Exercise Training in Patients With Heart Failure and Preserved Ejection Fraction
Heart failure with preserved ejection fraction (HFPEF) is common and characterized by exercise intolerance and lack of proven effective therapies. Exercise training has been shown to be effective in improving cardiorespiratory fitness (CRF) in patients with systolic heart failure. In this meta-analysis, we aim to evaluate the effects of exercise training on CRF, quality of life, and diastolic function in patients with HFPEF.
Methods and Results—
Randomized controlled clinical trials that evaluated the efficacy of exercise training in patients with HFPEF were included in this meta-analysis. Primary outcome of the study was change in CRF (measured as change in peak oxygen uptake). Effect of exercise training on quality of life (estimated using Minnesota living with heart failure score), and left ventricular systolic and diastolic function was also assessed. The study included 276 patients who were enrolled in 6 randomized controlled trials. In the pooled data analysis, patients with HFPEF undergoing exercise training had significantly improved CRF (mL/kg per min; weighted mean difference, 2.72; 95% confidence interval, 1.79–3.65) and quality of life (weighted mean difference, −3.97; 95% confidence interval, −7.21 to −0.72) when compared with the control group. However, no significant change was observed in the systolic function (EF−weighted mean difference, 1.26; 95% confidence interval, −0.13% to 2.66%) or diastolic function (E/A−weighted mean difference, 0.08; 95% confidence interval, −0.01 to 0.16) with exercise training in patients with HFPEF.
Exercise training in patients with HFPEF is associated with an improvement in CRF and quality of life without significant changes in left ventricular systolic or diastolic function.
Heart failure with preserved ejection fraction (HFPEF) is common, representing ≈50% of HF admissions.1,2 Exercise intolerance is the primary symptom among patients with HFPEF.3 Although pharmacological therapies, such as angiotensin-converting enzyme inhibitors and mineralocorticoid receptor antagonists have failed to a mortality benefit in HFPEF,2,4–6 there are several studies showing significant improvement in exercise capacity in response to these agents.7,8 Left ventricular (LV) diastolic dysfunction has been identified as one of the mechanisms underlying exercise intolerance in these patients.9 As a result, there has been a significant interest in novel therapeutic approaches that could improve diastolic function and ameliorate exercise intolerance in HFPEF.
Editorial see p 5
Clinical Perspective on p 40
Exercise training is one such therapeutic approach that is associated with significant improvement in cardiorespiratory fitness (CRF) in patients with HF and reduced EF.10,11 Although some studies have attributed this to exercise-induced favorable changes in LV function and cardiac output,11,12 others have identified peripheral adaptations in the arterial and skeletal muscle function as the primary contributor to improvement in fitness after exercise training.13,14 Exercise training is also associated with improved exercise tolerance among sedentary, obese, and hypertensive participants who are at high risk for HFPEF.15 Several recent studies have evaluated exercise training as a therapeutic management strategy in patients with HFPEF.16–21 Although these studies were not designed to address clinical end points, such as HF hospitalizations and mortality, they have demonstrated a variable degree of improvement in exercise tolerance and diastolic function in response to training. The aim of this meta-analysis is to assess the effects of exercise training on exercise tolerance, quality of life, and diastolic function in patients with HFPEF.
Data Sources and Searches
A comprehensive computerized literature search of Medline, EMBASE, OVID, Web of Science, and Cochrane databases was conducted using MeSH terms and keywords including HF, diastolic HF, HF with normal EF, HFPEF, exercise training, and cardiac rehabilitation. In addition, the institutional records were manually searched for available theses using the expertise of a medical librarian.
We initially evaluated all comparative studies, including randomized or nonrandomized parallel group trials, prepost within group design that enrolled adult patients (age, ≥18 years) with HFPEFF (Figure 1; Table I in the Data Supplement). However, only randomized controlled trials were included in the final analysis to maintain consistency and obtain robust pooled estimates. Primary outcome of the study was change in CRF (measured as change in peak oxygen uptake in mL/kg per minute). Secondary outcomes that were also assessed in the study included change in Minnesota living with HF (MLWHF) score, markers of diastolic function (changes in E/A ratio and early deceleration time), and LVEF. Studies failing to report ≥1 of the above predefined study outcomes were excluded from our analysis.
