European Journal of Heart Failure

European Journal of Heart Failure 2002 4(4):531-539; doi:10.1016/S1388-9842(02)00034-X

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© 2002 European Society of Cardiology

Prevalence of chronic heart failure in Southwestern Europe: the EPICA study

Fátima Ceia^a,*,1, Cândida Fonseca^a,1, Teresa Mota^b,2, Humberto Morais^c,3, Fernando Matias^c,3, António de Sousa^c,3, António Gouveia Oliveira^d,4 on behalf of the EPICA Investigators

^a Department of Internal Medicine, Medical Sciences School New University of Lisbon, Lisbon, Portugal
^b Department of Cardiology, Medical Sciences School New University of Lisbon, Lisbon, Portugal
^c EPICA Working Group Lisbon, Portugal
^d Datamédica, Lisbon, Portugal

^* Corresponding author. Av. Grão Vasco, 47-1°-Esq, 1500 Lisbon, Portugal. Tel.: +351-21-760-4573; fax: +351-21-301-7958

	Abstract

Top Notes Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. EPICA Investigators References

 
Aim: To estimate the prevalence of chronic heart failure (CHF) in mainland Portugal in 1998.

Methods and population: A community-based epidemiological survey involving subjects attending primary care centres selected by a combined two-stage sampling and stratified procedure. General practitioners (GPs) randomly selected in proportion to the population of the District, evaluated subjects attending primary care centres aged over 25 years, recruited consecutively and stratified by age. CHF cases were identified according to the Guidelines of the European Society of Cardiology for CHF diagnosis.

Results: 5434 eligible subjects were evaluated by 365 GPs; 551 patients with CHF were identified. The overall prevalence and 95% CI of CHF in mainland Portugal is 4.36% (3.69–5.02%), 4.33% in males (3.19–5.46%), and 4.38% in females (3.64–5.13%). Age-specific CHF prevalence was as follows: 1.36% in the 25–49 years-old group (0.39–2.33%), 2.93% in the 50–59 years-old group (5.58–9.37%), 7.63% in the 60–69 years-old group (5.58–9.37%), 12.67% in the 70–79 years-old group (10.73–14.6%), and 16.14% in group over 80 years old (13.81–18.47%). The prevalence of CHF due to systolic dysfunction was 1.3% and the prevalence of CHF with normal systolic function was 1.7%.

Conclusions: The overall prevalence of CHF in Portugal was slightly higher than that of other European studies and increases sharply with age. The prevalence of CHF due to systolic dysfunction is very similar to that reported by other recent European studies. The differences found may correspond to differences in methodology rather than actual differences in the population.

Key Words: Heart failure • Epidemiology • Prevalence • Echocardiography • Left ventricular dysfunction

Received November 19, 2001; Revised February 10, 2002; Accepted March 18, 2002

	1. Introduction

Top Notes Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. EPICA Investigators References

 
The social and economic burden of heart failure in Western societies is enormous [1,2]. Although the Framingham study suggests a slight reduction in the incidence of chronic heart failure (CHF) during the last three decades, it is likely that the number of CHF cases has increased as a result of general improvement in health care, leading to increased life expectancy and progressive ageing of the Western population [2–6]. Moreover, the effective treatment of chronic cardiovascular disorders, such as ischemic heart disease and hypertension, and other relevant diseases, such as diabetes mellitus, may actually postpone rather than prevent CHF [7].

Epidemiological data regarding CHF incidence, prevalence and prognosis in the population in general are scarce [4]. The current information available on CHF epidemiology is derived from hospital-based findings, small community surveys, clinical trials, national statistics or death certificates [8–16]. A better source of information, though limited, are the studies based on selected cohorts of the population monitored over time in order to detect the development of CHF [17–21]. Another common limitation of these studies is the broad definition of CHF, with an undefined level of diagnostic accuracy. The diagnosis of CHF in most studies relies on clinical judgement and chest X-ray data. The symptoms of CHF are generally non-specific; the signs being generally insensitive [7,22].

A number of clinical scoring systems based on combinations of symptoms and signs and/or electrocardiogram and chest X-ray data have been devised to aid diagnosis. These scores have shown variable correlations with objective criteria such as left ventricular (LV) ejection fraction or pulmonary capillary venous pressure. Furthermore, little is known about the validity and concordance between these scores, which reduces their usefulness as a diagnostic tool in clinical practice and epidemiological studies [9,13,17,20–29].

