Psychosomatics 49:42-48, January-February
doi: 10.1176/appi.psy.49.1.42
© 2008 Academy of Psychosomatic Medicine
Depressive Symptoms and Heart Failure Stages
Ana Azevedo, M.D., Ph.D.,
Paulo Bettencourt, M.D., Ph.D.,
Fernando Friões, M.D.,
Margarida Alvelos, M.D.,
Cassiano Abreu-Lima, M.D., Ph.D.,
Hans-Werner Hense, M.D., Ph.D., and
Henrique Barros, M.D., Ph.D.
Received June 6, 2006; revised August 16, 2006; accepted August 30, 2006. From the Dept. of Hygiene and Epidemiology, University of Porto Medical School; Porto, Portugal. Send correspondence and reprint requests to Ana Azevedo, M.D., Dept. of Hygiene and Epidemiology, University of Porto Medical School; Alameda Prof. Hernani Monteiro, 4200-319, Porto, Portugal; the Heart Failure Clinic, Dept. of Medicine, Hospital de S. João; Dept. of Cardiology, Hospital de S. João and University of Porto Medical School; and the Institute of Epidemiology and Social Medicine, University of Muenster; Muenster, Germany. e-mail: anazev{at}med.up.pt
© 2008 The Academy of Psychosomatic Medicine
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ABSTRACT
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The authors measured depressive symptoms cross-sectionally, across evolving stages of heart failure as defined by the American College of Cardiology, from low risk, through high risk for heart failure (Stage A), asymptomatic cardiac dysfunction (Stage B), up to symptomatic heart failure (Stage C), in a community sample of 338 noninstitutionalized adults age  45 years. Depressive symptoms were measured with the Beck Depression Inventory (BDI). Women scored significantly higher on the BDI. Adjusted BDI scores increased linearly with heart failure stages in women, whereas, in men, only Stage C was associated with a significantly higher score.
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INTRODUCTION
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There is an increased prevalence of depression in heart failure patients, and comorbid depression confers a worse prognosis, contributing to increased mortality and precipitating hospitalization.1,2 Most studies reporting on this association have been conducted on inpatients.3 Not only is the whole range of severity not represented in this group, but there may be transient mood disturbances associated with hospitalization itself.4 Recently, Gottlieb et al.5 extended previous knowledge about the prevalence of depression in heart failure to the outpatient population, about whom considerably less was known. Most studies addressing this issue were cross-sectional, and, therefore, a deeper look into the reported association, by establishing the temporal sequence of events, was not possible. It has been suggested that the link between depression and heart failure involves neurohormonal activation and immune-system regulation.6 These physiologic responses may either be the consequence of depression, thus explaining the role of depression as a risk factor for heart failure, or contribute to depression, with the two disorders representing consequences of a common stimulus. Possibly, both mechanisms are at work simultaneously.
Precursors and risk factors for heart failure are themselves associated with depression.7–14 If the higher prevalence of depression in heart failure patients is mainly a consequence of the association with those risk factors, we would expect this effect to be already present with asymptomatic precursors of heart failure. If, however, depression acts mainly through changing perceptions and symptoms, that is, if depressed patients are simply more sensitive to symptoms and express more severe fatigue, dyspnea, and functional impairment for the same objective cardiac physiological abnormalities, then it should be associated only or mainly with symptomatic heart failure. This issue has not been previously assessed, and it is the main objective of the present report.
The aim of this study was to assess depressive symptoms across the evolving stages of heart failure, as defined by the American College of Cardiology and the American Heart Association,15 in a community sample of Portuguese middle-aged and elderly adults.
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METHOD
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As part of a health and nutrition survey of the adult population of Porto, Portugal, we measured parameters of cardiac structure and function in 739 randomly selected participants age 45 years, to estimate the prevalence of heart failure stages in the population.16 Recruitment and data collection took place from January 2001 to December 2003; the proportion of participation was 70%.17 The local ethics committee approved the study, and participants provided written informed consent.
As previously reported,16 data were collected by trained interviewers using structured questionnaires plus a clinical interview and examination by a physician. Anthropometric measurements, a spirometry, and a resting, 12-lead electrocardiogram and echocardiogram were also performed. Echocardiograms were done by four cardiologists, using the same equipment (HP Sonos 5500) and recorded on videotape for later review by a single experienced cardiologist (CAL), blinded to clinical data. Participants were classified according to the stages of heart disease as defined by the American College of Cardiology and American Heart Association:15 Stage A: high risk for heart failure, including hypertension, diabetes mellitus, metabolic syndrome, coronary heart disease, smoking, excessive alcohol intake, without any abnormality that would result in classification in a more advanced stage; Stage B: asymptomatic heart disease, including left ventricular systolic dysfunction, left ventricular dilatation, moderate-to-severe valvular heart disease, and left ventricular hypertrophy; Stage C: symptomatic heart failure, including heart failure symptoms or signs, plus any of the abnormalities described in stage B, with the exception of left ventricular hypertrophy, which was considered to be responsible for those symptoms only in the absence of chronic lung disease; Stage D: advanced structural heart disease and marked symptoms of heart failure despite maximal medical therapy, and requiring specialized interventions.
