title: Abnormal calcium handling properties underlie familial hypertrophic cardiomyopathy pathology in patient-specific induced pluripotent stem cells.
abstract: Familial hypertrophic cardiomyopathy (HCM) is a prevalent hereditary cardiac disorder linked to arrhythmia and sudden cardiac death. While the causes of HCM have been identified as genetic mutations in the cardiac sarcomere, the pathways by which sarcomeric mutations engender myocyte hypertrophy and electrophysiological abnormalities are not understood. To elucidate the mechanisms underlying HCM development, we generated patient-specific induced pluripotent stem cell cardiomyocytes (iPSC-CMs) from a ten-member family cohort carrying a hereditary HCM missense mutation (Arg663His) in the MYH7 gene. Diseased iPSC-CMs recapitulated numerous aspects of the HCM phenotype including cellular enlargement and contractile arrhythmia at the single-cell level. Calcium (Ca(2+)) imaging indicated dysregulation of Ca(2+) cycling and elevation in intracellular Ca(2+) ([Ca(2+)](i)) are central mechanisms for disease pathogenesis. Pharmacological restoration of Ca(2+) homeostasis prevented development of hypertrophy and electrophysiological irregularities. We anticipate that these findings will help elucidate the mechanisms underlying HCM development and identify novel therapies for the disease.
authors.affiliation: Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Lan
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Lee
authors.forename: Ping
authors.initials: P
authors.lastname: Liang
authors.forename: Veronica
authors.initials: V
authors.lastname: Sanchez-Freire
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Nguyen
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Leng
authors.initials: L
authors.lastname: Han
authors.forename: Michelle
authors.initials: M
authors.lastname: Yen
authors.forename: Yongming
authors.initials: Y
authors.lastname: Wang
authors.forename: Ning
authors.initials: N
authors.lastname: Sun
authors.forename: Oscar J
authors.initials: OJ
authors.lastname: Abilez
authors.forename: Shijun
authors.initials: S
authors.lastname: Hu
authors.forename: Antje D
authors.initials: AD
authors.lastname: Ebert
authors.forename: Enrique G
authors.initials: EG
authors.lastname: Navarrete
authors.forename: Chelsey S
authors.initials: CS
authors.lastname: Simmons
authors.forename: Matthew
authors.initials: M
authors.lastname: Wheeler
authors.forename: Beth
authors.initials: B
authors.lastname: Pruitt
authors.forename: Richard
authors.initials: R
authors.lastname: Lewis
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Euan A
authors.initials: EA
authors.lastname: Ashley
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
authors.forename: Robert C
authors.initials: RC
authors.lastname: Robbins
authors.forename: Michael T
authors.initials: MT
authors.lastname: Longaker
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Wu
mesh_terms: D002118:Calcium / Q000378:metabolism*; D024722:Cardiac Myosins / Q000235:genetics; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology*; D020125:Mutation, Missense; D018995:Myosin Heavy Chains / Q000235:genetics
chemical_list: C501641:MYH7 protein, human; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains; D002118:Calcium