The American Journal of Medicine
Volume 120, Issue 9 , Pages 799-806, September 2007

Impact of Cardiac Rehabilitation on Depression and Its Associated Mortality

Presented in part to the Annual Scientific Sessions of the American Heart Association, Chicago, Illinois, November 2006.

  • Richard V. Milani, MD

      Affiliations

    • Corresponding Author InformationRequests for reprints should be addressed to Richard V. Milani, MD, Department of Cardiology, Ochsner Medical Center, 1514 Jefferson Highway, New Orleans, LA 70121.
    • ,
  • Carl J. Lavie, MD

Department of Cardiology, Ochsner Medical Center, New Orleans, La.

Article Outline

Abstract 

Purpose

Depression following major cardiac events is associated with higher mortality, but little is known about whether this can be reduced through treatment including cardiac rehabilitation and exercise training. We evaluated the impact of cardiac rehabilitation on depression and its associated mortality in coronary patients.

Patients and Methods

We evaluated 522 consecutive coronary patients (381 men, 141 women; aged 64±10 years) enrolled in cardiac rehabilitation from January 2000 to July 2005 and a control group of 179 patients not completing rehabilitation. Depressive symptoms were assessed by questionnaire at baseline and following rehabilitation, and mortality was evaluated after a mean follow-up of 1296±551 days.

Results

Prevalence of depressive symptoms decreased 63% following rehabilitation, from 17% to 6% (P <.0001). Depressed patients following rehabilitation had an over 4-fold higher mortality than nondepressed patients (22% vs 5%, P=.0004). Depressed patients who completed rehabilitation had a 73% lower mortality (8% vs 30%; P=.0005) compared with control depressed subjects who did not complete rehabilitation. Reductions in depressive symptoms and its associated mortality were related to improvements in fitness; however, similar reductions were noted in those with either modest or marked increases in exercise capacity.

Conclusion

In patients following major coronary events, cardiac rehabilitation is associated with both reductions in depressive symptoms and the excess mortality associated with it. Moreover, only mild improvements in levels of fitness appear to be needed to produce these benefits on depressive symptoms and its associated mortality.

Keywords: Coronary disease, Depression, Exercise, Mortality

 

Depression and depressive symptoms are prevalent in patients with coronary heart disease, comprising approximately 15%-20% of this population.1, 2, 3, 4 Although its presence identifies patients at high risk for adverse cardiovascular outcomes including myocardial infarction (MI) and death, it remains underappreciated as a coronary risk factor.5, 6, 7 Identification and treatment of depression are especially important in patients following recent coronary events where its presence may be particularly pathogenic, conferring a greater than 4-fold increase in risk of death in the post-MI setting.8, 9, 10, 11, 12 Complicating this increased risk is the observation that major depression following MI runs a chronic course untreated, with more than 95% of patients remaining depressed at 6 months and up to 70% remaining depressed at 1 year.2, 13

Clinical Significance

 


•Following major coronary events, cardiac rehabilitation and exercise training reduces the prevalence of depression, improves levels of fitness, and significantly reduce all-cause mortality in coronary patients.

•These data further support the importance of exercise training for both psychological health and overall survival.

We and others have described the short-term benefits of cardiac rehabilitation and exercise training upon depressive symptoms in coronary heart disease patients following major cardiac events.14, 15, 16, 17, 18, 19 Specifically, cardiac rehabilitation has been reported to reduce depressive symptoms and the prevalence of depression by 50%-70%. In a recent randomized trial, exercise training decreased depressive symptoms as effectively as antidepressant medications.20, 21 To date, however, the impact of reducing depressive symptoms utilizing cardiac rehabilitation has not been studied on major clinical events, including mortality. The present investigation studies the effects of rehabilitation upon depressive symptoms and subsequent long-term mortality and evaluates the relationship between exercise training and improvements in fitness on this behavior.

