Social determinants of health (SDoH), which encompass the economic, social, environmental, and psychosocial factors that influence health, play a significant role in the development of cardiovascular disease (CVD) risk factors as well as CVD morbidity and mortality. The COVID-19 pandemic and the current social justice movement sparked by the death of George Floyd have laid bare long-existing health inequities in our society driven by SDoH. Despite a recent focus on these structural drivers of health disparities, the impact of SDoH on cardiovascular health and CVD outcomes remains understudied and incompletely understood. To further investigate the mechanisms connecting SDoH and CVD, and ultimately design targeted and effective interventions, it is important to foster interdisciplinary efforts that incorporate translational, epidemiological, and clinical research in examining SDoH-CVD relationships. This review aims to facilitate research coordination and intervention development by providing an evidence-based framework for SDoH rooted in the lived experiences of marginalized populations. Our framework highlights critical structural/socioeconomic, environmental, and psychosocial factors most strongly associated with CVD and explores several of the underlying biologic mechanisms connecting SDoH to CVD pathogenesis, including excess stress hormones, inflammation, immune cell function, and cellular aging. We present landmark studies and recent findings about SDoH in our framework, with careful consideration of the constructs and measures utilized. Finally, we provide a roadmap for future SDoH research focused on individual, clinical, and policy approaches directed towards developing multilevel community-engaged interventions to promote cardiovascular health.

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Obesity and related chronic diseases (i.e. cardiovascular disease (CVD) and cancer) disproportionately affect African Americans (AA), shortening life expectancy and impacting quality of life. Life‐long exposure to adverse social determinants of health (SDoH) have been linked to obesity, warranting intensified research to further elucidate the ‘biology of adversity’ or the biologic consequences of adverse social conditions. Evidence suggests that exposure to chronic psychological and environmental stressors as SDoH leads to immune cell dysfunction, particularly for Natural Killer (NK) cells. Therefore, we examined changes in NK cell function in AA women, a group at high risk of Class III obesity (BMI ≥40 kg/m2). We have previously shown that NK cell degranulation is impaired in AA women with Class III obesity accompanied by a decrease in IFNg and TNFa, a loss in function driven by plasma LDL levels (b=‐0.35, p=0.03). A similar phenotype of dysfunctional NK cells could be achieved by overnight LDL treatment (50mg/dl) of healthy donor NK cells. To further determine the underlying signaling pathways, we employed proteomics of control and LDL treated NK cells. Here we identified 18 statistically significant regulated proteins (p<0.05), and 23 proteins approaching significance (p<0.07). Signaling pathway analysis revealed endolysosomal function, actin cytoskeleton regulation, and regulation of innate immune responses as significant pathways. Several proteins associated with autophagy and ubiquitination were also identified. This is of particular importance as LDL treatment of various cell types has been related to damaging lysosomes and a subsequent potential induction of lysophagy. Therefore, we investigated the impact of LDL on NK cell autophagy through western blot analysis of LC3 and p62 and found that enhanced autophagy is present in LDL treated NK cells. By employing the proteasome inhibitor MG‐132, we also found that the LDL‐induced increase in autophagy appears to be dependent on the activation of the 20S proteasome and subsequent ubiquitination of lysosomal proteins which results in depletion of functional lysosomes through lysophagy and is accompanied by NK cell function loss. In summary, we show a novel pathway potentially explaining obesity‐related NK cell function loss as a result of adverse SDoH in a population at highest risk for obesity‐related diseases like CVD and cancer. In the future, more research is needed to further understand the ‘biology of adversity’ and identifying targets for tailored interventions, ultimately reducing health inequities in chronic disease outcomes.

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Introduction: Chronic exposure to environmental stressors is associated with racial and ethnic disparities in cardiovascular disease (CVD) risk factors. African American (AA) women are at highest risk for obesity and subsequent CVD development. Obesity as a CVD risk factor and psychosocial stressors have been associated with altered Natural Killer (NK) cell distribution and function. Less is known about how perceived and objective neighborhood social environment relates to NK cell distribution and function. Hypothesis: More favorable neighborhood social environment would associate with a greater number and more functional NK cell population. Methods: We recruited 40 AA women from a Washington, DC community-based cohort and determined the NK cell profile using flow cytometry according to their CD3/CD56 expression on the cell surface. Neighborhood social environment was measured by neighborhood environment (NE) perceptions and objective neighborhood deprivation index (NDI). NE perceptions were measured using validated questionnaires to calculate overall NE perceptions, perceived neighborhood violence, physical/social environment, social cohesion, and safety (higher score=more favorable perceptions). NDI was measured using U.S. Census data on census-tract level features (i.e., housing characteristics, education, income, poverty) where higher NDI=lower NE socioeconomic level. Multivariable regression models were used to determine associations between neighborhood social environment and NK cell number. Additionally, regression models were adjusted for Atherosclerotic Cardiovascular Disease (ASCVD) risk and BMI, unless otherwise specified. Results: Among this community-based cohort of AA women (N=40 mean age 58.8 ±12.0; BMI 34.2 ±6.9), overall NE perceptions were associated with overall NK cell numbers before and after adjustments for ASCVD and BMI (β=0.48, p=0.007, β=0.50, p=0.004). Perceived lack of violence was associated with increased NK cell number (β=0.38, p=0.04) even after the adjustment for ASCVD and BMI (β=0.39, p=0.03). Similar trends were observed with social cohesion and NK cells (β=0.32, p=0.06) and with perceived favorable physical/social environment and NK cells (β=0.34, p=0.07). In contrast, we found that safety did not show any significant association with NK cell numbers (β=0.28, p=0.13). Finally, NDI as an objective measure of neighborhood SES did not associate with NK cell numbers (β=-0.05, p=0.74). Conclusion: Together, our data suggest that perceived neighborhood social environment associates with NK cell numbers, while objective measures do not. These findings suggest that changes in NK cell populations may be driven by perceived social environment factors and could alter CV risk. Future studies are needed to determine the potential impact of social environment stressors on NK cell subtypes, receptor expression, and function.

