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J Am Coll Cardiol, 2007; 49:2329-2336, doi:10.1016/j.jacc.2007.02.055 (Published online 1 June 2007).
© 2007 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: HEART FAILURE

A Meta-Analysis of the Effect of Exercise Training on Left Ventricular Remodeling in Heart Failure Patients

The Benefit Depends on the Type of Training Performed

Mark J. Haykowsky, PhD*,1,*, Yuanyuan Liang, PhD{dagger}, David Pechter, BA*, Lee W. Jones, PhD§, Finlay A. McAlister, MD, MSc||,2,3 and Alexander M. Clark, PhD{ddagger},2

* Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada
{dagger} Alberta Research Centre for Child Health Evidence, University of Alberta, Edmonton, Alberta, Canada
{ddagger} Faculty of Nursing, University of Alberta, Edmonton, Alberta, Canada
§ Department of Surgery, Duke University Medical Center, Durham, North Carolina
|| Division of General Internal Medicine, University of Alberta Hospital, Edmonton, Alberta, Canada.

Manuscript received December 14, 2006; revised manuscript received February 16, 2007, accepted February 20, 2007.

* Reprint requests and correspondence: Dr. Mark J. Haykowsky, 2-50, Corbett Hall, Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta T6G 2G4, Canada. (Email: mark.haykowsky{at}ualberta.ca).


   Abstract
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Methods
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 Discussion
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 References
 
Objectives: The aim of this study was to determine the effect of exercise training and type of exercise (aerobic vs. strength vs. combined training) on left ventricular (LV) remodeling in heart failure (HF).

Background: A number of randomized controlled trials have examined the effect of exercise training on LV remodeling in individuals with HF. However, the results of these trials have been inconclusive.

Methods: The authors searched MEDLINE (1966 to 2006), Cochrane Central Register of Controlled Trials (issue #3, 2006), CINAHL (1982 to 2006), EMBASE (1988 to 2006), PubMed (1966 to 2006), and reference lists of identified studies for randomized controlled trials examining the effects of exercise training on ejection fraction (EF), end-diastolic volume (EDV), and end-systolic volume (ESV) in clinically stable patients with HF. Primary study authors were also contacted if appropriate. Studies were selected and data were extracted independently by 2 reviewers. Weighted mean differences (WMD) were calculated using a random effects model.

Results: Fourteen trials reported EF data (n = 812 patients). Seven trials reported both EDV and ESV data (n = 569). Aerobic training significantly improved EF (9 trials, 538 patients, WMD = 2.59%; 95% confidence interval [CI] 1.44% to 3.74%), EDV (371 patients; WMD = –11.49 ml; 95% CI –19.95 to –3.02 ml) and ESV (371 patients; WMD = –12.87 ml; 95% CI –17.80 to –7.93 ml). Combined aerobic and strength training was not associated with significant improvements in EF, EDV, or ESV.

Conclusions: Aerobic training reverses LV remodeling in clinically stable individuals with HF. This benefit was not confirmed with combined aerobic and strength training.

Abbreviations and Acronyms
  CI = confidence interval
  EDV = end-diastolic volume
  EF = ejection fraction
  ESV = end-systolic volume
  HF = heart failure
  LV = left ventricle/ventricular
  SMD = standardized mean difference
  VO 2peak = peak oxygen consumption
  WMD = weighted mean difference

Heart failure (HF) is an increasingly common syndrome associated with poor prognosis and high health care costs (1). A cardinal feature of HF is the progressive chamber dilation and deterioration in pump function resulting from increased hemodynamic load and neurohormonal stress. This process, termed left ventricular (LV) remodeling (2), is associated with increased morbidity and mortality; therefore, interventions that halt or reverse ventricular remodeling should improve these clinical outcomes. Indeed, the favorable benefits associated with pharmacologic, electrophysiologic, or device therapies are due, in part, to these therapies’ ability to slow or reverse LV remodeling (3–8).

As part of the cadre of interventions to manage HF effectively, exercise training is now recommended by a number of international scientific organizations for patients with mild to moderate HF symptoms (9,10). This recognition stems from studies reporting that exercise training can improve peak oxygen consumption (VO 2peak) (9–11), muscle strength and mass (11), New York Heart Association functional class (12), and quality of life (9,13) in HF patients. Although exercise training can restore the abnormal autonomic, neurohormonal, and hemodynamic function associated with the HF syndrome (12,14–16), and, in some studies (17), has been shown to reverse LV remodeling in clinically stable HF patients, several other investigators (18,19) reported no benefits with exercise training on LV end-diastolic volume (EDV), end-systolic volume (ESV), or ejection fraction (EF). Thus, uncertainty remains regarding the effects of exercise training on LV remodeling in patients with HF. In an attempt to resolve this issue, we performed a meta-analysis to examine the effects of exercise training on these outcomes and determine whether the type of exercise training influenced these effects.