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Methods 

Patients 

We retrospectively evaluated 522 consecutive patients who were referred to, attended, and completed phase II cardiac rehabilitation (treatment group) between January 2000 and July 2005. All patients entered the program 2-6 weeks after a coronary event, including acute MI (30%), coronary bypass surgery (35%), and percutaneous coronary intervention (44% of patients; some patients had more than one clinical event). We further evaluated a control group of 179 patients who entered rehabilitation but dropped out within 2 weeks of entry (all patients received <5 sessions of rehabilitation) to evaluate the impact of depressive symptoms in patients not undergoing rehabilitation. All patients completed questionnaires before rehabilitation, and the treatment group completed questionnaires after rehabilitation. None of these patients were being treated with antidepressive medications. Survival status was obtained January 1, 2006, after a mean follow-up of 1296±551 days (range 109-2188 days) from the National Death Index. The protocol was approved by the Institutional Review Committee at Ochsner Clinic Foundation.

Behavioral Testing 

The Kellner Symptom Questionnaire is a 92-question assessment validated to assess behavioral characteristics, including symptoms of depression, anxiety, somatization, and hostility, with a lower score being more favorable for each behavioral symptom (scores can range from 0-17 units).22 Depressive symptoms were considered to be significant when the depression score exceeded 6 (>7 for hostility and anxiety, >8 for somatization) as previously described.15, 17, 19 The Medical Outcomes Short Form 36 survey was used to assess quality of life, with a high score indicating a more favorable quality-of-life trait.23

Protocol 

Protocol, data collection, and statistical analysis were performed as previously described.14, 24 Patients were referred to and participated in outpatient phase II cardiac rehabilitation consisting of 12 weeks of 36 educational and exercise sessions. Exercise intensity was individually prescribed within 10 beats of the anaerobic threshold obtained on entry cardiopulmonary exercise testing. Each session consisted of a 10-minute warm-up, 30 minutes of sustained aerobic exercise, followed by a cool-down period. Resistance training with light hand weights also was incorporated. At baseline, patients were instructed on the American Heart Association Step II diet with a Mediterranean modification, and dieticians, exercise physiologists, nurses, and physicians frequently encouraged patients to comply with both the exercise and dietary portions of the cardiac rehabilitation program. Daily lectures, as well as group sessions about heart disease risk factors, general information about coronary disease (symptoms, signs), and psychosocial adaptations to this disease were given for patients and spouses.

Height, weight, body mass index, age, sex, fasting blood lipids, high sensitivity C-reactive protein (hs-CRP), and peak oxygen consumption (peak VO2) were assessed at baseline and again 1 week after completing rehabilitation as previously described.14, 25, 26

Statistical Analysis 

Statview software 5.0.1 (SAS Institute; Cary, NC) was used for statistical analysis. Results are mean±SD or frequencies expressed as percentages. Differences in continuous variables between 2 groups were assessed by paired Student’s t test or nonparametric tests as appropriate. Univariate relations between variables were assessed as partial correlations. Two-tailed P ≤.05 was considered statistically significant. Logistic regression analysis was performed to determine independent predictors of mortality. Actuarial survival analysis was used to compute cumulative hazard over time.

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Results 

Baseline Characteristics 

The mean age of the 701 patients in treatment and control groups was 64±11 years, with 72% of the subjects male. The mean ejection fraction was 54±12%, and the mean peak VO2 was 16.2±5.2 mL/kg/min. Depressive symptoms were identified in 139 patients (20%) on entry into rehabilitation (26% controls, 17% treatment; P=.005). Table 1 highlights the baseline differences between treatment and control subjects. Table 2 outlines the baseline differences between treatment and control depressed patients.

