Preventing ventricular fibrillation by flattening cardiac restitution

Abstract

Ventricular fibrillation is the leading cause of sudden cardiac death. In fibrillation, fragmented electrical waves meander erratically through the heart muscle, creating disordered and ineffective contraction. Theoretical and 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 previous 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 experimental evidence supporting this idea. In particular, we identify the action of the drug bretylium as a prototype for the future development of effective restitution-based antifibrillatory agents. We show that bretylium acts in accord with the restitution hypothesis: by flattening restitution curves, it prevents wave break and thus prevents fibrillation. It even converts existing fibrillation, either to a periodic state (ventricular tachycardia, which is much more easily controlled) or to quiescent healthy tissue.

Neuro-cardiac interaction in malignant ventricular arrhythmia and sudden cardiac death

“…More spectacularly, DAM and verapamil converted VF into stable VT whereas procainamide did not lead to spatiotemporal organisation of VF. Similar findings were shown with bretylium in perfused swine right ventricular preparations, in which there was flattening of APD restitution curve, prevention of wavebreak and thus fibrillation induction and also converted VF into a periodic rhythm (Garfinkel et al 2000). These studies provide strong experimental support for the "restitution hypothesis" and opened up lines of investigations both to explore the importance of APD restitution in mechanisms underlying arrhythmogenic conditions and also the possibility of manipulating APD restitution to reduce wavebreak and prevent or treat fibrillation.…”

“…It was shown that APD alternans can lead to breakup of spiral waves into a fibrillatory state in a two dimensional tissue simulation without spatial inhomogeneities (Karma 1993). The role that APD restitution slope plays in the generation of fibrillation through wave break was subsequently verified by biological data (Riccio et al 1999;Garfinkel et al 2000). It was first shown in arterially perfused canine ventricular endocardial preparations that drugs that reduce the APD restitution slope (diacetyl monoxime (DAM) and verapamil) prevented the induction of VF whilst the drug procainamide which does not reduce APD restitution slope did not prevent VF induction (Riccio et al 1999).…”

Mechanisms for Discordant Alternans

“…20,25,26,32 Results from the present study suggest that discordant alternans that arises by the second scenario could be prevented by drugs that increase conduction velocity or reduce range of DI over which conduction velocity varies, even if concordant alternans is not preventable.…”

On the mechanisms for the conversion of ventricular fibrillation to tachycardia by perfusion with ruthenium red

“…Flattening of the APD restitution curve with verapamil, diacetyl monoxime [15], and bretylium [16] has been shown to convert VF to a periodic rhythm, or VT in canine or porcine ventricles.…”