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Sociedade Brasileira de Cardiologia • ISSN-0066-782X • Volume 106, Nº 6, June 2016
Figure 1 – Apical 4-chamber (A) and 2-chamber (B) views and short–axis views (C3, C5, C7) at
different levels of the left ventricle (LV) extracted from the three-dimensional (3D) echocardiographic
dataset are shown in the patient with Ebstein’s anomaly. The 3D image of the LV and calculated LV
volumetric and functional characteristics (EDV: end-diastolic volume; ESV: end-systolic volume;
EF: ejection fraction) are also demonstrated together with LV apical (white arrow), mid-ventricular and
basal (dashed arrow) rotations in the same counterclockwise direction, confirming absence of the LV
twist, called “rigid body rotation”. Page: 545
Editorial
Transcatheter Aortic Valve Implantation and Morbidity and Mortality-
Primordial Prevention and Wearable Health Devices: The Wearables
Related Factors: a 5-Year Experience in Brazil
in Cardiology
Review Article
Original Articles
Ambulatory Blood Pressure Monitoring: Five Decades of More Light
Early Markers of Atherosclerotic Disease in Individuals with Excess
and Less Shadows
Weight and Dyslipidemia
Clinicoradiological Session
Mortality from Circulatory System Diseases and Malformations in
Case 4/2016: 32-Year-Old Female, with Critical Pulmonary Valve
Children in the State of Rio de Janeiro
Stenosis. Operated at 4 months of Age, in Normal Healing Evolution
Prevalence of Risk for Obstructive Sleep Apnea Syndrome and
Case Report
Association With Risk Factors in Primary Care
Drug-Coated Balloon Treatment of Very Late Stent Thrombosis Due to
The Labdane Ent-3-Acetoxy-Labda-8(17), 13-Dien-15-Oic Decreases
Blood Pressure In Hypertensive Rats
Association between Spirituality and Adherence to Management in
Outpatients with Heart Failure
Functional Class in Children with Idiopathic Dilated Cardiomyopathy.
A pilot Study
Influence of Smoking Consumption and Nicotine Dependence Degree
in Cardiac Autonomic Modulation
Complicated Neoatherosclerosis
Image
Left Ventricular Rigid Body Rotation in Ebstein’s Anomaly from the
MAGYAR-Path Study
Letter to the Editor
Predictors of Atrial Fibrillation Recurrence in Hyperthyroid and
Euthyroid Patients
A JOURNAL OF SOCIEDADE BRASILEIRA DE CARDIOLOGIA - Published since 1948
Contents
Editorial
Primordial Prevention and Wearable Health Devices: The Wearables in Cardiology
Eduardo Campos Pellanda e Lucia Campos Pellanda
.....................................................................................................................................................................page 455
Original Articles
Atherosclerosis/Endothelium/Vascular
Early Markers of Atherosclerotic Disease in Individuals with Excess Weight and Dyslipidemia
Eduardo Menti, Denise Zaffari, Thais Galarraga, João Regis da Conceição e Lessa, Bruna Pontin, Lucia Campos
Pellanda, Vera Lúcia Portal
.....................................................................................................................................................................page 457
Pediatric Cardiology
Mortality from Circulatory System Diseases and Malformations in Children in the State of
Rio de Janeiro
Thais Rocha Salim, Gabriel Porto Soares, Carlos Henrique Klein, Glaucia Maria Moraes de Oliveira
.....................................................................................................................................................................page 464
Epidemiology
Prevalence of Risk for Obstructive Sleep Apnea Syndrome and Association With Risk Factors in
Primary Care
Kenia Vieira da Silva, Maria Luiza Garcia Rosa, Antônio José Lagoeiro Jorge, Adson Renato Leite, Dayse Mary
Silva Correia, Davi de Sá Silva, Diego Bragatto Cetto, Andreia da Paz Brum, Pedro Silveira Netto, Gustavo
Domingos Rodrigues
.....................................................................................................................................................................page 474
Farmacologia
The Labdane Ent-3-Acetoxy-Labda-8(17), 13-Dien-15-Oic Decreases Blood Pressure In
Hypertensive Rats
Janaina A. Simplicio, Marilia R. Simão, Sergio R. Ambrosio, Carlos R. Tirapelli
.....................................................................................................................................................................page 481
Heart Failure
Association between Spirituality and Adherence to Management in Outpatients with Heart Failure
Juglans Souto Alvarez, Livia Adams Goldraich, Alice Hoefel Nunes, Mônica Cristina Brugalli Zandavalli, Rafaela
Brugalli Zandavalli, Karlyse Claudino Belli, Neusa Sica da Rocha, Marcelo Pio de Almeida Fleck, Nadine Clausell
.....................................................................................................................................................................page 491
Arquivos Brasileiros de Cardiologia - Volume 106, Nº 6, June 2016
Cardiomyopathies
Functional Class in Children with Idiopathic Dilated Cardiomyopathy. A pilot Study
Aline Cristina Tavares, Edimar Alcides Bocchi, Guilherme Veiga Guimarães
.....................................................................................................................................................................page 502
Other Diagnostic Tests (not involving imaging)
Influence of Smoking Consumption and Nicotine Dependence Degree in Cardiac Autonomic Modulation
Ana Paula Soares dos Santos, Dionei Ramos, Gabriela Martins de Oliveira, Ana Alice Soares dos Santos, Ana
Paula Coelho Figueira Freire, Juliana Tiyaki Ito, Renato Peretti Prieto Fernandes, Luiz Carlos Marques Vanderlei,
Ercy Mara Cipulo Ramos
.....................................................................................................................................................................page 510
Percutaneous Valvopathy
Transcatheter Aortic Valve Implantation and Morbidity and Mortality-Related Factors: a 5-Year
Experience in Brazil
André Luiz Silveira Souza, Constantino González Salgado, Ricardo Mourilhe-Rocha, Evandro Tinoco Mesquita,
Luciana Cristina Lima Correia Lima, Nelson Durval Ferreira Gomes de Mattos1, Arnaldo Rabischoffsky,
Francisco Eduardo Sampaio Fagundes, Alexandre Siciliano Colafranceschi, Luiz Antonio Ferreira Carvalho
.....................................................................................................................................................................page 519
Review Article
Ambulatory Blood Pressure Monitoring: Five Decades of More Light and Less Shadows
Fernando Nobre e Décio Mion Junior
.....................................................................................................................................................................page 528
Arquivos Brasileiros de Cardiologia - Volume 106, Nº 6, June 2016
Clinicoradiological Session
Case 4/2016: 32-Year-Old Female, with Critical Pulmonary Valve Stenosis. Operated at 4 months
of Age, in Normal Healing Evolution
Edmar Atik
.....................................................................................................................................................................page 538
Case Report
Drug-Coated Balloon Treatment of Very Late Stent Thrombosis Due to Complicated Neoatherosclerosis
Fernando Alfonso, Teresa Bastante, Javier Cuesta, Amparo Benedicto, Fernando Rivero
.....................................................................................................................................................................page 541
Image
Left Ventricular Rigid Body Rotation in Ebstein’s Anomaly from the MAGYAR-Path Study
Attila Nemes, Kálmán Havasi, Péter Domsik, Anita Kalapos, Tamás Forster
.....................................................................................................................................................................page 544
Letter to the Editor
Predictors of Atrial Fibrillation Recurrence in Hyperthyroid and Euthyroid Patients
Levent Cerit
.....................................................................................................................................................................page 546
Arquivos Brasileiros de Cardiologia - Volume 106, Nº 6, June 2016
www.arquivosonline.com.br
A JOURNAL OF SOCIEDADE BRASILEIRA DE CARDIOLOGIA - Published since 1948
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SUPPORT
Back to The Cover
Editorial
Primordial Prevention and Wearable Health Devices: The Wearables
in Cardiology
Eduardo Campos Pellanda1 and Lucia Campos Pellanda2,3
Pontifícia Universidade Católica-Rio Grande do Sul – PUC-RS1; Instituto de Cardiologia/ Fundação Universitária de Cardiologia do Rio Grande
do Sul – IC-FUC/RS2; Universidade Federal de Ciências da Saúde de Porto Alegre – UFCSPA3, Porto Alegre, RS – Brazil
Epidemiology has shown the growing importance of
prevention as a way of dealing with the cardiovascular risk
epidemic. One of the fundamental changes in concepts in
recent decades was the shift in the prevention paradigm to
ever earlier stages, both in the disease development, affecting
an increasing number of individuals that have yet to develop
a pathological condition or those who are in the early and
treatable stages, as of the life line itself, looking for the origin
of chronic diseases in intrauterine life.1 Thus, the concept of
primordial prevention arose, that is, the prevention of the
actual risk factors.
Ideally, preventing the establishment of risk factors in a
population would keep it disease-free. Although utopian,
the scenario described is useful to guide prevention
strategies. One of the main current objectives is to reach
the greatest possible number of individuals before they
develop a risk profile.
In this sense, the revolution of wearables, or wearable
devices, has great potential to contribute to primary
prevention, by participating in the daily lives of individuals
with an all-inclusiveness that is impossible for isolated
interventions based solely on health services to achieve.
To understand the wearables, one must recall how the
computer ceased to be something detached to become
something that is always close to our bodies. The computational
device formats have evolved since the late 1970s, with the
introduction of the concept of personal machines, or personal
computers – the PCs. The term "personal" refers to a computing
device attached to the daily lives of individuals, not corporate
life. If they conquered the homes in the 1980s, in the middle
of the 1990s, there were devices of several sizes and formats
powered by batteries that allowed user mobility that was
unheard of. While wireless networks (data or voice) expanded
their reach, the telephone started to be carried along by people
and even steal the attention that was previously given to the
radio and watch.
Keywords
Cardiovascular Diseases / prevention and control; Risk
Management; Risk Factors; Internet / utilization; Social
Networking; Mobile Applications.
Mailing Address: Lucia Campos Pellanda •
Instituto de Cardiologia do Rio Grande do Sul / Fundação Universitária
de Cardiologia
Av. Princesa Isabel, 370, 3º andar. CEP 99620-000, Bairro Santana,
Porto Alegre, RS – Brazil.
E-mail: [email protected] / [email protected]
DOI: 10.5935/abc.20160094
455
This infrastructure allowed a radical change to occur
in the interface of the common user and computing, also
resulting in the birth of a mobile application ecosystem in
this new form of Internet access - the main one, for many
individuals. This mobile connection status is "always‑on"
and hyperpersonal, 2 in addition to allowing new forms
of communication in the metropolis environment.
The logical evolution would be the intense use of
mobile communication, as well as the miniaturization of
components and devices, which are used attached to the
body and not in pockets anymore.3,4
Thus, wearables can be not only always close to the
individual, but also collect, through sensors, the body's own
information, such as counting steps or measuring heart rate.
Because of the very small screens, or without displays, they are
at the same time, the smartphone extensions and information
entry points through voice.5
At this initial phase, they take familiar forms, such as
glasses (Google Glass) or watches (Apple Watch and Pebble,
among others). In both cases, there is an adaptation of the
original shapes of glasses and watches to process information.
Watches would potentially have lower resistance, as they
always provided some kind of extra information in addition
to the hour. As for glasses, they were always perceived as
intended for the amplification and correction of optical
realities, which makes their transformation less acceptable
socially at this historical moment.
At the moment, what seems clear is that people have
different points of information in their bodies, thus making
the perception of connection more natural and "invisible".
The worldwide sales of wearables should reach the
figure of 200 million units by 2019.6 Considering today's
scenario, we must think of wearables not only as a wearable
accessory, but as an information accessory that can help
the public or by capturing or reporting data. These two
possibilities and their combinations allow more than just
uploading data at times when people are not in front of the
screens, in addition to the new useful characteristic that
information on the wrist, for instance, can carry.
Simple data capture devices, such as straps with motion and
heart rate sensors, can generate a huge volume of information,
which allows not only individual patient monitoring, but also
the planning of collective prevention strategies. This type of
Big Data can be useful, for instance, to evaluate ecological
interventions, such as changing the urban layout, to promote
physical activity in a city’s population.7
Additionally, the monitoring itself can help change
behaviors, as it furthers individuals’ knowledge about
themselves and encourages them to take the leading role
when caring for their own health.8
Pellanda E & Pellanda L
Primordial prevention and wearable health devices: the wearables in cardiology
Editorial
This is another example of the need for new paradigms
in research on prevention. To be able to follow the
evolution of concepts in prevention and the change
in lifestyles at a time of mobile information, research
also needs to be innovative, transdisciplinary and agile.
The Brazilian Archives of Cardiology, in its role of
stimulating innovative research in cardiology, proposes
to carry out intervention studies in our country, so that
technological innovations can in fact contribute to the
improvement of health outcomes.
References
1.
Pellanda LC. Trajectories of cardiovascular health: life course epidemiology
in Brazil. Arq Bras Cardiol. 2014;102(5):418-9.
2. Pellanda EC. Internet móvel: novas relações na cibercultura derivadas
da mobilidade na comunicação. [Tese]. Porto Alegre: Departamento
Comunicação Social da PUCRS; 2005.
3. Ryan SE. Garments of paradise: wearable discourse in the digital age.
Cambridge (MA): The Mit Press; 2014.
4.
Greengerdn S. The Internet of things. Cambridge (MA): The Mit Press; 2014.
6.
International Data Corporation (IDC). IDC. Forecasts worldwide shipments
of wearables to surpass 200 million in 2019, driven by strong smartwatch
growth. [Cited in 2016 May 10]. Available from: http://www.idc.com/
getdoc.jsp?containerId=prUS41100116
7. Cummins P, Serruys PW. Sensors, wearables and devices in the e-age:
tomorrow’s world today. EuroIntervention. 2015;10(12):1373.
8. Mercer K, Li M, Giangregorio L, Burns C, Grindrod K. Behavior change
techniques present in wearable activity trackers: a critical analysis. JMIR
Mhealth Uhealth. 2016;4(2):e40.
5. Saffer D. Microinteractions, design with details. Sebastopol (CA): O’Reilly
Media Inc, 2013.
Arq Bras Cardiol. 2016; 106(6):455-456
456
Back to The Cover
Original Article
Early Markers of Atherosclerotic Disease in Individuals with Excess
Weight and Dyslipidemia
Eduardo Menti, Denise Zaffari, Thais Galarraga, João Regis da Conceição e Lessa, Bruna Pontin, Lucia Campos
Pellanda, Vera Lúcia Portal
Instituto de Cardiologia – Fundação Universitária de Cardiologia, Porto Alegre, RS – Brazil
Abstract
Background: Excessive weight is a cardiovascular risk factor since it generates a chronic inflammatory process that
aggravates the endothelial function.
Objective: To evaluate the endothelial function in individuals with excess weight and mild dyslipidemia using brachial artery
flow-mediated dilation (BAFMD), and the association of endothelial function with anthropometric and biochemical variables.
Methods: Cross-sectional study that included 74 individuals and evaluated anthropometric variables (body mass
index [BMI], waist-hip ratio [WHR], waist circumference [AC], and percentage of body fat [PBF]), biochemical (blood
glucose, insulinemia, ultrasensitive C-reactive protein, fibrinogen, total cholesterol, HDL-cholesterol, triglycerides,
and LDL-cholesterol) and endothelial function (BAFMD, evaluated by ultrasound). The statistical analysis was
performed with SPSS, version 16.0. To study the association between the variables, we used chi-square, Student’s t
and Mann-Whitney tests, and Pearson’s correlation. Logistic regression analyzed the independent influence of the
factors. Values of p < 0.05 were considered significant.
Results: The participants had a mean age of 50.8 years, and 57% were female. BMI, WC, WHR, and PBF showed no
significant association with BAFMD. The male gender (p = 0.02) and higher serum levels of fibrinogen (p = 0.02) were
significantly and independently associated with a BAFMD below 8%.
Conclusions: In individuals with excess weight and mild untreated dyslipidemia, male gender and higher levels of
fibrinogen were independently associated with worse BAFMD. (Arq Bras Cardiol. 2016; 106(6):457-463)
Keywords: Atherosclerosis; Biomarkers; Endothelium; Obesity; Dyslipidemias.
Introduction
When endothelial cells are exposed to risk factors such as
hypertension, smoking, insulin resistance, and obesity, they
are stimulated to express adhesion molecules on their surface,
recruiting several classes of leukocytes and promoting the
initial signaling mechanisms for cellular changes and atheroma
formation.1-4 Endothelial dysfunction may be detected even
before the occurrence of obstructive atherosclerotic plaques.5
The amount of nitric oxide released by endothelial cells
depends on the integrity of the endothelium and determines
the degree of vasodilation.6 The most used method to
estimate endothelial dysfunction is the evaluation of the
brachial artery diameter before and after distal tissue ischemia
(hyperemic reaction).7 This measurement has applications in
Mailing address: Vera Lucia Portal •
Instituto de Cardiologia / Fundação Universitária de Cardiologia (IC/
FUC). Rua Luciana de Abreu 471, sala 603 – Moinhos de Vento.
Postal Code 90570-080, Porto Alegre, RS – Brazil
E-mail: [email protected]; [email protected]
Manuscript received June 12, 2015; revised manuscript January 04, 2016;
accepted January 06, 2016.
DOI: 10.5935/abc.20160060
457
population studies, but its individual application has not been
established yet.8-10 Dilation values between 8 and 10% seem
to be the best discriminators between normal and abnormal
endothelial functions.8,11
Obesity and excessive weight are able to change the vascular
endothelium function.12,13 There is growing recognition that
obesity is characterized by a low degree of chronic and
subclinical inflammation.14,15 The exact mechanisms that
stimulate this sustained inflammation have not been elucidated
yet but are highly relevant to the atherothrombotic process.16,17
It is, thus, crucial to identify variables that could predict
the progression of the disease and the occurrence of clinically
significant events in obese individuals. This study evaluated the
occurrence of associations of anthropometric measures and
metabolic and inflammatory markers with endothelial function
assessed by brachial artery dilation in individuals with excess
weight and mild untreated dyslipidemia. The objective was to
identify the variable with a better ability to predict the occurrence
of subclinical atherosclerosis and, consequently, more useful in
the clinical follow-up of individuals with excess weight.
Methods
This study is part of a research conducted at Instituto de
Cardiologia involving individuals with excess weight and
Menti et al.
Atherosclerosis and obesity: in search of the missing link
Original Article
dyslipidemia. The sample was obtained by convenience,
and the study of the endothelial function was performed
in one in every four participants undergoing nutritional and
anthropometric follow-up, in a total of 74 individuals.
Inclusion criteria
The study included men and women aged 35–60 years,
with dyslipidemia and excess weight, and without a
history of clinically manifested cardiovascular disease.
Dyslipidemia was considered present when the levels of at least
one of the following biochemical parameters was abnormal:
total cholesterol (TC) > 200 mg/dL, and/or triglycerides
(TG) > 150 mg/dL, and/or HDL-cholesterol < 40 mg/dL in
men and < 50 mg/dL in women. Excess weight was assessed
with the body mass index (BMI), and the participants had BMI
values between 25 and 35 kg/m².
Exclusion criteria
Exclusion criteria were the occurrence of neoplasms,
infections, and liver, kidney and gastrointestinal disorders;
levels of LDL-cholesterol > 160 mg/dL and TG > 400 mg/dL;
pregnancy and lactation; alcohol consumption above four
doses a day; use of estrogen, nonsteroidal anti-inflammatory,
antiobesity agents, and vitamin supplementation; use of statins,
fibrates, and other lipid-lowering medications; unexplained
weight loss (greater than 2 kg) in the last 30 days.
Ethical aspects
The study was approved by the Ethics Committee in Research
(Comitê de Ética em Pesquisa, COEP) at Fundação Universitária
de Cardiologia. All patients were informed about the study by
reading and analyzing the free and informed consent form and
agreed to participate. The research protocol did not interfere
with any medical recommendation or prescription.
Study protocol
The selected individuals answered a standardized
questionnaire and their anthropometric measurements (BMI,
waist circumference [WC], waist-hip ratio [WHR], and body
fat percentage), metabolic profile (blood glucose, insulin,
TC, HDL-cholesterol, and TG), and inflammatory profile
(C-reactive protein [CRP] and fibrinogen) were analyzed.
The endothelial function was assessed with brachial artery
flow-mediated dilatation (BAFMD). The technique used in
this study was that recommended by the American Society
of Echocardiography and Society of Vascular Medicine and
Biology, based on the percentage modification of the brachial
artery diameter by reactive hyperemia7.
considered as overweight and those equal to or above 30 kg/m2
as obesity. The association of the variables was analyzed with
the chi-square test for dichotomous variables, Student's t test
for parametric continuous variables, and Mann-Whitney test
for nonparametric continuous variables. Results of ultrasensitive
CRP (usCRP) are presented as median since this is a variable
with a non-Gaussian distribution. Differences were considered
statistically significant for p values < 0.05. Additionally, logistic
regression was conducted to assess the independent influence of
factors significantly associated with the endothelial vasodilation
response and Pearson's correlation test to estimate the degree
of linear relationship between the serum level of fibrinogen and
the percentage of dilation of the brachial artery. We used the
statistical program SPSS, version 16.0 (SPSS Inc., Chicago, USA).
Results
The participants had a mean age of 50.88 ± 6.14 years,
and 57% were female. All individuals had excess weight with
a mean BMI value of 28.82 ± 2.60 kg/m2 and some degree of
dyslipidemia, with mean values of TC of 222.67 ± 34.24 mg/dL,
HDL-cholesterol of 45.68 ± 14.83 mg/dL, LDL-cholesterol of
146.05 ± 32.02 mg/dL, and TG of 154.66 ± 79.37 mg/dL
(Table 1). The WC was increased in 46.9% of the men and
75.0% of the women while the WHR was abnormal in 90.5%
of the men and 38.1% of the women. The percentage of body
fat varied between 14.81% and 36.14%, with a mean value of
Table 1 – Characteristics of the cohort
Characteristic
n
Statistics
Age (years)
74
50.88 ± 6.14
Female gender (%)
74
42 (57%)
Smokers (%)
74
11 (14.8%)
Body mass index (kg/m²)
74
28.82 ± 2.60
Waist circumference (cm)
74
Waist/hip ratio
74
Percentage of body fat (%)
74
M: 101.48 ± 7.25
F: 95.90 ± 12.90
M: 0.93 ± 0.05
F: 0.83 ± 0.06
M: 21.53 ± 3.28
F: 24.45 ± 4.29
Insulin
74
10.57 ± 6.09
Blood glucose (mg/dL)
74
101.45 ± 29.45
Total cholesterol (mg/dL)
74
222.67 ± 34.24
M: 39.52 ± 8.44
HDL-cholesterol (mg/dL)
74
Statistical analysis
LDL-cholesterol (mg/dL)
74
146.05 ± 32.02
The results are presented as mean ± standard deviation
for continuous variables. WC, WHR, and BMI were treated
as qualitative variables using cutoff points described in the
literature for values considered abnormal. Values of WC and
WHR were considered abnormal in men when above 102 cm
and 0.9, respectively, and in women when above 88 cm and
0.85, respectively. Values of BMI between 25 and 30 kg/m2 were
Triglycerides (mg/dL)
74
154.66 ± 29.45
Fibrinogen (mg/dL)
74
266.00 ± 63.06
74
0.29 ± 0.31
Ultrasensitive C-reactive protein (mg/L)
*
F: 50.24 ± 16.73
Data are presented as mean ± standard deviation and median
*
or value (percentage). HDL-cholesterol: high-density cholesterol;
LDL‑cholesterol: low-density lipoprotein cholesterol; M: male; F: females.
Arq Bras Cardiol. 2016; 106(6):457-463
458
Menti et al.
Atherosclerosis and obesity: in search of the missing link
Original Article
23.19 ± 4.12%. Only eight individuals had body fat percentage
values above those compatible with obesity (25% in men and
32% in women). The individuals were then subdivided into
groups of overweight and obesity. According to this criterion,
29.7% of the sample was composed of obese individuals.
The diameter of the brachial artery varied 7.80 ± 6.41%
during the BAFMD when compared with its baseline value
(Table 1). The median BAFMD value was 8%, which served
as a cutoff point for a qualitative analysis between individuals
with vasodilation responses above and below this value.
WC, WHR, and BMI, treated as qualitative variables,
showed no association with the degree of vasodilation
response treated as a continuous variable (verified by Student's
t test) or qualitative variable (verified with the chi-square test,
with a cutoff point of 8% for the BAFMD result) (Table 2).
The male gender showed a significant association with a worse
vasodilation response, i.e., men had more frequently BAFMD
values below 8% (p = 0.03) (Figure 1).
The biochemical results of the metabolic parameters
and inflammatory markers were treated as quantitative
variables and their associations with the endothelial function
were verified with Student's t test (Table 2). Fibrinogen was
the only biochemical parameter significantly associated
with the endothelial function (p = 0.02) (Figure 2).
When this association was evaluated by quartiles of dilation,
we observed that for dilatation values below 3.7%, the mean
serum fibrinogen was of 295.50 ± 50.41 mg/dL, whereas
for dilation values greater than 13.03%, the mean was
229.41 ± 48.95 mg/dL (Figure 3).
After we had observed the association of the male gender
and serum fibrinogen level with worse brachial artery
vasodilation response, we performed a logistic regression
analysis to verify whether this would be an independent
association. The results demonstrated that the associations
between endothelial function with male gender and serum
levels of fibrinogen remained significant. The male gender
increased the chances of a worse vasodilation response
by approximately three times (odds ratio [OR] 3.33; 95%
confidence interval [CI] 1.19 – 9.28, p = 0.02), while an
increase in 1 mg/dL in serum fibrinogen level increased
this risk in 1% (OR 1.01, 95%CI 1.00 – 1.01, p = 0.02).
Therefore, it would be expected that an increase of
100 mg/dL in serum fibrinogen level would increase in
approximately two times the risk of a worse vasodilation
brachial artery response.
The variables were additionally evaluated with Pearson's
correlation test, and the correlation factor with the dilation
of the brachial artery for fibrinogen was -0.31 (p = 0.008).
Discussion
In a cohort of individuals with excess weight, mild
dyslipidemia, and without clinically significant atherosclerotic
disease, we found that the male gender and high levels of
serum fibrinogen were associated with worse endothelial
function determined by BAFMD. Our study suggests the
relevance of measuring circulating fibrinogen as a marker of
subclinical atherosclerosis in individuals with excess weight
without manifested atherosclerotic disease.
The association of the male gender with worse endothelial
function is aligned with clinical and epidemiological
observations that the male gender is an important risk factor for
atherosclerotic disease. By studying the influence of risk factors
on endothelial function in asymptomatic individuals, different
researchers have demonstrated an independent and significant
association of the male gender with worse BAFMD.18-20
Table 2 – Association between anthropometric, metabolic and inflammatory variables with brachial artery flow-mediated dilatation
Variable
BAFMD < 8%
BAFMD ≥ 8%
p
Male gender
21
11
p = 0.03
BMI > 30 kg/m² †
10
12
p = 0.09
Abnormal WC †
Men: > 102 cm; Women: > 88 cm
24
29
p = 0.83
Abnormal WHR †
Men: > 0.85; Women: > 0.90
21
19
p = 0.51
Percentage of body fat ‡
23.04
23.34
p = 0.22
Insulin ‡
9.60
11.63
p = 0.15
Blood glucose
99.60
103.00
p = 0.59
LDL-cholesterol ‡
146.50
145.57
p = 0.90
HDL-cholesterol ‡
42.63
49.00
p = 0.06
Triglycerides ‡
167.11
141.14
p = 0.16
Fibrinogen ‡
281.55
248.62
p = 0.02
0.17
0.36
p = 0.14
UsCRP *
*nonparametric variable, association verified with the Mann-Whitney test; † association verified with the chi-square test; ‡ parametric variables, association verified with
Student’s t test. BAFMD: brachial artery flow-mediated dilatation; BMI: body mass index; WC: waist circumference; WHR: waist/hip ratio; LDL‑cholesterol: low‑density
lipoprotein cholesterol; HDL-cholesterol: high-density cholesterol; UsCRP: ultrasensitive C-reactive protein.
459
Arq Bras Cardiol. 2016; 106(6):457-463
Menti et al.
Atherosclerosis and obesity: in search of the missing link
Original Article
Figure 1 – Association between gender and brachial artery flow-mediated dilatation. BAFMD: brachial artery flow-mediated dilatation.
Figure 2 – Association between fibrinogen levels and brachial artery flow-mediated dilatation. BAFMD: brachial artery flow-mediated dilatation.
The inclusion of individuals with a mean age of 50 years in
our study confirms this association, since at this age men have
a higher cardiovascular risk than women.
Elevated fibrinogen levels are strongly associated with
atherosclerotic disease. The ARIC (Atherosclerosis Risk in
Communities) study has shown an increased risk of coronary
disease with higher levels of fibrinogen, with a relative risk
of 1.76. 21 In the PROCAM (Prospective Cardiovascular
Münster) study, the occurrence of death due to coronary
disease and nonfatal infarction was greater among individuals
with higher levels of fibrinogen. In that study, fibrinogen
levels were better risk predictors than BMI and levels of
LDL‑cholesterol.22 In a meta-analysis that included 22 studies
evaluating the association between serum concentration of
fibrinogen and cardiovascular disease, the estimated risk of
events in individuals with levels of fibrinogen in the highest
tercile was two times greater than that in individuals with
levels in the lowest tertile (OR 1.99, 95%CI 1.85 – 2.12).23
In children or adolescents with overweight or obesity, fibrinogen
has also been associated with usCRP elevation and with the
Arq Bras Cardiol. 2016; 106(6):457-463
460
Menti et al.
Atherosclerosis and obesity: in search of the missing link
Original Article
Figure 3 – Distribution of serum fibrinogen levels by quartiles of brachial artery flow-mediated dilatation results.
occurrence of four or more cardiovascular risk factors24.
In contrast, the association between fibrinogen and markers
of early atherosclerosis has already been demonstrated in
studies evaluating the carotid myointimal thickening and
BAFMD. In a series of asymptomatic individuals, elevated
fibrinogen levels were significantly related to increased
myointimal thickening, independent of other potentially
confounding variables. 25 The same has been observed
in another study that evaluated fibrinogen and usCRP as
markers of subclinical carotid atherosclerosis.26
Similarly, greater myointimal carotid thickening, worse
BAFMD, and higher concentrations of E-selectin and
thrombomodulin have shown association with serum
fibrinogen levels in obese children. 27 Fibrinogen has
also been described as more frequently increased in
individuals with type 2 diabetes mellitus with metabolic
syndrome than in those without metabolic syndrome.
In addition, fibrinogen increases the risk of microvascular
diseases, including diabetic retinopathy.28 A small study
that has only evaluated the influence of fibrinogen in
endothelium-dependent vasodilation has observed an
inverse relationship between plasma levels of fibrinogen
and degree of BAFMD.29 When individuals with manifested
heart disease are considered, fibrinogen also appears as a
marker of worse brachial artery vasodilation response.30
High serum levels of fibrinogen may promote vascular
disease by increasing blood viscosity, stimulating fibrin
formation, or increasing platelet-platelet interaction.
Fibrinogen may also be simply a marker of vascular disease
without contributing for its progression.31 The hepatic production
of fibrinogen is regulated by cytokines whose concentrations
461
Arq Bras Cardiol. 2016; 106(6):457-463
increase in response to different inflammatory processes.
In this context, excess weight has been associated with a higher
production of inflammatory cytokines by the adipose tissue.
This inflammatory status is due to a dysfunction in the interaction
between adipocytes and tissue macrophages.4,15,32 CRP is also
an acute phase inflammatory protein and its baseline levels are
independent risk predictors of myocardial infarction and stroke,
showing correlation with fibrinogen levels.33,34 Our study did not
confirm an association between CRP and fibrinogen, which can
be explained in part by the non-normal distribution of the CRP
levels and the low levels detected in the serum. Similarly, the
study lacked power to test the association between fibrinogen
levels and degree of excess weight. This relationship has already
been demonstrated in previous studies focusing on WC,35
body fat,36 BMI, and WHR.37 The narrow range of variation of
the anthropometric parameters in our cohort seems to have
influenced the lack of association of the adiposity measurements
with endothelium-dependent vasodilation.
Obese individuals have a low-degree chronic inflammatory
condition that manifests with worse flow-mediated vasodilation
response.38,39 A relationship has already been demonstrated
between markers of prothrombotic status, like fibrinogen and
prothrombin activity, with the degree of visceral adiposity and
other cardiovascular risk factors.40
Weight reduction is able to revert the deleterious
effect of excessive weight on endothelial function through
mechanisms not yet fully known.41-43 These observations
about fibrinogen levels in obese individuals bring an
additional element to the final consideration that fibrinogen
is intimately related to subclinical atherosclerotic disease in
individuals with excess weight.44
Menti et al.
Atherosclerosis and obesity: in search of the missing link
Original Article
Study limitations
The results of this study suggest an association between
male gender and fibrinogen levels with endothelial function
in individuals with excess weight and dyslipidemia.
However, since this was a cross-sectional study, it is unable to
determine a cause-effect relationship between these variables.
The verification of the association between inflammatory
markers and degrees of excess weight, as well as between the
degrees of excess weight and endothelial dysfunction may
have been compromised by the uniformity of the degrees of
adiposity and the sample size.
Conclusion
The results of this study suggest that fibrinogen is associated
with subclinical atherosclerosis in individuals with excess
weight. New studies should clarify this association and
establish the benefit of including fibrinogen as a marker in
clinical practice to evaluate this group of patients.
E, Zaffari D, Galarraga T, Conceição e Lessa JR, Portal VL.
Analysis and interpretation of the data: Menti E, Pellanda LC,
Portal VL. Statistical analysis: Menti E, Pellanda LC, Portal VL.
Obtaining financing: Menti E, Zaffari D, Portal VL. Writing
of the manuscript: Menti E, Portal VL. Critical revision of the
manuscript for intellectual content: Menti E, Portal VL.
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
Eduardo Menti, from Fundação Universitária de Cardiologia
do Rio Grande do Sul.
Author contributions
Conception and design of the research:Menti E, Zaffari D,
Galarraga T, Pontin B, Portal VL. Acquisition of data: Menti
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Back to The Cover
Original Article
Mortality from Circulatory System Diseases and Malformations in
Children in the State of Rio de Janeiro
Thais Rocha Salim1,2, Gabriel Porto Soares1,2, Carlos Henrique Klein2,3, Glaucia Maria Moraes de Oliveira1,2
Pós-Graduação em Cardiologia - Universidade Federal do Rio de Janeiro1; Instituto de Cardiologia Edson Saad - Universidade Federal
do Rio de Janeiro2; Escola Nacional de Saúde Pública da Fundação Oswaldo Cruz3, Rio de Janeiro, RJ, Brazil
Abstract
Background: The epidemiological profile of mortality in a population is important for the institution of measures to improve
health care and reduce mortality
Objective: To estimate mortality rates and the proportional mortality from cardiovascular diseases and malformations of
the circulatory system in children and adolescents.
Methods: This is a descriptive study of mortality from cardiovascular diseases, malformations of the circulatory system,
from all causes, ill-defined causes and external causes in children and adolescents in the state of Rio de Janeiro from
1996 to 2012. Populations were obtained from the Brazilian Institute of Geography and Statistics (Instituto Brasileiro de
Geografia e Estatística - IBGE) and deaths obtained from the Department of Informatics of the Unified Health System
(DATASUS)/Ministry of Health.
Results: There were 115,728 deaths from all causes, 69,757 in males. The annual mortality from cardiovascular diseases
was 2.7/100,000 in men and 2.6/100,000 in women. The annual mortality from malformations of the circulatory system
was 7.5/100,000 in men and 6.6/100,000 in women. Among the specific causes of circulatory diseases, cardiomyopathies
had the highest rates of annual proportional mortality, and from malformations of the circulatory system, it occurred due
to unspecified malformations of the circulatory system, at all ages and in both genders.
Conclusion: Mortality from malformations of the circulatory system was most striking in the first years of life, while
cardiovascular diseases were more relevant in adolescents. Low access to prenatal diagnosis or at birth probably prevented
the proper treatment of malformations of the circulatory system. (Arq Bras Cardiol. 2016; 106(6):464-473)
Keywords: Cardiovascular Defects; Heart Defects, Congenital / mortality; Heart Defects, Congenital / epidemiology;
Child Mortality.
