How antiarrhythmic Drugs Increase the Rate of Sudden Cardiac Death

Two large clinical trials of drugs that exhibited significant antiarrhythmic properties in single cells were found to increase the rate of sudden cardiac death in patients by two to three fold over untreated patients. We hypothesized that premature excitation within the drug-altered vulnerable region, a region that trails each excitation wave, might be one mechanism for initiating re-entrant tachyarrhythmias that could lead to ventricular fibrillation and sudden cardiac death. With numerical studies of a cardiac cell model, we probed the determinants of the vulnerable period. We found that antiarrhythmic drugs that block the sodium channel can increase the duration of the cardiac vulnerable period by both slowing conduction velocity and reducing the gradient of excitability. Coupling the dynamics of drug binding to ion channels with wave formation in a nonlinear excitable medium provides new insights into possible arrhythmogenic mechanisms.