Project Summary Heart failure with preserved ejection fraction (HFpEF) is the fastest growing form of heart failure, is almost exclusively found in older persons, particularly women, and is associated with a high morbidity and mortality rate. The primary chronic symptom in HFpEF patients is severe exercise intolerance measured objectively as decreased peak exercise oxygen uptake (peak VO2). By convention, the majority of work to date has focused on central (cardiac) limitations, however drug therapies targeting cardiac function do not improve peak VO2 or survival in HFpEF patients. We first reported that older HFpEF patients have multiple skeletal muscle abnormalities (i.e. decreased skeletal muscle size, reduced oxidative capacity and capillary-to-fiber ratio), which result in increased anaerobic metabolism during exercise. Accumulation of anaerobic metabolites within the exercising muscles is known to activate skeletal muscle afferent fibers (called metaboreceptors), that elicit a reflex-mediated increase in efferent muscle sympathetic (vasoconstrictor) nerve activity (MSNA). We propose a novel paradigm of exercise intolerance in older HFpEF patients whereby skeletal muscle abnormalities lead to overactivation of the muscle metaboreflex and MSNA mediated vasoconstriction that limits delivery of oxygenated blood to the active muscles. Further, exercise training mediated improvements in skeletal muscle function will alleviate the metaboreflex, thereby reducing MSNA and improve oxygen delivery to the contracting muscles. To test this novel paradigm, we will first perform an initial cross-sectional comparison of older (?60 years) HFpEF patients with age and sex-matched healthy controls, and then enter the patients into a randomized, controlled, single blind, trial of exercise training to test the following hypothesis: 1) that MSNA is elevated in older HFpEF patients compared to healthy controls, and is associated with reduced peak VO2; and 2) Exercise training will attenuate MSNA compared to attention control, and will correlate with improved peak VO2. In the cross- sectional comparison, we will perform the first ever direct measures of MSNA, using peroneal nerve microneurography, during dynamic exercise and post-exercise muscle ischemia (a metaboreflex stimuli) in HFpEF patients. The HFpEF patients will then be randomly assigned to a 16-week trial of supervised exercise training or attention control. Given the pathophysiology of exercise intolerance and mechanisms for improvement with exercise training is poorly understood, and no medications have been proven effective, our results have the potential to shift paradigms, and have a major impact on the management of older patients with HFpEF, while achieving the AREA mandate to expose students to meritorious research, and strengthen the research environment at the College of Nursing and Health Innovation, at the University of Texas at Arlington.