Stabilizer Cell Gene Therapy: A Less-Is-More Strategy to Prevent Cardiac Arrhythmias

Circ Arrhythm Electrophysiol. 2020 Sep;13(9):e008420. doi: 10.1161/CIRCEP.120.008420. Epub 2020 Jul 27.

Abstract

Background: In cardiac gene therapy to improve contractile function, achieving gene expression in the majority of cardiac myocytes is essential. In preventing cardiac arrhythmias, however, this goal may not be as important since transduction efficiencies as low as 40% suppressed ventricular arrhythmias in genetically modified mice with catecholaminergic polymorphic ventricular tachycardia.

Methods: Using computational modeling, we simulated 1-, 2-, and 3-dimensional tissue under a variety of conditions to test the ability of genetically engineered nonarrhythmogenic stabilizer cells to suppress triggered activity due to delayed or early afterdepolarizations.

Results: Due to source-sink relationships in cardiac tissue, a minority (20%-50%) of randomly distributed stabilizer cells engineered to be nonarrhythmogenic can suppress the ability of arrhythmogenic cells to generate delayed and early afterdepolarizations-related arrhythmias. Stabilizer cell gene therapy strategy can be designed to correct a specific arrhythmogenic mutation, as in the catecholaminergic polymorphic ventricular tachycardia mice studies, or more generally to suppress delayed or early afterdepolarizations from any cause by overexpressing the inward rectifier K channel Kir2.1 in stabilizer cells.

Conclusions: This promising antiarrhythmic strategy warrants further testing in experimental models to evaluate its clinical potential.

Keywords: arrhythmias; calcium cycling/excitation-contraction coupling; death; gene therapy; long QT syndrome; sudden; tachycardia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Action Potentials / genetics
  • Animals
  • Arrhythmias, Cardiac / genetics
  • Arrhythmias, Cardiac / metabolism
  • Arrhythmias, Cardiac / physiopathology
  • Arrhythmias, Cardiac / prevention & control*
  • Calcium Signaling / genetics*
  • Cell- and Tissue-Based Therapy*
  • Computer Simulation
  • Disease Models, Animal
  • Genetic Therapy*
  • Heart Rate / genetics
  • Mice
  • Models, Cardiovascular
  • Models, Genetic
  • Myocytes, Cardiac / metabolism*
  • Potassium Channels, Inwardly Rectifying / genetics
  • Potassium Channels, Inwardly Rectifying / metabolism
  • Rabbits
  • Tachycardia, Ventricular / genetics
  • Tachycardia, Ventricular / metabolism
  • Tachycardia, Ventricular / physiopathology
  • Tachycardia, Ventricular / prevention & control
  • Time Factors
  • Transduction, Genetic

Substances

  • Kir2.1 channel
  • Potassium Channels, Inwardly Rectifying

Supplementary concepts

  • Polymorphic catecholergic ventricular tachycardia