biostudies-literatureSmith JGWGerman Research FoundationNational Centre for the Replacement, Refinement and Reduction of Animals in ResearchBritish Heart FoundationBritain Israel Research and Academic Exchange PartnershipUna forma de hacer EuropaFEDERGerman Ministry of Education and ResearchFreie und Hansestadt HamburgEuropean CommissionGerman Centre for Cardiovascular ResearchEngineering and Physical Sciences Research CouncilCentro de Investigación Biomédica en RedEuropean Research CouncilInstituto de Salud Carlos IIIMedical Research CouncilUnión EuropeaNational Centre for the Replacement, Refinement & Reduction of Animals1226-1243https://www.ebi.ac.uk/biostudies/studies/S-EPMC6235010biostudies-literatureUnknown11(5)Hypertrophic cardiomyopathy (HCM) is a primary disorder of contractility in heart muscle. To gain mechanistic insight and guide pharmacological rescue, this study models HCM using isogenic pairs of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying the E99K-ACTC1 cardiac actin mutation. In both 3D engineered heart tissues and 2D monolayers, arrhythmogenesis was evident in all E99K-ACTC1 hiPSC-CMs. Aberrant phenotypes were most common in hiPSC-CMs produced from the heterozygote father. Unexpectedly, pathological phenotypes were less evident in E99K-expressing hiPSC-CMs from the two sons. Mechanistic insight from Ca²⁺ handling expression studies prompted pharmacological rescue experiments, wherein dual dantroline/ranolazine treatment was most effectiveStem cell reportsIsogenic Pairs of hiPSC-CMs with Hypertrophic Cardiomyopathy/LVNC-Associated ACTC1 E99K Mutation Unveil Differential Functional Deficits.PMC6235010G113/30PG/14/59/31000RM/13/30157NC/C013202/1SP/15/9/31605CB16/11/00425 6171379951DFG-Es-88/12-1, HA3423/5-1MR/M017354/1P47352/CRM04BX14CDLGFS/16/17/31663NC/C013105/1G0801098CRACK-IT:35911-259146RG/11/20/29266RG/14/1/30588MR/L012618/1RG/15/6/31436NC/K000225/1Eschenhagen TPatel AHansen AScott ESmith JGWDenning COwen THarding SEMarston SBarriales-Villa RMannhardt IBhagwan JRMosqueira DMonserrat LfalseIsogenic Pairs of hiPSC-CMs with Hypertrophic Cardiomyopathy/LVNC-Associated ACTC1 E99K Mutation Unveil Differential Functional Deficits.Hypertrophic cardiomyopathy (HCM) is a primary disorder of contractility in heart muscle. To gain mechanistic insight and guide pharmacological rescue, this study models HCM using isogenic pairs of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying the E99K-ACTC1 cardiac actin mutation. In both 3D engineered heart tissues and 2D monolayers, arrhythmogenesis was evident in all E99K-ACTC1 hiPSC-CMs. Aberrant phenotypes were most common in hiPSC-CMs produced from the heterozygote father. Unexpectedly, pathological phenotypes were less evident in E99K-expressing hiPSC-CMs from the two sons. Mechanistic insight from Ca²⁺ handling expression studies prompted pharmacological rescue experiments, wherein dual dantroline/ranolazine treatment was most effective2018-01-01T00:00:00Z2018 Nov2026-05-06T02:33:30.349Z2019-03-27T00:08:27ZS-EPMC62350103039297510.1016/j.stemcr.2018.10.006