Clinical outcomes and cardiovascular responses to exercise training ...

J Appl Physiol 119: 726 –733, 2015. First published March 6, 2015; doi:10.1152/japplphysiol.00904.2014.

Review

Exploring New Concepts in the Management of Heart Failure with Preserved Ejection Fraction: Is Exercise the Key for Improving Treatment? HIGHLIGHTED TOPIC

Clinical outcomes and cardiovascular responses to exercise training in heart failure patients with preserved ejection fraction: a systematic review and meta-analysis Gudrun Dieberg, Hashbullah Ismail, Francesco Giallauria, and X Neil A. Smart School of Science and Technology, University of New England, Armidale, New South Wales, Australia Dieberg G, Ismail H, Giallauria F, Smart NA. Clinical outcomes and cardiovascular responses to exercise training in heart failure patients with preserved ejection fraction: a systematic review and meta-analysis. J Appl Physiol 119: 726–733, 2015. First published March 6, 2015; doi:10.1152/japplphysiol.00904.2014.—Exercise training induces physical adaptations for heart failure patients with systolic dysfunction, but less is known about those patients with preserved ejection fraction. To establish whether ˙ O2 and related measures, quality of exercise training produces changes in peak V life, general health, and diastolic function in heart failure patients with preserved ejection fraction. We conducted a MEDLINE search (1985 to October 10, 2014), for exercise-based rehabilitation trials in heart failure, using search terms “exercise training, heart failure with preserved ejection fraction, heart failure with normal ˙ O2, and diastolic heart dysfunction”. Seven intervention ejection fraction, peak V studies were included providing a total of 144 exercising subjects and 114 control ˙ O2 increased by a mean difference (MD) subjects, a total of 258 participants. Peak V 2.13 ml·kg⫺1·min⫺1 [95% confidence interval (CI) 1.54 to 2.71, P ⬍ 0.00001] in exercise training vs. sedentary control, equating to a 17% improvement from baseline. The corresponding data are provided for the following exercise test ˙ E/V ˙ CO2 slope, MD 0.85 ml·kg⫺1·min⫺1 (95% CI 0.05 to 1.65, P ⫽ variables: V 0.04); maximum heart rate, MD 5.60 beats per minute (95% CI 3.95 to 7.25, P ⬍ 0.00001); Six-Minute Walk Test, MD 32.1 m (95% CI 17.2 to 47.1, P ⬍ 0.0001); and indices of diastolic function: E/A ratio, MD 0.07 (95% CI 0.02 to 0.12, P ⫽ 0.005); E/E= ratio MD ⫺2.31 (95% CI ⫺3.44 to ⫺1.19, P ⬍ 0.0001); deceleration time (DT), MD ⫺13.2 ms (95% CI ⫺19.8 to ⫺6.5, P ⫽ 0.0001); and quality of life: Minnesota Living with Heart Failure Questionnaire, MD ⫺6.50 (95% CI ⫺9.47 to ⫺3.53, P ⬍ 0.0001); and short form-36 health survey (physical dimension), MD 15.6 (95% CI 7.4 to 23.8, P ⫽ 0.0002). In 3,744 h patient-hours of training, not one death was directly attributable to exercise. Exercise training appears to effect several health-related improvements in people with heart failure and preserved ejection fraction. exercise training; cardio-respiratory fitness; heart failure with preserved ejection fraction

HEART FAILURE WITH PRESERVED ejection fraction (HFpEF) is defined as an inability of the ventricles to optimally accept blood from the atria with blunted end-diastolic volume response by limiting the stroke volume and cardiac output. Exercise intolerance and reduced quality of life are known as the primary chronic symptoms in HFpEF patients. HFpEF prevalence is higher in elderly and women and may be linked to hypertension, diabetes mellitus, and atrial fibrillation (2, 18). Chronic heart failure (CHF) patients with either normal or

Address for reprint requests and other correspondence: N. A. Smart, School of Science and Technology, Univ. of New England, Armidale, NSW 2351, Australia (e-mail: [email protected]). 726

abnormal systolic function have similar mortality rates (4). In the United States, CHF affects ⬃5 million individuals with heart failure, and more than 555,000 are newly diagnosed with CHF annually (22). Corresponding costs to the health care systems are enormous. A review by Smart (25) estimated the hospital-based exercise therapy treatment costs to prevent mortality in one CHF patient to be approximately (U.S.) $60,000/ yr. Meta-analyses have shown exercise training to be beneficial in HFpEF patients in terms of improved cardiorespiratory fitness (12, 30). In people with HFpEF, as well as systolic heart failure, ˙ O2) is impaired. Impaired peak cardiorespiratory fitness (peak V ˙ VO2 has been associated with increased mortality risk (10) and