The current recommendations for the diagnosis of CHF require symptoms, signs, objective response to CHF therapy, and objective evidence of cardiac dysfunction at rest [30]. However, only a few studies based on these recommendations have been published recently.

We initiated the EPICA project (EPidemiologia da Insuficiência Cardiaca e Aprendizagem—Epidemiology of Heart Failure and Learning) in 1997. The primary objective of the EPICA study was to estimate the overall and age- and gender-specific prevalence of CHF in the population resident in mainland Portugal in 1998, according to the ESC Guidelines for the diagnosis of CHF [30].

	2. Methods

Top Notes Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. EPICA Investigators References

 
This is a cross-sectional observational study based on subjects attending primary health care centres in the community. The sampling method was a combined stratified and two-stage random sampling. The primary sampling units were primary health care centres in the community. In order to ensure national coverage of the sample, health care centres were randomly selected from every district by sampling proportional to the population. In each primary health care centre, the subjects were enrolled in the study by systematic sampling and stratified by age group: 25–49 years, 50–59 years, 60–69 years, 70–79 years, and over 80 years.

The sample size requirements were defined on the basis of a desired prevalence precision of 1% in each stratum and an overall precision of 0.4%. Assuming a compliance of 80%, the target sample size was set at approximately 13 000 subjects with the following distribution/age group: 25–49 years, 1000 subjects; 50–59 years, 1000 subjects; 60–69 years, 2000 subjects; 70–79 years, 3000 subjects, 80 years and over, 6000 subjects. Five hundred centres were randomised for inclusion in this study, each centre being assigned to enrol 26 subjects. In each centre, the subjects were enrolled in the corresponding age groups consecutively, in proportions of 2, 2, 4, 6 and 12 subjects, respectively.

All the subjects with whom the investigators had contact since the beginning of the survey were eligible for inclusion in the study. This included subjects attending primary health care centres, as well as institutionalised subjects and subjects observed at home. Subjects attending for a specialised consultation (e.g. diabetes, hypertension), or attending the health care centre for the treatment of acute infectious or metabolic conditions, were excluded from the study.

The Boston questionnaire was selected as the screening instrument [9]. A Portuguese version was prepared by the translation-back translation method. Subjects scoring up to two points in the sum of part I (symptoms) and part II (physical examination) of the Boston questionnaire, and who were not taking any medication for CHF (diuretics in monotherapy or in association with ACE-inhibitors, digitalis or hydralazine plus nitrates) were considered as not having criteria for CHF. All subjects scoring three or more points in the sum of parts I and II, or with any of the above treatments irrespective of the score, were subjected to further investigation with a chest X-ray, 12-lead electrocardiogram, M-mode and bi-dimensional echocardiography, peak-flow evaluation and a laboratory evaluation. In accordance with the ESC Guidelines, full blood count, urea, blood glucose and erythrocytes were measured in all these patients; TSH was measured in subjects with atrial fibrillation or suspected thyroid dysfunction [30].

The study was approved by the National Medical Council, the Regional Health Authorities and the Ministry of Health. Informed consent was obtained from all the subjects included in the study.

2.1. Definition of cases
Heart failure was defined as a syndrome recognised by the physician on the basis of symptoms of exercise intolerance, signs of fluid retention and response to therapy, accompanied by objective evidence of cardiac dysfunction at rest, according to the Guidelines of the ESC Working Group on Heart Failure [30].

A total score of three or more points in the sum of parts I and II of the Boston questionnaire was considered sufficient indication of the presence of symptoms and signs of exercise intolerance and/or fluid retention. Objective evidence of cardiac dysfunction at rest was accepted when one or more of the following were observed by echocardiography: (1) LV shortening fraction below 28%; (2) Severe LV segmental dyskinesia and LV enlargement; (3) LV mass index greater than 134 g/m² in males and 110 g/m² in females; (4) LV posterior wall and inter-ventricular septum thickness greater than the 95 percentile of the predicted value; (5) left atrial diameter greater than the 95 percentile of the predicted value; (6) moderate to severe valvular lesions; (7) moderate to severe pericardial effusion; (8) right ventricular dilatation. Predicted values based on gender, age and body surface area were obtained from Henry's equations [31–34].

