latter situation, it
can cause heart failure with a poor prognosis4,7.
Our patient, who was not hypertensive, presented low
voltage complexes on the ECG, which were more prominent in
the frontal plane, an electrically inactive area in the anteroseptal
region, and diffuse changes in ventricular repolarization. This
pattern can be found in some diseases in addition to infiltrative
cardiomyopathies, such as decompensated hypothyroidism,
pericardial effusion, chronic obstructive pulmonary disease,
and obesity. Other electrocardiographic information, such
as the pattern of infarction, can be found with or without
obstructive coronary atherosclerotic disease by deposition of
substances in the microcirculation and small intramyocardial
arteries8.
Amyloidosis may be classified as primary, secondary, or
hereditary. Primary amyloidosis, in which AL is the primarily
involved protein, may be further subdivided into idiopathic
(localized forms) or associated with multiple myeloma or other
plasma cell dyscrasias (systemic forms)9.
Multiple myeloma is a neoplastic disorder of plasma cells
that affects individuals with an average age of 70 years at
diagnosis. Some characteristics of the patient in this case
could suggest multiple myeloma: age, male gender, renal
failure, and cylindruria. However, other important clinical
parameters were absent, such as hypercalcemia, anemia,
and bone disease. Also, the Bence-Jones protein, which
is present in up to 75% of the cases, was not detected on
urinary electrophoresis10.
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Congestive heart failure due to restrictive cardiomyopathy
Anatomopathological Session
The secondary type of amyloidosis results from deposits
of AA protein and frequently arises as a complication of
infectious or inflammatory processes, such as rheumatoid
arthritis (the most common cause), tuberculosis, systemic lupus
erythematosus, inflammatory bowel disease, syphilis, or even
neoplastic diseases. Pro-inflammatory cytokines, which are
present in these disorders, stimulate the hepatic production
of serum A amyloid11.
Finally, the hereditary type of the disease has an autosomal
dominant transmission and may involve several types of
amyloid proteins, such as the AA protein in some groups
of patients with familial Mediterranean fever, and the ATTR
protein (derived from the transthyretin or prealbumin) in
familial amyloid polyneuropathy12.
As for the treatment, measures to control symptoms related
to diastolic heart failure, such as volume control, should be
implemented. Diuretics and vasodilators should be administered
with caution since the cardiac output in these patients is greatly
dependent on increased venous pressures. Specific treatment
should be directed to the etiology of the amyloidosis13.
After an evaluation in the clinic on January, 2013, the
patient received medications that are proven to modify
the rates of hospitalization and mortality in heart failure
with reduced ejection fraction (beta-blockers, angiotensinconverting enzyme inhibitors, aldosterone antagonist), and
symptom-relieving agents (diuretics)14. The patient was
receiving enalapril 10 mg, spironolactone 25 mg, furosemide
60 mg, and carvedilol 12.5 mg.
After 8 months, due to the decompensated heart failure
and hypotension, the patient returned to the emergency room
and required hospitalization. The use of conventional therapy
for heart failure often worsens the progression of amyloidosis.
Therefore, cardiac amyloidosis should be suspected when
the patient’s clinical condition worsens in response to
conventional treatment, particularly in individuals older than
50 years. The therapy is exclusively symptomatic and should
not include digitalis, beta-blockers, angiotensin-converting
enzyme inhibitors, or calcium channel antagonists, since
some studies have shown an increased sensitivity to these
drugs which can lead to hypotension and intensification of
conduction disorders15.
Therefore, the decompensation of the patient’s heart
failure with deterioration of the ascites culminated in two
paracenteses, with the last paracentesis probably accompanied
by a puncture accident due to the appearance of bloody
fluid, decrease in red blood count, and hypovolemic shock
associated with cardiogenic shock, culminating in a mixed
refractory shock and cardiac arrest with pulseless electrical
activity (Dr. Sumaia Mustafa, Dr. Alice Tatsuko Yamada).
Diagnostic hypotheses:
1. Heart failure due to restrictive cardiomyopathy (probably
cardiac amyloidosis associated with multiple myeloma);
2. Decompensated heart failure;
3. Cause of death: mixed shock (hypovolemic + cardiogenic)
with cardiac arrest with pulseless electrical activity
(Dr. Sumaia Mustafa, Dr. Alice Tatsuko Yamada).
