BackgroundThe morning increase in asymptomatic ambulatory ischemia may be due to heightened coronary tone, increased physical activity, or both. If ambulatory ischemia is primarily due to physical activity, then alterations in the schedule of physical activity should be reflected in a corresponding alteration in the occurrence of ischemia. This study was designed to examine the relation between activity patterns and the frequency of ambulatory ischemic episodes and the effect of nadolol on these relations.Methods and ResultsA double-blind, randomized, placebocontrolled, crossover trial of nadolol versus placebo was performed in 20 patients with stable coronary artery disease. At the end of each 2-week treatment phase, patients were hospitalized for 48 hours. In the hospital, there was a regular activity day (awaken and assume normal activities at 8:00 AM) and a delayed activity day (awaken at 8:00 AM, arise at 10:00 AM, and begin normal activity at noon). Ambulatory ECG monitoring was performed throughout the hospitalization. On the regular activity day, there was a morning increase in heart rate and in the number of ischemic episodes during therapy with placebo that began at 8:00 AM. In contrast, on the delayed activity day, there was a 4-hour phase shift of the increases in heart rate and the increase in ischemic episodes (ie, at noon) corresponding to the onset of physical activities. Therapy with nadolol caused a 50% reduction in the total number of ischemic episodes (129 versus 65, placebo versus nadolol;P< .02). During nadolol therapy, there was no discernible circadian peak in the number of ischemic episodes on either activity day. During placebo treatment, 87% of ischemic episodes were preceded by an increase in heart rate ≤5 beats per minute. Although nadolol caused a significant reduction in the total number of episodes preceded by a heart rate increase compared with placebo (99 versus 38 episodes,P≤ .04), this therapy was associated with a significant increase in the number of episodes not associated with a heart rate increase (15 versus 21 episodes,P≤ .002).ConclusionsThe morning increase in ambulatory ischemic episodes is due to physical activity patterns. The majority of ischemic episodes are preceded by a heart rate increase, and it is these episodes that are primarily responsible for the morning increase in ischemia. Therapy with nadolol caused a reduction in the total number of ischemic episodes solely by reducing those episodes preceded by a heart rate increase. In contrast, nadolol caused a significant increase in the number of ischemic episodes not associated with a heart rate increase, perhaps in part because it potentiated coronary vasoconstriction.