The following six subtypes of heart failure were defined, based on the echocardiographic findings: (1) moderate to severe valvular disease was classified as heart failure due to valvular disease; (2) moderate to severe pericardial effusion was classified as heart failure due to pericardial disease; (3) right ventricular dilatation was classified as right heart failure; (4) multiple anomalies in which the predominant anomaly was impossible to identify with a single echocardiographic examination were classified as multifactorial heart failure; (5) LV shortening fraction below 28%, or severe LV dyskinesia and LV dilatation were classified as heart failure due to systolic dysfunction; (6) LV shortening fraction above 28% without severe LV dyskinesia, and with left atrial dilatation, or increased LV mass index, or increased thickness of the LV posterior wall or inter-ventricular septum were classified as heart failure with preserved systolic function.

2.2. Data management and quality control
The study protocol, study procedures and data-collection forms were presented to all participating investigators during training sessions before commencing the study. The subjects’ data were collected on structured forms suitable for optical character recognition and included demographic data, the Boston questionnaire, six other questionnaires for the diagnosis of heart failure (Framingham, Gothenburg, Duke, Walma, Gheorghiade and NHANES-I), present medication, NYHA classification of heart failure, etiological factors and associated diseases. Selected chest X-ray findings (cardiomegaly, cardio–thoracic ratio, alveolar pulmonary edema, interstitial pulmonary edema and bilateral pleural effusion) were recorded by the radiologist on a structured form. Electrocardiographic and echocardiographic findings were also recorded on structured forms.

The data were processed by a high-performance scanner (Fujitsu ScanPartner 600C) connected to a Pentium II computer with optical character recognition software (Teleforms, Cardiff Software Inc, San Marcos, CA). Data validation procedures included: (a) manual verification and correction of all rejected fields; (b) manual verification of all numeric fields (age, height, weight, blood pressure and echocardiographic measurements), by comparison with the source data; (c) computer tests for validity, consistency and omissions, with subsequent resolution by manual revision of the forms; (d) computer tests for protocol deviation, with the subsequent return of all cases with possible deviations to the investigators for revision. Corrections were made in 274 out of the 635 forms returned to the investigators.

2.3. Statistical analysis
All observations with missing data and all observations with protocol deviations were excluded from the analysis. Because protocol deviations were more likely to occur in subjects eligible for laboratory investigation, and in order to avoid the possibility of introducing a bias by excluding only patients with protocol deviations, all the investigator's subjects in the age group in which a protocol deviation had occurred were excluded from the analysis.

Prevalence estimates for the Portuguese population were obtained by projection of the sample estimates over the age and gender distribution of the general population determined by the 1991 population census (Instituto Nacional de Estatística—National Institute of Statistics, Lisbon, Portugal). In the calculation of population estimates, allowance was made for the clustering of cases within primary sampling units.

	3. Results

Top Notes Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. EPICA Investigators References

 
Between April and October 1998, 365 of the initial 500 investigators enrolled 6300 subjects. A total of 866 subjects (13.7%) were excluded from the analysis: 108 observations (1.7%) from 7 investigators were rejected; 201 (3.2%) had protocol deviations; 341 (5.4%) were excluded because the investigator's subjects were in the same age group in which a protocol deviation had occurred; 34 (0.5%) had incomplete data; 41 (0.7%) had no echocardiographic data due to technical failure; and 140 subjects (2.2%) were excluded because they had missed the second visit (105), died (13), had intercurrent disease (11), had moved residence (4), or were not able to complete the evaluation before the final date of the study (7).

The recruitment of subjects by age group was as follows, with the percentage of the targeted number in parentheses: 25–49 years, 675 (93%); 50–59 years, 661 (91%); 60–69 years, 1273 (83%); 70–79 years, 1698 (79%); 80 years and over, 1993 (46%).

The population eligible for analysis consisted of 5434 individuals, 2025 males and 3409 females, mean age 68.1±15.1 years. Distribution according to the scores in the Boston questionnaire (sum of parts I and II) was as follows: 4376 subjects (80.6%) with 0–2 points without medication for heart failure; 351 (6.5%) with 0–2 points and with medication for heart failure; and 707 (13.0%) with 3 or more points. Echocardiographic examinations were performed in 1022 of the 1058 subjects with indication for the examination according to the protocol. The 36 subjects who were not subjected to echocardiographic examination had had a previous definitive diagnosis of heart failure with recent objective evidence of cardiac dysfunction at rest. It was not possible to make complete measurements in 174 subjects (17.0%) due to poor echocardiographic window.

