d-arg-dmt-lys-phe-nh2 and Ventricular-Dysfunction--Left

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.

Topics: Animals; Biomarkers; C-Reactive Protein; Disease Models, Animal; Dogs; Energy Metabolism; Heart Failure; Infusions, Intravenous; Injections, Subcutaneous; Membrane Potential, Mitochondrial; Mitochondria, Heart; Myocytes, Cardiac; Natriuretic Peptide, Brain; Oligopeptides; Peptide Fragments; Reactive Oxygen Species; Recovery of Function; Stroke Volume; Time Factors; Tumor Necrosis Factor-alpha; Ventricular Dysfunction, Left; Ventricular Function, Left

Renovascular hypertension (RVH) impairs cardiac structure and left ventricular (LV) function, but whether mitochondrial injury is implicated in RVH-induced myocardial damage and dysfunction has not been defined. We hypothesized that cardiac remodeling in swine RVH is partly attributable to cardiac mitochondrial injury.. After 12 weeks of hypercholesterolemic (HC)-RVH or control (n=14 each), pigs were treated for another 4 weeks with vehicle or with the mitochondrial-targeted peptide (MTP), Bendavia (0.1 mg/kg subcutaneously, 5 days/week), which stabilizes mitochondrial inner-membrane cardiolipin (n=7 each). Cardiac function was subsequently assessed by multidetector-computed tomography and oxygenation by blood-oxygen-level-dependent magnetic resonance imaging. Cardiolipin content, mitochondrial biogenesis, as well as sarcoplasmic-reticulum calcium cycling, myocardial tissue injury, and coronary endothelial function were assessed ex vivo. Additionally, mitochondrial cardiolipin content, oxidative stress, and bioenergetics were assessed in rat cardiomyocytes incubated with tert-butyl hydroperoxide (tBHP) untreated or treated with MTP. Chronic mitoprotection in vivo restored cardiolipin content and mitochondrial biogenesis. Thapsigargin-sensitive sarcoplasmic reticulum Ca(2+)-ATPase activity that declined in HC-RVH normalized in MTP-treated pigs. Mitoprotection also improved LV relaxation (E/A ratio) and ameliorated cardiac hypertrophy, without affecting blood pressure or systolic function. Myocardial remodeling and coronary endothelial function improved only in MTP-treated pigs. In tBHP-treated cardiomyocytes, mitochondrial targeting attenuated a fall in cardiolipin content and bioenergetics.. Chronic mitoprotection blunted myocardial hypertrophy, improved LV relaxation, and attenuated myocardial cellular and microvascular remodeling, despite sustained HC-RVH, suggesting that mitochondrial injury partly contributes to hypertensive cardiomyopathy.

Topics: Animals; Antioxidants; Apoptosis; Cardiolipins; Cardiomyopathies; Disease Models, Animal; Enzyme Inhibitors; Female; Hypertension, Renovascular; Magnetic Resonance Angiography; Microvessels; Mitochondria, Heart; Mitochondrial Diseases; Multidetector Computed Tomography; Oligopeptides; Random Allocation; Renal Artery Obstruction; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sus scrofa; Swine; tert-Butylhydroperoxide; Ventricular Dysfunction, Left; Ventricular Remodeling