# Autonomic Dysfunction in Patients with HFpEF

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $670,447

## Abstract

PROJECT SUMMARY: Heart failure with preserved ejection fraction (HFpEF) accounts for greater than 50% of
the 6 million HF cases nationwide, and the prevalence relative to heart failure with reduced ejection fraction
(HFrEF) continues to rise at a rate of 1% per year, presenting an imminent need for further research addressing
the pathophysiology of this pervasive disease. The clinical presentation of HFpEF is defined by dyspnea upon
exertion and severe exercise intolerance, symptoms that are likely due, at least in part, to disease-related
changes in the peripheral circulation. While the mechanisms responsible for the loss of peripheral vascular
control in HFpEF have not been established, sympathetic nervous system (SNS) overactivity is likely to play a
key role. In the peripheral circulation, sympathetic vasomotor outflow causes vasoconstriction via activation of
alpha-adrenergic receptors located on the skeletal muscle vasculature, which serves to constrain limb blood
flow, both at rest and during physical activity. In the presence of pathologic elevations in SNS activity,
exaggerated vasoconstriction may therefore result in insufficient delivery of blood to the exercising muscle,
resulting in exercise intolerance and premature neuromuscular fatigue. As the regulation and functional
consequences of excess sympathoexcitation on vascular control have not been examined in patients with
HFpEF, this proposal seeks to address a significant knowledge gap in our understanding of HFpEF
pathophysiology. Specific Aim 1 is designed to evaluate disease-related changes in the arterial baroreflex,
which is a key regulator of SNS activity. It is hypothesized that that both cardiovagal and sympathetic baroreflex
sensitivity will be reduced, at rest and during exercise, in patients with HFpEF compared to healthy controls.
Both cardiopulmonary and carotid baroreflex responses will be assessed to delineate the impact of HFpEF on
overall arterial baroreflex function. Specific Aim 2 focuses on the transduction of sympathetic outflow in the
peripheral circulation, with the hypothesis that changes in arterial blood pressure and vascular conductance in
response to bursts of SNS activity will be exaggerated in patients with HFpEF. Specific Aim 3 will evaluate the
functional consequences of SNS overactivity at the end organ, utilizing pharmacologic inhibition of alpha-
adrenergic receptors via intra-arterial Phentolamine infusion to block expression of SNS activity. For this Aim, it
is hypothesized that regional alpha adrenergic receptor antagonism will normalize resting and exercising muscle
blood flow, and subsequently improve exercise tolerance and neuromuscular fatigue resistance, in patients with
HFpEF. Upon completion, findings from the proposed work hold the promise of offering new mechanistic insight
regarding HFpEF pathophysiology that may provide a pathway to improved clinical care and, ultimately, better
prognosis in this patient group.

## Key facts

- **NIH application ID:** 10793506
- **Project number:** 5R01HL162856-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** MARKUS AMANN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $670,447
- **Award type:** 5
- **Project period:** 2023-03-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10793506

## Citation

> US National Institutes of Health, RePORTER application 10793506, Autonomic Dysfunction in Patients with HFpEF (5R01HL162856-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10793506. Licensed CC0.

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