Ferric derisomaltose augments intrinsic skeletal muscle electron transport chain activity in heart failure: A FERRIC‐HF II molecular substudy

Aims Skeletal muscle energetic augmentation might be a mechanism via which intravenous iron improves symptoms in heart failure, but no direct measurement of intrinsic mitochondrial function has been performed to support this notion. This molecular substudy of the FERRIC‐HF II trial tested the hypothesis that ferric derisomaltose (FDI) would improve electron transport chain activity, given its high dependence on iron–sulfur clusters which facilitate electron transfer during oxidative phosphorylation. Methods and results Vastus lateralis skeletal muscle biopsies were taken before and 2 weeks after randomization. Mitochondrial complex I, II, and I&II respiration were quantified with respirometry of permeabilized fresh skeletal muscle biopsies. Net respiratory capacities, reflecting respiration that is truly available for adenosine triphosphate generation, were calculated by subtracting non‐phosphorylating LEAK respiration. Complex I–V and myoglobin protein levels, and skeletal muscle fibre type composition were assayed. Patients randomised to FDI ( n = 21) or placebo ( n = 19) were similar (age 66 ± 13 years, 73% men, left ventricular ejection fraction 37 ± 8%, 48% New York Heart Association class III, 50% diabetic). After 2 weeks, total complex I‐linked respiration (0.33 [interquartile range 0.24–0.37] vs. 0.19 [0.06–0.27] nmol/min/mg, p = 0.03) and net complex I‐linked respiration (0.21 [0.16–0.24] vs. 0.11 [0.04–0.16] nmol/min/mg, p = 0.01) were higher in patients allocated to FDI. There was no intergroup difference in other respiratory states, in mitochondrial abundance as reflected by complex I–V protein levels, and in skeletal muscle myoglobin and oxidative fibre type content. Conclusions Iron repletion induces an early, selective, and potentially direct enhancement of mitochondrial complex I‐dependent respiration in the skeletal muscle of heart failure patients. This could be harnessed to optimize repletion protocols to maximize patient benefits.