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HDL mimetic peptide CER-522 treatment regresses left ventricular diastolic dysfunction in cholesterol-fed rabbits
Nolwenn Merlet1, David Busseuil2, Teodora Mihalache-Avram2
1Montreal Heart Institute, Université de Montréal, Montreal, Canada; Department of Medicine, Université de Montréal, Montreal, Canada.
Insights
The HDL mimetic peptide CER-522 improved left ventricular diastolic dysfunction (LVDD) in rabbits. This peptide reduced inflammation, apoptosis, and coronary atherosclerosis, offering a potential therapeutic avenue.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Experimental Medicine
Background:
- High-density lipoprotein (HDL) infusions rapidly improve experimental atherosclerosis.
- The impact of HDL infusions on ventricular function, specifically left ventricular diastolic dysfunction (LVDD), is not well understood.
Purpose of the Study:
- To investigate the effects of the HDL mimetic peptide CER-522 on LVDD.
- To assess CER-522's impact on cardiac structure and function in a rabbit model.
Main Methods:
- Rabbits were induced with hypercholesterolemia and aortic valve stenosis to develop LVDD.
- Animals received escalating doses of CER-522 or saline over two weeks.
- Serial echocardiography and LV histology were employed to evaluate therapeutic effects.
Main Results:
- CER-522 significantly improved LVDD across multiple echocardiographic parameters.
- Treatment reduced macrophage infiltration in the myocardium and pericoronary adipose tissue.
- CER-522 decreased cardiomyocyte apoptosis and coronary atherosclerotic plaque burden.
Conclusions:
- The HDL mimetic peptide CER-522 demonstrates efficacy in improving LVDD in rabbits.
- CER-522 reduces key pathological processes including inflammation, apoptosis, and coronary atherosclerosis.
- These findings suggest CER-522 as a potential therapeutic agent for LVDD.
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 CER-522 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 30mg/kg CER-522 infusions 6 times over 2weeks. We performed serial echocardiograms and LV histology to evaluate the effects of CER-522 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 CER-522-treated rabbits. CER-522 treatment also resulted in decreased atheromatous plaques and internal elastic lamina area in coronary arteries.
Conclusions:
CER-522 improves LVDD in rabbits, with reductions of LV macrophage accumulation, cardiomyocyte apoptosis, coronary atherosclerosis and remodelling.
