Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study

Abstract

Background: Emotional stress is associated with increased risk of cardiovascular disease. We imaged the amygdala, a brain region involved in stress, to determine whether its resting metabolic activity predicts risk of subsequent cardiovascular events.

Methods: Individuals aged 30 years or older without known cardiovascular disease or active cancer disorders, who underwent ¹⁸F-fluorodexoyglucose PET/CT at Massachusetts General Hospital (Boston, MA, USA) between Jan 1, 2005, and Dec 31, 2008, were studied longitudinally. Amygdalar activity, bone-marrow activity, and arterial inflammation were assessed with validated methods. In a separate cross-sectional study we analysed the relation between perceived stress, amygdalar activity, arterial inflammation, and C-reactive protein. Image analyses and cardiovascular disease event adjudication were done by mutually blinded researchers. Relations between amygdalar activity and cardiovascular disease events were assessed with Cox models, log-rank tests, and mediation (path) analyses.

Findings: 293 patients (median age 55 years [IQR 45·0-65·5]) were included in the longitudinal study, 22 of whom had a cardiovascular disease event during median follow-up of 3·7 years (IQR 2·7-4·8). Amygdalar activity was associated with increased bone-marrow activity (r=0·47; p<0·0001), arterial inflammation (r=0·49; p<0·0001), and risk of cardiovascular disease events (standardised hazard ratio 1·59, 95% CI 1·27-1·98; p<0·0001), a finding that remained significant after multivariate adjustments. The association between amygdalar activity and cardiovascular disease events seemed to be mediated by increased bone-marrow activity and arterial inflammation in series. In the separate cross-sectional study of patients who underwent psychometric analysis (n=13), amygdalar activity was significantly associated with arterial inflammation (r=0·70; p=0·0083). Perceived stress was associated with amygdalar activity (r=0·56; p=0·0485), arterial inflammation (r=0·59; p=0·0345), and C-reactive protein (r=0·83; p=0·0210).

Interpretation: In this first study to link regional brain activity to subsequent cardiovascular disease, amygdalar activity independently and robustly predicted cardiovascular disease events. Amygdalar activity is involved partly via a path that includes increased bone-marrow activity and arterial inflammation. These findings provide novel insights into the mechanism through which emotional stressors can lead to cardiovascular disease in human beings.

Funding: None.

Figure 1:. Study cohort

Eligible patients were selected on the basis of pre-defined criteria. All patients meeting these criteria were included. Image analyses and event adjudication were performed by mutually blinded investigators. ¹⁸F-FDG=¹⁸F-fluorodeoxyglucose. MGH=Massachusetts General Hospital.

Figure 2:. Amygdalar, arterial, and bone-marrow uptake of ¹⁸F-FDG in individuals with and without subsequent cardiovascular disease events

Axial views of amygdala (upper left and right), coronal views of aorta (middle left and right), and coronal views of bone marrow (lower left and right) are shown. ¹⁸F-FDG uptake was increased in the amygdala, bone marrow, and arterial wall (aorta), in a patient who experienced an ischaemic stroke during the follow-up period (right) compared with a patient who did not (left). ¹⁸F-FDG=¹⁸F fluorodeoxyglucose. SUV=standardised uptake value. TBR=target-to-background ratio.

Figure 3:. Kaplan-Meier survival curves of low vs high amygdalar activity based on the 90th percentile cutoff (A) or the mean (SD) cutoff (B)

Event-free survival for the primary amygdalar endpoint (max max amygdalac—ie, the maximum standardised uptake value for the right and left amygdalae, corrected for background cerebral tissue activity) are shown. p values were calculated with the log-rank test, and cox regression analyses were done to calculate HRs. HR=hazard ratio.

Figure 4:. Serial mediation model for hypothesised pathway to a cardiovascular disease event

n=266. A single-mediator analysis showed that bone-marrow activity was a significant mediator of the relation between amygdalar activity and arterial inflammation. Another single-mediator analysis showed that arterial inflammation was a significant mediator of the relation between amygdalar activity and cardiovascular disease events. A serial two-mediator analysis testing the hypothesised indirect path of increased resting amygdalar activity leading to increased bone-marrow activity leading to increased arterial inflammation leading to cardiovascular disease events (red arrows) was significant. Additionally, excluding the path through bone-marrow activity, the residual path of increased resting amygdalar activity leading to increased arterial inflammation leading to cardiovascular disease event (blue arrows) was also significant. Amygdalar activity was assessed as the primary measure, max max amygdalac (ie, the maximum standardised uptake value for the right and left amygdalae, corrected for background cerebral tissue activity). Bone-marrow activity was measured by ¹⁸F-FDG uptake in vertebral bone marrow corrected for background uptake in the superior vena cava. Arterial inflammation was measured by ¹⁸F-FDG uptake in the aortic wall corrected for background uptake in the superior vena cava. In the figure, c represents the total effect of amygdalar activity on cardiovascular disease events, whereas c’ is the residual direct effect of amygdalar activity on cardiovascular disease events (independent of mediated effects). Standardised regression coefficients or log odds ratios are shown; all analyses incorporated age, sex, and baseline coronary artery calcification (as a control for pre-existing atherosclerotic disease burden) as covariates. The appendix contains additional explanation. ¹⁸F-FDG=¹⁸F fluorodeoxyglucose. *p=0.0073. †p<0.0001. ‡p=0.0044. §p=0.0432. ¶p=0.6409. ||p=0.2196. **p=0.013.

Figure 5:. Perceived stress associated with amygdalar activity (A), arterial inflammation (B), and CRP (C) in cross-sectional validation sub-study

Perceived stress was assessed with a validated questionnaire. Error bars in (B) and (C) represent the standard error of the mean. TBR=target-to-background ratio. CRP=C-reactive protein.

Figure 6:. A model of stress leading to atherosclerotic inflammation

Data suggest that at least two biologically significant pathways link amygdalar activity to cardiovascular disease events in human beings. One of these pathways is sympathetic. The other, which is the object of this study, includes activation of the bone marrow (and release of inflammatory cells), which in turn lead to atherosclerotic inflammation and its atherothrombotic manifestations.