Full-text articles were retrieved for all title-abstracts that met the inclusion criteria. Data extraction was then independently performed by the coprimary authors (A.P. and A.P.) using a standardized questionnaire. All discrepancies about the study inclusion or outcomes were resolved by the senior author (J.D.B.). In cases of multiple publications arising from a single trial, only the updated trial with the maximum number of patients was included.
Data Synthesis and Statistical Analysis
Meta-analysis of the outcomes was conducted using Metan and Metareg functions available for Stata version 12.1 statistical software (Stata Corporation, College Station, TX).22 The meta-analysis has been reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta Analyses guidelines.23 We primarily used fixed-effect modeling to conduct the meta-analysis of outcomes from included studies. We assessed for heterogeneity using the I2 test (I2≥25% was assumed to be a result of significant heterogeneity). In cases of significant heterogeneity, we reported a pooled estimate based on the random-effects model. Weighted mean differences (WMD) and corresponding 95% confidence intervals (CIs) were computed for all continuous outcomes. To assess the effect of demographic factors, such as age and sex on treatment outcomes, random-effect meta-regression models were constructed for the primary outcome (change in CRF). Furthermore, to account for differences in the baseline measures of CRF and MLWHF score between control and training groups, we conducted additional meta-regression analysis for these outcomes (change in CRF and change in MLWHF score) adjusting for their baseline values. The variables included in the meta-regression model were identified a priori to safeguard against false-positive results because of an overfitted model. Risk of bias analysis was performed using Cochrane collaboration’s assessment tool in RevMan version 5.2 software.24 Publication bias was assessed using the funnel plots and quantified by Egger regression test. All P values were 2 tailed with statistical significance specified at 0.05 and CI reported at the 95% level.
We included a total of 276 participants enrolled in 6 randomized controlled trials, with a mean follow-up duration of 12 to 24 weeks (weighted mean duration, 19 weeks). The baseline demographic and clinical characteristics of the study participants are summarized in Table 1. All 6 trials included well-compensated patients with HFPEF (EF, ≥45%), stabilized on cardiac medications with no recent hospitalizations. The HFPEF definition and exclusion criteria used in the included studies are discussed in Table 2. The exercise training protocol, control group care, and outcomes measured in the included trials are discussed in Table 3. The study participants had an echocardiographic and CRF assessment at baseline and follow-up.
|Gary et al16||Kitzman et al17||Edelmann et al18||Smart et al20||Alves et al19||Kitzman et al21|
|Total participants (control/training)||16/16||27/26||20/44||13/12||11/20||31/32|
|Mean age, y||68±11||69.5±5.5||65±7||64.4±6.4||62.9±10.2||70±7|
|Mean body mass index, kg/m2||33.5±6.5||0.5±6.5||31±5||32.1±6.4||28.4+4.5||32.1±6.6|
|NYHA class II, %||41||51||84||64||39||51|
|NYHA class III, %||59||21||16||0||55||49|
|Diabetes mellitus, %||31||17||14||16||35||24|
|Baseline systolic BP, mm Hg||NA||147±20||140±19||131±11||NA||146±17|
|Baseline heart rate, bpm||NA||69±13||66±11||NA||NA||NA|
|Presentation EF, %||≥45||≥50||≥50||≥45||≥55||≥50|
|Exercise capacity assessment||6-min walk test||Cycle Ergometer||Cycle Ergometer||Cycle Ergometer||Exercise treadmill test||Cycle Ergometer|
|6-min walk at baseline, feet||832±366||1452±332||1794±282||NA||NA||1450±300|
|Peak oxygen uptake baseline, mL/kg per minute||NA||13.3±2.6||16.3±4.8||13.2±3.9||13.6±4.9||14.1±3.0|
|Blinded assessment of outcomes||No||Yes||Yes||Yes||Yes||Yes|
|Trial||Criteria used for Defining HFPEF||Exclusion Criteria|
|Gary et al16||NYHA class II or III diastolic heart failure on chart reviewEjection fraction >50%Stabilized on cardiac medications for ≥3 mo||Significant coronary artery diseaseRenal insufficiency, uncontrolled hypertension|