8750-7587/15 Copyright © 2015 the American Physiological Society

http://www.jappl.org

Review

METHODS

Search Strategy Studies were identified through a MEDLINE search (1985 to October 10, 2014), Cochrane Controlled Trials Registry (1966 to October 10, 2014), CINAHL, SPORTDiscus, and the Science Citation Index. The search strategy included a mix of MeSH and free text terms for key concepts related to exercise training, heart failure with normal ejection fraction, and heart failure with preserved ejection ˙ O2, and diastolic heart failure for clinical trials of fraction, peak V exercise training in heart failure patients. Studies were included when patients exhibited baseline left ventricular ejection fraction above 45%. These searches were limited to prospective, randomized, or controlled trials and human studies, with no language restrictions on publications. Manuscript reference lists and latest journal editions were scrutinized for new references. Full journal articles were assessed by three reviewers (N. A. Smart, G. Dieberg, and H. Ismail) for relevance and eligibility. Methodological disagreements were resolved by reviewers through discussion. For two studies (9, 16), authors were contacted and requested to provide further data about the protocol for implementing desired exercise intensity.

•

727

Dieberg G et al.

Records identified through database searching (n = 32)

Additional records identified through other sources (n = 6)

Records screened (n = 19)

Records excluded (n = 11)

Eligibility

Screening

Records after duplicates removed (n = 19)

Full-text articles assessed for eligibility (n = 8)

Full-text articles excluded, with reasons (n=1)

Included

decreased quality of life in heart failure patients. As measured by traditional indices such as ejection fraction, systolic function appears largely normal under resting baseline conditions in HFpEF. However, studies have shown through global assessment of systolic function by other techniques, such as strain rate imaging, systolic abnormalities do exist in HFpEF patients (17). Despite the preservation of systolic function at rest, mortality rates in HFpEF are similar to those observed in systolic failure (5), highlighting the clear need for effective treatment strategies for these patients. Interestingly, conventional methods for treating heart failure have proven largely ineffective for HFpEF patients. Currently, effective therapeutic approaches for HFpEF are limited and focus primarily on managing cardiovascular risk factors, especially hypertension. Exercise therapy is a promising effective adjunct therapy that can delay disease progression, minimize pharmaceutical use, and improve functional limitations and quality of life. While, to date, ⬃100 randomized, controlled trials of exercise training have been published in systolic heart failure patients, strikingly, only 10 such trials exist examining HFpEF. In this meta-analysis, our purpose was to assess the effects of exercise on a number of outcome measures that are commonly used to assess clinical status in HFpEF. First, we evaluated the impact of exercise training on changes to exercise capacity in HFPEF patients compared with sedentary ˙ O2, V ˙ E/V ˙ CO2, heart rate, controls through examination of peak V and the Six-Minute Walk Test (6MWT). Second, we studied clinical measures of diastology, including early-to-late filling ratio (E/A), E/E= (a widely accepted noninvasive surrogate of left ventricular filling pressure) and deceleration of early ventricular filling. Third, we examined whether exercise training produces better quality of life and/or general health through use of the Minnesota Living with Heart Failure Questionnaire (MLHFQ) (21) and the SF-36 (which has established norms) (3). Finally, we examined whether rates of serious events, mortality, and hospitalization were more frequent with exercise training in HFPEF patients.

Identification

Exercise Training in Heart Failure with Preserved Ejection Fraction

Studies included in quantitative synthesis (meta-analysis) (n = 7)

Fig. 1. Consort statement.

Study Selection Included were randomized controlled designs of exercise training in heart failure patients with normal or preserved ejection fraction. Studies of heart failure patients with abnormal systolic function were excluded. All included studies are comparisons between exercise training and sedentary control. Records identified 32 papers through database searching. Six additional records from reference lists were added. Only principal studies, with the most subjects, were included— studies for which multiple publications existed from the same dataset. After initial screening, 19 studies were removed, which included overlapping studies, duplicates, duplicate data, abstracts, irrelevant articles (e.g., editorials and discussion papers). We further excluded 12 studies in which the control group received additional intervention, nonrelevant studies, and acute exercise responses. Seven studies of exercise training intervention were included (see Consort Statement, Fig. 1). Outcome Measures ˙ O2 (baseline and postexercise), We recorded the following; peak V ˙ E/V ˙ CO2, maximum heart rate, 6MWT, diastolic function [E/A and V E/E= ratios, deceleration time (DT)], MLHFQ, short form-36 health survey, participant completion rates, adverse medical events, hospitalization, and mortality. Data Synthesis We calculated patient-hours of exercise training and percentage ˙ O 2. change in peak V Assessment of Study Quality We assessed study quality using the 15-point TESTEX scale (29), which is a validated study quality assessment tool specific to exercise training studies. Median TESTEX score was 10, with two studies scoring 8, three scoring 10, and two studies scoring 12.

