Drugs, Wavefronts, and the Cardiac Vulnerable Period

The heart can be considered as a 3D mass of nonlinear excitable medium. With simple models of an excitable cell, one can probe arrhythmogenic processes with numerical experiments and possibly identify new therapeutic strategies. An important target for such experiments is the reduction in the incidence of sudden cardiac death in patients with cardiac disease. Potentially fatal cardiac rhythm disturbances are often initiated by extra endogenous heart beats. It was thought that drugs that reduced the frequency of extra heart contractions in individual cells would reduce the incidence of sudden cardiac death in patients. 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 2-3 fold over untreated patients even though the treated patients experienced an 80% reduction in extra heart beats. Presented here is a model of drug interactions with a cardiac cell that, when coupled with a nonlinear model of cardiac excitability, yields new insights into the proarrhythmic effects of supposedly antiarrhythmic drugs. With this model, a single unifying principle arises: that drug alteration of the dynamics of cardiac excitability displays both antiarrhythmic and proarrhythmic effects. In single cells, blockade of the Na channel (the action of antiarrhythmic drugs) reduces excitability and increases the interval of time that a cell remains inexcitable following a normal stimulation. When cells are coupled in 1, 2 and 3 D arrays, spatial gradients of excitability follow the activation wavefront. Reducing excitability and slowing the recovery dynamics of excitability in a multicellular medium extend the spatial gradient of the excitability recovery process. Consequently the vulnerable period, the interval of time during which an unsuppressed extra heart beat can initiate a fatal arrhythmia, is prolonged. Thus, reduced excitability, the drug property that contributes to the cellular " antiarrhythmic " response to extra stimulation is the same property that contributes to the multicellular " proarrhythmic " response (a prolonged vulnerable period and increased likelihood of initiating a fatal arrhythmia). Understanding the dynamics of drug binding to ion channels and wave formation in a nonlinear excitable medium is a major challenge and new insights will likely improve the development of suitable arrhythmia control strategies