MECHANISM OF LETHAL PROARRHYTHMIA OBSERVED IN THE CARDIAC-ARRHYTHMIA SUPPRESSION TRIAL - ROLE OF ADRENERGIC MODULATION OF DRUG-BINDING

A variety of recent in vivo studies have sought to clarify the mechani sm underlying the proarrhythmic response to flecainide in the Cardiac Arrhythmia Suppression Trial (CAST). Increased inducibility of relativ ely stable ventricular arrhythmias in subacute and chronic postinfarct ion models has been universally observed. The arrhythmogenesis has bee n explained in part by drug induced modulation of anisotropic conducti on in persistently ischemic tissue, increased durations of vulnerable windows, enhanced generation of unidirectional block with the introduc tion of extrastimuli, variability of repolarization within the ventric ular wall, and the creation of stable reentrant circuits with narrow c entral zones of propagation. While these data explain arrhythmogenesis in general, malignant ventricular arrhythmia capable of producing the excess sudden or arrhythmic death mortality in the CAST trial have no t been universally observed, nor have the proported beneficial effects of beta-blockade seen in the CAST trial and other studies been explai ned. Additional studies examining the adrenergic modulation of flecain ide binding have shown reversal of flecainide effects in normal tissue , but paradoxical amplification of flecainide induced conduction slowi ng in depolarized tissue. This variable effect in normal versus abnorm al tissue produces significant dispersions of conduction with an expec ted increased propensity for conduction failure in response to ectopy, increased liminal length for impulse propagation, enhanced vulnerabil ity to premature extrastimuli, and completed reentrant circuits in reg ions of depressed membrane potentials. This, along with the decrease i n action potential duration and accompanying refractoriness in the set ting of adrenergic modulation may favor more malignant double wavelet or unstable ventricular arrhythmias.