|Kitzman et al17,21||Symptoms and signs defined by NHANES HF score >3History of acute pulmonary edemaOR ≥2 of the following symptoms: dyspnea on exertion, paroxysmal nocturnal dyspnea, orthopnea, lower-extremity edema, or exertional fatigue.Well-compensated, stabilized on cardiac medications for ≥6 wk||Significant coronary artery disease, valvular heart disease, or pulmonary disease, anemia|
|Edelmann et al18||Symptomatic (NYHA II/III) with ejection fraction >50%Echo determined diastolic dysfunction in sinus rhythm≥1 cardiovascular risk factorStabilized on cardiac medications for ≥4 wk||Significant coronary artery disease, valvular heart disease or pulmonary disease, anemia, uncontrolled Hypertension, arrhythmia|
|Smart et al20||Significant dyspnea on exertion with delayed relaxation or pseudonormal filling on echo.||Hx of coronary artery disease COPD, valvular disease|
|Alves et al19||Signs and symptoms of heart failure with ejection fraction >55%||Uncontrolled hypertension, unstable angina, abnormal hemodynamic response, arrhythmias, ischemic ECG changes during treadmill test|
|Exercise Training Group Intervention||Control Group Intervention||Duration||Outcome Measured|
|Gary et al16||Self-monitored community based walking intervention+home education program.Walking intervention with ambulatory heart rate monitoring, initially at an intensity of 40% of target heart rate for wk 1 with gradual increase to 60% as tolerated||Weekly visits with home education program||12 wkvw||Exercise capacity as 6-min walk testQuality of life|
|Kitzman et al17,21||Supervised endurance training (track walking +cycling) 3× per wkWk 1–2: exercise at 40%–50% of peak VO2 with gradually increasing duration.Wk 3–16: exercise intensity at 60%–70% of peak VO2 and duration increased to 15–20 min||Telephone call follow-up every 2 wk without addressing exercise behavior||16 wk||Peak oxygen uptakeSystolic, diastolic function by echoLV dimensionsQuality of life|
|Edelmann et al18||Supervised, endurance (cycling)+resistance trainingWk 1–4: aerobic endurance training at 50% to 60% of baseline peak VO2Wk 5–12: aerobic endurance at 70% of baseline peak VO2+resistance training||Usual care and maintenance of usual activities||24 wk||Peak oxygen uptakeSystolic, diastolic function by echoLV dimensionsQuality of life|
|Alves et al19||Supervised endurance training on treadmill/cycle ergometerWk 1–4: training at 70%–75% of peak VO2Wk 5–24: training at 70%–75% of peak VO2.||Usual care with regular cardiologist follow-up||24 wk||Peak oxygen uptakeSystolic, diastolic function by echoLV dimensionsQuality of life|
|Smart et al20||Supervised, outpatient, cycle ergometer exercise trainingInitial intensity of 60%–70% peak VO2Exercise intensity uptitrated by 2–5 W/wk as tolerated||Usual care and maintenance of usual activity levels||16 wk||Peak oxygen uptakeSystolic, diastolic function by echoLV dimensionsQuality of life|
The Cochrane risk of bias assessment tool was used to perform quality assessment (Figure I in the Data Supplement). During quality assessment, random sequence generation was observed in all studies. Blinded assessment of outcomes was performed in 5 of the 6 included trials. Incomplete outcome data or selective reporting of results was not observed in any of the selected studies. We also did not observe any significant publication bias in the formal analysis.
Effect of Exercise Training on CRF
Four studies reported exercise capacity at baseline and after exercise training, using symptom-limited cardiopulmonary exercise testing on a bicycle ergometer or treadmill. A greater improvement in peak oxygen uptake was observed among patients with HFPEF undergoing exercise training versus usual care patients in all the included trials (Table II in the Data Supplement). There was no significant statistical heterogeneity across studies reporting peak oxygen uptake. Pooling across the 4 trials using fixed-effect meta-analysis showed that exercise training is associated with a significant improvement in peak oxygen uptake (mL/kg per minute) from baseline to follow-up among patients with HFPEF (WMD, 2.72; 95% CI, 1.79–3.65; P=0.0001; Figure 2). Meta-regression analysis showed no significant effect of age, sex, and baseline measure of peak oxygen uptake on the pooled WMD (age: meta-regression coefficient, −0.23; P=0.42; sex: meta-regression coefficient, −0.04; P=0.48; baseline line measure of peak oxygen uptake: meta-regression coefficient, 0.48; P=0.3).