The Beck Depression Inventory (BDI)18 was used to measure depressive symptoms. This scale includes 21 symptoms and attitudes, covering emotions, behavioral changes, and somatic symptoms. Each symptom is rated on a 4-point intensity scale, and the final score ranges from 0 to 63, with higher scores representing more severe depression. In addition to the original scale, we computed the score excluding somatic symptoms (fatigue, sleep, and appetite disturbances) that may result from heart failure rather than depression, and might therefore lead to an overestimation of the association between depression and heart failure stages. The questionnaire was self-administered at home. Subjects were given the questionnaire at the end of the interview with a prepaid envelope to return it with the responses. Illiterate subjects were helped either by relatives or by our staff during the interview. Despite reminding at the second evaluation at our department (for the cardiac assessment), only 345 participants returned the questionnaire with answers for all symptoms. An additional seven elderly subjects scored <24 on the Mini-Mental State Exam19 and were considered unable to provide reliable information. Therefore, only 338 subjects were available for the current analysis.
Data are described as mean (standard deviation [SD]) for normally distributed and median (interquartile range) for non-normally distributed continuous variables. Means or medians were compared between two groups by t-test or Mann-Whitney U test, respectively. Categorical data are presented as count (proportion). Proportions were compared by chi-square tests. The univariate association between the score on the BDI and other continuous variables was assessed with Spearman’s correlation. Median score was compared between groups by Mann-Whitney or Kruskal-Wallis tests, as appropriate. The association between heart failure stages and BDI score, adjusting for confounders, was assessed by linear regression. Although the BDI score was not normally distributed, after several attempts with different functions, it was not possible to transform it into a normally-distributed variable. However, the distribution of standardized residuals of the final model was close to normal, and the assumption of constant variance was respected. Therefore, we chose to use multiple linear regression of the raw BDI score on covariates. Separate models were fitted for women and men. The role of antidepressant drug use was assessed by sensitivity analysis, by fitting three models: including all subjects and adjusting for antidepressant drug use, including all subjects and not adjusting for antidepressant drug use, and excluding subjects with antidepressant drug use. Comparison of the first two models allowed the assessment of the role of antidepressant usage as a confounder. By restricting analysis to subjects who did not use antidepressants, we tested whether the association was stronger than in the whole group, which would be an argument for the role of antidepressant use as an effect-modifier. Adjusted mean values of the BDI score by heart failure stage were computed with the final linear-regression models by assigning the average value of the covariates to the regression coefficients derived. To test for linear trend, we included the ordinal variable "heart failure stages" as a continuous independent variable in the multiple-regression models.
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RESULTS
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Characteristics of the Study Sample
As shown in Table 1, subjects with data on BDI were mainly men, younger (particularly in the group of women), more educated, had more skilled occupations, and were married or living as married. Also, participants with information on BDI predominantly presented with earlier heart failure stages. Among these variables, only education, occupation, and marital status were independently associated with the probability of responding. When adjusting for these factors, heart failure stages were no longer significantly different between those with and without information on the BDI. Importantly, the use of antidepressant medication was similar in both groups (Table 1).
Determinants of Depressive Symptoms
As shown in Table 2, women showed significantly higher scores on the BDI than men (p <0.001). In women, the BDI score decreased with higher education and was lower in married women. Age, occupation, and retirement status were not significantly associated with depression in women. In men, depression increased significantly with age and retirement, with the latter effect being independent of age. Marital status, education level, and occupation were not significantly associated with depression in men. In both genders, in the crude analysis, the BDI score increased progressively through heart failure stages, with a significant linear trend, whether or not somatic symptoms were considered in computing the score (data not shown for the latter case).