J Appl Physiol • doi:10.1152/japplphysiol.00904.2014 • www.jappl.org

Review 728


•

Dieberg G et al.

Table 1. Patient and training characteristics for randomized control trials included in the meta-analysis on exercise training studies with HFpEF patients Study

Country

Sessions Attended, %

Alves et al. (1)

Portugal

Edelmann et al. (6)

Germany 34 participated in ⬎90%, 52 in 70–90% and 14 in ⬍70% of the exercise sessions.

Gary et al. (9)

USA

Karavidas et al. (15) Greece

Kitzmann et al. (16)

USA

Palau et al. (20)

Australia

Smart et al. (28)

Australia

100

100

100

86, final testing; 88, exercise training

100

87.6

Participants Included in the Final Analysis

Total patients N ⫽ 98 Exercise (⬎55% LVEF): n ⫽ 20, 22 m/9 f, mean age: 62.9. Control: n ⫽ 11 Exercise (45%–54% LVEF): n ⫽ 23, 24 m/9 f, mean age: 63.6. Control: n ⫽ 10 Exercise (⬍45% LVEF): n ⫽ 22, 27 m/7 f, mean age: 62.0. Control: n ⫽ 12 NYHA class I/II/III/IV Total patients: N ⫽ 64 Exercise: n ⫽ 44, 24 m/20 f, mean age: 64 Control: n ⫽ 20, 12 m/8 f, mean age: 65 NYHA class II/III

Total patients N ⫽ 28 Exercise: n ⫽ 15, 15 f, mean age: 67 Control: n ⫽ 13, 13f, mean age: 69 NYHA class II/III Total patients N ⫽ 30 Exercise: n ⫽ 15, 6 m/9 f, mean age: 69.4 Control: n ⫽ 15, 6 m/9 f, mean age: 68.5 NYHA class II/III Total patients N ⫽ 63 Exercise: n ⫽ 24, 23 m/9 f, mean age: 70 Control: n ⫽ 30, 25 m/6 f, mean age: 70 NYHA class II/III

Training Characteristics

Outcome Measures

6 mo of interval exercise training. First month, 3 sessions per week, and 15 min at 70–75% of maximal heart rate. Following 5 mo, 3 sessions per week, and 35 min at 70–75% of maximal heart rate

LVEF Diastolic function

32 sessions of continuous exercise training. Weeks 1–4, 2 sessions per week, 20–40 min ˙ O . Week at 50–60% of peak V 2 5 onward, 3 sessions per week ˙ at 70% of peak VO2 and resistance training, 15 reps at 60–65% 1 RM

LVEF ˙ O2 Peak V Heart rate 6MWT MLHF SF-36

12 wk of continuous exercise training (walking). 3 sessions per week, 20–40 min at 40% ⫺60% of the maximal heart rate 6 wk of functional electrical stimulation (FES) training. 5 sessions per week, 30 min at 25 Hz for 5 s followed by 5-s rest

6MWT MLHF

4 mo (⬃16 wk of continuous exercise training. 3 sessions per week, 60 min at 40–70% HRR

Total patients N ⫽ 26 Exercise: n ⫽ 14, 7 m/7 f, mean age: 68 Control: n ⫽ 12, 6 m/6 f, mean age: 74 NYHA class II/III/IV

12 wk of interval exercise training. 2 sessions per week, 20 min. Subjects started breathing at a resistance equal to 25–30% MIP for 1 wk, and each subsequent session was adjusted to 25–30% MIP.

Total patients N ⫽ 25 Exercise: n ⫽ 12, 7 m/5 f, mean age: 67 Control: n ⫽ 13, 6 m/7 f, mean age: 61 NYHA class I/II

16 wk of interval exercise training. 3 sessions per week, ˙O 30 min at 60–70% peak V 2

MLHF KCCQ BDI 6MWT Diastolic function BNP LVEF ˙ O2 Peak V ˙ E/V ˙ CO2 V Heart rate 6MWT Diastolic function EDV and ESV SBP and DBP MLHF SF-36 LVEF ˙ O2 Peak V ˙ E/V ˙ CO2 V Heart rate 6MWT Diastolic function NT-proBNP MLHF LVEF ˙ O2 Peak V ˙ E/V ˙ CO2 V Heart rate Diastolic function MLHF