Introduction
In Brazil, in the year 2012, cardiovascular diseases were the
leading cause of death in the general population, but children
and adolescents do not show that mortality profile.1 In children
younger than 1 year, cardiovascular diseases are the ninth
cause of death; in children aged 1 to 9 years, it is the eighth;
in those aged 10 to 14 years, the seventh; and in those aged
15 to 19 years, it is the fourth most important cause of death,
considering the chapters of the International Classification of
Diseases (ICD-10).1,2 External causes (EC) are the main cause
of death, except in children younger than 1 year, for whom
they occupy the sixth position. As for ill-defined causes (IDC)
of mortality, they range between the fifth and seventh positions
in those younger than 15 years, being the third most important
cause in children aged 15 to 19 years.1
Mailing Address: Gláucia Maria Moraes de Oliveira •
Universidade Federal do Rio de Janeiro – R. Prof. Rodolpho P. Rocco, 255
– Prédio do HU 8º andar – sala 6, UFRJ. Postal Code 21941-913, Cidade
Universitária, RJ – Brasil
E-mail: [email protected], [email protected]
Manuscript received November 01, 2015; revised manuscript January 13,
2016; accepted January 18, 2016.
DOI: 10.5935/abc.20160069
464
Children younger than 1 year have the highest rates
of overall mortality, with the main causes of deaths being
conditions originating in the perinatal period, which
corresponded to 58.6% of deaths in this age group in Brazil
in 2012.1,3
Child mortality is divided into two components: the
neonatal and the post-neonatal period.3 Its causal factors
are closely linked to health and nutrition, and to women’s
educational and socioeconomic level, as well as the quality
of care provided during prenatal care and delivery, and
assistance at birth.4 With the improvement of these factors,
there was a change in the distribution of infant mortality
composition from 1994 to 2012, with a reduction in
the post-neonatal period, but little has changed in the
neonatal period.5
The main causes of neonatal mortality are intrauterine and
intrapartum asphyxia, extreme prematurity and congenital
malformation.6,7 Among the congenital malformations, those
of the circulatory system have greater impact on mortality,
being classified as preventable causes of death, as they could
be reduced by early interventions.6 High mortality rates due
to malformations of the circulatory system (MCS) result from
prenatal diagnosis scarcity, resulting in ineffective treatment,
with consequent death.8
Salim et al.
Deaths from circulatory diseases and malformations in children in Rio de Janeiro
Original Article
Few national publications report studies on mortality
from circulatory system diseases and MCS in the pediatric
population. To know the epidemiological profile of mortality
of a population is important to implement improvement
measures of assistance in health and reduced mortality.
The aim of this study was to estimate the rates of mortality
per inhabitant and proportional mortality from circulatory
system diseases and MCS in children and adolescents.
Methods
Descriptive study of rates of mortality from circulatory
system diseases and MCS from all causes (AC), IDC and EC
in children and adolescents in the state of Rio de Janeiro
from 1996 to 2012. The children were divided into three age
groups: children younger than 1 year, children aged 1 to 4
years and 5 to11 years. Adolescents, as defined in the Statute
of Children and Adolescents, are those aged 12 to 17 years.9,10
Data related to the deaths were obtained from the
Department of Informatics of the Brazilian Unified Health
System (DATASUS) (http://tabnet.datasus.gov.br/cgi/sim/
dados/cid10_indice.htmdados). These data consist of sets
of all death certificates (DC) recorded in the state of Rio de
Janeiro, from 1996 to 2012, year by year. From each database
of annual data, we selected only the deaths of live births up
to the age of full 17 years.1,11 During the period, the code of
the underlying cause of death was used, according to ICD 10.2
Diseases of the circulatory system correspond to deaths
of which underlying cause was any one from Chapter IX of
ICD-10. The specific causes of death from circulatory diseases
were: rheumatic fever (I 00-09); hypertensive diseases (I
10-15); ischemic heart disease (I 20-21); pulmonary heart
diseases and pulmonary circulation diseases (I 26-28);
membranes (pericarditis I30-I32 and acute and subacute
endocarditis I33); valvular diseases (I34-39); myocarditis (I4041); cardiomyopathies (I42-43); conduction diseases (I44-49);
heart failure (I50); complications of heart disease and illdefined heart diseases (I51-52); hemorrhagic cerebrovascular
diseases (I60-62); cerebral infarction (I63); unspecified
cerebrovascular accident (I64); other cerebrovascular diseases
(I65-69); vascular diseases (I70-89); and other unspecified
diseases of the circulatory system (I95-99).
The deaths of which underlying cause was MCS
corresponds to the chapter XVII of the ICD-10 and were
discriminated in the categories heart chambers and septal
defects (Q20); cardiac septa (Q21); pulmonary and tricuspid
valves (Q22); aortic and mitral valves (Q23); others and nonspecified (Q24); great arteries (Q25); other vessels (Q26-28).
The deaths of which underlying causes were IDC correspond
to those of Chapter XVIII of the ICD-10. The deaths from EC
are those from Chapters XIX and XX of ICD-10, which were
also discriminated into categories: transportation accidents
(V01-99), other accidental trauma (W00-X59) and nonaccidental external causes (X60-Y98). Deaths were grouped
into four categories of time: 1996 to 1999, 2000 to 2004,
2005 to 2009 and 2010 to 2012.
Data related to the populations from 1996 to 2012 were
obtained from the DATASUS site (http://tabnet.datasus.gov.br/
cgi/deftohtm.exeibge/cnv/poprj.def). These population data
were grouped according to age, gender and periods, similarly
to the deaths, in order to estimate annual mortality rates per
100,000 inhabitants.
Total proportional mortality was calculated for each group
of causes, without exclusions, and from defined endogenous
causes, excluding the ill-defined and external causes, in
percentages.
Bar charts were built of the annual proportional mortality
from specific causes of the circulatory system (cardiovascular
diseases and MCS) per age and gender, from 1996 to 2012.
The quantitative procedures were performed using the
programs Excel-Microsoft12 and STATA.13
The study was carried out in accordance with the current
ethical principles and was approved by the research ethics
committee of Hospital Universitário Clementino Fraga Filho,
which belongs to Universidade Federal do Rio de Janeiro.
Results
From 1996 to 2012, there were 115,728 deaths from AC
in individuals younger than 18 years in the state of Rio de
Janeiro, of which 69,757 were males and 45,971 females. The
mean annual mortality from AC was 442.7 per 100,000 in
both genders, and 530.6 in the male and 353.8 in the female
gender. During the same period, there were 1,986 deaths, of
which the underlying cause was classified as cardiovascular
diseases, with 1,026 occurring in males and 958 in females.
Therefore, the annual mortality from cardiovascular diseases
was 2.6 deaths per 100,000 inhabitants in both genders, and
2.7 in males and 2.6 in females. The proportional mortality
from circulatory diseases, i.e., the percentage of deaths from
this group of causes in relation to total deaths, was 1.7, 1.5
and 2.1%, respectively.
During the same period, there were 5,287 deaths, of
which the underlying cause was classified as MCS, with 2,837
occurring in males and 2,450 in females. The annual mortality
from MCS was 7.0 per 100,000 in both genders, with 7.5 in
males and 6.6 in females, with proportional mortalities of 4.6,
4.1 and 5.3%, respectively.
However, 24,111 deaths were classified as caused by IDC
or EC, of which 18,906 in males and 5,205 in females, with a
proportional mortality of 20.8, 27.1 and 11.3%, respectively.
Excluding the diseases of which the underlying cause was
IDC or EC, the proportional mortality from circulatory system
diseases was 2.2% in both genders, 2.0% in males and 2.3%
in females, whereas the proportional mortality from MCS
increased to 5.8% in both genders, 5.6% in males and 6.0%
in females. It should also be noted that during the period,
there were 12,696 deaths due to malformations in any organ
or system, of which 6,719 occurred in males and 5,977 in
females. Thus, 41.6% of deaths occurred from MCS, of which
42.2% in males and 41.0% in females.
Results according to age groups can be seen in Tables 1 to
6. The largest mortality rates from AC were observed in males
in all age groups, with children younger than 1 year being the
group with the highest rates (Table 1). Mortality rates from
MCS in boys were higher than in girls in all groups, except
for those aged 5 to 11 years. Mortality rates from circulatory
Arq Bras Cardiol. 2016; 106(6):464-473
465
Salim et al.
Deaths from circulatory diseases and malformations in children in Rio de Janeiro
Original Article
Table 1 – Total Proportional mortality and by defined endogenous causes* and annual mortality per 100,000 in children** and adolescents due to
diseases and malformations of the circulatory system, and mortality from all causes, according to gender and age group, in the state of Rio de
Janeiro , 1996-2012
Male
Causes of death
Diseases of
the circulatory
system
Malformations
of the
circulatory
system
All causes
Female
Age <1
1-4 years
5-11 years
12-17 years
Age <1
1-4 years
5-11 years
12-17 years
Deaths
233
177
174
442
257
187
174
340
Total PM (%)
0.6
2.9
3.4
2.4
0.8
3.7
4.6
6.2
Endogenous PM (%)*
0.6
4.4
6.3
13.5
0.9
5.3
7.3
12.2
Mortality per 100,000
11.4
2.2
1.2
3.4
13.1
2.4
1.2
2.6
Deaths
2,385
283
95
74
2,038
259
102
51
5.9
4.6
1.9
0.4
6.4
5.2
2.7
0.9
Total PM (%)
Endogenous PM (%)*
6.4
7.0
3.5
2.3
6.9
7.3
4.3
1.8
Mortality per 100,000
116.3
3.5
0.6
0.6
104.0
3.3
0.7
0.4
Deaths
40,223
6,207
5,144
18,183
31,725
5,020
3,755
5,471
Mortality per 100,000
1962.1
76.2
35.0
138.3
1619.1
63.8
26.4
42.1
* Excluding the ill-defined and external causes (ICD-10 chapters XVIII to XXII); ** mortality of children younger than 1 year per live births. PM: proportional mortality.
system diseases were higher in girls than in boys in the groups
of children younger than 1 year and 1 to 4 years and similar in
those aged 5 to 11 years; however, in the group of adolescents
(12 to 17 years), it was the opposite, with the mortality rate
in boys being higher than in girls (Table 1).
As for the total proportional mortality from circulatory
system diseases and MCS, that is, without excluding IDC or
EC, the girls always showed higher rates than the boys’ in the
four age groups (Table 1). However, only the endogenous
proportional mortalities, excluding IDC and the EC, were
higher in boys in the age group of the adolescents, mainly
due to high mortality rates due to external causes in boys.
When adding the rates of endogenous proportional
mortality from diseases of the circulatory system and the
MCS, there was a relative increase in the participation of the
total, from approximately 7.2% in the first year of life to up to
15.8% in male adolescents. In girls, this progression was 7.8
to 14.0%. When evaluating the total proportional mortality,
without excluding IDC and EC, such difference was not
observed in males (Table 1).
466
the EC (Table 2). The fraction of trauma caused by accidents
became relevant as early as in the group of 1 to 4 years of
age (Table 2).
The period of 1996-1999 showed higher AC mortality
rates in all age groups in both sexes (Tables 3 to 6). In groups
aged 1-4 years, 5-11 years and in adolescents there was a
slight increase in AC mortality rates in the 2010-2012 period,
when compared with the two previous years in both genders
(Table 4). The exception occurred in adolescents, whose last
period showed the lowest AC mortality rate (Table 6).
Mortality rates from cardiovascular diseases increased
significantly only in children younger than 1 year, most
evidently in children in the last two periods, compared
to the first two (Table 3). In other age groups, there were
minor fluctuations, except in girls aged 1 to 4 years and
in adolescents, in whom, in the first period (1996-1999),
mortality rates from cardiovascular diseases were higher
(Tables 4 to 6).
The differences between total and endogenous proportional
mortality from diseases of the circulatory system increased
from the younger group to the older group of adolescents,
with more emphasis on the male gender, and the opposite
occurred with total and endogenous proportional mortalities
from MCS (Table 1).
Mortality rates from MCS exceeded more than one death
per thousand births in children younger than 1 year in both
genders (Table 1). In all study periods, MCS mortality rates in
boys were higher than in girls. At the age range 1 to 4 years,
MCS mortality rates were even higher than for circulatory
system diseases (Table 4). In the two older age groups, those
rates are quite low, and all represent less than one death per
100,000 individuals (Tables 5 and 6).
The IDC are more important in the group aged 1 to 4
years, both in boys and girls, which represented just over 10%
of all deaths (Table 2). In relation to the EC, transportation
accidents were the most important from 5 to 11 years; as
for non-accidental external causes, they were extremely
relevant in the group of adolescents, especially among boys,
in which approximately six in ten deaths were caused, mostly,
by injuries and aggression. Even among girls, approximately
two out of ten deaths were also caused by this fraction of
Among the specific causes of cardiovascular diseases,
cardiomyopathies showed the highest rates of annual
proportional mortality in both genders (Figure 1).
Cardiomyopathies were predominant mainly in the age group 1
to 4 years (25.4% in boys and 31% for girls). Cardiomyopathies
were followed by hemorrhagic cerebrovascular disease, with
predominance in the age range 5 to 11 years for males and 12
to 17 years in females. Heart disease complications were in the
third place, with a higher percentage in children younger than
Arq Bras Cardiol. 2016; 106(6):464-473
Salim et al.
Deaths from circulatory diseases and malformations in children in Rio de Janeiro
Original Article
Table 2 – Proportional mortality from ill-defined and external causes in children and adolescents, according to gender and age group in the
state of Rio de Janeiro, 1996-2012
Male
Causes of death
Ill-defined
Transportation accidents
Other accidental traumas
External non-accidental causes
All causes
Female
Age <1 year
1-4 years
5-11 years
12-17 years
Age <1 year
1-4 years
5-11 years
12-17 years
Deaths
1,607
709
296
816
1.248
506
282
488
PM (%)
4.0
11.4
5.8
4.5
3.9
10.1
7.5
8.9
Deaths
70
272
861
1,746
50
211
485
685
PM (%)
0.2
4.4
16.7
9.6
0.2
4.2
12.9
12.5
Deaths
996
901
872
1,526
740
546
421
353
PM (%)
2.5
14.5
17.0
8.4
2.3
10.9
11.2
6.5
Deaths
215
264
372
10,811
154
214
192
1,154
PM (%)
0.5
4.3
7.2
59.5
0.5
4.3
5.1
21.1
Deaths
40,223
6,207
5,144
18,183
31,725
5,020
3,755
5,.471
PM (%)
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
PM: prorpotional mortality.
Table 3 – Total proportional mortality and from defined endogenous causes* and annual mortality per 100,000 live births in the first year of life** from
diseases and malformations of the circulatory system, and from all causes, according to gender and age group, in the state of Rio de Janeiro, 1996-2012
Male
Causes of death
Diseases of the
circulatory system
Malformations of the
circulatory system
1996-1999
2005-2009
2010-2012
1996-1999
2000-2004
2005-2009
2010-2012
Deaths
53
51
77
41
57
69
71
43
Total PM (%)
0.4
0.5
0.9
0.8
0.5
0.9
1.0
1.1
Endogenous PM (%)*
0.4
0.6
0.9
0.9
0.6
1.0
1.1
1.2
Mortality per 100,000 LB
9.7
8.3
13.8
12.2
11.0
11.8
13.3
13.4
Deaths
630
572
645
394
551
517
511
318
Total PM (%)
4.5
5.8
7.1
7.8
5.1
6.6
7.1
7.8
Endogenous PM (%)*
Mortality per 100,000 LB
All causes
2000-2004
Female
4.9
6.2
7.6
8.5
5.5
7.1
7.6
8.5
115.7
93.6
115.7
116.9
106.1
88.4
95.8
98.8
Deaths
13,965
9,915
9,065
5,071
10,839
7,823
7,247
4,072
Mortality per 100,000 LB
2,563.9
1,622.4
1,626.7
1,504.9
2,087.1
1,337.9
1,358.1
1,265.5
* Excluding the ill-defined and external causes (ICD-10 chapters XVIII to XXII); ** mortality of children younger than 1 year per live births. PM: prorpotional mortality;
LB: live births.
1 year and aged 1 to 4 years, with a slight predominance of
females. Pulmonary heart and pulmonary circulation diseases
came after that, in both genders, in children younger than 1
year, followed by rheumatic fever at the age range of 12 to
17 and 5 to 11 years (Figure 1).
The greatest proportional mortality from MCS occurred
from unspecified MCS according to ICD 10, at all ages and in
both genders. They were followed by cardiac septal defects,
except in the group of children younger than 1 year in both
genders, in whom malformations of the great arteries came
next. In adolescent males, the second position was occupied
by malformations of other vessels (Figure 2).
Discussion
Diseases of the circulatory system are the leading
cause of adult mortality, especially those secondary to
atherosclerotic diseases, such as cerebrovascular disease
and ischemic heart disease, which together accounted for
over 60% of deaths from cardiovascular diseases in the
state of Rio de Janeiro in 2012.14 In children younger than
1 year of age, deaths due to malformations are among the
leading causes of death, second only to perinatal conditions.
Among the malformations, those of the circulatory
system are the main components.1 The MCS contribute
mostly to the deaths in children younger than 1 year and
Arq Bras Cardiol. 2016; 106(6):464-473
467
Salim et al.
Deaths from circulatory diseases and malformations in children in Rio de Janeiro
Original Article
Table 4 – Total proportional mortality and from defined endogenous causes* and annual mortality per 100,000 inhabitants aged 1 to 4 years,
from diseases and malformations of the circulatory system, and from all causes, according to gender and age group in the state of Rio de
Janeiro 1996-2012
Male
Causes of death
Diseases of the
circulatory system
Malformations of the
circulatory system
All causes
1996-1999
2000-2004
Female
2005-2009
2010-2012
1996-1999
2000-2004
2005-2009
2010-2012
Deaths
49
41
52
26
66
35
46
30
Total PM (%)
2.5
2.7
3.5
2.9
4.0
2.9
3.9
4.5
Endogenous PM (%)*
3.8
4.2
5.3
4.4
5.6
4.3
5.2
6.2
Mortality per 100,000
2.7
1.6
2.1
2.2
3.7
1.4
1.9
2.6
Deaths
79
77
80
27
80
64
73
32
Total PM (%)
4.0
5.1
5.4
3.1
4.8
5.3
6.1
4.8
Endogenous PM (%)*
6.2
7.9
8.1
4.6
6.8
7.8
8.3
6.7
Mortality per 100,000
4.3
3.0
3.2
2.2
4.5
2.6
3.0
2.7
1,996
1,519
1,477
884
1,669
1,218
1,192
671
107
.9
59.5
58.2
73.4
92.8
49.4
48.9
57.3
Deaths
Mortality per 100,000
* Excluding the ill-defined and external causes (ICD-10 chapters XVIII to XXII); PM: prorpotional mortality.
Table 5 – Total proportional mortality and from defined endogenous causes* and annual mortality per 100,000 inhabitants aged 5 to 11 years,
from diseases and malformations of the circulatory system, and from all causes, according to gender and age group in the state of Rio de
Janeiro, 1996-2012
Male
Causes of death
Deaths
Diseases of the
circulatory system
Malformations of the
circulatory system
1996-1999
2000-2004
2005-2009
2010-2012
1996-1999
2000-2004
2005-2009
2010-2012
41
35
60
27
48
39
50
26
Total PM (%)
2.8
2.9
4.3
3.4
4.7
4.7
4.7
4.2
Endogenous PM (%)*
5.9
5.7
7.2
5.9
8.0
7.5
7.0
6.6
Mortality per 100,000
1.2
0.8
1.3
1.1
1.5
0.9
1.1
1.1
Deaths
26
23
29
12
30
25
25
15
Total PM (%)
1.8
1.9
2.1
1.5
2.9
3.0
2.3
2.4
Endogenous PM (%)*
3.8
3.7
3.5
2.6
5.0
4.8
3.5
3.8
Mortality per 100,000
All causes
Female
0.8
0.5
0.6
0.5
0.9
0.6
0.6
0.6
Deaths
1,448
1,215
1,405
805
1,030
828
1,071
619
Mortality per 100,000
43.5
27.9
30.8
32.6
32.0
19.6
24.3
25.9
* Excluding the ill-defined and external causes (ICD-10 chapters XVIII to XXII). PM: prorpotional mortality.
aged 1 to 4 years, because these causes are often incompatible
with life and highly dependent on adequate hospital-medical
support for survival, leading to early mortality, with progressive
reduction in the following age groups. This behavior is opposite
to that of circulatory diseases, which show progressive increase
until they become the leading cause of death in adults after the
fifth decade of life.1
In adolescents of both genders, when analyzing the
endogenous proportional mortality, it can be observed that
diseases of the circulatory system, from that age group on,
are among the leading causes of death. However, at this age
range, the major cause of death from circulatory diseases is
468
Arq Bras Cardiol. 2016; 106(6):464-473
cardiomyopathy, not atherosclerotic disease, which occurs
predominantly at older ages.15
Among the MCS, unspecified diseases are the leading cause
of death at all age ranges and in both genders, suggesting low
access to prenatal diagnosis or at birth, preventing adequate
treatment, resulting in death. Some studies show that 30%
of MCS are not diagnosed within the first week of life.16,17
Measures such as prenatal care and performing obstetric
echocardiography could reduce these deaths, allowing early
diagnosis and patient referral to specialized treatment centers,
even before birth.17 However, a major problem constitutes the
service network of public and private health systems, not only
Salim et al.
Deaths from circulatory diseases and malformations in children in Rio de Janeiro
Original Article
Table 6 – Total proportional mortality and from defined endogenous causes* and annual mortality per 100,000 inhabitants aged 12 to 17
years, from diseases and malformations of the circulatory system, and from all causes, according to gender and age group in the state of Rio
de Janeiro, 1996-2012
Male
Causes of death
1996-1999
Diseases of the
circulatory system
Malformations of the
circulatory system
All causes
Female
2000-2004
2005-2009
2010-2012
1996-1999
2000-2004
2005-2009
2010-2012
Deaths
114
97
140
69
128
65
89
43
Total PM (%)
2.4
2.2
2.6
2.7
8.1
5.1
6.3
4.6
Endogenous PM (%)*
13.1
14.3
14.9
11.1
16.6
11.1
11.6
8.2
Mortality per 100,000
3.7
2.5
3.7
2.9
4.1
1.7
2.4
1.8
Deaths
18
19
20
14
12
14
11
10
Total PM (%)
0.4
0.4
0.4
0.6
0.8
1.1
0.8
1.1
Endogenous PM (%)*
2.1
2.8
2.1
2.3
1.6
2.4
1.4
1.9
Mortality per 100,000
0.6
0.5
0.5
0.6
0.4
0.4
0.3
0.4
Deaths
4.849
4.389
5.354
2.520
1.587
1.268
1.418
926
Mortality per 100,000
155.6
115.1
139.6
105.9
51.0
33.5
37.6
39.7
* Excluding the ill-defined and external causes (ICD-10 chapters XVIII to XXII). PM: prorpotional mortality.
in the state of Rio de Janeiro, but in the whole country, which
cannot treat 62% of children with MCS, reaching in some
regions of Brazil , 76 to 91% of cases16,18.
If one considers that the MCS can be treated, classifying
them in the category of preventable deaths, the appropriate
care of the pediatric population would result in significant
decrease in child mortality rates, mainly in the early neonatal
period.19,20 Additionally, the early treatment of children
with congenital heart disease prevents successive hospital
admissions for complications of the disease and ensures better
quality of life.21,22
It is observed that mortality from circulatory diseases
decreases up to the age range of 5 to 11 years, increasing again
in adolescents, whereas in MCS, the decrease is continuous and
much more pronounced. It must be considered that children
with MCS, often already repaired and that did not die in the
first year of life, can have complications and sequelae such as
heart failure, arrhythmias, endocarditis, among others, which
can lead to death in adolescence, increasing mortality from
circulatory system diseases in this age group.23
The complications of heart disease, which are the third
cause of circulatory system diseases and mean acquired
structural heart complications due to residual disease from
previous surgical treatments such as chordae tendineae or
papillary muscle rupture, intracardiac thrombosis, cardiomegaly,
acquired septal defect and other ill-defined or unspecified heart
diseases increase the occurrence of death from circulatory
system diseases.
The total proportional mortality from circulatory system
diseases in males does not increase as the age groups advance.
This finding is related to what is observed in the proportional
mortality from IDC and external causes, especially in the group
of the latter related to non-accidental EC, mainly comprising
injuries and aggression, as the impact of mortality from IDC and
EC in boys is observed mainly in adolescents. In females, the
participation of the sum of mortalities is constant throughout
childhood and adolescence, when IDC and EC are not
excluded. The predominance of the male gender in mortality
from EC found in this study has been observed in many parts
of the world.24,25
This fact is explained by the male gender’s greater exposure
to risk factors, such as alcohol, tobacco or other drugs, use
of firearms or knives, school absenteeism and inclusion in
activities considered illicit.26 As for the fact that intentionality
changes according to age, with a prevalence of accidents among
children and violence among adolescents, one must consider
that children are more exposed to accidents caused by their
own immaturity, curiosity, intense growth and development,
resulting in a higher proportion of accidental causes, especially
in the domestic environment.27 Whereas adolescents are more
vulnerable to violence, because of social marginality and drug
exposure, among other negative events.28,29
In the period from 2010 to 2012, the mortality rate from
AC in male adolescents showed a relevant decrease of 24%
compared to previous periods, which did not occur in females.
During the same period, in the state of Rio de Janeiro, there
was a decrease in deaths from homicides caused by the police,
recorded in the so-called acts of resistance to authority, in which
the main victims are male adolescents and young adults.30 This
fact may be related to this significant reduction in the mortality
rate.
The limitation of this study was the quality variation in
the filling-out of death certificates (DCs) over time and study
location, the state of Rio de Janeiro. However, the DCs are the
best available sources of mortality data.
Conclusion
In the state of Rio de Janeiro, from 1996 to 2012, there
was a progressive reduction in mortality from all causes in
children and adolescents. The highest mortality rates were
Arq Bras Cardiol. 2016; 106(6):464-473
469
Salim et al.
Deaths from circulatory diseases and malformations in children in Rio de Janeiro
Original Article
Proportional mortality from CSD causes
According to age range – female gender
Rheumatic fever
Hypertensive
Ischemic
Pulmonary heart disease
Membranes
Valvar
Myocarditis
Cardiomyopathy
Conduction
Heart failure
Heart disease complications
Hemorrhagic CBVD
Ischemic CBVD
Non-pspecified CBVD
Other CBVD
Vessels
Other unspecified CSD
0
2
4
6
8
10 12 14 16 18 20 22 24 26
Proportional mortality %
Younger than 1 year
From 5 to 11 years
28 30
From 1 to 4 years
From 12 to 17 years
Proportional mortality from CSD causes
According to age – male gender
Rheumatic fever
Hypertensive
Ischemic
Pulmonary heart disease
Membranes
Valvar
Myocarditis
Cardiomyopathy
Conduction
Heart failure
Heart disease complications
Hemorrhagic CBVD
Ischemic CBVD
Non-pspecified CBVD
Other CBVD
Vessels
Other unspecified CSD
0
2
4
6
8
10 12 14 16 18 20 22 24 26
Proportional mortality %
Younger than 1 year
From 5 to 11 years
28 30
From 1 to 4 years
From 12 to 17 years
Figure 1 – Annual proportional mortality from specific causes of the circulatory system in children and adolescents, by gender and age group in the state of Rio de
Janeiro, from 1996 to 2012. CSD: circulatory system diseases; CBVD: cerebrovascular disease.
470
Arq Bras Cardiol. 2016; 106(6):464-473
Salim et al.
Deaths from circulatory diseases and malformations in children in Rio de Janeiro
Original Article
Proportional mortality from MCS causes
According to age range – female gender
Heart chambers and septal defects
Cardiac septa
Pulmonary and tricuspid valves
Aortic and mitral valves
Unspecified and others
Great arteries
Other vessels
0
5
10
15
20
25 30 35 40 45 50
Proportional mortality %
Younger than 1 year
From 5 to 11 years
55
60
65
From 1 to 4 years
From 12 to 17 years
Proportional mortality from MCS causes
According to age – male gender
Heart chambers and septal defects
Cardiac septa
Pulmonary and tricuspid valves
Aortic and mitral valves
Unspecified and others
Great arteries
Other vessels
0
5
10
15
20
25 30 35 40 45 50
Proportional mortality %
Younger than 1 year
From 5 to 11 years
55
60
65
From 1 to 4 years
From 12 to 17 years
Figure 2 - Annual proportional mortality from specific causes of malformations of the circulatory system in children and adolescents, by gender and age group in the
state of Rio de Janeiro, from 1996 to 2012. MCS: malformations of the circulatory system.
Arq Bras Cardiol. 2016; 106(6):464-473
471
Salim et al.
Deaths from circulatory diseases and malformations in children in Rio de Janeiro
Original Article
observed in children younger than 1 year and in the male
gender. Mortality from malformations of the circulatory
system was higher in the early years, while mortality
from cardiovascular diseases became more important in
adolescents. There is a difference in the mortality profile
between the genders, as the boys died more frequently
from external causes and girls died mainly from endogenous
diseases. Deaths from circulatory system diseases became
relevant in male adolescents after deaths from external causes
were excluded, predominantly those caused by violence.
Author contributions
Conception and design of the research: Salim TR, Soares GP,
Oliveira GMM, Klein CH. Acquisition of data:Salim TR, Soares
GP, Oliveira GMM, Klein CH. Analysis and interpretation of
the data: Salim TR, Soares GP, Oliveira GMM, Klein CH.
Statistical analysis: Salim TR, Soares GP, Oliveira GMM,
Klein CH. Writing of the manuscript:Salim TR, Soares GP,
Oliveira GMM, Klein CH. Critical revision of the manuscript
for intellectual content: Salim TR, Soares GP, Oliveira GMM,
Klein CH. Supervision / as the major investigador:Salim TR.
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 Thais
Rocha Salim, from Universidade Federal do Rio de Janeiro.
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Arq Bras Cardiol. 2016; 106(6):464-473
473
Back to The Cover
Original Article
Prevalence of Risk for Obstructive Sleep Apnea Syndrome and
Association With Risk Factors in Primary Care
Kenia Vieira da Silva1, Maria Luiza Garcia Rosa1, Antônio José Lagoeiro Jorge2, Adson Renato Leite2, Dayse Mary
Silva Correia3, Davi de Sá Silva1, Diego Bragatto Cetto1, Andreia da Paz Brum1, Pedro Silveira Netto1, Gustavo
Domingos Rodrigues1
Departamento de Epidemiologia e Bioestatística - Universidade Federal Fluminense1; Departamento de Medicina Clínica - Universidade
Federal Fluminense2; Departamento de Fundamentos de Enfermagem e Administração - Universidade Federal Fluminense3, Niterói, RJ – Brazil
Abstract
Background: Obstructive sleep apnea syndrome (OSAS) is a chronic, progressive disease with high morbidity
and mortality. It is underdiagnosed, especially among women.
Objective: To study the prevalence of high risk for OSAS globally and for the Berlin Questionnaire (BQ) categories,
and to evaluate the reliability of the BQ use in the population studied.
Methods: Observational, cross-sectional study with individuals from the Niterói Family Doctor Program,
randomly selected, aged between 45 and 99 years. The visits occurred between August/2011 and December/2012.
Variables associated with each BQ category and with high risk for OSAS (global) were included in logistic
regression models (p < 0.05).
Results: Of the total (616), 403 individuals (65.4%) reported snoring. The prevalence of high risk for OSA was 42.4%,
being 49.7% for category I, 10.2% for category II and 77.6% for category III.
Conclusion: BQ showed an acceptable reliability after excluding the questions Has anyone noticed that you stop
breathing during your sleep? and Have you ever dozed off or fallen asleep while driving?. This should be tested in
further studies with samples mostly comprised of women and low educational level individuals. Given the burden of
OSAS-related diseases and risks, studies should be conducted to validate new tools and to adapt BQ to better screen
OSAS. (Arq Bras Cardiol. 2016; 106(6):474-480)
Keywords: Sleep Apnea Obstructive; Risk Factors; Prevalence; Surveys and Questionnaires.
Introduction
Obstructive sleep apnea syndrome (OSAS) is a chronic
and progressive disease of increasing importance, because
of its neurocognitive and cardiovascular sequelae, such as
systemic arterial hypertension (SAH).1 It is underdiagnosed,
mainly among women.2
Obstructive sleep apnea syndrome is characterized by
repeated episodes of complete or partial airflow cessation
in the upper airways (apnea and hypopnea, respectively).
Such changes are due to complete or partial airflow
obstruction at the pharynx level, often resulting in oxygen
desaturation and brief awakenings from sleep (arousals).2
In addition to polysomnography, considered gold standard
for the diagnosis of OSAS, some tools, such as scales,
Mailing Address: Antônio José Lagoeiro Jorge •
Rua Coronel Bittencourt, 66. Postal Code 24900-000, Boa Vista,
Maricá, RJ – Brazil
E-mail: [email protected]; [email protected]
Manuscript received April 06, 2015; revised manuscript October 19, 2015;
accepted February 04, 2016.
DOI: 10.5935/abc.20160061
474
despite not diagnosing the disorder, indicate the risk for
OSAS. Berlin Questionnaire (BQ) is one of them. It comprises
three categories of questions, which include snoring, daytime
sleepiness and diagnosis of hypertension and obesity.3
In Brazil, we identified only one study estimating the
prevalence of high risk for OSAS in the general population,
conducted in the city of São Paulo.4 Considering the high
prevalence of hypertension and the need to better understand
the behavior of the BQ in our population, a more careful
investigation is certainly extremely useful.
The present study was aimed at estimating the prevalence
of high risk for OSAS per BQ category and globally, in
addition to assessing the reliability of BQ in a population
cared for by the Niterói Family Doctor Program (FDP), Rio de
Janeiro state, Brazil.
Methods
The present study is part of the DIGITALIS Trial, 5
a cross‑sectional study of a random population sample
registered in the Niterói FDP, including individuals of both
sexes, aged from 45 to 99 years. Medical and nurse visits
were appointed at selected FDP healthcare units from August
2011 to November 2012, where blood and urine samples
Silva et al.
Risk for obstructive sleep apnea syndrome
Original Article
were collected, electrocardiography and echocardiography
performed, and a questionnaire specifically elaborated for
the study with validated tools, such as the BQ, was applied.
The researchers were trained in the procedures elaborated
and tested in the pilot-study, carried out in a FDP healthcare
unit not included in this study.
the appointment, or regular use of anti-hypertensive drugs.
Body mass index ≥30 kg/m2 was used to define obesity.
Statistical analysis
We calculated the absolute and relative frequencies of
the participants’ characteristics, of the responses considered
positive according to the BQ score, of the risk categories and
of high risk for OSAS (global). Differences were tested as
follows: between the proportions, by using Pearson chi-square
test, with continuity correction for dichotomous risk variables;
and between the means, by using non-paired Student t test.
Variables associated with each category and conveying high
risk for OSAS (global), with 0.20 significance in the difference
between proportions or means, were included in logistic
regression models, when statistical significance was established
as <0.05. Because the presence of SAH or obesity (BMI)
defines category III, those two variables were not assessed
on raw and adjusted analysis of category III. All analyses were
performed with the SPSS program, version 21 (IBM Corp.
Released 2012. IBM SPSS Statistics for Windows, Version
21.0. Armonk, NY: IBM Corp).
Initially, 942 individuals were invited, and 616 attended
the appointments, completed the questionnaire, underwent
anthropometric and clinical examinations, being included in
this study (35% missed the appointment). Table 1 shows sex
and age differences of those attending and completing the
investigation and those who did not.
Endpoint: High risk for OSAS measured via BQ. The BQ
comprises 10 items, organized into three categories
concerning snoring and apnea (5 items), daytime
sleepiness (4 items) with a subquestion about sleepiness
while driving (nodding off while driving a motor vehicle)
and history of SAH or obesity (1 item). Risk classification
(high risk versus non high risk) was based on the responses
in each category, as follows: category I – persistent
symptoms (>3-4 times/week) in at least 2 questions;
category II - persistent symptoms (>3-4 times/week) with
report of excessive daytime sleepiness or sleepiness while
driving a motor vehicle, or both; category III – history of
SAH or body mass index (BMI) ≥30 kg/m2. Individuals at
high risk for OSAS were those with positive scoring in at
least two BQ categories.4,6
Ethical considerations
This study was conducted according to the principles
established in CONEP Resolution 466/2012.
