Chronic Therapy With Elamipretide (MTP-131), a Novel Mitochondria-Targeting Peptide, Improves Left Ventricular and Mitochondrial Function in Dogs With Advanced Heart Failure

• Published in: Circulation. Heart failure Vol. 9; no. 2; p. e002206
• Main Authors: Sabbah, Hani N., Gupta, Ramesh C., Kohli, Smita, Wang, Mengjun, Hachem, Souheila, Zhang, Kefei
• Format: Journal Article
• Language: English
• Published: United States 01.02.2016
• Subjects: Animals; Biomarkers - blood; C-Reactive Protein - metabolism; Disease Models, Animal; Dogs; Energy Metabolism - drug effects; Heart Failure - blood; Heart Failure - drug therapy; Heart Failure - physiopathology; Infusions, Intravenous; Injections, Subcutaneous; Membrane Potential, Mitochondrial - drug effects; Mitochondria, Heart - drug effects; Mitochondria, Heart - metabolism; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Natriuretic Peptide, Brain - blood; Oligopeptides - administration & dosage; Oligopeptides - pharmacology; Peptide Fragments - blood; Reactive Oxygen Species - metabolism; Recovery of Function; Stroke Volume - drug effects; Time Factors; Tumor Necrosis Factor-alpha - blood; Ventricular Dysfunction, Left - blood; Ventricular Dysfunction, Left - drug therapy; Ventricular Dysfunction, Left - physiopathology; Ventricular Function, Left - drug effects; heart failure; myocardial energetics; cardiolipin; mitochondria; ventricular function
• ISSN: 1941-3289; 1941-3297
• DOI: 10.1161/CIRCHEARTFAILURE.115.002206

Elamipretide (MTP-131), a novel mitochondria-targeting peptide, was shown to reduce infarct size in animals with myocardial infarction and improve renal function in pigs with acute and chronic kidney injury. This study examined the effects of chronic therapy with elamipretide on left ventricular (LV) and mitochondrial function in dogs with heart failure (HF). Fourteen dogs with microembolization-induced HF were randomized to 3 months monotherapy with subcutaneous injections of elamipretide (0.5 mg/kg once daily, HF+ELA, n=7) or saline (control, HF-CON, n=7). LV ejection fraction, plasma n-terminal pro-brain natriuretic peptide, tumor necrosis factor-α, and C-reactive protein were measured before (pretreatment) and 3 months after initiating therapy (post-treatment). Mitochondrial respiration, membrane potential (Δψm), maximum rate of ATP synthesis, and ATP/ADP ratio were measured in isolated LV cardiomyocytes obtained at post-treatment. In HF-CON dogs, ejection fraction decreased at post-treatment compared with pretreatment (29 ± 1% versus 31 ± 2%), whereas in HF+ELA dogs, ejection fraction significantly increased at post-treatment compared with pretreatment (36 ± 2% versus 30 ± 2%; P<0.05). In HF-CON, n-terminal pro-brain natriuretic peptide increased by 88 ± 120 pg/mL during follow-up but decreased significantly by 774 ± 85 pg/mL in HF+ELA dogs (P<0.001). Treatment with elamipretide also normalized plasma tumor necrosis factor-α and C-reactive protein and restored mitochondrial state-3 respiration, Δψm, rate of ATP synthesis, and ATP/ADP ratio (ATP/ADP: 0.38 ± 0.04 HF-CON versus 1.16 ± 0.15 HF+ELA; P<0.001). Long-term therapy with elamipretide improves LV systolic function, normalizes plasma biomarkers, and reverses mitochondrial abnormalities in LV myocardium of dogs with advanced HF. The results support the development of elamipretide for the treatment of HF.