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Enhancing the Engraftment of Human Induced Pluripotent Stem Cell-derived Cardiomyocytes via a Transient Inhibition of Rho Kinase Activity
Published on: July 10, 2019
Pharmacologic therapy for engraftment arrhythmia induced by transplantation of human cardiomyocytes
Kenta Nakamura1, Lauren E Neidig2, Xiulan Yang3
1Institute for Stem Cell and Regenerative Medicine, University of Washington, 850 Republican Street, Brotman Building Room 453, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA; Division of Cardiology, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
Insights
Clinically approved antiarrhythmic drugs, amiodarone and ivabradine, effectively suppressed engraftment arrhythmia (EA) in a porcine model. This combination therapy significantly reduced mortality and heart failure, paving the way for safer cardiac remuscularization.
Area of Science:
- Cardiology
- Regenerative Medicine
- Pharmacology
Background:
- Heart failure post-myocardial infarction is a major cause of death.
- Human pluripotent stem cell-derived cardiomyocytes offer promising cardiac repair.
- Engraftment arrhythmia (EA) is a significant risk hindering clinical translation of cell therapy.
Purpose of the Study:
- To test if antiarrhythmic drugs can prevent mortality and reduce arrhythmia burden from EA.
- To provide proof-of-concept for pharmacologic prevention of EA in a large animal model.
Main Methods:
- A porcine model was used to study EA following myocardial infarction.
- Subjects received a combination of amiodarone and ivabradine.
- A control group received no treatment.
Main Results:
- None of the nine treated subjects experienced cardiac death, unstable EA, or heart failure.
- Five out of eight (62.5%) control subjects experienced adverse outcomes (HR=0.00; p=0.002).
- The combination therapy effectively suppressed EA and related mortality.
Conclusions:
- Pharmacologic treatment with amiodarone and ivabradine is a viable strategy to mitigate EA risks.
- This approach can improve the safety of cardiac remuscularization therapies.
- The findings support further clinical development of stem cell-based cardiac repair.
Abstract:
Heart failure remains a significant cause of morbidity and mortality following myocardial infarction. Cardiac remuscularization with transplantation of human pluripotent stem cell-derived cardiomyocytes is a promising preclinical therapy to restore function. Recent large animal data, however, have revealed a significant risk of engraftment arrhythmia (EA). Although transient, the risk posed by EA presents a barrier to clinical translation. We hypothesized that clinically approved antiarrhythmic drugs can prevent EA-related mortality as well as suppress tachycardia and arrhythmia burden. This study uses a porcine model to provide proof-of-concept evidence that a combination of amiodarone and ivabradine can effectively suppress EA. None of the nine treated subjects experienced the primary endpoint of cardiac death, unstable EA, or heart failure compared with five out of eight (62.5%) in the control cohort (hazard ratio = 0.00; 95% confidence interval: 0-0.297; p = 0.002). Pharmacologic treatment of EA may be a viable strategy to improve safety and allow further clinical development of cardiac remuscularization therapy.
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