Stress-Associated Neurobiological Pathway Linking Socioeconomic Disparities to Cardiovascular Disease

Abstract

Background: Lower socioeconomic status (SES) associates with a higher risk of major adverse cardiac events (MACE) via mechanisms that are not well understood.

Objectives: Because psychosocial stress is more prevalent among those with low SES, this study tested the hypothesis that stress-associated neurobiological pathways involving up-regulated inflammation in part mediate the link between lower SES and MACE.

Methods: A total of 509 individuals, median age 55 years (interquartile range: 45 to 66 years), underwent clinically indicated whole-body ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography imaging and met pre-defined inclusion criteria, including absence of known cardiovascular disease or active cancer. Baseline hematopoietic tissue activity, arterial inflammation, and in a subset of 289, resting amygdalar metabolism (a measure of stress-associated neural activity) were quantified using validated ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography methods. SES was captured by neighborhood SES factors (e.g., median household income and crime). MACE within 5 years of imaging was adjudicated.

Results: Over a median 4.0 years, 40 individuals experienced MACE. Baseline income inversely associated with amygdalar activity (standardized β: -0.157 [95% confidence interval (CI): -0.266 to -0.041]; p = 0.007) and arterial inflammation (β: -0.10 [95% CI: -0.18 to -0.14]; p = 0.022). Further, income associated with subsequent MACE (standardized hazard ratio: 0.67 [95% CI: 0.47 to 0.96]; p = 0.029) after multivariable adjustments. Mediation analysis demonstrated that the path of: ↓ neighborhood income to ↑ amygdalar activity to ↑ bone marrow activity to ↑ arterial inflammation to ↑ MACE was significant (β: -0.01 [95% CI: -0.06 to -0.001]; p < 0.05).

Conclusions: Lower SES: 1) associates with higher amygdalar activity; and 2) independently predicts MACE via a serial pathway that includes higher amygdalar activity, bone marrow activity, and arterial inflammation. These findings illuminate a stress-associated neurobiological mechanism by which SES disparities may potentiate adverse health outcomes.

Keywords: cardiovascular disease; neurobiology; positron emission tomography; socioeconomic disparities; stress.

Figure 1. (A) Study Cohort.

The study cohort was derived from a database of patients who had undergone whole-body ¹⁸F-FDG-PET/CT imaging at Massachusetts General Hospital. All subjects meeting pre-defined criteria were included. Image analyses, event adjudication, and determination of SES were performed by mutually blinded investigators. (B) Measurement of Tissue Activity. Amygdalar activity (corrected for background cerebral activity) and arterial ¹⁸F-FDG uptake (corrected for background blood activity) were measured as validated measures of stress-associated neurobiological activity and arterial inflammation, respectively.

Figure 2. Socioeconomic Status versus Amygdalar Activity and Arterial Inflammation.

Individuals were categorized according to quartiles of their neighborhood median income and neighborhood crime rates. Amygdalar activity (A) and arterial inflammation (B) were lower as neighborhood median income increased. Conversely, amygdalar activity was higher (C) and arterial inflammation trended towards an increase (D) as neighborhood crime rate increased. Amygdalar activity was adjusted for age and sex, and arterial inflammation was additionally adjusted for CVD risk factors. Error bars indicate standard error of the mean.

Figure 3. Socioeconomic Status versus MACE.

Individuals in the lowest quartile of neighborhood median income experienced a nearly 4-fold higher risk of MACE compared to those in the highest quartile (HR [95%CI]: 3.91 [1.30, 11.77], Cox regression p=0.015; log rank p=0.009). Abbreviation: Q-quartile.

Figure 4. A Hypothesized Pathway Linking Lower SES to MACE.

A serial 3-mediator analysis testing the hypothesized indirect path of: ↓SES → ↑amygdalar activity → ↑bone marrow activity→ ↑arterial inflammation → ↑MACE (red arrows) was significant (standardized log odds ratio [95% CI]= −0.0137 [−0.0570, −0.0003], p<0.05. Additionally, the path of: ↓SES→ ↑amygdalar activity → ↑arterial inflammation→ ↑MACE was also significant (−0.0137 [−0.0546, −0.0001], p<0.05). Exact p-values are not available for a dichotomous outcome measure, but in the employed bootstrap model, CIs that do not cross zero indicate p < 0.05. Abbreviations: MACE-major adverse cardiovascular event, SES-socioeconomic status.

Central Illustration. A Model of Lower Socioeconomic Status Leading to Major Adverse Coronary Events:

Prior data have demonstrated a link between low SES and higher rate of CVD. This study suggests that a biological pathway contributes to this link, involving, in series, higher AmygA, increased activation of the bone marrow (with release of inflammatory cells), which in turn leads to increased atherosclerotic inflammation and its atherothrombotic manifestations. Non-biological (and likely other biological) paths also exist. While the social variables involved in this pathway are notoriously difficult to change, the biological factors are potentially more modifiable.