HDL mimetic peptide CER-522 treatment regresses left ventricular diastolic dysfunction in cholesterol-fed rabbits

• Published in: International journal of cardiology 2016-07, Vol.215, p.364-371
• Main Authors: Merlet, Nolwenn, Busseuil, David, Mihalache-Avram, Teodora, Mecteau, Melanie, Shi, Yanfen, Nachar, Walid, Brand, Genevieve, Brodeur, Mathieu R, Charpentier, Daniel, Rhainds, David, Sy, Gavin, Schwendeman, Anna, Lalwani, Narendra, Dasseux, Jean-Louis, Rhéaume, Eric, Tardif, Jean-Claude
• Format: Article
• Language: English
• Subjects: Animals; Aortic Valve Stenosis - chemically induced; Aortic Valve Stenosis - physiopathology; Apoptosis - drug effects; Cardiovascular; Cells, Cultured; Cholesterol - administration & dosage; Cholesterol - adverse effects; Disease Models, Animal; Echocardiography-Doppler; High-density lipoprotein; Humans; Hypercholesterolemia - chemically induced; Hypercholesterolemia - physiopathology; Hypertrophy, Left Ventricular - drug therapy; Hypertrophy, Left Ventricular - physiopathology; Inflammation; Left ventricular diastolic dysfunction; Lipoproteins, HDL - chemistry; Macrophages - cytology; Macrophages - drug effects; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Peptidomimetics - administration & dosage; Peptidomimetics - pharmacology; Rabbits; Ventricular Dysfunction, Left - drug therapy; Ventricular Dysfunction, Left - physiopathology
• ISSN: 0167-5273; 1874-1754
• DOI: 10.1016/j.ijcard.2016.04.029

Abstract Objectives High-density lipoprotein (HDL) infusions induce rapid improvement of experimental atherosclerosis in rabbits but their effect on ventricular function remains unknown. We aimed to evaluate the effects of the HDL mimetic peptide CER­522 on left ventricular diastolic dysfunction (LVDD). Methods Rabbits were fed with a cholesterol- and vitamin D2 -enriched diet until mild aortic valve stenosis and hypercholesterolemia-induced LV hypertrophy and LVDD developed. Animals then received saline or 10 or 30 mg/kg CER­522 infusions 6 times over 2 weeks. We performed serial echocardiograms and LV histology to evaluate the effects of CER­522 therapy on LVDD. Results LVDD was reduced by CER-522 as shown by multiple parameters including early filling mitral deceleration time, deceleration rate, Em/Am ratio, E/Em ratio, pulmonary venous velocities, and LVDD score. These findings were associated with reduced macrophages (RAM-11 positive cells) in the pericoronary area and LV, and decreased levels of apoptotic cardiomyocytes in CER­522-treated rabbits. CER-522 treatment also resulted in decreased atheromatous plaques and internal elastic lamina area in coronary arteries. Conclusions CER­522 improves LVDD in rabbits, with reductions of LV macrophage accumulation, cardiomyocyte apoptosis, coronary atherosclerosis and remodelling.