Autopsy
The heart weighed 680 g and was increased in volume
due to moderate cavity dilation and wall thickening in
all four chambers (Figure 7). The myocardium had an
increased consistency. The endocardium of the atria, in
particular, was finely granular and brown-yellowish in
appearance. There were no significant changes in the
valves, and the coronary arteries were armed without
significant obstruction of their lumen.
Histological examination of the myocardium showed
extracellular deposits of amorphous and eosinophilic material
promoting atrophy of the contractile cells. These deposits
stained positive with Congo red when observed under
polarized light (Figures 8 and 9). This same material was
present in the interstitium of the cheek mucosa evaluated by
biopsy (Figure 10) according to data from the clinical history.
Deposits were also observed in the tunica media of muscular
arteries in both lungs (Figure 11) and in the renal hilum.
Bone marrow histological examination showed
hypercellularity of moderate degree for the patient's age, and
no signs of monoclonal proliferation. Immunohistochemical
reactions for immunoglobulin kappa and lambda light
chains were inconclusive, and CD138 labeling showed no
proliferation of plasma cells.
Autopsy findings included a 4-cm hepatic cyst in the right
lobe lined with flat cells without atypia, and retention cysts
in the right kidney. The right adrenal weighed 44 g and was
increased in volume and completely calcified. The histological
examination showed only calcification and was inconclusive
for the possibility of prior malignancy.
There was a voluminous serosanguinous ascites and a
serous pericardial effusion. We found no visceral or abdominal
vessel injury resulting from the paracentesis and the amount
of bloody material in the ascitic fluid was small.
Histologically, there were signs of congestive heart failure
in the lungs and liver (Dr. Vera Demarchi Aiello).
Diagnoses: Cardiovascular amyloidosis;
Congestive heart failure;
Calcified nodule in the right adrenal gland (Dr. Vera
Demarchi Aiello).
Mass spectrometry
Mass spectrometry gathers all qualities to establish an
unequivocal diagnosis of amyloidosis since it has a high sensitivity
and ability to identify the proteins through sequencing16.
Therefore, we adopted an approach based on shotgun
proteomics to identify the amyloid deposits in the sample.
Sections of heart tissue containing amyloid deposits
(confirmed by staining with Congo red) fixed in formalin
and embedded in paraffin were dissected and the proteins
were then extracted with Liquid Tissue® MS Protein Prep
Kit (Expression Pathology) according to the manufacturer's
protocol. After digestion with trypsin, the resulting peptides
were analyzed by high-resolution liquid chromatography-mass
spectrometry using the mass spectrometer Q-Exactive (Thermo
Arq Bras Cardiol. 2015; 105(4):430-439
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Congestive heart failure due to restrictive cardiomyopathy
Anatomopathological Session
Figure 7 – Gross Section of the heart base showing biatrial enlargement and thickening of the cardiac walls. Note the granular aspect of the right atrial endocardium
(area demarcated with an ellipse).
Figure 8 – Photomicrography of the ventricular myocardium showing atrophic cardiomyocytes due to deposits of amorphous eosinophilic material in the interstitium.
Hematoxylin and eosin staining (20x objective magnification).
Fisher Scientific). The acquisitions of spectral data were carried
out using the DDA (date dependent analysis) mode with a
selection of the 10 most abundant ions for sequencing by
HCD (Higher-energy collisional dissociation). The data were
processed with the software MaxQuant. The proteomic analysis
was performed in triplicate.
The processed data generated lists of proteins representing
the protein content of the sample. In total, 25 possible
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Arq Bras Cardiol. 2015; 105(4):430-439
amyloid proteins were investigated in these lists in order to
determine the identity of the deposited substance. There were
15 peptides belonging to transthyretin that together covered
76.2% of the full sequence of the protein.
To confirm the result, we also evaluated the abundance
of different peptides present in the sample. Among the 25
most abundant peptides, three belonged to transthyretin
(ALGISPFHEHAEVVFTANDSGPR, TSESGELHGLTTEEEFVEGIYK,
and GSPAINVAVHVFR). The others were assigned to actin,
Mustafa et al
Congestive heart failure due to restrictive cardiomyopathy
Anatomopathological Session
Figure 9 – Photomicrography of myocardial tissue obtained under polarized light. Note the greenish material that corresponds to amyloid substance stained by Congo
red (5x objective magnification).
