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www.arquivosonline.com.br 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 Scientific Director Raul Dias dos Santos Filho Surgical Cardiology Paulo Roberto B. Evora Arrhythmias/Pacemaker Mauricio Scanavacca Chief Editor Luiz Felipe P. Moreira Interventionist Cardiology Pedro A. Lemos Non-Invasive Diagnostic Methods Carlos E. Rochitte Pediatric/Congenital Cardiology Antonio Augusto Lopes Basic or Experimental Research Leonardo A. M. Zornoff Associated Editors Clinical Cardiology José Augusto Barreto-Filho Epidemiology/Statistics Lucia Campos Pellanda Arterial Hypertension Paulo Cesar B. V. Jardim Ergometrics, Exercise and Cardiac Rehabilitation Ricardo Stein First Editor (1948-1953) † Jairo Ramos Editorial Board Brazil Aguinaldo Figueiredo de Freitas Junior (GO) Alfredo José Mansur (SP) Aloir Queiroz de Araújo Sobrinho (ES) Amanda G. M. R. Sousa (SP) Ana Clara Tude Rodrigues (SP) André Labrunie (PR) Andrei Sposito (SP) Angelo A. V. de Paola (SP) Antonio Augusto Barbosa Lopes (SP) Antonio Carlos C. Carvalho (SP) Antônio Carlos Palandri Chagas (SP) Antonio Carlos Pereira Barretto (SP) Antonio Cláudio L. 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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 References 1. Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med. 1999;340(2):115-26. 2. Toth PP. Subclinical atherosclerosis: what it is, what it means and what we can do about it. Int J Clin Pract. 2008;62(8):1246-54. 3. Ministério da Saúde. Datasus. Morbidade hospitalar do SUS. Por local de internação. Brasil. [Acesso em 2011 jul 7]. Disponível em: http://tabnet. datasus.gov.br/cgi/tabcgi.exe?sih/cnv/nuf.def 4. 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Arq Bras Cardiol. 2016; 106(6):457-463 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. References 1. Ministério da Saúde. Datasus: informações de saúde, morbidade e informações epidemiológicas. [Citado em 2015 maio 10]. Disponível em: htp://www.datasus.gov.br. 2. Organização Mundial de Saúde. (OMS). 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Barros MD, Ximenes R, Limac ML. [Child and adolescent mortality due to external causes: trends from 1979 to 1995]. Rev Saúde Pública 2001;35(2):142-9. 27. Martins CB, Andrade SM. External causes among individuals under 15 years of age in a city in south Brazil: emergency care, hospitalizations and deaths . Rev Bras Epidemiol. 2005;8(2):194-204. 28. Phebo L, Moura AT. Urban violence: a challenge for pediatricians. J Pediatr (Rio J):2005;81(5 Suppl):S189-96. 29. Matos KF, Martins CB. Epidemiological profile of mortality by external causes in children, teenagers and young people in the capital of the State of Mato Grosso, Brazil, 2009. Epidemiol Serv Saúde. 2012;21(1):43-53. 30. Zeccone O. Indignos de vida: a forma jurídica da política de extermínio de inimigos na cidade do Rio de Janeiro. Rio de Janeiro: Editora Revan; 2015. 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. Risk for obstructive sleep apnea syndrome Original Article 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 References 1. Mancini MC, Aloe F, Tavares S. Apnéia do sono em obesos. Arq Bras Endocrinol Metab. 2000;44(1):81-90. 2. Pereira A. Síndrome da apnéia obstrutiva do sono: fisiopatologia. epidemiologia, consequências. diagnóstico e tratamento. Arq Med. 2007;21(5-6):159-73. 3. 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Prevalence of and risk factors for obstructive sleep apnea syndrome in Brazilian railroad workers. Sleep Med. 2012;13(8):1028-32. 13. Hiestand DM, Britz P, Goldman M, Phillips B. Prevalence of symptoms and risk of sleep apnea in the US population: results from the national sleep foundation in America poll. Chest. 2006;130(3):780-6. 