Abstract 8897: Transplantation of Human Embryonic Stem Cell-Derived Cardiomyocytes Decreased the Incidence of Arrhythmias in a Guinea Pig Acute Infarct Model
Introduction: The transplantation of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) has been shown to improve ventricular function in rodent infarct models. However, a number of important safety issues remain unresolved, including concerns about the risk of pro-arrhythmic effects. To address this, we conducted a transplantation study using primary electrocardiographic endpoints and the guinea pig model, as this species has a heart rate better matched to humans than do rats and mice.
Methods and Results: Ten days after undergoing near-transmural cryoinjury of the anterior left ventricle, immunosuppressed adult guinea pigs received direct intra-cardiac injections of 100x106 hESC-CMs (n=15 animals), 100x106 hESC-derived non-cardiac cells (non-CM, n=13), or vehicle alone (n=14). By histology at 28 days post-transplantation, the recipients of hESC-CMs showed engrafted human myocardium that occupied 8.4±1.5% of the scarred injury area, and no teratomas were identified. By echocardiography at 28 days post-transplantation, hESC-CM recipients had a significantly higher fractional shortening than did controls (hESC-CM: 25.4±0.8%, non-CM: 20.3±1.2%, vehicle: 21.0±1.3%, p<0.01). During telemetric ECG monitoring from days 3 through 28 days post-transplantation, a smaller fraction of hESC-CM recipients exhibited spontaneous ventricular tachycardia (VT) than in controls (20% of hESC-CM, 54% of non-CM, 28% of vehicle recipients). Moreover, when these animals were challenged with programmed electrical stimulation at 28 days post-transplantation, hESC-CM recipients showed a substantially reduced incidence of induced VT (6.7% of hESC-CM, 61.5% of non-CM, and 50.0% of vehicle recipients, p<0.05).
Conclusion: hESC-CM grafts survived in injured guinea pig hearts, and their transplantation resulted in preserved mechanical function, as well as a reduced incidence of both spontaneous and induced arrhythmias. The mechanistic basis of this arrhythmia-suppressive effect remains unknown, but it may provide a new rationale for the preclinical development of cardiac cell therapies based on hESC-CMs.
- © 2011 by American Heart Association, Inc.