This study protocol was submitted to the Research
Ethics Committee of the Medical School of the Antônio
Pedro University-affiliated Hospital, and approved
(CAAE:0077.0.258.000-10).
Exposure. Age: was recorded in complete years at the time
of the appointment and categorized into 10-year age ranges.
Type 2 diabetes mellitus (DM): report of previous medical
diagnosis of DM, fasting blood glucose ≥ 126 mg/dL measured
at the time of the appointment, or use of antidiabetic
medications. Arterial hypertension: previous diagnosis of SAH,
systolic blood pressure (SBP) ≥ 140 mm Hg and/or diastolic
blood pressure (DBP) ≥ 90 mm Hg measured at the time of
Results
The sample of 616 individuals included in this study
had the following characteristics: female sex, 61.9%; mean
age, 59.1±10.20 years; elementary educational level, 68%;
Table 1 – Characteristics of the individuals invited to participate in the study (assessed and not assessed)
Participants with complete information
Individuals who refused to participate or those
with incomplete information
N (%)
N (%)
Female
381 (61.9)
174 (53.4)
Male
235 (38.1)
152 (46.6)
Sex
Age group
45-49 years
110 (17.9)
70 (23.0)
50-59 years
246 (39.9)
105 (34.5)
60-69 years
150 (24.4)
65 (21.4)
70-79 years
86 (14.0)
47 (15.5)
24 (3.9)
17 (5.6)
80-99 years
Diabetes
151 (24.8)
Hypertension
448 (72.7)
Obesity (BMI≥30)
189 (30.7)
BMI: body mass index.
Arq Bras Cardiol. 2016; 106(6):474-480
475
Silva et al.
Risk for obstructive sleep apnea syndrome
Original Article
hypertensive, 72.7%; obese, 30.7%; and diabetic, 24.8%.
Individuals of the two extreme age groups assessed comprised
most of those excluded from the analysis.
Table 2 shows the scores of BQ responses and the
prevalence of high risk for OSAS per BQ category and globally.
Of all individuals assessed, 403 individuals (65.4%) reported
snoring. Three of four responses of category I scored between
22% and 38.5%, while for the question Has anyone noticed
that you stop breathing during your sleep?, only 1.8% of the
responses scored. In category II, two of the three questions
scored approximately 12%, but only 3.4% scored the question
Have you ever nodded off or fallen asleep while driving a
vehicle?. The global prevalence of high risk for OSAS was
42.4%, with 49.7% prevalence in category I, 10.2% in category
II, and 77.6% in category III. The prevalence of high risk for
OSAS in category I, according to age groups, had a bell shape
curve (p<0.01) and was higher among obese individuals
(p<0.01). Only sex associated with high risk for OSAS in
category II (p<0.1 and >0.05). The characteristics ‘female
sex’, ‘advanced age’ and ‘DM’ showed statistically significant
association with high risk for OSAS in category III (hypertension
and obesity). Age and DM (p<0.1 and >0.05) associated with
global prevalence of high risk for OSAS (Table 3).
Table 4 shows the difference of the means of age, SBP, DBP
and BMI according to the presence of high risk for OSAS.
In category I, there was association with age, BMI (p<0.01)
and DBP (p<0.1 and >0.05). In category II, none of the four
variables associated with high risk for OSAS. In category III,
the elderly showed higher prevalence of high risk for OSAS.
No statistically significant association was observed with global
prevalence of high risk for OSAS. In categories III and global,
SBP, DBP and BMI were not assessed.
Table 5 shows the results of logistic regressions including the
variables with p <0.2 in bivariate analyses. After adjusting, BMI
(positive association) and age (negative association) maintained
a statistically significant association with high risk for OSAS
in category I. Considering that only sex showed association
in category II, no adjustment was necessary. In category III,
sex (female), age (positive) and DM remained statistically
significant at level 0.05. Regarding global prevalence of high
risk for OSAS, DM lost statistical significance.
Discussion
In the present study, the BQ use showed a 42.4%
global prevalence of high risk for OSAS, slightly higher
than that found in two studies conducted in the city of
São Paulo. In the first study, Tufik et al.,4 assessing the
general population, have reported a 32.8% prevalence.
The second study, assessing railroad workers, has reported
a 35.03% prevalence. 7 The diagnosis of OSAS in both
Table 2 – Scores of the Berlin Questionnaire (BQ) responses and prevalence of high risk for OSAS per BQ categories and globally
Questions in the scoring categories
N (%)
Do you snore?
Yes
403 (65.4)
You snoring is...
Louder than talking or much louder than talking
138 (22.4)
How often do you snore?
3-4 times per week or almost every day
136 (22.1)
Has your snoring ever bothered other people?
Yes
219 (35.6)
Has anyone noticed that you stop breathing during your sleep?
3-4 times per week or almost every day
11 (1.8)
How often do you feel tired or fatigued after your sleep?
3-4 times per week or almost every day
96 (15.6)
During your waking time, do you feel tired or not up to par?
3-4 times per week or almost every day
96 (15.6)
Have you ever nodded off or fallen asleep while driving a vehicle?
Yes
21 (3.4)
Risk for OSAS
Category I
63 (10.2)
Category III
478 (77.6)
Global
261 (42.4)
OSAS: obstructive sleep apnea syndrome.
476
306 (49.7)
Category II
Arq Bras Cardiol. 2016; 106(6):474-480
Silva et al.
Risk for obstructive sleep apnea syndrome
Original Article
Table 3 – Prevalence of risk for OSAS1 defined via the Berlin Questionnaire per category and globally, according to risk variables
Risk for OSAS
Category I
N (%)
N (%)
Yes
No
N (%)
Yes
No
Category III
p value
N (%)
N (%)
Yes
No
0.074
Global
p value
N (%)
N (%)
Yes
No
0.001
183 (48.0)
198 (52.0)
46 (12.1)
335 (87.9)
313 (82.2)
68 (17.8)
168 (44.1)
213 (55.9)
Male
123 (52.3)
112 (47.7)
17 (7.2)
218 (92.8)
165 (70.2)
70 (29.8)
93 (39.6)
142 (60.4)
45-49
49 (44.5)
61 (55.5)
9 (8.2)
101 (91.8)
68 (61.8)
42 (38.2)
32 (29.1)
78 (70.9)
50-59
139 (56.5)
107 (43.5)
32 (13.0)
214 (87.0)
195 (79.3)
51 (20.7)
124 (50.4)
122 (49.6)
60-69
81 (54.0)
69 (46.0)
17 (11.3)
133 (88.7)
116 (77.3)
34 (22.7)
68 (45.3)
82 (54.7)
70-79
33 (38.4)
53 (61.6)
4 (4.7)
82 (95.3)
77 (89.5)
9 (10.5)
33 (38.4)
53 (61.6)
80-99
4 (16.7)
20 (83.3)
1 (4.2)
23 (95.8)
22 (91.7)
2 (8.3)
4 (16.7)
20 (83.3)
< 0.001
0.156
0.412
Diabetes
< 0.001
0.516
< 0.001
< 0.001
0.105
Yes
80 (53.0)
71 (47.0)
13 (8.6)
138 (91.4)
131 (86.8)
20 (13.2)
73 (48.3)
78 (51.7)
No
223 (48.7)
235 (51.3)
49 (10.7)
409 (89.3)
340 (74.2)
118 (25.8)
185 (40.4)
273 (59.6)
Yes
223 (49.8)
225 (50.2)
43 (9.6)
405 (90.4)
No
83 (49.4)
85 (50.6)
20 (11.9)
148 (88.1)
BMI ≥ 30
116 (61.4)
73 (38.6)
22 (11.6)
167 (88.4)
BMI < 30
190 (44.5)
237 (55.5)
41 (9.6)
386 (90.4)
1.00
Hypertension
1.000
< 0.001
BMI
p value3
0.308
Female
Age group
1
N (%)
0.339
Sex
2
Category II
p value
0.498
OSAS: obstructive sleep apnea syndrome; 2BMI: body mass index. 3Pearson chi-square test, with continuity correction for dichotomous risk variables.
Table 4 – Difference of the means according to the presence of high risk for OSAS defined via the Berlin Questionnaire per category and globally
Risk for sleep apnea via Berlin Questionnaire
p
value
Category I
p
value
Category II
p
value
Category III
p
value
Global
Yes
No
Yes
No
Yes
No
Yes
No
Mean ± SE
Mean ± SE
Mean ± SE
Mean ± SE
Mean ± SE
Mean ± SE
Mean ± SE
Mean ± SE
59.36 ± 0.44
Age
57.94 ± 0.50
60.45 ± 0.65
< 0.002
57.90 ± 1.02
SBP
137.55 ± 1.23
137.78 ± 1.35
0.899
136.53 ± 3.13 137.80 ± 0.95 0.676
0.201 60.18 ± 0.48 55.85 ± 0.75 < 0.001 58.77 ± 0.55 59.53 ± 0.59 0.347
DBP
83.60 ± 0.71
81.843 ± 0.69
0.078
82.47 ± 1.61
82.75 ± 0.52
0.865
BMI
28.92 ± 0.32
27.21 ± 0.29
< 0.001
28.91 ± 0.77
27.97 ± 0.23
0.200
OSAS: obstructive sleep apnea syndrome; SBP: systolic blood pressure; SE: standard error; DBP: diastolic blood pressure; BMI: body mass index. Student t test.
Arq Bras Cardiol. 2016; 106(6):474-480
477
Silva et al.
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Table 5 – Adjusted OR by logistic regression of risk for OSAS defined via the Berlin Questionnaire per category and globally
Variables
Age (continuous)
Category I
ORa (95%CI)
Category III
ORa (95%CI)
0.99 (0.98-0.99)
1.00 (1.00-1.01)
Global risk category
ORa (95%CI)
Age group
45-49
1
50-59
2.3 (1.30-3.50)
60-69
1.04 (0.53-2.04)
70-79
1.70 (0.98-2.94)
80-99
0.49 (0.10-2.41)
Sex (Female)
1.17 (1.06-1.29)
Diabetes
0.87 (0.81-0.95)
PAD continuous
1.00 (0.98-1.00)
BMI ≥ 30
1.02 (1.01-1.03)
1.33(0.88-2.00)
OSAS: obstructive sleep apnea syndrome; DBP: diastolic blood pressure; BMI: body mass index; ORa: adjusted OR.
studies was based on polysomnography. The prevalence
of OSAS in different scenarios varies according to the
distribution of sex, age groups, socioeconomic levels and
obesity in the population.4,8 Lemos et al.,9 assessing truck
drivers in São Paulo, have reported an 11.5% prevalence
of high risk for OSAS, estimated using the BQ. Their study
involved young and slim patients, mostly men. Another
study conducted in 40 primary care units, 8 in Germany,
6 in Spain and 26 in the United States, using the BQ, has
reported prevalences of high risk for OSAS varying from
19.9% in Springfield, USA, to 66.7% in Louisville, USA.6
The calculation of global high risk for OSAS via BQ
combines the risks of three categories, and all hypertensive
and/or obese individuals are classified as at risk in category III.
Obesity has been strongly associated with OSAS. Tufik et al.4
have found an OR of 10.5 (95%CI: 7.1-15.7). Association with
SAH seems to be less intense, even considering patients whose
blood pressure does not drop during sleep (non‑dipper), or
those with resistant hypertension [odds ratio (OR) of 2.27
(95%CI: 1.76-2.92),10 4.4 (95%CI: 1.2-16.31)11 and 7.74
(95%CI: 2.43–24.64),12 respectively]. The authors of the BQ
do not justify the inclusion of that category and have not
measured its impact on the calculation of high risk for OSAS.3
In our study population, 72.7% of the individuals were
classified as hypertensive, and 30.7%, as obese, increasing
the prevalence of high risk for OSAS in category III, and,
consequently, of global prevalence. In the study by Tufik et
al.,4 with OSAS prevalence slightly lower than that of high risk
for OSAS found in this study, mean age was smaller, as was the
prevalence of obesity (21.5%). Those authors have provided
no data on blood pressure. A North American study,13 in which
mean age and prevalence of obesity (25%) and of SAH (29%)
were lower than those found in our study, has reported a 27%
prevalence of high risk for OSAS. High prevalence of risk for
OSAS in category III has also been reported by Netzer et al.6
in Stuart, Florida (68.8%), closer to the prevalence in category
III found in the present study (77.6%).
478
Arq Bras Cardiol. 2016; 106(6):474-480
Considering that, an overestimated prevalence of SAH
and obesity could be suspected, and consequently, of OSAS.
According to the 2011 and 2012 Brazilian surveillance
system of risk factors and protection against chronic diseases
via telephone Vigitel (2011 and 2012), the prevalence of
self-reported diagnosis of hypertension in the city of Rio de
Janeiro was 59.7%, the highest among all Brazilian capitals
and the highest mean prevalence of all cities investigated for
the age group ≥65 years. These figures are smaller than the
77.6% found in this study for the population cared for by the
Niterói FDP. Regarding obesity, the Brazilian prevalence for
the age groups of 45 years and older was higher (20% versus
30.7%). It is worth noting, however, that the prevalence
of obesity recorded in Vigitel (2011 and 2012) was higher
among women and less educated individuals, major groups
in the present study.14,15
Primary snoring is believed to be the first stage of
severe OSAS, and its intensity is known to associate with
the severity of OSAS.16 Snoring has 82.6% sensitivity and
43% specificity to diagnose OSAS,17 thus the need to be
associated with other elements to define high risk for that
syndrome. In our study, the frequency of snoring was higher
(65.4%) than in two other studies using the BQ (52.2%
and 59%).3,13 Considering the higher percentage of obese
individuals in our study, that discrepancy was expected.
Our prevalences were lower than those of the two studies,
differing in the responses to the questions How often do
you snore?, Has your snoring ever bothered other people?
and mainly Has anyone noticed that you stop breathing
during your sleep?. However, the prevalence of high risk for
OSAS in category I (49.7%) was similar to those estimated
in most North American and European primary care clinics
assessed by Netzer et al.6
Non-restoring sleep and fatigue are common in adults
with OSAS.17 The frequencies of those conditions vary in
different populations. In the article by Netzer et al.,6 the
only question relates to dozing off or sleeping while driving,
Silva et al.
Risk for obstructive sleep apnea syndrome
Original Article
and the responses varied from 4% to 32%; in our study,
we observed 3.4%, similar to the smallest value reported
by Netzer et al.6 In the population cared for by the FDP,
few individuals drive a motor vehicle. However, in places
where women predominate, a lower prevalence of risk for
OSAS in category II is expected, because they complain
less than men do.18
OSAS. Second, there were 35% of losses (individuals who
refused to participate in the study), mainly among men and
individuals of the two extreme age groups (45 to 49 years
and 80 to 99 years). The participation of a larger number
of ill individuals, such as hypertensives, might have led to
overestimation of the prevalence of OSAS.
The comparison of the prevalence of high risk for OSAS in
the United States and Europe shows similar results in category
I (43.1% and 43.5%). However, the prevalence of high risk
for OSAS in category II (daytime sleepiness/fatigue) differed in
those areas, being three-times higher in the United States than
in Europe (32.4% and 11.8%).6 In our study, the prevalence of
high risk for OSAS in category II was closer to the European
one (10.2%).
Conclusion
Hypertension has been associated with OSAS, in studies
both using polysomnography19 and estimating the high risk
for OSAS via questionnaires, regardless of other risk factors.20
The OR found in such studies were greater than 2. In a critical
review, Mohsenin21 states that daytime hypertension is present
in up to 60% of patients with OSAS. In the present study, only
the difference of mean DBP associated with high risk for OSAS
in category I, and such association disappeared (ORa=1) after
adjusting for age and BMI. Margallo et al.22 have estimated the
association of blood pressure changes with high risk for OSAS
according to the modified BQ, with risk exclusion in category
III. Their results are comparable to those observed in our study
with statistically significant difference only for mean DBP.
The interruptions in airflow lead to brief awakenings that
cause daytime sleepiness and fatigue.17 The BQ is aimed
at capturing those changes by using questions grouped
into categories I and II. However, the frequency of positive
responses to those questions varies culturally, as observed
from the prevalence differences between North American
and European communities.6
In our study, the BQ reliability, tested with Cronbach
alpha, was 0.586 (weak) for category I. Cronbach alpha
increased to 0.618 (acceptable) by withdrawing the
question Has anyone noticed that you stop breathing during
your sleep?. For category II, Cronbach alpha was 0.521
(weak). By withdrawing the question Have you ever nodded
off or fallen asleep while driving a vehicle?, Cronbach alpha
increased to 0.705 (acceptable). Assessing BQ validation,
Cronbach alpha reached higher levels: 0.92 for category I
and 0.86 for category II, when excluding the question Have
you ever nodded off or fallen asleep while driving a vehicle?.
This can be attributed to the low educational level of most
individuals assessed, as well as to the higher percentage of
women in the study sample, which might have yield false
negative responses, mainly in category II.
The present study has some limitations worth noting.
First, due to its cross-sectional nature, we could not establish
whether SAH or obesity preceded the occurrence of
The global prevalence of high risk for OSAS, estimated
via BQ, in the population cared for by the FDP was 42.4%.
However, because of the losses, that prevalence might
have been overestimated. In addition, the high frequency
of SAH and obesity increased the prevalence of risk for
OSAS. The prevalences in the three BQ categories were
very different, but comparable to those reported in the
literature. The BQ reliability was lower in this study
population, whose educational level is lower than that
of other populations studied. Our data show that the
BQ reliability in populations mainly formed by female
and low-educational-level individuals increases when
excluding from the analysis the questions Has anyone
noticed that you stop breathing during your sleep? and
Have you ever nodded off or fallen asleep while driving
a vehicle?, indicating the importance of performing new
studies to validate that tool for that group.
Author contributions
Conception and design of the research: Silva KV, Rosa
MLG, Jorge AJL. Acquisition of data: Rosa MLG, Jorge AJL,
Leite AR, Correia DMS, Silva DS, Cetto DB, Brum AP, Silveira
Netto P, Rodrigues GD. Analysis and interpretation of the
data: Silva KV, Rosa MLG, Jorge AJL, Leite AR, Correia DMS.
Statistical analysis: Rosa MLG. Writing of the manuscript:
Silva KV, Rosa MLG, Jorge AJL. Critical revision of the
manuscript for intellectual content: Silva KV, Rosa MLG, Jorge
AJL, Leite AR, Correia DMS, Silva DS, Cetto DB, Brum AP,
Silveira Netto P, Rodrigues GD.
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
Kenia Vieira da Silv, from Universidade Federal Fluminense,
Instituto de Saúde Coletiva, Programa de Pós-Graduação em
Saúde Coletiva.
Arq Bras Cardiol. 2016; 106(6):474-480
479
Silva et al.
Risk for obstructive sleep apnea syndrome
Original Article
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Back to The Cover
Original Article
The Labdane Ent-3-Acetoxy-Labda-8(17), 13-Dien-15-Oic Decreases
Blood Pressure In Hypertensive Rats
Janaina A. Simplicio1,3, Marilia R. Simão2, Sergio R. Ambrosio2, Carlos R. Tirapelli3
Programa de Pós-Graduação em Farmacologia – Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP)1, Ribeirão
Preto, SP; Núcleo de Pesquisa em Ciências e Tecnologia – Universidade de Franca (UNIFRAN)2, Franca, SP; Departamento de Enfermagem
Psiquiátrica e Ciências Humanas – Laboratório de Farmacologia – Escola de Enfermagem de Ribeirão Preto (USP) 3, Ribeirão Preto, SP – Brazil
Abstract
Background: Labdane-type diterpenes induce lower blood pressure via relaxation of vascular smooth muscle; however,
there are no studies describing the effects of labdanes in hypertensive rats.
Objective: The present study was designed to investigate the cardiovascular actions of the labdane-type diterpene
ent-3-acetoxy-labda-8(17), 13-dien-15-oic acid (labda-15-oic acid) in two-kidney 1 clip (2K-1C) renal hypertension.
Methods: Vascular reactivity experiments were performed in aortic rings isolated from 2K-1C and normotensive (2K)
male Wistar rats. Nitrate/nitrite (NOx) measurement was performed in aortas by colorimetric assay. Blood pressure
measurements were performed in conscious rats.
Results: Labda-15-oic acid (0.1-300 µmol/l) and forskolin (0.1 nmol/l - 1 μmol/l) relaxed endothelium-intact and
endothelium-denuded aortas from both 2K-1C and 2K rats. Labda-15-oic acid was more effective at inducing relaxation
in endothelium-intact aortas from 2K pre-contracted with phenylephrine when compared to the endothelium-denuded
ones. Forskolin was more potent than labda-15-oic acid at inducing vascular relaxation in arteries from both 2K and 2K-1C
rats. Labda-15-oic acid-induced increase in NOx levels was lower in arteries from 2K-1C rats when compared to 2K rats.
Intravenous administration of labda-15-oic acid (0.3-3 mg/kg) or forskolin (0.1-1 mg/kg) induced hypotension in conscious
2K-1C and 2K rats.
Conclusion: The present findings show that labda-15-oic acid induces vascular relaxation and hypotension in hypertensive
rats. (Arq Bras Cardiol. 2016; 106(6):481-490)
Keywords: Labdane; Vascular Relaxation; Diterpene; Forskolin; Renovascular Hypertension.
Introduction
The treatment of arterial hypertension with plant-derived
products is well described in the literature.1-4 A great number
of medicinal plants with antihypertensive activity have been
chemically investigated and diterpenoids are pointed out
as their major constituents. For this reason, many studies
have focused on the cardiovascular properties of these
compounds. For example, the labdane-type diterpene
forskolin (7 beta-acetoxy-8, 13-epoxy-1 alpha,6 beta,9
alpha-trihydroxy-labd-14-ene-11-one) lowers blood pressure
by a mechanism that involves relaxation of vascular smooth
muscle.5-8 In the vasculature, forskolin activates the enzyme
adenylyl cyclase, which in turn increases the production of
cAMP and cAMP-dependent protein kinase (PKA) activation.9
Mailing Address: Carlos Renato Tirapelli •
Universidade de São Paulo - Escola de Enfermagem de Ribeirão Preto – Avenida
Bandeirantes 3900, Postal Code 14040-902, Ribeirão Preto, SP – Brazil
E-mail: [email protected], [email protected]
Manuscript received October 21, 2015; revised manuscript October 28,
2015; accepted February 23, 2016.
DOI: 10.5935/abc.20160058
481
Calcium extrusion across the plasma membrane and vascular
smooth muscle hyperpolarization are mechanisms also
related to the vascular actions of forskolin10. In humans,
intravenous administration of forskolin decreased vascular
resistance and reduced diastolic blood pressure (DBP).7,8
Other labdane-type diterpenes, such as labdane 8(17),
12E, 14-labdatrien-18-oic acid and labd-8 (17)-en-15-oic
acid were also described to induce vascular relaxation
and hypotension in normotensive rats. 11,12 We have
recently described that the labdane ent-3-acetoxy-labda8(17),13-dien-15-oic acid (labda-15-oic acid) induced
vascular relaxation via blockade of Ca2+ influx, activation
of the endothelial nitric oxide (NO)-cGMP pathway and
the opening of K+ channels. 13 Intravenous injection of
labda-15-oic acid induced a decrease in blood pressure in
normotensive rats and this response was partially attenuated
by L-NAME, suggesting a role for NO in such response.13 It
is important to note that lower doses of labda-15-oic acid
(0.3 - 3 mg/kg) were needed to induce hypotension when
compared to other labdanes previously tested, such as 8
(17), 12E, 14-labdatrien-18-oic acid (5-30 mg/kg)11 and
labd-8 (17)-en-15-oic acid (1-10 mg/kg).12 On the basis of
these initial results with labda-15-oic acid, we hypothesized
that this compound would induce vascular relaxation and
Tirapelli et al.
The labda-15-oic decreases blood pressure
Original Article
hypotension in hypertensive rats. In the present study we
sought to evaluate the cardiovascular actions of labda-15-oic
acid in hypertensive animals.
Methods
Isolation of labda-15-oic acid
The isolation of labda-15-oic acid was performed as
previously described.14 One hundred grams of oleoresin was
chromatographed over silica gel 60 H (Merck, art. 7736) using
vacuum liquid chromatography (VLC) with increasing amounts
of ethyl acetate (EtOAc) in n-hexane as eluent. This procedure
furnished six fractions (2000 ml each) that were named F1
(34.7 g; n-hexane), F2 (13.5 g; 20% EtOAc), F3 (11.4 g; 40%
EtOAc), F4 (9.7 g; 60% EtOAc), F5 (7.6 g; 80% EtOAc), and
F6 (17.8 g; EtOAc) after solvent evaporation. Fraction F4 was
initially chromatographed by VLC over silica gel 60 H (Merck,
art. 7736) as described above, to give additional fractions
(F4.1 to F4.5). Labda-15-oic acid (1132.0 mg) was obtained
from F4.3 through medium pressure chromatography (flash
chromatography) using silica gel 60 (Merck, art. 9385), isocratic
n-hexane: EtOAc:CHCl3 (5:2:3) as mobile phase, and a flow
rate of 5 ml/min.15 The purity of (-)-acetoxycopalic acid (98%)
was estimated by HPLC, mass spectrometric analysis and 1H
and 13C NMR spectral data.
Renovascular hypertension
Renovascular hypertension was induced in rats as previously
described. Briefly, male Wistar rats weighting between 180 and
200 g (35 days old) were anaesthetised with tribromoethanol
(250 mg/kg, i.p.) and after a midline laparotomy, a silver clip
with an internal diameter of 0.2 mm was placed around the
left renal artery. Normotensive two kidney (2K) rats were
submitted to laparotomy only. Systolic blood pressure (SBP)
was measured before and after 6 weeks of midline laparotomy
in non anaesthetized animals by pletysmography (tail-cuff) and
rats were considered to be hypertensive when SBP was higher
than 160 mmHg. At 6 weeks after surgery, rats were killed and
the thoracic aortas were isolated.16 A total of 26 2K rats and 28
2K-1C rats were used in the present study. All protocols were
approved by the Ethical Animal Committee of the Campus of
Ribeirão Preto - University of São Paulo (#09.1.1007.53.0).
Vessel ring preparation
The thoracic aorta was quickly removed, cleaned of adherent
connective tissues and cut into rings (5-6 mm in length).
Two stainless-steel stirrups were passed through the lumen of
each ring. One stirrup was connected to an isometric force
transducer (TRI201; Panlab, Spain) to measure tension in
the vessels. The rings were placed in a 5 ml organ chamber
that contained Krebs solution, gassed with 95% O2 / 5% CO2
maintained at 37°C. The composition of Krebs solution was as
follows (mmol/l): NaCl, 118.0; KCl, 4.7; KH2PO4, 1.2; MgSO4,
1.2; NaHCO3, 15.0; Glucose, 5.5; CaCl2, 2.5. The rings were
stretched until they reached a basal tension of 1.5 g, which
was determined by length-tension relationship experiments
and were then allowed to equilibrate for 60 min; during this
time, the bath fluid was changed every 15-20 min. For some
rings, the endothelium was removed mechanically by gently
rolling the lumen vessel on a thin wire. Endothelial integrity
was assessed qualitatively by the degree of relaxation caused
by acetylcholine (1 µmol/l) in the presence of contractile
tone induced by phenylephrine (0.1 µmol/l). For studies of
endothelium-intact vessels, a ring was discarded if relaxation
with acetylcholine was not 50% or greater. For studies of
endothelium-denuded vessels, a ring was discarded if there
was any degree of relaxation. Agonist concentration–response
curves were fitted using a nonlinear interactive fitting program
(Graph Pad Prism 3.0; GraphPad Software Inc., San Diego, CA,
USA). Agonist potencies and maximal responses were expressed
as pD2 (−logEC50) and Emax (maximum effect elicited by the
agonist), respectively.
Effect of labda-15-oic acid on aortic rings contracted with
phenylephrine or KCl
Steady tension was evoked by phenylephrine (concentrations
of 0.1 μmol/l for endothelium-intact rings and 0.03 μmol/l for
endothelium-denuded rings were used to induce contractions
of similar magnitude), and labda-15-oic acid was then added
in a stepwise fashion (0.1-300 μmol/l). The effect of labda-15oic acid on KCl-induced sustained contraction (30 mmol/l) in
intact or denuded rings was also examined. For comparison,
the effect of forskolin (0.1 nmol/l - 1 μmol/l) on the contractions
induced by phenylephrine and KCl in endothelium-intact and
endothelium-denuded rings was evaluated.
Blood pressure experiments
Blood pressure experiments were performed as previously
described.17 One day before the experiments, the rats were
anesthetised with tribromoethanol (250 mg/kg, i.p.), and a
catheter (a 4 cm segment of PE-10 heat-bound to a 13 cm
segment of PE-50 (Clay Adams, Parsippany, NJ, USA) was
inserted into the abdominal aorta through the femoral artery for
blood pressure and heart rate recording. A second catheter was
implanted into the jugular vein for intravenous administration of
drugs. Both catheters were implanted under the skin and exited
at the animal's back. During the experiment, freely moving
rats were kept in individual cages, and mean arterial pressure
(MAP) was recorded using an HP-7754A amplifier (Hewlett
Packard, USA) connected to a signal acquisition board (MP-100,
BIOPAC, USA) and processed by a computer. Labda-15-oic acid
(0.3 - 3 mg/kg) or forskolin (0.1 - 1 mg/kg) were administered
by intravenous bolus injection. Both labda-15-oic acid
(0.3-3 mg/kg) and forskolin (0.1 - 1 mg/kg) were administered
in different animals. Blood pressure responses were calculated
with base on the average mean blood pressure calculated at
the response's plateau.
Nitrate/Nitrite (NOx) measurements
NOx levels were measured in supernatants from
endothelium-intact aorta homogenates from 2K-1C and
2K rats. The rings were pre-contracted with phenylephrine
(0.1 µmol/l) and then exposed to labda-15-oic acid
(300 µmol/l). Supernatants were centrifuged using ultra
centrifugal filters (#UFC5010BK Amicon Ultra-0.5 mL
10 kDa, Millipore, Billerica, MA, USA). Nitrate was measure
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colorimetrically following the instructions of a commercially
available kit (#780,001, Cayman Chemical, Ann Arbor, MI,
USA). Results were normalized for protein concentration and
are expressed as nmol/mg protein. Protein concentrations in
all experiments were determined with protein assay reagent
(Bio-Rad Laboratories, Hercules, CA, USA).
Drugs
Labda-15-oic acid was prepared as stock solutions in
dimethyl sulfoxide (DMSO). The other drugs were dissolved
in distilled water. The bath concentration of DMSO did
not exceed 0.5%, which was shown to have no effect
per se on the basal tonus of the preparations or on the
agonist-mediated contraction or relaxation. For the in vivo
experiments, labda-15-oic acid was diluted in 10% DMSO
and then in saline. The concentration of DMSO in the
final solution had no effects per se on basal cardiovascular
parameters, as previously observed.18
in endothelium-intact and endothelium‑denuded rings
pre-contracted with phenylephrine were not significantly
different in aortas from 2K-1C and 2K rats (Table 2).
However, differences were found in the pD2 values for
labda-15-oic acid in endothelium-intact and denuded rings
pre-contracted with phenylephrine in aortas from 2K, but not
2K-1C rats. In the arteries pre-contracted with KCl, there was
no difference between the Emax and pD2 values for labda-15-oic
acid in endothelium-intact or denuded rings from both 2K‑1C
and 2K rats (Table 2). The Emax and pD2 values for labda‑15‑oic
acid in the rings pre-contracted with KCl were not different
from those found in phenylephrine‑pre‑contracted rings from
both 2K-1C and 2K rats.
Forskolin reduced the sustained contractions induced
by phenylephrine and KCl in endothelium-intact and
endothelium-denuded aortas from both 2K-1C and 2K rats
Statistical analysis
Results were expressed as means standard error of the
mean (S.E.M.). Data followed a normal distribution. Statistical
analysis was performed using one-way analysis of variance
(ANOVA) or paired Student’s t test. Post-hoc comparisons
were performed after ANOVA analysis using Newman-Keuls
multiple comparison test as indicated in the text and tables.
For all analyses, p values of less than 0.05 were considered
significant. Statistical analysis was carried out using the
program Graph Pad Prism 3.0 (GraphPad Software Inc., San
Diego, CA, USA).
Results
Blood pressure values in 2K-1C and 2K rats
MAP, DBP and SBP were significantly increased in 2K-1C
when compared to 2K rats (Table 1).
Vasorelaxant action of labda-15-oic acid on aortic rings
from 2K-1C and 2K rats
Labda-15-oic acid (Figure 1) reduced the sustained
contractions induced by phenylephrine and KCl in
endothelium‑intact and endothelium-denuded aortas from
both 2K-1C and 2K rats (Figure 2). The Emax values (percentage
of relaxation) for the relaxant effect of labda‑15-oic acid
Figure 1 – Chemical structure of ent-3-acetoxy-labda-8(17),13-dien15-oic acid (labda-15-oic acid; top) and 7 beta-acetoxy-8, 13-epoxy-1
alpha,6 beta,9 alpha-trihydroxy-labd-14-ene-11-one (forskolin, bottom).
Table 1 – Blood pressure values (mmHg) in 2K and 2K-1C rats
2K
2K-1C
Basal
After 6 weeks
Basal
After 6 weeks
MAP
104.3 ± 2.0
100.9 ± 1.6
105.7 ± 1.1
161.3 ± 10.4a
DBP
92.5 ± 1.8
89.8 ± 1.3
96.3 ± 1.1
138.4 ± 11.6a
SBP
127.9 ± 2.8
123.2 ± 2.9
124.6 ± 1.9
207.0 ± 9.2a
Values are means ± S.E.M of n = 12 animals for each group. aCompared to respective basal values (p < 0.05, paired Student’s t test). MAP: mean arterial pressure;
DBP: diastolic blood pressure; SBP: systolic blood pressure.
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Figure 2 – Relaxation responses induced by labda-15-oic acid on rat aortic rings. The relaxation induced by the labdane was studied on endothelium-intact (E+) and
endothelium-denuded (E-) rat aortic rings contracted with either phenylephrine (0.1 μmol/l) or KCl (30 mmol/l). Steady tension was evoked by phenylephrine or KCl and
then labda-15-oic acid (0.1 - 300 μmol/l) was added cumulatively.
Table 2 – Emax (% relaxation) and pD2 values for labda-15-oic acid and forskolin in endothelium-intact (E+) and endothelium-denuded (E-)
aortas from 2K and 2K-1C rats
Pre-contractile agent
Labda-15-oic acid
Forskolin
Labda-15-oic acid
Forskolin
2K
2K-1C
E+ (Emax)
E- (Emax)
Phenylephrine
93.7 ± 6.8 (7)
KCl
96.4 ± 4.4 (7)
Phenylephrine
110.7 ± 5.3 (7)
KCl
E+ (Emax)
E- (Emax)
79.2 ± 1.8 (6)
99.0 ± 7.4 (7)
88.8 ± 6.6 (6)
83.6 ± 6.6 (6)
103.9 ± 3.8 (7)
87.3 ± 7.4 (8)
104.0 ± 5.62 (6)
118.8 ± 5.2 (6)
107.7 ± 8.0 (6) a
92.6 ± 3.9 (6)
87.8 ± 3.9 (5)
105.9 ± 3.3 (6)
93.2 ± 7.1 (6)
E+ (pD2)
E- (pD2)
E+ (pD2)
E- (pD2)
Phenylephrine
KCl
a
a
a
4.8 ± 0.06 (7)
b
4.1 ± 0.04 (6)
4.8 ± 0.11 (7)
4.9 ± 0.08(6)
4.6 ± 0.08 (7)
4.3 ± 0.06 (6)
4.8 ± 0.10 (7)
4.5 ± 0.08 (8)
Phenylephrine
7.5 ± 0.21 (7) c
6.9 ± 0.17(6) b,c
8.0 ± 0.10 (6) c
7.3 ± 0.14(6) b,c
KCl
7.0 ± 0.16 (6)
7.0 ± 0.15(5)
7.3 ± 0.20 (6)
7.0 ± 0.12 (6) c
c
c
c
Numbers within parentheses indicate the number of isolated preparations. Values are means ± S.E.M. a Compared to labda-15-oic acid in aortas pre-contracted with
phenylephrine from 2K and 2K-1C rats;b Compared to respective group in E+ aortas from 2K and 2K-1C rats;c Compared to labda-15-oic acid in aortas pre-contracted
with phenylephrine or KCl from 2K and 2K-1C rats (p < 0.05, ANOVA followed by Newman-Keuls multiple comparison test).
