PROJECT SUMMARY/ABSTRACT Dyspnea on exertion (DOE) and exercise intolerance are hallmark symptoms of heart failure with preserved ejection fraction (HFpEF). The mechanisms of these symptoms are unknown, and no therapeutic strategy exists for these debilitating symptoms. As such, NHLBI working groups recommend prioritizing studies that advance understanding of HFpEF-related (patho)physiology and the primary causes of symptoms in these patients so that novel therapeutics can be developed. DOE and exercise intolerance are also very common symptoms of obesity. Obesity has reached epidemic levels and affects four-in-ten American adults. The prevalence of obesity rises to eight-in-ten adults in the HFpEF population yet, the role of obesity in provoking symptoms of DOE and exercise intolerance in HFpEF patients has, thus far, been neglected. Human studies demonstrate that obesity affects breathing mechanics, whereby lung volume subdivisions and maximal expiratory flow are decreased, which increases the risk of expiratory flow limitation, dynamic hyperinflation, and an altered breathing pattern during exercise. All these obesity-related mechanical ventilatory constraints ultimately 1) increase the oxygen (O2) cost of breathing and 2) impose a mechanical ceiling on ventilation (V̇E) during exercise, which could provoke DOE and reduce exercise capacity. Thus, we hypothesize that obesity is likely a significant contributor to DOE and exercise intolerance in patients with HFpEF. To date, the O2 cost of breathing and the effect of obesity-related mechanical ventilatory constraints on DOE and exercise intolerance remains untested in patients with HFpEF. Therefore, the overall aim of this K99/R00 proposal is to 1) investigate the O2 cost of breathing and examine how this impacts DOE and peak exercise capacity in patients with HFpEF, and 2) reduce obesity-related mechanical ventilatory constraints to potentially reduce DOE and increase exercise capacity in patients with HFpEF. To accomplish these goals, we will 1) investigate the interaction of HFpEF (underlying changes in pulmonary function) and obesity (obesity-related changes in pulmonary function) on the O2 cost of breathing during eucapnic voluntary hyperpnea, and its association with DOE during constant load exercise and peak exercise capacity, and 2) investigate the effects of breathing a low density helium-oxygen gas mixture (HeO2: 21% O2 and 79% He), which reduces obesity-related mechanical ventilatory constraints (HeO2 increases maximal expiratory flow, reduces the work of breathing, decreases expiratory flow limitation & dynamic hyperinflation, and increases VT expansion), on DOE during constant load exercise and peak exercise capacity. We anticipate these investigations will 1) further understanding of the role of obesity in provoking symptoms of DOE and exercise intolerance in HFpEF patients, 2) identify new mechanisms underlying symptoms of DOE and exercise intolerance, which could dramatically alt...