Effect of Exercise Training on Quality of Life
Five studies reported an effect of exercise training on quality of life (determined using the MLWHF questionnaire). Clinically meaningful improvement in MLWHF total score (>5-point reduction in MLWHF score from baseline to follow-up) was observed among patients with HFPEF undergoing exercise training in all the included trials (Table II in the Data Supplement). No significant heterogeneity was observed across the 5 trials. Pooling across the 5 studies using fixed-effect meta-analysis showed a statistically significant improvement in the quality of life score from baseline to follow-up as assessed by the MLWHF questionnaire among exercise training participants when compared with the usual care group (WMD, −3.97; 95% CI, −7.21 to −0.72; P=0.02; Figure 2). Meta-regression analysis showed no significant effect of baseline MLWHF score on the pooled WMD (meta-regression coefficient, −1.05; P=0.2).
Effect of Exercise Training on Diastolic and Systolic Function
Five studies reported the effect of exercise training on diastolic function. E/A and deceleration time were reported as measures of diastolic function reported in 3 studies, whereas one study reported only E/A and another reported only E/e′ (Table III in the Data Supplement). Pooling across all the available studies using fixed-effect meta-analysis showed no significant change in E/A (WMD, 0.08; 95% CI, −0.01 to 0.16; P=0.08; Figure 3) or early deceleration time (ms; WMD, 2.92; 95% CI, −18.56 to 24.41; P=0.79; Figure 3) with exercise training when compared with the control group participants. Similarly, we did not observe any significant change in systolic function (EF) with exercise training on fixed-effect meta-analysis of pooled data from the 5 studies (WMD, 1.26%; 95% CI, −0.13% to 2.66%; P=0.08; Figure 3; Table III in the Data Supplement).
Safety of Exercise Training
No major adverse effects of exercise training were reported in the included studies (Table 4).
|Studies||Exercise-Associated Adverse Events|
|Gary et al16||No adverse events|
|Kitzman et al17||No adverse events|
|Edelmann et al18||No serious adverse events. Palpitations (n=2); dyspnea (n=2); muscle discomfort (n=9)|
|Kitzman et al21||1 exercise patient with transient hypoglycemia|
|Smart et al20||Not reported|
In the present meta-analysis, we observe 2 important findings. First, exercise training improves CRF and quality of life in patients with HFPEF. Second, exercise training in these patients is not associated with any significant change in resting diastolic or systolic function. Taken together, these findings suggest that exercise training may improve CRF in patients with HFPEF through mechanisms independent of LV function.
Exercise training has been shown to improve fitness and quality of life in asymptomatic hypertensive participants who are at risk for HFPEF.15,25 Similarly, in patients with HF with reduced EF, studies have shown a consistent improvement in fitness and quality of life after exercise training.10,26 In the present study, we have extended these findings showing a favorable effect of exercise training on fitness and quality of life among patients with HFPEF.
The mechanism by which exercise training improved exercise tolerance in HFPEF is not completely clear. Exercise training has been shown to improve systolic and diastolic function in patients with HF and reduced EF.11,27 However, in the present study, there was no significant change in diastolic function with exercise training in patients with HFPEF. It is important to note that for our meta-analysis, we used E/A and early deceleration time as measures of diastolic function because they were most commonly reported. E/E′, a more specific measure of diastolic function,28 was only reported in 1 included study by Edelmann et al18 and was not used for pooled analysis. Interestingly, Edelman et al18 did show a significant improvement in E/E′ with exercise training.
Increased arterial stiffness and endothelial dysfunction have also been shown to contribute to exercise intolerance in patients with HFPEF.21,29–31 However, in a recent study by Kitzman et al,21 exercise training failed to improve the endothelial function and arterial stiffness in such patients. Another potential mechanism by which exercise training has been shown to improve CRF in asymptomatic, sedentary participants is through physiological remodeling and associated improvement in stroke volume and cardiac output. However, recent works by Fujimoto et al32 and Haykowsky et al33 have shown that exercise training in HFPEF patients is not associated with any significant change in cardiac output. The effect of exercise training on arterial stiffness, endothelial function, and cardiac output could not be assessed in the present meta-analysis because these outcomes were not reported in the majority of the clinical trials. Taken together, the available literature suggests that exercise training may improve exercise tolerance through peripheral mechanisms leading to an improved oxygen extraction in the active skeletal muscles.21,33,34 If so, this would mirror the results of studies investigating the mechanisms of improvement in exercise capacity after exercise training in patients with HF and reduced EF to some extent.14,35–37
Exercise intolerance is the primary symptom of HFPEF and an important determinant of quality of life.3,38 Although pharmacological interventions have been ineffective in reducing patient mortality with HFPEF, a substantial improvement in exercise capacity without a significant change in diastolic function was reported in a recent meta-analysis of all HFPEF drug trials.8 Similar results were observed in the present meta-analysis using exercise training in these patients. These findings suggest that exercise training can be used as an alternative therapeutic strategy for the improvement of symptoms in patients with HFPEF.