14. Ministério da Saúde. Secretaria de Vigilância em Saúde. Vigitel Brasil 2011: Vigilância de fatores de risco e proteção para doenças crônicas por inquérito telefônico. Brasília; 2012. 132 p: II (Série G. Estatística e Informação em Saúde). [Acesso em 2015 mar 30]. Disponível em: http://bvsms.saude.gov. br/bvs/publicacoes/vigitel_brasil_2011_fatores_risco_doencas_cronicas.pdf 15. Ministério da Saúde. Secretaria de Vigilância em Saúde. Vigitel. Departamento de Vigilância de Doenças e Agravos não Transmissíveis e Promoção de Saúde. 2012. Brasília; 2013. [Acesso em 2015 mar 30]. Disponível em: http://bvsms. saude.gov.br/bvs/publicacoes/vigitel_brasil_2012.pdf 16. Maimon N, Hanly PJ. Does snoring intensity correlate with the severity of obstructive sleep apnea? J Clin Sleep Med. 2010;6(5):475-8. 17. Zancanella E, Haddad FM, Oliveira LA, Nakasato A, Duarte BB, Soares CF, et al. Apneia obstrutiva do sono e ronco primário: diagnóstico - Projeto Diretrizes. Associação Brasileira de Otorrinolaringologia e outras / 2012. [Acesso em 2015 mai 24]. Disponível em: http://www.projetodiretrizes.org.br/diretrizes12/ apneia_obstrutiva_do_sono_e_ronco_primario_diagnostico.pdf 8. Udwadia ZF, Doshi AV, Lonkar SG, Singh CI. Prevalence of sleep-disordered breathing and sleep apnea in middle-aged urban Indian men. Am J Respir Crit Care Med. 2004;169(2):168-73. 18. Kapsimalis F, Kryger MH. Gender and obstructive apnea syndrome. Part 1: clinical features. Sleep. 2002;25(4):412-9. 9. Lemos LC, Marqueze EC, Sachi F, Lorenzi-Filho G, Moreno CR. Obstructive sleep apnea syndrome in truck drivers. J Bras Pneumol. 2009;35(6):500-6. 19. Young T, Peppard P, Palta M, Hla KM, Finn L, Morgan B, et al. Populationbased study of sleep-disordered breathing as a risk factor for hypertension. Arch Intern Med. 1997;157:1746–52. 10. Nieto FJ, Young TB, Lind BK, Shahar E, Samet JM, Redline S, et al; Pickering TG. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JAMA. 2000;283(14):1829-36. Erratum in: JAMA 2002;288(16):1985. 11. Hla KM, Young T, Finn L, Peppard PE, Szklo-Coxe M, Stubbs M. Longitudinal association of sleep-disordered breathing and nondipping of nocturnal blood pressure in the Wisconsin Sleep Cohort Study. Sleep. 2008;31(6):795-800. 480 12. Drager LF, Genta PR, Pedrosa RP, Nerbass FB, Gonzaga CC, Krieger EM, et al. Characteristics and predictors of obstructive sleep apnea in patients with systemic hypertension. Am J Cardiol. 2010;105(8):1135-9. Arq Bras Cardiol. 2016; 106(6):474-480 20. Lavie P, Herer P, Hoffstein V. Obstructive sleep apnoea syndrome as a risk factor for hypertension: population study.BMJ. 2000;320:479–82. 21. Mohsenin V. Obstructive sleep apnea and hypertension: a critical review. Curr Hypertens Rep. 2014 doi: 10.1007/s11906-014-0482-4 22. Margallo VS, Muxfeldt ES, Guimarães GM, Salles GF. Diagnostic accuracy of the Berlin questionnaire in detecting obstructive sleep apnea in patients with resistant hypertension. Journal of Hypertension. 2014;32:2030–37. 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 Arq Bras Cardiol. 2016; 106(6):481-490 482 Tirapelli et al. The labda-15-oic decreases blood pressure Original Article 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. 483 Arq Bras Cardiol. 2016; 106(6):481-490 Tirapelli et al. The labda-15-oic decreases blood pressure Original Article 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). Arq Bras Cardiol. 2016; 106(6):481-490 484 Tirapelli et al. The labda-15-oic decreases blood pressure Original Article (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. 485 Arq Bras Cardiol. 2016; 106(6):481-490 Tirapelli et al. The labda-15-oic decreases blood pressure Original Article 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 Arq Bras Cardiol. 