Figure 10 – Biopsy of the cheek mucosa performed approximately 1 month before death. Note that the mucosal chorion reacts positively to Congo red (photomicrography
obtained under conventional microscopy with a 10x objective magnification).
myosin, desmin, and myoglobin, confirming the identity of the
amyloid protein (Dr. Fabio Mitsuo Lima and Dr. Valdemir
Melechco Carvalho- Fleury Group).
Conclusion
Cardiovascular amyloidosis due to deposition of
transthyretin (Dr. Vera Demarchi Aiello, Dr. Jussara
Bianchi Castelli, Dr. Fabio Mitsuo Lima and Dr. Valdemir
Melechco Carvalho).
Comments:
This case demonstrates how important it is in amyloidosis
to investigate the deposited substance. Amyloidosis is a
generic name to describe a group of diseases characterized
by extracellular deposits of different substances in different
organs. These substances are fibrillar proteins that become
insoluble with changes in their spatial conformation. More than
20 types of proteins have been described in these deposits16.
From an anatomopathological perspective, the deposits can
be characterized by immunohistochemical reactions, but with
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Congestive heart failure due to restrictive cardiomyopathy
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Figure 11 – Photomicrography of a peripheral muscular pulmonary artery showing areas of positivity for deposits of amyloid in the arterial wall (Congo red staining
photographed under conventional microscopy, 5x objective magnification).
some restrictions as described below. The cardiovascular system
is most often affected by the AL protein (deposits of light-chain
immunoglobulin), senile, and familial forms17,18.
The pathologist may identify neoplastic proliferation of
plasmocytes producing the deposited immunoglobulins
by bone marrow examination labeled for these cells.
In tissue preparations, the pathologist may demonstrate by
immunohistochemistry if the deposited substance is one
of these immunoglobulins. Some authors recommend a
biopsy of other organs before the endomyocardial biopsy
to confirm the diagnosis and identify the type of amyloid19.
In this case, immunohistochemical labeling was not helpful
in establishing the diagnosis, because it was inconclusive to
the type of protein deposited.
Although there are reports in the literature of identification
of transthyretin in tissues by immunohistochemical
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Arq Bras Cardiol. 2015; 105(4):430-439
reactions, this was not possible in this case. However, with
mass spectrometry analysis, we identified that the deposited
protein was transthyretin, which is usually present in senile
and familial forms of amyloidosis. In this patient, the familial
form was less likely due to the exclusive involvement of
heart and blood vessels. However, only a genetic research
and evaluation of other members of the family could
exclude it completely.
Another point that deserves discussion in this case is the
laboratory report of high levels of immunoglobulin E. We could
assume that this referred to the deposited protein, but the
diagnostic methods performed to complement the autopsy
revealed that this was not the case.
Dr. Vera Demarchi Aiello and Dr. Jussara Bianchi Castelli
(Pathology Laboratory, InCor, FMUSP).
Mustafa et al
Congestive heart failure due to restrictive cardiomyopathy
Anatomopathological Session
References
1. Bocchi EA, Marcondes-Braga FG, Ayub-Ferreira SM, Rohde LE, Oliveira WA,
Almeida DR, et al. Sociedade Brasileira de Cardiologia. III Diretriz brasileira
de insuficiência cardíaca crônica. Arq Bras Cardiol. 2009;93(1 supl. 1):1-71.
11. Ohdama S, Akagawa S, Matsubara O, Yoshizawa Y. Primary diffuse alveolar
septal amyloidosis with multiple cysts anda calcification. Eur Respir J.
1996;9(7):1569-71.
2.
12. Rahman JE, Helou EF, Geizer-Bell R, Thompson RE, Kuo C, Rodriguez ER, et
al. Noninvasive diagnosis of biopsy-proven cardiac amyloidosis. J Am Coll
Cardiol. 2004;43(3):410-5.
Nogueira PR, Rassi S, Corrêa Kde S. Epidemiological, clinical e therapeutic profile
of heart failure in a tertiary hospital. Arq Bras Cardiol. 2010;95(3):392-8.
3. Yancy CW, Jessuo M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH et al;
American College of Cardiology Foundation/American Heart Association
Task Force on Practice Guidelines. 2013 ACCF/ AHA guideline for the
management of heart failure: a report of the American College of Cardiology
Foundation/American Heart Association Task Force on Pratice Guidelines.