˙ O2, maximal oxygen consumption; FES, functional electrical stimulation; peak HR, maximal heart rate; MHR, maximum heart rate; HRR, heart Peak V rate reserve; m/f, male/female; MIP, inspiratory muscle trainer; 1 RM, ⫽ 1 repetitive maximum; 6MWT, Six-Minute Walk Test; LVEF, left ventricular ejection fraction; EDV, end diastolic volume; ESV, end systolic volume; MLHF, Minnesota Living with Heart Failure Questionnaire; SF-36, short form-36 ˙ E/V ˙ CO2, ventilatory equivalent for carbon dioxide; KCCQ, Kansas City Cardiomyopathy Questionnaire; BDI, Beck depression inventory; health survey; V SBP, systolic blood pressure; DBP, diastolic blood pressure; BNP, brain natriuretic peptide; and NT-proBNP, N-terminal prohormone of brain natriuretic peptide.


Review Exercise Training in Heart Failure with Preserved Ejection Fraction

•

Dieberg G et al.

729

Fig. 2. Cardiorespiratory variables. A: ˙ O2 for exercise training change in peak V studies with heart failure patients with preserved ejection fraction (HFpEF) patients. B: ˙ E/V ˙ CO2 for exercise training change in V studies with HFpEF patients. C: change in maximum heart rate for exercise training studies with HFpEF patients. D: change in Six-Minute Walk Test (6MWT) for exercise training studies with HFpEF patients.

Statistical Analyses

Exercise Training Parameters

Revman 5.1 software (The Nordic Cochrane Centre, Copenhagen, Denmark) was used for data analysis. Continuous data were reported as means and SD. Revman 5.1 enabled calculation of postintervention change from baseline for SD, using change in mean values, number of subjects, and P value or preferably 95% CIs. In many cases in which exact P values were not provided, we used default values e.g., P ⬍ 0.05 became P ⫽ 0.049. Mean difference (MD) in these data from baseline was analyzed. We used a 5% level of significance and a 95% CI to report change in outcome measures. Egger plots were produced to identify sources of publication bias (7).

Program length for high-intensity training varied from 6 to 26 wk and frequency from two to five sessions weekly. Three studies used walking and cycle training, one used only walking, one used cycling only, one used functional electrical stimulation, and one inspiratory muscle training.

RESULTS

Included Studies Seven studies met selection criteria (1, 6, 9, 15, 16, 20, 28), providing a total of 144 exercising subjects and 114 control subjects, a total of 258 participants (Table 1). Total patienthours of exercise training reported were 3,744 h.

Outcome Measures Change in peak V˙O2. Data from four studies showed MD for ˙ O2 was 2.13 ml·kg⫺1·min⫺1 [95% confidence interval (CI) peak V 1.54 to 2.71, P ⬍ 0.00001] in exercise vs. control (Fig. 2A). Change in peak V˙E/V˙CO2 slope. Data from three studies ˙ CO2 slope showed MD was 0.85 units higher (95% ˙ E/V for V CI 0.05 to 1.65, P ⫽ 0.04) in exercise vs. control (see Fig. 2B). Change in heart rate. Data from four studies showed MD for maximum heart rate was 5.60 bpm (95% CI 3.95


Review 730


•

Dieberg G et al.

Fig. 3. Diastolic function. A: change in E/A ratio for exercise training studies with HFpEF patients. B: change in E/E= ratio for exercise training studies with HFpEF patients. C: change in deceleration time for exercise training studies with HFpEF patients.

to 7.25, P ⬍ 0.00001) in exercise vs. control (see Fig. 2C). Change in 6MWT. Data from five studies for 6MWT resulted in a MD of 32.1 m (95% CI 17.20 to 47.05, P ⬍ 0.0001) with exercise vs. control (see Fig. 2D).

exercise training patient. Overall, there were 3,744 patienthours of exercise training reported. There were insufficient adverse event data to justify analyses.

Change in Diastolic Function

Median TESTEX score was 10 (maximum 15) for all studies (see Table 3). Funnel (Egger) plots of the analysis showed minimal evidence of publication bias.