2016; 106(6):481-490 486 Tirapelli et al. The labda-15-oic decreases blood pressure Original Article 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. 487 Arq Bras Cardiol. 2016; 106(6):481-490 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. Tirapelli et al. The labda-15-oic decreases blood pressure Original Article 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. Arq Bras Cardiol. 2016; 106(6):481-490 488 Tirapelli et al. The labda-15-oic decreases blood pressure Original Article 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). References 1. Alonso A, Martínez-González MA. Olive oil consumption and reduced incidence of hypertension: the SUN study. Lipids. 2004;39(12):1233-8. 2. Herrera-Arellano A, Flores-Romero S, Chávez-Soto MA, Tortoriello J. Effectiveness and tolerability of a standardized extract from Hibiscus sabdariffa in patients with mild to moderate hypertension: a controlled and randomized clinical trial. Phytomedicine 2004; 11(5):375-82. 3. 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Tirapelli CR, Ambrosio SR, Coutinho ST, De Oliveira DC, Da Costa FB, De Oliveira AM. Pharmacological comparison of the vasorelaxant action displayed by kaurenoic acid and pimaradienoic acid. J Pharm Pharmacol. 2005;57(8):997-1004. 32. El Bardai S, Wibo M, Hamaide M.C, Lyoussi B, Quetin-Leclercq J, Morel N. Characterisation of marrubenol, a diterpene extracted from Marrubium vulgare, as an L-type calcium channel blocker. Br J Pharmacol. 2003;140(7):1211-6. 33. Tirapelli CR, Ambrosio SR, de Oliveira AM, Tostes RC. Hypotensive action of naturally occurring diterpenes: a therapeutic promise for the treatment of hypertension. Fitoterapia. 2010;81(7):690-702. 34. Anjos Neto M, Lunardi CN, Rodrigues GJ, Bendhack LM. Vasodilatation induced by forskolin involves cyclic GMP production. J Biophysical Chem. 2011;2(4):373-9. 35. Campbell NR, Brant R, Johansen H, Walker RL, Wielgosz A, Onysko J, et al; Canadian Hypertension Education Program Outcomes Research Task Force. Increases in antihypertensive prescriptions and reductions in cardiovascular events in Canada, Hypertension. 2009;53(2):128-34. 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):491-501 496 Alvarez et al. Spirituality and heart failure therapy Original Article 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 References 1. Jaarsma T, van der Wal MH, Lesman-Leegte I, Luttik ML, Hogenhuis J, Veeger NJ, et al. Effect of moderate or intensive disease management program on outcome in patients with heart failure: Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH). Arch Intern Med. 2008;168(3):316-24. 20. Santos IS, Tavares BF, Munhoz TN, Almeida LS, Silva NT, Tams BD, et al. [Sensitivity and specificity of the Patient Health Questionnaire-9 (PHQ-9) among adults from the general population]. Cad Saúde Pública. 2013;29(8):1533-43. 2. Artinian NT, Magnan M, Sloan M, Lange MP. Self-care behaviors among patients with heart failure. Heart Lung. 2002;31(3):161-72. 21. Fleck MP, Louzada S, Xavier M, Chachamovich E, Vieira G, Santos L, et al. [Application of the Portuguese version of the abbreviated instrument of quality life WHOQOL-bref]. Rev Saude Publica. 2000;34(2):178-83. 3. Riegel B, Moser DK, Anker SD, Appel LJ, Dunbar SB, Grady KL, et al. State of the science: promoting self-care in persons with heart failure: a scientific statement from the American Heart Association. Circulation. 2009;120(12):1141-63. 22. Mussi CM, Ruschel K, de Souza EN, Lopes AN, Trojahn MM, Paraboni CC, et al. Home visit improves knowledge, self-care and adhesion in heart failure: Randomized Clinical Trial HELEN-I. Rev Lat Am Enfermagem. 2013;21 Spec No:20-8. 