title: Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study.
abstract: 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.
  
  
  
  Individuals aged 30 years or older without known cardiovascular disease or active cancer disorders, who underwent18F-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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  None.
authors.affiliation: Cardiology 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.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Tawakol
authors.affiliation: Cardiac MR PET CT Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Amorina
authors.initials: A
authors.lastname: Ishai
authors.affiliation: Cardiac MR PET CT Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Richard Ap
authors.initials: RA
authors.lastname: Takx
authors.affiliation: Cardiac MR PET CT Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Amparo L
authors.initials: AL
authors.lastname: Figueroa
authors.affiliation: Cardiac MR PET CT Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Abdelrahman
authors.initials: A
authors.lastname: Ali
authors.affiliation: Cardiac MR PET CT Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Kaiser
authors.affiliation: Radiology Department, Weil Cornell Medical College, New York, NY, USA.
authors.forename: Quynh A
authors.initials: QA
authors.lastname: Truong
authors.affiliation: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Chloe Je
authors.initials: CJ
authors.lastname: Solomon
authors.affiliation: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Calcagno
authors.affiliation: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Mani
authors.affiliation: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Cheuk Y
authors.initials: CY
authors.lastname: Tang
authors.affiliation: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Willem Jm
authors.initials: WJ
authors.lastname: Mulder
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Murrough
authors.affiliation: Cardiac MR PET CT Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Udo
authors.initials: U
authors.lastname: Hoffmann
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Nahrendorf
authors.affiliation: Department of Psychology, Tufts University, Medford, MA, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Shin
authors.affiliation: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Zahi A
authors.initials: ZA
authors.lastname: Fayad
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Roger K
authors.initials: RK
authors.lastname: Pitman
mesh_terms: D000368:Aged; D000679:Amygdala / Q000000981:diagnostic imaging* / Q000378:metabolism*; D001158:Arteries / Q000503:physiopathology; D050197:Atherosclerosis / Q000503:physiopathology; D001853:Bone Marrow / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000523:psychology*; D003430:Cross-Sectional Studies; D019788:Fluorodeoxyglucose F18; D006410:Hematopoiesis / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D008137:Longitudinal Studies; D008875:Middle Aged; D010465:Perception; D000072078:Positron Emission Tomography Computed Tomography; D019275:Radiopharmaceuticals; D012307:Risk Factors; D013315:Stress, Psychological / Q000378:metabolism*
chemical_list: D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18