Persistent muscle deficiency following myocardial infarction (MI), attributable to the fact that the adult human heart is one of the least regenerative organs, contributes to heart failure (HF) progression and its growing prevalence worldwide. To-date, cardiology practice has been limited to managing HF progression and palliative. Direct remuscularization, or the transplantation of cardiomyocytes, seeks to address post-MI muscle deficiency by replacing lost or damaged heart muscle. Graft-induced ventricular tachycardias (VTs) remain a critical concern, however. In several preclinical large animal studies, graft-induced VTs were widespread a week after treatment; while most VTs revolved by 3 weeks, VT persisted in some animals. Why and how such high rates of acute VT transiently occur in vivo while some persist remains a mystery. To explore this, I will implement a recently developed modeling framework that can accurately represent the early process of electromechanical engraftment and incorporate morphological and membrane kinetic differences between PSC-CMs and host ventricular cardiomyocytes. I will test a novel hypothesis that graft-induced VTs are driven by a focal mechanism during early engraftment but driven by a reentrant mechanism later on. To explore this, I will study how targeted remuscularization with PSC-CMs alters the dynamics of VT and VT burden in whole, 3D models of the post-MI ventricles. If cardiac arrhythmias can be addressed, targeted direct remuscularization holds the potential to prevent the onset of HF but also treat post-MI reentrant VT.
Advances in stem cell biology, cardiac development, and tissue engineering have revolutionized our capabilities to generate cardiomyocytes, integrate them into functional cardiac tissues, and directly remuscularize the ventricles after myocardial infarction (MI). Despite indications that direct remuscularization can restore ventricular contractility, how to integrate new cardiac muscle without causing potentially life-threatening ventricular arrhythmias has remained elusive and a critical roadblock in clinical translation. The proposed research project seeks to build and leverage a broad biophysical simulation framework to explore and understand arrhythmia mechanisms and to use a principled approach for evaluating the arrhythmia consequences of targeted direct remuscularization in a personalized manner.