Change in E/A ratio. Data from three studies showed the MD for diastolic function (E/A ratio) was 0.07 (95% CI 0.02 to 0.12, P ⫽ 0.005) with exercise vs. control (Fig. 3A). Change in E/E= ratio. Data from four studies showed the MD for diastolic function (E/E= ratio) was ⫺2.31 (95% CI ⫺3.44 to ⫺1.19, P ⬍ 0.0001) with exercise vs. control (Fig. 3B). Change in deceleration time. Data from three studies for deceleration time (DT) showed a MD of ⫺13.2 ms (95% CI ⫺19.8 to ⫺6.5, P ⫽ 0.0001) with exercise vs. control (Fig. 3C). Change in Quality of Life Data from six studies showed MD for MLHFQ was ⫺6.50 (95% CI ⫺9.47 to ⫺3.53, P ⬍ 0.0001) with exercise vs. control (see Fig. 4A). Change in the Short Form-36 Health Survey Data from two studies showed MD for the physical dimension of the short form-36 health survey was 15.6 (95% CI 7.35 to 23.8, P ⫽ 0.0002) with exercise vs. control (see Fig. 4B). Adverse Events All studies reported adverse events (deaths, hospitalizations, and cardiovascular events), see Table 2. There were no deaths reported from exercise training or control groups in any of the included studies. One hospital admission was reported from an

Study Quality

Heterogeneity ˙ E/V ˙ CO2 slope and 6MWT showed Only the analyses of V high heterogeneity. DISCUSSION

This meta-analysis indicates that, in HFpEF patients, the magnitude of gain in cardiorespiratory fitness is similar to that seen in systolic heart failure patients exercising at moderate intensity (13, 14). In HFpEF, exercise training elicits improvements in cardiac (diastolic) function, health-related quality of ˙ CO2 slope, maximum heart rate, and ˙ E/V life, general health, V 6-min walk distance, which complement improvements seen in cardiorespiratory fitness. Change in peakV˙O2,V˙E/V˙CO2 Slope, Maximum Heart Rate, and 6-Minute Walk Test ˙ O2 observed with exercise The improvements in peak V training are complemented with changes in maximum heart ˙ E/V ˙ CO2 slope. This current analysis produced rate, but not in V ˙ peak VO2 changes of similar effect size seen previously (30). Although one trial has established a ⫺4.4 unit improvement in ˙ E/V ˙ CO2 slope (28), our analysis does not identify an improveV ment with exercise training. A previous meta-analysis did not


Review Exercise Training in Heart Failure with Preserved Ejection Fraction

•

731

Dieberg G et al.

Fig. 4. Quality of life. A: change in Minnesota Living with Heart Failure Questionnaire (MLHFQ) for exercise training studies with HFpEF patients. B: change in the physical dimension of the short form-36 health survey for exercise-training studies with HFpEF patients.

˙ E/V ˙ CO2 slope in HFpEF patients (30). A analyze change in V previous report established a strong prognostic relationship ˙ O2, V ˙ E/V ˙ CO2 slope, and mortality in heart between peak V failure patients with reduced systolic function (23). Our analysis showed maximum heart rate to be higher after exercise training; the resultant increase in maximal cardiac output ˙ O2 improved with would at least partially explain why peak V ˙ ˙ training. Although VE/VCO2 slope did not decrease in our analysis, a reduction would imply improved ventilatory efficiency and would likely contribute to improved cardiorespiratory fitness. A mean 10-12 bpm increase in maximum heart rate after training has been reported in systolic heart failure and HFpEF in previous trials (26, 28). Diastolic Function Our analysis of E/A ratio is the first to identify that exercise training may significantly improve this aspect of diastolic function. Neither individual studies, nor pooled analyses published previously, have shown a postexercise training benefit. Our analysis of E/E= confirms the finding of Edelmann et al. (6), but not the findings of the pooled analysis of Taylor et al. (30). E/E= is a surrogate for filling pressure, and our analysis suggests a small reduction (improvement) is elicited with exercise training in HFpEF patients. We suspect that these changes in E/E= do not account for all of the improvement in

˙ O2. Therefore, we acknowledge that some changes may peak V be due to improved endothelial function (11). Deceleration time (DT) was also significantly reduced in our analysis; this is the first analysis to demonstrate such a benefit. Together, these three measures of diastolic function have shown a trend toward normalization after exercise training. While improved diastolic function due to exercise training has been previously demonstrated in healthy people (19), previous work in HFpEF has failed to show a trend toward improved E/A and DT in people with HFpEF (20). Unfortunately, study-level (as opposed to patient-level) meta-analyses do not allow examination of the relationship between changes in noninvasive measures of cardiac function to other comprehensive measures of systole/ diastole generated by catheterization, e.g., pressure-volume loops. Further well-designed and appropriately powered studies of HFpEF are required to provide clarification of how noninvasive and catheter-based techniques interrelate to avoid speculation regarding the probable long-term consequences of chronically increased left ventricular pressures (8). Quality of Life and General Health Our analysis showed HFpEF patients exhibited reductions (improvements) in MLHFQ scores of similar magnitude to those seen in patients with systolic heart failure (27). Our analyses also showed HFpEF patients exhibited increased (im-

