Targeting Myocardial Energetics in the Failing Heart: Are We There Yet?

See Article by Daubert et al It has long been recognized that key components of the cardiac energetic system are downregulated in the failing heart. Under normoxic conditions, mitochondrial oxidative phosphorylation generates ≈95% of the ATP content in the heart,1 which is essential for the process of excitation contraction, as well as maintenance of membrane transport systems. Studies in patients with end-stage cardiomyopathy have shown that the total adenine nucleotide pool (ATP, ADP, and AMP), creatine kinase activity (required for ATP synthesis), creatine phosphate concentration, and the Cr/ATP ratio (a marker of impaired energy metabolism) are all decreased in the failing heart, which has given rise to the notion that the failing heart is an engine out of fuel.1,2 Although multiple mechanisms have been proposed to explain the profoundly abnormal energetics in the failing heart, recent advances in our understanding of mitochondrial biology3 have raised the intriguing possibility that mitochondria-targeted therapeutics may lead to improved energy production in the heart.4 Accordingly, a study in this issue of the Circulation: Heart Failure by Daubert et al,5 which evaluates the safety of elamipretide, a novel mitochondria-targeted peptide, in heart failure patients with a reduced ejection fraction (HFrEF) is of considerable interest.5 Daubert et al5 conducted a double-blind placebo-controlled ascending-dose trial with elamipretide in patients with HFrEF (<35%) who were receiving evidence-based medical therapies for heart failure. Patients were randomized to a single 4-hour intravenous infusion of …