4. Murray SA, Kendall M, Grant E, Boyd K, Barclay S, Sheikh A. Patterns of social, psychological, and spiritual decline toward the end of life in lung cancer and heart failure. J Pain Symptom Manage. 2007;34(4):393-402. 23. Development of the World Health Organization WHOQOL-BREF quality of life assessment. The WHOQOL Group. Psychol Med. 1998;28(3):551-8. 5. Ni H, Nauman D, Burgess D, Wise K, Crispell K, Hershberger RE. Factors influencing knowledge of and adherence to self-care among patients with heart failure. Arch Intern Med. 1999;159(14):1613-9. 6. Moser DK, Doering LV, Chung ML. Vulnerabilities of patients recovering from an exacerbation of chronic heart failure. Am Heart J. 2005;150(5):984. 7. Wu JR, Moser DK, De Jong MJ, Rayens MK, Chung ML, Riegel B, et al. Defining an evidence-based cutpoint for medication adherence in heart failure. Am Heart J. 2009;157(2):285-91. 24. Rector TS, Cohn JN. Assessment of patient outcome with the Minnesota Living with Heart Failure questionnaire: reliability and validity during a randomized, double-blind, placebo-controlled trial of pimobendan. Pimobendan Multicenter Research Group. Am Heart J. 1992;124(4):1017-25. 25. Kubo SH, Schulman S, Starling RC, Jessup M, Wentworth D, Burkhoff D. Development and validation of a patient questionnaire to determine New York Heart Association classification. J Card Fail. 2004;10(3):228-35. 26. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16(9):606-13. 8. Krantz MJ, Ambardekar AV, Kaltenbach L, Hernandez AF, Heidenreich PA, Fonarow GC. Patterns and predictors of evidence-based medication continuation among hospitalized heart failure patients (from Get With the Guidelines-Heart Failure). Am J Cardiol. 2011;107(12):1818-23. 27. de Lima Osorio F, Vilela Mendes A, Crippa JA, Loureiro SR. Study of the discriminative validity of the PHQ-9 and PHQ-2 in a sample of Brazilian women in the context of primary health care. Perspect Psychiatr Care. 2009;45(3):216-27. 9. 28. Koenig HG, Bussing A. The Duke University Religion Index (DUREL): a fiveitem measure for use in epidemiological studies. Religions. 2010;1(1):78-85. Fonarow GC, Yancy CW, Heywood JT. Adherence to heart failure quality-ofcare indicators in US hospitals: analysis of the ADHERE Registry. Arch Intern Med. 2005;165(13):1469-77. 10. Bekelman DB, Dy SM, Becker DM, Wittstein IS, Hendricks DE, Yamashita TE, et al. Spiritual well-being and depression in patients with heart failure. J Gen Intern Med. 2007;22(4):470-7. 11. Jones AM, O’Connell JE, Gray CS. Living and dying with congestive heart failure: addressing the needs of older congestive heart failure patients. Age Ageing. 2003;32(6):566-8. 12. Westlake C, Dracup K. Role of spirituality in adjustment of patients with advanced heart failure. Prog Cardiovasc Nurs. 2001;16(3):119-25. 13. Park CL, Aldwin CM, Choun S, George L, Suresh DP, Bliss D. Spiritual peace predicts 5-year mortality in congestive heart failure patients. Health Psychol. 2016;35(3):203-10. 29. WHOQOL SRPB Group. A cross-cultural study of spirituality, religion, and personal beliefs as components of quality of life. Soc Sci Med. 2006;62(6):1486-97. 30. Thomas CM. The influence of self-concept on adherence to recommended health regimens in adults with heart failure. J Cardiovasc Nurs. 2007;22(5):405-16. 31. Dickson VV, McCarthy MM, Howe A, Schipper J, Katz SM. Sociocultural influences on heart failure self-care among an ethnic minority black population. J Cardiovasc Nurs. 2013;28(2):111-8. 32. Mills PJ, Redwine L, Wilson K, Pung MA, Chinh K, Greenberg BH, et all. The Role of Gratitude in Spiritual Well-being in Asymptomatic Heart Failure Patients. Spiritual Clin Pract (Wash D C ). 2015;2(1):5-17. 14. Black G, Davis BA, Heathcotte K, Mitchell N, Sanderson C. The relationship between spirituality and compliance in patients with heart failure. Prog Cardiovasc Nurs. 2006;21(3):128-33. 