Circulation. 2013;128(16):e240-327.
4.
Hassan W, Al-Sergani H, Mourad W, Tabbas R. Amyloid heart disease: new
frontiesanda insights in pathophysiology, diagnosis, and management. Tex
Heart Inst. J. 2005;32(2):178-84.
5. Report of WHO/ISFC task force on the definition and classification of
cardiomyopathies. Br Heart J. 1980;44(6):672-3.
6. Lachmann HJ, Hawkins PN. Amyloidosis and the lung. Chron Respir Dis.
2006;3(4):203-14.
7.
8.
Dubrey SM, Cha K, Simms RW, Skinner M, Falk RH. Eletrocardiography and
Doppler echocardiography in secondary (AA) amyloidosis. Am J Cardiol.
1996;77(4):313-5.
Kushwaha SS, Fallon JT, Fuster V. Restrictive cardiomyopathy. N Engl J Med.
1997;336(4):267-76.
9. Khan MF, Falk RH. Amyloidosis. Postgrad Med J. 2001;77(913):686-93.
10. Pa l u m b o A , A n d e r s o n K . M u l t i p l e m y e l o m a . N E n g l J M e d .
2011;364(11):1046-60.
13. Salemi V, Fernandes F, Nastari L, Mady C. Cardiomiopatias restritivas. In:
Mesquita ET, Lagoeiro AJ, Mesquita JE. Insuficiencia cardíaca com fração de
ejeção normal. São Paulo: Atheneu; 2009. p. 197-211.
14. Sacks CA, MD, Jarcho JA, Curfman GD. Paradigm shifts in heart-failure
therapy: a timeline. N Engl J Med. 2014;371(11):989-91.
15. Somaio Neto F, Silva CJ, Domingues JS, Assis RP, Borges RS, Prado SP, et
al. The importance of accuracy of clinical examination in the diagnosis of
cardiac amyloidosis. Case report. Rev Bras Clin Med. 2009;7:198-201.
16. Vrana JA, Gamez JD, Madden BJ, Theis JD, Bergen HR 3rd, Dogan
A. Classification of amyloidosis by laser microdissection and mass
spectrometry-based proteomic analysis in clinical biopsy specimens. Blood.
2009;114(24):4957-9.
17. Dubrey SW, Hawkins PN, Falk RH. Amyloid diseases of the heart:
assessment, diagnosis, and referral. Heart. 2011;97(1):75-84.
18. Diagnosis and management of the cardiac amyloidoses. Circulation.
2005;112(13):2047-60.
19. Fine NM, Arruda-Olson AM, Dispenzieri A, Zeldenrust SR, Gertz MA, Kyle
RA, et al. Yield of noncardiac biopsy for the diagnosis of transthyretin cardiac
amyloidosis. Am J Cardiol. 2014;113(10):1723-7.
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Back to the Cover
Case Report
Percutaneous Treatment of Mitral Paraprosthetic Regurgitation: an
Alternative to Surgery
Roney Orismar Sampaio, Alessandra Gomes de Oliveira, George Barreto Miranda, Pedro Alves Lemos Neto,
Marcelo Luiz Campos Vieira, Flávio Tarasoutchi
Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (USP), São Paulo, SP – Brazil
Introduction
Paraprosthetic regurgitation occurs in approximately
7%–17% of patients undergoing mitral valve replacement and
2%–10% of patients undergoing aortic valve replacement1,2.
Typically, this regurgitation is discrete and does imply major
clinical complications; however, when it is moderate or
severe, the consequences can be serious, leading to heart
failure and/or hemolysis3,4. It is estimated that approximately
1%–5% of cases develop to more clinically severe conditions1,4.
The main causes of paraprosthetic regurgitation are calcification
of the valvular annulus, infection, suture technique, and size
and shape of the prosthesis1,5.
Usually, surgical treatment is considered as the first
treatment option for symptomatic patients4. In 1992, however,
an alternative treatment via percutaneous occlusion of the
paravalvular orifice was proposed for cases in which the patient
faces high risk from surgical treatment6-8.
