Gene Transfer of Connexin43 Mutants Attenuates Coupling in Cardiomyocytes

Abstract

Abstract-Modification of electrical conduction would be a useful principle to recruit in preventing or treating certain arrhythmias, notably ventricular tachycardia (VT G ap junctions are channels that permit intercellular communication. In mammalian tissues these channels are ubiquitously expressed and serve diverse biological functions. 1 Within the heart, gap junctions mediate electrical impulse transmission which underlies its coordinated mechanical activity. 2 Acquired heart disease and the ensuing gap junction remodeling can alter electrical conduction in a manner which begets arrhythmias. For example, this was found to be true of ventricular tachycardia (VT) occurring after chronic myocardial infarction (MI) where focal conduction slowing forms an essential part of the arrhythmogenic substrate. 2 The clinical burden of this pathophysiology is evidenced by the fact that post-MI VT is a substantial cause of sudden cardiac death (SCD). 3 Contemporary therapies for VT/SCD include antiarrhythmic drugs, implantable defibrillators, and catheter-based radiofrequency ablation. The first of these has met with limited efficacy in clinical trials largely because of increased proarrhythmic events. 3 Defibrillators, although efficacious, are associated with a considerable cost and do not directly impact the underlying pathophysiology. Radiofrequency ablation is associated with modest success rates even when performed by highly-experienced operators and, furthermore, many patients are not amenable to this approach. 3 Studies exploring new treatment approaches, such as gene therapy, are emerging with a recent example reporting inhibition of post-MI VT in a porcine model by targeting repolarization. 4 With these issues in mind, a novel alternative approach based on gene transfer technology targeting gap junctional intercellular communication (GJIC) was pursued. This approach has several potential advantages including targeting of the mechanism causing the conduction disturbance, creation of a nondestructive therapy, and the potential to confer a permanent effect depending on the vector employed.Here we explore the potential of a genetic inhibitor or loss-of-function approach directed at GJIC. Specifically, overexpression of internal loop mutants of the Cx43 gene are employed to uncouple cells connected by gap junctions. These mutants result in gap junctions that lack electrical communication when heterologously expressed in cell pairs. 5

A Mutation Causing Brugada Syndrome Identifies a Mechanism for Altered Autonomic and Oxidant Regulation of Cardiac Sodium Currents

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Origin, development, and differentiation of cardiac fibroblasts

“…The coupling of cardiomyocytes to CFs can allow for electrical transmission across an infarcted area of the heart which is essential for the heart to continue to beat synchronously; however, it can also predispose to arrhythmogenesis [4, 75–83]. Altering Cx43 expression has been shown to modulate intercellular coupling [72, 84], and the risk of post-infarction ventricular tachycardia is significantly reduced when electrical coupling is enhanced by engrafting Cx43 expressing myocytes in the heart [82]. Gene therapy with dominant negative mutants of Cx43 has been investigated as a method of decreasing coupling in the context of atrial fibrillation and ventricular tachycardia.…”

Targeted MicroRNA Interference Promotes Postnatal Cardiac Cell Cycle Re-Entry

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