Table 1. Baseline Differences in Treatment and Control Subjects on Entry into Cardiac Rehabilitation
Treatment (n=522)Control (n=179)P-value
Age (years)64±1063±12NS
% Male73%69%NS
Body mass index (kg/m2)28.5±5.129.2±5.8NS
Active smokers (%)1%10%<.0001
Hypertensives (%)33%78%<.0001
Diabetes (%)22%33%.01
Married (%)72%75%NS
Peak VO2 (Ml/kg/min)16.6±5.214.8±4.9<.0001
Total cholesterol (mg/dL)167±38174±37.04
HDL−cholesterol (mg/dL)41±1342±15NS
LDL−cholesterol (mg/dL)97±3699±36NS
Triglycerides (mg/dL)148±84182±156.0004
hs-CRP (mg/dL)5.7±9.310.1±17.3<.0001
Ejection fraction (%)54±1255±11NS
Depression3.3±4.04.6±4.8.001
Anxiety4.1±4.65.4±5.1.002
Hostility2.5±3.52.9±3.8NS
Somatization6.6±3.97.9±4.4.0005
Quality of life102.9±17.893.7±18.6<.0001
Table 2. Baseline Differences in Depressed Treatment and Control Subjects on Entry into Cardiac Rehabilitation
Treatment (n=91)Control (n=48)P-value
Age (years)62±1261±14NS
% Male70%52%.04
Body mass index (kg/m2)28.6±5.429.4±5.9NS
Active smokers (%)4%6%NS
Hypertensives (%)34%71%<.0001
Diabetes (%)24%26%NS
Married (%)78%67%NS
Peak VO2 (mL/kg/min)16.0±5.213.5±3.9.004
Total cholesterol (mg/dL)169±34176±39NS
HDL−cholesterol (mg/dL)40±1245±16.06
LDL−cholesterol (mg/dL)96±3096±29NS
Triglycerides (mg/dL)162±76189±153NS
hs-CRP (mg/dL)6.5±10.110.3±19.8NS
Ejection fraction (%)53±1354±14NS
Depression10.7±3.411.3±3.6NS
Anxiety10.7±4.911.6±4.5NS
Hostility7.0±4.95.8±5.4NS
Somatization10.2±3.911.0±4.1NS
Quality of life83.5±15.077.9±17.1.06

Treatment Group Characteristics and Effects of Cardiac Rehabilitation and Exercise Training 

Of the 522 patients comprising the treatment group, depressive symptoms were identified in 91 (17%) patients on entry into rehabilitation. Table 3 highlights the baseline differences between treatment subjects based on the presence or absence of depressive symptoms. The effects of rehabilitation in the depressed cohort are described in Table 4. Following rehabilitation, the prevalence of depressive symptoms fell 63% (Figure 1) from 17% on entry, to 6% upon completion of the program (P <.0001).

Table 3. Baseline Differences in Cardiac Rehabilitation Patients with and without Depression upon Study Entry
Depressed (n=91)Nondepressed (n=431)P-value
Age (years)62±1265±10.017
% Male70%74%NS
Body mass index (kg/m2)28.6±5.428.5±5.0NS
Active smokers (%)4%0.6%.02
Hypertensives (%)34%31%NS
Diabetes (%)24%21%NS
Married (%)78%71%NS
Peak VO2 (mL/kg/min)16.0±5.216.8±5.2NS
Total cholesterol (mg/dL)169±34166±38NS
HDL−cholesterol (mg/dL)40±1241±13NS
LDL−cholesterol (mg/dL)96±3098±37NS
Triglycerides (mg/dL)162±76146±86NS
hs-CRP (mg/dL)6.5±10.15.5±9.1NS
Ejection fraction (%)53±1354±11NS
Depression10.7±3.41.8±1.8<.0001
Anxiety10.7±4.92.7±3.0<.0001
Hostility7.0±4.91.6±2.1<.0001
Somatization10.2±3.95.9±3.5<.0001
Quality of life83.5±15.0107.0±15.4<.0001
Table 4. Benefits of Cardiac Rehabilitations and Exercise Training in Depressed Coronary Patients (n=91)
BeforeAfterP-value
Body mass index (kg/m2)28.6±5.428.3±5.3NS
Peak VO2 (Ml/kg/min)16.0±5.217.9±5.8<.0001
Total cholesterol (mg/dL)169±34169±33NS
HDL−cholesterol (mg/dL)40±1243±11.002
LDL−cholesterol (mg/dL)96±30101±41NS
Triglycerides (mg/dL)162±76147±95NS
hs-CRP (mg/dL)6.4±10.14.8±6.8.04
Depression score10.7±3.43.9±4.2<.0001
Anxiety score10.7±4.94.5±4.3<.0001
Hostility score7.0±4.93.4±4.2<.0001
Somatization score10.2±3.96.4±4.1<.0001
Quality of life score83.4±15.0107.4±17.7<.0001

