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European Journal of Heart Failure 2007 9(6-7):587-593; doi:10.1016/j.ejheart.2007.02.008
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© 2007 European Society of Cardiology

Impact of heart failure and left ventricular function on long-term survival — Report of a community-based cohort study in Taiwan

Chien-Hua Huanga,b, Kuo-Liong Chienb,c, Wen-Jone Chena,b, Fung-Chang Sungd, Hsiu-Ching Hsub, Ta-Chen Sub and Yuan-Teh Leeb,e,*

a Department of Emergency Medicine, National Taiwan University Medical College and National Taiwan University Hospital, Taipei, Taiwan
b Department of Internal Medicine (Cardiology), National Taiwan University Medical College and National Taiwan University Hospital, Taipei, Taiwan
c Institute of Preventive Medicine, School of Public Health, National Taiwan University, Taipei, Taiwan
d Institute of Environmental Medicine, China Medical University, Taichung, Taiwan
e Department of Internal Medicine (Cardiology), Min-Sheng General Hospital, Taoyuan, Taiwan

* Corresponding author. Department of Internal Medicine (Cardiology), National Taiwan University Hospital, #7 Chung-Shan S. RD, Taipei, Taiwan, 100. Tel: +886 2 2395 9911; fax: +886 2 2351 9736. E-mail address: ytlee{at}ha.mc.ntu.edu.tw


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Acknowledgments
 References
 
Background: There is little community-based information on heart failure (HF) prognosis in ethnic Chinese populations, in whom there is a low prevalence of coronary heart disease.

Aims: To study the impact of HF and left ventricular function on long-term all-cause mortality.

Methods and results: This community-based prospective cohort study included 2660 subjects (1215 men, 1445 women, mean age 54.4±11.9 years) over a 10 year follow-up period. The prevalence of HF was 5.5%. Hypertension was the most common factor related to HF. The five and ten year all-cause mortality was higher in the HF/preserved LVEF group (14.1% and 24.4%) and the HF/impaired LVEF group (29.2% and 48.2%) than in the HF-free group (6.0% and 14.6%, p<0.0001 for both). In multivariable Cox analyses, controlling for sex, LV mass, atrial fibrillation, hypertension, coronary heart disease, HF/preserved LVEF and HF/impaired LVEF were important predictors of all-cause mortality (p=0.007).

Conclusions: Hypertension is a major heart failure related disease. HF and LV systolic dysfunction are associated with a significant increase in all-cause mortality in an ethnic Chinese population.

Key Words: Heart failure • Systolic function • All-cause mortality • Community-based • Chinese

Received April 26, 2006; Revised December 26, 2006; Accepted February 26, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Acknowledgments
 References
 
Heart failure is a progressive cardiac disease with a high mortality risk. Despite modern treatments, prognosis is still poor and primary prevention for the development of heart failure is important [1-3]. Approximately 43,000 individuals die of HF in the United States each year and 4.6 million Americans have been diagnosed with HF [1].

The risk factors and underlying cardiovascular diseases causing heart failure have distinct patterns and prognosis in different racial groups [4,5]. Ischaemic heart disease is most frequently associated with HF in western countries. However, in the Asian-Chinese population, the prevalence of coronary heart disease is lower than in western countries and it has been proposed that hypertension is the major cause of HF in this population [5]. The prevalence of diastolic heart failure is high in the hospital-based Chinese population [6] but the occurrence of ventricular fibrillation is less than in western countries [7]. Whether prognosis is affected by this different spectrum of underlying cardiovascular diseases remains unclear.

Heart failure has become a frequent diagnosis in the Chinese population [5,6]. However, although Chinese comprises a substantial proportion of the world population; to date only hospital-based, small-scale HF-related studies have been reported in ethnic Chinese countries [4,6].

