Management of Engraftment Arrhythmias Associated with Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Transplantation

BackgroundHuman induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) represent a highly promising approach for cell-based replacement therapy in heart failure. However, the development of graft-related ventricular arrhythmias immediately following transplantation impedes its clinical translation. To date, there have been no reports worldwide characterizing the features of engraftment arrhythmias after hiPSC-CMs transplantation in human. Consequently, this study aims to analyze the characteristics of ventricular arrhythmias and the efficacy of antiarrhythmic drugs following hiPSC-CMs transplantation, and to identify risk factors associated with the occurrence of ventricular arrhythmias. MethodsThis study enrolled patients who underwent coronary artery bypass grafting (CABG) combined with hiPSC-CMs implantation under general anesthesia with cardiopulmonary bypass at our hospital between November 2023 and November 2025. Patients were assigned to low- and medium-dose groups based on the injected cardiomyocyte dose: 0.5x10 cells and 1.5x10 cells, respectively. Eleven patients were enrolled in each dose group. Ventricular tachycardia-related parameters were compared between the two groups after hiPSC-CMs implantation, and the characteristics of ventricular tachycardia episodes as well as the effectiveness of antiarrhythmic drugs were analyzed. A multivariate logistic regression model was applied to analyze risk factors influencing the occurrence of ventricular arrhythmias. ResultsNo statistically significant differences were observed between the two groups in terms of gender, age, LVEF, LVEDD, myocardial infarction percentage, intraoperative CPB time, mean heart rate, QRS duration, QTc interval, PVC burden, or daily dose of beta-blocker or cell viability (P > 0.05). The incidence of VT was significantly higher in the medium-dose group compared to the low-dose group (P < 0.05). No statistically significant differences were observed between the groups regarding the time interval from hiPSC-CMs implantation to initial VT onset, the slowest frequency at initial VT onset, the fastest VT frequency, or VT duration (P > 0.05). Further analysis of VT in both groups at different time points after implantation revealed that the incidence of VT in the medium-dose group was significantly higher than that in the low-dose group on days 14, 21, and 28. However, comparisons of the fastest VT frequency at various time points and the incidence of VT at day 7 between the two groups showed no statistically significant differences (P > 0.05). Among all enrolled patients, VT occurred in 12 patients (54.5%). Based on ECG localization, the origin of VT in all cases was identified at the cell injection site. The time from hiPSC-CMs injection to initial VT onset ranged from 5 to 20 days (median 8.5 days). VT persisted for 9 to 411 days (median 59 days) before spontaneous termination, with 9 patients (75% of those with VT) experiencing VT lasting more than 1 month. The slowest frequency at initial VT onset ranged from 55 to 96 bpm (72.58 {+/-} 9.86 bpm), while the fastest recorded frequency reached 111 to 185 bpm (146.33 {+/-} 21.44 bpm). Hemodynamics remained stable in all patients during increases in VT frequency. Throughout the observed VT episodes, QRS morphology was consistently monomorphic, although cycle length varied. During VT episodes, overdrive pacing via the temporary epicardial atrial lead successfully suppressed but did not terminate VT. While overdrive pacing failed to reduce the frequency of VT, it provided a critical window for optimizing antiarrhythmic drug therapy to control VT. Cardioversion also failed to terminate VT. Administration of beta-blockers, ivabradine, or amiodarone controlled the VT frequency to a range of 55-95 bpm (79.67 {+/-} 12.51 bpm) but likewise did not terminate the arrhythmia. VT terminated spontaneously in patients, after which it either did not recur, recurred intermittently, or reoccurred as sustained VT after a period of time. Multivariate logistic regression analysis indicated that the dose of hiPSC-CMs injection was an independent influencing factor for the risk of VT onset (P < 0.05). ConclusionThe ectopic arrhythmia (EA) is primarily driven by an automaticity mechanism. It is characterized by early onset (median 8.5 days) and prolonged duration (median 59 days), with the cell injection dose identified as an independent risk factor (OR=9.00). Within the controlled dose range (0.5-1.5x10 cells) and under strict clinical management, this type of arrhythmia can be effectively monitored and managed.