Table 2. Study withdrawals and adverse events in the included exercise training studies with HFpEF patients Withdrawals Study

Adverse Events

Exercise

Control

Exercise

Control

Alves et al. (1) Edelmann et al. (6)

2 2

3 1

0 deaths, hospitalizations, or cardiac events 0 deaths, hospitalizations, or cardiac events

Gary et al. (9) Karavidas et al. (15) Kitzmann et al. (16) Palau et al. (20) Smart et al. (28)

1 0 8 2 4

3 0 1 2 1

0 deaths, hospitalizations, or cardiac events 0 deaths or hospitalizations, 5 cardiac events (palpitations or dyspnea) 0 deaths, hospitalizations, or cardiac events 0 deaths, hospitalizations, or cardiac events 0 deaths, 1 hospitalization, and 0 cardiac events 0 deaths, hospitalizations, or cardiac events 0 deaths, hospitalizations, or cardiac events


0 0 0 0 0

deaths, deaths, deaths, deaths, deaths,

hospitalizations, hospitalizations, hospitalizations, hospitalizations, hospitalizations,

or or or or or

cardiac cardiac cardiac cardiac cardiac

events events events events events

Review 732

Overall TESTEX, total out of 15 points. #Three points possible: 1 point if adherence ⬎85%, 1 point if adverse events are reported, and 1 point if exercise attendance is reported. *Two points possible: 1 point if primary outcome is reported and 1 point if all other outcomes are reported.

10 10 8 8 12 10 12 NO NO NO NO NO NO NO YES YES YES YES YES YES YES NO NO NO NO NO NO NO YES (2) YES (2) YES (2) YES (2) YES (2) YES (2) YES (2) YES YES YES YES YES YES YES YES YES YES YES YES NO YES YES (2) YES (2) Unclear (0) YES YES (3) YES (2) YES (3) NO NO NO NO YES YES NO YES YES YES YES YES YES YES YES YES YES YES YES YES YES Ref. 1 Ref. 6 Ref. 9 Ref.15 Ref.16 Ref.20 Ref.28

Reference Study

YES YES YES YES YES YES YES

Allocation Concealed

NO NO NO NO NO NO YES

Assessors Blinded

Outcome Measures Assessed ⬎85% of Participants# Groups Similar at Baseline Randomly Allocated Participants Eligibility Criteria Specified

Table 3. Study quality assessment of included studies using TESTEX scale

Intention to Treat Analysis

Reporting of BetweenGroup Statistical Comparisons

Point Measures and Measures of Variability Reported*

Activity Monitoring in Control Group

Relative Exercise Intensity Review

Exercise Volume and Energy Expended

Overall TESTEX


•

Dieberg G et al.

proved) SF-36 scores. The effect size was of a similar magnitude to improvements seen previously in heart failure patients with normal (HFpEF) and abnormal systolic function (26). Limitations The major limitation of this analysis is that only seven datasets currently exist, and associated sample sizes were generally small. In terms of study quality, the median TESTEX score for the included studies indicated of good study quality and comprehensive reporting. There were insufficient data to warrant analysis of study withdrawal, adverse events, hospitalization, and mortality rates. Heterogeneity scores indicated the majority of our analyses ˙ CO2 slope and 6MWT may ˙ E/V were justified, but those of V exhibit heterogeneity at levels too high to justify these analyses. Meta-analysis of continuous data is problematic; we adjusted for baseline difference in primary outcomes between allocation groups by measuring preintervention vs. postintervention change. Often, we were accurately able to calculate change in SD, but in cases in which exact P values were not provided by study reports, we used default values e.g., P ⬍ 0.05 or P ⬍ 0.001 in our calculations, which may introduce errors. Our funnel plots appear to suggest negligible risk of publication bias. We suggest that unpublished datasets with perhaps negative results do not exist. Finally, we acknowledge that factors related to volume of exercise may explain some of the outcomes reported; for example, intuitively one suspects longer study duration variations may yield better results, but the small number of included studies precluded subanalyses of exercise volume parameters. Previous work by one of our authors shows that people with HFpEF typically tend to be five or more years older and more likely to be female than their systolic dysfunction counterparts (26). While the precise volume of screening to identify people with HFpEF for this work were not published, it can be revealed that screening of more than 4,000 echocardiograms yielded less than 20 exercise training participants. The explanation of this low yield is that for the purposes of scientific rigor, trials of HFpEF need to demonstrate participants do not have ischemic heart disease. Isolation from any hint of ischemic heart disease is rare in HFpEF and, therefore, makes suitable trial participants extremely difficult to find. This is possibly the primary explanation why over 100 randomized exercise training trials exist in systolic heart failure patients, while only 7 exist to date in HFpEF. In terms of expected health benefits for people with HFpEF who undertake exercise, one may expect extended survival in one person for approximately every 17 people treated for one year with exercise (24). These data were generated from systolic heart failure studies, but as the expected, improvement ˙ O2 from exercise training is similar in HFpEF, one in peak V would expect the survival benefit to be comparable. Conclusions Exercise training does yield improvements in cardiorespiratory fitness, diastolic function, quality of life, and general health in heart failure patients with preserved ejection fraction.


