Mechanisms of Impaired Skeletal Muscle Blood Flow and Exercise Intolerance in Veterans with Heart Failure with Preserved Ejection Fraction: Efficacy of Knee Extensor Training

Heart failure (HF) with preserved ejection fraction (HFpEF) is the most prevalent HF phenotype, currently
affecting ~3.1 million Americans 1 and disproportionately afflicting Veterans compared to non-Veterans.2
Although the VA has prioritized studies in this Veteran patient group, HFpEF remains the leading cause of
hospitalization 3 and mortality 4 within the VA Health Care System. Unfortunately, the treatment of HFpEF is
challenging, as traditional HF pharmacotherapy has failed at improving survival in this patient group, in part, due
to poor understanding of HFpEF pathophysiology.5 Clearly, this unmet need warrants new lines of research to
improve our knowledge of HFpEF and to identify alternative, therapeutic approaches to better rehabilitate this
patient group. One chief symptom of HFpEF is severe exercise intolerance, an important predictor of quality of
life, functional capacity, and mortality.6 In these patients, severe exercise intolerance is attributable to a disease-
related loss of “peripheral vascular control,” as evidenced by a marked attenuation in exercising skeletal muscle
blood flow.7 Loss of peripheral vascular control is manifested as dysfunctions of the autonomic nervous system
(ANS) and vasodilatory ability of the microvasculature, thereby restraining skeletal muscle blood flow and O2
delivery and limiting the capacity for sustained physical activity.8 Indeed, insufficient microvascular blood flow
and O2 delivery of the lower limbs have been linked to reduced functional capacity, as determined via six-minute
walk test (6MWT), thereby exacerbating physical inactivity and exercise intolerance.9 To date, the contribution
of ANS and vascular dysfunction to disease-related changes in functional capacity and exercising limb blood
flow has not been evaluated in Veterans with HFpEF, and the proposed research aims to address this significant
knowledge gap. There is some indication that aerobic exercise training may improve peripheral vascular function
in HFpEF10 , though the mechanisms have yet to be elucidated. Our group is particularly interested in the efficacy
of knee extensor (KE) training to improve functional and vascular outcomes in HFpEF, as it provides the
opportunity to study peripheral responses to exercise training with minimal cardiac involvement. Our group has
utilized this exercise model to investigate peripheral vascular control,7 although no studies to date have
capitalized on this unique exercise training modality in Veterans with HFpEF. Thus, the purpose of this CDA-2
proposal is to determine the role of ANS dysfunction (Specific Aim 1) and of vascular dysfunction (Specific
Aim 2) on exercising skeletal muscle blood flow and exercise tolerance in Veterans with HFpEF (acute phase)
and the efficacy of KE training to improve these aspects of HFpEF pathophysiology (chronic phase). These
proposed studies are highly relevant to Veteran Health, as they seek to address an unmet need within the VA
Health Care System by (a) improving our understanding of HFpEF pathophysiology and (b) determining the
efficacy of a unique exercise training modality to restore functional capacity and exercise tolerance in Veterans
with HFpEF. It is anticipated that knowledge gained will offer new insight that will ultimately advance clinical
practice in rehabilitative medicine, improving quality of care for Veterans suffering from this pervasive disease.
My long-term career goal is to become an independent VA scientist with expertise in neurovascular and exercise
physiology in Veterans with HFpEF. To meet this long-term career goal, this CDA-2 application will provide
immediate unique skills and expertise via additional mentorship and scientific/professional training (i.e.,
knowledge, technical research, and transferrable skills) in rehabilitative medicine and clinical domains in the
context of neurovascular and exercise physiology. Successful identification of peripheral vascular control
mechanisms behind exercise intolerance upon completion of this CDA-2 will provide critical information for
optimal exercise rehabilitation in Veterans with HFpEF and preliminary data for subsequent VA Merit Award and
NIH R01 applications.

Grant Number: 5IK2RX003670-04
NIH Institute/Center: VA
Principal Investigator: Kanokwan Bunsawat