Exercise Intolerance In Heart Failure With Preserved Ejection Fraction Linked To Energetic Decline

Introduction: Heart failure (HF) with preserved ejection fraction (HFpEF) is associated with severe exercise intolerance (EI) and exertional fatigue. Impaired skeletal muscle high-energy phosphate metabolism has been reported in HFpEF patients and postulated as a potential contributor to EI. However, whether EI is more closely related to rapid energetic decline during exercise, or reduced mitochondrial oxidative capacity remains unknown. Hypothesis: We hypothesized that six-minute walk distance (6MWD) is more closely related to the rate of skeletal muscle energetic decline during exercise than mitochondrial oxidative capacity in HFpEF. Methods: Calf muscle energetics were measured by phosphorus magnetic resonance spectroscopy ( 31 PMRS). The rate of phosphocreatine (PCr) decline normalized to work performed during graded plantar flexion exercise to volitional fatigue and the time for PCr post-exercise recovery, an established metric inversely related to mitochondrial oxidative capacity, were measured in 64 HFpEF patients (age: 65 ± 11 years; 53% women). Results: The mean rate of PCr decline, PCr recovery time, and 6MWD were 52 ± 108 μmol/g wet weight/KJ, 80 ± 45 seconds, and 296 ± 109 meters, respectively. The 6MWD was inversely related to the rate of PCr decline (r = -0.46; P = 0.0002; Figure, A ) but not significantly related to the PCr recovery time (r = -0.06; P = 0.66; Figure, B ), as determined by Pearson’s correlation coefficients. Conclusions: EI, as measured by 6MWD, in HFpEF patients is closely associated with impaired skeletal muscle metabolism, specifically rapid skeletal muscle PCr decline during exercise rather than mitochondrial oxidative capacity. This suggests that impaired glycolytic metabolism and substrate delivery may contribute metabolically to EI in HFpEF patients.