BALTIMORE—The much-remarked morning peak in adverse cardiovascular events, including stroke, may be in part an effect of circadian regulation. Plasminogen activator inhibitor-1 (PAI-1), which prevents fibrinolysis, is tightly controlled by the circadian system, according to research presented at the 27th Annual Meeting of the Associated Professional Sleep Societies. The level of PAI-1 is highest at a circadian phase equivalent to 7 am, said Frank A.J.L. Scheer, PhD, Assistant Professor of Medicine at Harvard Medical School in Boston.
Behavior does not appear to affect the level of PAI-1. When subjects moved from a supine to an upright position during a tilt table test, PAI-1 level did not change significantly. The level also did not change after subjects at rest on exercise bicycles began to pedal. “The influence of the circadian system is quite substantial,” and these stressors did not have a significant effect, said Dr. Scheer.
Participants Underwent a Forced-Synchrony Protocol
Dr. Scheer and colleagues studied 12 healthy subjects, including six women. For two weeks before admission to the study, the participants went to bed at the same time every night and slept for eight hours. Subjects then spent two baseline days and nights in individual rooms in the laboratory.
On the third day, the patients began a 10-day, forced-synchrony protocol, during which lights were kept dim to minimize their influence on the circadian system. The rooms provided no time cues. Participants’ sleep episodes were advanced by four hours during each sleep–wake cycle. This 20-hour sleep–wake cycle was well outside the circadian system’s range of entrainment. The protocol allowed the researchers to separate the influence of the behavioral sleep–wake cycle and that of the internal body clock on physiology.
During a test battery, the subjects were exposed to mental stress, a tilt table test, and an exercise test. The battery was intended to indicate the effect of the circadian timing system on PAI-1, the effect of behavioral stressors on PAI-1, and whether behavioral stressors and the circadian system interact.
The investigators used core body temperature as a marker of circadian phase. They assessed plasma PAI-1 levels before and during a 60° passive head tilt that lasted 15 minutes, and before and during a 15-minute cycling exercise at 60% of subjects’ maximum heart rate.
PAI-1 Has an Endogenous Circadian Rhythm
During the forced-synchrony protocol, subjects’ circadian profiles were elevated with respect to their behavioral sleep–wake cycles. This change might have to do with the fact that the researchers measured endogenous circadian rhythm during the test battery, said Dr. Scheer.
Endogenous circadian modulation was associated with a 1.24-ng/mL fluctuation in PAI-1 that was almost as large as that observed in the sleep–wake cycle (1.34 ng/mL), indicating that the circadian modulation contributed considerably to that observed during a regular sleep–wake cycle. Subjects’ levels of PAI-1 showed a second increase during the regular sleep–wake cycle a few hours after awakening. The test battery did not appear to be responsible for the increase, which occurred before the battery was administered. PAI-1 levels reached a main peak at similar times, whether they were influenced by sleep–wake cycle or by the endogenous circadian cycle.
“PAI-1 has an endogenous circadian rhythm independent of behavioral sleep–wake cycle in humans,” said Dr. Scheer. “PAI-1 peaks in the biological morning and seems to contribute to what we normally see during the day–night cycle. The morning peak may have homeostatic advantage, but in the vulnerable population, it may exaggerate existing risk,” he concluded.
—Erik Greb
Senior Associate Editor