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(Figure 3). The Emax values for the relaxant effect of forskolin
in endothelium-intact and endothelium‑denuded rings
pre-contracted with phenylephrine were not significantly
different in aortas from 2K-1C and 2K rats (Table 2).
However, differences were found in the pD 2 values
for forskolin in endothelium-intact and denuded rings
pre‑contracted with phenylephrine in aortas from both
2K-1C and 2K rats. In the arteries pre-contracted with KCl,
there was no difference between the Emax or pD2 values for
forskolin in endothelium-intact or denuded rings from both
2K-1C and 2K rats (Table 2).
forskolin produced a decrease in MAP in conscious 2K-1C and
2K rats. The MAP values returned to basal levels after injection
of labda-15-oic acid. On the other hand, MAP values did not
return to basal levels after administration of forskolin at 1 mg/kg
(Figure 5). Labda-15-oic acid induced a more pronounced fall
in blood pressure in 2K when compared to 2K-1C rats. On the
other hand, forskolin was found to be more effective at inducing
decrease in MAP in 2K-1C when compared to 2K rats (Figure 5).
Values of blood pressure before and after drug administration
are described in Table 3.
The E max values for forskolin in endothelium-intact
and endothelium-denuded rings pre-contracted with
phenylephrine, but not KCl, were significantly different
from those found for labda-15-oic acid in both 2K-1C and
2K rats. The pD2 values for forskolin in endothelium-intact
and denuded rings pre-contracted with either phenylephrine
or KCl were significantly different from those found for
labda‑15-oic acid in both 2K-1C and 2K rats (Table 2).
NOx measurements
Blood pressure experiments
Discussion
Figure 4 shows representative tracings for the effect of
labda‑15-oic acid and forskolin on blood pressure of 2K
and 2K‑1C rats. The maximal variation in MAP induced by
labda‑15-oic acid and forskolin in conscious 2K-1C and 2K rats
is presented in Figure 5. A bolus injection of labda-15-oic acid or
The present findings show that labda-15-oic acid was more
effective at inducing vascular relaxation in endothelium-intact
aortas from 2K rats pre-contracted with phenylephrine when
compared to the endothelium-denuded ones. This result
is in accordance with previous finding from our laboratory
Figure 6 show that NOx basal levels in aortas from 2K‑1C rats
are lower than those found in aortas from 2K rats. Labda‑15-oic
acid induced nitrate generation in endothelium‑intact aortas
from both 2K-1C and 2K rats. Labda-15-oic acid-induced
nitrate generation was lower in arteries from 2K-1C rats when
compared to 2K rats (Figure 6).
Figure 3 – Relaxation responses induced by forskolin on rat aortic rings. The relaxation induced by the labdane was studied on endothelium-intact (E+) and
endothelium‑denuded (E-) rat aortic rings contracted with either phenylephrine (0.1 μmol/l) or KCl (30 mmol/l). Steady tension was evoked by phenylephrine or KCl and
then forskolin (0.1 nmol/l - 1 μmol/l) was added cumulatively.
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Figure 4 – Representative traces of the hypotensive action displayed by labda-15-oic acid (0.3 – 3 mg/kg) and forskolin (0.1 – 1 mg/kg) on conscious 2K and 2K-1C rats.
Traces represent the mean values of the maximal decrease in mean arterial pressure of 5 to 6 animals.
Figure 5 – Effect of labda-15-oic acid (0.3 – 3 mg/kg) and forskolin (0.1 – 1 mg/kg) on mean arterial pressure (MAP). Maximal variation in MAP (mmHg) induced by
intravenous injection of the labdanes was evaluated in conscious 2K and 2K-1C rats. Each bar represents the mean ± S.E.M. of 5 to 6 experiments. *Compared with
vehicle; #Compared with 2K rats (p < 0.05, ANOVA followed by Newman-Keuls multiple comparison test).
showing that the relaxation induced by labda-15-oic acid is
partially dependent on the endothelial cGMP-NO pathway.13
On the other hand, in aortas from 2K-1C rats, no difference on
labda‑15‑oic acid‑induced relaxation was observed between
endothelium‑intact and denuded rings. Altered vascular
tone is a characteristic feature of most forms of experimental
and human hypertension and has been associated with
endothelial dysfunction with consequent impairment of
endothelium‑dependent vasodilatation and reduced NO
signalling.19-21 Since endothelial-derived NO partially mediates the
vasorelaxant effect of labda-15-oic acid, the decrease in potency
for the relaxant action of the labdane in aortas from 2K-1C rats
might be due to the decreased NO bioavailability described in
hypertensive states. In fact, this hypothesis is strengthened by the
fact that labda-15-oic acid-induced nitrate generation in arteries
from 2K-1C was lower than that found in arteries from 2K rats.
It is also important to note that we found lower basal NOx content
in arteries from 2K-1C when compared to aortas from 2K rats,
further corroborating previous observations showing decreased
availability of basal NO in renovascular hypertension.22-24
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Table 3 – Blood pressure values (mmHg) in 2K and 2K-1C rats before and after drug administration (labda-15-oic acid or forskolin) and its
respective values ∆MAP and %∆MAP
MAP (mmHg)
Before
After
∆MAP
%∆MAP
Vehicle
103.5 ± 6.7 (5)
98.9 ± 7.0
4.6 ± 2.4
4.4 ± 2.3
Labda-15-oic acid 2K
Labda-15-oic acid (0.3 mg/kg)
100.5 ± 5.5 (5)
96.3 ± 8.4
4.2 ± 3.3
4.8 ± 3.8
Labda-15-oic acid (1 mg/kg)
99.8 ± 6.2 (5)
70.6 ± 15.6
29.2 ± 12.7
30.3 ± 13.6
Labda-15-oic acid (3 mg/kg)
98.5 ± 6.4 (5)
48.6 ± 12.4a
49.9 ± 8.5b
53.6 ± 10.9 b
163.7 ± 15.2 (6)
159.3 ± 16.2
4.4 ± 3.0
3.0 ± 2.3
Labda-15-oic acid 2K-1C
Vehicle
Labda-15-oic acid (0.3 mg/kg)
161.6 ± 15.8 (6)
154.0 ± 16.5
7.6 ± 3.3
5.2 ± 2.5
Labda-15-oic acid (1 mg/kg)
160.0 ± 15.6 (6)
148.0 ± 15.7
12.0 ± 3.6
7.9 ± 2.7
Labda-15-oic acid (3 mg/kg)
160.2 ± 15.8 (6)
109.7 ±19.2a
50.5 ± 9.9b
33.8 ± 8. 4b
Forskolin 2K
Vehicle
113.9 ± 3.0 (5)
107.5 ± 4.3
6.4 ± 1.7
5.7 ± 1.5
Forskolin (0.1 mg/kg)
104.9 ± 4.5 (5)
90.9 ± 5.2a
14.0 ± 2.7
13.4 ± 2.8
Forskolin (0.3 mg/kg)
108.1 ± 5.0 (5)
75.8 ± 10.8a
32.3 ± 10.0b
29.9 ± 9.6b
Forskolin (1 mg/kg)
107.4 ± 4.0 (5)
77.0 ± 3.1a
30.4 ± 5.2b
27.9 ± 3.8b
3.7 ± 2.5
Forskolin 2k-1C
Vehicle
169.1 ± 12.8 (5)
163.3 ± 15.1
5.8 ± 4.6
Forskolin (0.1 mg/kg)
170.4 ± 16.6 (5)
153.2 ± 12.9a
17.2 ± 6.1
9.4 ± 3.1
Forskolin (0.3 mg/kg)
167.6 ± 16.3 (5)
130.9 ± 12.4
36.7 ± 5.7
b
21.7 ± 2.5b
Forskolin (1 mg/kg)
166.0 ± 16.9 (5)
97.1 ± 16.0a
68.9 ± 8.5b
42.4 ± 6.2b
a
Numbers within parentheses indicate the number of animals. Values are means ± S.E.M. Significant difference compared to baseline, before drug infusion (p < 0.05,
paired Student’s t test). bCompared with vehicle (p < 0.05, ANOVA followed by Newman-Keuls multiple comparison test). MAP: mean arterial pressure.
a
The activation of K+ channels leads to hyperpolarization of
vascular smooth muscle cells, decrease in voltage-dependent
Ca2+ channel activity, and vasodilatation.25 The activation of
voltage-dependent and ATP-sensitive K+ channels, as well
as large-conductance and low-conductance Ca2+-activated
K+ channels was described to play a role in the vasorelaxant
response induced by labda-15-oic acid13. It is well established
that endothelium-dependent vasodilatation and smooth
muscle cell hyperpolarization are impaired in aortic segments
from 2K‑1C hypertensive rats.26 Abnormal function of vascular
smooth muscle large-conductance Ca2+-activated K+ channels
and ATP-sensitive K+ channels play a key role in the impaired
relaxation of aortas from 2K-1C rats,27,28 and may also contribute
to the decreased endothelium-dependent vasodilatation
induced by labda-15-oic acid in aortas from 2K-1C rats.
In the present study, no differences were found in
the inhibitory action displayed by labda-15-oic acid in
arteries pre-contracted with KCl in both 2K and 2K-1C rats.
The contraction induced by KCl on smooth muscle is mediated
by cell membrane depolarisation and an increase in Ca2+
influx through voltage-operated Ca2+ channels.29,30 Thus, we
can suggest that labda-15-oic acid blocks extracellular Ca2+
influx through interference with voltage-operated channels
in 2K and 2K-1C rats.
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Forskolin relaxed endothelium-intact and endotheliumdenuded aortas pre-contracted with phenylephrine, but
not KCl, to a greater extent than labda-15-oic acid in both
2K and 2K-1C rats. Moreover, forskolin was more potent
than labda-15-oic acid at inducing vascular relaxation in
arteries pre-contracted with phenylephrine or KCl in both
2K and 2K-1C rats. Possible explanations for these effects
are related to the chemical structure of the labdanes and/
or their mechanisms of action. Analyzing the chemical
structure of labda-15-oic acid and forskolin (Figure 1) we
observe that, despite the fact that these two compounds
are classified as labdane type-diterpenes, it is noteworthy
the presence of great number of hydrogen-bond-donor
groups (HBD; hydrophilic group), highlighting the hydroxyl
moieties at C-1, C-6 and C-9, in the forskolin skeleton in
comparison with the chemical structure of labda-15-oic
acid, which contains only two hydrophilic groups at C-3
and C-16. Moreover, it is also possible to observe that these
natural compounds differ from each other in their inverted
configurations of the carbons C-5, C-9 and C-10. Previous
studies have shown that chemical differences on diterpenes
alter their cardiovascular properties,17,31 and might be the
source of discrepancy between the effects of labda-15-oic
acid and forskolin here described.
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Figure 6 – Effect of labda-15-oic acid on nitrate levels in endothelium-intact aortic rings from 2K and 2K-1C rats. Each bar represents the mean ± S.E.M. of 6 to
8 independent preparations. *Compared with basal values for 2K rats; #Compared with basal values for 2K-1C rats; ƒCompared with stimulation with labda-15-oic acid
in 2K-1C rats (p < 0.05, ANOVA followed by Newman-Keuls multiple comparison test).
Labdanes exert their cardiovascular effects by acting at
multiple sites,11,12,32 and for this reason, several intracellular
pathways were described to mediate the vascular
relaxation induced by these compounds.33 The increase
in cAMP levels, due to activation of adenylyl cyclase and
the subsequent activation of PKA is the main mechanism
underlying the vascular relaxation induced by the labdane
forskolin.9 However, forskolin also increases endothelial
production of NO via activation of eNOS.34 On the other
hand, the mechanisms underlying the vasorelaxant action
of labda-15-oic acid are not related to adenylyl cyclase
activation and involve blockage of extracellular Ca2+ influx,
increased endothelial NO production and the opening of K+
channels.13 The differences in the mechanisms underlying
the vascular responses of these two labdanes could also
be responsible for the different cardiovascular responses
displayed by labda-15-oic acid and forskolin.
of labda-15-oic acid induced a short-lasting hypotension in
2K and 2K-1C rats, further showing that labda-15-oic acid
exert antihypertensive effect in vivo. Labda-15-oic acid
induced a less pronounced decrease in blood pressure
compared to forskolin, further strengthening the idea that
chemical differences alters the hypotensive action displayed
by labdane-type diterpenes. It is also important to note that
labda-15-oic acid causes hypotension through peripheral
vasodilatation, mediated in part by NO,13 while forskolin
effects are mainly mediated by activation of adenylate
cyclase and the increase in cAMP levels.5-9 This observation is
relevant since, as mentioned before, endothelial dysfunction
with consequent impairment of endothelium-dependent
vasodilatation and reduced NO signalling is a characteristic
feature of hypertension. 19-21 This characteristic of the
hypertensive state could explain, at least in part, the reduced
effect of labda-15-oic acid in comparison to forskolin.
Improvements in the pharmacological treatment of
hypertension contribute to a reduction in the incidence of
cardiovascular diseases.35 Labdane-type diterpenes could
be considered a promising source of new prototypes for
the discovery and development of novel cardiovascular
therapeutic agents. The hypotensive action of labdane-type
diterpenes is related to their myorelaxant action. 5,6,11,12
Recently, we described that labda-15-oic acid induces
vascular relaxation and hypotension in normotensive rats.13
Since labda-15-oic acid relaxed aortas from 2K‑1C rats, we
hypothesized that the labdane could exert antihypertensive
action in vivo. In the present study, intravenous administration
Some limitations for the present study should be considered.
Despite the fact that labda-15-oic acid decreased blood pressure
in an animal model of renovascular hypertension, it is not
possible to guarantee that this labdane will be also effective on
other animal models of hypertension or human hypertension.
Another point that should be considered is that the vasorelaxant
effect of the labdane should also be tested in resistance vessels
since those are more important in the regulation of blood
pressure. Finally, our findings show the effects of labda-15-oic
acid after intravenous injection of the compound but we do
not have information on the bioavailability and cardiovascular
effects of this compound after oral administration.
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Conclusions
Author contributions
Diterpenes likely fulfill the definition of a pharmacological
preconditioning class of compounds and may have
therapeutic use in cardiovascular diseases. Using a combined
in vivo and in vitro approach, the present investigation
shows for the first time that labda-15-oic acid induces
vascular relaxation in arteries from 2K-1C hypertensive
rats. Administration of the labdane in vivo induced a
fall in blood pressure in hypertensive rats. The initial
experimental studies on the cardiovascular effects of
labdanes are important and needed, since such information
is a prerequisite to any rational and safety use of these
compounds in the treatment of hypertension.
Conception and design of the research: Simplicio JA,
Tirapelli CR; Acquisition of data: Simplicio JA, Simão
MR; Analysis and interpretation of the data: Simplicio JA,
Simão MR, Ambrosio SR, Tirapelli CR; Statistical analysis:
Simplicio JA; Obtaining financing: Tirapelli CR; Writing of the
manuscript: Simplicio JA; Critical revision of the manuscript
for intellectual content: Ambrosio SR, Tirapelli CR.
Acknowledgements
We thank Drs. Evelin C. Carnio and Marcelo E. Batalhão
for blood pressure measurements. This work was supported
by Fundação de Amparo à Pesquisa do Estado de São Paulo
(FAPESP - 2010/01009-3 and 2011/13630-7). J.A.S. is
supported by a master fellowship from CAPES.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
This study was funded by FAPESP.
Study Association
This study is associated with the Post Graduate Program
in Pharmacology - Faculty of Medicine of Ribeirão Preto,
University of São Paulo (USP).
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Arq Bras Cardiol. 2016; 106(6):481-490
490
Back to The Cover
Original Article
Association between Spirituality and Adherence to Management in
Outpatients with Heart Failure
Juglans Souto Alvarez1, Livia Adams Goldraich1, Alice Hoefel Nunes2, Mônica Cristina Brugalli Zandavalli2, Rafaela
Brugalli Zandavalli2, Karlyse Claudino Belli3, Neusa Sica da Rocha4, Marcelo Pio de Almeida Fleck4, Nadine Clausell1
Heart Failure Program, Division of Cardiology, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul1, Universidade
Federal do Rio Grande do Sul2, Hospital de Clinicas de Porto Alegre3, Division of Psychiatry, Hospital de Clinicas de Porto Alegre, Universidade
Federal do Rio Grande do Sul4, Porto Alegre – Brazil
Abstract
Background: Spirituality may influence how patients cope with their illness.
Objectives: We assessed whether spirituality may influence adherence to management of outpatients with heart failure.
Methods: Cross sectional study enrolling consecutive ambulatory heart failure patients in whom adherence to multidisciplinary
treatment was evaluated. Patients were assessed for quality of life, depression, religiosity and spirituality utilizing validated
questionnaires. Correlations between adherence and psychosocial variables of interest were obtained. Logistic regression
models explored independent predictors of adherence.
Results: One hundred and thirty patients (age 60 ± 13 years; 67% male) were interviewed. Adequate adherence score was
observed in 38.5% of the patients. Neither depression nor religiosity was correlated to adherence, when assessed separately.
Interestingly, spirituality, when assessed by both total score sum (r = 0.26; p = 0.003) and by all specific domains, was
positively correlated to adherence. Finally, the combination of spirituality, religiosity and personal beliefs was an independent
predictor of adherence when adjusted for demographics, clinical characteristics and psychosocial instruments.
Conclusions: Spirituality, religiosity and personal beliefs were the only variables consistently associated with compliance
to medication in a cohort of outpatients with heart failure. Our data suggest that adequately addressing these aspects on
patient’s care may lead to an improvement in adherence patterns in the complex heart failure management. (Arq Bras Cardiol.
2016; 106(6):491-501)
Keywords: Heart Failure; Medication Adherence / psychology; Surveys and Questionnaires; Outpatients; Spirituality; Religion.
Introduction
Heart failure (HF) continues to challenge multidisciplinary
health care teams.1 Its prevalence remains elevated and its
management usually requires poly-pharmacy along with
satisfactory self-awareness of the disease.2,3 The course of
HF, in its chronicity and frequently inexorable outcomes,
shares similarities with many cancer diseases and resembles
their impact on poor quality of life standards.4 Patients face
important limitations to adequately adhere to the complexity
of HF management.5
Adherence appears as an important aspect in the course
of HF. It influences patients’ pattern of decompensation and
subsequent hospital re-admissions.6 In addition, adequate
adherence standards may help to improve quality of life.7
Mailing Address: Nadine Clausell •
Rua Ramiro Barcelos, 2350, Division of Cardiology – room 2060.
Postal Code 90035903, Rio Branco, Porto Alegre, RS – Brazil.
E-mail: [email protected]
Manuscript received November 25, 2015; revised manuscript December 02,
2015; accepted February 19, 2016.
DOI: 10.5935/abc.20160076
491
Many factors are thought to influence patient adherence
to HF management. Clinical aspects such as comorbidities
commonly associated with HF have been addressed in this
regard.5 Socio‑economic background, psychological aspects and
patients’ level of formal education have also been investigated
as influential in adherence patterns in the HF population.8,9
Nonetheless, data addressing such issues on large cohorts being
followed in specialized HF clinics remains scarce.
Spirituality has recently been studied in the setting of
chronic diseases with poor quality of life and predictable
ominous outcomes. Spiritual wellbeing refers to one’s
spirituality as “the state of affairs”.10 This concept has
been applied to unravel specifics on spiritual status in the
palliative care setting, but very little data exists on spirituality
associated to such a chronic and prevalent condition as HF.
Spirituality has been shown to potentially influence how
patients with HF cope with their syndrome, consequently
having an impact on functional status, health status and
quality of life.11, 12 Recent data indicates that spirituality
could favorably influence mortality in patients with HF.13
However, how spirituality relates to adherence patterns in
stable outpatients with HF remains relatively unexplored.
Few reports with controversial results, partially limited by
convenience sampling and instruments utilized, failed to
Alvarez et al.
Spirituality and heart failure therapy
Original Article
demonstrate a positive association between spirituality and
degree of compliance in HF patients.14 Nevertheless, for
many other chronic disorders there is sustained evidence
that spirituality could improve compliance.15
In this study, we examined associations between spirituality
and adherence to management in outpatients with HF,
independently of psychosocial and educational background.
Patients and Methods
Study design
This is a cross-sectional study which enrolled HF outpatients
followed at a tertiary care University Hospital in Porto Alegre,
Brazil, from August, 2012 to June, 2013. The study protocol was
approved by the Institutional Research and Ethics Committee
and all enrolled participants signed a written informed consent
prior to study entry.
Participants
Consecutive ambulatory patients (mainly composed by
patients with newly diagnosed left ventricular dysfunction,
post HF hospital admission and/or refractory symptoms)
being followed for a minimum of six months in the HF Clinic
at the Hospital de Clínicas de Porto Alegre were invited
to participate. Patients in any New York Heart Association
functional class, regardless of HF etiology, were eligible.
Exclusion criteria were inability to understand the study
protocol and to answer the questions without assistance due
to cognitive impairment or auditory deficit.
Study end-points and procedures
Patients were assessed for adherence to therapy, quality of
life, depression, religiosity and spirituality utilizing validated
questionnaires. All utilized instruments were previously
validated to Brazilian Portuguese language.16-21 Interviews were
performed following the clinic appointment by research staff
previously trained in questionnaire application. Time required
for answering all the instruments ranged from 50 to 70 minutes.
Patients answered questions orally and staff filled questionnaires
as requested. Demographics and clinical characteristics were
obtained from electronic chart review and clinical data were
acquired during the clinic visit by a researcher who was unaware
of questionnaire results. Definitions of psychosocial variables of
interest are detailed below.
Adherence to therapy. The adherence to pharmacologic
and non-pharmacologic therapy was assessed according to the
Repetitive Education and Monitoring For Adherence for Heart
Failure (REMADHE) study protocol, which has been adapted
and is currently used in clinical practice in our HF Clinic.17,22
The questionnaire is composed by ten-questions involving
four domains: use of medications (one question); food and
fluids (seven questions); alcohol consumption (one question);
and medical appointments (one question). The score ranges
between 0 and 26 points, with higher scores indicating better
patient’s adherence. A REMADHE score equal to or higher
than 18 points indicates adequate level of adherence.22
Quality of life: Two instruments were used to assess
quality of life: generic and disease-specific questionnaires.
Generic quality of life assessment was performed with the
utilization of the World Health Organization Quality of
Life (WHOQoL-Bref) while disease-specific was assessed
by the Minnesota Living With Heart Failure Questionnaire
(MLHFQ).23,24 The WHOQoL-Bref is an abbreviated version
of the WHOQOL-100 which is composed of 26 questions:
a question about quality of life in general, a question about
satisfaction with one’s self health status, and 24 questions
divided into four domains – physical, psychological, social
relations and environment. The MLHFQ evaluates quality
of life related to HF symptomatology within the previous
month and correlates proportionally to functional class.25
Higher WHOQoL-Bref scores indicate better quality of
life in general, whereas lower MLHFQ represent better
HF-related quality of life.
Depression: Depression was evaluated by the Patient
Health Questionnaire (PHQ-9), which is a screening tool for
detection of depression, based on symptom occurrence within
the previous two weeks. It comprehends nine questions based
on the major criteria for the diagnosis of major depression
according to the Diagnostic and Statistical Manual of Mental
Disorders, 4th edition (DSM-IV).26,27 Depression is classified,
according to the score, as moderate depressive symptoms
(total score between 10 and 14), moderate major depression
(score between 15 and 19) and severe major depression (score
equal or higher than 20).26
Religiosity, Spirituality and Personal Beliefs: Two
instruments were used to evaluate these dimensions.
1) The Duke University Religion Index (DUREL) scale is a
tool for assessment of spirituality that is focused on religious
aspects.28 Its transcultural adaptation was developed and
validated by Moreira-Almeida.18 The DUREL scale has five
items that describe three dimensions of religiosity, known to
best correlate with health-related outcomes: organizational
(ORA); non-organizational (NORA); and intrinsic religiosity
(IR). The score ranges from 1 to 30 points and higher scores
indicate elevated levels of religiosity.
2) The World Health Organization Quality of Life
Spirituality, Religiosity and Personal Beliefs (WHOQoL-SRPB)
instrument is an additional module of the WHOQOL to
evaluate spirituality, religion and personal beliefs (SRPB) as
a component of the quality of life construct. It is composed
by 32 items distributed in eight factors (Spiritual Connection,
Meaning of Life, Awe & Wonder, Wholeness & Integration,
Spiritual Strength, Inner Peace, Hope & Optimism and Faith) in
a general index composed of 4 items (SRPB Global), originally
of the SRPB domain of the WHOQOL-100.19,29
Statistical analyses
Normally distributed (according to Shapiro-Wilks testing)
continuous variables were expressed as mean ± standard
deviation, while non-normally distributed ones were expressed
as median and interquartile ranges. Categorical variables
were reported as absolute numbers and percentages.
Normally distributed continuous variables were analyzed by
unpaired t-test. Non-normally distributed continuous variables
Arq Bras Cardiol. 2016; 106(6):491-501
492
Alvarez et al.
Spirituality and heart failure therapy
Original Article
were analyzed using Mann Whitney U test. Chi-square test
(or exact Fisher test when appropriate) was used to compare
categorical variables. Spearman coefficients were used for
evaluation of correlations between adherence and psychosocial
variables of interest. Kruskal Wallis was used to compare scores
of spirituality across REMADHE quartiles. Logistic regression
models were used to explore the association of spirituality to
an adequate level of adherence (REMADHE ≥ 18 points).
Adjusting covariates for multivariable models were tested for
colinearity and selected among demographic, clinical and
psychosocial variables of either clinical or statistical significance.
The report by Black and co-workers, that correlated spirituality
and adherence utilizing different instruments, was used to
estimate a sample size of 130 subjects in the current study
(α = 5%, β = 80%; effect size 25%).14 All analyses were
performed using the SPSS 20.0 statistical package (SPSS Inc.,
Chicago, IL, USA). A p value lower than 0.05 was considered of
statistical significance.
Results
One hundred and thirty patients were interviewed
between August, 2012 and June, 2013. Demographic and
clinical characteristics of the studied population are detailed
in Table 1. A description of the average scores obtained
through the study instruments is provided in Table 2.
Overall, there was a low level of adherence, according to
REMADHE scores. Adequate adherence was observed in
38.5% of the population.
The correlations between the adherence score with clinical
characteristics and psychosocial scores are demonstrated in
Table 3. A description of associations of demographic and
clinical variables with the adherence score is also described in
the Supplemental Table. Among demographics, REMADHE score
differed only according to marital status. Clinical characteristics
associated to higher adherence scores were ischemic HF etiology,
presence of an implantable cardiac defibrillator and chronic
kidney impairment. Adherence was positively correlated to the
generic quality-of-life measure, but not to the disease-specific
HF score. Neither depression nor religiosity was correlated to
adherence. Interestingly, spirituality, when assessed by both
total WHOQoL-SRPB score sum and by many specific domains,
was positively correlated to adherence. Although significantly
correlated to adherence score, the magnitude of spirituality
association was relatively weak (Figure 1). Notably, there was
a trend towards higher spirituality scores across quartiles of the
adherence score (Figure 2).
Spirituality was also found to be significantly
correlated to other psychosocial variables evaluated.
WHOQoL‑SRPB was moderately correlated to both generic
(WHOQoL‑Bref [r = 0.47; p = 0.0001]) and disease-specific
(MLHFQ [r = -0.34; p = 0.0001]) measures of quality‑of‑life.
There was an inverse correlation between WHOQoL‑SRPB
and depression classification by PHQ-9 (r = –0.49;
p < 0.0001). Of note, there was a positive correlation between
WHOQoL-SRPB and religiosity assessed by DUREL (r= 0.55;
p= 0.0001), which was also observed within domains of both
instruments (Table 4).
493
Arq Bras Cardiol. 2016; 106(6):491-501
Table 1 – Demographics and clinical characteristics of the
study population
N
130
Demographics
Age, years
60 ± 13
Gender, male
88 (67.5%)
Ethnicity
Caucasian
African-descendent
Other
113 (87%)
9 (7%)
8 (6%)
Education
Functionally illiterate
Elementary, non-graduated
Elementary, graduated
High school, non-graduated
High school, graduated
5 (4%)
79 (61%)
26 (20%)
6 (5%)
14 (11%)
Marital status
Single
Married
Divorced
Widowed
Heart failure history
Etiology
Ischemic
Idiopathic
Hypertensive
Valvular
Alcoholic
Other
Ejection fraction, %
31 (24%)
78 (60%)
15 (11.5%)
6 (4.5%)
42 (32.5%)
28 (21.5%)
29 (22.5%)
14 (10%)
10 (7.5%)
7 (5%)
36 ± 13
Functional class, NYHA
I-II
III-IV
Cardiac devices (ICD or CRT-D)
Hospital admissions in the previous year
None
One
More than one
97 (74.5%)
33 (25.5%)
23 (18%)
82 (63%)
26 (20%)
22 (17%)
Comorbidities
Hypertension
75 (57.5%)
Dyslipidemia
64 (49%)
Previous myocardial infarction
39 (30%)
Previous cardiac surgery
24 (18.5%)
Diabetes
50 (38.5%)
COPD
10 (7.5%)
Chronic kidney impairment
52 (40%)
Previous stroke
20 (15.5%)
Collagen tissue disease
11 (9%)
Smoking, past or present
66 (50.5%)
Alcoholism, past or present
29 (22.5%)
Neoplasia
18 (14%)
NYHA: New York Heart Association; ICD: implantable cardiac defibrillator;
CRT-D: cardiac resynchronization therapy-defibrillator; COPD: chronic
obstructive pulmonary disease. Data expressed as mean ± SD and
number (percentage). Ejection fraction assessed by bi-dimensional
echocardiography (Simpson method).
Alvarez et al.
Spirituality and heart failure therapy
Original Article
Table 2 – Description of psychosocial instruments applied in the
study population
N
Table 3 – Correlations of clinical and psychosocial variables with
adherence score (REMADHE)
130
Adherence (REMADHE)
16.2 ± 4.1
r
p
Clinical characteristics
Quality of life
Age, years
0.10
0.24
Generic (WHOQoL-Bref)
Ejection fraction, %
-0.09
0.30
NYHA functional class
0.03
0.70
0.21
0.02
Total
13.0 ± 3.7
Domains
Quality of Life
Physical
12.2 ± 3.1
Psychological
14.1 ± 2.7
Social
13.7 ± 2.1
Environmental
14.8 ± 1.9
Disease-specific (MLHFQ)
Depression (PHQ-9)
50.5 ± 16.9
4.8 ± 5.3
Religiosity (DUREL)
Total
23.5 ± 4.6
Intrinsic
15.5 ± 2.8
Organizational
3.3 ± 1.6
Non-organizational
4.7 ± 1.3
Total
Domains
Physical
0.13
0.16
Psychological
0.28
0.001
Social
0.08
0.36
Environmental
0.21
0.01
Disease-specific (MLHFQ)
-0.09
0.29
Depression (PHQ-9)
-0.12
0.16
0.13
0.14
0.20
0.02
Religiosity (DUREL)
Total
Spirituality (WHOQoL-SRPB)
Total
Generic (WHOQoL-Bref)
3.8 ± 0.61
Intrinsic
Organizational
Domains
0.02
0.79
-0.006
0.95
0.26
0.003
Connect
0.31
< 0.0001
Meaning
0.23
0.008
Awe
0.27
0.002
Whole
0.19
0.02
Strength
0.21
0.02
Peace
0.23
0.01
Hope
0.19
0.03
Faith
0.27
0.002
Non-organizational
Connect
3.7 ± 0.7
Meaning
3.9 ± 0.6
Spirituality (WHOQoL-SRPB)
Awe
3.8 ± 0.8
Total
Whole
3.7 ± 0.6
Domains
Strength
3.8 ± 0.8
Peace
3.8 ± 0.7
Hope
3.8 ± 0.8
Faith
3.8 ± 0.7
REMADHE: Repetitive Education and Monitoring for Adherence for
Heart Failure; WHOQoL-Bref: World Health Organization Quality of Life;
MLHFQ: Minnesota Living with Heart Failure Questionnaire; PHQ‑9: Patient
Health Questionnaire 9; DUREL: Duke University Religion Index;
WHOQoL‑SRPB: World Health Organization Quality of Life Spirituality,
Religiosity and Personal Beliefs; Data expressed as mean ± SD.
Among multivariable models to identify clinical and
psychosocial variables associated to the presence of adequate
adherence, WHOQoL-SRPB was an independent predictor
when adjusted for demographics, clinical characteristics
and psychosocial instruments (Table 5). Aside from
WHOQoL‑SRBP, DUREL was the only additional psychosocial
instrument to demonstrate borderline significance for
association to adequate adherence.
Discussion
The main finding of the present study is that SRPB were
consistently associated with adherence to treatment in a
cohort of HF patients followed in a tertiary care clinic.
REMADHE: Repetitive Education and Monitoring for Adherence for Heart
Failure; NYHA: New York Heart Association; WHOQoL-Bref: World Health
Organization Quality of Life; MLHFQ: Minnesota Living with Heart Failure
Questionnaire; PHQ-9: Patient Health Questionnaire 9; DUREL: Duke
University Religion Index; WHOQoL‑SRPB: World Health Organization
Quality of Life Spirituality, Religiosity and Personal Beliefs; r: indicates
Spearman coefficients; p: for Spearman coefficients.
Importantly, in our study, this association was independent
of relevant demographic and clinical data known to
influence adherence to HF management.
This is the first study to show a clear association of spirituality
and adherence to treatment in HF. However, our study cannot
determine if there is a direct effect of spirituality in adherence
or if spirituality is only a marker of broader and more complex
Arq Bras Cardiol. 2016; 106(6):491-501
494
Alvarez et al.
Spirituality and heart failure therapy
Original Article
Figure 1 – Correlation plot between adherence (REMADHE) and spirituality (WHOQoL-SRPB) scores (Spearman coefficient = 0.26; p = 0.003)
5
WHoQoL-SRPB, points
4,5
4
3,5
3
Quartile 1
Quartile 2
Quartile 3
Quartile 4
2,5
2
1,5
1
0,5
0
REMADHE quartiles
Figure 2 – Score of spirituality (WHOQoL-SRPB) according to quartiles of adherence as per REMADHE score. p-value of 0.052 by Kruskal-Wallis test Error bars represent
standard-deviation.
495
Arq Bras Cardiol. 2016; 106(6):491-501
Alvarez et al.
Spirituality and heart failure therapy
Original Article
Table 4 – Correlations between spirituality and religiosity scores
DUREL
DUREL-ORA
DUREL-NORA
DUREL-IR
r
p
r
p
r
p
r
p
WHOQoL-SRPB
0.55
0.0001
0.36
0.0001
0.29
0.001
0.57
0.0001
Connect
0.54
0.0001
0.29
0.0001
0.34
0.0001
0.59
0.0001
Meaning
0.38
0.0001
0.19
0.03
0.18
0.04
0.44
0.0001
Awe
0.36
0.0001
0.27
0.02
0.10
0.25
0.38
0.0001
Whole
0.47
0.0001
0.30
0.0001
0.27
0.002
0.48
0.0001
Strength
0.49
0.0001
0.33
0.0001
0.28
0.001
0.51
0.0001
Peace
0.39
0.0001
0.27
0.002
0.20
0.02
0.41
0.0001
Hope
0.37
0.0001
0.29
0.001
0.22
0.01
0.31
0.0001
Faith
0.54
0.0001
0.33
0.0001
0.34
0.0001
0.56
0.0001
DUREL: Duke University Religion Index; ORA: organizational religious activity; NORA: non-organizational religious activity; IR: intrinsic religiosity;
WHOQoL‑SRPB: World Health Organization Quality of Life Spirituality, Religiosity and Personal Beliefs; r: indicates Spearman coefficient; p: for Spearman coefficients.