   Methods
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Results
 Discussion
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Data sources.   The authors searched MEDLINE (1966 to 2006); Cochrane Central Register of Controlled Trials (issue #3, 2006), CINAHL (1982 to 2006), EMBASE (1988 to 2006), PubMed (1966 to 2006) using the following MESH terms and text words: heart failure, exercise, exercise therapy, exercise test, therapeutic exercise, cardiac rehabilitation, and kinesiotherapy. We also hand-searched reference lists of all identified studies, previous systematic reviews (20), and the Cochrane Collaboration’s review of exercise rehabilitation for HF. We excluded non-English articles.

Study selection.   Two investigators (M.J.H. and A.M.C.) independently reviewed the titles and abstracts of all citations to identify studies reporting the effect of exercise training on EF and/or LV volumes in patients with HF. Both investigators obtained the full text of potentially relevant articles and independently reviewed them using prestandardized data abstraction forms and eligibility criteria defined a priori. We excluded studies that were not randomized or were crossover trials, did not have a usual care control group, had an intervention group that also received a pharmacologic intervention, or had HF patients who were not clinically stable for at least 1 month before the exercise intervention.

Data extraction and quality assessment.   The 2 investigators extracted all outcome data independently. When necessary, original investigators were contacted to clarify data. Authors for 2 studies provided further data. Quality was assessed using the previously validated Jadad scale (21) (a 5-point scale based on adequacy of reporting for randomization, double-blinding, and disclosure of withdrawals and dropouts) and adequacy of allocation concealment.

Data synthesis and analysis.   Data were analyzed using the change from baseline data for both exercise and control groups. Results were combined as weighted mean differences (WMD) with 95% confidence intervals (CI) using a random effects model. Heterogeneity was quantified using the I2 statistic. As we anticipated heterogeneity on the basis of type of exercise, we planned to explore differences in effects for different types of exercise training (aerobic training, strength training, or combined aerobic and strength training). Sensitivity analyses were performed to examine the robustness of the effect by using standardized mean difference (SMD) for LV volume data. In addition, we conducted sensitivity analyses to determine whether blinding of the person assessing EF, EDV, and ESV to group allocation influenced the magnitude of any observed effects. Publication bias was tested visually using the funnel plot (22) and quantitatively using the Begg adjusted-rank correlation test (23) and Egger regression asymmetry test (24).


   Results
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Discussion
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Study selection and evaluation.   We identified 1,647 citations from electronic databases. After initial screening, 19 full manuscripts were reviewed, but 5 of these manuscripts were excluded because they did not report EF (n = 2), did not include a control group (n = 2), or were an additional publication from an already included trial (n = 1) (Fig. 1).


Figure 1
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  		Figure 1 Flow of Trials Through the Selection Process

 
Studies included in the systematic review.   Fourteen unique randomized trials were identified (Table 1). (12,13,17–19,25–33). The trials included clinically stable patients with HF symptoms and impaired LV systolic function (weighted mean EF = 23%), who were relatively young (mean age 57 ± 5 years) and predominantly men (89%). Most trials incorporated aerobic training at an intensity between 60% and 80% of baseline VO 2peak for 20 to 60 min per exercise session (12,13,17,19,26–28,31,33) (Table 1). Four trials examined the effects of combined aerobic and strength training (18,29,30,32), and one trial examined strength training alone (25). The length of the training program varied between 2 and 12 months.


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  		Table 1 Description of Included Studies
 
No trial was double-blind (which is not surprising given the type of intervention), and very few trials described randomization procedures. Only 4 trials (12,17,18,25) stated that the persons assessing EF, EDV, and ESV were blinded to group allocation (i.e., blinded ascertainment of outcomes). Therefore, trials scored relatively poorly on the Jadad scale: 7 received a score of 1 of 5, 5 studies received a score of 2 of 5, and 2 studies scored 3 of 5.

Quantitative data synthesis.   Exercise Training and LV Ejection Fraction
Although exercise training was associated with a significant improvement in EF when data from all trials were pooled (14 trials; 812 patients; WMD = 1.83%; 95% CI 0.45% to 3.21%), this analysis demonstrated substantial heterogeneity (I2 = 49.2%). However, the results from the trials of aerobic training demonstrated relatively consistent benefits in EF (9 trials, 538 patients, WMD = 2.59%; 95% CI 1.44% to 3.74%, I2 = 17.2%) (Fig. 2). The 1 trial testing strength training alone was inconclusive (WMD in EF = –4.5%, 95% CI –13.14% to +4.14%). Trials testing combined training (aerobic plus strength exercise) were also inconclusive (4 trials, 249 patients, WMD for EF = 0.37%; 95% CI –2.23% to +2.97%, I2 = 25.7%).