Review Exercise Training in Heart Failure with Preserved Ejection Fraction GRANTS This work received no financial support and has no relationship to industry. DISCLOSURES No conflicts of interest, financial or otherwise, are declared by the authors. AUTHOR CONTRIBUTIONS Author contributions: G.D., H.I., F.G., and N.A.S. conception and design of research; G.D., H.I., F.G., and N.A.S. analyzed data; G.D., H.I., F.G., and N.A.S. interpreted results of experiments; G.D., F.G., and N.A.S. prepared figures; G.D., H.I., F.G., and N.A.S. drafted manuscript; G.D., H.I., F.G., and N.A.S. edited and revised manuscript; G.D., H.I., F.G., and N.A.S. approved final version of manuscript. REFERENCES 1. Alves AJ, Ribeiro F, Goldhammer E, Rivlin Y, Rosenschein U, Viana JL, Duarte JA, Sagiv M, Oliveira J. Exercise training improves diastolic function in heart failure patients. Med Sci Sports Exerc 44: 776 –785, 2012. 2. Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, Gong Y, Liu PP. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 355: 260 –269, 2006. 3. Brazier JE, Harper R, Jones NM, O’Cathain A, Thomas KJ, Usherwood T, Westlake L. Validating the SF-36 health survey questionnaire: new outcome measure for primary care. BMJ 305: 160 –164, 1992. 4. Burkhoff D. Mortality in heart failure with preserved ejection fraction: an unacceptably high rate. Eur Heart J 33: 1718 –1720, 2012. 5. Bursi F, Weston SA, Redfield MM, Jacobsen SJ, Pakhomov S, Nkomo VT, Meverden RA, Roger VL. Systolic and diastolic heart failure in the community. JAMA 296: 2209 –2216, 2006. 6. Edelmann F, Gelbrich G, Dungen HD, Fröhling S, Wachter R, Stahrenberg R, Binder L, Töpper A, Lashki DJ, Schwarz S, HerrmannLingen C, Löffler M, Hasenfuss G, Halle M, Pieske B. Exercise training improves exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction: results of the Ex-DHF (Exercise training in Diastolic Heart Failure) pilot study. J Am Coll Cardiol 58: 1780 –1791, 2011. 7. Egger M, Davey Smith G, Schneider M, Minder C. Bias in metaanalysis detected by a simple, graphical test. BMJ 315: 629 –634, 1997. 8. Fontes-Carvalho R, Leite-Moreria A. Heart failure with preservd ejection fraction: fighting misconceptions for a new approach. Arq Bras Cardiol 96: 504 –514, 2011. 9. Gary RA, Sueta CA, Dougherty M, Rosenberg B, Cheek D, Preisser J, Neelon V, McMurray R. Home-based exercise improves functional performance and quality of life in women with diastolic heart failure. Heart Lung 33: 210 –218, 2004. 10. Guazzi M, Myers J, Peberdy MA, Bensimhon D, Chase P, Pinkstaff S, Arena R. Echocardiography with tissue Doppler imaging and cardiopulmonary exercise testing in patients with heart failure: a correlative and prognostic analysis. Int J Cardiol 143: 323–329, 2010. 11. Hambrecht R, Hilbrich L, Erbs S, Gielen S, Fiehn E, Schoene N, Schuler G. Correction of endothelial dysfunction in chronic heart failure: additional effects of exercise training and oral L-arginine supplementation. J Am Coll Cardiol 35: 706 –713, 2000. 12. Holland DJ, Kumbhani DJ, Ahmed SH, Marwick TH. Effects of treatment on exercise tolerance, cardiac function and mortality in heart failure with preserved ejection fraction: a meta-analysis. J Am Coll Cardiol 57: 1676 –1686, 2011. 13. Ismail H, McFarlane JR, Dieberg G, Smart NA. Exercise training program characteristics and magnitude of change in functional capacity of heart failure patients. Int J Cardiol 171: 62–65, 2014. 14. Ismail H, McFarlane JR, Nojoumian AH, Dieberg G, Smart NA. Clinical outcomes and cardiovascular responses to different exercise training intensities in patients with heart failure: a systematic review and meta-analysis. JACC Heart Fail 1: 514 –522, 2013.

