title: Electrical Integration of Human Embryonic Stem Cell-Derived Cardiomyocytes in a Guinea Pig Chronic Infarct Model.
abstract: BACKGROUND
  Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) were recently shown to be capable of electromechanical integration following direct injection into intact or recently injured guinea pig hearts, and hESC-CM transplantation in recently injured hearts correlated with improvements in contractile function and a reduction in the incidence of arrhythmias. The present study was aimed at determining the ability of hESC-CMs to integrate and modulate electrical stability following transplantation in a chronic model of cardiac injury.
  
  
  RESULTS
  At 28 days following cardiac cryoinjury, guinea pigs underwent intracardiac injection of hESC-CMs, noncardiac hESC derivatives (non-CMs), or vehicle. Histology confirmed partial remuscularization of the infarct zone in hESC-CM recipients while non-CM recipients showed heterogeneous xenografts. The 3 experimental groups showed no significant difference in the left ventricular dimensions or fractional shortening by echocardiography or in the incidence of spontaneous arrhythmias by telemetric monitoring. Although recipients of hESC-CMs and vehicle showed a similar incidence of arrhythmias induced by programmed electrical stimulation at 4 weeks posttransplantation, non-CM recipients proved to be highly inducible, with a ∼3-fold greater incidence of induced arrhythmias. In parallel studies, we investigated the ability of hESC-CMs to couple with host myocardium in chronically injured hearts by the intravital imaging of hESC-CM grafts that stably expressed a fluorescent reporter of graft activation, the genetically encoded calcium sensor GCaMP3. In this work, we found that only ∼38% (5 of 13) of recipients of GCaMP3+ hESC-CMs showed fluorescent transients that were coupled to the host electrocardiogram.
  
  
  CONCLUSIONS
  Human embryonic stem cell-derived cardiomyocytes engraft in chronically injured hearts without increasing the incidence of arrhythmias, but their electromechanical integration is more limited than previously reported following their transplantation in a subacute injury model. Moreover, non-CM grafts may promote arrhythmias under certain conditions, a finding that underscores the need for input preparations of high cardiac purity.
authors: Department of Pathology, Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA Department of Cardiovascular Medicine, Shinshu University, Matsumoto, Japan.
authors: Yuji
authors: Y
authors: Shiba
authors: Department of Pathology, Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA Department of Bioengineering, Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.
authors: Dominic
authors: D
authors: Filice
authors: Department of Pathology, Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA Gilead Sciences, Fremont, CA, USA.
authors: Sarah
authors: S
authors: Fernandes
authors: Department of Medicine/Cardiology, Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.
authors: Elina
authors: E
authors: Minami
authors: Department of Pathology, Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.
authors: Sarah K
authors: SK
authors: Dupras
authors: Department of Pathology, Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.
authors: Benjamin Van
authors: BV
authors: Biber
authors: Department of Pathology, Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.
authors: Peter
authors: P
authors: Trinh
authors: Department of Cardiovascular Medicine, Shinshu University, Matsumoto, Japan.
authors: Yusuke
authors: Y
authors: Hirota
authors: Geron Corporation, Menlo Park, CA, USA Cardiovascular Institute, Stanford University, Stanford, CA, USA.
authors: Joseph D
authors: JD
authors: Gold
authors: Department of Medicine/Cardiology, Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.
authors: Mohan
authors: M
authors: Viswanathan
authors: Department of Pathology, Center for Cardiovascular Biology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA laflamme@u.washington.edu.
authors: Michael A
authors: MA
authors: Laflamme
keywords: cardiomyocyte; cell transplantation; electrophysiology; human embryonic stem cell (hESC)