Multimodality Assessment of HFpEF Skeletal Muscle Reveals Differences in the Machinery of Energy Fuel Metabolism

Aims: Skeletal muscle (SkM) abnormalities may impact exercise capacity in patients with Heart Failure with Preserved Ejection Fraction (HFpEF). We sought to quantify differences in SkM oxidative phosphorylation capacity (OxPhos), fiber composition, and the SkM proteome between HFpEF, hypertensive (HTN), and Healthy participants. Methods: 59 subjects (20 Healthy, 19 HTN, 20 HFpEF) performed a maximal-effort cardiopulmonary exercise test to define peak oxygen consumption (VO2, peak), ventilatory threshold (VT), and VO2 efficiency (ratio of total work performed to O2 consumed). SkM OxPhos was assessed using Creatine Chemical-Exchange Saturation Transfer (CrCEST, n=51), which quantifies unphosphorylated Cr, before and after plantar flexion exercise. The half-time of Cr recovery (t1/2, Cr) was taken as a metric of in vivo SkM OxPhos. In a subset of subjects (Healthy=13, HTN=9, HFpEF=12), percutaneous biopsy of the vastus lateralis was performed for myofiber typing, mitochondrial morphology, and proteomic and phosphoproteomic analysis. Results: HFpEF subjects demonstrated lower VO2,peak, VT, and VO2 efficiency than either control group (all p<0.05). The t1/2, Cr was significantly longer in HFpEF (p=0.005), indicative of impaired SkM OxPhos, and correlated with cycle ergometry exercise parameters. HFpEF SkM contained fewer Type-I myofibers (p=0.003). Proteomic analyses demonstrated (a) reduced levels of proteins related to OxPhos that correlated with exercise capacity and (b) reduced ERK signaling in HFpEF. Conclusions: HFpEF patients demonstrate impaired functional capacity and SkM OxPhos. Reductions in the proportions of type 1 myofibers, proteins required for OxPhos, and altered phosphorylation signaling in the SkM may contribute to exercise intolerance in HFpEF.