Project Summary:
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.