Circadian Rhythm of Vascular Function in Midlife Adults

Abstract

Objective- Adverse cardiovascular events occur more frequently in the morning than at other times of the day. Vascular endothelial function (VEF)-a robust cardiovascular risk marker-is impaired during this morning period. We recently discovered that this morning impairment in VEF is not caused by either overnight sleep or the inactivity that accompanies sleep. We determined whether the endogenous circadian system is responsible for this morning impairment in VEF. We also assessed whether the circadian system affects mechanistic biomarkers, that is, oxidative stress (malondialdehyde adducts), endothelin-1, blood pressure, and heart rate. Approach and Results- Twenty-one (11 women) middle-aged healthy participants completed a 5-day laboratory protocol in dim light where all behaviors, including sleep and activity, and all physiological measurements were evenly distributed across the 24-hour period. After baseline testing, participants underwent 10 recurring 5-hour 20-minute behavioral cycles of 2-hour 40-minute sleep opportunities and 2 hours and 40 minutes of standardized waking episodes. VEF, blood pressure, and heart rate were measured, and venous blood was sampled immediately after awakening during each wake episode. Independent of behaviors, VEF was significantly attenuated during the subjective night and across the morning ( P=0.04). Malondialdehyde adducts and endothelin-1 exhibited circadian rhythms with increases across the morning vulnerable period and peaks around noon ( P≤0.01). Both systolic ( P=0.005) and diastolic blood pressure ( P=0.04) were rhythmic with peaks in the late afternoon. Conclusions- The endogenous circadian system impairs VEF and increases malondialdehyde adducts and endothelin-1 in the morning vulnerable hours and may increase the risk of morning adverse cardiovascular events in susceptible individuals. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT02202811.

Keywords: adult; biomarkers; circadian rhythm; oxidative stress; sleep.

Figure 1.. Forced desynchrony (FD) Protocol

Participants completed a 5-day protocol in time isolation. After a baseline 8-h control night, participants completed 10 alternating 2-h 40-min sleep and wake intervals, such that sleep opportunities were evenly spaced across the 24-h day. White bars represent wakefulness in typical room lighting (150 lux), black bars sleep opportunities (dark), and gray bars dim-light waking periods (<3 lux). Black circles represent measurements of VEF, MDA, ET-1, BP and HR. White circles represents a sample profile of dim-light melatonin onset (DLMO). The diagonal line represents an individual’s circadian time.

Figure 2.. Circadian variations in flow mediated dilation

Circadian variations in FMD% (panel A) and FMD normalized to hyperemic shear rate (panel B). FMD and Normalized FMD are low during the subjective night and across the vulnerable morning period and recover during the afternoon. Grey shaded area represents habitual sleep time (~311 PM - ~7 AM) in our participants. Data are reported as mean ± SEM.

Figure 3.. Sinusoidal variation in L-FMC, MDA, ET-1, SBP and DBP

L-FMC (n = 14, panel A) displays a sinusoidal profile with a trough during the subjective night and a peak in the afternoon. Plasma levels of MDA (n = 16, panel B) and ET-1 (n = 16, panel C) displays sinusoidal variation with a trough during the subjective night and a peak around noon. Systolic BP (n = 21, panel D) and diastolic BP (n = 21, panel E) are rhythmic and sinusoidal with a trough during the biological night and a peak in the evening. Grey shaded area represents habitual sleep time (~11 PM- ~7 AM) in our participants. Circadian model is plotted from the cosinor analyses. Raw observed values are binned by circadian phase within subject and then averaged within group, and plotted as mean ± SEM.