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J Appl Physiol 119: 724–725, 2015;
doi:10.1152/japplphysiol.00570.2015.
Editorial
Exploring New Concepts in the Management of Heart
Failure with Preserved Ejection Fraction: Is Exercise the Key for Improving
Treatment?
HIGHLIGHTED TOPIC
Exploring new concepts in the management of heart failure with preserved
ejection fraction: is exercise the key for improving treatment?
Kerry S. McDonald1 and Craig A. Emter2
1
2
Department of Medical Pharmacology and Physiology, University of Missouri-Columbia, Columbia, Missouri; and
Department of Biomedical Sciences, University of Missouri-Columbia, Columbia, Missouri
Address for reprint requests and other correspondence: C. A. Emter, Dept.
of Biomedical Science, Univ. of Missouri-Columbia, 1600 E. Rollins, E117
Veterinary Medicine, Columbia, MO 65211 (e-mail: [email protected]).
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assess the influence of exercise in fostering new discoveries.
Articles will provide novel insight into the treatment and
pathology of HFpEF from leading clinicians and basic scientists in humans and animal models. Over the next 3 months, 7
minireviews and several research articles will be published in
the Journal of Applied Physiology that we hope will provide
“one-stop shopping” regarding current conceptual understanding of the etiology and treatment of HFpEF.
The first month will contain reviews emphasizing clinical
approaches to using exercise in the treatment of HFpEF. The
first is a systematic review and meta-analysis regarding cardiovascular clinical outcomes in HFpEF patients after chronic
exercise training. Dr. Neil Smart and his team (5) provide a
comprehensive epidemiological analysis of the most recent
clinical trials exploring exercise as a therapeutic option to treat
HFpEF. The second review comes from Drs. Satyam Sarma
and Ben Levine (10), who explore exercise oxygen kinetics in
HFpEF. Skeletal muscle oxygen delivery and utilization has
been shown to be impaired in HFpEF patients, and their
analysis explores how specific exercise programs may improve
peripheral efficiency and subsequent aerobic performance. In
the third review, a group led by Drs. Mark Haykowsky and
Dalane Kitzman (6) examine mechanisms underlying exercise
intolerance in HFpEF patients. Both central and peripheral
impairments play an important role in the reduced cardiac
reserve observed in HFpEF, and these limitations to exercise
capacity are presented as novel therapeutic options.
In the second month, the focus shifts to the coronary vasculature and a thorough examination of its mechanistic role in
developing heart failure. The initial offering comes from a
collaboration headed by Drs. Daphne Merkus and Dirk
Duncker (7) that provides a unique perspective on the heart’s
vascular response to acute exercise in both HFpEF and HFrEF.
A number of concepts are outlined and discussed in reference
to the regulation of coronary blood flow during acute exercise
and how chronic exercise training may be used to treat cardiovascular dysfunction in a setting of heart failure. Second, a
recent paradigm has implicated the coronary endothelium as a
primary mechanism driving the development of HFpEF (9).
Dr. Li Zuo and his colleagues (12) review the research surrounding this concept and examine the integrative influence of
reactive oxygen species and nitric oxide acting through the
coronary endothelium to promote pathological remodeling and
increase myocardial stiffness.
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diagnosed with heart failure
(HF) have HF with preserved ejection fraction (HFpEF) (1).
Despite having preserved systolic function at rest, these patients display reduced cardiac functional reserve and morbidity/mortality rates similar to values observed in HF patients
with reduced systolic function (HFrEF). Although HFpEF has
been clinically recognized for over 30 years, our understanding
of the disease and approach to treating it remains a mystery.
The pathological mechanisms underlying HFpEF and the efficacy of conventional HF treatments in these patients are
controversial and poorly understood (11). Indeed, conventional
HF treatments have largely failed to improve the prognosis of
this HF subgroup (4). Furthermore, a divergence is becoming
more apparent regarding the pathology underlying HFpEF vs.
those patients exhibiting HFrEF (2). These findings illustrate
the critical need for research examining the mechanisms underlying this phenotypical divergence and development of
novel treatment strategies for HFpEF patients.
Exercise is an outstanding tool to identify mechanisms
underlying cardiovascular function in health and disease, and it
holds excellent promise as a treatment option. Previous research, including the recently completed HF-ACTION clinical
trial, indicates exercise training is a safe and effective therapeutic modality in the treatment of HFrEF patients. However,
a limitation of the HF-ACTION trial was patients displaying
HFpEF were not included. Using exercise clinically in the
treatment of HFpEF takes on added significance given conventional HF treatments have failed to improve prognoses in this
HF subgroup. Little is known in regard to exercise training in
patients with HFpEF, and a limited number of human and
animal studies have been conducted examining exercise training in this disease setting. Consequently, exercise may serve as
an effective therapeutic intervention to improve clinical outcomes in HFpEF patients, yet remains underutilized because
the mechanisms whereby exercise exerts its beneficial effects
remain largely unknown.