We therefore established a community-based prospective cohort study in the Chin-Shan community in Taiwan, a Chinese population-based island country at the rim of the Asian Pacific Ocean, to investigate cardiovascular events in the Asian-Chinese population [8]. The aim of the study was to evaluate the association between risk factors, systolic function status and all-cause mortality over a 10-year follow-up period, in a population with a low prevalence of coronary heart disease.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 Acknowledgments
 References
 
2.1. Study design and population
The Chin-Shan community cardiovascular cohort (CCCC) study was established to conduct a longitudinal investigation of cardiovascular diseases in Taiwan [8]. All residents aged more than 35 years based on the 1991 residential registration files in the Chin-Shan community were eligible to be included. Subjects were excluded if we were unable to contact them after five attempts or if they declined to participate. For 1991-1992 a population of 3602 eligible subjects was identified. However, 942 of these subjects (26.2%) did not have echocardiographic measurements for 1992-1993 and were therefore excluded from the study. The reason for this missing data was that the subjects failed to attend for the echocardiographic evaluation. The remaining 2660 subjects were included in the study. The current report uses baseline data collected in 1991-1992, and the echocardiographic results collected in 1992-1993. The leading causes of death, which were mainly cardiovascular disease and cancer, were similar to the national mortality patterns in Taiwan between 1990 and 1994 [8]. The investigation conforms with the principles outlined in the Declaration of Helsinki and the study protocol was approved by our institutional review board. All participants signed the informed consent for study.

2.2. Laboratory tests
Details of the laboratory measurements have been described elsewhere [8]. In brief, a blood sample was drawn after a 12-hour overnight fast, immediately refrigerated, and then transported to the National Taiwan University Hospital (NTUH) within 6 h. Samples were stored at –70 °C prior to batch assay. Standard enzymatic methods were used to determine serum cholesterol and triglycerides (Merck 14,354 and 14,366, respectively).

2.3. Data collection and interpretation
In 1992, as part of the study project, a clinic was set up by a team composed of twenty senior medical students, two assistant nurses, ten cardiologists and local practitioners. This new clinic specializing in cardiology was located at the Chin-Shan Community Health Center. The medical students received 3 months training, which included communication skills and home visits, basic medical knowledge, practice evaluations, differentiation and documentation of history taking, physical examinations and instructions for completion of the study questionnaire.

Information collected for each patient included socio-demographic characteristics, lifestyle, dietary characteristics, personal and family histories of diseases and hospitalisations. HF symptoms including paroxysmal nocturnal dyspnoea, orthopnoea, dyspnoea on exertion and nocturnal cough were evaluated. Heart failure related signs, including neck vein distension, pulmonary basal rales, S3 gallop, leg oedema and hepatomegaly were assessed. Hospital medical records were checked for each participant if available. Physical inactivity was defined as no regular aerobic exercise session at least three times a week or sessions lasting less than 20 min each time. All evaluations of symptoms and signs of HF were confirmed by a cardiologist from NTUH.

2.4. Echocardiographic measurements
All subjects underwent echocardiographic examination by a cardiologist using standardized procedures. A two-dimensional parasternal long-axis view of the left ventricle (LV) was obtained according to the standard procedure recommended by the American Society of Echocardiography. The LV dimensions at end-diastole and at end-systole were measured and used to calculate left ventricular ejection fraction (LVEF) quantitatively. The LVEF was assessed by the area-length method in the apical four chamber view if regional wall motion abnormality was noted. LV mass was calculated from the Penn convention, according to the equation of Devereux and Reichek [9]. Reliability of echocardiographic measures was calculated by a simple replication one-way analysis of variance test and the values were between 0.70 to 0.85 in the various echocardiographic measurements [9]. End-diastolic relative wall thickness (RWT) was calculated as twice the posterior wall thickness divided by the LV end-diastolic dimension as previously described [10]. Systolic dysfunction was defined as an LV ejection fraction of less than 0.55 on echocardiographic measurement [11,12].

2.5. Diagnostic criteria
The diagnosis of HF was made by a cardiologist from NTUH, based on the Framingham criteria with corroborative information from clinical data, related examinations and hospital records, if available. The correlation of heart failure symptoms and underlying cardiac disease was also evaluated to make sure that the diagnosis of heart failure was correct. Hypertension was defined according to the criteria established by the Fifth Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure [13]. We adopted the following criteria, a systolic blood pressure higher than 140 mmHg or a diastolic blood pressure higher than 90 mmHg, and/or receiving anti-hypertensive medication. Cerebrovascular disease was confirmed by a neurologist from NTUH using the criteria previously described [14,15]. Coronary heart disease was diagnosed as a history of myocardial infarction or electrocardiographic evidence of definite Q wave by the Minnesota Code [16]. Diabetes mellitus was defined as fasting blood sugar levels higher than 140 mg/dl or use of oral hypoglycaemic agents or insulin injections. Left ventricular hypertrophy (LVH) was diagnosed from ECG criteria, including QRS duration, Sokolow-Lyon voltage and sex-specific Cornell voltage [17,18].

