Pharmacologic Therapy for Engraftment Arrhythmia Induced by Transplantation of Human Cardiomyocytes

Abstract

Background: Engraftment arrhythmias (EAs) are observed in large animal studies of intramyocardial transplantation of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) for myocardial infarction. Although transient, the risk posed by EA presents a barrier to clinical translation. Objectives We hypothesized that clinically approved antiarrhythmic drugs can prevent EA-related mortality as well as suppress tachycardia and arrhythmia burden. Methods: hPSC-CM were transplanted into the infarcted porcine heart by surgical or percutaneous delivery to induce EA. Following a screen of antiarrhythmic agents, a prospective study was conducted to determine the effectiveness of amiodarone plus ivabradine in preventing cardiac death and suppressing EA. Results: EA was observed in all subjects, and amiodarone-ivabradine treatment was well-tolerated. None of the treated subjects experienced the primary endpoint of cardiac death, unstable EA or heart failure compared to 5/8 (62.5%) in the control cohort (hazard ratio 0.00; 95% confidence interval, 0-0.297; p = 0.002). Overall survival including two deaths in the treated cohort from immunosuppression-related infection showed borderline improvement with treatment (hazard ratio 0.21; 95% confidence interval, 0.03-1.01; p = 0.05). Without treatment, peak heart rate averaged 305 +/- 29 beats per min (bpm), whereas in treated subjects peak daily heart rate was significantly restricted to 185+/-9 bpm (p = 0.006). Similarly, treatment reduced peak daily EA burden from 96.8 +/- 2.9% to 76.5 +/- 7.9% (p = 0.003). Antiarrhythmic treatment was safely discontinued after approximately one-month of treatment without recrudescence of arrhythmia. Conclusions: The risk of engraftment arrhythmia following hPSC-CM transplantation can be reduced significantly by combined amiodarone and ivabradine drug therapy.

Scalable manufacturing of clinical‐grade differentiated cardiomyocytes derived from human‐induced pluripotent stem cells for regenerative therapy

“…115 It has been considered that ventricular arrhythmia is caused by automaticity of hPSC-CMs. 114,116 In the clinical application of human heart regeneration, cell sheets generated by autologous skeletal muscles were transplanted to the hearts of patients. 117 It has been mentioned that this approach is feasible for the treatment of cardiomyopathy.…”

“…In the case of MHC‐matched allogeneic transplantation of monkey‐PSC‐CMs, cardiac function was recovered, but post‐transplant ventricular arrhythmia was also observed 115 . It has been considered that ventricular arrhythmia is caused by automaticity of hPSC‐CMs 114,116 . In the clinical application of human heart regeneration, cell sheets generated by autologous skeletal muscles were transplanted to the hearts of patients 117 .…”

Therapeutic payload delivery to the myocardium: Evolving strategies and obstacles

“… 77 , 78 , 79 Other combinations for the injectate (including cardiac stem cells, umbilical cord MSCs, and other cellular repair promoters) were developed and tested using the transepicardial delivery route for acute MI in animal models and small clinical trials. 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 For example, in a porcine MI model, transepicardial delivery of human MSCs with tyrosine-protein kinase kit + human cardiac stem cells revealed a synergistic effect in scar size reduction and restoration of systolic function. 88 …”

Transplantation of Human Pluripotent Stem Cell-Derived Cardiomyocytes for Cardiac Regenerative Therapy

“…In addition to potential tumorigenicity and immune rejection, a major roadblock for intramyocardial injection is hPSC-CM graft-associated arrhythmias. Recent evidence has demonstrated the feasibility of pharmacological therapy for hPSC-CM-induced arrhythmias after intramyocardial injection ( 80 ). Arrhythmia risk may increase with graft size and, therefore, thorough cell dose-response studies are needed.…”