The Human Endogenous Circadian System Causes Greatest Platelet Activation during the Biological Morning Independent of Behaviors

Abstract

BackgroundPlatelets are involved in the thromboses that are central to myocardial infarctions and ischemic strokes. Such adverse cardiovascular events have day/night patterns with peaks in the morning (∼9AM), potentially related to endogenous circadian clock control of platelet activation. The objective was to test if the human endogenous circadian system influences (1) platelet function and (2) platelet response to standardized behavioral stressors. We also aimed to compare the magnitude of any effects on platelet function caused by the circadian system with that caused by varied standardized behavioral stressors, including mental arithmetic, passive postural tilt and mild cycling exercise.Methodology/Principal FindingsWe studied 12 healthy adults (6 female) who lived in individual laboratory suites in dim light for 240 h, with all behaviors scheduled on a 20-h recurring cycle to permit assessment of endogenous circadian function independent from environmental and behavioral effects including the sleep/wake cycle. Circadian phase was assessed from core body temperature. There were highly significant endogenous circadian rhythms in platelet surface activated glycoprotein (GP) IIb-IIIa, GPIb and P-selectin (6–17% peak-trough amplitudes; p≤0.01). These circadian peaks occurred at a circadian phase corresponding to 8–9AM. Platelet count, ATP release, aggregability, and plasma epinephrine also had significant circadian rhythms but with later peaks (corresponding to 3–8PM). The circadian effects on the platelet activation markers were always larger than that of any of the three behavioral stressors.Conclusions/SignificanceThese data demonstrate robust effects of the endogenous circadian system on platelet activation in humans—independent of the sleep/wake cycle, other behavioral influences and the environment. The ∼9AM timing of the circadian peaks of the three platelet surface markers, including platelet surface activated GPIIb-IIIa, the final common pathway of platelet aggregation, suggests that endogenous circadian influences on platelet function could contribute to the morning peak in adverse cardiovascular events as seen in many epidemiological studies.

Human circadian system causes a morning peak in prothrombotic plasminogen activator inhibitor-1 (PAI-1) independent of the sleep/wake cycle

“…Participants had 2 baseline 24-hour days in normal room lighting conditions (;90 lux wake episodes/0 lux sleep episodes), followed by a forced desynchrony protocol (FD) consisting of 12 standardized 20-hour "days" with controlled activity, posture, meals, sleep, room temperature, and light (,4 lux), as previously published. [9][10][11][12] On the second baseline day and each 20-hour day, participants underwent a standardized test battery, 12 which included a 15-minute 60°p assive head-up tilt test and a 15-minute steady-state cycle ergometer test at 60% of maximal predicted heart rate. Core body temperature derived from a rectal thermistor was continuously recorded and used to determine circadian period and phase, with minimum core body temperature assigned as 0°(equivalent to ;4:30 AM in these participants).…”

“…[9][10][11][12] Of these factors, platelet activation and cortisol had endogenous circadian peaks, and plasma epinephrine the steepest circadian increase, during the vulnerable window for adverse cardiovascular events, around 9 AM. Furthermore, in response to exercise, the largest circadian increase in epinephrine and largest circadian decrease in cardiac vagal modulation also occurred around 9 AM.…”

Features of Circadian Rhythms in Patients with Cerebrovascular Diseases

“…There are reports that chronobiological disorders are detected in patients with arterial hypertension [70][71][72], diabetes mellitus [73][74][75], cardiac ischemia [11,12,14,61,66], dementia [67][68][69][70], etc. Nowadays there is a lot of data on the existence of chronobiological patterns in the development of stroke and myocardial infarction (MI) [11,12,14].…”

Human circadian rhythms and exercise: Significance and application in real-life situations

“…In the morning under free-living conditions, blood pressure increases on wake-up stress consisting of postural change associated with rising, beginning ambulation, and increased sympathetic activity 49) . Simultaneously, other physiological conditions such as endothelial function [50][51][52] and blood characteristics 53,54) also have been reported to contribute to the morning peak in adverse cardiovascular events. Data from large-scale meta-analyses have confirmed that the incidence of acute myocardial infarction 55) and sudden cardiac death 56) is two to three times more likely during the three hours after waking from nocturnal sleep than at other times of day.…”