Abstract 090: Long-term Therapy with a Bendavia (MTP-131), a Novel Mitochondria-Targeting Peptide, Normalizes Cardiolipin Biosynthesis and Remodeling in Left Ventricular Myocardium of Dogs with Advanced Heart Failure

Abstract

Background: Cardiolipin (CL) is a signature phospholipid of the mitochondrial inner membrane and responsible for modulation of activities of various enzymes essential for oxidative phosphorylation. Cardiac CL is biosynthesized in a series of steps from phosphatidic acid and remodeled into a form which contains four 18:2 fatty acid chains, tetralinoleol CL [(18:2) 4 CL]. Long-term therapy with Bendavia (MTP-131), a novel mitochondria-targeting peptide, was previously shown to improve left ventricular (LV) function, increase ATP synthesis, and increase the activity and protein levels of mitochondria cytochrome c oxidase (complex IV) in LV myocardium of dogs with advanced heart failure (HF). This study examined the effects of Bendavia on total CL and (18:2) 4 CL in LV myocardium of dogs with HF. Methods: LV tissue was obtained from 12 dogs with microembolization-induced HF randomized to 3 months therapy with subcutaneous injections of Bendavia (0.5 mg/kg once daily, n=7) or saline (Control, n=7). LV tissue from 7 normal dogs was used for comparison. Total CL and (18:2) 4 CL were measured using electrospray ionization mass spectroscopy and quantified in nmol/mg of non-collagen protein (NCP). Results: Total CL was significantly decreased in LV myocardium of Control dogs compared to normal dogs (19.1±1.1 vs. 26.7±1.4 nmol/mg, p<0.05) as was (18:2) 4 CL (14.2±0.9 vs. 20.5±1.2 nmol/mg, p<0.05). Long-term therapy with Bendavia significantly increased both total CL (23.6±1.1 nmol/mg) and (18:2) 4 CL (17.8±1.0 nmol/mg) to near normal levels in LV myocardium of treated HF dogs compared to untreated HF Controls (p<0.05). Conclusions: Total CL and (18:2) 4 CL are decreased in LV myocardium of dogs with HF. Treatment with Bendavia normalizes total CL and (18:2) 4 CL. These findings are consistent with observed normalization of mitochondrial complex IV activity, normalization of rate of ATP synthesis and improvement of global LV performance in dogs with HF after long-term therapy with Bendavia.