2.6. Outcome
All mortality events were ascertained by reviewing medical records and death certificates from the local statistics office, and through bi-annual follow-up household visits. All preliminary diagnoses, medical records, death certificates and interviews with patient relatives, for the purpose of gathering information of related events, were presented to and verified by the study committee [19].

2.7. Statistical analysis
The ANOVA test was used for comparison of the difference in continuous variables between the different HF/LVEF groups. Kaplan-Meier survival curves were used for the survival studies of the HF patients and a log-rank test was performed for evaluating the difference. Multivariable Cox analyses with stepwise model were constructed to estimate the hazard ratios and 95% confidence intervals of HF/LVEF and other covariates to predict the occurrence of mortality event. Data analysis was performed using SAS software (Version 6.11).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 Acknowledgments
 References
 
The study population of 2660 subjects included 1215 men and 1445 women. The mean age was 55.5±11.9 years for the men, 53.5±11.8 years for the women and 54.4±11.9 years overall. In the study population overall, 4.61% of subjects were aged over 75 years.

3.1. Prevalence of heart failure according to sex and age
The prevalence of HF was 5.5% (95% CI: 4.7%, 6.7%). The cumulative percentage of subjects with LV systolic dysfunction according to different LVEF cut-off values is shown in Table 1. Using an LVEF of 55% as the cut-off value to define LV systolic dysfunction, the percentage of patients with LVEF <55% was 10.5% [95% CI: 9.4-11.8%] for the overall population. The prevalence rate was 4.6% for HF/preserved LVEF and 0.9% for HF/impaired LVEF. Women had a lower prevalence of LVEF <55% compared to men in each age group (Table 2).


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  		Table 1 Cumulative percentage of subjects with impaired systolic function according to different LVEF cut-off values

 


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  		Table 2 Prevalence of systolic dysfunction (LVEF<55%) according to age and sex

 
3.2. Left ventricular systolic dysfunction vs. risk factors
Individuals with impaired LV systolic function were more likely to have atrial fibrillation (2.5% vs. 0.84%, p=0.018) and a poorer NYHA functional class (NYHA functional class III or IV, 8.57% vs. 5.17% p=0.017, Table 3).


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  		Table 3 Prevalence of heart failure risk factors according to left ventricular ejection fraction

 
3.3. Clinical characteristics and factors related to HF/LVEF status
The HF/impaired LVEF group was older than the other two groups (p<0.001, Table 4). The prevalence of coronary heart disease, hypertension and physical inactivity was greater in the HF/impaired LVEF group (p=0.044, 0.007 and <0.001 respectively). The prevalence of atrial fibrillation in the ECG recording was also greater in the HF/impaired LVEF group (p=0.002).


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  		Table 4 Univariate analyses of clinical characteristics and left ventricular geometry in participants without heart failure and in those with heart failure according to left ventricular systolic function

 
3.4. Echocardiographic measures stratified by HF/LVEF status
The left ventricular end-diastole and end-systole diameters were significantly larger in the HF/impaired LVEF group as compared to the other two groups (p=0.007 and <0.001, respectively). The thickness of the left ventricular septum and the relative wall thickness, which is an indicator of left ventricular hypertrophy, was greatest in the HF/preserved LVEF group (p=0.001 and 0.010 respectively). The body surface area corrected left ventricular mass was greatest in the HF/impaired LVEF group (p<0.001, Table 4). More concentric hypertrophy and eccentric hypertrophy, evaluated by the LV relative wall thickness and LV mass corrected by surface area were noted in the HF/preserved LVEF group (30.9% and 35.0%) and HF/impaired LVEF group (37.5% and 29.1%) compared to no HF group (27.5% and 23.1%, p<0.001 by chi-square test).

