In silico assessment of arrhythmic risk following the implantation of engineered heart tissues in porcine hearts with varying infarct locations

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Abstract Engineered heart tissues (EHTs) have shown promise in partially restoring ejection fraction after myocardial infarction (MI); however, their potential to introduce electrophysiological heterogeneities and promote arrhythmias remains underexplored. This study assessed the arrhythmogenic risk following immature EHT engraftment in infarcted ventricles using computational simulations that replicate preclinical protocols. EHT computational models were developed and integrated into nine validated porcine-specific biventricular models from pigs with left circumflex (LCx, n=4) or left anterior descending (LAD, n=5) MIs. Ventricular tachycardia (VT) susceptibility was evaluated using an S1-S2 stimulation protocol across varying pacing sites and coupling intervals, accounting for infarct characteristics, implantation site, conductivity, and the ventricular conduction system (CS). VT burden was quantified with a 0-1 inducibility score (IS). In silico reentrant activity reproduced the arrhythmic patterns observed experimentally in porcine MI models. VT vulnerability was greater in LAD than in LCx infarcts, consistent with a larger infarct size. Inclusion of the CS modified VT burden by providing conduction shortcuts that either facilitated or suppressed reentry. Remuscularization directly on the MI region (IS = 0.49) heightened VT inducibility in dense, transmural scars (IS = 0.16), whereas lateral EHT implantation (IS = 0.35) reduced this risk with respect to direct implantation. In non-transmural scars, VT inducibility varied with the implantation site. Matching EHT conductivity to host myocardium lowered or contained arrhythmogenicity (LCx-IS: from 0.5 to 0.25; LAD-IS: stable at 0.57). These results highlight the latent arrhythmic risk of EHT-mediated remuscularization after MI, identifying infarct substrate, EHT conductivity, and implantation site as critical determinants, and emphasize the importance of incorporating the CS for accurate risk assessment. Author summary Remuscularization with engineered heart tissue patches has shown preclinical potential to restore cardiac ejection fraction after myocardial infarction. However, the introduction of electrophysiological heterogeneities from these patches remains underexplored. To address this, we performed in silico investigations of post-infarction arrhythmogenesis and its progression after patch engraftment in porcine models with vessel-specific infarcts, applying a comprehensive arrhythmia inducibility protocol. We first computationally reproduced the experimentally observed arrhythmic patterns in pigs. Before patch engraftment, we found that larger infarcts increased ventricular tachycardia vulnerability. The inclusion of the ventricular conduction system modified arrhythmic outcomes, as electrical shortcuts could either facilitate or suppress reentry. Following remuscularization, highly transmural scars exhibited higher arrhythmicity, with lateral patch implantation mitigating it compared to direct placement. In contrast, for poorly transmural scars, the relationship between arrhythmia inducibility and patch location was unclear, highlighting digital twins as a tool for personalized risk prediction. When host-like patch conductivity was used, arrhythmia inducibility after engraftment was reduced or contained. Overall, our results: i) reveal the latent arrhythmogenicity associated with patch-mediated remuscularization of infarcted hearts; ii) identify infarction substrate, patch conductivity, and implantation site as key arrhythmogenic determinants; and iii) emphasize the importance of accurately modeling the cardiac conduction system.

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