The contribution of nonreentrant mechanisms to malignant ventricular arrhythmias

Evidence obtained from experimental animals and man indicates that reentry is a major mechanism underlying arrhythmogenesis. However, focal or nonreentrant mechanisms also appear to be operative under a wide variety of pathophysiologic conditions. For example, results obtained using three-dimensional (3D) mapping from 232 simultaneous sites in the feline heart in vivo revealed that nonreentrant or focal mechanisms were prominent during both ischemia and reperfusion. During early ischemia, nonreentrant mechanisms were responsible for initiation of ventricular tachycardia (VT) in 25% of cases and, in cases where VT was initiated by reentry, it often could be maintained by a nonreentrant mechanism. During reperfusion of ischemic myocardium, nonreentrant mechanisms were responsible for initiation of VT in 75% of cases. Most importantly, the transition from VT to ventricular fibrillation in response to reperfusion was secondary to acceleration of a nonreentrant mechanism in either the subendocardium or subepicardium. Potential cellular mechanisms include: 1) sarcolemmal accumulation of amphiphiles such as long-chain acylcarnitines and lysophosphatidylcholine; 2) alpha- and beta-adrenergic mediated effects of catecholamines on the transient inward current (ITI) secondary to an increase in intracellular Ca2+; and 3) alpha-adrenergic receptor-induced decrease in IK mediated by activation of protein kinase C. Recent findings obtained using 3D intraoperative mapping in patients with refractory VT and a previous myocardial infarction also indicate that both reentrant and nonreentrant or focal mechanisms contribute. For example, in 13 selected patients, mapping was of a sufficient resolution to define the mechanisms of 10 runs of VT. Intraoperative mapping indicated that five runs of VT were initiated by intramural reentry, whereas five runs of VT were initiated by a focal or nonreentrant mechanism. The mechanisms underlying ventricular arrhythmias associated with ischemic cardiomyopathy have recently been delineated in dogs after multiple sequential intracoronary embolizations with microspheres (with a decrease in mean ejection fraction from 64% to 25%). Spontaneous VT initiated by focal mechanisms from the subendocardium in 82% and epicardium in 18%, with no evidence of macroreentry. Thus, in divergent pathophysiologic settings, nonreentrant mechanisms appear to contribute importantly to the genesis of lethal ventricular arrhythmias, suggesting that development of novel therapeutic approaches should be directed at inhibition of not only reentrant circuits, but also nonreentrant mechanisms, including triggered activity.