According to the criteria defined in the study, 551 subjects (208 males and 343 females) were classified as having heart failure. The estimated prevalence of all types of heart failure in the population over 25 years of age is 4.36% (3.69–5.02%, 95% CI), 4.33% in males (3.19–5.46%, 95% CI), and 4.38% in females (3.64–5.13%, 95% CI). The estimated prevalence of all types of heart failure by age group is as follows (Fig. 1): 25–49 years, 1.36% (0.39–2.33%, 95% CI); 50–59 years, 2.93% (5.58–9.37%, 95% CI); 60–69 years, 7.63% (5.58–9.37%, 95% CI); 70–79 years, 12.67% (10.73–14.60%, 95% CI); and 80 years and over, 16.14% (13.81–18.47%, 95% CI).

View larger version (13K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Age-specific estimated prevalence of all types of heart failure in the population over 25 years of age. Error bars: 95% CI.

 
The estimated prevalence of the different types of heart failure in the population over 25 years of age are presented in Table 1 and Table 2. According to these results, approximately 40% of the cases of heart failure in the community have preserved systolic function, 30% are due to systolic dysfunction, 16% are due to valvular disease, 11% are due to right heart failure, 2% are multifactorial and 1% are due to pericardial disease. The age- and gender-specific prevalence rates of heart failure with preserved systolic function and due to systolic dysfunction are presented in Fig. 2.

View this table: [in this window] [in a new window]   Table 1 Estimated prevalence of the types of heart failure in the population over 25 years of age

 

View this table: [in this window] [in a new window]   Table 2 Estimated prevalence of the types of heart failure in the population over 25 years of age (absolute numbers)

 

View larger version (10K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Age- and gender-specific estimated prevalence rates of heart failure with preserved systolic function (top) and systolic dysfunction (bottom) in the population over 25 years of age. Solid circles: males; open circles: females; error bars: 95% CI.

 
The population estimate of proportion of subjects with previously diagnosed heart failure is 46.3% (39.2–53.4%, 95% CI). The population estimate of the distribution of heart failure by NYHA functional classes is 35.4% in class I, 29.9% in class II, 23.5% in class III, 4.9% in class IV, and 6.2% were not classified.

The prevalence of risk factors and possible causes of heart failure was calculated for the subjects with CHF: a previous diagnosis of high blood pressure had been made in 66% of the subjects; coronary artery disease was suspected in 29%; coronary artery disease was confirmed by coronarteriography, isotopic scintigraphy or by a sequel of a myocardial infarction on the ECG in 8%; valvular disease was diagnosed in 26%; COPD or pulmonary thromboembolism was diagnosed in 20%; 14% had an alcohol intake over 80 g/day; and diabetes mellitus was diagnosed in 11%. Atrial fibrillation was present in 13% of all patients with CHF.

	4. Discussion

Top Notes Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. EPICA Investigators References

 
Heart failure is not a disease per se. It is a constellation of signs and symptoms produced by complex circulatory and neurohormonal responses to cardiac dysfunction. The syndrome may occur as the end result of a number of underlying diseases, such as coronary artery disease, hypertension, valvular defects, viral infection and toxic cardiac aggression, which vary from country to country and over time [35,36]. Therefore, the results of different epidemiological studies should be compared with care.

EPICA is an epidemiological study that uses the current standards for sampling methodologies, and CHF definition [30]. The sampling basis for the study was the population registered at the primary health care centres in mainland Portugal.

One obvious limitation of our study lies in the fact that the sampled population consisted of subjects attending primary care centres in the community instead of the general population. All the individuals in Portugal have their GP. As the population seen by GPs tends to be sicker than the general population, we can admit that the patients seen in the surgeries have more severe heart disease. On the other hand, we excluded the specialised consultations attended by more cardiovascular and sicker patients. Although we had no other statistical method to adjust for this potential bias, the decision to sample this population was based on practicability, since the evaluation of heart failure requiring echocardiographic, electrocardiographic and X-ray examinations in the general population could imply excessive costs and an unacceptably low proportion of compliance. With this design, only 105 subjects (1.7%) refused to participate, safeguarding the results from one form of selection bias that would have occurred in a population-based study. In addition, according to the ESC Guidelines the diagnostic examinations were indicated in all the subjects investigated. Therefore, the study did not imply discomfort or costs that were not medically justified.

The study fulfilled the objectives proposed with fewer study centres than originally planned, but with an acceptable investigator participation rate. The good quality of the data is reflected in the small number of cases excluded and of missing data.

In comparison to most population-based studies already published, this study has the advantages of a nation-wide coverage, a larger sample size, the coverage of institutionalised subjects, direct evaluation by the physician, and the use of objective methods for the evaluation of cardiac function and structure, covering all types of CHF.

