By what molecular mechanisms do social determinants impact cardiometabolic risk?

Abstract

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.

Keywords: Cardiometabolic Disease; Chronic Stress; Immune System; Inflammation; Psychosocial and Environmental Stressors; Social Determinants of Health.

Figure 1. Effects of chronic psychosocial and environmental stressors (PSES) on the stress response

From left to right: Activation of the SNS releases catecholamines, mainly norepinephrine and epinephrine, from postganglionic sympathetic nerve terminals which act on adrenergic receptors. Activation of the sympathetic-adrenomedullary (SAM) axis releases catecholamines into circulation via the adrenal medulla. Chronic activation of these stress responses and repeated release of catecholamines may lead to a noncanonical pro-inflammatory response facilitated by β2-adrenergic receptors. Release of dopamine from sympathetic nerves may also play a role in the effects of chronic stress, particularly via immune modulation and increased activity of the NRLP3 inflammasome. The HPA axis is also activated by stress and results in the release of CRF, ACTH, and cortisol. Each hormone has been associated with adverse effects of chronic stress. Most notably, glucocorticoid resistance leads to an increase in pro-inflammatory signaling, with increased levels of NF-κB, TNFα, and IL-6.

Figure 2. The neural–hematopoietic axis and chronic PSES

Using 18F-FDG PET/CT, chronic PSES have been shown to increase activity of the amygdala which has been associated with increased activity of the bone marrow and spleen as well as arterial inflammation. It is hypothesized that sympathetic afferents stimulate hematopoiesis in the bone marrow, and possibly spleen, which results in increased migration of immune cells to arteries and may lead to cardiovascular disease.

Figure 3. The impact of chronic PSES on the immune system

PSES have been reported to alter immune cell distribution, immune cell function, and induce chronic inflammation partially due to an imbalance of pro-/anti-inflammatory cytokine levels. Effects of both acute and chronic stress have been reported, and each has been connected to CVD. Acute stress has been shown to alter monocytes as well as increase immune-cell platelet aggregates, which may be related to atherosclerosis. Chronic stress due to PSES has been shown to shift cytokine expression towards pro-inflammatory signaling. Specific chronic PSES are highlighted, such as socioeconomic disadvantage which has been associated with altered monocyte receptor expression. Childhood trauma and psychosis as chronic stressors have been linked to an imbalance of Th17, Tregs, and NK cells which may affect immune function.

Figure 4. Chronic PSES induce epigenetic changes which promote proinflammatory signaling

Various PSES have been shown to lead to DNA methylation and demethylation as well as histone modification, all of which affect expression of genes. The addition of a methyl group to cytosine serves to block transcription of the affected gene, while the removal a methyl group can promote transcription. Histones can be modified by the addition or removal of acetyl or methyl groups which also affect transcription. Through an interplay of these mechanisms, PSES have been shown to alter cytokine and immune cell responses potentially accelerating atherogenesis.

Figure 5. Chronic PSES induce telomere shortening

Chronic PSES have been shown to shorten telomeres potentially via increased inflammation and oxidative stress. Shortened telomeres have been associated with CVD.

Figure 6. Future research directions

In this review, we have highlighted studies which have investigated the impact of chronic stress or stress-related biomarkers on cellular signaling pathways. However, there are several important directions for future research. (1) Future research should be performed by interdisciplinary teams of epidemiologists, basic/translational, behavioral, and social scientists, clinicians, and statisticians with active engagement of the community in which the research is being done. (2) Interdisciplinary teams need to work with communities who have been historically underrepresented and marginalized in biomedical research using established community engagement methods as many referenced studies in this review inadequately represent diverse populations including Asian, Latinx, non-Hispanic Black, Native American/Alaska Native, and Native Hawaiian/Pacific Islander populations as well as sexual and gender minority populations of all racial/ethnic groups. (3) Teams should use longitudinal studies over the life course to examine signaling pathways and markers (i.e. immune cell characterization, various ‘-omics’, and cytokines and stress-related biomarkers) as mediators of the relationships between social determinants of health (SDoH) and cardiometabolic health factors. (4) Teams should also create multi-level interventions which simultaneously target both policies that impact SDoH (i.e. housing, education, occupation, physical and social neighborhood environment) and behaviors related to cardiometabolic health (i.e., physical activity, stress, reduction, diet, and sleep). (5) These multi-level interventions can be used to investigate key signaling pathways linked to cardiometabolic outcomes and most amenable to health behavior change.