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Improvement of aortic valve stenosis by ApoA-I mimetic therapy is associated with decreased aortic root and valve remodelling in mice.

ABSTRACT: BACKGROUND AND PURPOSE: We have shown that infusions of apolipoprotein A-I (ApoA-I) mimetic peptide induced regression of aortic valve stenosis (AVS) in rabbits. This study aimed at determining the effects of ApoA-I mimetic therapy in mice with calcific or fibrotic AVS. EXPERIMENTAL APPROACH: Apolipoprotein E-deficient (ApoE(-/-) ) mice and mice with Werner progeria gene deletion (Wrn(?hel/?hel) ) received high-fat diets for 20 weeks. After developing AVS, mice were randomized to receive saline (placebo group) or ApoA-I mimetic peptide infusions (ApoA-I treated groups, 100?mg·kg(-1) for ApoE(-/-) mice; 50?mg·kg(-1) for Wrn mice), three times per week for 4 weeks. We evaluated effects on AVS using serial echocardiograms and valve histology. KEY RESULTS: Aortic valve area (AVA) increased in both ApoE(-/-) and Wrn mice treated with the ApoA-I mimetic compared with placebo. Maximal sinus wall thickness was lower in ApoA-I treated ApoE(-/-) mice. The type I/III collagen ratio was lower in the sinus wall of ApoA-I treated ApoE(-/-) mice compared with placebo. Total collagen content was reduced in aortic valves of ApoA-I treated Wrn mice. Our 3D computer model and numerical simulations confirmed that the reduction in aortic root wall thickness resulted in improved AVA. CONCLUSIONS AND IMPLICATIONS: ApoA-I mimetic treatment reduced AVS by decreasing remodelling and fibrosis of the aortic root and valve in mice.

SUBMITTER: Trapeaux J

PROVIDER: S-EPMC3724114 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Improvement of aortic valve stenosis by ApoA-I mimetic therapy is associated with decreased aortic root and valve remodelling in mice.

Trapeaux J J Busseuil D D Shi Y Y Nobari S S Shustik D D Mecteau M M El-Hamamsy I I Lebel M M Mongrain R R Rhéaume E E Tardif J-C JC

British journal of pharmacology 20130801 7

<h4>Background and purpose</h4>We have shown that infusions of apolipoprotein A-I (ApoA-I) mimetic peptide induced regression of aortic valve stenosis (AVS) in rabbits. This study aimed at determining the effects of ApoA-I mimetic therapy in mice with calcific or fibrotic AVS.<h4>Experimental approach</h4>Apolipoprotein E-deficient (ApoE(-/-) ) mice and mice with Werner progeria gene deletion (Wrn(Δhel/Δhel) ) received high-fat diets for 20 weeks. After developing AVS, mice were randomized to re ...[more]

PMID: 23638718

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Project description:BackgroundAortic valve stenosis is the most common type of valvular heart disease in the USA and Europe. Aortic valve stenosis is considered similar to atherosclerotic disease. Some studies have evaluated statins for aortic valve stenosis.ObjectivesTo evaluate the effectiveness and safety of statins in aortic valve stenosis.Search methodsWe searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS - IBECS, Web of Science and CINAHL Plus. These databases were searched from their inception to 24 November 2015. We also searched trials in registers for ongoing trials. We used no language restrictions.Selection criteriaRandomised controlled clinical trials (RCTs) comparing statins alone or in association with other systemic drugs to reduce cholesterol levels versus placebo or usual care.Data collection and analysisPrimary outcomes were severity of aortic valve stenosis (evaluated by echocardiographic criteria: mean pressure gradient, valve area and aortic jet velocity), freedom from valve replacement and death from cardiovascular cause. Secondary outcomes were hospitalisation for any reason, overall mortality, adverse events and patient quality of life.Two review authors independently selected trials for inclusion, extracted data and assessed the risk of bias. The GRADE methodology was employed to assess the quality of result findings and the GRADE profiler (GRADEPRO) was used to import data from Review Manager 5.3 to create a 'Summary of findings' table.Main resultsWe included four RCTs with 2360 participants comparing statins (1185 participants) with placebo (1175 participants). We found low-quality evidence for our primary outcome of severity of aortic valve stenosis, evaluated by mean pressure gradient (mean difference (MD) -0.54, 95% confidence interval (CI) -1.88 to 0.80; participants = 1935; studies = 2), valve area (MD -0.07, 95% CI -0.28 to 0.14; participants = 127; studies = 2), and aortic jet velocity (MD -0.06, 95% CI -0.26 to 0.14; participants = 155; study = 1). Moderate-quality evidence showed no effect on freedom from valve replacement with statins (risk ratio (RR) 0.93, 95% CI 0.81 to 1.06; participants = 2360; studies = 4), and no effect on muscle pain as an adverse event (RR 0.91, 95% CI 0.75 to 1.09; participants = 2204; studies = 3; moderate-quality evidence). Low- and very low-quality evidence showed uncertainty around the effect of statins on death from cardiovascular cause (RR 0.80, 95% CI 0.56 to 1.15; participants = 2297; studies = 3; low-quality evidence) and hospitalisation for any reason (RR 0.84, 95% CI 0.39 to 1.84; participants = 155; study = 1; very low-quality evidence). None of the four included studies reported on overall mortality and patient quality of life.Authors' conclusionsResult findings showed uncertainty surrounding the effect of statins for aortic valve stenosis.The quality of evidence from the reported outcomes ranged from moderate to very low. These results give support to European and USA guidelines (2012 and 2014, respectively) that so far there is no clinical treatment option for aortic valve stenosis.

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Improvement of aortic valve stenosis by ApoA-I mimetic therapy is associated with decreased aortic root and valve remodelling in mice.

Publications

Improvement of aortic valve stenosis by ApoA-I mimetic therapy is associated with decreased aortic root and valve remodelling in mice.

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