There is an ongoing debate on the definition of heart failure and a lack of gold-standards to assess the presence of the syndrome in population-based studies. According to the ESC Guidelines on the diagnosis of CHF, objective evidence of cardiac dysfunction must be present, in addition to symptoms or medication for CHF, in order to be establish the presence of heart failure [30]. Cardiac dysfunction at rest was characterised by echocardiography. The EPICA study is the first study on the prevalence of heart failure that strictly follows those Guidelines. The cases of CHF were defined according to internationally accepted criteria and subject screening was based on a validated, standardised instrument—the Boston questionnaire—with minimum modifications for its adaptation to the conditions of the study protocol [9].

The inclusion of echocardiography in the diagnosis of CHF is a major advance in epidemiological studies [16,30,32,37]. The above mentioned ESC Guidelines do not clearly define the echocardiographic criteria for the various types of cardiac dysfunction. The only dysfunction clearly mentioned in the Guidelines is systolic dysfunction, with no reference to any cut-off for ventricular function parameters. It was necessary to define objective echocardiographic criteria for cardiac dysfunction for the EPICA study. We defined LV systolic dysfunction as a fractional shortening below 28% (which is equivalent to an ejection fraction under 45%) or severe segmental disynergy with LV dilation, compromising systolic function, regardless of the fractional shortening measured by echocardiography [32,38]. For practical reasons the echocardiograms were carried out in the community, therefore, it was impossible to evaluate the ejection fraction by 2D echocardiography because, it is time-consuming and requires an experienced observer [32]. The echocardiographic signs of cardiac dysfunction that are usually correlated to diastolic dysfunction (LA dilation and increased LV mass index due to LV concentric hypertrophy) were defined as CHF with preserved LV function [39].

Until recently, studies evaluating the prevalence of heart failure in large Caucasian populations in Europe and the USA used scores based on clinical and radiological criteria [3,8–15,17–20]. Objective evidence of cardiac dysfunction at rest was not included in the diagnostic criteria and CHF with normal systolic function was also often included. Because of different diagnostic criteria and the age groups studied, the prevalence of CHF varied substantially from study to study. The NHANES-I study indicated an overall prevalence of 2% for a population aged between 25 and 74 years in the USA [13]. In the Framingham study, the overall prevalence of CHF was 0.7% for those aged between 50 and 89 years, varying between 0.1 and 7.9% with age [17]. In the Rochester study, in 1986, the prevalence of CHF in those over 35 years was 1.9%, increasing from 1 to 7.6% with age [40]. In Europe, the Gothenburg studies showed that the prevalence of CHF also increases with age, reaching 13.6% at 75 years of age [18,19]. In the Netherlands, the study of the population over 45 years of age attending general practice consultations showed that the prevalence of CHF varied from 0.5% in the younger subjects to 16.1% in subjects over 75 years old [41]. In subjects of both sexes over 25 years old attending general practice consultations in England and Wales, the overall prevalence was 0.89%, varying between 0.01% until the age of 44 years and 14% in those over the age of 85 years [42].

Apart from EPICA, few other studies on the prevalence of CHF included echocardiography in their methodology to characterise cardiac dysfunction [43,44].

McDonagh et al. used echocardiography to study a population aged between 25 and 74 years, included in the Glasgow MONICA coronary risk factor survey [43].

Although, the overall prevalence of LV systolic dysfunction (defined as LVEF30%) was 2.9%, only 1.5% of the subjects were symptomatic.

If we compare the prevalence of CHF due to LV systolic dysfunction in the EPICA study (0.85–1.75%) with the prevalence of symptomatic LV systolic dysfunction in the study by McDonagh et al. (1.5%) we find that the values are comparable.

Mosterd et al. evaluated the overall prevalence of CHF in 1677 subjects above the age of 55 years in Rotterdam [44]. The definition of CHF was exclusively clinical—presence of dyspnea, oedema and rales, heart failure therapy and previous evidence of heart disease. In this population, the overall prevalence of CHF was 3.9%. A sub-population underwent echocardiography for evaluation of LV shortening fraction. The criteria for ventricular systolic dysfunction was a LV shortening fraction below 25%. With this cut-off point, less stringent than that used by McDonagh et al., the prevalence of systolic dysfunction was 3.7% of which 40% were symptomatic, leading to a calculated prevalence of CHF due to systolic dysfunction of 1.4%.