Depressive Symptoms and Survival 

All-cause mortality was assessed in control patients based on the presence or absence of depressive symptoms. In this cohort, depressed subjects had a nearly 3-fold higher mortality compared with nondepressed subjects (30% vs 11%, P=.003).

All-cause mortality was further evaluated in the treatment cohort based on the presence or absence of depressive symptoms at completion of rehabilitation (Figure 2). In this cohort, depressed patients had more than a 4-fold higher mortality (22% vs 5%, P=.0004) than nondepressed patients.

Time-dependent actuarial hazard for survival was assessed in depressed and nondepressed treatment patients (Figure 3). Depressed patients demonstrated an early and incremental increased mortality compared with nondepressed patients (P <.001).

By multivariate analysis, peak VO2, age, ejection fraction, and depressive symptoms remained independent predictors of death in the cardiac rehabilitation cohort (Table 5).

Table 5. Multivariate Analysis of Independent Predictors of Mortality in Patients who Completed Cardiac Rehabilitation (n=522)
VariableChi-squareP-value
Peak VO213.8.0002
Age9.4.002
Ejection fraction7.1.008
Depression5.7.017

Impact of Cardiac Rehabilitation and Exercise Training on Depressive Symptoms and Subsequent Survival 

In order to evaluate the potential impact of rehabilitation on mortality in depressed subjects, we assessed mortality in treatment and control depressed patients identified at entry into cardiac rehabilitation (Figure 4). Depressed control patients had an almost 4-fold increase in mortality compared with depressed patients completing cardiac rehabilitation (30% vs 8%; P=.0005).

Changes in depression status during the course of rehabilitation was obtained and evaluated as a function of subsequent mortality. Patients with depressive symptoms at baseline who became nondepressed during the program appeared to have similar low mortality (6%), as did the 418 patients without depressive symptoms at either time (mortality 5%). In contrast, the 25 patients who had depressive symptoms at both baseline and postrehabilitation, as well as the 8 patients who did not meet criteria for depressive symptoms at baseline but did postrehabilitation, had high mortality (15% and 25%, respectively). Of the 25 patients, none of these patients developed interim cardiovascular events while enrolled in cardiac rehabilitation.

In order to examine the singular impact of exercise training upon depressive symptoms, treatment patients were divided into 3 groups based on changes in peak VO2 during the course of cardiac rehabilitation (Figure 5). Those patients who did not improve functional status (exhibited as either no gain or a loss in peak VO2) were labeled “VO2 loss” (n=102), those with a mild improvement (≤10% increase in peak VO2) were labeled “mild VO2 gain” (n=135), and those patients who increased peak VO2 by >10% as “high VO2 gain” (n=285). The prevalence of depressive symptoms was assessed in each of these groups at entry and completion of rehabilitation and subsequent mortality was obtained. There were no statistical differences in prevalence of depressive symptoms at baseline among the 3 groups. In the VO2 loss group, the prevalence of depressive symptoms remained unchanged (18% on entry to 14% on completion; P=NS) and the corresponding mortality was relatively high at 15%. In patients with mild VO2 gain, the prevalence of depressive symptoms fell from 17% to 5% (P=.004) and the mortality was only 6%. Patients with high VO2 gain demonstrated similar improvements compared with those with only mild VO2 gain, with the prevalence of depressive symptoms decreasing from 18% to 5% (P <.0001) accompanied by a mortality of only 4%.

