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In this work, we generated cardiomyocytes derived from isogenic human induced pluripotent stem cells to model the heterozygous pathogenic MYH7 missense variant, E848G, which is associated with left ventricular hypertrophy and adult-onset systolic dysfunction. MYH7E848G\/+ increased cardiomyocyte size and reduced the maximum twitch forces of engineered heart tissue, consistent with the systolic dysfunction in MYH7E848G\/+ HCM patients. Interestingly, MYH7E848G\/+ cardiomyocytes more frequently underwent apoptosis that was associated with increased p53 activity relative to controls. However, genetic ablation of TP53 did not rescue cardiomyocyte survival or restore engineered heart tissue twitch force, indicating MYH7E848G\/+ cardiomyocyte apoptosis and contractile dysfunction are p53-independent. Overall, our findings suggest that cardiomyocyte apoptosis is associated with the MYH7E848G\/+ HCM phenotype in vitro and that future efforts to target p53-independent cell death pathways may be beneficial for the treatment of HCM patients with systolic dysfunction.<\/jats:p>","DOI":"10.3390\/ijms24054909","type":"journal-article","created":{"date-parts":[[2023,3,6]],"date-time":"2023-03-06T03:49:08Z","timestamp":1678074548000},"page":"4909","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Cardiomyocyte Apoptosis Is Associated with Contractile Dysfunction in Stem Cell Model of MYH7 E848G Hypertrophic Cardiomyopathy"],"prefix":"10.3390","volume":"24","author":[{"given":"Alexander M.","family":"Loiben","sequence":"first","affiliation":[{"name":"Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98109, USA"},{"name":"Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA"},{"name":"Department of Medicine\/Cardiology, University of Washington, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Ming","family":"Chien","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98109, USA"},{"name":"Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA"},{"name":"Department of Medicine\/Cardiology, University of Washington, Seattle, WA 98109, USA"},{"name":"Cardiology\/Hospital Specialty Medicine, VA Puget Sound HCS, Seattle, WA 98108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4211-886X","authenticated-orcid":false,"given":"Clayton E.","family":"Friedman","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98109, USA"},{"name":"Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA"},{"name":"Department of Medicine\/Cardiology, University of Washington, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie S.-L.","family":"Chao","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell and Regenerative Medicine, School of Medicine, University of Washington, Seattle, WA 98109, USA"},{"name":"Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA"},{"name":"Department of Medicine\/Cardiology, University of Washington, Seattle, WA 98109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhard","family":"Weber","sequence":"additional","affiliation":[{"name":"Department of Medicine\/Cardiology, University of Washington, Seattle, WA 98109, 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