Peak oxygen uptake during cardiopulmonary exercise testing predicts myocardial mitochondrial oxidative capacity

Introduction Heart failure (HF) affects approximately 2% of the adult population and represents a growing public health burden. Mitochondrial dysfunction has emerged as a key pathophysiological mechanism contributing to impaired myocardial energy utilization in HF. High-resolution respirometry allows detailed assessment of mitochondrial function in muscle tissue obtained from endomyocardial biopsy and provides insights into cellular bioenergetic capacity. Reduced cardiopulmonary exercise capacity is a hallmark of HF and is commonly evaluated by cardiopulmonary exercise testing (CPX). In particular, peak oxygen uptake (VO2max) is an established prognostic marker in HF. However, the relationship between myocardial mitochondrial function and exercise capacity has not been systematically investigated. Methods In a single-center prospective cohort study between January 2025 and February 2026 we included heart transplant recipients undergoing routine endomyocardial biopsy of the interventricular septum. Participants additionally underwent cardiopulmonary exercise testing (CPX) to quantify peak oxygen uptake (VO2max). Mitochondrial function was assessed in saponin-permeabilized myocardial fibers using high-resolution respirometry. Maximum mitochondrial oxidative phosphorylation (OXPHOS) capacity was measured at saturated concentrations of malate, ADP, octanoyl-carnitine, glutamate and succinate. Results 13 participants (8 male) were included. Median age was 43 years (ICQ 36-63). We observed a positive correlation between OXPHOS capacity and VO2max (p=0.021, r=0.63). Furthermore, we identified a relationship between FCCP-stimulated maximal uncoupled respiration and VO2max (p=0.014, r=0.66). In addition, VO2max was tightly associated with markers of mitochondrial efficiency and respiratory reserve capacity. Specifically, the ratio of OXPHOS capacity and leak respiration (RCR, p=0.008, r=0.69) showed a direct correlation with VO2max, whereas the ratio of leak respiration and maximal uncoupled oxidative capacity (LCR, p=0.008, r=-0.70) inversely correlated with VO2max. Conclusion Our results indicate a correlation between ex-vivo myocardial OXPHOS capacity and in-vivo VO2max. Thus, VO2max may serve as a non-invasive surrogate marker of myocardial OXPHOS capacity and coupling efficiency.