3.5. Mortality analyses according to HF/LVEF status
A total of 370 subjects died during this 10 year follow-up study. The 5 year survival was 94.05% for the no HF group, 85.91% for the HF/preserved LVEF group and 70.83% for the HF/impaired LVEF group (p=0.001 by chi-square test). The 10 year survival was 85.41% for the no HF group, 75.64% for the HF/preserved LVEF group and 51.94% for the HF/impaired LVEF group (p<0.001 by chi-square test). The overall survival difference was analyzed by the Kaplan-Meier survival curve, significant differences were found between the three groups as shown in Fig. 1 (chi-square=39.27, df=2, p<0.001 by log-rank test). In addition to HF and LV systolic function, there were some other contributing factors related HF status and outcome in these patients. Male sex (p<0.001), coronary heart disease (p<0.001), hypertension (p<0.001), diabetes mellitus (p<0.001), LVH in ECG (p<0.001) and atrial fibrillation (p<0.001) were all related to mortality in the univariate analysis. The body surface area corrected LV mass was larger (p<0.001) in the mortality group in the univariate analysis. Therefore, multivariable Cox analysis was employed to study the net effect of HF with different LV systolic functions on mortality. After controlling for all the significant factors in the univariate analyses, participants with HF/preserved LVEF and HF/impaired LVEF had a higher all-cause mortality risk compared to the non-HF participants, with hazard ratios of 1.66 and 2.04 respectively (test for trend, p=0.007, Table 5).


Figure 01
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  		Fig. 1 The Kaplan-Meier survival curves of the no HF, HF/preserved LVEF and HF/impaired LVEF groups. The numbers at risk at the interval of every 2.5 years were marked in the x-axis. The overall survival rate was lowest in the HF/impaired LVEF group as compared to the 2 other groups. (p<0.001 by the log-rank test, df=2).

 


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  		Table 5 Cox multiple regression analysis of the factors related to all-cause mortality

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 Acknowledgments
 References
 
This is the first prospective community-wide cohort study designed to evaluate the impact of HF symptoms and left ventricular dysfunction on overall mortality in an ethnic Chinese population. According to our stratification by LV systolic function, the overall mortality rate was greater in the population of HF with impaired LV systolic function after controlling for associated factors. Systolic function is critical to long-term prognosis in this ethnic Chinese population. The overall prevalence of HF with preserved or impaired systolic function was 5.53% in our study, which is comparable to previous studies, 3.4% in the Rotterdam study [20], 2.5% in the Framingham study [2] and 11% for men and 8.5% for women in studies in Sweden [21,22].

The 5 and 10 year survival of the HF/preserved LVEF and HF/impaired LVEF groups in this study was higher than previous community-based studies in western countries. In the Framingham study, the 5 year survival rate of HF patients was 35% for men and 53% for women, and the 10 year survival was 15% for men and 29% for women [2]. It is possible that these differences may be due to fact that the Framingham study was performed more than 10 years earlier. In the more recent Minnesota study, the 5 year survival for newly diagnosed HF patients who survived the initial acute stage was 41% [3]. This difference in HF survival between Asian-Chinese and western populations is probably related to the different patterns of underlying disease. It is known that the prevalence of coronary heart disease is low in Asian-Chinese people. Less than 10% of HF patients had a diagnosis of coronary heart disease in our cohort. The most frequent cause of HF was hypertension. However, the prevalence of coronary heart disease is about 50-64% in reports from western countries. It has been reported that the annual rate of cardiac death for HF patients without cardiac ischaemia is 4.8% per year and 11.8% for those with ischaemia [23]. Differences in the incidence of cardiac ischaemia and the possible different treatment strategies needed for a population with less coronary heart disease will impact on prognosis. The survival rate of heart failure patients with preserved systolic function was better than for those with impaired systolic function. This is in accordance with data from some previous studies [24]; however, two recently published studies showed similar survival rates irrespective of the presence or absence of systolic dysfunction in hospitalised heart failure patients [25,26]. The extrapolation of survival data from hospital-based, predominantly white population studies to a community-based study in a different ethnic group is not always appropriate. In line with our findings, a hospital-based study of Chinese in Hong-Kong, reported a high prevalence of HF with preserved systolic function [6]. The high prevalence of hypertension may be the major reason for this phenomenon. The association between hypertension and HF with preserved systolic function has been proposed in previous studies [27,28].