  • View full-size image.
  • Figure 5. 

    Prevalence of depression and subsequent mortality based on changes in peak oxygen consumption (VO2) during cardiac rehabilitation and exercise training. *P <.001 compared with VO2 loss.

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Discussion 

There are several important implications of this study. First, depressive symptoms are prevalent in the coronary heart disease population, particularly in patients following major coronary events. Second, the presence of depressive symptoms, regardless of age or sex, confers a marked increase in all-cause mortality risk over time. Third, cardiac rehabilitation is associated with a marked reduction in the prevalence of depressive symptoms corresponding to a significant improvement in survival. Finally, the full benefits of cardiac rehabilitation on depressive symptoms and subsequent survival seem to be achieved by only a modest improvement in exercise capacity.

Psychosocial factors, including depression, have been shown to be potent risk factors for the development of MI and death.9, 10, 27, 28, 29 The Interheart study evaluated cardiovascular risk factors in 29,972 people from 52 countries to investigate risk of first MI. Nine independent risk factors, including psychosocial factors, accounted for 90% of the population attributable risk in men and 94% in women. These psychosocial factors, which included depression, increased the odds of first MI by nearly 3-fold and accounted for 33% of the population attributable risk for the development of MI, a magnitude similar to standard risk factors such as smoking, diabetes and hypertension.30 Within this psychosocial index, depression alone increased the odds of MI by nearly 2-fold.31 Following a major cardiac event, the risk of subsequent MI and death related to depression appears much higher.9, 32, 33, 34 Moreover, several studies have documented the poor recovery and durability of untreated depression following MI.4, 13, 35

As a result, there is strong interest in determining whether prognosis can be improved in cardiac patients with depression. The ENRICHD (Enhancing Recovery in Coronary Heart Disease Patients) trial randomized depressed post-MI patients to cognitive behavior therapy and after an average follow-up of 29 months found improvement in depression and social isolation without any change in survival.36 However, the ENRICHD investigators noted the association between self-reported exercise following MI and reduced depression and improved survival.37 Carney et al have shown that patients who remained depressed despite treatment had worse outcomes than those patients who were either not depressed at baseline or who become less depressed following treatment.38 Data from a recent randomized trial demonstrated that exercise training can decrease depressive symptoms as effectively as antidepressant medications.20, 21 To our knowledge, our investigation is the first to demonstrate a survival benefit resulting from reducing depressive symptoms and improving fitness in cardiac patients.

We and others have demonstrated the marked benefits of cardiac rehabilitation and exercise training on conventional as well as psychological factors,15, 16, 39, 40, 41 with data from meta-analyses and other trials demonstrating improvements in overall mortality.42, 43 Whether or not this survival benefit comes from improvement in exercise capacity or some other mechanism has been uncertain. Previously, Vanhees et al demonstrated that peak VO2 evaluated after physical training and its change in response to physical training are independent predictors of cardiovascular mortality, such that every 1% increase in peak VO2 results in a 2% decrease in cardiovascular death.44 Our data support the importance of cardiac rehabilitation in improving exercise capacity but also in reducing symptoms of depression and its accompanying high mortality.