Findings in our study are similar to those in the meta-analysis of Taylor et al,39 who evaluated the effect of exercise training on HFPEF. However, more recent randomized control trials have been published since the latter study was completed in November 2011.19–21 The present work, with twice as many study participants, represents an updated and more comprehensive evaluation of the effect of exercise training in patients with HFPEF. Moreover, the previous meta-analysis included both randomized and nonrandomized clinical trials that may have lead to potential bias because it was impossible to remove interference of unknown confounding factors completely.
There are several limitations in this study. First, we only have 6 clinical trials included in the meta-analysis reflecting the scarcity of randomized control trials in literature addressing this issue. This could be because of several challenges that are associated with exercise training trials among patients with HFPEF. These include nonadherence and high drop out rates among training participants, time and resource intense nature of intervention, and difficulties with selection of right patient population that will benefit from exercise training. Furthermore, the sample size of some included trials was small resulting in wide CIs for point estimates associated with study outcomes. This highlights the significance of pooled analysis that has been conducted in the present study. Second, the standard measure of diastolic function E/E′ was not consistently reported in all the included clinical trials and was, therefore, not used for pooled analysis. Third, echocardiographic parameters are reported in only 4 of the 6 included studies and the meta-analysis may not be adequately powered to draw definitive conclusions about the effect of exercise training on echocardiographic parameters. Additional studies with larger sample size are needed to determine the effect of exercise training on echocardiographic outcomes. Fourth, the mean follow-up duration in these clinical trials was relatively short (12–24 weeks), and longer duration follow-up may be needed to observe significant changes in LV remodeling and diastolic function. Fifth, none of the included trials reported clinical outcomes, such as HF hospitalization or mortality; therefore, we were unable to assess these points. Furthermore, it is difficult to evaluate the sustainability of effects of exercise training intervention on CRF among patients with HFPEF in the present meta-analysis because all the trials measured outcomes at the end of follow-up. Finally, as with all meta-analyses, selection bias cannot be completely ruled out because articles were only retrieved from published trials.
Taken together, the findings from our study suggest that exercise training in patients with HFPEF improves CRF and quality of life without a significant change in LV diastolic function. Additional studies among patients with HFPEF with well-characterized phenotype that have longer follow-up duration, use more efficient and less resource intense exercise training protocols, and assess relevant clinical end points are needed to determine whether exercise training can be used as an effective management strategy for these patients in the real world.
Sources of Funding
Dr Berry receives funding from (1) the Dedman Family Scholar in Clinical Care endowment at University of Texas Southwestern Medical Center, (2) grant 13GRNT14560079 from the American Heart Association and (3) grant 14SFRN20740000 from the American Heart Association prevention network.
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Patients with heart failure with preserved ejection fraction (HFPEF) are older and most commonly present with symptoms of exercise intolerance. Although exercise training is well accepted as a management strategy for heart failure with reduced ejection fraction, its role in the management of patients with HFPEF is not well established. In the present meta-analysis, we observed that exercise training is associated with significant improvements in cardiorespiratory fitness and quality of life among patients with HFPEF. These findings suggest that exercise training could be used as an alternative therapeutic strategy for management of patients with HFPEF. This study also provides some insight into the potential mechanisms through which training may improve fitness among these patients. We did not observe any significant changes in left ventricular diastolic function with exercise training, suggesting that other mechanisms may play an important role in exercise training-associated improvement of fitness among these patients. Additional studies that use more efficient, less resource intense training protocol and assess relevant clinical end points such as HF hospitalization and mortality are needed to determine whether exercise training can be established as an effective management strategy for HFPEF in the real world.