Depressive Symptoms and Heart Failure Stages
In Figure 1, we present adjusted mean BDI scores and their 95% confidence intervals (CI) by heart failure stages, in the whole study sample and grouped by sex. Means were adjusted for age and education in both sexes, marital status in women, and retirement status in men. Adjusted BDI scores increased linearly with heart failure stages in women (regression coefficients [ standard error {SE}]) for dummy variables: Stage A: 2.88 (1.33), p=0.03; Stage B: 3.69 (1.87), p=0.05; Stage C: 7.38 (2.55), p=0.004, as compared with the reference class "Low Risk"), whereas, in men, only Stage C was associated with significantly higher score (Stage A: 0.50 (1.14), p=0.67; Stage B: 1.18 (1.46), p=0.42; Stage C: 5.89 (2.23), p=0.009, as compared with the reference class "Low Risk;" Figure 1). The same pattern of association was observed when using the score that excluded somatic symptoms (data not shown).
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FIGURE 1. Adjusted Mean (95% Confidence Interval) of Beck Depression Inventory (BDI) Score and BDI Cognitive-Affective Subscale (Somatic Symptoms Omitted) by Stages of Heart Failure
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Antidepressant drug use was similar across heart failure stages (10.7% among low-risk subjects; 8.4% in Stage A, 3.6% in Stage B, and 10.5% in Stage C; p=0.43) and consisted of selective serotonin reuptake inhibitors in 19 (68%) of medicated subjects. In the sensitivity analysis to assess how to account for the role of antidepressant drug use, we observed that adjustment for this variable did not change the estimates on the association between BDI score and heart failure stages, whereas exclusion of subjects taking antidepressant drugs yielded stronger correlation between BDI and heart failure stages. Therefore, we did not adjust for antidepressant drug use in the presented final models.
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DISCUSSION
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Main Findings
In this study, we found a linear association between BDI score and evolving heart failure stages in women. In men, only the more advanced, symptomatic, Stage C of heart failure showed a higher score.
Interpretation of Study Results
Suggested explanations for the higher prevalence of depression in heart failure patients include a shared pathophysiology,6 with neurohormonal activation, rhythm disturbances, and inflammation playing a role in the development, progression, and outcomes of heart failure. These physiologic responses may be either the consequence of depression, thus explaining the role of depression as a risk factor for heart failure, or contribute to depression, with the two disorders representing consequences of a common stimulus. Possibly both mechanisms are at work simultaneously.
According to the neurohormonal model, heart failure develops as a result of the activation of endogenous neurohormonal systems in reaction to an initial noxious insult to the heart. The sympathetic nervous system is one of those systems whose activation becomes maladaptive, thereby perpetuating the clinical condition of heart failure, contributing to the progression from asymptomatic to symptomatic. Studies have consistently documented hyperactivity of the hypothalamic-pituitary-adrenal axis in patients with depression, which, in turn, augments sympathetic activity via central regulatory pathways. Although not all studies demonstrated elevated plasma catecholamine levels in patients with depression, administration of selective serotonin reuptake inhibitors to healthy volunteers led to a suppression of sympathetic activity. The similarity of these neurohormonal changes in both heart failure and depression, proposed also to explain the association of depression with coronary heart disease, suggests that depression can speed the development of heart failure in vulnerable persons or speed the progression of heart failure in established disease. It is not clear whether activation of these systems in depressed patients is a consequence of depressive symptoms or they contribute to depression symptoms. In the latter case, activation of neurohormonal systems such as the sympathetic nervous system in heart failure could contribute to the development of depression in vulnerable persons. Thus, depression in heart failure patients would not be merely an emotional response secondary to symptoms and functional impairment.
Inflammatory markers, particularly proinflammatory cytokines such as tumor necrosis factor, interleukin-1, and the interleukin-6 family, are elevated in heart failure patients and have been implicated in the pathogenesis and progression of heart failure. Biomechanical stress, ischemia, immune activation, and neurohormones all can induce the inflammatory cascade: early in the development of heart failure, this cascade plays an adaptive role because activation of proinflammatory cytokines initially allows the myocardium to respond to tissue injury and maintain homeostasis through the promotion of tissue repair. However, much like the neurohormonal activation, this response eventually becomes pathogenic, leading to left ventricular remodelling, contractile dysfunction, uncoupling of myocardial beta-adrenergic receptors, and cardiac myocyte apoptosis. Elevated plasma levels of proinflammatory cytokines are also characteristic of depression, representing a response to acute or chronic psychological distress. The presence of even mild-to-moderate depressive symptoms in healthy men without a diagnosis of major depression suggests that depression may have a harmful physiological impact before it becomes clinically apparent. Conversely, there is some evidence that interleukins and other cytokines might actually cause depression. It is currently not clear yet whether inflammation seen in depressed patients is a trait-marker of depression or whether inflammation contributes to the pathogenesis of depression.
