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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.

Author information​

Tawakol A1, Ishai A2, Takx RA2, Figueroa AL2, Ali A2, Kaiser Y2, Truong QA3, Solomon CJ4, Calcagno C4, Mani V4, Tang CY4, Mulder WJ4, Murrough JW5, Hoffmann U2, Nahrendorf M6, Shin LM7, Fayad ZA4, Pitman RK8.

1Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Cardiac MR PET CT Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: atawakol@mgh.harvard.edu.

2Cardiac MR PET CT Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

3Radiology Department, Weil Cornell Medical College, New York, NY, USA.

4Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

5Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

6Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA.

7Department of Psychology, Tufts University, Medford, MA, USA.

8Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.