33. Oman D, Kurata JH, Strawbridge WJ, Cohen RD. Religious attendance and cause of death over 31 years. Int J Psychiatry Med. 2002;32(1):69-89. 15. Stewart WC, Adams MP, Stewart JA, Nelson LA. Review of clinical medicine and religious practice. J Relig Health. 2013;52(1):91-106. 34. Kark JD, Shemi G, Friedlander Y, Martin O, Manor O, Blondheim SH. Does religious observance promote health? mortality in secular vs religious kibbutzim in Israel. Am J Public Health. 1996;86(3):341-6. 16. Carvalho VO, Guimaraes GV, Carrara D, Bacal F, Bocchi EA. Validation of the Portuguese version of the Minnesota Living with Heart Failure Questionnaire. Arq Bras Cardiol. 2009;93(1):39-44. 17. Bocchi EA, Cruz F, Guimaraes G, Pinho Moreira LF, Issa VS, Ayub Ferreira SM, et al. Long-term prospective, randomized, controlled study using repetitive education at six-month intervals and monitoring for adherence in heart failure outpatients: the REMADHE trial. Circ Heart Fail. 2008;1(2):115-24. 18. Taunay TC, Gondim Fde A, Macêdo DS, Moreira-Almeida A, Gurgel LA, Andrade LM, et al. Validity of the Brazilian version of the Duke Religious Index (DUREL). Rev Psiquiatr Clin. 2012;39(4):130-5. 19. Panzini RG, Maganha C, Rocha NS, Bandeira DR, Fleck MP. Brazilian validation of the Quality of Life Instrument/spirituality, religion and personal beliefs. Rev Saude Publica. 2011;45(1):153-65. 35. Feinstein M, Liu K, Ning H, Fitchett G, Lloyd-Jones DM. Burden of cardiovascular risk factors, subclinical atherosclerosis, and incident cardiovascular events across dimensions of religiosity: The multi-ethnic study of atherosclerosis. Circulation. 2010;121(5):659-66. 36. Naghi JJ, Philip KJ, Phan A, Cleenewerck L, Schwarz ER. The effects of spirituality and religion on outcomes in patients with chronic heart failure. J Relig Health. 2012;51(4):1124-36. 37. Roy C, Whetsell MV, Frederickson K. The Roy adaptation model and research. Nurs Sci Q. 2009;22(3):209-11. 38. Ross L, Austin J. Spiritual needs and spiritual support preferences of people with end-stage heart failure and their carers: implications for nurse managers. J Nurs Manag. 2015; 23(1):87-95. Arq Bras Cardiol. 2016; 106(6):491-501 498 Alvarez et al. Spirituality and heart failure therapy Original Article 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 Alvarez et al. Spirituality and heart failure therapy Original Article 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):491-501 500 Alvarez et al. Spirituality and heart failure therapy Original Article 501 Arq Bras Cardiol. 2016; 106(6):491-501 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):502-509 503 Tavares et al. Functional class in children with cardiomyopathy Original Article Figure 1 – Functional class for male children. Figure 2 – Functional class for female children. 504 Arq Bras Cardiol. 2016; 106(6):502-509 Tavares et al. Functional class in children with cardiomyopathy Original Article (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. References 1. 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J Heart Lung Transplant. 2003;23(7):832-8. 27. Bunchaft G. Kellner SRO. Estatística sem mistérios. 2ª. ed. Petrópolis: Vozes; 1999. 28. Tanaka H, Monahan KD, Seals DR. Age-predicted maximal heart rate revisited. J Am Coll Cardiol. 2001;37(1):153-6. Tavares et al. Functional class in children with cardiomyopathy Original Article 29. Malina RM. Bouchard C. Alterações em tecidos adiposos durante o crescimento. In: Malina RM. Atividade física do atleta jovem: do crescimento à maturação. São Paulo: Roca; 2002. p. 127-42. 35. Carvalho VO, Bocchi EA, Guimarães GV. The Carvedilol’s beta-blockade in heart failure and exercise training’s sympathetic blockade in healthy athletes during the rest and peak effort. Cardiovasc Ther. 2010;28(2):87-92. 