Due to methodological differences between studies in the definition of cases, sample selection, population coverage and nationality, the results of the three studies can not be directly compared. However, the agreement on the prevalence of symptomatic LV systolic dysfunction is remarkable.

In the EPICA study, the prevalence of CHF increases with age in both sexes and tends to be slightly higher in men up to the age of 70, then it stabilises. In women, it continues to increase with age and becomes greater than the prevalence for men in the 70–79 years-old age group. This aspect, which was also mentioned by Mosterd et al., is probably related to the shorter life expectancy of men and the lack of cardiovascular protection in women after menopause [44].

No reliable estimates of the prevalence of CHF due to isolated LV diastolic dysfunction are currently available. This is largely attributable to the heterogeneity of the diagnostic criteria of CHF and the lack of consensus concerning the non-invasive assessment of this condition [45]. Numerous reports suggest that about one third to half of the patients with CHF do not have any abnormality in ventricular systolic function, especially in the elderly population [46]. Most studies were hospital-based, though a few community-based studies were carried out in the primary care setting [16,47–49]. CHF with preserved LV systolic function is expected to be more common in elderly and hypertensive patients, as suggested in the EPICA study. Nevertheless, the data should be considered with caution, as the EPICA study was not specifically designed to assess the prevalence of the different subtypes of CHF and specific methodology to characterise LV diastolic dysfunction may not be robust.

In conclusion, the overall prevalence of CHF in the community in Portugal is high and affects mainly older patients. CHF with LV systolic dysfunction is more frequent in males below the age of 80 years. CHF with preserved LV systolic function affects mainly older females.

The scarcity and discrepancies in data on CHF with preserved ventricular systolic function, particularly in the community, make it urgent to carry out population-based studies to characterise its epidemiological aspects and behaviour.

Heart failure is an important public health problem deserving adequate planning for investigation, education, prevention and treatment. Prevention of its risk factors and early recognition and treatment may prolong life with better quality and reduce costs. Therefore, health authorities, schools of medicine, health care providers and the public in general must be aware of this condition.

	Appendix A. EPICA Investigators

Top Notes Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. EPICA Investigators References