The focus of this Journal of Applied Physiology Highlighted
Topic is to 1) examine mechanisms currently considered fundamental to the disease process, 2) cover exciting new developments in the therapeutic management of HFpEF, and 3)
APPROXIMATELY 50% OF ALL PATIENTS
Editorial
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DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the
author(s).
AUTHOR CONTRIBUTIONS
K.S.M. and C.A.E. drafted manuscript; K.S.M. and C.A.E. edited and
revised manuscript; K.S.M. and C.A.E. approved final version of manuscript.
REFERENCES
1. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J 32: 670–679, 2011.
2. Borlaug BA, Redfield MM. Diastolic and systolic heart failure are
distinct phenotypes within the heart failure spectrum. Circulation 123:
2006 –2014, 2011.
3. Campbell KS, Sorrell VL. Cell and molecular level mechanisms contributing to diastolic dysfunction in HFpEF. J Appl Physiol; doi:10.1152/
japplphysiol.01168.2014.
4. Desai A. Heart failure with preserved ejection fraction: time for a new
approach? J Am Coll Cardiol 23: 272–274, 2013.
5. Dieberg G, Ismail H, Giallauria F, Smart NA. Clinical outcomes and
cardiovascular responses to exercise training in preserved ejection fraction
heart failure patients: systematic review and meta-analysis. J Appl Physiol;
doi:10.1152/japplphysiol.00904.2014.
6. Haykowsky MJ, Tomczak CR, Scott JM, Patterson DI, Kitzman DW.
Determinants of exercise intolerance in patients with heart failure and
reduced or preserved ejection fraction. J Appl Physiol; doi:10.1152/
japplphysiol.00049.2015.
7. Heinonen I, Sorop OE, de Beer VJ, Duncker DJ, Merkus D. What can
we learn about treating heart failure from the heart’s response to acute
exercise: focus on the coronary microcirculation. J Appl Physiol; doi:
10.1152/japplphysiol.00053.2015.
8. Heinzel FHF, Jin G, Sedej S, Edelmann F. Myocardial hypertrophy and
its role in heart failure with preserved ejection fraction. J Appl Physiol;
doi:10.1152/japplphysiol.00374.2015.
9. Paulus WJ, Tschope C. A novel paradigm for heart failure with preserved
ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll
Cardiol 62: 263–271, 2013.
10. Sarma S, Levine BD. Soothing the sleeping giant: improving skeletal
muscle oxygen kinetics and exercise intolerance in HFpEF. J Appl
Physiol; doi:10.1152/japplphysiol.01127.2014.
11. Sharma K, Kass DA. Heart failure with preserved ejection fraction:
mechanisms, clinical features, and therapies. Circ Res 115: 79 –96, 2014.
12. Zuo L, Chuang CC, Hemmelgarn BT, Best TM. Heart failure with
preserved ejection fraction: defining the function of ROS and NO. J Appl
Physiol; doi:10.1152/japplphysiol.01149.2014.
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This provides an appropriate transition into the third month,
where the attention will turn to the myocardium and an analysis
of cellular and molecular factors contributing to the development of HFpEF. Indeed, two prominent clinical features of
HFpEF are diastolic dysfunction and myocardial hypertrophy.
Drs. Ken Campbell and Vincent Sorrell (3) summarize changes
to the cardiomyocyte, such as calcium handling and altered
sarcomeric protein expression, that may cause diastolic dysfunction associated with HFpEF and discuss how these mechanisms may be manipulated to improve left ventricular function in these patients. Our final review comes from a team led
by Drs. Frank Heinzel and Frank Edelmann (8), who explore
the mechanisms driving myocardial structural abnormalities
associated with HFpEF. This analysis focuses on left ventricular hypertrophy and associated structural changes presented in
a diagnostic and therapeutic context and examines the impact
of exercise on the remodeling process.
Ultimately, the goal of this collection is to stimulate new
conversations and questions in an effort to improve understanding and treatment of a disease that has proven difficult to
treat clinically. Is the best approach to treat the myocardium as
has been traditionally done? What about the coronary vasculature or peripheral mechanisms? Is a combination of all these
systemic avenues necessary? Finally, is the integrated effect of
exercise on the entire cardiovascular system our best therapeutic option given the vast amount of clinical comorbidities that
accompany HFpEF? We hope this Journal of Applied Physiology Highlighted Topic provides a basis for the scientific
community to move forward in designing novel therapeutic
options to effectively treat these patients.