30. Heys M, Lin SL, Lam TH, Leung GM, Schooling CM. Lifetime growth and blood pressure in adolescence: Hong Kong’s ‘’Children of 1997’’ birth cohort. Pediatrics. 2013;131(1):e62-72. 36. Silva RJ, Petroski EL. Consumo máximo de oxigênio e estágio de maturação sexual de crianças e adolescentes. Revista de desporto e Saúde. 2007;4(1):13-9. 31. Neuhauser HK, Thamm M, Ellert U, Hense WH, Rosario AS. Blood pressure percentiles by age and height from nonoverweight children and adolescents in Germany. Pediatrics. 2011;127(4):e978-88. 37. Tavares AC, Bocchi EA, Teixeira-Neto IS, Guimarães GV. A meta-analysis of cardiopulmonary exercise testing in pre-pubertal healthy children. Medical Express. (São Paulo, online). 2016;3(1). São Paulo. Jan/Feb. 2016. 32. Akiyama E, Sugiyama S, Matsuzawa Y, Konishi M, Suzuki H, Nozaki T, et al. Incremental prognostic significance of peripheral endothelial dysfunction in patients with heart failure with normal left ventricular ejection fraction. J Am Coll Cardiol. 2012;60(18):1778-86. 38. Eisenmann JC, Pivarnik JM, Malina RM. Scaling peak VO2 to body mass in young male and female distance runners. J Appl Physiol (1985). 2001;90(6):2172-80. 33. Hechter SJ, Fredriksen PM, Liu P, Veldtman G, Merchant N, Freeman M, et al. Angiotensin-converting enzyme inhibitors in adults after the Mustard procedure. Am J Cardiol. 2001;87(5):660-3. 34. Sherwood A, Steffen PR, Blumenthal JA, Kuhn C, Hinderliter AL. Nighttime blood pressure dipping: the role of the sympathetic nervous system. Am J Hypertens. 2002;15(2 Pt 1):111-8. 39. Armstrong N, Davies B. The metabolic and physiological responses of children to exercise and training. Physical Edication Review. 1984;7(2):90-105. 40. van den Broek SA, van Veldhuisen DJ, de Graeff PA, Landsman ML, Hillege H, Lie K. Comparison between New York Heart Association classification and peak oxygen consumption the assessment of functional status and prognosis in patients with mild to moderate chronic congestive heart failure secondary to either ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 1992;70(3):359-63. 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):510-518 511 Santos et al. Smoking and cardiac autonomic modulation 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 512 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):510-518 515 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. 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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):519-527 522 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 patientsu ndergoingCoreValve® 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. References 1. Cribier A, Eltchaninoff H, Bash A, Borenstein N, Tron C, Bauer F, et al. Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis: first human case description. Circulation. 2002;106(24):3006-8. 2. Leon MB, Smith CR, Mack M, Miller DC, Moses JW, Svensson LG, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med. 2010;363(17):1597-607. 3. Adams DH, Popma JJ, Reardon MJ, Yakubov SJ, Coselli JS, Deeb GM, et al. Transcatheter aortic-valve replacement with a self-expanding prosthesis. N Engl J Med. 2014;370(19):1790-8. 4. Popma JJ, Adams DH, Reardon MJ, Yakubov SJ, Kleiman NS, Heimansohn D, et al. Transcatheter aortic valve replacement using a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme risk for surgery. J Am Coll Cardiol. 2014;63(19):1972-81. 5. Mack MJ, Leon MB, Smith CR, Miller DC, Moses JW, Tuzcu EM, et al. 5-year outcomes of transcatheter aortic valve replacement or surgical aortic valve replacement for high surgical risk patients with aortic stenosis (PARTNER 1): a randomised controlled trial. Lancet. 2015;385(9986):2477-84. 