Case Report
A 70-year-old male patient received a mechanical
mitral prosthesis implant in 2002 during his fourth heart
surgery. At that time, the patient presented multiple
postoperative complications: septic shock requiring high
doses of vasoactive medications, acute renal failure
and atrial fibrillation, and prolonged hospitalization.
After this period, the patient made good progress and had
no limitations on daily activities, until 3 years previously,
when he began to experience recurrent hematuria due to
intravascular hemolysis. The patient was clinically followed
until June 2012, when the hemolysis markedly worsened, in
association with heart failure up to functional class III [New
York Heart Association (NYHA)]. On physical examination,
there was a regurgitant systolic murmur +++/4 in the mitral
area and crackle at the base of the lungs.
Keywords
Mitral Valve / surgery; Heart Valve Prosthesis Implantation;
Prosthesis-Related Infections / complications; Heart Failure;
Hemolysis; Atrioventricular Block.
Mailing Address: Roney Orismar Sampaio •
Rua Comandante Garcia d’Avila, 412, Morumbi. Postal Code 05654040,
São Paulo, SP – Brazil
E-mail: [email protected]; [email protected]
Manuscript received May 06, 2014; revised manuscript September 24,
2014; accepted September 30, 2014.
DOI: 10.5935/abc.20150115
440
Laboratory examinations showed the following:
lactate dehydrogenase (LDH) 3256 U/L [reference value
(RV): 85‑227 U/L], haptoglobin 0.2 g/L (RV: 0.3–2.0 g/L),
hemoglobin (Hb) 7.3 g/dL (RV: 13.0–18.0 g/dL), hematocrit (Hct)
22% (RV: 40.0-52.0%), and hemoglobinuria. Two‑dimensional
transesophageal echocardiography demonstrated the
mechanical prosthesis with normal mobility for its elements
as well as moderate/significant periprosthetic regurgitation
(Figures 1A and B) associated with maximum LA–LV diastolic
gradient estimated at 13 mmHg (average, 4 mmHg). The valve
area was estimated at 3.2 cm2. Because of the difficulty in
accurately determining the size of the regurgitant orifice and
subsequently choosing the best occlusion device, we performed
three-dimensional transesophageal echocardiography.
This technique identified both anterior and posterior
periprosthetic insufficiency: anterior gap of 22 mm along the
long axis and posterior gap of approximately 12 mm (Figure 1C).
Because of the risk of many postoperative complications (as in
2002) and the high surgical risk associated with a fifth heart
surgery, in a joint decision along with the patient and family,
we opted for percutaneous treatment.
Treatment
Two percutaneous devices, “Duct Occluder 8 mm ×
6” and “5 mm VSD,” were implanted, with a significant
reduction in postimplant regurgitation (there was a decrease of
approximately 70% in the anterior orifice) (Figure 2). A second
3D echocardiography (Figure 1D) was performed 45 days
after the procedure and demonstrated good positioning of
the occlusion devices and minimum residual paraprosthetic
reflux. Six months after the procedure, the patient presented
with a second-degree atrioventricular block, Mobitz II,
and two episodes of presyncope; a DDD pacemaker was
implanted. The patient improved to functional class I (NYHA).
Physical examination at this time showed a slight systolic
murmur of mitral regurgitation (+/4) and improved laboratory
results (LDH 728 U/L, Hb 10.5 g/dL, Hct 32.3%).
Discussion
Paraprosthetic reflux is a significant complication of valve
replacement surgery. Percutaneous closure of a paraprosthetic
orifice is now considered a safe procedure, providing
an alternative to surgery in patients with a high surgical
risk. However, there are still few reports of percutaneous
intervention in patients with paraprosthetic regurgitation.
In 2006, Pate et al.9 published a study of 10 patients
who were not candidates for surgery and underwent
percutaneous closure of mitral paravalvular leak; this author
Sampaio et al.
Percutaneous treatment of paraprosthetic regurgitation
Case Report
(A) 2D transesophageal echocardiogram (B) 2D TE, preoperative
(TE), preoperative
(C) 3D TE, preoperative
(D) 3D TE, postoperative
Figure 1 – (A) Two-dimensional transesophageal echocardiogram (2D-TEE). (A) Preoperative 2D-TEE (B and C); (C) preoperative 3D-TEE; (D) post-operative 3D-TEE
A
B
Image from hemodynamics laboratory
showing catheter positioned in the
paraprosthetic orifice before its release
Image from hemodynamics laboratory
showing the device in place
Figure 2 – (A) Hemodynamics laboratory image of the catheter in the paraprosthetic orifice before deployment. (B) Hemodynamics laboratory image of the deployed device.
