Mechanism of lethal proarrhythmia observed in the cardiac arrhythmia suppression trial: Role of adrenergic modulation of drug binding

Douglas L. Packer, Thomas M. Munger, Susan B. Johnson, Kevin T. Cragun

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


A variety of recent in vivo studies have sought to clarify the mechanism underlying the proarrhythmic response to flecainide in the Cardiac Arrhythmia Suppression Trial (CAST). Increased inducibility of relatively stable ventricular arrhythmias in subacute and chronic postinfarction models has been universally observed. The arrhythmogenesis has been explained in part by drug induced modulation of anisotropic conduction in persistently ischemic tissue, increased durations of vulnerable windows, enhanced generation of unidirectional block with the introduction of extrastimuli, variability of repolarization within the ventricular wall, and the creation of stable reentrant circuits with narrow central 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 not been universally observed, nor have the proported beneficial effects of β-blockade seen in the CAST trial and other studies been explained. Additional studies examining the adrenergic modulation of flecainide binding have shown reversal of flecainide effects in normal tissue, but paradoxical amplification of flecainide induced conduction slowing in depolarized tissue. This variable effect in normal versus abnormal tissue produces significant dispersions of conduction with an expected increased propensity for conduction failure in response to ectopy, increased liminal length for impulse propagation, enhanced vulnerability to premature extrastimuli, and completed reentrant circuits in regions of depressed membrane potentials. This, along with the decrease in action potential duration and accompanying refractoriness in the setting of adrenergic modulation may favor more malignant double wavelet or unstable ventricular arrhythmias.

Original languageEnglish (US)
Pages (from-to)455-467
Number of pages13
JournalPACE - Pacing and Clinical Electrophysiology
Issue number2 II
StatePublished - 1997


  • antiarrhythmic drugs
  • flecainide
  • myocardial infarction
  • proarrhythmia
  • sudden cardiac death
  • ventricular arrhythmia
  • ventricular tachycardia

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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