Download Exercise Training in Heart Failure With Preserved Ejection Fraction

Journal of the American College of Cardiology
© 2011 by the American College of Cardiology Foundation
Published by Elsevier Inc.
EDITORIAL COMMENT
Exercise Training
in Heart Failure With
Preserved Ejection Fraction
Beyond Proof-of-Concept*
Dalane W. Kitzman, MD
Winston-Salem, North Carolina
In this issue of the Journal, Edelmann et al. (1) report the
results of the first multicenter trial of exercise training in
patients with heart failure and preserved ejection fraction
(HFpEF). The investigators are to be congratulated on an
important contribution to the field. Their study design was
exemplary. It was randomized, controlled, and single blind;
patients were well-characterized; expired gas analysis was
included, which allowed objective quantification of exercise
capacity and level of exercise effort; and the intervention
included strength as well as endurance training. Although
their study is described as a pilot, it successfully tested the
key outcome of exercise capacity, showing a 2.6 ml/kg/min
(16%) increase in peak exercise oxygen consumption (VO2)
(1). This improvement is potent, easily surpasses the threshold of clinically meaningful change (1 ml/kg/min, 10%, or 1
min), and is similar in magnitude to the average reported in
See page 1780
the many training studies in HF with reduced ejection
fraction (HFrEF) (2– 4) as well as the 3 single-center
studies previously reported in HFpEF (5–7). Particularly
when combined with other reported studies, their results
provide solid proof-of-concept that exercise training in
HFpEF patients is safe and effective at improving their
severe exercise intolerance. This is an important finding
since exercise intolerance is the primary chronic symptom in
HFpEF patients and the major determinant of their severely
reduced quality of life. Against the background of the
relatively disappointing results of large pharmacological
*Editorials published in the Journal of the American College of Cardiology reflect the
views of the authors and do not necessarily represent the views of JACC or the
American College of Cardiology.
From the Section on Cardiology, Wake Forest University School of Medicine,
Winston-Salem, North Carolina. This work was supported in part by grants
R37AG18915 and P30AG21332 from the National Institutes of Health. Dr. Kitzman
has received research funding from Novartis; is a consultant for Boston Scientific and
Relypsa; and has stock ownership with Gilead.
Vol. 58, No. 17, 2011
ISSN 0735-1097/$36.00
doi:10.1016/j.jacc.2011.07.024
intervention trials in this disorder to date, these strongly
positive results are especially welcome (8).
What are the next logical steps to build on these strong
results? Future avenues for development of this promising
nonpharmacological therapy include 8 “Ms”: understanding
Mechanisms; exploring different Modes of exercise training;
CoMbining with other therapeutic strategies; enhancing
long-term Maintenance of gains in physical function; More
inclusive and generalizable patient populations; tackling
Multiple comorbidities; testing effects on Mortality and
other clinical endpoints; and addressing the Money issues of
cost effectiveness and third-party reimbursement.
Mechanisms. Mechanisms matter because understanding
them allows the opportunity to perfect and enhance the
effectiveness of a new therapy, as well as to develop next
generation treatments and the studies needed to test them.
Understanding the mechanisms of training-related improvements in exercise intolerance requires careful measurements, not only of peak exercise VO2, but also of its
determinants, cardiac output and arterial-venous oxygen
difference before and after an intervention (9). Optimally,
these factors should be measured simultaneously during
exercise along with peak VO2, and although this can be
challenging in humans, it is feasible with a number of
techniques that have been developed (9 –12). Such studies
are currently lacking in HFpEF, although in the present
study, resting Doppler early annulus velocity improved and
correlated moderately with peak VO2 (1). Nevertheless, the
several reported mechanistic studies in the related condition
of HFrEF may give us early insight. These indicated that
training-related improvements in peak VO2 result from
favorable changes in cardiac, peripheral vascular, and skeletal muscle function that increase oxygen delivery to and
utilization by the active muscles (3,10,13). A counterintuitive, important, and underappreciated conclusion from the
body of work of training mechanisms in HFrEF is that
peripheral, noncardiac factors such as skeletal muscle play a
substantial role (3,9,10).
Modality. All the reported studies of training in HFpEF
have primarily utilized traditional endurance exercise training (1,5–7). The present study incorporated a strength
training component, which has been shown to accelerate
improvements in skeletal muscle bulk and function. Propelled partly by mechanistic insights, other newer training
modalities have been developed. High-intensity aerobic
interval training may be superior to continuous moderateintensity endurance exercise training for improving resting
cardiac, peripheral vascular, and skeletal muscle function in
HFrEF (14). The variety of exercise conditioning methods
has expanded dramatically in recent years, and some may be
applicable to HFpEF patients. A potentially robust, but
much less developed, technique is tailoring of regimens to
the specific deficits measured within individual patients
(12). Understanding mechanisms will facilitate such
developments.
