title: Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts.
abstract: Transplantation studies in mice and rats have shown that human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) can improve the function of infarcted hearts, but two critical issues related to their electrophysiological behaviour in vivo remain unresolved. First, the risk of arrhythmias following hESC-CM transplantation in injured hearts has not been determined. Second, the electromechanical integration of hESC-CMs in injured hearts has not been demonstrated, so it is unclear whether these cells improve contractile function directly through addition of new force-generating units. Here we use a guinea-pig model to show that hESC-CM grafts in injured hearts protect against arrhythmias and can contract synchronously with host muscle. Injured hearts with hESC-CM grafts show improved mechanical function and a significantly reduced incidence of both spontaneous and induced ventricular tachycardia. To assess the activity of hESC-CM grafts in vivo, we transplanted hESC-CMs expressing the genetically encoded calcium sensor, GCaMP3 (refs 4, 5). By correlating the GCaMP3 fluorescent signal with the host ECG, we found that grafts in uninjured hearts have consistent 1:1 host–graft coupling. Grafts in injured hearts are more heterogeneous and typically include both coupled and uncoupled regions. Thus, human myocardial grafts meet physiological criteria for true heart regeneration, providing support for the continued development of hESC-based cardiac therapies for both mechanical and electrical repair.
authors.affiliation: Department of Pathology, Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98109, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shiba
authors.forename: Sarah
authors.initials: S
authors.lastname: Fernandes
authors.forename: Wei-Zhong
authors.initials: WZ
authors.lastname: Zhu
authors.forename: Dominic
authors.initials: D
authors.lastname: Filice
authors.forename: Veronica
authors.initials: V
authors.lastname: Muskheli
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kim
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Palpant
authors.forename: Jay
authors.initials: J
authors.lastname: Gantz
authors.forename: Kara White
authors.initials: KW
authors.lastname: Moyes
authors.forename: Hans
authors.initials: H
authors.lastname: Reinecke
authors.forename: Benjamin
authors.initials: B
authors.lastname: Van Biber
authors.forename: Todd
authors.initials: T
authors.lastname: Dardas
authors.forename: John L
authors.initials: JL
authors.lastname: Mignone
authors.forename: Atsushi
authors.initials: A
authors.lastname: Izawa
authors.forename: Ramy
authors.initials: R
authors.lastname: Hanna
authors.forename: Mohan
authors.initials: M
authors.lastname: Viswanathan
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Gold
authors.forename: Michael I
authors.initials: MI
authors.lastname: Kotlikoff
authors.forename: Narine
authors.initials: N
authors.lastname: Sarvazyan
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Kay
authors.forename: Charles E
authors.initials: CE
authors.lastname: Murry
authors.forename: Michael A
authors.initials: MA
authors.lastname: Laflamme
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology / Q000628:therapy*; D002118:Calcium / Q000032:analysis / Q000378:metabolism; D004558:Electric Stimulation; D055724:Electrophysiological Phenomena; D053595:Embryonic Stem Cells / Q000166:cytology*; D005456:Fluorescent Dyes / Q000032:analysis; D006168:Guinea Pigs; D006335:Heart Injuries / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008163:Luminescent Measurements; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000166:cytology / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000502:physiology / Q000637:transplantation*; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000503:physiopathology / Q000628:therapy
chemical_list: D005456:Fluorescent Dyes; D002118:Calcium