Computational Modeling of Effects of

Background: Patients with arrhythmogenic cardiomyopathy (ACM) due to pathogenic variants in Methods: We used established computational models of ventricular cell electrophysiology to define the effects of varying levels of successful gene therapy on conduction in patients with Results: We observed a non-linear relationship between conduction velocity and the proportion of transduced cells. Conduction velocity increased only modestly when up to 40% of myocytes were transduced. Conduction block did not occur in tissue constructs with moderate levels of uncoupling (0.10 or 0.15 of normal) as this degree of coupling was sufficient to allow electrotonic current to pass through diseased cells. Thus, low levels of transduction, likely to occur in phase 1 clinical trials, do not appear to pose a major safety concern. However, our models did not incorporate potential effects of fibrosis and immune signaling, both of which will presumably be present in Conclusions: The extent of successful ventricular myocyte transduction anticipated to be achieved in What is Known: Patients with arrhythmogenic cardiomyopathy due to pathogenic variants in What the Study Adds: At anticipated levels of successful transduction of ventricular myocytes, little change in conduction velocity will be achieved in patients with arrhythmogenic cardiomyopathy due to variants in