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Recent cohort studies identify obesity as a major adverse modifier of disease penetrance, severity, and clinical course. In this review, we provide an overview of these clinical findings. Moreover, we explore putative mechanisms underlying obesity\u2010induced sensitization and aggravation of the HCM phenotype. We hypothesize obesity\u2010related stressors to impact on cardiomyocyte structure, metabolism, and homeostasis. These may impair cardiac function by directly acting on the primary mutation\u2010induced myofilament defects and by independently adding to the total cardiac disease burden. Last, we address important clinical and pharmacological implications of the involvement of obesity in HCM disease modification.<\/jats:p>","DOI":"10.1161\/jaha.120.018641","type":"journal-article","created":{"date-parts":[[2020,11,11]],"date-time":"2020-11-11T10:08:32Z","timestamp":1605089312000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":37,"title":["Unraveling the Genotype\u2010Phenotype Relationship in Hypertrophic Cardiomyopathy: Obesity\u2010Related Cardiac Defects as a Major Disease Modifier"],"prefix":"10.1161","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7047-2538","authenticated-orcid":false,"given":"Edgar E.","family":"Nollet","sequence":"first","affiliation":[{"name":"Department of Physiology Amsterdam UMC Vrije Universiteit Amsterdam Amsterdam Cardiovascular Sciences Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1362-7019","authenticated-orcid":false,"given":"B. 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