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      Calcific Aortic Valve Disease: a Developmental Biology Perspective

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          Abstract

          Purpose of Review

          This review aims to highlight the past and more current literature related to the multifaceted pathogenic programs that contribute to calcific aortic valve disease (CAVD) with a focus on the contribution of developmental programs.

          Recent Findings

          Calcification of the aortic valve is an active process characterized by calcific nodule formation on the aortic surface leading to a less supple and more stiffened cusp, thereby limiting movement and causing clinical stenosis. The mechanisms underlying these pathogenic changes are largely unknown, but emerging studies have suggested that signaling pathways common to valvulogenesis and bone development play significant roles and include Transforming Growth Factor-β (TGF-β), bone morphogenetic protein (BMP), Wnt, Notch, and Sox9.

          Summary

          This comprehensive review of the literature highlights the complex nature of CAVD but concurrently identifies key regulators that can be targeted in the development of mechanistic-based therapies beyond surgical intervention to improve patient outcome.

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          Most cited references146

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          Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis.

          Hyperlipidemia has been suggested as a risk factor for stenosis of the aortic valve, but lipid-lowering studies have had conflicting results. We conducted a randomized, double-blind trial involving 1873 patients with mild-to-moderate, asymptomatic aortic stenosis. The patients received either 40 mg of simvastatin plus 10 mg of ezetimibe or placebo daily. The primary outcome was a composite of major cardiovascular events, including death from cardiovascular causes, aortic-valve replacement, nonfatal myocardial infarction, hospitalization for unstable angina pectoris, heart failure, coronary-artery bypass grafting, percutaneous coronary intervention, and nonhemorrhagic stroke. Secondary outcomes were events related to aortic-valve stenosis and ischemic cardiovascular events. During a median follow-up of 52.2 months, the primary outcome occurred in 333 patients (35.3%) in the simvastatin-ezetimibe group and in 355 patients (38.2%) in the placebo group (hazard ratio in the simvastatin-ezetimibe group, 0.96; 95% confidence interval [CI], 0.83 to 1.12; P=0.59). Aortic-valve replacement was performed in 267 patients (28.3%) in the simvastatin-ezetimibe group and in 278 patients (29.9%) in the placebo group (hazard ratio, 1.00; 95% CI, 0.84 to 1.18; P=0.97). Fewer patients had ischemic cardiovascular events in the simvastatin-ezetimibe group (148 patients) than in the placebo group (187 patients) (hazard ratio, 0.78; 95% CI, 0.63 to 0.97; P=0.02), mainly because of the smaller number of patients who underwent coronary-artery bypass grafting. Cancer occurred more frequently in the simvastatin-ezetimibe group (105 vs. 70, P=0.01). Simvastatin and ezetimibe did not reduce the composite outcome of combined aortic-valve events and ischemic events in patients with aortic stenosis. Such therapy reduced the incidence of ischemic cardiovascular events but not events related to aortic-valve stenosis. (ClinicalTrials.gov number, NCT00092677.) 2008 Massachusetts Medical Society
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            Mutations in NOTCH1 cause aortic valve disease.

            Calcification of the aortic valve is the third leading cause of heart disease in adults. The incidence increases with age, and it is often associated with a bicuspid aortic valve present in 1-2% of the population. Despite the frequency, neither the mechanisms of valve calcification nor the developmental origin of a two, rather than three, leaflet aortic valve is known. Here, we show that mutations in the signalling and transcriptional regulator NOTCH1 cause a spectrum of developmental aortic valve anomalies and severe valve calcification in non-syndromic autosomal-dominant human pedigrees. Consistent with the valve calcification phenotype, Notch1 transcripts were most abundant in the developing aortic valve of mice, and Notch1 repressed the activity of Runx2, a central transcriptional regulator of osteoblast cell fate. The hairy-related family of transcriptional repressors (Hrt), which are activated by Notch1 signalling, physically interacted with Runx2 and repressed Runx2 transcriptional activity independent of histone deacetylase activity. These results suggest that NOTCH1 mutations cause an early developmental defect in the aortic valve and a later de-repression of calcium deposition that causes progressive aortic valve disease.
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              Clinical factors associated with calcific aortic valve disease. Cardiovascular Health Study.

              The aim of this study was to determine the prevalence of aortic sclerosis and stenosis in the elderly and to identify clinical factors associated with degenerative aortic valve disease. Several lines of evidence suggest that degenerative aortic valve disease is not an inevitable consequence of aging and may be associated with specific clinical factors. In 5,201 subjects > or = 65 years of age enrolled in the Cardiovascular Health Study, the relation between aortic sclerosis or stenosis identified on echocardiography and clinical risk factors for atherosclerosis was evaluated by using stepwise logistic regression analysis. Aortic valve sclerosis was present in 26% and aortic valve stenosis in 2% of the entire study cohort; in subjects > or = 75 years of age, sclerosis was present in 37% and stenosis in 2.6%. Independent clinical factors associated with degenerative aortic valve disease included age (twofold increased risk for each 10-year increase in age), male gender (twofold excess risk), present smoking (35% increase in risk) and a history of hypertension (20% increase in risk). Other significant factors included height and high lipoprotein(a) and low density lipoprotein cholesterol levels. Clinical factors associated with aortic sclerosis and stenosis can be identified and are similar to risk factors for atherosclerosis.
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                Author and article information

                Contributors
                +1-614-355-5752 , joy.lincoln@nationwidechildrens.org
                Journal
                Curr Cardiol Rep
                Curr Cardiol Rep
                Current Cardiology Reports
                Springer US (New York )
                1523-3782
                1534-3170
                8 March 2018
                8 March 2018
                2018
                : 20
                : 4
                : 21
                Affiliations
                [1 ]ISNI 0000 0004 0392 3476, GRID grid.240344.5, Center for Cardiovascular Research, , The Research Institute at Nationwide Children’s Hospital, ; 575 Children’s Drive, WB4239, Columbus, OH 43215 USA
                [2 ]ISNI 0000 0004 0392 3476, GRID grid.240344.5, The Heart Center, , Nationwide Children’s Hospital, ; Columbus, OH USA
                [3 ]ISNI 0000 0001 2285 7943, GRID grid.261331.4, Department of Pediatrics, , The Ohio State University, ; Columbus, OH USA
                Article
                968
                10.1007/s11886-018-0968-9
                5842494
                29520694
                f3d6af15-e4eb-4aef-b00e-a0cab09cd753
                © The Author(s) 2018

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                Categories
                Regenerative Medicine (SM Wu, Section Editor)
                Custom metadata
                © Springer Science+Business Media, LLC, part of Springer Nature 2018

                Cardiovascular Medicine
                heart valve,calcification,valvulogenesis,cell signaling,extracellular matrix

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