6. Sarmento-Leite R, Quadros A, Prates P, Zanatta L, Salgado P, Grando T, et al. Implante valvular aórtico percutâneo: experiência inicial do Sul do Brasil. Rev Bras Cardiol Invas. 2008;16(4):398-405. 7. Kappetein AP, Head SJ, Genereux P, Piazza N, van Mieghem NM, Blackstone EH, et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. J Am Coll Cardiol. 2012;60(15):1438-54. 8. Leon MB, Piazza N, Nikolsky E, Blackstone EH, Cutlip DE, Kappetein AP, et al. Standardized endpoint definitions for Transcatheter Aortic Valve Implantation clinical trials: a consensus report from the Valve Academic Research Consortium. J Am Coll Cardiol. 2011;57(3):253-69. 9. Sousa AL, Feijo AL, Salgado CG, Branco RV, Falcão CH, Assad JA, et al. Implante de válvula aórtica percutânea: experiência inicial no estado do Rio de Janeiro. Rev Bras Cardiol. 2010;23(1):35-42. 10. Holmes DR Jr, Brennan JM, Rumsfeld JS, Dai D, O’Brien SM, Vemulapalli S, et al. Clinical outcomes at 1 year following transcatheter aortic valve replacement. JAMA. 2015;313(10):1019-28. 11. Walther T, Hamm CW, Schuler G, Berkowitsch A, Kotting J, Mangner N, et al. Perioperative results and complications in 15,964 transcatheter aortic valve replacements: prospective data from the GARY registry. J Am Coll Cardiol. 2015;65(20):2173-80. 12. Duncan A, Ludman P, Banya W, Cunningham D, Marlee D, Davies S, et al. Long-term outcomes after transcatheter aortic valve replacement in high‑risk patients with severe aortic stenosis: the U.K. transcatheter aortic valve implantation registry. JACC Cardiovasc Interv. 2015;8(5):645-53. 13. Zweiker D, Maier R, Lamm G, Maurer E, Heigert M, Neunteufl T, et al. The Austrian transcatheter aortic valve implantation (TAVI) Registry--3 years’ data. Int J Cardiol. 2014;177(1):114-6. 14. Wenaweser P, Stortecky S, Heg D, Tueller D, Nietlispach F, Falk V, et al. Short-term clinical outcomes among patients undergoing transcatheter aortic valve implantation in Switzerland: the Swiss TAVI registry. EuroIntervention. 2014;10(8):982-9. 15. de Brito FS Jr, Carvalho LA, Sarmento-Leite R, Mangione JA, Lemos P, Siciliano A, et al. Outcomes and predictors of mortality after transcatheter aortic valve implantation: results of the Brazilian registry. Catheter Cardiovasc Interv. 2015;85(5):E153-62. 16. Thyregod HG, Steinbrüchel DA, Ihlemann N, Nissen H, Kjeldsen BJ, Petursson P, et al. Transcatheter versus surgical aortic valve replacement in patients with severe aortic valve stenosis: 1-year results from the all-comers NOTION randomized clinical trial. J Am Coll Cardiol. 2015;65(20):2184-94. 17. Barbash IM, Escarcega RO, Minha S, Ben-Dor I, Torguson R, Goldstein SA, et al. Prevalence and impact of pulmonary hypertension on patients with aortic stenosis who underwent transcatheter aortic valve replacement. Am J Cardiol. 2015;115(10):1435-42. 18. Roselli EE, Abdel Azim A, Houghtaling PL, Jaber WA, Blackstone EH. Pulmonary hypertension is associated with worse early and late outcomes after aortic valve replacement: implications for transcatheter aortic valve replacement. J Thorac and Cardiovasc Surg. 2012;144(5):1067-74. 19. Ferro CJ, Chue CD, de Belder MA, Moat N, Wendler O, Trivedi U, et al; UK TAVI Steering Group; National Institute for Cardiovascular Outcomes Research. Impact of renal function on survival after transcatheter aortic valve implantation (TAVI): an analysis of the UK TAVI registry. Heart. 2015;101(7):546-52. 20. Sinning JM, Ghanem A, Steinhauser H, Adenauer V, Hammerstingl C, Nickenig G, et al. Renal function as predictor of mortality in patients after percutaneous transcatheter aortic valve implantation. JACC Cardiovasc Interv. 2010;3(11):1141-9. 21. Azarfarin R, Ashouri N, Totonchi Z, Bakhshandeh H, Yaghoubi A. Factors influencing prolonged ICU stay after open heart surgery. Res Cardiovasc Med. 2014;3(4):e20159. Arq Bras Cardiol. 