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Bicuspid aortic valve, whereby the aortic valve forms with two instead of three cusps, is the most common cause of AS in younger patients due to primary anatomic narrowing of the valve. In addition, the secondary onset of premature calcification, likely induced by altered hemodynamics, further obstructs left ventricular outflow in bicuspid aortic valve patients. In adults, degenerative AS involves progressive calcification of an anatomically normal, tricuspid aortic valve and is attributed to lifelong exposure to multifactoral risk factors and physiological wear-and-tear that negatively impacts valve structure-function relationships. AS continues to be the most frequent valvular disease that requires intervention, and aortic valve replacement is the standard treatment for patients with severe or symptomatic AS. While the positive impacts of surgical interventions are well documented, the financial burden, the potential need for repeated procedures, and operative risks are substantial. In addition, the clinical management of asymptomatic patients remains controversial. Therefore, there is a critical need to develop alternative approaches to prevent the progression of left ventricular outflow obstruction, especially in valvar lesions. This review summarizes our current understandings of AS cause; beginning with developmental origins of congenital valve disease, and leading into the multifactorial nature of AS in the adult population.<\/jats:p>","DOI":"10.1161\/circresaha.120.317978","type":"journal-article","created":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T18:00:44Z","timestamp":1619719244000},"page":"1330-1343","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":37,"title":["Genetic and Developmental Contributors to Aortic Stenosis"],"prefix":"10.1161","volume":"128","author":[{"given":"Punashi","family":"Dutta","sequence":"first","affiliation":[{"name":"The Herma Heart Institute, Section of Pediatric Cardiology, Children\u2019s Wisconsin, Milwaukee, WI (P.D., J.F.J., H.K., J.L.)."},{"name":"Department of Pediatrics, Medical College of Wisconsin, Milwaukee (P.D., J.F.J., J.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanne F.","family":"James","sequence":"additional","affiliation":[{"name":"The Herma Heart Institute, Section of Pediatric Cardiology, Children\u2019s Wisconsin, Milwaukee, WI (P.D., J.F.J., H.K., J.L.)."},{"name":"Department of Pediatrics, Medical College of Wisconsin, Milwaukee (P.D., J.F.J., J.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hail","family":"Kazik","sequence":"additional","affiliation":[{"name":"The Herma Heart Institute, Section of Pediatric Cardiology, Children\u2019s Wisconsin, Milwaukee, WI (P.D., J.F.J., H.K., J.L.)."},{"name":"Department of Biomedical Engineering, Marquette University &amp; Medical College of Wisconsin, Milwaukee (H.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1517-6888","authenticated-orcid":true,"given":"Joy","family":"Lincoln","sequence":"additional","affiliation":[{"name":"The Herma Heart Institute, Section of Pediatric Cardiology, Children\u2019s Wisconsin, Milwaukee, WI (P.D., J.F.J., H.K., J.L.)."},{"name":"Department of Pediatrics, Medical College of Wisconsin, Milwaukee (P.D., J.F.J., J.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","volume-title":"Aortic Stenosis","author":"Pujari SH","year":"2020","unstructured":"Pujari, SH, Agasthi, P. 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