Generation of a novel in-vitro model of the infarct border zone to study human ventricular arrhythmias

Introduction: Ventricular arrhythmias (VA) are a leading cause of worldwide mortality. It is thought that post-myocardial infarction VA results from the presence of slowly conducting viable strands at the infarct border zone (IBZ), forming the basis for reentry. We aimed to develop an in-vitro anatomical model of the IBZ to study VA. To this end, we combined advanced micropatterning and human-induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CMs) technologies.

Methods: A 2D simplified micropatterned model was created to study the IBZ using a DMD-based maskless photolithography system known as Primo. The process involves coating a culture dish with a combination of anti-fouling materials that block protein connections to the plate, a photoinitiator gel, and laser patterning of the pre-designed micro-pattern. The plate is then coated by ECM and hiPSC-CMs to generate the desired tissue geometry. Optical mapping was used to characterize the conduction properties in the model and the impact of geometry on arrhythmogenesis.

Results and conclusion: We designed a simplified model of a compact scar to model VA arising at the IBZ using the Primo system. This model includes surviving cardiomyocyte strands within the scar that include structural inhomogeneity (stenosis) within the surviving conducting fibers. This stenosis can facilitate uni-/bi- directional conduction blocks due to sink-source mismatches. Using optical mapping we show there is a homogenous repolarization pattern in the model. It can be concluded that the eventual conduction abnormalities and reentry initiation are due to different width sizes of the stenosis rather than dispersion of repolarization.