? DESCRIPTION (provided by applicant): Heart failure with preserved ejection fraction (HFpEF) is the most common form of HF and is nearly unique to the older persons. Exercise intolerance is the primary manifestation of HFpEF and severely reduces quality-of- life (QOL). However, its pathophysiology is poorly understood and its optimal treatment remains undefined. Multiple lines of evidence indicate that increased adiposity and abnormalities in skeletal muscle are major contributors to exercise intolerance in older HFpEF patients. Obesity is one of the strongest risk factors for HFpEF, and 85% of older HFpEF patients have the overweight/obese phenotype. We have found that HFpEF patients have reduced total lean mass, increased thigh muscle fat infiltration, reduced capillarity and percent type I fibers, and trends for reduced mitochondrial mass and function; all of which were related to reduced peak VO2. In our recent study in obese older HFpEF patients, both caloric restriction (CR) and aerobic exercise training (AT) increased peak VO2 equally and their combination was strongly additive and improved QOL. Improved peak VO2 was related to reduced fat mass, increased percent lean mass, improved thigh muscle composition and trends for increased mitochondrial mass and function, which were greatest with CR. These data strongly support combined CR+AT as a novel treatment for HFpEF. However, about 35% of the weight lost during CR was muscle mass and was not prevented by AT. This muscle mass loss is a concern because it could have hindered the gains in peak VO2, and has been associated with increased disability, hospitalizations, and death. Thus, a logical next step is to build on our successes by finding strategies to further increase peak VO2 during CR+AT by retaining muscle mass and improving mitochondrial function. Multiple lines of evidence indicate that resistance training (RT) could be an ideal addition to CR+AT for HFpEF. In other populations, RT increases muscle mass and mitochondrial function, and increases peak VO2 in magnitude similar to AT and the two have additive and complementary effects. We reported that RT during CR in obese older non-HF adults reduces loss of muscle mass nearly 50%. In our pilot study, we found that RT improves mitochondrial function in older obese adults. However RT has not been tested in HFpEF or during CR in any type of HF. The primary aim of the proposed study is to conduct a randomized, single-blinded 24- week intervention trial of RT added to CR+AT in 100 overweight/obese (BMI > 28), HFpEF patients age >60 years to test the hypotheses that addition of resistance training to AT during CR will improve peak VO2 and will increase muscle mass. A secondary, mechanistic aim will determine if the addition of RT to CR+AT improves muscle mitochondrial function. If successful, this innovative study will define the optimal non- pharmacological intervention for exercise intolerance in the growing population of overweight/obese older HFpEF patients. It will also: advance a new paradigm regarding the role of muscle in HFpEF pathophysiology, test a novel intervention, and provide the first mechanistic insights regarding mitochondrial function in HFpEF.

R01AG018915

2001-02-15

2021-03-31