Table 5 – Logistic regression models for association of spirituality (WHOQoL-SRPB) to adequate adherence to therapy
(REMADHE ≥ 18 points)
Model 1
WHOQoL-SRPB, 1-point increase
β coefficient
OR (CI 95%)
p
1.01
2.76 (1.31 – 5.81)
0.007
Age, 1-year increase
-0.01
0.98 (0.95 – 1.01)
0.32
Ejection fraction, 1% increase
-0.01
0.98 (0.95 – 1.02)
0.40
Marital status, married
0.56
1.75 (0.76 – 4.08)
0.19
Instruction, ≥ elementary school graduation
0.31
1.36 (0.59 – 3.11)
0.47
Model 2
WHOQoL-SRPB, 1-point increase
β coefficient
OR (CI 95%)
p
1.17
3.23 (1.49 – 7.01)
0.003
Heart failure of ischemic etiology
-0.31
0.73 (0.32 – 1.67)
0.45
Implantable cardiac defibrillator
-0.91
0.40 (0.15 – 1.05)
0.06
Chronic kidney disease
-0.72
0.48 (0.21 – 1.08)
0.08
Marital status, married
-0.36
0.69 (0.31 – 1.57)
0.38
β coefficient
OR (CI 95%)
p
Model 3
WHOQoL-SRPB
-0.12
4.89 (1.64 – 14.58)
0.004
WHOQoL-Bref
1.59
1.03 (0.98 – 1.06)
0.19
MLHFQ
0.03
1.02 (0.98 – 1.06)
0.26
PHQ-9
0.02
1.03 (0.92 – 1.16)
0.60
DUREL
0.03
0.89 (0.79 – 1.00)
0.05
WHOQoL-SRPB: World Health Organization Quality of Life Spirituality, Religiosity and Personal Beliefs; REMADHE: Repetitive Education and Monitoring for
Adherence for Heart Failure; OR: odds ratio; CI: confidence interval; WHOQoL-Bref: World Health Organization Quality of Life; MLHFQ: Minnesota Living with Heart
Failure Questionnaire; PHQ-9: Patient Health Questionnaire 9; DUREL: Duke University Religion Index.
Model 1 – adjusted for demographic and clinical variables selected by clinical significance;
Model 2 – adjusted for demographic and clinical variables selected by significance in univariate analyses;
Model 3 – adjusted for other psychosocial instruments of quality-of-life, depression and religiosity; Odds ratio represents the magnitude of association per 1-point
increase in each score
Arq Bras Cardiol. 2016; 106(6):491-501
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effect. For example, someone who is spiritualized is probably
more prone to follow recommendations coming from
someone he has a close relationship with (e.g., a physician).
We identified three previous studies addressing the possible
interactions between HF and spirituality.14,30,31 Black et
al.14 sent a package of instruments (Spiritual Assessment
Scale and the Heart Compliance Questionnaire) by mail
to a convenience sample of 213 patients with a return rate
of 45%. The authors did not find a significant correlation
between spirituality and compliance. The study by Thomas30
using a convenience sample of 97 patients showed a positive
result with moral‑ethical-spiritual self which accounted for
10.8% of the variance in adherence. Dickson et al.31 studying
socio‑cultural influences on HF self-care in an ethnic minority,
black population, using a mixed-methods strategy, found that
spirituality was linked to self-care. More recently, issues related
to wellbeing were shown to impact positively in patients with
stage B asymptomatic HF - spirituality apparently played a role
in mediating these effects.32
Although religiosity and spirituality have been associated
with better healthcare practices, such observations failed
to translate into better cardiovascular disease outcome
in an adequately-powered study. 33-35 The hypothesis
that SRPB could affect compliance in chronic diseases
and, particularly, in HF has also been raised by different
authors.14,30,36 There are some possible models proposed
to explain such relationship. Black et al.14 suggested that
spiritual beliefs influence health beliefs which could lead
to the practice of health-related activities such as the use
of medications, control of weight, and diet compliance.
Thomas30 applied the Roy’s Self Concept model to identify
several potential predictors of medical compliance.30, 37
In this model, any stimulus is perceived either as a threat
or a challenge to one’s self-concept of body image, body
sensation, self-consistency and moral-ethical-spiritual self.
Briefly, stimuli perceived as a threat are reacted to in a
negative way and consequently avoided, while stimuli
perceived as a challenge are reacted to in a positive way and
consequently followed. Thomas30 found that patients who
perceived the HF regimen as a threat either to body image,
self-consistency, body sensation or self-ideal were less likely
to adhere to it. On the contrary, those to whom the regimen
was perceived as a challenge to moral-ethical-spiritual self
were most likely to adhere to medical therapy. Lastly, a
recent survey conducted on HF patients showed that they
would have welcomed spiritual care in their management.38
Our study has some limitations. First, as we used a crosssectional design we can only conclude about association
between spirituality and adherence, but not a causal
relationship. Second, our sample was obtained in Brazil, a
country where spirituality and religion are very notoriously
important values. Additional studies are necessary to assess if
497
Arq Bras Cardiol. 2016; 106(6):491-501
these findings are replicable in different cultural and religious
backgrounds. Finally, the effect of spirituality in adherence to
different aspects of the HF management - pharmacological
and non-pharmacological therapy - was not individually
assessed. The REMADHE tool used in our study does not
discriminate between the various components of the HF
management in depth. If available, such information could
be useful to better allocate the role of multidisciplinary
care, vis a vis the spirituality of patients, and be taken into
consideration accordingly, to improve patients´ adherence.
Conclusions
Our study highlights that spirituality could be an
important variable associated with adherence to treatment
in the setting of outpatients with HF, suggesting that
physicians and health professionals should be aware of
its importance to improve clinical practice outcomes and
implement measures to address the spiritual needs of
patients. Further studies are warranted to better determine
whether pharmacologic and non-pharmacologic measures
in the management of HF are equally influenced by
spirituality-related behavior.
Author contributions
Conception and design of the research: : Alvarez JS,
Goldraich LA, Nunes AH, Rocha NS, Fleck MPA, Clausell N.
Acquisition of data: Alvarez JS, Zandavalli MCB, Zandavalli
RB, Belli KC. Analysis and interpretation of the data: Alvarez
JS, Goldraich LA, Nunes AH, Rocha NS, Fleck MPA. Statistical
analysis: Alvarez JS, Goldraich LA, Nunes AH, Rocha NS.
Obtaining financing: Alvarez JS. Writing of the manuscript:
Alvarez JS, Goldraich LA, Nunes AH, Clausell N. Critical
revision of the manuscript for intellectual content: Alvarez JS,
Goldraich LA, Nunes AH, Rocha NS, Fleck MPA, Clausell N.
Supervision / as the major investigador: Alvarez JS, Clausell
N. Formatting and translation: Zandavalli RB.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
This study was funded by Fundo de Incentivo à Pesquisa
do Hospital das Clínicas de Porto Alegre.
Study Association
This article is part of the thesis of master submitted by
Juglans Souto Alvarez, from Universidade Federal do Rio
Grande do Sul.
Alvarez et al.
Spirituality and heart failure therapy
Original Article
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Does religious observance promote health? mortality in secular vs religious
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et al. Long-term prospective, randomized, controlled study using repetitive
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Andrade LM, et al. Validity of the Brazilian version of the Duke Religious
Index (DUREL). Rev Psiquiatr Clin. 2012;39(4):130-5.
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35. Feinstein M, Liu K, Ning H, Fitchett G, Lloyd-Jones DM. Burden of
cardiovascular risk factors, subclinical atherosclerosis, and incident
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Supplemental Table – Adherence score according to demographics and clinical characteristics.
REMADHE, points
p (t test)
Demographics
Age
< 60
15.9 ± 4.1
≥ 60
16.6 ± 3.7
0.31
Gender
Male
16.6 ± 3.8
Female
15.6 ± 4.2
0.16
Ethnicity
Caucasian
16.5 ± 3.9
Other
15.2 ± 3.8
0.23
Education
Elementary graduated or higher degree
16.0 ± 3.8
Other
16.5 ± 4.0
0.56
Marital status
Married
17.0 ± 4.1
Other
15.2 ± 3.5
0.01
Heart failure history
Etiology
Ischemic
17.4 ± 3.6
Non-ischemic
15.8 ± 4.0
0.02
Ejection fraction
≤ 35%
16.4 ± 3.9
> 35%
16.2 ± 3.9
0.83
Functional class, NYHA
I-II
16.1 ± 4.0
III-IV
16.8 ± 3.7
0.38
Cardiac Defibrillator
Yes
17.7± 3.2
No
16.0 ± 4.1
0.05
Admissions in the previous year
None
16.1 ± 4.0
Any
16.6 ± 3.8
0.52
Comorbidities
Hypertension
Yes
16.6 ± 3.7
No
15.9 ± 4.2
0.34
Previous myocardial infarction
499
Yes
17.2 ± 3.6
No
15.9 ± 4.0
Arq Bras Cardiol. 2016; 106(6):491-501
0.11
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to be continued
Previous cardiac surgery
Yes
16.5 ± 4.4
No
16.3 ± 3.9
0.8
Diabetes
Yes
16.0 ± 3.7
No
16.5 ± 4.0
0.50
Chronic kidney impairment
Yes
17.2 ± 3.8
No
15.8 ± 3.9
0.04
Previous stroke
Yes
16.6 ± 2.7
No
16.3 ± 4.1
0.69
Smoking, past or present
Yes
14.3 ± 4.1
No
15.8 ± 4.2
0.28
Alcoholism, past or present
Yes
16.1 ± 4.0
No
16.9 ± 3.7
0.34
Neoplasia
Yes
15.6 ± 4.4
No
16.4 ± 3.9
0.38
Arq Bras Cardiol. 2016; 106(6):491-501
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Back to The Cover
Original Article
Functional Class in Children with Idiopathic Dilated Cardiomyopathy.
A Pilot Study
Aline Cristina Tavares, Edimar Alcides Bocchi, Guilherme Veiga Guimarães
Instituto do Coração (InCor), Hospital Sírio-libanês (HSL), São Paulo, SP – Brazil
Abstract
Background: Idiopathic dilated cardiomyopathy (IDCM), most common cardiac cause of pediatric deaths, mortality descriptor:
a low left ventricular ejection fraction (LVEF) and low functional capacity (FC). FC is never self reported by children.
Objective: The aims of this study were (i) To evaluate whether functional classifications according to the children, parents and
medical staff were associated. (iv) To evaluate whether there was correlation between VO2 max and Weber’s classification.
Method: Prepubertal children with IDCM and HF (by previous IDCM and preserved LVEF) were selected, evaluated and
compared. All children were assessed by testing, CPET and functional class classification.
Results: Chi-square test showed association between a CFm and CFp (1, n = 31) = 20.6; p = 0.002. There was no
significant association between CFp and CFc (1, n = 31) = 6.7; p = 0.4. CFm and CFc were not associated as well
(1, n = 31) = 1.7; p = 0.8. Weber’s classification was associated to CFm (1, n = 19) = 11.8; p = 0.003, to CFp
(1, n = 19) = 20.4; p = 0.0001and CFc (1, n = 19) = 6.4; p = 0.04).
Conclusion: Drawing were helpful for children’s self NYHA classification, which were associated to Weber’s stratification.
(Arq Bras Cardiol. 2016; 106(6):502-509)
Keywords: Heart Failure; Cardiomyopathy, Dilated / mortality; Stroke Volume; Child; Pilot Projects.
Introduction
Idiopathic dilated cardiomyopathy (IDCM) – characterized
by left ventricular dilatation and systolic dysfunction of
undetermined cause,1-3 has a high incidence among the
pediatric population4 and an unfavorable outcome,2,5,6 and
is thus a target for reasearch.1
To date, it is known that the only predictors of death or
cardiac transplantation in children with IDCM are a low LVEF
and low functional capacity.7
LVEF is easily measured by echocardiography.
Functional capacity, in turn, may be determined using
peak oxygen consumption (VO2) in the cardiopulmonary
exercise test (CPET)9,10 or scales representing the functional
class.3,11,12 CPET findings provide an objective assessment
of the functional capacity,9,13 whereas the scales represent
a subjective assessment.13
the stratification, and treatment. Thus, the objective of
this study is to fill this gap and evaluate whether there is a
correlation between the objective functional capacity (by
peak O2 consumption – peak VO2) and the functional class
as proposed by the family, the medical team and the child
itself, and whether there is a correlation between peak VO2
and Weber stratification.12
Methods
8
However, the scales are not always related to the
objective values of CPET, 13,14 and this may impair the
communication between parents and the medical team,
Mailing Address: Aline Cristina Tavares •
Av. Dr. Enéas de Carvalho Aguiar, 44. Laboratório de Insuficiência Cardíaca,
Bloco 1, 1º andar. Postal Code 05403-900 – InCor, São Paulo – Brazil
E-mail: [email protected]
Manuscript received July 10, 2015; revised manuscript November 30, 2015;
accepted January 18, 2016.
DOI: 10.5935/abc.20160066
502
Sample
This is a pilot, cross-sectional, prospective, randomized,
consecutive study. Children of both genders with IDCM
and children with HF with preserved LVEF (secondary to
previous IDCM) were selected from the outpatient clinic
of the Medical Unit of Pediatric Cardiology and Congenital
Heart Defects of Instituto do Coração – InCor, Hospital das
Clinicas da Faculdade de Medicina da Universidade de São
Paulo - HCFMUSP.
The inclusion criteria were: (i) patients diagnosed with
current IDCM or HF for previous IDCM with preserved
LVEF; (ii) patients clinically stable; (iii) patients receiving
drug therapy continuously for the past 3 months; (iv) older
than 5 years; 15,16 (v) age equivalent to the prepubertal
phase –Tanner-Whithouse scale stages 1 to 3;17 (vi) previous
echocardiographic study performed at least 6 months earlier.
Children with complex ventricular arrhythmias or atrial
fibrillation; in the postoperative recovery period; with
Tavares et al.
Functional class in children with cardiomyopathy
Original Article
neuromuscular, renal or pulmonary diseases; with diabetes
mellitus; and/or those who refused to participate in the study
or in the assessments were not included.
The children, as well as their guardians (as established in
articles 1634,18 and 1852,19 subsection V of the Civil Code,
and in Law 8069/90 and 10406/2002),20 included in any of
the groups, were given information on the objectives of the
research and the tests participants should undergo. In addition,
all children participating and their parents or guardians were
informed that the children should keep taking their regular
medication throughout the study. All children or guardians
gave written informed consent to participate.
The children were included according to the inclusion
criteria and were assessed provided they were cleared by
the medical team.
Assessments
All children were assessed as regards their functional class,
anthropometric data and CPET.
Functional class
The modified functional classification used was adapted
from a functional classification previously described
elsewhere and applied in studies assessing children with
cardiomyopathies,3,21 as follows:
Class I – Heart disease with no limitation of physical
activities. Schoolchildren are able to attend physical education
classes until the end.
Class II – Slight limitation of physical activities.
Comfortable at rest, but ordinary activities may result in
tachycardia, fatigue or dyspnea. Schoolchildren attend
physical education classes, but are unable to stay until
the end.
Class III – Marked limitation of physical activities. Less than
ordinary activities, such as walking less than a block, may cause
fatigue, tachycardia or dyspnea. Schoolchildren are unable to
attend physical education classes.
Class IV – Unable to carry on any physical activity without
discomfort. Symptoms are present at rest and increase during
activity.
Based on this description, a graphic representation of
the four functional classes was elaborated by this study’s
author, both for male and female children (Figures 1 and 2,
respectively), so that the guardians and the children could
use it. In order to make these drawings, the image taken
into consideration was the one with which children in the
same age range as those participating in the study could
identify themselves.
Initially, the physician following up the children would give
his/her opinion on which functional class the children were
in. This baseline assessment was made without the presence
of the guardians or the children themselves. This information
was expressed as functional class according to the medical
team (FCm).
Next, the parents or guardians would give their opinion
on the functional class the children were in, according to
figures 1 and 2. This classification was made without the
presence of the physicians or even the children themselves.
This information was expressed as functional class according
to parents or guardians (FCp).
Later, the children would perform a self-assessment
of their functional class using the graphic representation
(Figures 1 and 2). This self-perceived functional class was
expressed as functional class according to the children
themselves (FCc).
Anthropometric data
Data on age, gender, height, body mass and body mass
index (BMI) were collected.
Echocardiographic data
Analysis of the cardiac function using echocardiography
was considered for studies performed up to six months
prior to inclusion.
Echocardiographic studies were performed according
to recommendations from the guidelines for the pediatric
population, using the Teicholz method.22 Data on LVEF,
end-diastolic left ventricular size, end-systolic left ventricular
diameter, and left ventricular wall thickness were collected. Size
and thickness values were corrected for body surface area (BSA)
using a formula appropriate for children weighing more than
10 kg, as follows: BSA = (weight *4 +7) / (weight + 90),23 in
which weight is expressed in kg.
Children, whose medical record contained a previous
echocardiographic study performed no later than six months
prior to the collection of the other data, would have their
echocardiographic data retrieved from that previous study.
Children with no previous echocardiographic study underwent
the test, from which the data were further collected.
Cardiopulmonary exercise test
The children underwent a cardiopulmonary exercise test
(CPET) in a programmable treadmill (Marquette series 2000,
Marquette Electronics, Milwaukee, WI, USA), according to
the modified Balke ramp protocol.21,24-26
CPET was performed two hours after a caffeine-free light
meal, in a room with controlled temperature (21°C to 23°C),
after a 2-minute rest, in the upright position on the treadmill.25
During the beginning of the resting , exercise, and
recovery periods, the children had their pulmonary
ventilation as well as oxygen and carbon dioxide
concentrations in the inhaled and exhaled air volumes
continuously monitored (Sensormedics, model Vmax 229,
Yorba Linda, CA, USA), breath by breath. During CPET,
continuous 12-lead heart rhythm monitoring was performed
(Marquette MAX 1, Marquette Electronics, Milwaukee, WI,
USA) and systemic blood pressure (BP) was measured every
minute (HP68S Hewlett-Packard multiparameter monitor,
USA, or HP M1008B Hewlett-Packard oscillometric BP
transducer, USA).24-26
Criteria for exercise termination were the absolute
indications recommended by the ACC/AHA Guidelines
Update For Exercise Testing, when exhaustion was reached
Arq Bras Cardiol. 2016; 106(6):502-509
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Figure 1 – Functional class for male children.
Figure 2 – Functional class for female children.
504
Arq Bras Cardiol. 2016; 106(6):502-509
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(respiratory quotient > 1.0)25 or in the presence of signs or
symptoms that could result in cardiac injury, such as angina,
headache, dizziness, syncope, excessive dyspnea, fatigue,
ST-segment depression or elevation greater than 3 mm,
arrhythmia, supraventricular or ventricular tachycardia,
atrioventricular block or progressive decrease in BP.25
Table 1 – Sample characterization
Total (19)
Demographics
Age (years)
8.7 ± 1.9
Gender (F/M)
10/9
Statistical Analysis
Body mass (kg)
30.7 ± 8.5
The statistical analysis was carried out using the SPSS 12.0
software program for Windows (SPSS Inc., Chicago, IL, USA).
Height (m)
1.26 ± 0.45
The Shapiro-Wilk test was used to check the normality of
data in the population.
Patient demographics were expressed in a descriptive
manner, in absolute numbers, percentages or mean and standard
deviation. Functional classes were presented as absolute numbers.
Quantitative variables regarding the cardiopulmonary exercise
test were expressed as mean and standard deviation.
The chi-square test (χ2) was used to analyze the association
between categorical variables of the functional class, as
assessed by the medical team, guardians and children.
The Pearson correlation coefficient was used for normal
data, and the Spearman correlation, for non-parametric data,
in order to correlate quantitative data. These correlations
were interpreted as directly proportional (if +) or inversely
proportional (if -), and weak (if 0.1 to 0.29), moderate (if 0.3
to 0.59), strong (if 0.6 to 0.79), very strong (if 0.8 to 0.99) or
perfect (if 1).27
Results
Initially, 77 children were screened to comprise the
sample. Only 31 met all inclusion criteria; however, only 19
agreed to participate in the study. The post-hoc Bonferroni
test showed that there was no significant effect for gender
among the children.
None of the 19 children presented any hemodynamic
instability during the cardiopulmonary exercise test.
The children were using the following medications:
acetyl salicylic acid, captopril, carvedilol, digoxin, enalapril,
spironolactone, furosemide, and topimarate.
Table 1 shows the characterization of the overall sample,
with details on its demographics and echocardiographic data.
According to the medical team, 13 children were classified
as FC I, five as FC II, one as FC III, and none as FC IV.
According to parents, 13 children were classified as FC I,
four as FC II, one as FC III and one as FC IV.
According to the self-assessment, 11 children classified
themselves as FC I, six as FC II, two as FC III. No children
classified themselves as FC IV.
Table 2 shows FCm, FCp, FCc, and peak VO2 reached in
the cardiopulmonary exercise test for each participant.
The chi-square test showed an association between FCm and
FCp (1, n = 31) = 20.6; p = 0.002. No significant association
was found between FCp and FCc (1, n = 31) = 6.7; p = 0.4.
FCm and FCc were not associated either (1, n = 31) = 1.7;
p = 0.8.
BMI (kg/m2)
30.7 ± 8.5
BSA (m2)
111.2 ± 41.5
Echocardiographic data
– LVEF (%)
46.7 ± 13.8
– Systolic LV size
48.3 ± 9.8
– Diastolic LV size
37.5 ± 12.2
– Relative LV wall thickness
0.26 ± 0.06
BSA: body surface area; IDCM: children with idiopathic dilated
cardiomyopathy and LVEF < 40%; LVEF: left ventricular ejection fraction;
HF: heart failure; BMI: body mass index.
Table 2 – Cardiopulmonary exercise test data
All (19)
SBP (mmHg)
– rest
102.2 ± 12.4
– peak
120.5 ± 18.1
DBP (mmHg)
– rest
59.2 ± 10.6
– peak
69.7 ± 13.7
HR (bpm)
– rest
91.2 ± 10.8
– maximum
162.1 ± 18.7
VO2-peak (mL/kg/min)
25.5 ± 6.7
VE/VCO2 slope
37.4 ± 6.4
RER
1.02 ± 0.04
PetO2
54.3 ± 30.3
Time (min)
10.9 ± 4.3
HR: heart rate; DBP: diastolic blood pressure; SBP: systolic blood
pressure; PetO2: pressure of end-tidal O2; RER: respiratory exchange
ratio; VE/VCO2 slope: slope of the line between ventilation (VE) and carbon
dioxide production (VCO2), VO2 peak: peak oxygen consumption.
According to the peak VO 2 found in CPET, Weber
classification was significantly associated with the three
functional classes described in this study, using the χ 2
test: Weber classification and FCm (1, n = 19) = 11.8;
p = 0.003; Weber classification and FCp (1, n = 19) = 20.4;
p = 0.0001; Weber classification and FCc (1, n = 19) = 6.4;
p = 0.04. (Figure 3).
Arq Bras Cardiol. 2016; 106(6):502-509
505
Tavares et al.
Functional class in children with cardiomyopathy
Original Article
Figure 3 – Functional class, Weber classification, and peak oxygen consumption. c: child; FC: functional class; m: medical team; p: parents or guardians; VO2 peak: peak
oxygen consumption. ap = 0.003; bp = 0.0001; cp = 0.04.
Children from the sample reached 84% of the maximum
HR, according to the formula proposed by Tanaka (maximum
HR = 208 – [0.7 x age]),28 with this maximum HR being
approximately 35 bpm lower than that proposed.
shorter than those with HF. This may have resulted from low
weight gain during childhood31 because of a low systemic
supply secondary to impaired cardiac output that children
with more severely affected hearts show.32
Peak VO2 and LVEF values showed a weak non-significant
correlation between each other (r = 0.27; p = 0.25).
Likewise, LVEF was not related to the other data obtained
from CPET.
The medications used were consistent with those
described in the literature for the treatment of IDCM or HF
in the pediatric population, including angiotensin‑converting
enzyme inhibitors,33 betablockers and diuretics1.26
Finally, Table 3 shows all data from the present study,
including data on the functional classes (FCm, FCp, FCc) and
peak VO2 as measured by cardiopulmonary exercise test, for
each study subject.
The cause of short stature in children with IDCM and
of high drug doses may be similar to that of nocturnal dip.
The latter, in turn , is related to severity of symptoms and
greater sympathetic activity.34 In this regard, further studies
are probably necessary to establish these associations.
Discussion
Like for adults, exercise tolerance is known to be
predictive of mortality in children with heart failure. 7
Additionally, the experience with cardiopulmonary exercise
test21,25 in healthy children16 and in those with HF for IDCM25
older than 6 years,16,25,32 show that the cardiovascular and
metabolic responses are similar to those observed in adults
with the same clinical characteristics.17
Although the study sample had a small number of
participants, our findings show that the cardiopulmonary
exercise test is safe in the populations described; that peak
VO2 findings are related to the stratification data using Weber
classification;12 and that drawings can be an additional
resource for the assessment of children with IDCM and HF
(for previous IDCM) with preserved LVEF.
As regards the anthropometric data, all children enrolled
were in the prepubertal phase,17 thus there was no influence
of hormones on the results obtained.29
Although all children included in the present study had
been in the same age range in which linear growth occurs
(from 7 to 11 years of age),30 children with IDCM were
506
Arq Bras Cardiol. 2016; 106(6):502-509
In our CPET assessments, we observed that both groups of
children with IDCM and those with HF with preserved LVEF
are unable to reach the maximum age-predicted HR in the
exercise test. These findings are corroborated by results of studies
conducted in adults with HF35 and in children with IDCM,17 in
which 80% of the maximum HR in the mean for age was reached,
and are similar to those found in the present study, in which the
values are between 82% and 84% of the maximum HR.
Tavares et al.
Functional class in children with cardiomyopathy
Original Article
Table 3 – Data on functional classes and peak oxygen consumption on cardiopulmonary exercise test
Subject
FCm
FCp
FCc
VO2 peak
1
1
1
1
34.6
2
2
1
3
32
3
2
1
1
17.6
4
1
1
1
30.3
5
2
1
2
27
6
2
2
1
25
7
1
1
2
23.4
8
1
4
2
15.6
9
1
1
3
31
10
2
2
1
36.9
11
1
1
1
35.8
12
1
2
1
26
13
1
2
1
15.6
14
1
1
2
14.8
15
1
1
2
27.3
16
1
1
1
24
17
1
1
2
18.4
18
1
1
1
30
1
1
1
31.3
19
FCc: functional class according to the children themselves. FCm: functional class according to the medical team; FCp: functional class according to parents or
guardians; VO2 peak: peak oxygen consumption.
Peak VO2 values found in the present study were different in
the two groups. This probably resulted from the fact that peak
VO2 is believed to occur between 13 and 14 years of age,16,21,29
i.e., the parameters related to this indicator are expected to
be rising during the prepubertal period, phase in which the
participants were assessed.29,36 Although a systematic review by
the present study’s author had shown that peak VO2 values in
prepubertal girls are, on average, 20% lower than those found
in prepubertal boys,37 because of the influence of hormones and
body fat,37,38 this finding was not observed here after post-hoc
Bonferroni test. We can suppose that the small sample size had
a negative influence on the analysis of this variable.
Even with peak VO2 values lower than expected,37 all
children reached the maximum test according to the criteria
of exercise termination mentioned by ACC/AHA Guidelines
Update for Exercise Testing,39 because the modified Balke
protocol used is appropriate to the study population, and
the protocol-demanded response to exercise is similar to
the physiological response to exercise in children. That is,
the time to reach 50% of peak VO2 values in children is
shorter than that for adults; children are less dependent on
the glycogenic pathway to meet the demands than adults;
the use of fatty acids as an energy source is greater during
childhood; and children show lower levels of blood lactate
(which makes it more difficult to reach exhaustion), lower
pulmonary ventilation (VE, L/min) and lower carbon dioxide
production (VCO2, mL/min).29,39
Since the information on the functional class as assessed
by the children, their guardians and the medical team was
not correlated, the data prove to be subjective, which
is corroborated by previous studies.13,14 However, it was
correlated with peak VO 2 values on CPET, 40 according
to Weber’s criteria, which are very frequently used for
stratification and prognosis in adults.12 Since, to date, no
such prognostic assessment exists in the scientific literature
regarding children with IDCM and HF, the measurement will
probably continue to be subjective, corroborating previous
findings from 2001, in which objective values on CPET did
not correlate with the functional class as assessed by the
medical team.13
Conclusion
Peak VO2 peak are related to stratification data by Weber
classification, and the drawings shown to prepubertal children
may be an additional resource for the assessment of children
with IDCM and HF (for previous IDCM) and preserved LVEF.
Author contributions
Conception and design of the research: Tavares AC,
Bocchi EA, Guimarães GV. Acquisition of data: Tavares
AC. Analysis and interpretation of the data: Tavares AC,
Guimarães GV. Statistical analysis: Tavares AC, Guimarães
GV. Obtaining financing: Tavares AC, Guimarães GV. Writing
Arq Bras Cardiol. 2016; 106(6):502-509
507
Tavares et al.
Functional class in children with cardiomyopathy
Original Article
of the manuscript: Tavares AC, Bocchi EA. Critical revision of
the manuscript for intellectual content: Tavares AC, Bocchi
EA, Guimarães GV. Drafting of the figures (dolls): Tavares AC.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
Sources of Funding
This study was funded by FAPESP 2011/08985-0.
Study Association
This article is part of the thesis of doctoral submitted by
Aline Cristina Tavares, from Instituto do Coração (INCOR),
Hospital das clínicas da Faculdade de Medicina da USP.
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Arq Bras Cardiol. 2016; 106(6):502-509
509
Back to The Cover
Original Article
Influence of Smoking Consumption and Nicotine Dependence
Degree in Cardiac Autonomic Modulation
Ana Paula Soares dos Santos1, Dionei Ramos1, Gabriela Martins de Oliveira1, Ana Alice Soares dos Santos1, Ana
Paula Coelho Figueira Freire1, Juliana Tiyaki Ito2, Renato Peretti Prieto Fernandes3, Luiz Carlos Marques Vanderlei1,
Ercy Mara Cipulo Ramos1
Departamento de Fisioterapia – Faculdade de Ciências e Tecnologia da Universidade Estadual Paulista – UNESP1, Presidente Prudente, SP;
Departamento de Clínica Médica – Faculdade de Medicina da Universidade de São Paulo (USP)2; Secretaria Municipal de Saúde de Presidente
Prudente3, Presidente Prudente, SP – Brazil
Abstract
Background: Smoking consumption alters cardiac autonomic function.
Objective: Assess the influence of the intensity of smoking and the nicotine dependence degree in cardiac autonomic
modulation evaluated through index of heart rate variability (HRV).
Methods: 83 smokers, of both genders, between 50 and 70 years of age and with normal lung function were divided
according to the intensity of smoking consumption (moderate and severe) and the nicotine dependency degree (mild,
moderate and severe). The indexes of HRV were analyzed in rest condition, in linear methods in the time domain (TD),
the frequency domain (FD) and through the Poincaré plot. For the comparison of smoking consumption, unpaired t test or
Mann-Whitney was employed. For the analysis between the nicotine dependency degrees, we used the One-way ANOVA
test, followed by Tukey’s post test or Kruskal-Wallis followed by Dunn’s test. The significance level was p < 0,05.
Results: Differences were only found when compared to the different intensities of smoking consumption in the
indexes in the FD. LFun (62.89 ± 15.24 vs 75.45 ± 10.28), which corresponds to low frequency spectrum component in
normalized units; HFun (37.11 ± 15.24 vs 24.55 ± 10.28), which corresponds to high frequency spectrum component in
normalized units and in the LF/HF ratio (2.21 ± 1.47 vs 4.07 ± 2.94). However, in the evaluation of nicotine dependency,
significant differences were not observed (p > 0.05).
Conclusion: Only the intensity of smoking consumption had an influence over the cardiac autonomic modulation of
the assessed tobacco smokers. Tobacco smokers with severe intensity of smoking consumption presented a lower
autonomic modulation than those with moderate intensity. (Arq Bras Cardiol. 2016; 106(6):510-518)
Keywords: Smoking; Tobacco Use / complications; Tobacco Use Disorders.
Introduction
It is known that smoking is considered a serious public
health problem with high incidence worldwide. It is
estimated that there are 1.3 billion tobacco smokers in
the world.1 Therefore, the consequences of the use of
tobacco have, in the last few years,2 aroused the attention
of researchers. The chronic use of tobacco creates tobaccorelated diseases, the most common of which being related
to the respiratory system.3 However, it is clear that smoking
has an important extrapulmonary toxicity,3 which could
Mailing Address: Ana Paula Soares dos Santos •
Departamento de Fisioterapia – Faculdade de Ciências e Tecnologia –
Universidade Estadual Paulista (FCT/UNESP). Rua Roberto Simonsen, nº 305 –
Centro Educacional. Postal Code 19060-900, Presidente Prudente, SP – Brazil
E-mail: [email protected]
Manuscript received October 20, 2015; manuscript revised January 04,
2016; accepted February 23, 2016.
DOI: 10.5935/abc.20160063
510
represent serious risk factors for cardiovascular diseases and
their respective complications, such as the damage of cardiac
autonomic modulation.4,5
The changes that smoking causes in the cardiac autonomic
modulation are thoroughly described in literature6,7 and can
be evaluated through the heart rate variability (HRV),8 a noninvasive method, which describes the fluctuations between
consecutive heartbeats.9 Eryonucu et al.6 found that smokers
present lower rates of HRV, a result that is similar to those
found by Barutcu et al.7 when assessing the HRV during
controlled breathing exercises and muscle strength tests.
The intensity of smoking consumption, assessed by the
number of cigarettes consumed per day, may influence
the severity of the alterations observed in the autonomic
modulation. Kupari et al.10 verified that individuals that smoked
ten or more cigarettes per day presented greater impairment
in cardiac autonomic modulation as compared to those
who smoked less. Additionally, the risk of death for smokers
increases according to the number of cigarettes smoked per
day and the years of smoking.
Santos et al.
Smoking and cardiac autonomic modulation
Original Article
The intensity of smoking consumption is strongly
associated with the level of nicotine dependency, often times
seen as the main determinant of the frequent use of cigarettes
to avoid withdrawal symptoms.11,12 As a consequence of this
more intense habit, the damages caused by smoking take
bigger proportions.12,13
In spite of its importance, research in pertinent literature
did not find studies that addressed the influence of nicotine
dependency levels and smoking consumption in cardiac
autonomic modulation. This represents a significant gap in
the literature, considering that information of this nature could
give smokers a more complete orientation on the importance
of early cessation of this habit, as well as add elements of the
exposed theme to the literature.
In this context, the objective of this study is to evaluate the
influence of the intensity of smoking consumption and nicotine
dependency degree on cardiac autonomic modulation
through the index of HRV.
Methods
Population
Observational, cross-sectional study, in which 83 smokers
were evaluated, determined by sample size calculation, with
the LF/HF ratio as its variable. The magnitude of assumed
significant difference was 1,8, considering a standard
deviation of 1,19, based on a pilot study conducted with
80% beta-risk. The sample size, per evaluated group, resulted
in 16 individuals of both genders, between 50 and 70 years
of age, with normal lung function evidenced by spirometry.
These individuals participated in a cessation program
called PROCAT (Program of Anti-Tobacco Orientation and
Awareness) of the University of Science and Technology
Faculdade de Ciências e Tecnologias – FCT/UNESP, whose
objective is the treatment of smokers through cognitivebehavioral and drug therapy.13
This study did not include individuals who used narcotics
or medications that influenced cardiac autonomic activity,
alcoholics, or individuals with known diseases such as infections,
metabolic or cardiorespiratory diseases. The flowchart of study
losses is presented in Figure 1.
The volunteers were properly informed of the procedures
and objective of this study. After agreement, they signed
an informed consent to be part of the possible sample.
