Novel Approaches for Improving Vascular Function in Veterans with HFpEF

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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 vascular dysfunction in HFpEF have not been established, chronic inflammation and associated production of reactive oxygen species (ROS), stemming from HFpEF-associated comorbidities and inactivity, appear to play a crucial role. The peripheral vasculature of this patient group represents an area that is particularly vulnerable to the harmful effects of ROS, which interact with, and reduce bioavailability of, nitric oxide (NO). The proposed work thus seeks to examine the mechanisms linking inflammation, vascular health, and exercise tolerance in Veterans with HFpEF, and identifying which aspects of this cascade could be targeted to improve physical capacity and vascular function in this patient group. Using a randomized, double-blind, crossover design, a series of experiments are proposed that will combine novel methodology with targeted pharmacologic interventions to selectively determine the importance of NO substrate, enzymatic cofactor bioavailability, and inflammation/ROS to disease-related changes in NO signalling in HFpEF. Specific Aim 1 will test the hypothesis that chronic enteral L-Citrulline administration (100mg/kg) will increase NO substrate, leading to an increase in NO bioavailability and a subsequent improvement in vascular function. Specific Aim 2 will explore whether administration of tetrahydrobiopterin (BH4), an essential cofactor for endothelial NO synthase, can improve enzymatic coupling and therefore restore vascular function in patients with HFpEF. Specific Aim 3 will evaluate the potential pleiotropic properties of atorvastatin, a HMG CoA reductase inhibitor, to reduce inflammation and oxidative stress, leading to improvement in physical capacity and vascular function. Each Specific Aim will combine in vivo and ex vivo assessments to comprehensively determine the impact of the proposed interventions on the cascade of inflammation, oxidative stress and exercise intolerance in this patient group. Upon completion, it is anticipated that the proposed work focused on developing a better understanding of the mechanisms that contribute to impaired peripheral vascular function in HFpEF, and pinpointing novel strategies to alleviate vascular dysfunction and promote physical cpacity, will translate 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 Veteran patient group.