Arq Bras Cardiol. 2015; 105(4):440-442
441
Sampaio et al.
Percutaneous treatment of paraprosthetic regurgitation
Case Report
noted a 70% success rate for this procedure, associated with
clinical improvement. However, four patients required a
second intervention.
In 2011, Sorajja et al.10 published a study of 115 patients
who underwent the percutaneous procedure, with technical
success in 77% of cases and clinical improvement in 67%.
The total number of complications 30 days after the
procedure was 8.7%: death in two cases (1.7%), stroke in
three cases (2.6%), vascular complications in one case (0.9%),
hemothorax in four cases (3.5%), and emergency surgery in
one case (0.9%).
In addition, in 2011, Ruiz et al.8 showed that in retrospective
analysis of 43 patients, procedural success was observed in
86% of cases and clinical improvement was observed in 77%.
In this present case, 6 months after percutaneous treatment,
the patient developed atrioventricular block and required
a pacemaker. After an extensive review of the literature,
we found no reports of second-degree atrioventricular
block as a late complication of percutaneous closure of
the paraprosthetic mitral valve orifice1. Even in the aortic
position, where it may be more common considering the
anatomy of the conduction system, there are no reports of this
complication. The risk of this event (late implant pacemaker
for AVB) seems to have been random, particularly in closing
the paraprosthetic mitral orifice; however, it cannot be ruled
out. Nevertheless, the fact the pacemaker was implanted
6 months after the procedure is also relevant, which in our
view leaves it unclear whether a possible complication exists
and is yet to be described. Therefore, this event should be
noted and followed in the literature.
Therefore, we conclude that a percutaneous procedure
to correct paraprosthetic regurgitation is feasible in patients
with a high surgical risk and has a significant clinical impact.
Author contributions
Conception and design of the research: Sampaio RO, Oliveira
AG, Lemos Neto PA. Acquisition of data: Sampaio RO, Oliveira
AG, Lemos Neto PA, Vieira MLC. Analysis and interpretation
of the data: Sampaio RO, Miranda GB, Lemos Neto PA, Vieira
MLC. Writing of the manuscript: Sampaio RO, Oliveira AG,
Miranda GB, Lemos Neto PA, Tarasoutchi F. Critical revision of the
manuscript for intellectual content: Sampaio RO, Tarasoutchi F.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This study is not associated with any thesis or
dissertation work.
References
1. Kliger C, Eiros R, Isasti G, Einhorn B, Jelnin V, Cohen H, et al. Review of
surgical prosthetic paravalvular leaks: diagnosis and catheter-based closure.
Eur Heart J. 2013;34(9):638-49.
6. Hourihan M, Perry SB, Mandell VS, Keane JF, Rome JJ, Bittl JA, et al
Transcatheter umbrella closure of valvular and paravalvar leaks. J Am Coll
Cardiol. 1992;20(6):1371-7.
2. Hammermeister K, Sethi GK, Henderson WG, Grover FL, Oprian
C, Rahimtoola SH. Outcomes 15 years after valve replacement with
mechanical versus a bioprostetic valve: final report of the Veterans Affairs
randomized trial. J Am Coll Cardiol. 2000;36 (4):1152-8.
7. Ruiz CE, Cohen H, Del Valle-Fernandes R, Jelnin V, Perk G, Kronzon I.
Closure of prosthetic paravalvular leaks: a long way to go. Eur Heart J Suppl.
2010;12(Suppl E):E52-62.
3.
Kim MS, Casserly IP, Garcia JA, Klein AJ, Salcedo EE, Carroll JD. Percutaneous
transcatheter closure of prosthetic mitral paravalvar leaks: are we there yet?
JACC Cardiovasc Interv. 2009;2(2):81-90.
4.
Buellesfeld L, Meier B. Treatment of paravalvular leaks through interventional
techniques. Multimed Man Cardiothorac Surg. 2011;2011(924):mmc
ts.2010.004895.
5. Sampaio RO, Silva FC Jr, Oliveira IS, Padovesi CM, Soares JA, Silva WM, et
al. Evolução pós-operatória de pacientes com refluxo protético valvar. Arq
Bras Cardiol. 2009;93(3):283-9.