In this study, we identified some epidemiological characteristics and factors related to HF in a Chinese population. The association between physical activity and HF is seldom studied but has become an important issue recently [29]. In the NHANES I epidemiologic follow-up study, physical inactivity was an independent risk factor associated with a significantly higher risk of HF in the US general population [1]. This finding is compatible with our study. Although cause-effect cannot be claimed in our study, we found that physical inactivity was more common in the HF population with either preserved or impaired LV systolic function. In addition to hypertension and coronary heart diseases, which are well known risk factors of HF, atrial fibrillation was also found to be significantly more common in the HF group in this study. Supraventricular arrhythmias, particularly atrial fibrillation, frequently precipitate the onset of either systolic or diastolic heart failure [30]. However, the interactions between atrial fibrillation and different levels of LV systolic function in HF patients are not clear. We found that the group with HF and impaired LV systolic function had a greater incidence of co-existing atrial fibrillation than those with preserved systolic function and those without HF symptoms.

4.1. Limitations
This study has some limitations. Firstly, it was a prevalence study not an incident study. Therefore, although factors, such as coronary heart disease, hypertension, and diabetes, are thought to be the risk factors for HF, the cause-effect interaction cannot be concluded from this study. These risk factors were associated with HF in our ethnic Chinese population and this could form the basis for future studies. Secondly, another issue with prevalence studies is the potential for selection bias. Individuals with more severe HF may be less likely to be picked up by this sampling scheme, because they may spend more time in the hospital and/or be less likely to survive long enough to participate. Thus, prevalence studies may overestimate HF survival. Thirdly, the diagnosis of heart failure may be controversial since there is no perfect definition for heart failure thus far. Invasive parameters such as central venous pressure are difficult to measure in a community-based study. In our study, the symptoms and signs suggested in Framingham's criteria and the available hospital records were used for diagnosis to minimize bias. The cut point of preserved and impaired LV systolic function is not perfect in this study, as there is no simple binary division between "preserved" and "impaired" systolic function. LVEF cut points of 0.4, 0.5 or 0.55 have been used in previous HF studies. A difference in presentation between HF patients with normal LV systolic function and mild dysfunction was reported in previous study [12]. In our study we used an LVEF cut point of 0.55 to define LV systolic dysfunction, and found different patterns of survival and epidemiological characteristics between groups with different LV systolic function. The use of LV ejection fraction as an index of LV performance is also debatable and other parameters may have different implications; however, LVEF has been widely used in many prior studies. Echocardiographic examinations were performed around 2 years after the start of the study and therefore LVEF values may not represent those at the onset of HF. Also, because we did not re-evaluate newly diagnosed heart failure cases in the follow-up period, these data are not available.

In the study, the demographics of respondents and non-respondents were different with older and more female subjects with less coronary artery disease in the non-respondent group. Although no difference in the incidence of coronary events was observed between the two groups, the difference in the age and sex distribution could affect the prevalence of other diseases which might impact on all-cause mortality. The prevalence of symptomatic LV systolic dysfunction was less than in prior studies [20]. Thus it is important to screen and treat potential undiagnosed patients in the Chinese community. The number of cases of heart failure with impaired systolic function was small in our population, which may limit the significance and power of the study although the survival difference between HF/preserved LVEF and HF/impaired LVEF was statistically significant. The percentage of heart failure with preserved systolic function was high in the study, this may be due to potential undiagnosed patients and the low number of patients with symptomatic systolic dysfunction. More large scale studies and screening for these patients are needed in the future.

Medication usage during the 10 year follow-up period was not recorded in detail and different medications could affect outcome if the populations were under different treatment policies. Drugs were adjusted according to the individual's clinical condition at intervals during the 10 year follow-up, this made the recording of detailed medication history and analyzing any effects on mortality difficult.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
Acknowledgments
 References
 
HF and LV systolic function are related to all-cause mortality in an ethnic Chinese population. Survival rates at 5 and 10 years are higher and the prevalence of coronary heart disease is lower in Taiwan as compared to western countries. Hypertension is the major disease associated with heart failure. Coronary heart disease, atrial fibrillation and physical inactivity are also associated with heart failure and LV systolic dysfunction. These results highlight the importance of the management of hypertension for the prevention of HF in Asian-Chinese people.


   Acknowledgments
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Acknowledgments
References
 
We thank the cardiologists at National Taiwan University Hospital for their assistance in this study.

This study was partly supported by the National Science Council (# NSC 93-2314-B-002-218 and NSC 92-2314-B-002-197) in Taiwan.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 Acknowledgments
 References
 

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