Aggravation of arrhythmia by antiarrhythmic drugs, and the important role of underlying ischemia

It has been recognized that antiarrhythmic agents, although intended to prevent or limit arrhythmia, may actually cause an unexpected and unpredictable worsening of arrhythmia.’ Reported risk factors for this complication include significantly reduced left ventricular function, congestive heart failure and history of sustained ventricular tachyarrhythmia.2 The results of the Cardiac Arrhythmia Suppression Trial (CAST)3 increased concerns about arrhythmia aggravation, because 2 widely used an&-rhythmic agents resulted in an increased mortality when administered to patients with a recent myocardial infarction and no overt congestive heart failure who had frequent but only single ventricular premature beats. In CAST, the increase in mortality was observed in all patient groups analyzed, but was especially significant in those with several previous infarctions and a subendocardial infarction. In these patients, the risk of arrhythmia aggravation was as high (risk ratio 3.4) as that observed in those with more severe disease, sub stantial left ventricular dysfunction and history of serious arrhythmia. Furthermore, the occurrence of proarrhythmia, previously reported to be an early complication with antiarrhythmic drugs, was observed throughout the entire follow-up period and was also a late event. Patients exhibited “late” proarrhythmia despite initial suppression of spontaneous ventricular arrhythmia during the titration phase of the study. It is likely that during follow-up, myocardial remodeling and healing altered the underlying substrate, affecting the action of these drugs. One proposed hypothesis is that these patients had ongoing myocardial ischemia that further modified the underlying myocardial substrate, and transiently converted a stable myocardium into 1 that was unstable and potentially arrhythmogenic, capable of generating and supporting a reentrant arrhythmia. In the case of ischemia, the presence of antiarrhythmic drugs may further enhance this potential and is perhaps more likely to result in arrhythmia aggravation. It has been observed that during acute coronary occlusion, there is spatial heterogeneity of blood flow between ischemic and nonischemic tissue. Several investigators proposed that this can even occur in a normal heart, but to a such smaller degree. Marcus et al4 studied the spatial distribution of left ventricular perfusion in 24 awake dogs using radiolabeled microspheres. At the conclusion of the infusion, the left ventricular myo