Figure 2
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  		Figure 2 Exercise Training and Ejection Fraction

AT = aerobic training; CI = confidence interval; ST = strength training; WMD = weighted mean differences.

 
Exercise Training and Left Ventricular Volumes
Seven of 14 trials examined the effect of exercise training on LV volumes (12,13,17–19,32,33). Aerobic training was performed in 5 of these trials (12,13,17,19,33); combined aerobic and strength training was performed in the remaining trials (18,32). Overall, exercise training was associated with a significant decline in EDV (569 patients; WMD = –9.75 ml; 95% CI –16.64 to –2.86 ml) and ESV (569 patients; WMD = –12.31 ml; 95% CI –17.12 to –7.49 ml). Although aerobic training led to significant improvements in EDV (371 patients; WMD = –11.49 ml; 95% CI –19.95 to –3.02 ml) and ESV (371 patients; WMD = –12.87 ml; 95% CI –17.80 to –7.93 ml) (Figs. 3 and 4),Go the effects of combined aerobic and strength training were inconclusive for both EDV (198 patients; WMD = +0.39 ml; 95% CI –25.84 to +26.62 ml, I2 = 0%) (Fig. 3) and ESV (WMD = –0.73 ml; 95% CI –23.19 to +21.72 ml; I2 = 0%) (Fig. 4).


Figure 3
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  		Figure 3 Exercise Training and End-Diastolic Volume

Abbreviations as in Figure 2.

 

Figure 4
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  		Figure 4 Exercise Training and End-Systolic Volume

Abbreviations as in Figure 2.

 
Given that the investigators of 2 aerobic intervention trials (17,33) referenced their volume data to body surface area, and the remaining aerobic trials reported absolute volumes, we performed sensitivity analysis using the SMD. These results further confirmed that aerobic training was associated with a significant and favorable decline in EDV (SMD = –0.36; 95% CI –0.56 to –0.15; I2 = 0%) and ESV (SMD = –0.50; 95% CI –0.72 to –0.28; I2 = 8.6%).

Our analysis of the impact that blinding of the person assessing EF, EDV, and ESV had on the observed results revealed an inconsistent effect. For EF, the 4 trials that reported blinded ascertainment of outcomes reported a smaller and less consistent effect with exercise training (blinded trials: WMD = 0.80%, 95% CI –2.86% to 4.46% but with 83% heterogeneity; nonblinded trials: WMD = 2.17%, 95% CI 1.00% to 3.34% with 0% heterogeneity). However, the blinded outcome ascertainment trials reported nonsignificantly greater benefits than the nonblinded outcome trials on EDV (blinded trials: WMD = –15.5 ml, 95% CI –35.81 to 4.80 ml; nonblinded trials: WMD = –7.14 ml, 95% CI –13.80 to –0.48 ml) and ESV (blinded trials: WMD = –16.91 ml, 95% CI –30.78 to –3.04 ml; nonblinded trials: WMD –11.08 ml, 95% CI –16.44 to –5.71 ml).

Additional End Points
Aerobic exercise training was associated with a statistically significant increase in VO 2peak (9 trials; 538 patients; WMD = 2.98 ml·kg·min–1; 95% CI 2.47 to 3.49 ml·kg·min; I2=16.3%), whereas the effect of combined aerobic and strength training on this end point remains uncertain (88 patients; WMD = 1.83 ml·kg·min; 95% CI –1.87 to +5.53 ml·kg·min; p value for heterogeneity = 0.002; I2 = 83.7%).

Publication bias.   There was no evidence of publication bias (Begg adjusted-rank correlation test, p = 0.66; Egger regression asymmetry test, p = 0.92).


   Discussion
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Conclusions
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This review indicates that aerobic exercise training reverses ventricular remodeling in clinically stable individuals with HF. The favorable changes in LV volumes and EF associated with aerobic training were supplementary to pharmacologic benefits; that is, they occurred despite the patients being prescribed medications with a proven antiremodeling effect (Table 1). Overall, the magnitude of the improvement in EF is consistent with the magnitude of benefits seen with angiotensin-converting enzyme inhibitors or cardiac resynchronization therapy (3,34).

The mechanism whereby aerobic training attenuates LV remodeling is not known; however, it may be due to the reduction in vasoconstrictive neurohormones or a decline in hemodynamic loading. Braith et al. (14) and others (12,15,33) have reported that aerobic training reduces resting plasma angiotensin II, aldosterone, vasopressin, atrial natriuretic peptide, brain natriuretic peptide, epinephrine, and norepinephrine levels. Coats et al. (16) also reported that short-term aerobic training is associated with a decrease in sympathetic tone and a concomitant increase in vagal activity in stable HF patients. The improved sympathovagal balance, coupled with the decline in vasoconstrictive neurohormones, is associated with a reduction in vascular load that may attenuate LV remodeling. Indeed, Hambrecht et al. (12,15) have shown that the reduction in resting LV end-diastolic volume and increase in peak exercise stroke volume that occurred with aerobic training were related to the decline in resting and peak exercise systemic vascular resistance, respectively (12). Belardinelli et al. (27,35) extended these findings by demonstrating that aerobic training also improves myocardial contractility and diastolic filling in individuals with ischemic cardiomyopathy and impaired LV systolic function. Our finding of increased EF after aerobic training is likely attributable to enhanced preload, myocardial contractility, and vascular reserve.

