Exercise Training as Therapy for Heart Failure

Despite a variety of pharmacologic and device therapies for persons with chronic heart failure (HF), prognosis and quality of life (QOL) remain poor. Exercise intolerance is a major symptom in chronic HF patients (the primary symptom in persons with preserved ejection fraction -- HFpEF) and is a strong determinant of their reduced QOL. Exercise training (ET) improves exercise intolerance and QOL in patients with HF with reduced ejection fraction (HFrEF), and has become an accepted adjunct therapy for these patients based on a fairly extensive evidence base, including a number of mostly small randomized trials.

The NHLBI-funded HF-ACTION trial (O'Connor et al., JAMA 2009) compared a personalized supervised and home-based aerobic exercise program plus guideline-based pharmacologic and device therapy with guideline-based therapy alone in persons with HF and reduced ejection fraction (HF-rEF). The exercise arm showed a modest reduction in cardiovascular hospitalizations and mortality and improved QOL. However, problems with adherence in the exercise arm likely dampened the potential benefit. This landmark study leaves unanswered a number of key questions, including the role of exercise dose; the relative benefit of different types of aerobic exercise including interval training and resistance training relative to aerobic training; and optimization of adherence.

Also not addressed by HF-ACTION was the role of exercise training in persons with HFpEF, the fastest growing form of heart failure, which predominates among older persons and has a higher prevalence of women than does HFrEF. Given the lack of evidence-based therapies for HFpEF, in contrast to HFrEF, the potential benefit from exercise therapy may be greater and the need to find an effective therapy that much more urgent. The first published randomized trial of exercise training in HFpEF (Kitzman et al., Circulation Heart Failure 2010) showed a significant improvement in aerobic capacity (peak VO2) and other measures of fitness in such patients. This has now been confirmed by others, including a small multicenter study (Edelmann et al., Journal of the American College of Cardiology 2011).

Workshop participants were asked to identify knowledge gaps and to suggest general approaches in basic and clinical investigation to evaluate and translate the potential role of exercise training in the treatment of heart failure. They were asked to address the following questions:

1. What more needs to be learned about the pathophysiology of exercise intolerance in HFpEF (and HFrEF) in order to design better exercise treatments?
2. What do we need to learn regarding the mechanisms of exercise training, and of the training-related improvements (or lack thereof)?
3. Can we begin rehabilitation earlier and in more severe, decompensated patients?
4. What do we know about the need to tailor exercise regimens to specific HF populations, e.g., persons with multiple co-morbidities, frail elderly, and women?
5. What evolving, innovative new exercise training modalities and combinations should be tested?
6. How can we decrease the research cost of exercise training interventions, while increasing their generalizability and dissemination (e.g., home therapy, community centers, avoidance of ECG monitoring)?
7. How can we improve long-term adherence and maintenance?
8. Is there a more efficient, yet clinically meaningful, outcome than mortality or exercise capacity in trials of HFpEF and HFrEF?

Recommendations

1. Better elucidate the basic mechanisms of impaired cardiac, vascular, and peripheral muscle function and the impact of exercise training on them. Examples might include determining the mechanistic basis for the decreased muscle oxygen diffusing capacity in heart failure and the effect of exercise training in reversing it.
2. Better "phenotype" the predominant mechanism of exercise intolerance to better optimize exercise training approaches. Clarify differences between patients with HFrEF vs. HFpEF; effects of obesity, sarcopenia, chronotropic incompetence, impaired peripheral vascular responses, and other factors.
3. Determine the best measurements to assess/quantify exercise intolerance in HF patients and their responses to exercise training. Potential candidates include peak VO2, ventilatory threshold, critical power, ventilatory variables, treadmill time/ estimated METS, and 6-minute walk.
4. Develop interventions to improve adherence to exercise training programs/regimens. Examples include better defining causes of non-adherence and developing educational, motivational tools, user-engaging and personalized training programs.
5. Optimize exercise training regimens through better tailoring to different types of patients. Training variables to consider include exercise mode, duration of program, when to begin, frequency, intensity, and novel training techniques (high intensity intervals, prolonged sessions, optimal mix of aerobic, resistance, balance, flexibility). Patient variables to consider include age, gender, comorbidities, frailty, and socioeconomic factors
6. Test combinations of exercise training with other lifestyle interventions, drugs, and devices. Examples might include formal cardiac rehabilitation, caloric and sodium restriction, new drugs, cardiac resynchronization therapy, and conventional cardiac pacing.

Publication Plans

The workshop participants will develop a meeting proceedings report for publication in a peer-reviewed cardiovascular journal.

Participating Division

Division of Cardiovascular Sciences

NHLBI Contacts

Lawton Cooper, MD, MPH
cooperls@nhlbi.nih.gov

Jerome Fleg, MD
flegj@nhlbi.nih.gov

Workshop Participants

Chair:

• Dalane Kitzman, MD, Wake Forest University Health Science

Participants:

• Barry A. Borlaug, MD, Mayo Clinic and Foundation
• Mark Haykowsky, PhD, University of Alberta
• William E. Kraus, MD, Duke University Medical Center
• Benjamin D. Levine, MD, University of Texas Southwestern Medical Center at Dallas
• Marc Alan Pfeffer, MD, PhD, Harvard Medical School
• Ileana L. Piña, MD, MPH, Albert Einstein College of Medicine
• David C. Poole, PhD, Kansas State University
• Gordon R. Reeves, MD, Jefferson Medical College
• David Whellan MD, MHS, Jefferson Medical College

Last Updated: December 2012