Muscle metabolism, metabolic modulators and disabling exercise intolerance in the daily life of patients with heart failure and preserved ejection fraction - Heart failure with preserved ejection fraction (HFpEF) is the fastest growing form of heart failure, and is characterized by severe exercise intolerance (EI), exertional fatigue, disability-associated reduced quality of life, and increased mortality. The cause of the severe EI in HFpEF remains unclear, but prior reports and our preliminary data suggest that impaired skeletal muscle energy metabolism may contribute. Previously, our group demonstrated that HFpEF patients experience a rapid decrease in skeletal muscle high energy phosphates (HEP) during exercise, as detected with non-invasive phosphorus magnetic resonance spectroscopy (31P MRS). Other studies found that HFpEF patients have decreased skeletal muscle oxygen delivery and consumption compared to controls. However, due to methodological limitations, it is unknown whether this is due to primary impairments in mitochondrial oxidative metabolism, or whether HFpEF patients have attenuated peripheral blood flow that secondarily limits mitochondrial oxygen utilization. With the need for better in vivo methods to answer this important research question, we recently developed a novel interleaved MRS/MRI tool to simultaneously measure muscle metabolism and peripheral blood flow. Moreover, new clinically available metabolic modulators such as sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been shown to improve clinical outcomes, but their impact on muscle metabolism in HFpEF has not been studied or related to EI. Finally, conventional EI measures during laboratory exercise testing fail to account for activities of daily living or sedentary behavior, but these can now be measured with recent advancements in wearable health technology. However, the relationship between these measures and skeletal muscle energetics have not been investigated in HFpEF patients. Therefore, we will leverage our new MRS/MRI tool to test the central hypothesis that abnormalities in skeletal muscle HEP metabolism are closely linked to manifestations of EI and fatigue in the daily lives of HFpEF patients and can be attenuated with new metabolic modulators. The specific aims are: (1) optimize and refine our novel interleaved MRS/MRI tool and investigate whether rapid HEP decline during exercise occurs despite preserved blood flow in HFpEF patients, (2) explore whether metrics of activities of daily living are closely related to conventional measures of EI and muscle metabolism in HFpEF, and (3) investigate whether SGLT2i administration improves muscle metabolism and reduces EI in HFpEF. The combination of these three elements will give the PI vital experience in developing clinical MRS/MRI research tools, evaluating wearable health device data, and conducting a clinical longitudinal study that will generate crucial preliminary data for a future randomized controlled trial using metabolic modulators. This Pathway to Independence award will be supported by excellent career development resources at Johns Hopkins and mentorship from experts in MR, metabolism, heart failure, wearable technology, and clinical trial design. The new tools and approaches will provide novel insights into EI in HFpEF as well as transferable skills that the PI can leverage in his future research endeavors.