 
Abel Rito, Abílio Malheiro, Abílio Oliveira, Acácio Fernandes, Adelaide Fraga, Adelino Correia, Afonso Videira, Albano Sá Melo, Alberto Beirão, Albino Parreira, Aldina Oliveira, Alexandre Ornelas, Alfredo Couto, Alípio Branco, Álvaro Mendes, Amauri Martins, Américo Moreira, Américo Felício, Américo Orfão, Ana Paiva, Ana Bonaparte, Ana Afonso, Ana Durão Ferreira, Ana Maia Santos, Ana Macedo, Ana Figueiredo, Ana Ribeiro, Ana Sousa Paiva, Ana Evangelista, Ana Santana, Ana Cunha, Ana Nascimento, Ana Paula Ferreira, Ana Lemos, Ana Morais, Anabela Jorge, Angelina Mendes, Annete Oliveira, António Oliveira Ramos, António Freitas, António Barbosa Magalhães, António Maia, António Castro Correia, António Vieira, António Ferreira Costa, António Fernandes Correia, António Barroso Silva, António Passão Lopes, António Faria, António Jesus Silva, António Canotilho, António Silva Marques, António Moreira, António Almeida Ferreira, António Gomes Silva, António Gravato Sousa, António Parente Salvado, António Sousa Fernandes, António Silva Caio, António Miguelote Castro, António Sequeira, António Almeida Silva, Arlindo Santos, Armando Monteiro, Arménio Laranjeiro, Artur Alves Santos, Artur Coelho, Artur Barbosa, Augusto Neves, Augusto Rente, Augusto Magalhães, Augusto Molinar, Augusto Valente, Beatriz Graça, Camilo Monteiro Silva, Cândida Martins, Carlos Chieira, Carlos Faria Ferreira, Carlos Lacerda, Carlos Alberto Marques, Carlos Pinheiro, Carlos Baguinho Almeida, Carlos Laginha, Carlos Oliveira Nunes, Carlos Manuel Santos, Carlos Silva Guerra, Carlos Santos Neves, Celeste Costa, Celeste Vilar, Celestino Roboredo, Célia Candeias, Célia Resende, César Branquinho, César Rodrigues, Cristina Perico, Cristino Agostinho, David Aires, Delfina Souto, Dilermando Sobral, Dina Gaspar, Dina Sousa, Edite Duarte, Eduardo Miranda, Eduardo Pedro, Elisete Gonçalves, Enrique Zwolinsky, Ernestino Caniço, Eugénia Silva, Eugénio Fecha, Eunice Monteiro, Fernanda Sardinha, Fernanda Gonçalves, Fernanda Domingos, Fernanda Ferreira, Fernando Cardoso, Fernando Ferreira, Fernando Silva Lopes, Fernando Sousa, Fernando Felgueiras, Fernando Cruz Gomes, Fernando Santos Almeida, Fernando Manuel Pinto, Fernando Tavares Morais, Fernando Azevedo, Fernando Andrade, Francisco Mendes, Francisco Seixas, Francisco Costa, Francisco Vieira Lino, Francisco Henriques, Francisco Brito, Gilberto Coutinho, Graça Azevedo Lopes, Helder Gomes Silva, Helena Arvelos, Helena Antunes, Helena Nunes Silva, Helena Martins Duarte, Henrique Machado, Henrique Mora, Hernani Pinho, Hugo Barbedo, Hugo Corte Real, Idálio Dourado , Irene Godinho, Isabel Costa, Isabel Eusébio, Isabel Ferreira Silva, Isabel Barros Silva, Isabel Oliveira Martins, João Carvalho, João Lobato Nunes, João Cocharra Almeida, João Machado Tavares, João Borges Lima, João Valdoleiros, João Fatela David, João Roque Reis, Joaquim Melo Rocha, Joaquim Maia Rodrigues, Joaquim Sousa Santos, Joaquina Coelhoso, Joaquina Rosário, Jorge Leandro, Jorge Oliveira Fernandes, Jorge Carmo Silva, Jorge Silva Pereira, José A. Frey Ramos, José A. Costa, José A. Canhoto, José A. Cabaço, José A. Macedo, José A. Barros, José Borges Ferreira, José Varandas, José Cândido Costa, José Carlos Silva, José Carlos Singeis, José F. Martins, José Geraldes Simões, José Lima Ribeiro, José Joaquim Vieira, José J. Brás, José M. Dias, José M. Henriques, José M. Sousa Silva, José M. Póvoas, José M. Mendes Dias, José M. Oliveira Santos, José M. Guerra, José M. Mesquita, José Nuno Coutinho, José Silva Ferreira, José Moreira Ramos, José Gomes Eusébio, Judite Oliveira, Júlia Marques, Júlia Sarmento Santos, Júlio Correia Oliveira, Laura Gonçalves, Laura Sande Castro, Leokadia Silva, Licínio Fialho, Lopo Antunes, Lucilino Ferreira, Ludovina Brito, Luís Martinho, Luís Oliveira Pinto, Luís Santiago, Luís Oliveira Sequeira, M. Adelaide Valente, M. Águeda Vidal Dias, M. Alexandra Duarte, M. Alice Vala, M. Amélia Vitorino, M. ângela Pererira, M. Antónia Ralha, M. Antónia Santos Soares, M. Antonieta Lúcio Sousa, M. Arlete Gomes, M. Arlete Damas, M. Arlete Rodrigues, M. Armanda Fonseca, M. Ascenção Ferreira, M. Basseliça Moreira, M. Beatriz Alves Lopes, M. Beatriz Pererira, M. Benedita Cavaleiro, M. Benedita Seixas Santos, M. Carmo Rosário, M. Carmo Morais Branco, M. Claudina Lopes, M. Conceição Alves Barros, M. Conceição Monteiro, M. Conceição Pinheiro, M. Conceição Abrantes, M. Dias Ruas, M. Conceição Monteiro Marques, M. Cristina Barradas, M. Cristina Galvão, M. Dores Cruz, M. Elisabete Ferreira, M. Elvira Costa Alves, M. Elvira Costa Silva, M. Emília Rodrigues, M. Emília Fernandes, M. Eugénia Ferreira, M. Fátima Veiga, M. Fátima Franco, M. Felicidade Ferreira, M. Fernanda Tomás Almeida, M. Fernanda Coimbra, M. Fernanda Rosa Pais, M. Fernanda Luís, M. Fernanda Miranda, M. Filomena Afonso, M. Filomena Maia Vicente, M. Filomena Vela, M. Filomena Andrade, M. Flávia Pinto Silva, M. Gabriela Machado, M. Glória Alves, M. Graça Correia Silva, M. Helena Infante, M. Helena Margarido, M. Helena Morgado, M. Idalina Rodrigues, M. Isabel Mota, M. Isabel Pinote, M. Isabel Braizinha, M. Isabel Zenha, M. Isabel Morais, M. Isilda Miguel, M. João Queiroz, M. Joaquina Espírito Santo, M. José Cercas, M. José Simões, M. José Santiago, M. José Martinho, M. José Colaço, M. José Carvalho, M. Luciana Carvalho, M. Luísa Amaral, M. Luísa Nunes, M. Luísa Mota Almeida, M. Luísa Caria, M. Luísa Amorim, M. Luísa Romeiro, M. Luísa Cunha, M. Lurdes Sobreira, M. Lurdes Costa Ferreira, M. Lurdes Silva Ribeiro, M. Luz Amorim, M. Manuel Silva Cunha, M. Manuela Costa Santos, M. Manuela Cabrita, M. Manuela Pinto Ribeiro, M. Manuela Ventura Leite, M. Margarida Andrade, M. Margarida Viana, M. Margarida Lopes Santos, M. Margarida Castanheira, M. Natália Reis, M. Nazaré Santos, M. Paula Boavista, M. Paz Correia Alves, M. Rosário Monteiro, M. Rosário Branco, M. Salomé Caetano, M. Suzete Polónia, M. Teresa Almeida Castro, M. Teresa Loureiro, M. Teresa Amaral Vale, M. Teresa Faria Pelixo, M. Teresa Lourenço, M. Teresa Sarmento Alves, M. Teresa Libório, M. Violeta Pimpão, Manuel Almeida Gomes, Manuel Saraiva, Manuel Miller, Manuel Afonso Pereira, Manuel Rocha Monteiro, Manuel Gaspar Silva, Manuel Felgueiras Ramos, Manuel Veloso Júnior, Manuel Espírito Santo, Manuel Santos Carvalho, Manuel Viana Costa, Manuel Correia Silva, Manuel Santos Soares, Manuela Melo, Marcelino Silva, Márcio Pinto, Margarida Fonseca, Margarida Albuquerque, Margarida Mota, Mariana Godinho, Marília Silva, Marina Claro, Mário Matos, Mário Pinto Oliveira, Matilde Esteves, Mauro Melo, Miguel Montenegro, Miguel Craveiro Costa, Nelson Sousa, Noémia Branco, Nuno Leite, Olívia Ribeiro Santos, Paulino Rodrigues, Paulo Coelho Santos, Paulo Andrade, Pedro Brandão, Pedro Sigalho, Pedro Soares Silva, Raul Cunha, Raul Torres, Rogério Sousa, Rosa M. Rodrigues Cruz, Rosa M. Neves Cardoso, Rosa M. Silva Ferreira, Rosa Feliciano, Rui Cernadas, Rui Silva Pinto, Rui Albuquerque Soares, Rui Vaz, Rui Medon, Rui Sousa Coelho, Sara Macias, Sebastião Emídio, Teotónio Castro, Tomás Aquino Lopes, Urânia Fernandes, Vasco Almeida, Victor Rodrigues Lopes, Virgílio Abreu, Vítor M. Beato, Vítor M. Silva Santos.

