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Unlike in atherosclerosis, and despite the heavy clinical toll, to date, no pharmacotherapy has proven effective to halt calcific aortic valve disease progression, with invasive and costly aortic valve replacement representing the only treatment option currently available. This substantial gap in care is largely because of our still-limited understanding of both normal aortic valve biology and the key regulatory mechanisms that drive disease initiation and progression. Drug discovery is further hampered by the inherent intricacy of the valvular microenvironment: a unique anatomic structure, a complex mixture of dynamic biomechanical forces, and diverse and multipotent cell populations collectively contributing to this currently intractable problem. One promising and rapidly evolving tactic is the application of multiomics approaches to fully define disease pathogenesis. Herein, we summarize the application of (epi)genomics, transcriptomics, proteomics, and metabolomics to the study of valvular heart disease. We also discuss recent forays toward the omics-based characterization of valvular (patho)biology at single-cell resolution; these efforts promise to shed new light on cellular heterogeneity in healthy and diseased valvular tissues and represent the potential to efficaciously target and treat key cell subpopulations. Last, we discuss systems biology- and network medicine-based strategies to extract meaning, mechanisms, and prioritized drug targets from multiomics datasets.<\/jats:p>","DOI":"10.1161\/circresaha.120.317979","type":"journal-article","created":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T14:00:44Z","timestamp":1619704844000},"page":"1371-1397","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":110,"title":["Multi-Omics Approaches to Define Calcific Aortic Valve Disease Pathogenesis"],"prefix":"10.1161","volume":"128","author":[{"given":"Mark C.","family":"Blaser","sequence":"first","affiliation":[{"name":"Cardiovascular Division, Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (M.C.B., E.A.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8245-7287","authenticated-orcid":true,"given":"Simon","family":"Kraler","sequence":"additional","affiliation":[{"name":"Center for Molecular Cardiology, University of Zurich, Schlieren, CH (S.K., T.F.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas F.","family":"L\u00fcscher","sequence":"additional","affiliation":[{"name":"Center for Molecular Cardiology, University of Zurich, Schlieren, CH (S.K., T.F.L.)."},{"name":"Heart Division, Royal Brompton &amp; Harefield Hospitals, London, United Kingdom (T.F.L.)."},{"name":"National Heart and Lung Institute, Imperial College, London, United Kingdom (T.F.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7835-2135","authenticated-orcid":true,"given":"Elena","family":"Aikawa","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Department of Medicine, Center for Interdisciplinary Cardiovascular Sciences (M.C.B., E.A.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA."},{"name":"Cardiovascular Division, Department of Medicine, Center for Excellence in Vascular Biology (E.A.), Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCOUTCOMES.112.966002"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0735-1097(96)00563-3"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.900027"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2007.09.033"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.2147\/CEOR.S112691"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2014.08.053"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.90.2.844"},{"key":"e_1_3_4_9_2","volume-title":"The Aortic Valve","author":"Thubrikar M","year":"1990","unstructured":"Thubrikar, M. 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