To determine whether the onset of myocardial infarction occurs randomly throughout the day, we analyzed the time of onset of pain in 2999 patients admitted with myocardial infarction. A marked circadian rhythm in the frequency of onset was detected, with a peak from 6 a.m. to noon (P less than 0.01). In 703 of the patients, the time of the first elevation in the plasma creatine kinase MB (CK-MB) level could be used to time the onset of myocardial infarction objectively. CK-MB-estimated timing confirmed the existence of a circadian rhythm, with a three-fold increase in the frequency of onset of myocardial infarction at peak (9 a.m.) as compared with trough (11 p.m.) periods. The circadian rhythm was not detected in patients receiving beta-adrenergic blocking agents before myocardial infarction but was present in those not receiving such therapy. If coronary arteries become vulnerable to occlusion when the intima covering an atherosclerotic plaque is disrupted, the circadian timing of myocardial infarction may result from a variation in the tendency to thrombosis. If the rhythmic processes that drive the circadian rhythm of myocardial-infarction onset can be identified, their modification may delay or prevent the occurrence of infarction.

Two hundred ninety patients with acute myocardial infarction were treated according to random assignment with an intravenous infusion of either 80 mg of recombinant tissue plasminogen activator (rt-PA) over 3 h or 1.5 million units of streptokinase over 1 h. Patients received an intravenous bolus of heparin (5,000 U [USP]) before pretreatment coronary angiography and a continuous infusion (1,000 U/h) starting 3 h later. The frequency of major and minor hemorrhagic events (33% rt-PA, 31% streptokinase) and associated transfusions (22% rt-PA, 20% streptokinase) were comparable in both groups. More than 70% of bleeding episodes in each group occurred at catheterization or vascular puncture sites. Precipitable fibrinogen levels, measured in plasma samples collected in the presence of a protease inhibitor (aprotinin), declined in rt-PA and streptokinase groups by averages of 26 and 57% at 3 h and by 33 and 58% at 5 h, respectively (rt-PA versus streptokinase, p less than 0.001). At 5 h the plasma plasminogen declined by 57% (rt-PA) and 82% (streptokinase) (p less than 0.001); plasma fibrin(ogen) degradation products were higher in streptokinase-treated patients (244 +/- 12 micrograms/ml, mean +/- SE) than in rt-PA-treated patients (97 +/- 9 micrograms/ml, p less than 0.001). At 27 h, plasma fibrinogen and plasminogen levels were lower and fibrin(ogen) degradation products higher than pretreatment levels in both groups. The frequency of hemorrhagic events was higher in patients with greater changes in plasma factors at 5 h; within treatment groups the levels of fibrin(ogen) degradation products correlated with bleeding complications (p less than 0.005). Thus, in the doses administered, rt-PA induces systemic fibrinogenolysis that is substantially less intense than that induced by streptokinase. The high frequency of bleeding encountered is related to the protocol used, including vigorous anticoagulation, arterial punctures and thrombolytic therapy. These findings emphasize the need for avoidance of invasive procedures and for meticulous care in the selection and management of patients subjected to thrombolytic therapy.

The time of onset of ischemic stroke was determined for 1,167 of 1,273 patients during the collection of data by four academic hospital centers between June 30, 1983, and June 30, 1986. More strokes occurred in awake patients from 10:00 AM to noon than during any other 2-hour interval. The incidence of stroke onset declined steadily during the remainder of the day and early evening. The onset of stroke is least likely to occur in the late evening, before midnight.

Patients with diabetes mellitus experience a more adverse outcome after acute myocardial infarction compared with nondiabetic patients, although the mechanisms responsible for these findings are not clear. From the Multicenter Investigation of the Limitation of Infarct Size (MILIS) study, the course of acute infarction in 85 diabetic patients was compared with that in 415 nondiabetic patients, all of whom had serial assessments of left ventricular function. The diabetic patients experienced a more complicated in-hospital and postdischarge course than did the nondiabetic patients, including a higher incidence of postinfarction angina, infarct extension, heart failure and death, despite the development of a smaller infarct size and similar levels of left ventricular ejection fraction. Although diabetic patients had a worse profile of cardiovascular risk factors at the time of the index infarction, the increased incidence of adverse outcomes among them persisted despite adjustment for these baseline imbalances. Diabetic women had a poor baseline risk profile compared with the other groups categorized by gender and diabetic status, and experienced an almost twofold increase in cardiac mortality despite development of the smallest infarct size during the index event. The duration of diabetes and the use of insulin at the time of the index infarction were associated with a better in-hospital mortality rate, but the duration of diabetes did not exert a major influence on the outcome of the diabetic patients. The factors responsible for the increased incidence of adverse outcomes among diabetic patients may be related to an acceleration of the atherosclerotic process, diastolic left ventricular dysfunction associated with diabetic cardiomyopathy or other unidentified unfavorable processes.