High-Density Lipoprotein (HDL) mimetic peptide CER-522 induces regression of experimental left ventricular diastolic dysfunction

Purpose: High-density lipoprotein (HDL) infusions induce rapid improvement of atherosclerosis and aortic valve stenosis (AVS) in animals but their effect on left ventricular diastolic dysfunction (LVDD) remains unknown. Our study aimed at evaluating the effects of the HDL mimetic peptide CER-522 on LVDD in a rabbit model of AVS. Methods: Thirty-five (35) male New-Zealand White rabbits were fed with a 0.5% cholesterol- and vitamin D2-enriched diet until mild AVS was detected by echocardiography (mean duration of diet: 16 weeks). Animals were then randomized to receive saline (control group, n = 11) or the HDL mimetic peptide CER-522 at doses of 10 mg/kg (n = 12) or 30 mg/kg (n = 12) 3 times per week for 2 weeks. Serial echocardiograms and end-of-study histological examination of the aortic valve and left ventricle were performed. Results: Aortic valve area increased at day 10 in the CER-522 10 mg/kg group (P = 0.016) and at day 14 in both the CER-522 10 and 30 mg/kg treated groups compared to controls (P = 0.011 and P = 0.033, respectively). Aortic root strain index was higher in both CER-522 treated groups vs controls at 14 days of treatment (P = 0.007 and P = 0.047, respectively). At day 14, compared to controls, CER-522 normalized early filling deceleration time (P < 0.001 for both treated groups) and E wave deceleration rate (P < 0.001 for both treated groups), decreased E/Em ratio (P < 0.001 and P = 0.001 for the 10 and 30 mg/kg groups, respectively) and increased Em/Am ratio (P < 0.001 and P = 0.025). Although all groups had similar amount of global LVDD before treatment, moderate LVDD was present in 36.4, 16.7 and 0% of animals in the control, CER-522 10 and 30 mg/kg groups respectively at study end (P = 0.216 and P < 0.001 for 10 and 30 mg/kg groups vs controls). Histological analyses showed that RAM-11 positive cells (macrophages) in LV myocardium and pericoronary fibrosis were reduced with CER-522 10 mg/kg compared to controls (P = 0.006 and P = 0.018). The number of apoptotic cardiomyocytes was reduced by CER-522 30 mg/kg vs controls (P = 0.010; P=NS for 10 mg/kg). Coronary artery atheroma area was decreased in both CER-522 groups vs controls (P = 0.028 and P = 0.044 for 10 and 30 mg/kg groups), as was the case for the coronary external/internal elastic lamina area ratio (P = 0.003 and P = 0.010). Conclusions: The HDL mimetic peptide CER-522 improves LVDD in rabbits while also reducing cardiomyocyte apoptosis, mild AVS, aortic root rigidity and coronary atherosclerosis.

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