While it is well known from numerous epidemiologic investigations that social determinants (socioeconomic, environmental, and psychosocial factors exposed to over the life-course) can dramatically impact cardiovascular health, the molecular mechanisms by which social determinants lead to poor cardiometabolic outcomes are not well understood. This review comprehensively summarizes a variety of current topics surrounding the biological effects of adverse social determinants (i.e., the biology of adversity), linking translational and laboratory studies with epidemiologic findings. With a strong focus on the biological effects of chronic stress, we highlight an array of studies on molecular and immunological signaling in the context of social determinants of health (SDoH). The main topics covered include biomarkers of sympathetic nervous system and hypothalamic–pituitary–adrenal axis activation, and the role of inflammation in the biology of adversity focusing on glucocorticoid resistance and key inflammatory cytokines linked to psychosocial and environmental stressors (PSES). We then further discuss the effect of SDoH on immune cell distribution and characterization by subset, receptor expression, and function. Lastly, we describe epigenetic regulation of the chronic stress response and effects of SDoH on telomere length and aging. Ultimately, we highlight critical knowledge gaps for future research as we strive to develop more targeted interventions that account for SDoH to improve cardiometabolic health for at-risk, vulnerable populations.

Social determinants of health (SDoH) include socioeconomic, environmental, and psychological factors that impact health. Low neighborhood socioeconomic status (nSES) is a SDoH that associates with cardiovascular mortality in longitudinal studies. While nSES as a chronic stress contributes to adverse health outcomes, the molecular mechanisms and pathogenesis are poorly understood. Previously, we found that residing in lower nSES areas may alter monocyte expression of C‐C chemokine receptor type 2 (CCR2), a regulator of monocyte recruitment during atherogenesis. To explore the effects of nSES as a chronic stress on monocyte CCR2 expression, we treated monocytes in vitro for 4 hours with catecholamines (epinephrine [Epi], norepinephrine [NE], or dopamine [DA]) used as stress biomarkers. Only DA increased CCR2 expression in a dose‐dependent manner (p<0.01), especially on non‐classical monocytes (NCM). In our current study, we investigated DA receptor signaling to learn which pathways may contribute to increases in CCR2 expression. Dopamine acts on five known receptors, the D1‐like receptors (D1 and D5) and D2‐like receptors (D2, D3, and D4). First, we performed flow cytometry on untreated monocytes and found D2 receptors were most abundant on the surface of all monocyte subsets (ie., classical monocytes [CM], intermediate monocytes [IM], and NCM as determined by CD14/CD16 expression). Furthermore, spearman correlation between D2‐like receptor surface expression and surface CCR2 expression in NCM suggested D2‐like receptor signaling (R2=0.79, p=0.04). Because the D2‐like receptor response is known to decrease cAMP levels compared to a D1‐like receptor response, a cAMP assay was performed on monocytes with DA treatment. Indicative of D2‐signaling, cAMP levels were found to be lower in DA‐treated monocytes compared to untreated controls (ctr 29.78pmol/ml vs DA 22.97 pmol/ml; p=0.038). We then investigated downstream mechanisms following DA signaling that could result in increased CCR2 expression. Filamin A (FlnA), a prominent actin‐cross‐linking protein, is known to regulate CCR2 recycling. We examined the expression of FlnA by flow cytometry and RT‐qPCR on flow sorted monocytes with and without DA treatment. There was a significant decrease in FlnA expression in NCM (p < 0.05), indicating a slowing of CCR2 recycling. Expression of an associated scaffold protein mRNA, b‐arrestin 1, was decreased by 66% in NCM (p= 0.008). Overall, we provide a novel immunological mechanism, driven by DA signaling and CCR2, for how nSES may contribute to atherogenesis. Future studies should investigate the importance of DA in CVD development and progression in populations disproportionately experiencing chronic stress due to SDoH.