Graft-host coupling changes can lead to engraftment arrhythmia: a computational study.

Area of Science:

• Cardiovascular Science
• Regenerative Medicine
• Computational Biology

Background:

• Myocardial infarction (MI) leads to scar tissue and heart failure.
• Human pluripotent stem cell-derived cardiomyocytes (hPSC-CM) show promise for cardiac repair but can cause engraftment arrhythmias (EA).
• The mechanisms underlying EA, a transient post-transplantation arrhythmia, are not fully understood.

Purpose of the Study:

• To investigate the hypothesis that time-varying, spatially heterogeneous electrical coupling between hPSC-CM grafts and host myocardium contributes to EA.
• To computationally model the influence of graft-host electrical coupling, scar tissue, and graft conductivity on EA susceptibility.

Main Methods:

• Created computational slice models based on histological images of infarcted ventricles with varying graft configurations.
• Simulated electrical coupling at the graft-host perimeter under different conditions (non-conductive scar, slow-conducting scar, host myocardium replacement).
• Quantified the effect of varying intrinsic graft conductivity and spatial distribution on EA propensity.

Main Results:

• EA susceptibility exhibited a non-monotonic relationship with increasing graft-host coupling, initially rising then falling.
• Different spatial arrangements of graft, host, and scar significantly altered EA susceptibility curves.
• Increasing intrinsic graft conductivity and replacing scar with host myocardium or slow-conducting scar reduced EA vulnerability.

Conclusions:

• Spatiotemporally heterogeneous graft-host electrical coupling is a key factor influencing EA dynamics after hPSC-CM transplantation.
• Graft location relative to scar and dynamic electrical coupling are critical determinants of EA burden.
• This computational framework provides a basis for optimizing hPSC-CM delivery strategies to minimize EA.