Preventing ventricular fibrillation by flattening cardiac restitution

Ventricular fibrillation is the leading cause of sudden cardiac death. In f ibrillation, fragmented electrical waves meander erratically through the he art muscle, creating disordered and ineffective contraction. Theoretical an d computer studies, as well as recent experimental evidence, have suggested that fibrillation is created and sustained by the property of restitution of the cardiac action potential duration (that is, its dependence on the pr evious diastolic interval). The restitution hypothesis states that steeply sloped restitution curves create unstable wave propagation that results in wave break, the event that is necessary for fibrillation. Here we present e xperimental evidence supporting this idea. In particular, we identify the a ction of the drug bretylium as a prototype for the future development of ef fective restitution-based antifibrillatory agents. We show that bretylium a cts in accord with the restitution hypothesis: by flattening restitution cu rves, it prevents wave break and thus prevents fibrillation. It even conver ts existing fibrillation. either to a periodic state (ventricular tachycard ia, which is much more easily controlled) or to quiescent healthy tissue.