Heart failure is the tip of an iceberg. Many of the disturbances mentioned above as being in common with both heart failure and depression are at play during the continuum that leads up to overt heart failure. Particularly, neurohormonal activation is initially triggered as an adaptive response, but eventually becomes maladaptive and perpetuates the process through a positive feedback mechanism. Moreover, precursors and risk factors for heart failure, namely coronary heart disease (as cause, consequence, and prognostic factor),7–9 hypertension,10 diabetes mellitus,11 obesity,12,13 smoking,13 and excessive alcohol consumption,14 are, themselves, associated with a higher prevalence of depression. If the higher prevalence of depression in heart failure patients is mainly a consequence of the association with those risk factors, we would expect this effect to be already present with asymptomatic precursors of heart failure. If, however, depression acts mainly through changing perceptions and symptoms; that is, if depressed patients are simply more sensitive to symptoms and express more severe fatigue, dyspnea, and functional impairment with the same objective cardiac physiological abnormalities, then it should be associated only or mainly with symptomatic heart failure. Two studies have reported on the impact of depression on the future development of heart failure,20,21 and these have shown that depression is not simply a consequence of heart failure. In the current study, we observed a significant association of depression with early, asymptomatic stages of heart failure in women, with the strength of the association increasing with the severity of heart failure. However, in men, only the symptomatic Stage C was associated with depressive symptoms.
Women tend to be more depressed, express more emotional reactions, and somatize more than men.22 According to previous studies, depression may be more common in women with heart failure.2,23,24 In the present study, we showed that women are, in general, more depressed than men, but the effect of Stage C heart failure in comparison with the reference class of subjects at low risk of heart failure is similar in men and women. The main difference between the sexes was that a higher BDI score was found in intermediate, asymptomatic stages only in women. It is possible that depressive symptoms are simply more easily expressed by women. If that is the case, what we need are more sensitive tools to detect depression in men. It is likely, however, that this is not the only explanation for our finding; otherwise the BDI score in women at Stage C should be even higher.
Strengths and Limitations of the Study
The low proportion of participation in BDI testing may limit both internal and external validity. The low participation rate in answering BDI questions is most likely related to self-administration of the scale, given that a very high response rate was obtained from the same sample in other questionnaires, which were obtained by personal interview. The relatively low educational level and the old age of the subjects may have contributed to some difficulty in their answering the BDI questionnaire. Given the sociodemographic correlates of depressive symptoms in this sample and the characteristics of nonrespondents to the BDI, we assume that those for whom data were not available had more depressive symptoms. In consequence, the association between heart failure stages and depressive symptoms was probably underestimated. Of note, in cross-sectional studies, the strength and direction of the effect of selection bias remain undetermined, which may limit the interpretation of our study results. In order to maximize the validity of the tool we used to measure depression, we excluded elderly subjects with cognitive defects as assessed by the Mini-Mental State Exam19 and also omitted all those questionnaires that were not complete; that is, we did not calculate scores when data on one or more symptoms were missing. It has been argued that the association between heart failure and the score on questionnaires to assess depression, such as the BDI, may be overestimated, because some somatic symptoms that are attributed to depression in those scores might be due to heart failure. In order to avoid this bias, we computed the scores in two ways: first, as recommended in the original scale; and, then, excluding symptoms of fatigue, sleep, and appetite disturbances. The conclusions were not meaningfully changed, which means that the observed association does not depend on those shared manifestations. The questionnaire was administered and returned before the results of the clinical examinations were made available to participants. This approach helped avoid a labeling effect that could otherwise have influenced the subjects’ emotional status.
In most previous studies, the role of antidepressant drugs has been accounted for by adjustment for this factor in multivariate models. In this study, we concluded that, in fact, antidepressant use is not a confounder because the estimates were not changed by its inclusion as an independent variable. Our data argue in favor of its acting as an effect-modifier, since the observed associations were stronger when excluding subjects with antidepressant drug use, presumably because those drugs attenuate depressive symptoms. The small number of subjects using these drugs regularly did not allow us to do stratified analysis or statistically assess interaction with a product-term in the models.
Despite the cross-sectional design, the classification of subjects into evolving stages of heart failure allowed us to come closer to a longitudinal perspective and to demonstrate higher scores on a depression scale in women at early, asymptomatic stages of heart failure. These results show that the association between depression and heart failure is not merely explained by the emotional effect of medical illness. If future studies confirm that depression contributes to a more likely or faster progression of symptomatic heart failure, we can make a clearer prediction of future heart failure.
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ACKNOWLEDGMENTS
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This study was supported by the Fundação para a Ciência e a Tecnologia (POCTI/SAU-ESP/61492/2004).
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REFERENCES
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ABSTRACT
INTRODUCTION