This research was submitted to the appreciation of the Ethics
Committee FCT/UNESP and by approved them (process n°
18/2011). All procedures were in accordance with Resolution
466/2012 of the National Health Counsil.
Experimental Protocol
The protocol was carried out in the morning in order to
soften the influences of the circadian rhythm, in a room
with a controlled temperature of 23°C and relative air
humidity between 50 and 60%. Before the evaluation,
the individuals were asked to abstain from smoking ,
caffeine and physical activities for 12 hours prior to the
execution of the protocol. The confirmation of the period
of smoking abstinence was done through the uptake of
carbon monoxide levels in exhaled air by using the Micro
CO monoximeter (Micro Medical Limited, Rochester,
England); values of under six parts per million (ppm) were
considered to be abstinent.14
Figure 1 – Flowchart of study losses.
Arq Bras Cardiol. 2016; 106(6):510-518
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Santos et al.
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Original Article
On the first day of the protocol, the characterization of
the population was initially carried out through interviews
with the volunteers to gather personal information,
smoking habits (cigarettes per day and years of smoking to
calculate packs/years)15 and degree of nicotine dependency.
The characterization was concluded with the Fagerström
questionnaire, which made it possible to separate the
smokers into groups.
To separate the smokers according to their smoking
consumption, the rate of packs/year was calculated by dividing
the number of cigarettes smoked daily by 20 (number of
cigarettes in a pack) and then multiplying that number by the
years of smoking.15 Smokers were considered moderate when
their smoking habits were between 10 and 20 packs per years
and severe when that number surpassed 20 packs/year.16
Within the same degree of nicotine dependency, however,
smokers were divided according to their scores in the
Fagerström questionnaire, which consists of six questions
that address some of the smoking habits such as the time of
the first cigarette of the day, number of cigarettes throughout
the day, discomfort for not being able to smoke in places
where it is prohibited, satisfaction from smoking, frequency
of smoking in the morning and illness occurrences. Each of
these alternatives receives a score which allows the rating of
three degrees of dependency: mild (0 to 3 points), moderate
(4 to 6 points) and severe (7 to 10 points).17
Still on the first day of the protocol, anthropometric
data was measured: weight (digital anthropometric scale
W110 H – Welmy) and height (Stadiometer Standard Sanny)
to calculate the Body Mass Index (BMI), and finally the lung
function was calculated by using a portable spirometer
(MIR – Spirobank – Italy) connected to a microcomputer.
The criteria for the selection and analysis of the curves were
in accordance with American Thoracic Society and European
Respiratory Society.18 The values of normality were relative
to the Brazilian population.19
On the second day of the protocol, the HRV was measured
by capturing the heart rate (HR), beat by beat, using the
cardiofrequencimeter Polar S810i. A chest strap for the
capturing of HR was placed at the level of the xiphoid process
of the sternum and an HR receptor strap was placed on the wrist
to record the received data. After being fit with the equipment,
the volunteers were asked to stay seated for 20 minutes, resting,
breathing spontaneously.20,21
Analysis of the indexes of heart rate variability
To analyse the indexes of HRV, 256 RR intervals selected
from the most stable part of the chart were used after digital
filtering, completed by manual filtering to eliminate artifacts
and ectopic beats; only series with over 95% of sinus beats
were included in the study. The analysis was processed by the
software Kubios (University of Kuopio, Finland).22
In the time domain (TD), the duration of RR intervals
and the indexes RMSSD (Root Mean Square of Successive
Differences) and SDNN (Standard Deviation of Normal to
Normal intervals) were used, both expressed in milliseconds
(ms). In the frequency domain (FD), there was use of the
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Arq Bras Cardiol. 2016; 106(6):510-518
low frequency spectrum component (LF, 0.04 – 0.15 Hz),
which represents sympathetic and parasympathetic activity,
with predominance of high frequency and sympathetic
(HF, 0.15 – 0.40 Hz), this represents parasympathetic activity,
in absolute values (ms²) and in normalized units (un), as well
as the LF/HF ratio.23,24 The spectral analysis was calculated
using the fast Fourier transform algorithm.8
The Poincaré plot was also used for the analysis of the
HRV. The plot represents, graphically, a correlation between
consecutive RR intervals, in which each point is represented
- on the horizontal axis X (abscissa) by the previous normal
RR interval, and on the vertical axis Y (ordinate) by the
following RR interval - and it may be analysed quantitatively
and qualitatively through the assembly of an ellipse
formed by the graphical representation of the RR intervals.
The center of this ellipse is determined by the average of
the RR intervals.25,26
For the quantitative analysis of the plot, through the
adjustment of the ellipse of the shape formed by the attractor,
the following indexes were calculated: SD1 (standard
deviation of the instantaneous beat to beat variability); SD2
(standard deviation of the long-term continuous R-R intervals);
and the SD1/SD2 ratio, which shows the ratio between short
and long-term variations of the RR intervals.9,27
The qualitative plot analysis was done through the analysis of
the shapes formed by its attractor. The following patterns were
considered: I) a shape in which an increase in the dispersion
of RR intervals is observed with an increase in intervals was
considered characteristic of a normal plot; II) a shape with
little beat-to-beat global dispersion and without an increase
in the dispersion of long-term RR intervals was considered
characteristic of a plot with smaller variability.28
Statistical analysis
To analyse the data, the statistical program Graphpad
Prism® was used. The normal distribution of data was
assessed through the Shapiro-Wilk test, and the description of
the results was done as mean values ± standard deviation or
median [interquartile intervals 25-75%]. To analyse the different
intensities of smoking consumption, the unpaired t test or MannWhitney test was used, depending on the normality of the data.
For the different degrees of nicotine dependency, the One-way
ANOVA followed by Tukey’s test or Kruskal-Wallis’ test followed
by Dunn’s test were used, also depending on the normality of
the data. Significance level used in the study: p < 0.05.
Results
Characteristics of individuals and lung funtion
Table 1 presents the personal, anthropometric and
spirometric data of the smokers, separated according to
intensity of smoking consumption. The groups were similar
in relation to BMI and lung function. Statistically significant
differences were found between moderate and severe smokers
when the groups were compared by age, cigarettes smoked
per day, years of smoking and packs/year.
Santos et al.
Smoking and cardiac autonomic modulation
Original Article
Table 1 – Characterization of smokers divided according to intensity of smoking consumption in relation to age, BMI, spirometric values and
smoking habits, expressed in mean ± standard deviation and median [Interquartile interval 25 – 75%]
Variables
N
Moderate smokers
Severe smokers
34
49
p
Anthropometry
Gender (M/F)
Age (years)
BMI (kg/m2)
(7/27)
(29/20)
53.76 ± 4.14*
56.10 ± 4.74
52.00 [50.00 – 56.25]
56.00 [52.00 – 59.00]
26.46 ± 4.84
26.12 ± 4.72
26.54 [22.28 – 29.94]
26.00 [22.24 – 28.84]
95.40 ± 11.33
95.68 ± 8.30
96.52 [86.00 – 104.30]
95.07 [90.58 – 99.89]
99.26 ± 12.47
97.81 ± 8.18
102.50 [87.14 – 108.80]
97.08 [91.14 – 103.20]
78.38 ± 4.60
78.46 ± 6.21
78.50 [75.35 – 82.15]
77.65 [73.85 – 83.28]
91.74 ± 22.93
96.97 ± 29.23
92,65 [78.20 – 105.00]
89.78 [77.81 – 116.30]
28.79 ± 7.85*
38.31 ± 7.46
29.00 [20.00 – 35.50]
38.00 [33.00 – 42.50]
0.0213
0.7673
Spirometric values
FEV1 (% Pred)
FVC (% Pred)
FEV1/FVC
FEF25-75% (% Pred)
0.9112
0.5851
0.9560
0.4571
Smoking consumption history
Time of smoking (years)
Cigarettes/day
Packs/year
12.82 ± 4.59*
22.55 ± 6.77
10.00 [10.00 – 16.25]
20.00 [20.00 – 20.00]
17.05 ± 3.30*
42.74 ± 13.34
18.63 [14.75 – 20.00]
40.00 [30.75 – 50.00]
< 0.0001
< 0.0001
< 0.0001
N: number of volunteers; M: male; F: female; BMI: body mass index; kg: kilogram; - m: meter; FEV1: forced expiratory volume in the first second; FVC: forced vital
capacity; FEV1/FVC: ratio between FEV1 and FVC; FEF25-75%: forced expiratory flow between 25 and 75% of FVC; (*) Statistically significant difference in comparison
to severe smokers.
Table 2 presents the personal, anthropometric and
spirometric data of the smokers, separated according to
nicotine dependency. The groups were similar as related to
age, BMI and lung function. In the Fagerström questionnaire,
according to the score obtained, there was statistically
significant difference between the groups only in relation to
nicotine dependency.
Indexes of HRV of smokers according to the intensity of
smoking consumption and degree of nicotine dependency
Table 3 depicts the indexes of HRV of the smokers, divided
according to the intensity of smoking consumption. Statistically
significant differences were found in the LF and HF indexes
un, LF/HF ratio, and SD1/SD2 ratio.
Table 4 depicts the HRV indexes of the smokers
divided into groups, according to the degree of nicotine
dependency. No significant differences were found in the
analysed indexes.
Qualitative analyses of the Poincaré plot
The qualitative analyses of the Poincaré plot is expressed
in figures 2 and 3, which show standard examples of the plot
in smokers that presented SD1 and SD2 index values close to
the mean, according to the intensity of smoking consumption
and the degree of nicotine dependency, respectively.
Discussion
The present study evaluated the influence of smoking
consumption and degree of nicotine dependency over cardiac
autonomic modulation of smokers by using HRV indexes.
The main results showed that smoking consumption alone
had influence over the cardiac autonomic modulation of the
assessed smokers. In the indexes that describe the HRV in
the FD, the LFun index and the LF/HF ratio were increased
in severe smokers, as opposed to the HFun index, which
was significantly smaller in this group. This characterizes a
sympathetic predominance in severe smokers, in comparison
Arq Bras Cardiol. 2016; 106(6):510-518
513
Santos et al.
Smoking and cardiac autonomic modulation
Original Article
Table 2 – Characterization of smokers devided according to nicotine dependency in relation to age, BMI, spirometric values and score in the
Fagerström questionnaire, expressed in mean ± standard deviation and median [Interquartile interval 25 – 75%]
Variables
N
Mild smokers
Moderate smokers
Severe smokers
18
33
32
p
Anthropometry
Gender (M / F)
Age (years)
BMI (kg/m²)
(5 / 13)
(15 / 18)
(16 / 16)
56.06 ± 5.63
55.36 ± 3.75
54.41 ± 4.87
56.50 [50.00 – 60.25]
55.00 [52.00 – 59.00]
53.00 [50.25 – 57.00]
25.19 ± 5.03
26.90 ± 4.94
26.22 ± 4.38
25.36 [21.94 – 26.99]
26.46 [22.31 – 30.68]
26.62 [22.46 – 28.63]
94.05 ± 13.30
93.60 ± 8.06
98.57 ± 8.19
93.21 [83.47 – 104.30]
94.10 [88.43 – 98.65]
98.12 [92.42 – 105.80]
98.30 ± 11.98
97.11 ± 10.67
99.86 ± 8.41
98.18 [89.99 – 107.90]
97.42 [87.31 – 104.30]
100.20 [91.34 – 105.80]
77.08 ± 5.27
77.82 ± 6.12
79.85 ± 4.99
76.60 [73.75 – 80.60]
77.20 [73.45 – 82.75]
79.60 [77.00 – 83.60]
87.05 ± 28.98
89.20 ± 22.64
105.30 ± 27.33
90.15 [60.04 – 105.00]
87.58 [77.26 – 100.90]
95.08 [85.32 – 123.90]
2.66 ± 0.84†
5.48 ± 0.61*
7.84 ± 1.01
3.00 [3.00 – 3.00]
6.00 [5.00 – 6.00]
7.50 [7.00 – 8.75]
0.4043
0.4977
Spirometric values
FEV1 (% Pred)
FVC (% Pred)
FEV1/FVC%
FEF25-75% (% Pred)
0.1629
0.6472
0.2816
0.0586
Smoking Dependency
Fagerström (SCORE)
< 0.0001
N: number of volunteers; M: male; F: female; BMI: body mass index; kg: kilogram; m: meter; FEV1: forced expiratory volume in the first second; FVC: forced vital
capacity; FEV1/FVC: ratio between FEV1 and FVC; FEF25-75%: forced expiratory flow between 25 and 75% of FVC; (*) Statistically significant difference in comparison
to severe smokers. (†) Statistically significant difference in comparison to moderate and severe smokers.
to moderate smokers. Carcigi et al.29 found an enlarged
LF/HF ratio in smokers with a consumption of over
20 cigarettes/day in comparison to non-smokers. Baructu et al.7
observed that the length of smoking consumption showed a
positive correlation with the LF/HF ratio, which characterizes
a smaller vagal modulation and larger sympathetic modulation
the longer the length of smoking consumption.
In the quantitative of the Poincaré plot, the SD1/SD2 ratio,
which represents the ratio between the long and short-term
variations of records of RR intervals, was significantly larger in
moderate smokers, who, when compared to severe smokers,
had better HRV.
The qualitative Plot analysis did not show differences in
the dispersion of RR intervals. However, the analyses of the
plot of the different degrees of nicotine dependency showed
that mild and moderate smokers present larger RR intervals
when compared to severe smokers, but without significant
differences. Reduced RR intervals, like the ones found in
severe smokers, suggest a higher HR in resting in these
individuals, which may be more predisposed to the surging
of cardiovascular events.30 The HR may have a direct effect
on the cardiovascular system, because it increases myocardial
consumption of oxygen and induces fatigue, in addition to
being associated with higher pressure levels.30
514
Arq Bras Cardiol. 2016; 106(6):510-518
In this study, the studied population is considered
between adults and seniors, between 50 and 70 years
old, which may justify, in part, the obtained results in
the analysed HRV indexes. The results show that the
participants in the severe smokers group, separated by the
intensity of smoking consumption, were older than the ones
in the moderate smokers group. Literature shows that there
is an influence of age in the autonomic modulation, that is,
the older the individual, the higher the sympathetic action
that can be observed; so this factor may have influenced
the observed results.31,32
Age is an important determinant in autonomic modulation,
with aging being associated to a progressive cardiac vagal
decline as age advances,31 which may be considered a
limitation in the present study. Paschoal et al. 32 found
a reduction of the indicative values of parasympathetic
activity and an increase in cardiac sympathetic activity, as
from the 5th decade of life, in healthy individuals, when
compared to younger individuals. Hering et al.33 showed
that the autonomic responses depend on age in smokers as
well and may result from alterations in the responses of the
adrenal medulla, reduced clearance of norepinephrine and/
or inhibition of the process of norepinephrine reabsorption,
caused by chronic exposure to smoking.
Santos et al.
Smoking and cardiac autonomic modulation
Original Article
Table 3 – HRV indexes evaluated in the different groups of smokers according to the intensity of smoking consumption expressed in mean ±
standard deviation and median [Interquartile interval 25 – 75%]
Variables
N
RR (ms)
SDNN (ms)
RMSSD (ms)
LFms2
HFms2
LFun
HFun
LF/HF
SD1 (ms)
SD2 (ms)
SD1/SD2
Moderate smokers
Severe smokers
34
49
819.40 ± 173.00
831.40 ±145.50
828.00 [743.50 – 885.80]
828.00 [743.50 – 885.80]
30.47 ± 12.77
31.20 ± 13.79
29.00 [22.75 – 34.25]
31.00 [20.00 – 41.50]
23.61 ± 9.54
21.01 ± 11.03
22.45 [16.23 – 29.53]
18.70 [13.40 – 26.90]
77.82 ± 115.20
104.20 ± 138.40
43.00 [25.00 – 86.25]
58.00 [23.50 – 128.00]
39.68 ± 49.93
32.69 ± 43.95
23.50 [14.25 – 48.00]
16.00 [7.00 – 39.00]
62.89 ± 15.24*
75.45 ± 10.28
64.85 [54.33 – 74.23]
77.30 [66.30 – 82.50]
37.11 ± 15.24*
24.55 ± 10.28
35.15 [25.78 – 45.68]
22.70 [17.50 – 33.70]
2.21 ± 1.47*
4.07 ± 2.94
1.84 [1.19 – 2.89]
3.40 [1.96 – 4.72]
16.99 ± 6.85
15.12 ± 7.90
16.25 [11.65 – 21.08]
13.40 [9.55 – 19.30]
47.03 ± 20.01
48.30 ± 21.41
46.70 [32.85 – 53.43]
46.70 [31.10 – 58.50]
0.38 ± 0.13*
0.31 ± 0.11
0.35 [0.27 – 0.45]
0.29 [0.23 – 0.36]
p
0.6467
0.5943
0.1538
0.3617
0.0776
< 0.0001
< 0.0001
0.0002
0.1473
0.7354
0.0204
N : number of volunteers; ms: milliseconds; SDNN: Standard Deviation of Normal to Normal intervals; RMSSD: Root Mean Square of Successive Differences; LF: low
frequency; un: normalized unit; HF: high frequency; SD1: standard deviation of the instantaneous beat to beat variability; SD2: standard deviation of the long-term
continuous R-R intervals; (*) Statistically significant difference in comparison to severe smokers.
The biggest chronicity of smoking was shown to be related to
lower vagal activity and higher sympathetic activity, as verified
in other studies,7,10,29 which characterize the decrease of HRV
indexes in smokers.6 The reduction of HRV may be associated
to health damages, and is a concerning factor associated to
the increase in mortality and morbidity in several conditions.9
No differences were found in the cardiac autonomic
modulation of the evaluated smokers, when comparing
different degrees of nicotine dependency. This non-difference
may support the evidence that personality traits may be more
strongly associated to the dependency than the smoking itself.34
Some authors are investigating the association between nicotine
dependency and psychiatric disturbances such as depression,
anxiety, schizophrenia, among others.35,36 Such evidence
may appear from the assumption that, in the Fagerström
questionnaire, only one question addresses the quantity of
cigarettes smoked, per day, by the individual, while the others
are related to his/her behavior.
As a limitation of the study, the lack of a control group consisting
of non-smoking individuals, and of tests to detect asymptomatic
heart diseases may be pointed out. These factors could have
contributed to a better understanding of the obtained results.
Conclusion
Only the intensity of smoking consumption had influences
over cardiac autonomic modulation of the evaluated smokers.
Smokers with severe smoking consumption intensity presented
worse autonomic modulation than moderate ones.
Acknowledgements
To the Fundação de Amparo à Pesquisa do Estado de São
Paulo - The Research Support Foundation of São Paulo (FAPESP) for financing this present study.
Author contributions
Conception and design of the research: Santos APS, Ramos
D, Ito JT, Vanderlei LCM, Ramos EMC; Acquisition of data:
Santos APS, Oliveira GM, Santos AAS, Freire APCF; Analysis and
Arq Bras Cardiol. 2016; 106(6):510-518
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Santos et al.
Smoking and cardiac autonomic modulation
Original Article
Table 4 – Indexes of HRV evaluated in the different groups of smokers according to the degree of nicotine dependency expressed in mean ±
standard deviation and median [Interquartile interval 25 – 75%]
Variables
N
RR (ms)
SDNN (ms)
RMSSD (ms)
LFms2
HFms2
LFun
HFun
LF/HF
SD1 (ms)
SD2 (ms)
SD1/SD2
Mild smokers
Moderate smokers
Severe smokers
18
33
32
844.70 ± 82.51
840.5 ± 171.40
811.80 ± 179.10
839.00 [788.00 – 937.00]
868.00 [782.00 – 888.00]
824.50[732.30 – 892.30]
29.78 ± 11.10
32.18 ± 14.16
30.69 ± 13.57
30.00 [24.75 – 36.00]
31.00 [22.50 – 40.00]
29.00 [20.50 – 40.25]
21.78 ± 7.44
23.68 ± 10.16
20.82 ± 12.10
22.25 [17.23 – 26.98]
22.40 [15.40 – 30.45]
18.50 [13.53 – 26.15]
75.22 ± 56.72
108.20 ± 172.90
88.72 ± 105.20
56.50 [21.75 – 131.00]
50.00 [24.00 – 101.50]
45.00 [24.25 – 118.80]
28.11 ± 21.93
41.12 ± 43.32
34.31 ± 58.25
22.00 [14.25 – 36.50]
24.00 [8.50 – 56.00]
15.50 [8.25 – 36.50]
66.72 ± 11.07
68.81 ± 14.61
73.72 ± 14.35
68.35 [60.13 – 75.80]
71.10 [60.45 – 80.05]
78.30 [65.53 – 83.00]
33.28 ± 11.07
31.19 ± 14.61
26.28 ± 14.35
31.65 [24.20 – 39.88]
28.90 [19.95 – 39.55]
21.70 [17.00 – 34.48]
2.34 ± 1.19
3.02 ± 2.15
4.14 ± 3.32
2.16 [1.50 – 3.13]
2.46 [1.53 – 4.04]
3.61 [1.90 – 4.88]
15.71 ± 5.40
17.04 ± 7.27
14.98 ± 8.65
16.15 [12.33 – 19.65]
16.10 [11.05 – 21.80]
13.40 [9.65 – 18.83]
47.24 ± 19.07
49.88 ± 20.89
46.64 ± 21.47
46.50 [37.48 – 53.28]
48.60 [32.10 – 60.45]
45.80 [30.60 – 54.48]
0.34 ± 0.08
0.35 ± 0.13
0.32 ± 0.13
0.34 [0.28 – 0.39]
0.33 [0.25 – 0.42]
0.29 [0.23 – 0.38]
p
0.6632
0.9287
0.3369
0.9648
0.2748
0.0630
0.0630
0.0628
0.3330
0.7365
0.3203
N: number of volunteers; ms: milliseconds; SDNN: Standard Deviation of Normal to Normal intervals; RMSSD: Root Mean Square of Successive Differences; LF: low
frequency; un: normalized unit; HF: high frequency; SD1: standard deviation of the instantaneous beat to beat variability; SD2: standard deviation of the long-term
continuous R-R intervals.
Figure 2 – Qualitative analysis of the Poincaré plot in the different intensities of smoking consumption: moderate (individual A – SD1: 16,9 and SD2: 47) and severe
(individual B – SD1: 15,2 and SD2: 50,4).
516
Arq Bras Cardiol. 2016; 106(6):510-518
Santos et al.
Smoking and cardiac autonomic modulation
Original Article
Figure 3 – Qualitative analysis of the Poincaré plot in the different degrees of nicotine dependency: mild (individual A – SD1: 16.9 and SD2: 47), moderate (individual
B – SD1: 17.8 and SD2: 52.9) and severe (individual C – SD1: 13.4 and SD2: 46.7).
Sources of Funding
interpretation of the data: Santos APS, Santos AAS, Freire APCF;
Statistical analysis: Santos APS; Obtaining financing: Ramos EMC;
Writing of the manuscript: Santos APS; Critical revision of the
manuscript for intellectual content: Ramos D, Freire APCF, Ito JT,
Fernandes RPP, Vanderlei LCM, Ramos EMC.
Potential Conflict of Interest
No potential conflict of interest relevant to this article
was reported.
This study was funded by FAPESP.
Study Association
This article is part of the thesis of master submitted by
Juliana Tiyaki Ito, from Universidade Estadual Paulista “Jùlio
de Mesquita Filho”.
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Back to The Cover
Original Article
Transcatheter Aortic Valve Implantation and Morbidity and
Mortality-Related Factors: a 5-Year Experience in Brazil
André Luiz Silveira Souza1,2, Constantino González Salgado1,3, Ricardo Mourilhe-Rocha1,3, Evandro Tinoco
Mesquita1,2, Luciana Cristina Lima Correia Lima1, Nelson Durval Ferreira Gomes de Mattos1, Arnaldo Rabischoffsky1,
Francisco Eduardo Sampaio Fagundes1, Alexandre Siciliano Colafranceschi1, Luiz Antonio Ferreira Carvalho1
Hospital Pró-Cardíaco1; Pós-graduação em Ciências Cardiovasculares -Universidade Federal Fluminense2; Pós-graduação em Ciências
Médicas - Universidade do Estado do Rio de Janeiro3, Rio de Janeiro, RJ − Brazil
André Luiz Silveira Souza and Constantino González Salgado had the same participation in this article
Abstract
Background: Transcatheter aortic valve implantation has become an option for high-surgical-risk patients with aortic
valve disease.
Objective: To evaluate the in-hospital and one-year follow-up outcomes of transcatheter aortic valve implantation.
Methods: Prospective cohort study of transcatheter aortic valve implantation cases from July 2009 to February 2015.
Analysis of clinical and procedural variables, correlating them with in-hospital and one-year mortality.
Results: A total of 136 patients with a mean age of 83 years (80-87) underwent heart valve implantation; of these, 49%
were women, 131 (96.3%) had aortic stenosis, one (0.7%) had aortic regurgitation and four (2.9%) had prosthetic valve
dysfunction. NYHA functional class was III or IV in 129 cases (94.8%). The baseline orifice area was 0.67 ± 0.17 cm2
and the mean left ventricular-aortic pressure gradient was 47.3±18.2 mmHg, with an STS score of 9.3% (4.8%-22.3%).
The prostheses implanted were self-expanding in 97% of cases. Perioperative mortality was 1.5%; 30-day mortality,
5.9%; in-hospital mortality, 8.1%; and one-year mortality, 15.5%. Blood transfusion (relative risk of 54; p = 0.0003) and
pulmonary arterial hypertension (relative risk of 5.3; p = 0.036) were predictive of in-hospital mortality. Peak C-reactive
protein (relative risk of 1.8; p = 0.013) and blood transfusion (relative risk of 8.3; p = 0.0009) were predictive of 1-year
mortality. At 30 days, 97% of patients were in NYHA functional class I/II; at one year, this figure reached 96%.
Conclusion: Transcatheter aortic valve implantation was performed with a high success rate and low mortality.
Blood transfusion was associated with higher in-hospital and one-year mortality. Peak C-reactive protein was associated
with one-year mortality. (Arq Bras Cardiol. 2016; 106(6):519-527)
Keywords: Aortic Valve Stenosis / surgery; Mortality; Prosthesis Implantation; Balloon Valvuloplasty; Cohort Studies.
Introduction
Transcatheter aortic valve implantation (TAVI) was first
introduced in 2002 as an alternative treatment for patients with
aortic stenosis (AoS) at extreme risk for surgery.1 As from 2008, it has
become available in Brazil, in parallel with major technological
advances and the publication of large-scale randomized clinical
trials demonstrating the benefits of this treatment in the relief of
symptoms as well as in mortality reduction.2-6 TAVI indications also
expanded to the treatment of bioprosthetic valve dysfunction and
selected cases of aortic regurgitation.
Mailing address: Ricardo Mourilhe Rocha •
Universidade do Estado do Rio de Janeiro e Hospital Pró-Cardíaco.
Rua Voluntários da Pátria, 445/1.401 e 1.402, Botafogo,
Postal Code 22270-000, Rio de Janeiro, RJ – Brazil
E-mail: [email protected]
Manuscript received July 01, 2015; revised manuscript received
December 28, 2015; accepted January 18, 2016.
DOI: 10.5935/abc.20160072
519
In order to make concepts uniform and establish comparable
parameters, a group of highly regarded authors, under the name
of Valve Academic Research Consortium (VARC), proposed
procedure-related criteria of success and complications.7,8
Despite its importance, many authors were initially reluctant
to adhere to the VARC criteria, possibly because their strict
concepts could lead to the perception of unfavorable results.
The first case series of TAVI in the State of Rio de Janeiro was
published in 2010,9 and these patients as well as the progression
of the technique have been followed up ever since, thus adjusting
the assessments to the VARC criteria. In this study, we evaluated
the success rate, morbidity and mortality throughout in-hospital
and one-year follow-up in a 5-year-experiece with TAVI.
Methods
study population
Prospective cohort study of consecutive cases of TAVI
between July 2009 and February 2015. TAVI was indicated
Souza & González et al.
Transcatheter aortic valve implantation-related morbidity and mortality
Original Article
Statistical analysis
for patients with severe heart valve stenosis, severe aortic
regurgitation or bioprosthetic aortic valve dysfunction at a
high surgical risk. Demographic, echocardiographic, laboratory
and procedural data were assessed during the in-hospital and
one-year outpatient follow-up. Heart failure symptoms were
classified according to the New York Heart Association (NYHA)
criteria, and the success and complications criteria were based
on VARC 2: hospital discharge, aortic regurgitation < grade
2/4, mean left ventricular-aortic pressure gradient (LV-Ao)
< 20 mmHg, and use of only one prosthesis. Definitions of
complications by VARC are described elsewhere, and include
criteria of acute myocardial infarction (AMI) and stroke 7.
Chronic renal failure (CRF) was defined as an estimated
glomerular filtration rate < 60 mL/minute using the Cockroft
and Gault formula. Acute renal failure (ARF) was defined by
the Acute Kidney Injury Network (AKIN) classification system
as follows: stage 1, if serum creatinine (Cr) elevation between
1.5 and 1.99 times; stage 2, if between 2 and 2.99 times; and
stage 3, if greater than 3 times or need for dialytical support.7
Continuous variables were expressed as mean and standard
deviation, for parametric variables; or median and interquartile
range for non-parametric variables. Categorical variables were
expressed as absolute and percentage values. Numerical data
were compared using the t test for parametric variables, and
the Mann-Whitney test for non-parametric variables. The chi
square test or Fisher’s exact test were used to compare
proportions. The Kaplan-Meier method was used to adjust
the 1-year survival curve. The significance level was set at
5%. Logistic regression analysis was carried out to evaluate
the simultaneous influence of different variables, by means
of the stepwise forward analysis, at a significance level of 5%,
selecting the smallest subgroup of independent variables able
to better predict death. The statistical analysis was processed
by the SAS® version 6.11 statistical software (SAS Institute, Inc.,
Cary, North Carolina) and Statistical Package for the Social
Sciences (SPSS), version 18.0.
Pre-procedural assessment
Results
Indications were evaluated by the cardiology team, which
was comprised of cardiology clinicians, interventionists,
surgeons, anesthetists, and echocardiographers. Once TAVI
was indicated, all patients would undergo coronary
angiography and assessment of coronary artery disease,
with occasional indication of coronary angioplasty, which was
left to the discretion of the surgeon. Aorta and iliac branches
were measured by angiography and/or CT angiography to
define the prostheses and vascular approach to be used.
TAVI was performed in 136 patients with a mean age
of 83 years (80 to 87); 49.3% were women (Table 1).
The indications were as follows: 131 (96.3%) patients
with AoS, one (0.7%) with aortic regurgitation, and four
(2.9%) with bioprosthetic aortic valve dysfunction. The risk
of surgical mortality using the Surgeons Thoracic Society
(STS) score was 9.3% (4.8-22.3%), and an STS ≥ 15% was
observed in 39.8% of cases.
Procedural technique
All patients received antibiotic prophylaxis with cefazolin
2 g prior to the intervention. Acetylsalicylic acid (ASA) 200 mg
and clopidogrel 300 mg were administered on the day before
the procedure, except when contraindicated in the cases of
low platelet count < 80 x 103 /mm3 or other comorbidities.
The procedures were performed in the hemodynamics
laboratory or in the hybrid room, under sedation or general
anesthesia, and transesophageal echocardiography (TEE)
monitoring . Temporary transvenous pacemakers were
implanted to help in balloon valvuloplasty and/or prosthesis
implantation, by means of induction of tachycardia, and
were kept on the on-demand mode for 48 hours. The choice
of of whether or not to pre-dilate the valve was left to
the surgeon’s discretion. The prostheses used were the
self‑expanding CoreValve® (Medtronic, Minneapolis, MN)
and the balloon-expanding Edwards-SAPIEN XT® (Edwards
Lifesciences, Irvine, CA). After TAVI, the patients were sent
to the intensive care unit and underwent daily laboratory
assessments in the first 7 days.
Late follow-up
The outpatient follow-up was performed via phone
calls at 30 days, 6 months and 1 year, and clinical,
echocardiographic and adverse events data were recorded.
The study was approved by the local Research Ethics
Committee under registration 423, on April 8, 2011. All patients
gave written informed consent to participate in the study.
Other comorbidities were hypothyroidism (18.4%), previous
malignancy (8.1%); asthma (5.9%); hepatic cirrhosis (2.2%);
digestive hemorrhage (2.2%); porcelain aorta (2.2%); abdominal
aortic aneurysm (4.4%); previous aortic balloon valvuloplasty
(3.7%); and previous alcohol septal ablation (1.5%).
The baseline laboratory tests showed: type-B Brain
Natriuretic Peptide (BNP) of 258 pg/mL (128 to 616 pg/mL),
and greater than 200 pg/mL in 40.0%; Cr 1.2±0.8 mg/dL;
platelets 194 x 103 /mm3 (156 to 236 x 103 /mm3); and
hemoglobin 11.8 mg/dL (10.4 to 13.1 mg/dL). Baseline
C-reactive protein (CRP) was elevated (> 0.3 mg/dL) in
57.8% of cases. Medications used by the patients are shown
in Table 2. Blood transfusion prior to the procedure was
made in eight patients (5.8%).
Findings of the baseline TEE are shown in Table 3.
Ejection fraction (EF) < 50% was found in 26.5% of patients,
and bicuspid aortic valve, in 2.9%. A mean LV-Ao gradient
< 40 mmHg was found in 46/131 cases (35.1%).
In addition to angiography of the iliac and femoral arteries,
CT angiography of these arteries was also performed in 17.6%
of individuals. Coronary percutaneous interventions were
performed prior to TAVI in eight patients (5.9%) and peripheral
percutaneous interventions in four (2.95%) (one in carotid,
two in iliac and one in subclavian artery).
The first 29 procedures (21.3%) were performed under
sedation, and all the subsequent 107 (78.7%), under general
anesthesia – in these cases, always monitored by TEE. A total
of 52 procedures (38.2%) were performed in a hybrid room,
as from March 2013.
Arq Bras Cardiol. 2016; 106(6):519-527
520
Souza & González et al.
Transcatheter aortic valve implantation-related morbidity and mortality
Original Article
Table 1 – Demographics
Table 2 – Medications used prior to transcatheter aortic valve implantation
n = 136
Age
83 (80-87)
ACEI/ARB
63 (46.23%)
Female gender
67 (49.3%)
Betablocker
47 (34.6%)
Calcium antagonist
30 (22.2%)
Nitrates
13 (9.6%)
BMI
25.3 (22.6-29-4)
Presentation
Syncope
40 (29.4%)
Diuretics
66 (48.5%)
Angina pectoris
28 (20.6%)
Digitalis
8 (5.9%)
Heart failure
Coumarin
NYHA functional class
II
7 (5.1%)
III
71 (52.2%)
IV
58 (42.6%)
Systemic hypertension
80 (67.2%)
Diabetes mellitus
51 (37.5%)
Hypercholesterolemia
65 (47.8%)
Previous AMI
17 (12.5%)
Coronary artery disease
77 (56.6%)
Previous CABG
30 (25.2%)
Previous PCI, days
46 (33.8%)
> 30
29 (21.3%)
< 30
17 (12.5%)
Previous stroke
8 (5.9%)
Peripheral vascular disease
32 (23.5%)
COPD
13 (9.6%)
Chronic kidney failure
70 (51.5%)
Pulmonary arterial hypertension
33 (24.3%)
Sinus rhythm
102 (75%)
Permanent atrial fibrillation
14 (10.3%)
Previous pacemaker
19 (14.7%)
Logistic euroSCORE (%)
STS mortality (%)
EF< 50%
19.1 (11.4-31.1)
9.3 (4.8-22.3)
36 (26.5%)
BMI: body mass index; NYHA: New York Heart Association; AMI: acute
myocardial infarction; CABG: coronary artery bypass grafting;
PCI: percutaneous coronary intervention; COPD: chronic obstructive
pulmonary disease; STS: Surgeons Thoracic Society; EF: ejection fraction.
The vascular access was the femoral artery in 129 cases
(94.9%), left subclavian artery in six (4.4%), and aorta in one
(0.8%). All vascular accesses were made via arteriotomy and
further surgical vascular suture. A hemostasis device was used
in only one case.
