Regression of aortic valve stenosis by ApoA‐I mimetic peptide infusions in rabbits

Abstract

Background and purpose: Aortic valve stenosis (AVS) is the most common valvular heart disease, and standard curative therapy remains open heart surgical valve replacement. The aim of our experimental study was to determine if apolipoprotein A-I (ApoA-I) mimetic peptide infusions could induce regression of AVS. Experimental approach: Fifteen New Zealand White male rabbits received a cholesterol-enriched diet and vitamin D 2 until significant AVS was detected by echocardiography. The enriched diet was then stopped to mimic cholesterol-lowering therapy and animals were allocated randomly to receive saline (control group, n ¼ 8) or an ApoA-I mimetic peptide (treated group, n ¼ 7), three times per week for 2 weeks. Serial echocardiograms and post mortem valve histology were performed. Key results: Aortic valve area increased significantly by 25% in the treated group after 14 days of treatment (P ¼ 0.012). Likewise, aortic valve thickness decreased by 21% in the treated group, whereas it was unchanged in controls (P ¼ 0.0006). Histological analysis revealed that the extent of lesions at the base of valve leaflets and sinuses of Valsalva was smaller in the treated group compared with controls (P ¼ 0.032). The treatment also reduced calcification, as revealed by the loss of the positive relationship observed in the control group (r ¼ 0.87, P ¼ 0.004) between calcification area and aortic valve thickness. Conclusions and implications: Infusions of ApoA-I mimetic peptide lead to regression of experimental AVS. These positive results justify the further testing of high-density lipoprotein (HDL)-based therapies in patients with valvular aortic stenosis. Regression of aortic stenosis, if achieved safely, could transform the clinical treatment of this disease.

Light to Moderate Alcohol Consumption Is Associated With Lower Risk of Aortic Valve Sclerosis

“…39,40 On a parallel note, recombinant apolipoprotein A1 Milano reversed aortic valve stenosis and positively affected valve remodeling in experimental settings. [40][41][42] In line with these data, a recent proteomic study 43 revealed that apolipoprotein A1 and fibrinogen were significantly enriched in the valves of patients submitted to aortic valve replacement as compared with normal aortic valves. Although the presence of apolipoprotein A1 might be a protective mechanism against increased levels of low-density lipoprotein cholesterol, lipoprotein(a), and triglycerides on the aortic valve surface, the presence of fibrinogen seems Prevalence odds ratio (95% CI) for aortic valve sclerosis according to average alcohol consumption in the last 30 days (adjusted for age, sex, educational level, smoking, physical inactivity, and waist-to-height ratio).…”

Effect of Recombinant Human Lecithin Cholesterol Acyltransferase Infusion on Lipoprotein Metabolism in Mice

“…Proteoliposomes were made by mixing of [ 14 C]cholesterol (1.25 Ci/ml; PerkinElmer Life and Analytical Sciences, Boston, MA) and cholesterol (final concentration, 72 M; Sigma-Aldrich, St. Louis, MO) and phosphatidylcholine (1.2 mM, ␣-L-lecithin; Calbiochem-EMD, La Jolla, CA) in chloroform and drying down under nitrogen. Lipids were solubilized in an assay buffer (110 mM Tris-HCl, 140 mM NaCl, and 1 mM EDTA, pH 7.4) containing an amphipathic peptide ETC-642 (PVLDL-FRELLNELLEALKQKLK; Busseuil et al, 2008) and sodium cholic acid (final concentration, 62 mM; Sigma-Aldrich). After dialysis, proteoliposomes were stabilized by adding of equal volume of 2% BSA (w/v) with ␤-mercaptoethanol (10 mM) in the assay buffer and then incubated 20 min at 37°C.…”

Lipid Lowering in Aortic Stenosis

“…In a recent hypercholesterolemic rabbit model, infusion of apolipoprotein A-I mimetic peptides resulted in regression of experimental AS including attenuation of valvular calcification. 10 These data suggest highdensity lipoprotein-based therapies as a potent candidate for AS treatment. It is noteworthy that in the investigations by Miller et al, 4 even though aortic valve superoxide levels, myofibroblast activation, valvular calcium burden, and proosteogenic signaling were reduced after normalization of blood cholesterol levels, no regression of valvular fibrosis occurred.…”