442
Arq Bras Cardiol. 2015; 105(4):440-442
8. Ruiz CE, Jelin V, Kronzon I, Dudy Y, Del Valle-Fernandez R, Einhorn BN,
et al. Clinical outcomes in patients undergoing percutaneous closure of
periprosthetic paravalvular leaks. J Am Coll Cardiol. 2011;58(21):2210-7.
9.
Pate GE, Al Zubaidi A, Chandavimol M, Thompson CR, Munt BI, Webb JG.
Percutaneous closure of prosthetic paravalvular leaks: case series and review.
Catheter Cardiovasc Interv. 2006;68(4):528-33.
10. Sorajja P, Cabalka AK, Hagler DJ, Rihal CS. Percutaneous repair of
paravalvular prosthetic regurgitation: acute and 30-day outcome in 115
patients. Circ Cardiovasc Interv. 2011;4(4):314-21.
Back to the Cover
Image
Persistent Left Superior Vena Cava in Permanent Pacemaker
Implantation
Jerson Hernando Quitián1,2, José Julian Carvajal1,2, Mariana Soto1,2, Guillermo Mora1,2,3
Hospital Universitario Fundación Santa Fe de Bogotá1; Universidad de los Andes2; Universidad Nacional de Colombia3, Bogotá – Colombia
This was an 84-year-old male patient, with worsening
functional class from NYHA III/IV to IV/IV and palpitations.
No syncope. Physical examination revealed bradycardia, the
rest was uneventful. Electrocardiogram showed Mobitz II
atrioventricular block. Patient was scheduled for permanent
pacemaker implantation.
tricuspid valve. Subsequently, the guide was withdrawn
3 cm. The guide withdrawal, without moving the electrode,
is associated with the passage of the electrode through the
tricuspid valve. The electrode was advanced and finally the
active fixation mechanism was deployed1.
Subclavian vein access was performed via direct
puncture. The guide wire was advanced, entered the
subclavian vein and descended parallel to the spine without
crossing over to the right side. Subsequently, the guide
wire traversed the coronary sinus and ended in the right
atrium. Persistent left superior vena cava was diagnosed.
During fluoroscopic observation, another feature that aids in
the diagnosis is left paravertebral shadow above the aortic
bow. The electrode was initially introduced with a straight
guide reaching into the right atrium (RA). Afterwards, the
straight guide was replaced by a conventional J guide and
the electrode was pushed towards the anterolateral wall
of the RA. The electrode tip was thus lying against the
Author contributions
Keywords
Heart Defects, Congenital; Vena Cava, Superior;
Pacemaker, Artificial.
Mailing Address: Mariana Soto •
Hospital Universitario Fundación Santa Fe de Bogotá. Calle 94A 16-76,
Chico. Postal Code NA, Bogota, Bogota – Colombia
E-mail: [email protected]
Manuscript received February 10, 2015; revised manuscript March 06,
2015; accepted March 17, 2015.
DOI: 10.5935/abc.20150116
443
Conception and design of the research, Acquisition of
data, Writing of the manuscript and Critical revision of the
manuscript for intellectual content: Quitián JH, Carvajal JJ,
Soto M, Mora G
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
There were no external funding sources for this study.
Study Association
This study is not associated with any thesis or dissertation
work.
Quitián et al.
Persistent left superior vena cava in device implantation
Image
Reference
1. Mora G. A Novel method of placing right ventricular leads in patients with
persistent left superior vena cava using a conventional J Stylet. Indian Pacing
Electrophysiol J. 2014;14(2):65–74.
Arq Bras Cardiol. 2015; 105(4):443-444
444
Back to the Cover
Erratum
January 2015 Issue, vol. 104 (1), pages 32-44
The original article “Cost-Effectiveness of High, Moderate and Low-Dose Statins in the Prevention of Vascular Events in the
Brazilian Public Health System” published in the January 2015 issue of the Brazilian Archives of Cardiology [Arq Bras Cardiol.
2015; 104 (1): 32-44], was published in the Portuguese version as “Effectiveness of High, Moderate and Low-Dose Statins in
the Prevention of Vascular Events in the Brazilian Public Health System”. A correction was made in the Portuguese version.
DOI: 10.5935/abc.20150138
445