Abstract 12241: Low-Efficiency Gene Editing is Capable of Suppressing Arrhythmogenesis in Long QT Syndrome Type II: Computer Simulation Study

Abstract

Background: Long QT Syndrome Type II (LQT2) is a congenital cause of arrhythmia and sudden cardiac death due to mutations in ion channel hERG responsible for the rapid inward rectifying potassium current (I Kr ). Progress in gene therapy may result in a viable treatment for LQT2. However, the gene transduction efficacy required to prevent cardiac arrhythmias in LQT2 is unknown. We used computer simulation to examine the minimum gene transduction efficacy necessary to suppress early afterdepolarizations (EADs). Hypothesis: Low transduction efficacy of hERG is sufficient to suppress EADs through electrotonic coupling between transduced I Kr (+) and non-transduced I Kr (-) cardiomyocytes (Fig 1A). Methods: Computational models of rabbit and human cardiac tissue were implemented in 2D (100 x 100 cells) and 3D (13 x 13 x 13 cells) with a multi-state Markov model for I Kr and a dynamic gap junction resistance model. Gene transduction efficacy was modeled by varying the percentage of I Kr (+) cardiomyocytes from 0-100%. Spatial heterogeneity in gene delivery was modeled by varying the cluster size of I Kr (+) cells from 1-400 cells. I Kr (+) cell clusters were distributed randomly in the tissue. Results: In 2D, EADs were suppressed with 14% I Kr (+) cells (rabbit model) and 12% I Kr (+) cells (human model) (Fig 1B). In 3D, the minimum transduction efficacy was further reduced to 10% (rabbit model) which likely reflects the impact of increased cell-cell coupling. Clustering I Kr (+) cells required greater transduction efficacy (Fig 1C). Detailed ionic current trajectory analysis suggests that the sufficiently large gap junction current from I Kr (+) cells during phase 2 of the action potential can prevent I Kr (-) cells from undergoing the Andronov-Hopf bifurcation that leads to EADs. Conclusions: Computational models suggest low-efficiency gene editing is a viable approach for suppressing arrhythmogenesis in LQT2 patients.