Nearly half of US adults present with HTN, one of the strongest risk factors for cardiovascular disease (CVD) and a leading cause of CVD mortality. Blood pressure (BP) displays a circadian rhythm, and abnormalities in diurnal BP variation are linked to CVD morbidity and mortality. Emerging evidence suggests that the circadian rhythmicity of behavioral factors within the 24-h day can alter BP levels and their natural variation patterns. Interestingly, the alarming HTN prevalence rates have paralleled the shift from a predominantly daytime to a delayed lifestyle, in which eating and activity occur at night and sleep is restricted. Intervention studies suggest that the effect of circadian disruption on BP is similar in magnitude but opposite in direction to that of the Dietary Approaches to Stop Hypertension (DASH) diet and certain anti-hypertensive drugs. However, these studies do not reflect habitual patterns of behavior in a real-life setting, do not capture long-term health effects of milder circadian misalignment that is highly prevalent in the population, and have yet to elucidate underlying mechanisms. The research goal of this K99/R00 award is to evaluate the associations of circadian rest-activity rhythms (CRAR), a measure of circadian rhythmicity in the free-living setting, with HTN risk and diurnal BP variation and investigate epigenetic pathways as an underlying mechanism. I am seeking the Pathway to Independence Award to gain the additional training needed to accomplish my long-term career goal: to be an interdisciplinary independent scientist who specializes in the intersection of behavioral risk factors, circadian rhythms, and epigenetics in relation cardiovascular risk. The training component of this project will provide expertise in: 1) circadian concepts and methods, 2) design and analysis of human epigenetics (DNA methylation) studies, 3) advanced statistical methods, and 4) collection and interpretation of ambulatory BP monitoring (ABPM) data. This will be accomplished through formal coursework, directed readings and didactic instruction, research apprenticeships, attendance to scholarly seminars and conferences, and mentored career development activities including grant writing. The research component of this project will leverage objective sleep and activity data from the Multi-Ethnic Study of Atherosclerosis (MESA) and use non-parametric methods to estimate circadian rhythm of rest-activity patterns.
In Aim 1, we will investigate associations of CRAR with HTN prevalence and incidence and elucidate potential sex and racial/ethnic differences.
In Aim 2, we will examine the relations between CRAR, epigenetic age (a measure of biological aging based on DNA methylation patterns), and BP and determine whether epigenetic age acceleration mediates associations of CRAR with HTN. To extend this work in preparation for an R01, for Aim 3, we will conduct a pilot study to examine the associations between CRAR, epigenetic age, and 24-h ABPM measures. The training and research activities will result in scientific presentations, publications, and preliminary data and prepare me to successfully compete for R01 funding during the R00 phase.
Given that circadian disruptions are ubiquitous in modern society, this study will investigate whether circadian rest-activity rhythms (CRAR), a measure of circadian rhythmicity in a free-living setting, are associated with hypertension risk and with measures of diurnal blood pressure (BP) variation that may have greater prognostic significance in predicting cardiovascular events. The study will also determine whether epigenetic age, a measure of biological aging based on DNA methylation patterns, mediates associations of CRAR with BP and provide evidence for a biologically plausible mechanistic model of CRAR's influence on HTN risk. Rest-activity rhythms are potentially modifiable; therefore, gaining a better understanding of the relationship between CRAR and BP as well as underlying epigenetic mechanisms related to aging and age-related disease may inform hypertension prevention guidelines to address the timing, regularity and periodicity of lifestyle activities and lead to novel precision behavioral interventions that lower cardiovascular risk.
