Investigation of Sex and Gender Differences in Cardiovascular Risk in Rural Communities

Women living in the rural United States experienced a disproportionate increase in premature coronary heart disease (CHD) mortality between 2009 and 2017 compared to other demographic groups, which otherwise enjoyed a reduction in CHD events. Worsening mental health is a growing concern in rural areas and may disproportionately affect rural women due to constraining gender stereotypes, lack of social and economic resources, and limited access to care. These factors in turn may increase CHD risk in women through autonomic, neuroendocrine, and inflammatory response pathways. We anticipate that both gender (social constructs) and sex (biological factors) and their interplay are implicated. Our overarching hypothesis is that rural women have disproportionally high exposure to social adversity and psychological stress, leading to sex- specific hormonal, inflammatory, autonomic, and cardiovascular consequences that collectively increase CHD risk. We also hypothesize that these effects are more likely to occur during women's reproductive years in part through alterations in reproductive physiology and inflammation. Partnering with the ongoing RURAL (Risk Underlying Rural Areas Longitudinal) cohort study, we will study a diverse sample of approximately 3,800 people of age 25-64 years from 10 rural counties in the Southern US undergoing detailed cardiovascular phenotyping and psychosocial evaluation. We will examine everyday stress using a novel smartphone-based tool and leverage data from wristband wearables to evaluate sleep and circadian patterns that in our studies were associated with psychological stress. We will also examine cardiac autonomic function to provide insight on brain-heart reactivity to daily stress with a novel multi-modal ambulatory heart monitor that measures electrocardiography (ECG), pulse waveform, respiration, and movement. Finally, we will examine inflammatory and reproductive hormonal pathways potentially related to both stress and CHD, to help understand the disproportionately accelerated CHD risk in young women. In aim 1, we examine differences in social adversity and mental health factors between women and men in rural communities, and in the relationship of these exposures with cardiometabolic risk profile and subclinical CHD. In aim 2, we will examine differences in daily stress and stress-related cardiovascular physiology between women and men by conducting a week-long ecological momentary assessment with physiological monitoring to examine daily perceived mood/stress, stressful life events, and corresponding autonomic stress responses with a multi-sensor chest patch that examines both cardiac and vascular autonomic effects. In aim 3, we examine whether social adversity, mental health factors, and stress in everyday rural life are related to immune alterations (interleukin-6) and reproductive aging (anti-Mullerian hormone). This study will be the first to examine multifactorial biopsychosocial determinants underlying disturbing trends in CHD among rural women and will sharpen our understanding of sex-related disparities in young and middle-aged populations.