Long-term therapy with Bendavia (MTP-131), a novel mitochondria-targeting peptide, reverses mitochondrial abnormalities in left ventricular myocardium of dogs with advanced heart failure

Background: Mitochondria (MITO) of failed human hearts and hearts of dogs with experimental heart failure manifest functional abnormalities characterized by reduced state-3 respiration, reduced membrane potential (Δψm) and increased opening of membrane permeability transition pores (mPTP). These abnormalities lead to reduced ATP synthesis that adversely impacts LV function. Bendavia (MTP-131), a novel, first in class, MITO-targeting peptide, has been shown to improve LV systolic function in dogs with chronic heart failure and to improve ATP synthesis in multiple organs including heart, kidney and skeletal muscle in other animal models of disease. The present study tested the hypothesis that long-term therapy with Bendavia reverses functional MITO abnormalities in dogs with chronic heart failure. Methods: Studies were performed in cardiomyocytes isolated from LV myocardium of 14 HF dogs produced by intracoronary microembolizations (LV ejection fraction ∼30%). Dogs were randomized to 3 months monotherapy with subcutaneous injections of Bendavia (0.5 mg/kg once daily, n=7) or saline (Control, n=7). MITO state-3 respiration was measured using a Clark electrode. Δψm was measured using the dye JC-1 and mPTP was measured based on the rate of calcein exit from MITO. MITO ATP synthesis was measured using the bioluminescent ApoSENSORTM assay kit. Results: Compared to Control, Bendavia significantly improved MITO state-3 respiration, increased Δψm, decreased the rate of calcein exit from MITO thus decreasing mPTP opening and increased in ATP synthesis (Table). View this table: Indexes of mitochondria function Conclusions: Therapy with Bendavia reverses abnormalities of MITO function in LV myocardium of dogs with chronic heart failure and increases ATP synthesis. The latter can explain the observed improvement of LV systolic function following long-term therapy with Bendavia in dogs with HF.