The impact of cardiac rehabilitation upon depressive symptoms is likely multi-factorial. Cardiac rehabilitation is centered around progressive exercise training, which has been shown to exert a salutary effect on certain emotions.24, 45, 46, 47, 48 In a review of the literature, Byrne and Byrne reported a favorable trend between exercise status and mood states, particularly depression.49 The Alameda County Study used questionnaires to measure depressive symptoms and physical activity in 8023 adults over 3 time periods, beginning in 1965. Individuals with low physical activity were at significantly greater risk for depression at a 9-year follow-up evaluation. Additionally, those individuals who had been inactive in 1965 but increased their activity levels by 1974 were at no greater risk for depression in 1983 than those who had been highly active all along, suggesting “the high risk of depression associated with inactivity is modified if the activity level is changed.”50 Recent data also emphasize the benefits of exercise on cognitive function and brain plasticity.51 In the current investigation, we attempted to isolate the exercise component of cardiac rehabilitation by grouping subjects based on changes in peak VO2 over the course of the program. Patients with no improvement in exercise capacity attained no significant reduction in depressive symptoms, whereas those who achieved a modest (1%-10% increase in peak VO2) or more robust (>10% increase in peak VO2) enhancement in exercise capacity demonstrated more than a 70% reduction in the prevalence of depressive symptoms. Moreover, survival mirrored reduction in depressive symptoms, with the best outcomes occurring in groups who improved peak VO2. This suggests not only a favorable relationship between exercise training and depressive symptoms, but also that only a modest enhancement in overall fitness is required to attain the benefits of this intervention on both this behavior and subsequent survival.

Another possible mechanism of reducing depressive symptoms in cardiac rehabilitation is the education of the patient and spouse. The program includes educational sessions on coronary heart disease and risk factor modification, with frequent opportunities for addressing patient/spouse concerns, thus empowering the patient to modify their own recovery. This results in a mechanism by which patients become involved in their own health care, coined “information involvement,” which has been shown to influence coping and social-emotional recovery following major cardiac events.52, 53 Socialization and bonding with other patients, who are at various stages of recovery and rehabilitation, is an important component of the intervention program and likely contributes to the favorable effects seen upon depression.15, 54, 55 Finally, dietary changes, including increased consumption of foods rich in n-3 fatty acids as part of the Mediterranean diet, are part of our recommendations, and deficiencies in this important nutrient have been correlated to depression, although our study did not allow for analysis of this factor.56, 57

Although a limitation to this study was the lack of a randomized nonrehabilitation control group where depressive symptoms were assessed at 2 points in time (which makes establishing cause and effect more difficult), we have previously demonstrated lack of improvement in most coronary risk factors, including behavioral factors, in control subjects not entering cardiac rehabilitation following major coronary heart disease events.26 Moreover, data specifically examining depression in coronary patients over time suggest that the disorder is fairly resistant and likely to remain if left untreated.13, 35 Finally, cardiac rehabilitation is a clinically proven modality for reducing morbidity and mortality in coronary patients, and a randomized control group not receiving this therapy would be medically unethical.39, 40, 42, 43 Another study limitation may be selection bias, because the study group did not represent all patients who have coronary events but rather those selected for referral and who attended and completed the formal cardiac rehabilitation program. In addition, the instrument used to assess depressive symptoms is not as well established as some other instruments and has not been demonstrated previously to predict adverse events, nor has it been used in clinical trials of depression. Nevertheless, our incidence rate of depressive symptoms upon entry into cardiac rehabilitation was very similar to that of other investigators, and suggests that our sample was representative of patients following acute cardiac events. More importantly, depressive symptoms demonstrated in this study were associated with markedly increased mortality in both patients not completing rehabilitation and those patients with depressive symptoms following cardiac rehabilitation, thus validating the prognostic impact of this specific assessment. Finally, our study assessed all-cause mortality, a very powerful endpoint. Although our depressed coronary patients did not have interim events during cardiac rehabilitation, our data do not allow us to determine the impact of cardiac rehabilitation and depression on other potentially important endpoints.

In conclusion, depressed patients following major coronary events have a significantly higher mortality than nondepressed patients. Depressive symptoms and the excess mortality associated with them can be substantially reduced utilizing cardiac rehabilitation and exercise training. Exercise therapy and its associated improvement in fitness appears to be the major mechanism affecting depressive symptoms and subsequent mortality.

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PII: S0002-9343(07)00564-5

doi:10.1016/j.amjmed.2007.03.026

The American Journal of Medicine
Volume 120, Issue 9 , Pages 799-806, September 2007

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