Evaluation of the Functional and Electrophysiological Effects of Pluripotent Stem Cell Derived Cardiomyocytes in a Porcine Model

Abstract

Myocardial infarction results in the death of up to 1 billion highly specialised cardiomyocytes. Transplantation of pluripotent stem cell derived cardiomyocytes (PSC-CMs) to replace damaged cells represents a novel therapeutic prospect, with exciting pre-clinical data confirming PSC-CMs can remuscularise injured hearts. However, potentially lethal ventricular arrhythmias have emerged as a predictable complication following engraftment of intramyocardially injected PSC-CMs. As such, there is an urgent need to gain mechanistic insights and treatment strategies to control or prevent these engraftment arrhythmias (EAs).

In the first phase of work, we develop and validate a reproducible porcine model of myocardial infarction and PSC-CM transplantation, successfully generating EAs and histologically detectable PSC-CM graft.

In the second phase of work, we optimise a protocol for the acquisition of cardiac magnetic resonance imaging in porcine subjects, facilitating assessment of the structural and functional effects of PSC-CM therapy.

In the third phase of work, we unveil mechanistic insights and provide treatment strategies to mitigate EAs Specifically, we identify atrial and pacemaker-like cardiomyocytes as culprit arrhythmogenic subpopulations. We further show that pharmacologic and interventional anti-arrhythmic strategies can control and potentially abolish EAs.

In the final phase of work, we show that PSC-CM therapy improves left ventricular ejection fraction post myocardial infarction, particularly when EAs are mitigated with anti-arrhythmic therapy.

This thesis therefore lays the groundwork for the next phase of pre-clinical development of PSC-CM therapy. Future work will focus on the development of PSC-CMs devoid of arrhythmogenic potential, which can be electrophysiologically and functionally assessed post transplantation using the described porcine model.