ATTENUATION OF CIRCADIAN VARIATION BY COMBINED ANTIANGINAL THERAPY WITH SUPPRESSION OF MORNING AND EVENING INCREASES IN TRANSIENT MYOCARDIAL-ISCHEMIA

The circadian variation of total ischemic activity was examined during 3289 hours of ambulatory ECG monitoring in 101 patients with stable angina pectoris and proved coronary artery disease, who were not receiving any prophylactic antianginal therapy. The 101 patients displayed 411 episodes of ischemia, 312 (76%) of which were silent; a circadian rhythm was noted for the occurrence of total and silent ischemia. Thirty-eight percent of the ischemic episodes occurred between 6 AM and 12 noon, and total and silent ischemia were significantly more frequent during this period compared with the other three 6-hour periods (p < 0.01); a lesser peak was noted in the evening. The effects of metoprolol and combined therapy with metoprolol and nifedipine on the circadian variation of ischemic activity were studied in two subgroups of patients in a random, double-blind study design (31 patients receiving metoprolol and 42 receiving combined therapy). During therapy with metoprolol the morning increase in ischemic activity was attenuated, and the highest frequency of ischemia was then noted in the evening (6 AM to 12 noon compared with 6 PM to 12 midnight; p < 0.05). Combined therapy abolished the morning peak as did metoprolol monotherapy, but even the evening increase in ischemic activity was attenuated (p < 0.05). The diurnal distribution of the mean heart rate at the onset of ischemia, when patients were off therapy, showed a morning increase similar to the increase in ischemic activity but no second peak in the evening. A significant (p < 0.01) and equal reduction in the mean heart rate at the onset of ischemia was noted during therapy with metoprolol and combined therapy. This decrease in the heart rate at the onset of ischemia indicates that the main antiischemic effect of metoprolol is mediated through a reduction in myocardial oxygen demand, with the most pronounced effect in the morning hours when the sympathetic tone is highest. However, attenuation of both the morning and evening peaks of ischemic activity during combined therapy suggests that a decrease in the myocardial oxygen supply may be more detrimental in the evening. This may have clinical relevance in regard to the use of various antiischemic drugs and the time of administration.