Circadian misalignment increases cardiovascular disease risk factors in humans

Abstract

Shift work is a risk factor for hypertension, inflammation, and cardiovascular disease. This increased risk cannot be fully explained by classic risk factors. One of the key features of shift workers is that their behavioral and environmental cycles are typically misaligned relative to their endogenous circadian system. However, there is little information on the impact of acute circadian misalignment on cardiovascular disease risk in humans. Here we show-by using two 8-d laboratory protocols-that short-term circadian misalignment (12-h inverted behavioral and environmental cycles for three days) adversely affects cardiovascular risk factors in healthy adults. Circadian misalignment increased 24-h systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 3.0 mmHg and 1.5 mmHg, respectively. These results were primarily explained by an increase in blood pressure during sleep opportunities (SBP, +5.6 mmHg; DBP, +1.9 mmHg) and, to a lesser extent, by raised blood pressure during wake periods (SBP, +1.6 mmHg; DBP, +1.4 mmHg). Circadian misalignment decreased wake cardiac vagal modulation by 8-15%, as determined by heart rate variability analysis, and decreased 24-h urinary epinephrine excretion rate by 7%, without a significant effect on 24-h urinary norepinephrine excretion rate. Circadian misalignment increased 24-h serum interleukin-6, C-reactive protein, resistin, and tumor necrosis factor-α levels by 3-29%. We demonstrate that circadian misalignment per se increases blood pressure and inflammatory markers. Our findings may help explain why shift work increases hypertension, inflammation, and cardiovascular disease risk.

Keywords: circadian misalignment; hypertension; inflammatory markers; night work; shift work.

Fig. 1.

Circadian alignment protocol (Top) and circadian misalignment protocol (Bottom). On day 1 of both protocols, participants received an ad libitum lunch at ∼12:00 PM. Light levels indicated are in the horizontal angle of gaze: ∼90 lx, to simulate typical room light intensity, ∼450 lx during the first three baseline wake episodes to enhance circadian entrainment, 30-min periods of ∼450 lx to simulate the morning commute both preceding the day work shift (circadian alignment protocol) and after the night work shift (circadian misalignment protocol), ∼4 lx to permit assessment of the dim-light melatonin onset, and 0 lx during scheduled sleep episodes. Light blue bars represent meals (wide bar) and snacks (narrow bar).

Fig. 2.

Effects of circadian misalignment on blood pressure and heart rate levels. DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood pressure; TP, test period; TSW, time since wake. Gray bar, sleep opportunity. Probability values are based on 24-h analyses. Data are represented as mean ± SEM.

Fig. 3.

Effects of circadian misalignment on sleep opportunity-associated dipping in blood pressure and heart rate. DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood pressure; TP, test period. Data are represented as mean ± SEM.

Fig. 4.

Effects of circadian misalignment on urinary epinephrine and norepinephrine excretion rates. TP, test period. Gray bar, sleep opportunity. Probability values are based on 24-h analyses. Data are represented as mean ± SEM.

Fig. 5.

Effects of circadian misalignment on wake period cardiac vagal modulation. pNN20, percentage of consecutive heartbeat intervals differing by >20 ms; RMSSD, root mean square differences of consecutive heartbeat intervals; TP, test period. Data are represented as mean ± SEM.

Fig. S1.

Effects of circadian misalignment on wake period cardiac vagal modulation. pNN50, percentage of consecutive heartbeat intervals differing by >50 ms; TP, test period. Data are represented as mean ± SEM.

Fig. 6.

Effects of circadian misalignment on interleukin-6 and high-sensitivity C-reactive protein levels. hs-CRP, high-sensitivity C-reactive protein; IL-6, interleukin-6; TP, test period; TSW, time since wake. Gray bar, sleep opportunity. Probability values are based on 24-h analyses. Data are represented as mean ± SEM.

Fig. 7.

Effects of circadian misalignment on resistin and tumor necrosis factor-alpha levels. TNF-α, tumor necrosis factor-α; TP, test period; TSW, time since wake. Gray bar, sleep opportunity. Probability values are based on 24-h analyses. Data are represented as mean ± SEM.

Fig. 8.

Effects of circadian misalignment on plasminogen activator inhibitor-1 and tissue plasminogen activator activity levels. PAI-1, plasminogen activator inhibitor-1; TP, test period; tPA, tissue plasminogen activator; TSW, time since wake. Gray bar, sleep opportunity. For tPA data, n = 6. Probability values are based on 24-h analyses. Data are represented as mean ± SEM.