Kitzman
Exercise Training in Patients With HFPEF
JACC Vol. 58, No. 17, 2011
October 18, 2011:1792–4
Combination therapy. Combining exercise training with
other therapies, including medications, devices, and other
nonpharmacological interventions, has the potential for
synergism. For instance, some data have suggested that
angiotensin inhibition may be synergistic with exercise
training for improving arterial and skeletal muscle function.
Approximately 20% to 25% of patients with HFpEF, like
those with HFrEF, have chronotropic incompetence that
contributes to their exercise intolerance, such that strategies
combining physiological pacing with exercise training may
be beneficial. Exercise training may pair particularly well
with other nonpharmacological interventions, including
lifestyle interventions, such as nutrition, and disease management strategies. Indeed, clinical cardiac rehabilitation
programs for coronary artery disease patients routinely
include these in a multidimensional approach. In this light,
research studies that strive to isolate the effects of exercise
training alone (5) likely underestimate the full range of
potential benefits from a rehabilitation approach to HFpEF.
Maintenance. In the Edelmann et al. (1) study, HFpEF
patients had good compliance (81%) with exercise training;
however, the training follow-up duration was only 3
months. The other 3 studies reported in HFpEF, like those
in other conditions, have been short term as well. However,
long-term maintenance in physical training interventions is
often suboptimal. In the HF-ACTION (Heart Failure: A
Controlled Trial Investigating Outcomes of Exercise Training) trial of long-term endurance training in HFrEF patients, even though multiple, prospectively designed, intensive, and sustained strategies were applied to optimize
adherence, at 1-year follow-up, adherence in minutes per
week was only about 58% of target and declined further
during the second year (15). Throughout the 3-year study,
about 30% of patients exercised at or above the goal of 120
min/week. Until this stubborn issue is better addressed, it
will remain a major limitation to broad application of
exercise training interventions, no matter how impressive
the short-term gains (4).
More inclusive and multiple comorbidities. The average
patient age in the Edelmann et al. study (1) was 65 years,
and about 56% were women, which is laudable. However,
this is significantly lower than the average age of HFpEF
patients in the United States, which is ⬎75 years, and about
66% are women (16). As is traditional for HF training
studies, the Edelmann et al. (1) study included stable,
well-compensated outpatients. However, the patients likely
at greatest risk of physical disability are recently hospitalized
patients. Furthermore, typical HFpEF patients have on
average 5 or more comorbidities, and these worsen physical
function, increase overall risk, and appear to drive clinical
outcomes (16,17). Inclusion of very elderly, recently hospitalized patients with multiple comorbidities in future trials
will be challenging but will enhance generalizability (4,16).
Mortality. The effect of training on mortality and other
clinical endpoints in HFpEF will eventually need to be
addressed. However, it should be emphasized that the
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demonstrated improvements in exercise capacity, symptoms, and quality of life are independently valid outcomes,
and that particularly in very elderly patients, such outcomes
can be at least as valuable as prolonging survival (9,16). The
HF-ACTION trial was designed to definitively test
whether exercise training improved clinical endpoints in
HFrEF patients, after meta-analyses of ⬎13 smaller studies
strongly suggested benefit. Although the study was adequately powered with 2,133 patients and was well-designed
and executed, the results showed only a marginal benefit on
overall mortality and cardiovascular events (15). Since overall
events rates are generally lower in HFpEF patients, an even
larger sample size will likely be required to test this patient
population. Of note, rehospitalization rates in HFpEF are
similar to HFrEF and have considerable impact on quality of
life and financial burden, such that this may be a fruitful
intermediate therapeutic target (4). Badly needed are novel
metrics that capture the range of outcomes that are most
important to HF patients, particularly the very elderly.
Money. Although the Centers for Medicare and Medicaid
Services is currently reviewing the HF-ACTION trial
results, heart failure is not a Medicare reimbursable indication for cardiac rehabilitation in most states. Unfortunately,
insistence upon demonstration of mortality improvement
before approving reimbursement overlooks the valuable and
clearly demonstrated benefits on function and quality of life
(9,16). Studies that use more efficient, less resource-intense
exercise training techniques, novel outcomes, and appropriate cost-effectiveness analyses will help advance the field and
make this therapy more widely available (4). For instance,
because HFpEF patients have less coronary disease and
fewer ventricular dysrhythmias than HFrEF patients, it may
be possible to streamline selected, appropriately screened
patients toward community-based exercise programs (7).
In summary, exercise training is a promising and potent
therapy that addresses what is arguably the most important
outcome in elderly HFpEF patients. The present study by
Edelmann et al. (1) has established proof-of-concept. Now,
the challenge is to understand mechanisms, refine the
therapeutic regimen, enhance long-term adherence, and
expand generalizability and availability.
Reprint requests and correspondence: Dr. Dalane W. Kitzman,
Section on Cardiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina
27157-1045. E-mail: [email protected].
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Key Words: diastolic dysfunction y diastolic heart failure y exercise
training y heart failure with preserved ejection fraction y therapy.