The role of alpha-adrenergic vasoconstriction on blood flow to exercising skeletal muscle in patients with heart failure with preserved ejection fraction

Heart Failure (HF) is a leading cause of hospitalization and mortality among older adults in America1. Veterans,
in particular, appear to have a greater risk of developing HF than non-Veterans and hospital readmission rates
of Veterans are disproportionately higher than the national average 2. Of all HF cases in the U.S., approximately
half can be described as HF with preserved ejection fraction (HFpEF)3. Although the VA has prioritized studies
in this Veteran patient group, HFpEF remains the leading cause of hospitalization4 and mortality5 within the VA
Health Care System. Little is currently known about the pathophysiology of HFpEF and as a result few effective
treatment options have been developed thus far for this patient population6. In contrast, there is extensive
literature on HF with reduced ejection fraction (HFrEF), for which there are many effective treatment options.
Further, traditional HFrEF pharmacotherapies have failed to improve outcomes in HFpEF, indicating a
delineation between the pathophysiologies of HFrEF and HFpEF. Therefore, a clear need exists for new lines of
research to improve our understanding of HFpEF to identify alternative therapeutic approaches for this patient
group. One chief symptom of HFpEF is severe exercise intolerance, an important predictor of quality of life,
functional capacity, and mortality7. A primary contributing factor to exercise intolerance and associated adverse
risks is the §-50% lower aerobic exercise capacity (VO2peak) in patients with HFpEF8. While many factors may
contribute to this deficit, disease-related changes in the vasculature of the exercising skeletal muscle likely plays
a pivotal role. Our laboratory has recently identified marked reductions in blood flow to exercising skeletal muscle
in HFpEF patients9, although there is a knowledge gap regarding the underpinnings of this deficit. Given the tight
relationship between blood flow and oxygen (O2) delivery, mechanisms that regulate blood flow to exercising
skeletal muscle are important determinants of oxygen consumption (VO2) and thus, these mechanisms represent
a good target of investigation for understanding low VO2peak in HFpEF. The sympathetic nervous system (SNS)
LV D SULPDU\ UHJXODWRU RI SHULSKHUDO EORRG IORZ DFWLQJ WKURXJK Į-adrenergic signaling. During exercise, blood flow
and O2 delivery to skeletal muscle is fine-tuned by the interaction of Į-adrenergic vasoconstriction and local
IDFWRUV UHOHDVHG GXULQJ FRQWUDFWLRQ WKDW FRXQWHUDFW Į-adrenergic vasoconstriction, a phenomenon known as
“functional sympatholysis”. There is emerging evidence for overactivity of SNS activity in patients with
HFpEF10,11, which is likely to contribute significantly to the observed reduction in exercising muscle blood flow
through excessive sympathetic vasoconstriction in the peripheral vasculature. However, direct measurements of
arterial and venous O2 across the skeletal muscle have not been made, and thus the actual impact of sympathetic
vasoconstriction and diminished blood flow on skeletal muscle VO2 remains unknown in HFpEF. Further, the
HIILFDF\ RI IXQFWLRQDO V\PSDWKRO\VLV VSHFLILFDOO\ UHJDUGLQJ Į1-adrenergic vasoconstriction, is known to diminish
with advancing age and in a variety of patient groups but has not been evaluated in patients with HFpEF. Thus,
the overall research objective of this CDA-1 application is to determine the extent to which Į-adrenergic
vasoconstriction may limit leg blood flow and VO2 (Aim 1) and the ability of exercising muscle to counteract SNS-
mediated vasoconstriction (Aim 2) as potential mechanisms underlying low VO2peak in Veterans with HFpEF. My
long-term career goal is to become an independent VA scientist with expertise in neurovascular and exercise
physiology in Veterans with various forms of cardiovascular disease. To meet this long-term career goal, this
CDA-1 application will provide unique skills and expertise via additional mentorship and scientific/professional
training (i.e., knowledge, technical research, and transferrable skills) in clinical science and research domains in
the context of vascular and exercise physiology. Successful identification of vascular mechanisms underpinning
exercise intolerance in HFpEF upon completion of this CDA-1 will provide critical information for optimal
treatment of Veterans with HFpEF and training necessary for a subsequent VA CDA-2 Award application.

Grant Number: 1IK1CX002567-01A2
NIH Institute/Center: VA
Principal Investigator: Jeremy Alpenglow