Regional Disparity of Skeletal Muscle Microvascular Dysfunction in Systolic Heart Failure

Exercise intolerance in systolic heart failure (HF), defined as physical limitations from fatigue or shortness of breath, is associated with worse mortality and poor quality of life. Causes for exercise intolerance are multifactorial but are not solely attributed to cardiac dysfunction alone. Much evidence has suggested that skeletal muscle microvascular dysfunction (MVD), particularly in the legs, is a key contributor to the reduction in exercise capacity in these patients. Additionally, abnormalities in the skeletal muscle microvasculature have been found to appear early in animal models of heart failure, prior to the development of myocardial alterations like fibrosis or hypertrophy. Yet no study has investigated the relative contributions of peripheral vs central cardiac changes on exercise intolerance in systolic HF. Additionally, despite its association with exercise intolerance and early onset, the mechanisms underlying the development of skeletal muscle MVD remain poorly understood. Noninvasive assessments of microvascular function have shown evidence for a regional disparity in MVD, in which dysfunction is more pronounced in the lower, compared to the upper, extremities. Yet relative differences in peripheral skeletal muscle MVD has never been explored, particularly within the lower extremity. We propose to evaluate pre- and post-exercise assessments of noninvasive measures of skeletal muscle MVD in the distal leg as well as invasive hemodynamics, and compare their prediction of exercise capacity (Aim 1) in patients with systolic HF undergoing cardiac catheterization. We also plan to compare differential gene expression and vascular density between distal and proximal leg muscles by obtaining biopsies of the thigh and calf (Aim 2). Completion of these aims will provide several novel insights. If noninvasive metrics of lower extremity skeletal muscle MVD are more predictive of functional status than cardiac factors, these data will support further investigation of noninvasive measurements of skeletal muscle microvascular blood flow in HF, identifying potential diagnostic and therapeutic targets. Further, data generated from Aim 2 will provide an unbiased analysis of differentially expressed genes that will be further interrogated by pathway analysis to inform mechanistic insight into MVD in patients with HF. This data may help us target molecular signaling pathways for further analysis. The Specific Aims of this proposal will advance the training of the PI as a translational investigator studying advanced heart failure, hemodynamics, and skeletal muscle MVD, and will additionally provide novel insights into the regional disparity of skeletal muscle MVD in HF. Therefore, results from this proposal will provide a foundation for future investigations into skeletal muscle MVD diagnosis, pathogenesis, and treatment in patients with chronic HF. Project Number: 1K23HL183841-01 | Fiscal Year: 2026 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Michele Esposito | Institution: MEDICAL UNIVERSITY OF SOUTH CAROLINA, CHARLESTON, SC | Award Amount: $188,568 | Activity Code: K23 | Study Section: Special Emphasis Panel[ZRG1 RCCS-U (94)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K23HL18384101