Endogenous circadian mechanisms underlying cardiovascular risk

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT Endogenous circadian clocks exist in all cells and tissues, including the autonomic nervous system, heart, and vasculature. The resultant rhythms prepare the cardiovascular (CV) system for optimal function to match the daily anticipated behavioral and environmental cycles, such as altered posture and increased activity after awakening in the morning. However, the morning is also the most vulnerable time for adverse CV events, including myocardial infarction, stroke and sudden cardiac death. Dr. Shea has pioneered the use of intensive, multi-day laboratory experiments and uncovered substantial endogenous circadian rhythms across the CV system in healthy humans. Dr. Shea also discovered that circadian rhythms exist in the CV reactivity to stressors (i.e., there are different CV responses to identical stressors at different times of day). Dr. Shea’s work has led to the concept that circadian rhythms in the CV system act as a ‘double-edged sword’: the normal amplified responses in the morning aid the transition from sleep to activity in healthy individuals, but such exaggerated responses are potentially perilous in individuals with underlying CV risk factors who are susceptible to adverse events. Dr. Shea will lead a multi-disciplinary team of outstanding investigators to examine the broad question of how the circadian system interacts with behavior-related CV responses to produce predictable daily variations in CV risk profiles. To compare with healthy controls, studies will be performed in populations with increased underlying susceptibility to CV disease, such as hypertension, midlife adults, and obstructive sleep apnea. The overall team has expertise in circadian, sleep, stress, exercise and CV physiology, and positron emission tomographic imaging of the balance of pre- and post-synaptic adrenergic function in the left ventricle in resting humans. The investigators will use outstanding purpose-built facilities to perform the necessary intensive, multi- day studies with nursing, bio-nutrition and clinical support services integrated with the team’s physiological expertise. Dr. Shea has >30 years’ experience performing clinical research mainly focused on circadian rhythms in healthy humans and their impact on CV disease risk factors, and he has performed the majority of the CV physiology studies in humans that use validated circadian protocols. Dr. Shea has been well-funded with 25 consecutive years as PI of investigator-initiated federal grants. Dr. Shea’s publications are well-cited with a mean relative citation ratio of 3.84 for original research papers in the past decade [2009-18], which is higher than the 90% percentile for all NIH-funded papers in the same field [NIH Office of Portfolio Analysis: iCite Tool]). Due to the fast emerging recognition of the magnitude and extent of circadian rhythms throughout the body, including circadian rhythms in drug targets, we are on the cusp of meaningful chronotherapeutic trials in CV medicine that consider internal circadian time. These preclinical studies performed in this Research Program will provide the critical and timely background needed to fully exploit these opportunities to improve therapy of CV disease.