2016; 106(6):519-527 526 Souza & González et al. Transcatheter aortic valve implantation-related morbidity and mortality Original Article 22. Escarcega RO, Lipinski MJ, Magalhaes MA, Baker NC, Minha S, Okubagzi PG, et al. Impact of blood transfusions on short- and long-term mortality in patients who underwent transcatheter aortic valve implantation. Am J Cardiol. 2015;115(1):93-9. 28. Bernardi FL, Gomes WF, de Brito FS Jr, Mangione JA, Sarmento-Leite R, Siqueira D, et al. Surgical cutdown versus percutaneous access in transfemoral transcatheter aortic valve implantation: Insights from the Brazilian TAVI registry. Catheter Cardiovasc Interv. 2015;86(3):501-5. 23. Takagi K, Latib A, Al-Lamee R, Mussardo M, Montorfano M, Maisano F, et al. Predictors of moderate-to-severe paravalvular aortic regurgitation immediately after CoreValve implantation and the impact of postdilatation. Catheter Cardiovasc Interv. 2011;78(3):432-43. 29. Sinning JM, Vasa-Nicotera M, Chin D, Hammerstingl C, Ghanem A, Bence J, et al. Evaluation and management of paravalvular aortic regurgitation after transcatheter aortic valve replacement. J Am Coll Cardiol. 2013;62(1):11-20. 24. Seiffert M, Conradi L, Terstesse AC, Koschyk D, Schirmer J, Schnabel RB, et al. Blood transfusion is associated with impaired outcome after transcatheter aortic valve implantation. Catheter Cardiovasc Interv. 2015;85(3):460-7. 30. Dvir D, Webb JG, Piazza N, Blanke P, Barbanti M, Bleiziffer S, et al. Multicenter evaluation of transcatheter aortic valve replacement using either SAPIEN XT or CoreValve: Degree of device oversizing by computed-tomography and clinical outcomes. Catheter Cardiovasc Interv. 2015;86(3):508-15. 25. Tchetche D, Van der Boon RM, Dumonteil N, Chieffo A, Van Mieghem NM, Farah B, et al. Adverse impact of bleeding and transfusion on the outcome post-transcatheter aortic valve implantation: insights from the Pooled-RotterdAm-Milano-Toulouse In Collaboration Plus (PRAGMATIC Plus) initiative. Am Heart J. 2012;164(3):402-9. 26. Sinning JM, Scheer AC, Adenauer V, Ghanem A, Hammerstingl C, Schueler R, et al. Systemic inflammatory response syndrome predicts increased mortality in patients after transcatheter aortic valve implantation. Eur Heart J. 2012;33(12):1459-68. 27. Krumsdorf U, Chorianopoulos E, Pleger ST, Kallenbach K, Karck M, Katus HA, et al. C-reactive protein kinetics and its prognostic value after transfemoral aortic valve implantation. J Invasive Cardiol. 2012;24(6):282-6. 527 Arq Bras Cardiol. 2016; 106(6):519-527 31. Nuis RJ, Rodes-Cabau J, Sinning JM, van Garsse L, Kefer J, Bosmans J, et al. Blood transfusion and the risk of acute kidney injury after transcatheter aortic valve implantation. Circ Cardiovasc Interv. 2012;5(5):680-8. 32. Smith CR, Leon MB, Mack MJ, Miller DC, Moses JW, Svensson LG, et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med. 2011;364(23):2187-98. 33. Goel SS, Ige M, Tuzcu EM, Ellis SG, Stewart WJ, Svensson LG, et al. Severe aortic stenosis and coronary artery disease: implications for management in the transcatheter aortic valve replacement era: a comprehensive review. J Am Coll Cardiol. 2013;62(1):1-10. 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 Review Article 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):528-537 533 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. References 1. Riva-Rocci S. Um nuovo sfigmomanometro. Gazz Med Torino. 1896;47:981-1001. 2. Ayman D, Goldshine AD. Blood pressure determinations by patients with essential hypertension. Am J Med Sci. 1940;200:465-74. 12. 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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