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.

PUBLIC HEALTH RELEVANCE: Heart failure with preserved ejection fraction (HFpEF) accounts for greater than 50% of all heart failure (HF) cases nationwide, and the prevalence of this form of HF relative to heart failure with reduced ejection fraction (HFrEF) is growing by approximately 10% per decade. The proposed project seeks to determine the regulation and functional consequences of sympathetic nervous system (SNS) overactivity in patients with HFpEF. Findings from this study may provide new information that translates directly into an improved ability to perform activities of daily living, which is likely to lead to improved quality of life and a better prognosis in this patient group.