Heart valve pre-dilatation was performed in 110 patients
(80.9%) and direct implantation, in 26 (19.1%). The self‑expanding
CoreValve® prosthesis was implanted in 132 patients (97%) and the
balloon-expanding Edwards SAPIEN XT® prosthesis, in four (3%).
521
n = 136
Arq Bras Cardiol. 2016; 106(6):519-527
7 (5.1%)
Antiarrhythmic drugs
25 (18.4%)
Statins
77 (56.6%)
Vasoactive drugs
4 (2.9%)
ACEI: angiotensin-converting-enzyme inhibitor; ARB: angiotensin
receptor blocker.
VARC2 success was achieved in 83.1% of cases. After TAVI,
the invasive LV-Ao gradient dropped from 54.8 ± 25.5 mmHg
to 1.7 ± 3.4 mmHg (p < 0.001). An additional intervention
for correction of paraprosthetic aortic valve regurgitation
was required in 55 cases (40.4%); balloon post-dilatation in
48 (35.5%); additional prosthesis implantation in six (4.4%);
and prosthesis repositioning by loop traction in one (0.7%).
Post‑TAVI aortic regurgitation was considered absent in
53 patients (39%), mild in 71 (52.2%) and moderate in eight
(5.9%) – all due to paraprosthetic regurgitation.
ARF occurred in 15.4% of patients, and 2.2 reached
stage 3. The volume of contrast medium used was 143.0 ±
37.1 mL. There was one case of ischemic stroke with no
sequela. There was no procedure-related AMI.
New permanent pacemaker implantation was required in
29/118 cases (24.5%).
The blood transfusion rate after TAVI was 21.3%
(29 patients), of which eight received transfusion of two or
three units of red blood cell concentrate, and ten received
four or more. Perioperative bleeding related to the vascular
access occurred in three cases; however, blood transfusions
were performed for other complications such as LV perforation
and hemothorax.
The length of hospital stay was 7 ± 22 days. Prolonged
hospital stay (> 7 days) occurred in 51/125 cases (40.8%),
with a maximum of 212 days.
Perioperative mortality rate was 1.5%; 30-day mortality
was 5.9%, and in-hospital mortality was 8.1%. When the
subgroup of in-hospital death was compared to that of
patients discharged, we observed that the first showed
higher baseline BNP [770 pg/mL (320-1.260) vs 227 pg/mL
(123‑553); p = 0.017]; a higher incidence of pulmonary
arterial hypertension (54.6% vs 21.6%; p = 0.024); CRF
(81.8% vs 51.2%; p=0.048); and ARF (45.5% vs. 11.2%;
p = 0.008). Post-dilatation (70% vs. 35.2%; p = 0.034) and
blood transfusion after TAVI (90.9% vs. 17.1%; p < 0.0001)
were also more frequent. In the first week, there was higher
Souza & González et al.
Transcatheter aortic valve implantation-related morbidity and mortality
Original Article
Discussion
Table 3 – Baseline echocardiogram
n = 136
AVA
0.67 ± 0.17
Peak LV-Ao gradient (mmHg)
78.8 ± 29.5
Mean LV-Ao gradient (mmHg)
47.3 ±18.2
Aortic regurgitation
Absent
43 (31.6%)
Mild
76 (55.9%)
Moderate
11 (8.1%)
Severe
6 (4.4%)
Mitral regurgitation
Absent
19 (14.0%)
Mild
89 (65.4%)
Moderate
20 (14.7%)
Severe
8 (5.9%)
EF (%)
59.5 ± 17.0
LV end-diastolic diameter (mm)
50.6 ± 10.5
Interventricular septum (mm)
12.0 ± 2.3
Upper wall (mm)
11.9 ± 2.1
PASP (mmHg)
44.1 ± 14.4
AVA: aortic valve area; LV-Ao: left ventricular-aortic; EF: ejection fraction;
PASP: pulmonary artery systolic pressure.
peak CRP [13.1 mg/dL (6.8-17.5) vs 7.8 mg/dL (4.7‑11.0);
p = 0.039] and lower platelet count [99 x 10 3 /mm 3
(71‑128) vs 143 x 103 /mm3 (105-167); p = 0.030] among
in-hospital death patients (Table 4). After logistic regression
analysis, blood transfusion after TAVI (p = 0.0003) and
pulmonary arterial hypertension (p = 0,036) were identified
as independent predictors of in-hospital death (Table 5).
The follow-up lasted 2.5 ± 1.4 years. Progression of
symptoms according to NYHA functional classes is shown
in Figure 1.
Accumulated overall one-year mortality was 18.3% (20/109)
(Figure 2), of which cardiovascular mortality accounted for
seven cases (two sudden deaths, one AMI for stent thrombosis,
one for heart failure, two for hemorrhagic stroke and one for
LV perforation When the subgroup of one-year death was
compared to the group of survivors, we observed that the
first group showed, among the pre-procedural characteristics,
higher rates of chronic obstructive pulmonary disease (30% vs
6.7%; p = 0.008); logistic euroSCORE [31% (16-42) vs 19%
(10-28); p = 0.006]; STS score [22% (12-36) vs 8% (4-19);
p = 0.0005]; baseline CRP [1.7 mg/dL (0.2-2.3) vs 0.30 mg/dL
(0.2-1.0); p = 0.01]; direct TAVI (40% vs 15.7%; p = 0.02);
post-TAVI blood transfusion (60% vs 16.9%; p=0.0002);
peak CRP [13.1 mg/dL (8.2-16.2) vs 7.5 mg/dL (4.4-10.6);
p = 0.001]; and lower rates of general anesthesia (55% vs
78.7%; p = 0.032) and TEE (50% vs 77.5%; p=0.016).
According to the logistic regression analysis, post-TAVI blood
transfusion (p = 0.0009) and peak CRP (p = 0.013) were
independent predictors of one-year death (Table 5).
This article describes the 5-year experience on
self‑expanding prosthetic heart valve implantation via
femoral artery by means of arteriotomy in a medical center
that has one of the highest case series in Brazil. Throughout
this period, important conceptual changes had the following
consequences: (1) lower tolerance to the presence of aortic
regurgitation after the procedure; (2) adoption of general
anesthesia associated with TEE monitoring, which enabled a
more accurate quantification of the degree of paraprosthetic
regurgitation and assessment of structural complications;
(3) performance of procedures in a hybrid room; and (4)
formalization of a team of cardiology specialists to share
decision making.
The population characteristics are not different from
those presented in most of the registries,10-14 including the
national registry.15
Procedural success by VARC2 criteria achieved 83.1%
in our cohort, whereas in the national registry it reached
76.3%. Currently, the literature demands considerable
attention to the definitions adopted in the short-term
results. The VARC2 criteria for device-implantation success
include a mean transprosthetic gradient < 20 mmHg,
absent or mild aortic regurgitation, and single-prosthesis
implantation. As an example, Thyregod et at.16 recently
reported to have adopted VARC2 criteria and found a
97.9% procedural success rate, although they had described
the presence of moderate aortic regurgitation in 14.5%
of cases, which would reduce the success rate to 83.4%.
The finding of an overall 30-day mortality of 5.9% in a
group of very severely ill patients (mean STS of 15%) is a
relevant fact. Registries from other countries showed 30-day
mortality rates ranging from 5.2% to 10%,10-12 with 9.1% in
the Brazilian national registry.15 Likewise, we should take
care when comparing these results, once the VARC2 criteria
recommend the description of in-hospital mortality, and not
of 30-day mortality. In this case-series, this variation implied
a 2.2% absolute increase, because three cases showed clinical
complications that resulted in multiple organ failure and death
after 1 month. To better understand the in-hospital course,
in keeping with VARC updating, this short-term analysis was
carried out using in-hospital mortality, while investigating
in‑hospital and one-year mortality-associated variables.
Independent factors associated with in-hospital mortality
were the presence of pulmonary arterial hypertension
and post-TAVI blood transfusion. Pulmonary arterial
hypertension is one of the clinical risk factors for early
death, regardless of procedural complications 17,18 like
CRF,19,20 which, in this analysis, was associated with early
mortality. Blood transfusion was the most important
independent variable for in-hospital mortality, although
no distinction was made regarding its indication. We could
speculate that this is a marker of severity common to three
clinical situations: long intensive care unit stay,21 previous
anemia followed by minor bleeding, 22-24 or significant
perioperative bleeding. 25
The one-year accumulated overall mortality was 18.3%, one
third of which was cardiovascular mortality. The independent
Arq Bras Cardiol. 2016; 106(6):519-527
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Souza & González et al.
Transcatheter aortic valve implantation-related morbidity and mortality
Original Article
Table 4 – Variables related to in-hospital and one-year mortality
Age, years
Female gender
BMI (kg/m2)
IH Death
(n = 11)
Alive IH
(n = 125)
p value
1-year death
(n = 20)
Alive 1-year
(n = 89)
p value
84 (84-86)
83 (80-87)
0.28
84 (80-88)
83 (80-87)
0.43
45.5%
49.6%
0.52
60.0%
48.3%
0.24
24.7 (23-5-28.3)
25.3 (22.4-29.6)
0.65
24.9 (23.5-27.3)
25.3 (22.9-30.2)
0.81
0.28
50.0%
57.3%
0.52
50.0%
37.1%
NYHA class
II
36.4%
53.6%
IV
54.6%
41.6%
SH
72.7%
70.4%
0.59
55.0%
68.5%
0.19
DM
54.6%
36.0%
0.19
54.6%
36.0%
0.19
CAD
63.6%
56.0%
0.44
55.0%
53.9%
0.57
Previous CABG
27.3%
25.6%
0.57
30.0%
23.6%
0.37
Previous PCI
27.3%
34.4%
0.45
30.0%
33.7%
0.49
PVD
9.1%
24.8%
0.22
20.0%
20.2%
0.62
COPD
18.2%
8.8%
0.28
30.0%
6.7%
0.008
CRF
81.8%
51.2%
0.048
60.0%
47.2
0.22
PAH
54.6%
21.6%
0.024
40.0%
22.5%
0.09
euroSCORE
31.2 (12.6-52.2)
18.7 (11.2-30.7)
0.09
31.2 (16.3-42.0)
19.9 (10.4-28.2)
0.006
STS score
14.2 (6.5-30.5)
9.3 (4.8-20.8)
0.25
22.6 (11.9-36.2)
7.9 (4.4-19.6)
0.0005
EF < 50% (TEE)
36.4%
25.8%
0.33
40.0%
24.7%
0.14
Baseline Cr (mg/dL)
1.3 (0.7-1.7)
1.1 (0.9-1.50)
0.59
1.3 (0.9-1.4)
1.1 (0.9-1.3)
0.46
Baseline Hb (mg/dL)
11.4 (10.2-12.9)
11.8 (10.4-13.10
0.48
11.8 (9.0-12.9)
11.8 (10.7-13.3)
0.46
Pre platelets
(x 103/mm3)
189 (127-250)
195 (158-236)
0.53
218 (148-247)
193 (163-237)
0.49
Baseline BNP
(pg/mL)
770 (320-1260)
227 (123-553)
0.017
536 (149-836)
230 (121-519)
0.065
Baseline CRP
(mg/dL)
1.8 (0.2-5.5)
0.3 (0.2-1.0)
0.96
1.7 (0.2-2.3)
0.3 (0.2-1)
0.01
General anesthesia
90.9%
77.6%
0.27
55.0%
78.7%
0.032
TEE
81.8%
77.6%
0.54
50.0%
77.5%
0.016
Direct TAVI
36.4%
17.6%
0.13
40.0%
15.7%
0.02
Post-dilatation
70.0%
35.2%
0.034
47.4%
15.7%
0.15
AoR ≥ 2/4
12.5%
5.5%
0.40
15.0%
4.6%
0.12
Blood transfusion post
90.9%
17.1%
< 0.0001
60.0%
16.9%
0.0002
1.9 (1.1-3.4)
1.2 (0.9-1.5)
0.06
1.3 (1.0-2.3)
1.2 (0.9-1.5)
0.16
45.5%
11.2%
0.008
30.0%
12.4%
0.058
8.1 (7.5-11.4)
9.6 (8.2-10.9)
0.32
8.1 (7.4-11.2)
9.6 (8.3-10.9)
0.13
99 (71-128)
143 (105-167)
0.03
125 (73-175)
143 (106-167)
0.29
13.1 96.6-17.5)
7.8 (4.7-11.0)
0.04
13.1 (8.2-16-2)
7.5 (4.4-10.6)
0.001
Cr in 72 hours
(mg/dL)
ARF
Nadir Hb (mg/dL)
Platelets post
(x 103/mm3)
Peak CRP (mg/dL)
IH: in-hospital; BMI: body mass index; NYHA, New York Heart Association; SH: systemic hypertension; DM: diabetes mellitus; CAD: coronary artery disease;
CABG: coronary artery bypass grafting; PCI: percutaneous coronary intervention; PVD: peripheral vascular disease; COPD: chronic obstructive pulmonary
disease; CRF: chronic renal failure; PAH: pulmonary arterial hypertension; STS: Surgeons Thoracic Society; EF: ejection fraction; Cr: serum creatinine;
Hb: hemoglobin; BNP: type-B brain natriuretic peptide; CRP: C-reactive protein; TEE: transesophageal echocardiogram; TAVI: transcatheter aortic valve
implantation; AoR: aortic regurgitation; ARF: acute renal failure.
523
Arq Bras Cardiol. 2016; 106(6):519-527
Souza & González et al.
Transcatheter aortic valve implantation-related morbidity and mortality
Original Article
Table 5 – Logistic regression for in-hospital and one-year death
Significant variable
Coefficient
SE
p value
RR
95%CI
Blood transfusion post
3.9959
1.1075
0.0003
54.4
6.20-477
PAH
1.6666
0.7943
0.036
5.29
1.12-25.1
Blood transfusion post
2.1113
0.6367
0.0009
8.26
2.37-28.8
Peak CRP
0.1361
0.0550
0.13
1.15
1.03-1.28
In-hospital death
1-year death
SE: standard error; RR: relative risk; 95%CI: 95% confidence interval; PAH: pulmonary arterial hypertension; CRP: C-reactive protein.
I
II
III
IV
100%
75%
50%
25%
0%
Baseline
30-day,
6-month
1-year
Figure 1 – Baseline, 30-day, 6-month, and 1-year NYHA functional class. NYHA = New York Heart Association.
1.0
Survival
0.8
0.6
0.4
0.2
0.0
0
Cases
under risk 109
30
60
104 102
90 120 150 180 210 240 270 300 330 360
Follow-up period (days)
102
100
100
98
96
95
92
91
91
85
Figure 2 – One-year survival Kaplan-Meier curve.
Arq Bras Cardiol. 2016; 106(6):519-527
524
Souza & González et al.
Transcatheter aortic valve implantation-related morbidity and mortality
Original Article
risk factors for one-year mortality were post-TAVI blood
transfusion and peak CRP. Escarcega et al. reported 37% of
blood transfusion and, in additon to the increase in in-hospital
mortality, they also verified an increase in one-year mortality
in this subgroup (28% vs 13%; p = 0.001).22
Like in coronary interventions, in TAVI there is a complex
association between vascular complications, bleeding
and blood transfusion, with the development of ARF
and Systemic Inflammatory Response Syndrome (SIRS) –
the latter being able to occur in a disproportionate fashion
in relation to the triggering events described. Sinning et
al.26 described that SIRS occurred in 40.1% of TAVI cases
and was associated with higher 30-day mortality in addition
to being an independent predictor of one-year mortality
(hazard ratio – HR = 4.3; p < 0.001). The biomarker most
frequently used in clinical practice for the assessment of
SIRS is CRP, with a peak around day 3 after TAVI.27 Peak CRP
in the in-hospital death subgroup was twice higher than
that found among survivors.
The access was exclusively surgical, aiming to minimize
vascular complications and bleedings. However, Bernardi
et al.,28 compared the percutaneous and surgical accesses
and did not identify differences between vascular
complications, bleeding, 30-day mortality or one-year
mortality, although they had found a tendency toward
a higher frequency of peripheral vascular disease in the
surgical access group (16.8% vs10.4%; p=0.07).28 In the
national registry, the percutaneous access was finalized with
a hemostasis device in 45.6% of cases.15
After the first 30 cases, the anesthetic regimen was
changed from sedation to general anesthesia, incorporating
three‑dimensional TEE to the procedure. With this strategy,
we aimed to measure the valve annulus in the procedure
room, instead of previously using CT angiography,
thus having the benefit of reducing nephrotoxicity.
This strategy permits a thorough assessment of the degree
of paraprosthetic regurgitation. In the Brazilian registry,
as well as in our cohort, the use of TEE was associated
with lower mortality,14 although this finding could merely
have reflected our learning curve.
When the valve implantation technique was assessed,
we observed that the pre-dilatation rate of 78.9% among
our cases was higher than the 61% of the national
registry.14 Our perception is that there was a tendency of
direct implantation in the more severe cases to avoid the
pacemaker-induced tachycardia maneuver.
The prognostic impact of moderate or severe
paraprosthetic aortic regurgitation was a concept
adopted as from 2011. 8 Only 5.9% of cases of the
present study showed this type of post-procedural
complication, whereas other studies with predominance
of self‑expanding valves described rates between 10% and
15%.4,16,29 The fact that intervention was made in 40% of
cases shows an aggressive management of paraprosthetic
aortic regurgitation when compared to 16.1% to 26.5%
of interventions described by other authors.23,30 Maybe for
this reason, post-TAVI moderate aortic regurgitation was
not predictive of poor prognosis in this study. However,
525
Arq Bras Cardiol. 2016; 106(6):519-527
we cannot fail to mention that post‑dilatation was more
frequent in the in-hospital death group, even with no
directly related complications having been identified.
This finding could reflect a selection bias of a subgroup
with a less favorable anatomy. Alternatively, we should
remember that pre- and post‑balloon dilatation are
performed under pacemaker‑induced tachycardia, and
this leads to systemic hypoperfusion, which, in turn, had
been previously related to SIRS.26
The incidence of ARF was lower in comparison to a
mean of 20% of other case series.20,30 Sinning et al29 observ​
ed that, in patients​u
​ ndergoing​CoreValve® i​ mplantation,
ERF correlated with peripheral vascular disease, SIRS​
and residual aortic regurgitation, but not directly with
volume of contrast medium. Nuis et al.31 observed that
the number of blood transfusions within the first 24 hours
is the main risk factor for ARF, which also correlated with
peripheral vascular disease, heart failure, and leukocytosis
within the first 72 hours. Thus, ARF seems to correlate
with hemodynamic instability, especially in the context of
bleeding and blood transfusion, with further SIRS.
The virtual absence of stroke during hospital stay
was much lower than the 4 to 5% described in other
studies. 3,32 We should point out that, in our protocol,
antiplatelet agents are previously administered, and a
careful technique is observed in the manipulation of the
valve with the guidewire, in addition to a strict control
of heparinization.
Management of coronary artery disease is another key
issue, because it is present in half the cases of AoS. The extent
of myocardial infarction and its possible relation to ventricular
dysfunction suggests that it plays a role in the outcome and,
currently, revascularization strategies are controversial. 33
The strategy adopted was to perform revascularization in
the cases in which a large ischemic area had been estimated
by coronary angiography. In this cohort, there was no case
of procedure-related AMI, which may suggest that this is an
adequate strategy.
Limitations
This study reflected the real-life practice, with inclusion
of patients that would have been otherwise excluded in
randomized studies. Because it is a prospective cohort,
a selection bias cannot be ruled out. Despite the significant
number considering the national figures, our case series
is small compared to international registries in which
predictors of poor prognosis were identified. Additionally,
because of the sample size, some variables such as ARF stage
or blood transfusion volume could not be stratified, with
the purpose of more accurately predicting adverse events.
The follow-up by phone calls made it difficult to have a
consistent late outpatient assessment of aortic regurgitation
and ventricular dysfunction.
Conclusion
Transcatheter aortic valve implantation in patients with
severe aortic valve disease and at high surgical risk was
Souza & González et al.
Transcatheter aortic valve implantation-related morbidity and mortality
Original Article
performed with a high success rate and low mortality.
Relief of symptoms and one-year survival were high despite
the severity of disease. Blood transfusion was associated
with in-hospital and one-year mortality. Peak C-reactive
protein was associated with one-year mortality.
Author contributions
Conception and design of the research: Souza ALS,
Salgado CG, Mourilhe-Rocha R, Mesquita ET; Acquisition
of data: Souza ALS, Salgado CG, Lima LCLC; Analysis and
interpretation of the data, Statistical analysis, Writing of
the manuscript and Critical revision of the manuscript for
intellectual content: Souza ALS, Salgado CG, Mourilhe‑Rocha
R; Obtaining financing: Souza ALS, Salgado CG; Procedure
and valvar implants: Souza ALS, Salgado CG, Colafranceschi
AS, Mattos NDFG and Carvalho LAF; Echocardiogram:
Rabischoffsky A; Anesthesias procedures: Fagundes FES;
Vascular accesses and stand-by surgeon: Colafranceschi AS.
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 Doctoral submitted by André
Luiz Silveira Souza and Constantino González Salgado, from
Universidade Federal Fluminense e Universidade do Estado do Rio
de Janeiro. The authors shared the same participation in this article.
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an analysis of the UK TAVI registry. Heart. 2015;101(7):546-52.
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Nickenig G, et al. Renal function as predictor of mortality in patients
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PG, et al. Impact of blood transfusions on short- and long-term mortality
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Back to The Cover
Review Article
Ambulatory Blood Pressure Monitoring: Five Decades of More Light
and Less Shadows
Fernando Nobre1 and Décio Mion Junior2
Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo1 - Ribeirão Preto, SP; Faculdade de Medicina da Universidade de São
Paulo2, SP – Brazil
“Indeed, it is somewhat paradoxical that a clinical condition
such as arterial hypertension, which is defined in terms of blood
pressure values only, may be diagnosed on the basis of few
occasional blood pressure measurements, and that life-long
treatment is often instituted following measurements taken
over just a few minutes”
Alberto Zanchetti
(AJH 1997; 10:1068-1080)
Abstract
Casual blood pressure measurements have been extensively
questioned over the last five decades. A significant percentage of
patients have different blood pressure readings when examined in
the office or outside it. For this reason, a change in the paradigm
of the best manner to assess blood pressure has been observed.
The method that has been most widely used is the Ambulatory
Blood Pressure Monitoring – ABPM. The method allows
recording blood pressure measures in 24 hours and evaluating
various parameters such as mean BP, pressure loads, areas under
the curve, variations between daytime and nighttime, pulse
pressure variability etc. Blood pressure measurements obtained
by ABPM are better correlated, for example, with the risks of
hypertension. The main indications for ABPM are: suspected
white coat hypertension and masked hypertension, evaluation
of the efficacy of the antihypertensive therapy in 24 hours, and
evaluation of symptoms. There is increasing evidence that the
use of ABPM has contributed to the assessment of blood pressure
behaviors, establishment of diagnoses, prognosis and the efficacy
of antihypertensive therapy. There is no doubt that the study of
24-hour blood pressure behavior and its variations by ABPM has
brought more light and less darkness to the field, which justifies
the title of this review.
Introduction
Since Riva-Roc­ci1 created the sphygmomanometer in
1886, casual blood pressure measurement have been used
for the assessment of blood pressure and establishment of
Keywords
Blood Pressure Monitoring, Ambulatory / trends; Hypertension;
White Coat Hypertension; Medication Therapy Management.
Mailing Address: Fernando Nobre •
Av. Independência, 3767, Jd. Califórnia. Postal Code 14026-150, Ribeirão
Preto, SP – Brazil
E-mail: [email protected]
Manuscript received June 01, 2015; revised manuscript December 23,
2015; accepted January 06, 2016.
DOI: 10.5935/abc.20160065
528
diagnosis, prognosis, efficacy and treatment of hypertension.
However, the value of casual blood pressure has been
questioned in all these contexts in the last five decades.
Since the study published by Ai­man & Goldshi­ne in 1940,2
it has been known that a significant percentage of patients
have higher blood pressure measures when they are taken in
the clinic setting than at home. In addition, blood pressure
measures taken by different observers – the patient, the
physician, or the nurse – are also different, particularly when
taken by the physician, who obtains the highest measures.3,4
This may lead to erroneous blood pressure readings, incorrect
diagnosis and inappropriate management of the disease.5,6
These aspects have changed the paradigm of the best
method to assess blood pressure behavior. The ambulatory
blood pressure monitoring (ABPM) is the method of choice for
24 hour-blood pressure monitoring considering its advantages
established in previous reviews and guidelines.7-11
This is especially due to advances in the techniques for 24-blood
pressure monitoring and use of state-of-the-art equipment,
which have been more appropriate, easier to use, relatively low
cost, validated by strict international protocols, automatic, and
electronically sophisticated, offering reliable performance.12
Another reason for the increasing use of ABPM is the
evidence that blood pressure readings obtained by this
method are more correlated with the effects of hypertension,
as compared with others.13-15
The history of ABPM
In the 60’s decade (i.e. five decades ago), Kain et al.16
demonstrated the benefits of ABPM, and the attractive possibility
of measuring blood pressure during patients’ daily activities.
According to a search performed on MEDLINE database
on May 11, 2015, since 2001, more than 2000 articles have
been published every five years, showing the importance of
this revolutionary method in the establishment of diagnosis
and prognosis of patients with altered blood pressure, and
in the assessment of the antihypertensive therapy. The first
study, published in 1962, was crucial for demonstrating the
assessment of 24-hour blood pressure without an observer,
using a semi-automatic method.17
Figure 1 depicts a sequence of 24-hour blood pressure
monitors in three different moments, and the evolution of
these devices over time.
The use of ABPM has been consolidated in Brazil, similarly
to what has occurred in the world. In 1982, Prof. Mauricio
Wajngarten and colleagues presented, for the first time, a
24-hour blood pressure recording in the Brazilian Congress
of Cardiology (Figure 2).
Nobre & Mion Junior
Five decades of ABPM
Review Article
A
B
C
Figure 1 – From left to right: 24-hour blood pressure monitoring devices used in 1966 (A), 1988 (B) and 2015 (C) (Authors’ personal archive).
Figure 2 – Continuous blood pressure monitoring in healthy subjects (presented in the in the Brazilian Congress of Cardiology in 1982).
The use of ABPM has spread in our community by means
of courses offered throughout the country. One example was
the PRONAM – Programa Nacional de Atualização em MAPA
e Hipertensão (National Program for ABPM and Hypertension
Update), an on-site course, run by the authors in more than
150 editions from 1996. The program has been run by the
Corporate University of the Brazilian Society of Cardiology since
2011, as one of the strategies of distance education in cardiology.
ABPM in our days
Besides, under our supervision and with the contribution
of specialists in the field, five editions of the book MAPA
- Monitorização Ambulatorial da Pressão Arterial (ABPM Ambulatory Blood Pressure Monitoring) were published in
1995, 1998, 2004, 2007 and 2014. One of them was translated
to Spanish and offered in Spanish-speaking countries in 2001.
Nowadays, it is possible to monitor blood pressure
measures during 24-hour periods or longer, with assessment
of hemodynamic parameters that reflect blood pressure
fluctuations: mean systolic and diastolic blood pressures,
pressure overload, areas under the curve, blood pressure
changes between sleep and wakefulness, blood pressure
The Brazilian Societies of Cardiology, Hypertension
and Nephrology have published guidelines on ABPM
since 1993.18-22
Additionally, international guidelines that regulated the
(rational and scientifically correct) use of ABPM,8-10,23-25
including in children and adolescents26, have contributed to
a broad, consistent use of the method.
Arq Bras Cardiol. 2016; 106(6):528-537
529
Nobre & Mion Junior
Five decades of ABPM
Review Article
variability, pulse pressure, among others. These data may be
represented in an analytical summary or graphics showing the
variability of blood pressure by time.27
Therefore, the use of ABPM has considerably increased.
This is explained by the fact that the measures obtained
by ABPM better reflect blood pressure behavior. Also, the
development of more comfortable, reliable, safer devices
significantly decreased the limitations for the routine use of
the method.
1. Suspected white coat hypertension (Recommendation grade I, level of
evidence A)
2. Assessment of normotensive patients with target-organ lesions at the
physician’s office, i.e. wit suspected masked hypertension (Recommendation
grade I, level of evidence A)
The increasing use of ABPM in clinical practice may
increase, since health insurance plans from all over the
world, probably motivated by these data, have added ABPM
to the list of exams considered as ‘useful’ and acceptable
to be performed.
3. Evaluation of the efficacy of the antihypertensive therapy:
a) When casual blood pressure remains elevated despite optimization of
the antihypertensive therapy for the diagnosis of persistent hypertension
(Recommendation grade IIa, level of evidence B) or white coat effect
(Recommendation grade IIa, level of evidence B), or
b) When casual blood pressure is controlled and there are signs of
persistence (Recommendation grade IIa, level of evidence B), or progression
(Recommendation grade I, level of evidence B) of target-organ lesions
Indications, advantages and limitations
1. Evaluation of symptoms, specially hypotension (Recommendation grade I,
level of evidence D)
The indications, advantages and limitations of ABPM,
according to the V Brazilian guidelines for the use of ABPM22
are described in Tables 1, 2 and 3.
With respect to the indication of ABPM, it is worth
mentioning that in 2001, i.e., more than one decade ago, the
Centers for Medicare and Medcaid Services recommended the
reimbursement of the exam cost for patients with suspected white
coat hypertension.28 In 2011, the National Institute for Health
and Care Excellence (NICE) recommended the use of ABPM for
all individuals with blood pressure ≥ 140/ 90 mm Hg, measured
at the physician’s office, for considering it a cost‑effective
procedure29. This recommendation allows the diagnosis of white
coat hypertension, with cost savings, according to a study that
used a cost-effectiveness analysis, based on the probabilistic
Markov model.30 However, patients with marked hypertension
are not included in NICE recommendation, since they are
normotensive in the physician’s office. This situation tends to
be solved as the costs of the ABPM decreases, and the exam
may be indicated for hypertensive and normotensive patients.31
ABPM and its contribution for the assessment of blood
pressure behavior and establishment of diagnosis
The use of ABPM in the assessment of blood pressure
behaviors has spread and been corroborated by national18-22
and international8-10,23-27 guidelines. In general, the main
objective of using ABPM is based on the decision whether
or not to treat the patient on the basis of his/her blood
pressure measures. Considering that the beginning of the
antihypertensive therapy will be based on blood pressure
measures, two types of error, undesirable and potentially
harmful to the patient may occur in case the values do
not represent the real behavior of blood pressure. First, if
casual blood pressure, i.e. taken in the physician’s office,
overestimates the real value, therapy may be unnecessarily
started; on the other hand, if it underestimates the real
value, the patient may be deprived of a beneficial therapy.
Therefore, it is crucial to obtain reliable values, truly
representative of blood pressure behavior.
Thanks to the use of ABPM, today we know that blood
pressure values obtained in the office setting may be
higher, similar or lower than those obtained by the method.
From these differences, four diagnosis may be identified:
530
Table 1 – Main indications for 24-hour ambulatory blood pressure
monitoring22
Arq Bras Cardiol. 2016; 106(6):528-537
Table 2 – Main advantages of 24-hour ambulatory blood pressure
monitoring22
1. Multiple measures of blood pressure for 24 hours. Assessment of blood
pressure during daily activities and during sleep.
2. Assessment of blood pressure circadian rhythm
3. Assessment of blood pressure means, overload and variability. Identification
of “alarming reaction”
4. Placebo effect reduction
5. Assessment of the antihypertensive effect in 24 hours
6. Possibility of risk stratification
Table 3 – Limitations of 24-hour ambulatory blood pressure
monitoring22 (Recommendation grade I, level of evidence D)
1. When the cuff cannot be adjusted due to arm circumference
2. When systolic pressure values are very high
3. Clinical situations associated with movement disorders (e.g. Parkinson’s disease)
4. When pulse is irregular due to cardiac arrhythmias (atrial fibrillation and atrial flutter)
5. Presence of auscultatory gaps during manual measurement of blood pressure
normotension, hypertension, white coat hypertension
(detected in the physician’s office only), and masked
hypertension (white coat normotension).22
Normotension is characterized by normal blood pressure
values in the office (< 140/90 mmHg) and in 24-hour ABPM
(≤ 125/75 mmHg), while hypertension is characterized by
abnormal blood pressure values in the office (≥ 140/90 mmHg)
and in ABPM (≥ 130/85 mmHg).22
White coat hypertension occurs in 15-30% of individuals
with elevated blood pressure in the office setting.8 It occurs
when abnormal blood pressure values are obtained in the office
(≥ 140/90 mmHg) and normal values are obtained during the
ABPM (≤ 135/85 mmHg).22,32 Interestingly, in this case, there
Nobre & Mion Junior
Five decades of ABPM
Review Article
therapy.37,38 It is defined by the presence of normal blood
pressure values obtained in the office (< 140/90 mmHg)
and abnormal ABPM values (> 130/85 mm Hg).22 There is
a change of diagnosis from hypertension during daily living
to normotension in the office setting. Multivariate analysis
studies have identified as associated risk factors: masked
hypertension, male sex, smoking, and body mass index.39
Masked hypertension is associated with increased risk of
cardiovascular morbidity and mortality. However, since office
measures are normal, this risk may be underestimated.40
A meta-analysis of 12 studies, involving 4,884 untreated
subjects – 2,467 normotensive, 1,641 hypertensive subjects,
and 776 with masked hypertension – showed an association
between masked hypertension and increased risk of structural
changes in left ventricle. The risk observed in subjects with
masked hypertension is nearly twice as high as that among
normotensive subjects (Figure 4).34 The anti-hypertensive
therapy seems to be the rational choice for these patients,
although no randomized studies evaluating this procedure
have been performed so far.37,38
is a change from the diagnosis of normotension detected out
of the office setting to the diagnosis of hypertension detected
in the office. Since there are no pathognomonic signs of white
coat hypertension, the most common characteristics that help
in the diagnosis are: elderly patients, women, pregnant women,
non-smokers, patients with diagnosis of stage 1 hypertension
after blood pressure readings in the office, and individuals
without target-organ lesions.33 The attributable risk of white coat
hypertension has been extensively discussed.32 Some studies
have indicated that white coat hypertension has an intermediate
cardiovascular risk, between normotension and hypertension,
closer to normotension though (Figure 3).34 The IDACO study,
a cohort study involving 7,295 persons followed for 10.6 years,
showed that the incidence of cardiovascular events in untreated
subjects with white coat hypertension was not different from
that observed in normotensive, untreated subjects.35 There is no
evidence of benefit from interventions in this group of patients.32
These patients need to be followed, and the change of life
habits is imperative.8,32 It is recommended that the diagnosis of
white coat hypertension be confirmed within 3-6 months, and
the patient should be followed every year by ABPM to detect
progression of hypertension, since these patients have a higher
probability to develop established hypertension.8
ABPM and prognosis of patient with arterial hypertension
Perloff et al,42 in 1983, were pioneers in assessing more
than one thousand hypertensive patients by ABPM and by
office measurements, and showed that ABPM measures are an
independent indicator of prognosis. Twenty-four hour-values
were more consistent than casual or office blood pressure in
determining the risk level.
On the other hand, the white coat effect or white coat
phenomenon is defined by the difference between office
blood pressure and ambulatory (ABPM) blood pressure,
without changing the diagnosis from normotension to
hypertension. When the differences are higher than 20 and
10 mm Hg for systolic and diastolic pressure, respectively, the
white coat effect is considered significant. It occurs in almost
all individuals, at higher or lower degrees,36 with a mean of
27 mmHg increase in systolic blood pressure.4,32
Longitudinal studies have given irrefutable evidence of the
independent association between ABPM blood pressure and the
risk for cardiovascular disease in the general population and in
hypertensive individuals.13-15 Based on these studies, the ABPM
has been considered a more consistent risk marker as compared
with conventional methods to measure blood pressure.
