Prokaryotic voltage-gated sodium channels are more effective than endogenous Nav1.5 channels in rescuing cardiac action potential conduction: an in silico study

Abstract

Methods to augment Na⁺ current in cardiomyocytes hold potential for the treatment of various cardiac arrhythmias involving conduction slowing. Because the gene coding cardiac Na⁺ channel (Na_v1.5) is too large to fit in a single adeno-associated virus (AAV) vector, new gene therapies are being developed to enhance endogenous Na_v1.5 current (by overexpression of chaperon molecules or use of multiple AAV vectors) or to exogenously introduce prokaryotic voltage-gated Na⁺ channels (BacNa_v) whose gene size is significantly smaller than that of the Na_v1.5. In this study, based on experimental measurements in heterologous expression systems, we developed an improved computational model of the BacNa_v channel, Na_vSheP D60A. We then compared in silico how Na_vSheP D60A expression vs. Na_v1.5 augmentation affects the electrophysiology of cardiac tissue. We found that the incorporation of BacNa_v channels in both adult guinea pig and human cardiomyocyte models increased their excitability and reduced action potential duration. When compared with equivalent augmentation of Na_v1.5 current in simulated settings of reduced tissue excitability, the addition of the BacNa_v current was superior in improving the safety of conduction under conditions of current source-load mismatch, reducing the vulnerability to unidirectional conduction block during premature pacing, preventing the instability and breakup of spiral waves, and normalizing the conduction and ECG in Brugada syndrome tissues with mutated Na_v1.5. Overall, our studies show that compared with a potential enhancement of the endogenous Na_v1.5 current, expression of the BacNa_v channels with their slower inactivation kinetics can provide greater anti-arrhythmic benefits in hearts with compromised action potential conduction.NEW & NOTEWORTHY Slow action potential conduction is a common cause of various cardiac arrhythmias; yet, current pharmacotherapies cannot augment cardiac conduction. This in silico study compared the efficacy of recently proposed antiarrhythmic gene therapy approaches that increase peak sodium current in cardiomyocytes. When compared with the augmentation of endogenous sodium current, expression of slower-inactivating bacterial sodium channels was superior in preventing conduction block and arrhythmia induction. These results further the promise of antiarrhythmic gene therapies targeting sodium channels.

Keywords: Brugada syndrome; arrhythmia; bacterial sodium channel; fibrosis; reentry.