Improving Mitochondrial Function Improves the Plasma Metabolite Profile in Experimental Heart Failure

Abstract

Background We recently reported a strong association of plasma metabolite profile with survival in patients with heart failure and reduced ejection fraction (HFrEF). Mitochondrial function is perturbed in HFrEF, but whether plasma metabolite levels are linked to mitochondrial dysfunction is unknown. Elamipretide, a 4 amino acid peptide, normalizes mitochondrial energy production and thus provides a tool to test the association of mitochondrial function with the plasma metabolome in HFrEF. Methods Dogs (n=14) underwent intracoronary micro-embolization to induce HFrEF (pre-treatment EF 35%) and then were randomized 1:1 to elamipretide or placebo for 3 months. Targeted plasma metabolomic profiling was performed to quantitate 8 organic acids (OA), 23 amino acids (AA), and up to 59 acylcarnitines (AC) at pre-treatment and end of study. The association of changes in metabolite levels with treatment were tested using the Wilcoxon rank sum test on the principal components (PC) of each of the three metabolite classes. We also tested the correlation of metabolite levels with mitochondrial maximal rate of ATP synthesis in HF dog myocardium. We then attempted to confirm associations of interest in a human HFrEF cohort (n=1060) using bivariate Cox models. Result There was no association of plasma AA or AC changes with elamipretide treatment. However, there was a near-significant association of the first PC of OA changes (p=0.073), with treatment leading to lower plasma levels of OA compared to placebo (Figure). The OA also trended towards inverse relationship to maximal rate of ATP synthesis in dogs (correlation coef -0.09 to -0.67, mean -0.29), pyruvate having the strongest association (Coef =-0.67, p=0.012). In humans with HFrEF, directionally congruent and statistically significant associations with mortality risk were seen for 6 of these 8 OA (Table). Conclusion In dogs with HFrEF improving mitochondrial function using elamipretide resulted in favorable changes in plasma metabolites, specifically OA, which were risk-associated in human HFrEF. Our data suggest that mitochondrial dysfunction is the mechanism linking these plasma metabolomic abnormalities with worse survival in HFrEF.