EPICA Steering Committee A. Bensabat Rendas, Ana Jorge, Carlos Ribeiro, Constantino Sakellarides, Guilherme Jordão, Hugo Madeira, J. A. Esperança Pina, João Martins e Silva, J. Pereira dos Reis, J. Sousa, Luís Providência, Manuel Carrageta, Mário Cerqueira Gomes, M. Luisa Costa, M. Pinho da Silva, Pedro Vanzeller, Rafael Ferreira, Salvador Massano Cardoso.

	Acknowledgements

 
The EPICA Project is supported by Servier Research Group, and has the scientific sponsorship of the Portuguese Society of Cardiology and of the Working Group on Heart Failure of the European Society of Cardiology. We are especially grateful to Prof. John G. Cleland for his collaboration.

	Notes

Top Notes Abstract 1. Introduction 2. Methods 3. Results 4. Discussion Appendix A. EPICA Investigators References

 
¹ Address: Serviço de Medicina, Hospital de S. Francisco Xavier, 1400 Lisbon, Portugal.

² Address: Serviço de Cardiologia, Hospital de Pulido Valente, 1750 Lisbon, Portugal.

³ Address: Grupo de Investigação EPICA, Av. António Augusto de Aguiar 128, 1050 Lisbon, Portugal.

⁴ Address: R. Garcia de Orta, 70-2°, 1200-680 Lisbon, Portugal.

⁵ See Appendix A.

	References

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