An unexpected finding was that strength training was not associated with demonstrable benefit in LV remodeling; indeed, the favorable antiremodeling role of aerobic exercise was not confirmed when this mode of exercise was combined with strength training. This may be because of the heightened systolic and diastolic pressure loading that occurs with strength training (36–38). Moreover, the strength-training-mediated increase in LV wall stress, coupled with the impaired contractile and preload reserve, could explain why LV stroke volume and EF do not increase when HF patients perform this type of exercise (36,37).

Our finding that aerobic training is associated with a significant increase in VO 2peak is similar to previous systematic reviews that examined the effect of exercise rehabilitation on clinical outcomes in HF (39,40). Indeed, a recent meta-analysis by Piepoli et al. (41) found that exercise training was associated with a reduction in overall mortality in individuals with HF. Importantly, 8 of the 9 trials included in their analysis incorporated aerobic exercise training. A limitation of previous meta-analyses (39,40) is that they did not examine the effect of exercise or mode of exercise training on LV remodeling. Also, in contrast to previous reviews (20,39), we excluded studies that were not strictly randomized.

Study limitations.   As with most meta-analyses, our conclusions are constrained by the restricted nature of trial participants: the vast majority of HF patients in these trials were clinically stable younger men with systolic dysfunction, which is not typical of the demographic profile in population-based studies of HF patients (42). A more representative population is currently being recruited to the HF-ACTION trial, the largest randomized controlled trial to date examining the effect of exercise training on clinical outcomes in HF (9). Another limitation of our analysis is low use of beta-blockers in the studies included. Indeed, beta-blockers have been shown to have a greater effect on LV size and ejection fraction compared to that found with exercise training in this meta-analysis (8). An additional limitation is the lack of trials examining the effect of strength training alone on LV remodeling. Finally, our conclusions were constrained by the quality of the trials reviewed, the majority of which did not incorporate blinding at any stage. In particular, only 4 of these trials included blinded outcomes ascertainment (i.e., the persons assessing EF, EDV, and ESV were not blinded to treatment group allocation in most of these trials). Although we did not find a consistent difference in the effects demonstrated in blinded and nonblinded trials, future trials of the impact of exercise training on LV remodeling should incorporate blinded outcomes ascertainment, given the known interobserver variability in assessments of EF, EDV, and ESV with current techniques.


   Conclusions
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 Abstract
 Methods
 Results
 Discussion
 Conclusions
References
 
Aerobic training is an inexpensive and effective nondrug, nondevice, nonsurgical intervention that reverses ventricular remodeling and improves VO 2peak in clinically stable individuals with HF and LV systolic dysfunction. These benefits were not confirmed with combined aerobic and strength training.


   Acknowledgments
 
The authors thank the investigators listed in reference 32 for providing further details about their study.


   Footnotes
 
1 Dr. Haykowsky holds a Canadian Institutes of Health Research (CIHR) New Investigator award. Back

2 Drs. Clark and McAlister hold salary awards from the Alberta Heritage Foundation for Medical Research. Back

3 Dr. McAlister also holds a CIHR New Investigator Award and the Merck Frosst/Aventis Chair in Patient Health Management at the University of Alberta. Back


   References
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 HypertensionHome page
A. J. Chicco, S. A. McCune, C. A. Emter, G. C. Sparagna, M. L. Rees, D. A. Bolden, K. D. Marshall, R. C. Murphy, and R. L. Moore
Low-Intensity Exercise Training Delays Heart Failure and Improves Survival in Female Hypertensive Heart Failure Rats
Hypertension, April 1, 2008; 51(4): 1096 - 1102.
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 J Am Coll CardiolHome page
M. J. Haykowsky, Y. Liang, D. Pechter, L. W. Jones, F. A. McAlister, and A. M. Clark
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J. Am. Coll. Cardiol., December 11, 2007; 50(24): 2356 - 2356.
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V. Conraads, P. Beckers, and C. J. Vrints
Exercise in Chronic Heart Failure: Does it Need to Be "Anti-Remodeling"?
J. Am. Coll. Cardiol., December 11, 2007; 50(24): 2355 - 2356.
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S. A. Rubin
Exercise Training in Heart Failure: Contradictory or Conventional?
J. Am. Coll. Cardiol., June 19, 2007; 49(24): 2337 - 2340.
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