Abstract Body (Do not enter title and authors here): Background:
Chronic stress is associated with cardiovascular disease (CVD) in part through neural mechanisms that potentiate inflammation. Disrupted social connections are associated with higher chronic stress. As such, we hypothesized that: 1) previously married (divorced, separated) individuals have higher major adverse cardiovascular event (MACE) risk compared to married individuals and 2) that greater activation of stress-related neural-immune mechanisms contributes to this relationship.

Methods:
Participants (N=75,638) enrolled in the Mass General Brigham Biobank were studied. Marital status and MACE were identified using survey data and ICD-10 codes, respectively. A subset (N=1,121) underwent clinical ¹⁸F-FDG-PET imaging, enabling assessment of stress-related neural activity as the ratio of the amygdala to prefrontal cortex activity (AmygAc). Clinical high-sensitivity C-reactive protein (hs-CRP) levels were assessed in another subset of the cohort (N=10,358). Linear and Cox regression and mediation analyses were used.


Results:
Among participants (median age 62 years; 53% female), 2,978 subjects developed MACE after Biobank enrollment. Previously married (vs. currently married) individuals had greater MACE risk (HR 1.33 [95% CI: 1.20,1.57], p=<0.001, Figure 1A) , higher AmygAc (B=0.23 [95% CI: 0.06-0.40], p=0.009) and higher hs-CRP (B=0.19 [95% CI: 0.13-0.25], p=<0.001). MACE risk remained significant after adjustment for key confounders (Table 1), and both the AmygAc and CRP were higher among divorced or separated individuals (Figure 1B and 1C). Moreover, increased AmygAc and hs-CRP associated with increased MACE risk (HR=1.24 [1.14-1.36], p=<0.001 and 1.13 [1.09-1.16], p=<0.001, respectively), and both AmygAc and hs-CRP mediated the relationship between marital status and MACE (p<0.05).


Conclusions:
Our findings suggest that divorced and separated individuals are at an increased risk for MACE. This relationship appears to be driven in part by stress-related neural-immune mechanisms.