•

Dieberg G et al.

733

15. Karavidas A, Driva M, Parissis JT, Farmakis D, Mantzaraki V, Varounis C, Paraskevaidis I, Ikonomidis I, Pirgakis V, AnastasiouNana M, Filippatos G. Functional electrical stimulation of peripheral muscles improves endothelial function and clinical and emotional status in heart failure patients with preserved left ventricular ejection fraction. Am Heart J 166: 760 –767, 2013. 16. Kitzman DW, Brubaker PH, Herrington DM, Morgan TM, Stewart KP, Hundley WG, Abdelhamed A, Haykowsky MJ. Effect of endurance exercise training on endothelial function and arterial stiffness in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single-blind trial. J Am Coll Cardiol 62: 584 –592, 2013. 17. Kraigher-Krainer E, Shah AM, Gupta DK, Santos A, Claggett B, Pieske B, Zile MR, Voors AA, Lefkowitz MP, Packer M, McMurray JJ, Solomon SD, PARAMOUNT Investigators. Impaired systolic function by strain imaging in heart failure with preserved ejection fraction. J Am Coll Cardiol 63: 447–456, 2014. 18. Lam CS, Donal E, Kraigher-Krainer E, Vasan RS. Epidemiology and clinical course of heart failure with preserved ejection fraction. Eur J Heart Fail 13: 18 –28, 2011. 19. Obert P, Mandigout S, Vinet A, N’Guyen LD, Stecken F, Courteix D. Effect of aerobic training and detraining on left ventricular dimensions and diastolic function in prepubertal boys and girls. Int J Sports Med 22: 90 –96, 2001. 20. Palau P, Dominguez E, Nunez E, Schmid JP, Vergara P, Ramón JM, Mascarell B, Sanchis J, Chorro FJ, Núñez J. Effects of inspiratory muscle training in patients with heart failure with preserved ejection fraction. Eur J Prev Cardiol 21: 1465–1473, 2014. 21. Rector TS, Cohn JN. Assessment of patient outcome with the Minnesota Living with Heart Failure questionnaire: reliability and validity during a randomized, double-blind, placebo-controlled trial of pimobendan. Pimobendan Multicenter Research Group. Am Heart J 124: 1017–1025, 1992. 22. Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Soliman EZ, Sorlie PD, Sotoodehnia N, Turan TN, Virani SS, Wong ND, Woo D, Turner MB, American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation 125: e2–e220, 2012. 23. Sarullo FM, Fazio G, Brusca I, Fasullo S, Paterna S, Licata P, Novo G, Novo S, Di Pasquale P. Cardiopulmonary exercise testing in patients ˙ O2 and with chronic heart failure: prognostic comparison from peak V ˙ E/V ˙ CO2 slope. Open Cardiovasc Med J 4: 127–134, 2010. V 24. Smart N. What is the number needed to treat when exercise training heart failure patients? J Exer Physiol online, 12: 1–5, http://epublications.bond.edu.au/hsm_pubs/142. 25. Smart N. Exercise training for heart failure patients with and without systolic dysfunction: an evidence-based analysis of how patients benefit. Cardiol Res Pract pii. 837238, 2011. 26. Smart N, Haluska B, Jeffriess L, Marwick TH. Exercise training in systolic and diastolic dysfunction: effects on cardiac function, functional capacity, and quality of life. Am Heart J 153: 530 –536, 2007. 27. Smart N, Haluska B, Jeffriess L, Case C, Marwick TH. Cardiac contributions to exercise training responses in patients with chronic heart failure: a strain imaging study. Echocardiography 23: 376 –382, 2006. 28. Smart NA, Haluska B, Jeffriess L, Leung D. Exercise training in heart failure with preserved systolic function: a randomized controlled trial of the effects on cardiac function and functional capacity. Congest Heart Fail 18: 295–301, 2012. 29. Smart NAWM, Ismail H, Giallauria F, Vigorito C, Cornelissen V, Dieberg G. Validation of a new tool for the assessment of study quality and reporting in exercise training studies:TESTEX. Int J Evid Based Healthc 13: 9 –18, 2015. 30. Taylor RS, Davies EJ, Dalal HM, Davis R, Doherty P, Cooper C, Holland DJ, Jolly K, Smart NA. Effects of exercise training for heart failure with preserved ejection fraction: A systematic review and metaanalysis of comparative studies. Int J Cardiol 162: 6 –13, 2012.
