Circadian Variation in Vascular Function and Regenerative Capacity in Healthy Humans Ibhar Al Mheid, MD; Frank Corrigan, MD; Farheen Shirazi, MD; Emir Veledar, PhD; Qunna Li, MS; Wayne R. Alexander, MD, PhD; W. Robert Taylor, MD, PhD; Edmund K. Waller, MD, PhD; Arshed A. Quyyumi, MD Background-—Progenitor cells (PCs) are mobilized in response to vascular injury to effect regeneration and repair. Recruitment of PCs requires intact nitric oxide (NO) synthesis by endothelial cells, and their number and activity correlate with cardiovascular disease risk burden and future outcomes. Whereas cardiovascular vulnerability exhibits a robust circadian rhythm, the 24-hour variation of PCs and their inter-relation with vascular function remain unknown. We investigated the circadian variation of PCs and vascular function with the hypothesis that this will parallel the pattern observed for cardiovascular events (CVEs). Methods and Results- —In 15 healthy subjects (9 men, 3716 years), circulating PCs and vascular function were measured at 8 AM, noon, 4 PM,8 PM, midnight, 4 AM (only PCs counts), and 8 AM the following day. Circulating PCs were enumerated as mononuclear cells (MNCs; CD45 med ) that express CD34 as well as CD133, and their activity was assessed as the number of colonies formed by culturing MNCs. Vascular function was evaluated by measurement of endothelium-dependent, flow-mediated vasodilation (FMD) of the brachial artery and tonometry-derived indices of arterial stiffness. Higher CD34 + and CD34 + /CD133 + cell counts were observed at 8 PM than any other time of the day (P-ANOVA=0.038 and <0.001; respectively) and were lowest at 8 AM. PC colony formation was highest at midnight (P-ANOVA=0.045) and lowest in the morning hours. FMD was highest at midnight and lowest at 8 AM and 8 PM, and systemic arterial stiffness was greatest at 8 AM and lowest at 4 PM and midnight (P-ANOVA=0.03 and 0.01; respectively). Conclusion- —A robust circadian variation in PC counts and vascular function occurs in healthy humans and both exhibit an unfavorable profile in the morning hours that parallels the preponderance of CVEs at these times. Whether these changes are precipitated by awakening and time-dependent physical activity or governed by the endogenous circadian clock needs to be further investigated. ( J Am Heart Assoc. 2014;3:e000845 doi: 10.1161/JAHA.114.000845) Key Words: arterial stiffness • circadian variation • endothelial function • progenitor cells V ulnerability to adverse cardiovascular disease (CVD) events, such as myocardial ischemia, infarction, sudden cardiac death, and cerebrovascular accidents, are subject to an intrinsic circadian rhythm with greatest prevalence during the morning hours. 1–4 A similar circadian variability is observed in likely physiological precipitants, including heart rate and blood pressure (BP), vasoconstrictor tone, blood viscosity and fibrinolytic activity, platelet aggregability, epinephrine and norepinephrine levels, in addition to cortisol levels and plasma renin activity. 5–12 Other precipitants of CVD events include impaired endo- thelial cell (EC) function and increased systemic arterial stiffness, which precede and contribute to the development of CVD and are long-term predictors of morbidity and mortal- ity. 13 Indeed, vascular dysfunction and reduced nitric oxide (NO) bioavailability promote a proinflammatory and -coagula- tory milieu that also triggers acute vascular events. 13,14 Whereas several studies confirm the presence of significant changes in vascular endothelial function by the time of day, which may differ between patient populations, others dem- onstrate no significant circadian or diurnal variation. 15–21 Recently, bone-marrow (BM)-derived progenitor cells (PCs) have been identified and quantitated in the circulation. PCs are released into the bloodstream in response to vascular injury, homing to areas of ischemia, and actively participate in tissue repair and regeneration. 22 In experimental models, mobilization of PCs is dependent on endothelial nitric oxide From the Emory University School of Medicine, Atlanta, GA. Correspondence to: Arshed A. Quyyumi, MD, Emory Clinical Cardiovascular Research Institute, 1462 Clifton Road, Suite 507, Atlanta, GA 30322. E-mail: aquyyum@emory.edu Received January 27, 2014; accepted March 26, 2014. ª 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. DOI: 10.1161/JAHA.114.000845 Journal of the American Heart Association 1 ORIGINAL RESEARCH Downloaded from http://ahajournals.org by on January 10, 2022