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

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(v)1.5) is too large to fit in a single adeno-associated virus (AAV) vector, new gene therapies are being developed to enhance endogenous Na(v)1.5 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(v)1.5. In this study, based on experimental measurements in heterologous expression systems, we developed an improved computational model of the BacNa(v) channel, Na(v)SheP D60A. We then compared in silico how Na(v)SheP D60A expression vs. Na(v)1.5 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(v)1.5 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(v)1.5. Overall, our studies show that compared with a potential enhancement of the endogenous Na(v)1.5 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.

Automated summary

This study compares the effects of enhancing endogenous sodium current and expressing slower-inactivating bacterial sodium channels on the electrophysiology of cardiac tissue through computational modeling. The results show that expressing bacterial sodium channels can provide greater anti-arrhythmic benefits in hearts with compromised action potential conduction.