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Design of Engineered Heart Tissues to Minimize Arrhythmic Risk After Implantation in Infarcted Hearts

Abstract:

Implantation of engineered heart tissues (EHTs) built from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) may restore cardiac function after myocardial infarction (MI). However, this might entail high arrhythmic risk due to poor electrical coupling and cellular organization in the EHTs. We used an in silico porcine-specific biventricular (BiV) model of MI with an engrafted EHT and we assessed the impact of the EHT electrical conductivity (EHTc) (10%, 50% and 90% of that in healthy myocardium) and the hiPSC-CM alignment (EHTal) (random, parallel and perpendicular to the nearby epicardium) on the electrophysiological properties of the coupled BiV-EHT model. Results showed that the action potential duration (APD) in the EHT was largely driven by the APD in the host tissue, especially for the highest EHTc. Besides, higher EHTc values led to lower repolarization time gradients (RTGs) in the coupled BiV-EHT model, thus implying lower arrhythmic risk. In mean for all tested EHTal cases, the maximum RTG was reduced by 72.4 ms/mm when EHTc was increased from 10% to 90%. Varying EHTal had minor electrophysiological effects on the engrafted EHT. In conclusion, proarrhythmicity after EHT engraftment on infarcted ventricles highly depends on EHTc while EHTal plays a negligible role.