Masked hypertension of white coat normotension occurs
in 10-40% of patients not receiving anti-hypertensive
White coat hypertension x normontension
Study
Verdecchia 1994
Kario 2001
Fagard 2005
Ohkubo 2005
Hansen 2006
Piedomenico 2008
Statistics of each study
Odds ratio
Lower
limit
Upper
limit
1.170
0.760
1.000
0.950
0.960
0.970
0.964
0.253
0.164
0.372
0.389
0.500
0.381
0.654
5.402
3.529
2.686
2.322
1.842
2.468
1.421
Odds ratio (CI 95%)
P-value
0.201
–0.350
0.000
–0.112
–0.112
–0.064
–0.186
0.841
0.726
1.000
0.910
0.902
0.949
0.852
0.1
0.2
0.5
1
2
5
10
n = 7961 Eventos = 696
Figure 3 – Odds ratio of patients with white coat hypertension compared with normotensive patients.34
Arq Bras Cardiol. 2016; 106(6):528-537
531
Nobre & Mion Junior
Five decades of ABPM
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Some parameters obtained by 24-hour ABPM may
contribute to evaluate the prognosis. They will be individually
evaluated, as follows:
The decrease in blood pressure during sleep can be
calculated by (mean daytime pressure – mean nighttime
pressure) x 100 ÷ mean daytime pressure. Thus, according
to this calculation of pressure reduction between daytime
and nighttime, individuals may be classified as: dippers
(≥ 10%), nondippers (< 10%), reverse dippers (≤ 0%) or
extreme dippers (≥ 20%).22
Mean arterial pressure
Cardiovascular risk is better correlated with 24-hour mean
arterial pressure values than with office blood pressure.43-46
Conen & Bamberg47 showed, in a meta-analysis, that a
10‑mmHg increase in 24-hour systolic pressure is associated
with a 27% elevation of the risk for cardiovascular events,
regardless of office blood pressure. In another meta-analysis,
Fagard et al.15 analyzed four prospective studies conducted
in Europe, and showed that daytime and nighttime blood
pressure measured by 24-hour ABPM have a prognostic value
for cardiovascular mortality, coronary disease, and stroke,
independently of office blood pressure. Nighttime pressure
and the night– day blood pressure ratio showed a prognostic
value for all outcomes, whereas daytime blood pressure
did not add prognostic precision to nighttime pressure.
This corroborates the importance of ABPM, since this is the
only non-invasive method to measure ambulatory blood
pressure during sleep time.
There are evidences that 24-hour blood pressure
behavior, considering these both periods of the day, is
important for the prognosis.49 Ben-Dov et al.50 followed
3957 for a mean of 6.5 years, and observed that the
mortality rate was higher in nondippers compared with
dippers. Extreme dippers and dippers had similar risk.
In another study,51 nondippers and reverse dippers had
higher mortality risk. However, these individuals were older,
and had a higher prevalence of non-white subjects, smokers,
diabetes, hypertension, coronary disease, congestive heart
failure and renal failure. Therefore, although nondipping
and reverse dipping pose a higher mortality risk, this is
associated with other cardiovascular risk factors.
In an international database including 8,711 individuals
from 10 popuIations, isolated nighttime hypertension, i.e.,
subjects with increased blood pressure during sleep and
normal awake blood pressure, was associated with increased
total mortality risk and cardiovascular events. The mechanisms
of nighttime hypertension and its correlation with poor
prognostic have not been elucidated. Increased sympathetic
activity, reduced baroreceptor sensitivity or autonomic
dysfunction, a decrease in sodium excretion during daytime,
nocturnal sodium excretion,53 increased activity during the
night, sleep apnea, insulin resistance, endothelial dysfunction,
or all of these factors may be involved.
Taken together, these evidences suggest that blood pressure
values obtained by ABPM provide a better correlation with
causal measures for total, cardiac and cerebrovascular risk.46
Relationship between sleep and wakefulness
ABPM is the only method to assess arterial pressure during
sleep and the blood pressure behavior between daytime and
nighttime in a 24-hour period.
O’Brien et al,48 in 1988, in a letter published in The Lancet,
suggested that patients who do not demonstrate a drop of
10% or more in blood pressure values between daytime and
nighttime have a higher risk for cerebrovascular accident.
With respect to siesta, in the study by Gomes, Pierin and
Mion,54 407 underwent ABPM during siesta (118 ± 58 minutes).
Siesta had an effect on cardiac structural parameters, and on
Masked hypertension x normontension
Study
Bjorklund 2003
Fagard 2003
Ohkubo 2005
Hansen 2006
Piedomenico 2008
Statistics of each study
Odds ratio
Lower
limit
Upper
limit
2.770
1.650
2.560
1.660
2.650
2.088
1.149
0.526
1.410
1.056
1.177
1.557
6.676
5.172
4.649
2.610
5.966
2.812
Odds ratio (CI 95%)
P-value
2.270
0.859
3.088
2.195
2.354
4.844
0.023
0.390
0.002
0.028
0.019
0.000
0.1
n = 7961 Eventos = 696
Figure 4 – Odds ratio of patients with masked hypertension compared with normotensive patients.34
532
Arq Bras Cardiol. 2016; 106(6):528-537
0.2
0.5
1
2
5
10
Nobre & Mion Junior
Five decades of ABPM
Review Article
systolic and diastolic pressure during daytime. Patients with a
0-5% reduction in arterial pressure had thicker interventricular
septum and posterior wall as compared with those with a
reduction greater than 5%.
Then, the use of ABPM to assess the decrease in blood
pressure and the mean values during sleep may provide
important prognostic information for the clinical practice.
Va­ria­bi­lity
The 24-hour ABPM offers an adequate short-term
variability evaluation of between-measurement intervals
not longer than 15 minutes. However, the method
does not assess more complex parameters of blood
pressure variability, including spectral index and analysis
of baroreflex sensitivity, since it does not provide a
beat‑by‑beat recording of arterial pressure.8,55
Longitudinal studies have shown that short-term variability
may contribute to cardiovascular risk. Patients with increased
arterial pressure variability have a higher risk for developing
white coat hypertension of masked hypertension.56, 57
More recently, a new index for short-term blood pressure
variability has been proposed – the average real variability
(ARV) – which is a more reliable representation of time series
variability than standard deviation, and may be less sensitive
to the relative low sampling frequency of the ABPM devices.
The results suggest that the ARV adds prognostic value to the
ABPM and may be used in therapeutic approaches to control
blood pressure variability. It has been shown that 48 blood
pressure readings in 24 hours were appropriate to calculate
the ARV without loss or prognostic information.58, 59
Blood pressure variability is not routinely assessed in
ABPM, since its normal values have not been established.
It is still unknown whether a reduction in short-term variability
induced by the therapy is associated with a decrease in mortality
and morbidity. Also, whether the antihypertensive therapy is
indicated not only to reduce mean 24-hour blood pressure,
but also to stabilize blood pressure and optimize cardiovascular
protection. Dolan & O’Brien60 and Boggia et al.61 highlight
that blood pressure variability on ABPM does not enhance the
prediction of cardiovascular risk compared to the mean blood
pressure, particularly in low-risk individuals.
Pulse pressure
Pulse pressure has been considered an important prognostic
marker, especially in patients aged greater than 55 years.50
It should be mentioned, however, that this measure is strongly
influenced by an alerting reaction during measuring by the
physician in the office, especially concerning systolic arterial
pressure. Thus, measurements of pulse pressure in the office
setting may be overestimated. Verdecchia et al.63 studied 2010
patients using ABPM and, according to the tertile distribution
of pulse pressure distribution, the rate of total cardiovascular
events was 1.19; 1.81 and 4.92, and that of fatal events was
0.11, 0.17 and 1.23. In these studies, patients with pulse
pressure by ABPM higher than 53 mmHg were considered
of high risk. Prospective, well-designed studies using ABPM
are needed to establish the real prospective meaning of pulse
pressure in the general population.
Area under the pressure curve
Areas under the pressure curve have been studied by
Nobre and Mion,64 who showed a direct relationship between
the areas and left ventricle mass. Thus, these areas may be
used as a parameter in the assessment of blood pressure
behavior and target-organ lesions.
ABPM and evaluation of the antihypertensive therapy efficacy
The need of an adequate control of blood pressure in
24 hours is well-established. The assessment and follow‑up
of hypertensive patients under treatment, using ABPM,
seems to be more efficient than office measurements.53
Nonetheless, two issues need to be considered. First, will the
cost of ABPM for hypertension control in treated patients be
higher compared with office measurements? Second, is there
any evidence that treated patients with controlled hypertension
based on ABPM information will have a better prognosis,
expressed by lower morbidity and mortality rates?
Regarding the first issue, Staes­sen et al. 66 showed,
in an elegant study published in 1997, involving
419 hypertensive patients receiving antihypertensive drug
treatment (213 based on ABPM compared with 206 based
on office measurements), that the cost of the use of ABPM
was not higher than office measurements during the study
period. This was explained by the fact that individuals
with white coat hypertension were excluded from the
group receiving antihypertensive therapy, the number of
antihypertensive drugs was lower in the group monitored
by ABPM, and the number of physician visits was lower in
the ABPM group as compared with the group monitored by
office measurements. Cost analysis in both groups revealed
that the costs of ABPM were outweighed by less intensive
drug treatment and fewer physician visits.
With respect to the second issue, Schrader et al. 67
demonstrated in a prospective, randomized study on
851 patients, that morbidity and mortality were lower
in patients that underwent ABPM for the evaluation of
antihypertensive treatment. A total of 1298 patients were
included in the study, and 851 of them concluded the 5-year
follow-up period. Blood pressure control was assessed by
office measurements in 439 patients, and by ABPM in
412 patients. In the ABPM group, 20 primary events (total
morbidity and mortality and cerebrovascular events) were
registered, whereas in the other group, 35 primary events
have occurred (p = 0.037). In addition, 22% of patients
had white coat hypertension and were excluded from the
antihypertensive drug treatment.
Also, Cle­ment et al68. showed that ambulatory systolic
pressure higher than 135 mmHg had a strong correlation
with the prognosis of patients treated with antihypertensive
therapy, independently of blood pressure measured at the
physician’s office.
In relation to the role of ABPM in the guidance of the
antihypertensive treatment, further studies to confirm and
extend the information that the use of this method will lead
to lower morbidity and mortality from arterial hypertension
are needed.
Arq Bras Cardiol. 2016; 106(6):528-537
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Nobre & Mion Junior
Five decades of ABPM
Review Article
One practical issue that remains unsolved is: despite
the above considerations about the method to assess blood
pressure for 24 hours, how can ABPM be reasonably applied
in the clinical practice?
ABPM, will provide the necessary evidence for the extensive
use of the method. As a result, the benefits of the method
in favor of the understanding of hypertension and necessary
care for its treatment will be fully explored.
To answer this question, we suggest a number of
evaluations, based on the algorithm of the Canadian
guidelines69 for the use of ABPM to identify blood pressure
behaviors (Figure 5).
The analysis of new parameters (other than those
classically used today), such as the area under the pressure
curve, possibility of evolution of the devices, and use of the
ABPM in specific populations should be incorporated to the
clinical practice soon.
Pers­pec­ti­ves
Cheaper, more reliable and more comfortable monitors,
in addition to studies showing the reduction in cardiovascular
morbidity and mortality by the ABPM, used in the diagnosis
and antihypertensive treatment, should be the near future of
24-hour ABPM.
Similarly to casual blood pressure measures, which started
to be used in the end of 19th century when technique and
criteria of normality were unknown, and above all, the benefits
of measuring blood pressure were not clear, ABPM started to
be used in comparable conditions in the end of 20th century
and 21st century.
If considerable effort had not been dedicated for the
improvement of the method to obtain blood pressure
measures using a sphygmomanometer, if reference values
had not been obtained by epidemiological studies and their
application well established, we would not know even the
most basic and essential concepts of the risks of hypertension
and the benefits of its control. And this is how we should
procedure with ABPM also. A cautious use of the method,
based on scientific data supporting the increase in the use of
Therefore, after these considerations, it can be stated that
the ABPM is definitely indicated for suspected white coat
hypertension, white coat normotension or masked hypertension,
and for establishing blood pressure behavior as in hypertension
during sleep. In addition, it is the best prognostic marker in
different types of blood pressure behavior, with relevant role
in the assessment of the antihypertensive treatment.
The studies on blood pressure behavior and its variations
during people’s daily activity have undoubtedly become less
obscure, enlightened by the advent of ABPM, which completes
five decades of clinical application and progression.
Figure 5 – Algorithm suggesting the rational application of ambulatory blood pressure monitoring to evaluate blood pressure behaviors. OBP: office blood pressure;
ABPM: ambulatory blood pressure monitoring; HBPM: home blood pressure monitoring; SBP: systolic blood pressure/ DBP: diastolic blood pressure. ABPM: ambulatory
blood pressure monitoring; HBPM: home blood pressure monitoring; OBP: office blood pressure.
534
Arq Bras Cardiol. 2016; 106(6):528-537
Nobre & Mion Junior
Five decades of ABPM
Review Article
Therefore, it is fair to say, in light of these data, that the
title of this review: “Ambulatory blood pressure monitoring:
five decades of more enlightenment and less darkness” is
clearly justified.
We believe that, in consonance with the title of this review,
the ABPM has shed light to the understanding of blood
pressure behaviors in the last five decades, drastically reducing
the darkness of the diagnosis of hypertension and blood
pressure variations. The ABPM allowed the establishment of
the prognosis of patients with altered blood pressure and the
assessment of antihypertensive drug treatment in use.
and interpretation of the data: Nobre F, Mion Junior D.
Writing of the manuscript: Nobre F, Mion Junior D. Critical
revision of the manuscript for intellectual content: Nobre F,
Mion Junior D.
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: Nobre F, Mion
Junior D. Acquisition of data: Nobre F, Mion Junior D. Analysis
Study Association
This study is not associated with any thesis or dissertation work.
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Nobre & Mion Junior
Five decades of ABPM
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Database on Ambulatory Blood Pressure in Relation to Cardiovascular
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estimate blood pressure variability without loss of prognostic information?
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D, et al. A new algorithm for the diagnosis of hypertension in Canada. Can
J Cardiol. 2015;31(5):620-30.
Arq Bras Cardiol. 2016; 106(6):528-537
537
Back to The Cover
Clinicoradiological Session
Case 4/2016: 32-Year-Old Female, with Critical Pulmonary Valve
Stenosis. Operated at 4 Months of Age, in Normal Healing Evolution
Edmar Atik
Edmar Atik´s Private Clinic, SP – Brazil
Clinical Data: Good clinical evolution was observed after
correction of marked critical pulmonary valve stenosis, with
central orifice with one (01) mm of diameter of valve opening,
in a case of right heart failure and cyanosis by right to left shunt
through foramen ovale, on an emergency basis, with circulatory
arrest without cardiopulmonary bypass, at 4 months of age.
On that occasion, a commissurotomy of the trivalvular
pulmonary valve through the pulmonary trunk was performed.
Mild systolic murmur in the pulmonary area, though less intense
than before surgery, which remained audible until adolescence.
Currently, the patient is able to carry out routine activities and
does not refer any symptoms. The patient has led a normal life,
having graduated in law at a traditional university with normal
and well tolerated physical performance.
Physical Examination: good general state, eupneic,
acyanotic, normal pulse. Weight: 57 Kgs. Height: 158 cm,
right upper limb blood pressure: 110/70 mm Hg, HR: 74 bpm.
The aorta was not palpated at the suprasternal notch. In the
precordium, apex beat was not palpated and there were no
systolic impulses. Heart sounds were normal and there was
no audible cardiac murmur. The liver was not palpated and
lungs were clear.
Supplementary Exams
Electrochardiogram showed junctional rhythm and
discreet end disorder of conduction through the right
branch with complex rSr in V1 with normal duration of QRS
of 0.094 seconds. AP = -30o; AQRS = -10o; AT = +10o
(Figure 2). ECG, done before the surgery at 4 months
old, highlighted the significant right ventricular and atrial
overload with electrical signals of systolic pressure of the right
ventricle greater than systemic pressure with depression of
ST segment in the right precordials and QR waves from V1
to V5, largely negative T waves from V1 to V6 and peaked
P wave with 5 to 6 mm amplitude from V2 to V4; AP = +50°,
AQRS = + 170°, AT = -60°. (Figure 1).
Chest X-Ray showed cardiac area slightly enlarged, three
years after surgery, and completely normal at 32 years of age,
Keywords
Pulmonary Valve Stenosis/physiopathology; Pulmonary
Valve Stenosis/surgery; Heart Defects; Congenital/surgery.
Mailing Address: Edmar Atik •
Medical Office. Rua Dona Adma Jafet, 74 conj.73, Bela Vista.
Postal Code 01308-050, São Paulo, SP – Brazil
E-mail: [email protected], [email protected]
Manuscript received July 15, 2015; revised manuscript April 5, 2016;
accepted April 5, 2016.
DOI: 10.5935/abc.20160090
538
with normal pulmonary vasculature (Figure 2), in contrast with
clear cardiomegaly from enlargement of right cavities in the
periods of immediate pre and post-surgery (Figure 1).
Echocardiogram showed cardiac cavities with normal
dimensions, normal biventricular function without valvular
abnormalities, except for a slightly thickened pulmonary
valve showing pressure gradient of 10 mm Hg and without
any valve insufficiency. There was patent foramen ovale with
minimal passage to the right atrium.
Clinical Diagnosis: Critical pulmonary valve stenosis
operated with circulatory arrest in infant period, at 4 months
of age, in evolution for long term anatomic and functional cure.
Clinical Rationale: Evolutionary clinical findings were
consistent with the diagnosis of prior pulmonary valve
stenosis given the persistency of end disorder of conduction
through the right branch on electrocardiogram, electric
expression of marked right ventricular overload prior to
surgical correction. The absence of residual systolic murmur
highlights good progress, and when this condition includes
residual pressure gradient at the pulmonary valve, it should
be under 10 mm Hg, as shown in the echocardiogram.
Another favorable element is the normal size of the cardiac
area in the chest X-Ray, which highlights anatomic and
functional normality.
Differential Diagnosis: Operated congenital heart diseases
which show the same clinical and laboratory aspects are those
represented by interventricular and interatrial communication,
patent ductus arteriosus, coarctation of the aorta, transposition
of the great arteries, and anomalous pulmonary venous
drainage, among the main ones.
Conduct: In view of the anatomic and functional
normalization, a healthy and normal life with assurance of
the capability to perform any kind of human activity without
restrictions is recommended.
Comments: The anatomic and functional normality, after
correction of the pulmonary valve stenosis, may only be
obtained through proper surgical conduct, under direct vision,
in valve anatomy without dystrophies and well constituted
valves, as well as a normal sized pulmonary annulus.
This surgical idea maintains that percutaneous commissurotomy
with rupture of the valve, and not of the commissure,
generally results in a less favorable evolution, especially if it
is related to varied degrees of pulmonary valve insufficiency.
However, according to reports found in the literature, more
deeply marked degrees of pulmonary valve insufficiency
occur in 20 to 30% of cases and require further surgical
procedures with placement of a biological valve, regardless of
the previously employed technique, surgical or percutaneous.
Thus the percutaneous procedure became routine in clinical
practice.1,2 Most patients who undergo percutaneous treatment
evolve favorably, since pulmonary valve insufficiency does not
Atik
Cure for early operated critical pulmonary stenosis
Clinicoradiological Session
Figure 1 – Chest X-Rays show enlarged cardiac area, with decreased pulmonary vasculature in periods pre and immediate to surgery for correction of pulmonary valve
stenosis, and with electrocardiogram with marked overload of right cardiac cavities with signs of suprasystemic systolic pressure.
Figure 2 – Chest X-Rays show slightly enlarged and fully normal cardiac area, respectively 3 and 32 years after surgical correction of pulmonary valve stenosis.
Electrocardiogram with minimal end disorder of conduction through the right branch.
Arq Bras Cardiol. 2016; 106(6):538-540
539
Atik
Cure for early operated critical pulmonary stenosis
Clinicoradiological Session
occur in 12%, is mild in 64%, moderate in 18%, and severe in
6%.2 The results, in general, are comparable between the two
procedures, surgical or percutaneous. Thus we can state than
the best evolution is related to a more adequate anatomy of
the pulmonary valve, especially when a commissurotomy is
flawlessly performed, surgically or percutaneously.
References
1.
540
Xu XD, Liu SX, Zhao XX, Qin YW. Comparison of medium-term results of
transcatheter correction versus surgical treatment for secundum type atrial septal
defect combined with pulmonary valve stenosis. Int Heart J. 2014;55(4):326-30.
Arq Bras Cardiol. 2016; 106(6):538-540
2. Al Balushi AY, Al Shuaili H, Al Khabori M, Al Maskri S. Pulmonary valve
regurgitation following balloon valvuloplasty for pulmonary valve stenosis:
Single center experience. Ann Pediatr Cardiol. 2013;6(2):141-4.
Back to The Cover
Case Report
Drug-Coated Balloon Treatment of Very Late Stent Thrombosis Due
to Complicated Neoatherosclerosis
Fernando Alfonso, Teresa Bastante, Javier Cuesta, Amparo Benedicto, Fernando Rivero
Hospital Universitario de La Princesa, Madrid – Spain
Abstract
We describe the treatment of a patient presenting with
very‑late stent thrombosis with the use of a drug-coated
balloon. In this patient, optical coherence tomography
disclosed that ruptured and complicated neoatherosclerosis
was the underlying substrate responsible for the episode of
very-late stent thrombosis. The potential use of drug-coated
balloons in this unique scenario is discussed.
Introduction
In-stent restenosis (ISR) and stent thrombosis remain
major causes of stent failure1-3. ISR is usually a result of severe
smooth muscle cell proliferation, but recent data suggest that
neoatherosclerosis may also be the responsible pathological
substrate3. Treatment of patients with ISR usually involves the
use of drug-eluting stents or drug-coated balloons (DCB)3.
Alternatively, stent thrombosis may occur as a result of sudden
thrombotic occlusion of a previously patent stent or result
from ruptured neoatherosclerosis with associated thrombosis.
Treatment of stent thrombosis is very challenging and includes
aggressive balloon angioplasty or repeat stent implantation1.
However, to the best of our knowledge, the use of
DCB in patients presenting with stent thrombosis as a
result of complicated neoatherosclerosis has not been
previously reported.
Case Report
A 64-year-old man with hypercholesterolemia was
admitted for a prolonged (3 hours) episode of chest pain at
rest associated with nausea. Fourteen years before he had
recieved a bare-metal stent for a severe lesion in the mid left
anterior descending coronary artery. On admission, the ECG
showed extensive T-wave inversion on the anterior leads.
Urgent coronary angiography revealed a severe focal and
eccentric lesion, with some haziness, at the mid segment
Keywords
Coronary Artery Disease; Percutaneous Coronary Intervention;
Drug-Eluting Stents/adverse effects; Coronary Restenosis;
Coronary Thrombosis/complications
Mailing Address: Fernando Alfonso •
Cardiac Department. Hospital Universitario de La Princesa. Diego de
León 62. Postal Code 28006, Madrid – Spain
E-mail: [email protected]
Manuscript received April 19, 2015; revised manuscript June 30, 2015;
accepted July 7, 2015.
DOI: 10.5935/abc.20160089
541
of the stent, resulting in a TIMI 2 coronary flow (Figure 1A).
Optical coherence tomography (OCT) disclosed a
well‑expanded and apposed stent, nicely covered by a thin
ring of bright homogeneous neointima at the proximal and
distal stent segments. However, neoatherosclerosis (glistening
neointima overlying large lipid pools [+] shadowing the
underlying stent struts) was readily recognized in the mid
part of the stent (Figure 2A). In addition, a clear confined
rupture of the fibrous cap was also identified (yellow arrows,
Figure 2B) close to an occlusive lipid plaque associated with
a large red thrombus (Figure 2C). Thromboaspiration was
successful in improving the angiographic image and coronary
flow, but only obtained a limited amount of red thrombus.
High-pressure (22 bar) dilation with a noncompliant balloon
yielded a good angiographic result. Then, a DCB (3 mm in
diameter) was inflated for 60 seconds at this site, with an
excellent final angiographic result and no images of residual
dissections (Figure 1B). OCT confirmed a large lumen and
thin residual neointima along the entire stent segment, but
disclosed some minor intra-stent dissections (white arrows,
Figure 2D, E, F) and some small residual laden thrombi at
sites with residual neoatherosclerosis. The patient had an
uneventful clinical outcome (peak troponin T 427 ug/L) and
was discharged two days later.
Discussion
Very-late stent thrombosis remains a rare, but devastating
complication in patients undergoing percutaneous coronary
interventions1. Recent studies suggest that neoatherosclerosis
plays a major role in selected patients presenting with
this feared complication 2. Pathological studies suggest
that neoatherosclerosis not only occurs more frequently
but also earlier in patients treated with drug-eluting
stents, as compared with those receiving conventional
bare‑metal stents2. Currently, OCT, with its unique resolution
(15 µm), represents the technique of choice for the
diagnosis of neoatherosclerosis. Multiple studies have
confirmed the importance of OCT in the diagnosis of
neoatherosclerosis resulting in either in-stent restenosis or
stent thrombosis1,3. Likewise, the use of DCB in patients
presenting with in-stent restenosis has been well established3.
Although neoatherosclerosis constitutes the underlying
substrate in some of these patients, particularly in those
treated with drug‑eluting stents, the role of DCB in this specific
anatomic subset remains to be elucidated. Our findings
strongly suggest that DCB might also provide an attractive
therapeutic strategy for selected patients with very late stent
thrombosis as a result of neoatherosclerosis. Prospective
studies are warranted to further define the potential role of
this novel therapy in this challenging scenario.
Alfonso et al.
Drug-coated balloon treatment of stent thrombosis
Case Report
Figure 1 – A) Coronary angiography with a cranial angulation showing a tight lesion (resulting in a luminal filling defect) in the mid part of the stent (arrow), on the proximal
left anterior descending coronary artery that had a TIMI 2 flow. B) Final result after DCB angioplasty.
Figure 2 – Optical coherence tomography images after thromboaspiration. A) Neoatherosclerosis with a glistening bright neointima and a heterogeneous pattern
caused by large lipid pools (+). Notice that attenuation prevents adequate visualization of the underlying metallic stent struts. B) Ruptured neoatherosclerotic plaque
(arrows). C) Occlusive neoatherosclerosis with thrombus. D, E, F) Optical coherence tomography images after DCB treatment. A large lumen was visualized along
the entire stent length with some residual neointima, small dissections and residual thrombi (arrows). Confined residual lipid zones (+) were still recognized within
the stent. (* = denotes wire artefact)
Arq Bras Cardiol. 2016; 106(6):541-543
542
Alfonso et al.
Drug-coated balloon treatment of stent thrombosis
Case Report
Conclusion
DCB constitutes an attractive therapeutic strategy
for selected patients with stent thrombosis as a result of
complicated neoatherosclerosis.
Author contributions
Conception and design of the research and Writing of
the manuscript: Alfonso F; Acquisition of data and Analysis
and interpretation of the data: Alfonso F, Bastante T; Critical
revision of the manuscript for intellectual content: Alfonso F,
Cuesta J, Benedicto A, Rivero 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. Alfonso F, Sandoval J. New insights on stent thrombosis: in praise of large
nationwide registries for rare cardiovascular events. JACC Cardiovasc Interv.
2012;5(2):141-4.
2. Nakazawa G, Otsuka F, Nakano M, Vorpahl M, Yazdani SK, Ladich E, et al.
The pathology of neoatherosclerosis in human coronary implants bare-metal
and drug-eluting stents. J Am Coll Cardiol. 2011;57(11):1314-22.
543
Arq Bras Cardiol. 2016; 106(6):541-543
3. Alfonso F, Byrne RA, Rivero F, Kastrati A. Current treatment of in-stent
restenosis. J Am Coll Cardiol. 2014;63(24):2659-73.
Back to The Cover
Image
Left Ventricular Rigid Body Rotation in Ebstein’s Anomaly from the
MAGYAR-Path Study
Attila Nemes, Kálmán Havasi, Péter Domsik, Anita Kalapos, Tamás Forster
2nd Department of Medicine and Cardiology Center, University of Szeged, Szeged – Hungary
A 70-year-old female patient with Ebstein’s anomaly (EA) that
had never undergone palliation was assessed (the case originates
from the MAGYAR-Path Study). Complete two‑dimensional
(2D) Doppler and three-dimensional (3D) speckle-tracking
echocardiography were carried out with commercially available
Toshiba ArtidaTM echocardiography equipment. During 2D
echocardiography, the septal leaflet‑tricuspid annulus distance
showed to be 25 mm, confirming EA. While the right ventricle
(RV) was enlarged with tricuspid annular plane systolic
excursion > 23 mm and mitral regurgitation grade III, left
ventricular (LV) size and function showed to be normal with
an ejection fraction of 56% without wall motion abnormalities.
However, all LV regions moved in almost the same
counterclockwise direction, confirming absence of LV twist,
called “rigid body rotation” (RBR) (Figure 1). The mean global
LV radial, circumferential, longitudinal, 3D and area strain
parameters showed to be 11.5 ± 10.0%, -25.5 ± 15.4%,
-18.6 ± 10.2%, 15.2 ± 10.8% and -34.7 ± 20.8%, respectively.
EA is a congenital heart defect in which septal and posterior
leaflets of the tricuspid valve are displaced towards the RV
Keywords
Congenital Heart Defects; Ebstein Anomaly; Torsion,
Mechanical; Rotation
Mailing Address:Attila Nemes •
Semmelweis street 6. Postal Code 6725, Szeged – Hungary
E-mail: [email protected], [email protected]
Manuscript received on November 13, 2015; manuscript revised on
November 17, 2015; accepted on November 30, 2015.
DOI: 10.5935/abc.20160050
544
apex, leading to RV partial atrialization, although the anatomic
annulus of the valve is in the normal position.1 Malformation
and displacement of the anterior leaflet can also be present.
To the best of our knowledge, this is the first report to
demonstrate LV-RBR, a known feature in LV myocardial
mechanics, in a single patient with unrepaired EA. LV-RBR could
be partially explained by the impaired ventricle-to-ventricle
interactions due to displaced tricuspid valve leaflet attachments,
alterations in the anatomic myocardial fiber orientation, but
other reasons could also not be excluded.
Author contributions
Conception and design of the research and v: Nemes A,
Havasi K; Acquisition of data and Analysis and interpretation
of the data: Domsik P, Kalapos A; Critical revision of the
manuscript for intellectual content: Havasi K, Forster T.
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.
Back to The Cover
Nemes et al.
LV-RBR in Ebstein’s anomaly
Image
Figure 1 – Apical 4-chamber (A) and 2-chamber (B) views and short–axis views (C3, C5, C7) at different levels of the left ventricle (LV) extracted from the three-dimensional
(3D) echocardiographic dataset are shown in the patient with Ebstein’s anomaly. The 3D image of the LV and calculated LV volumetric and functional characteristics
(EDV: end-diastolic volume; ESV: end-systolic volume; EF: ejection fraction) are also demonstrated together with LV apical (white arrow), mid-ventricular and basal
(dashed arrow) rotations in the same counterclockwise direction, confirming absence of the LV twist, called “rigid body rotation”.
References
1. Geerdink LM, Kapusta L. Dealing with Ebstein’s anomaly. Cardiol Young
2014;24(2):191-200.
Arq Bras Cardiol. 2016; 106(6):544-545
545
Back to The Cover
Letter to the Editor
Predictors of Atrial Fibrillation Recurrence in Hyperthyroid and
Euthyroid Patients
Levent Cerit
Department of Cardiology - Near East University Hospital, Nicosia, Cyprus
To the Editor,
I have read with great interest the article entitled “Predictors
of Atrial Fibrillation Recurrence in Hyperthyroid and Euthyroid
Patients” by Gürdoğan et al.,1 recently published in Arquivos
Brasileiros de Cardiologia. The investigators reported that rates
of atrial fibrillation (AF) recurrence were similar in hyperthyroid
and euthyroid patients and that the duration of AF was the
only predictor of AF recurrence in both.
Hyperthyroidism is a well-known risk factor for paroxysmal
and permanent AF. Marrakchi et al.2 have reported that a
low serum thyroid-stimulating hormone (TSH) level is an
independent risk factor for AF. All other factors predisposing
to AF were mentioned and discussed in that article.
Additionally, Demir et al.3 have found a strong relationship
between vitamin D deficiency and nonvalvular AF. Serum
vitamin D levels correlated with high sensitive C-reactive
protein levels and left atrial diameter, and were significantly
associated with AF in Chinese patients with nonvalvular
persistent AF. 4 Hanafy et al. 5 have revealed the direct
electromechanical effects of vitamin D administration on the
left atrium and found that vitamin D could effectively prevent
and terminate AF.
In the light of this knowledge, Gürdoğan et al.1 should have
reported the vitamin D levels of the patients in their study and
discussed the association between the levels of this vitamin
and AF recurrence.
Keywords
Atrial Fibrillation; Hyperthyroidism; Euthyroid Sick
Syndromes; Thyroid Disease.
Mailing Address: Levent Cerit •
The Institute of Environmental Sciences, Bogazici University, Turkey. Near
East University Hospital, Near East Street. Postal Code 07100, Nicosia
E-mail: [email protected], [email protected]
Manuscript received February 25, 2016; revised manuscript February 29,
2016; accepted March 04, 2016.
DOI: 10.5935/abc.20160085
References
1.
Gürdoğan M, Ari H, Tenekecioğlu E, Ari S, Bozat T, Koca V, et al. Predictors
of atrial fibrillation recurrence in hyperthyroid and euthyroid patients. Arq
Bras Cardiol. 2016;106(2):84-91.
2. Marrakchi S, Kanoun F, Idriss S, Kammoun I, Kachboura S. Arrhythmia and
thyroid dysfunction. Herz. 2015;40(Suppl 2):101-9.
3. Demir M, Uyan U, Melek M. The effects of vitamin D deficiency on atrial
fibrillation. Clin Appl Thromb Hemost. 2014: 20(1): 98-103.
546
4.
Chen WR, Liu ZY, Shi Y, Yin W, Wang H, Sha Y, et al. Relation of low vitamin
D to nonvalvular persistent atrial fibrillation in Chinese patients. Ann
Noninvasive Electrocardiol; 2014:19(2): 166-73.
5. Hanafy DA, Chang SL, Lu YY, Chen YC, Kao YH, Huang JH, et al.
Electromechanical effects of 1,25-dihydroxyvitamin D with antiatrial
fibrillation activities. J Cardiovasc Electrophysiol. 2014:25(3): 317-23.
Cerit
Atrial fibrillation and thyroid function
Letter to the Editor
Reply
We are pleased that Dr. Cerit showed great interest in our
article entitled ‘’Predictors of Atrial Fibrillation Recurrence in
Hyperthyroid and Euthyroid Patients’’ published in Arquivos
Brasileiros de Cardiologia.1
Recent studies have found that vitamin D deficiency is
related to nonvalvular AF.2,3 However, the relationship between
this deficiency and nonvalvular AF is not dependent on the
occurrence of thyroid disorder. In the study published by
Demir et al.,2 the TSH levels were normal in all AF groups.
In addition, thyroid dysfunction was an exclusion criterion in
the studies by both Demir et al.2 and Chen et al.3 We did
not evaluate the vitamin D levels in our study’s participants,
which we can add as a limitation of our research. However,
the participants in our study did not report any symptom
or treatment of vitamin D deficiency. After thyroid surgery,
in particular, patients may have vitamin D deficiency and
hypothyroidism, but none of the patients in our study had
prior thyroid surgery.
Considering the above, large-scale trials are still necessary
to evaluate the relationship between vitamin D levels, thyroid
function, and AF. We thank Dr. Cerit for this great contribution
to our work.
Dr. Hasan ARI
References
1. Gürdoğan M, Ari H, Tenekecioğlu E, Ari S, Bozat T, Koca V, et al. Predictors
of atrial fibrillation recurrence in hyperthyroid and euthyroid patients. Arq
Bras Cardiol. 2016; 106(2):84-91.
3. Chen WR, Liu ZY, Shi Y, Yin W, Wang H, Sha Y, et al. Relation of low vitamin
D to nonvalvular persistent atrial fibrillation in Chinese patients. Ann
Noninvasive Electrocardiol. 2014;19(2):166-73.
2. Demir M, Uyan U, Melek M. The effects of vitamin D deficiency on atrial
fibrillation. Clin Appl Thromb Hemost. 2014:20(1):98-103.
Arq Bras Cardiol. 2016; 106(6):546-547
547