Morning resistance to thrombolytic therapy.

The Multi-center Investigation on the Limitation of Infarct Size (MILIS), begun just before the thrombolytic era of the treatment of acute myocardial infarction (MI), focused in part on the timing of therapies designed to limit infarct size.1 Careful recording of the time of both the onset of symptoms and of the rise of creatine kinase-MB enzyme activity permitted accurate timing of infarction, revealing a circadian pattern with a distinct morning peak. The database of the larger Thrombolysis in Myocardial Infarction (TIMI) II trial allowed prospective testing of our earlier observation in MILIS. The increased incidence of onset in the morning (6 am to noon, 34%), compared with night (midnight to 6 am, 15%), was even more prominent than in MILIS.2 Indeed, in almost one half of a subgroup of patients in TIMI, infarction began between 6 am and noon. Rather than relegating these curious findings to the files, Muller, Tofler, and a growing number of other investigators sensed correctly that research into the mechanisms responsible for the morning peak in the onset of infarction might lead to a better understanding of the pathogenesis of this condition3 and thereby aid in the development of preventive strategies. Their efforts have taken several interesting directions. First, in addition to acute MI, a morning increase in sudden death was described4 and found to be secondary to ventricular fibrillation, rather than to other arrhythmias.5 In the Cardiac Arrhythmia Suppression Trial (CAST), the higher mortality in patients receiving type 1c antiarrhythmic drugs could be explained in part by an excess of morning deaths in patients receiving these agents.6 A circadian variation in the frequency of sudden death appears to be especially prominent in patients with heart failure; Moser et al7 reported a 2.5-fold increase in the risk of …