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

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.

[1]  S. Yusuf,et al.  Association of psychosocial risk factors with risk of acute myocardial infarction in 11 119 cases and 13 648 controls from 52 countries (the INTERHEART study): case-control study , 2004, The Lancet.

[2]  R. Collins,et al.  Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. , 1998, The New England journal of medicine.

[3]  Enhancing Cardiac Rehabilitation With Stress Management Training , 2016 .

[4]  Joseph E LeDoux,et al.  Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[5]  Andrew Steptoe,et al.  Stress and cardiovascular disease , 2012, Nature Reviews Cardiology.

[6]  G. Haegeman,et al.  Selective transrepression versus transactivation mechanisms by glucocorticoid receptor modulators in stress and immune systems. , 2008, European journal of pharmacology.

[7]  T. Brady,et al.  Measurement of arterial activity on routine FDG PET/CT images improves prediction of risk of future CV events. , 2013, JACC. Cardiovascular imaging.

[8]  Georgia E. Hodes,et al.  Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress , 2014, Proceedings of the National Academy of Sciences.

[9]  PET Mapping of Neurofunctional Changes in a Posttraumatic Stress Disorder Model , 2016, The Journal of Nuclear Medicine.

[10]  Yundai Chen,et al.  Chronic unpredictable stress accelerates atherosclerosis through promoting inflammation in apolipoprotein E knockout mice. , 2010, Thrombosis research.

[11]  S. Rauch,et al.  A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder. , 2005, Archives of general psychiatry.

[12]  Hackjin Kim,et al.  Functional neuroimaging studies of the amygdala in depression. , 2002, Seminars in clinical neuropsychiatry.

[13]  G. Bergström,et al.  Social disruption stress increases IL-6 levels and accelerates atherosclerosis in ApoE-/- mice. , 2012, Atherosclerosis.

[14]  Johan Kuiper,et al.  Acute and chronic psychological stress as risk factors for cardiovascular disease: Insights gained from epidemiological, clinical and experimental studies , 2015, Brain, Behavior, and Immunity.

[15]  C. Pariante,et al.  Effects of Cytokines on Glucocorticoid Receptor Expression And Function , 1999 .

[16]  Lisa M Shin,et al.  Neuroimaging Studies of Amygdala Function in Anxiety Disorders , 2003, Annals of the New York Academy of Sciences.

[17]  M. Kivimäki,et al.  Psychological distress and risk of peripheral vascular disease, abdominal aortic aneurysm, and heart failure: pooling of sixteen cohort studies. , 2014, Atherosclerosis.

[18]  C. Pariante,et al.  Insufficient glucocorticoid signaling and elevated inflammation in coronary heart disease patients with comorbid depression , 2015, Brain, Behavior, and Immunity.

[19]  T. Kamarck,et al.  A global measure of perceived stress. , 1983, Journal of health and social behavior.

[20]  Ralph Weissleder,et al.  Chronic variable stress activates hematopoietic stem cells , 2014, Nature Medicine.

[21]  Z. Fayad,et al.  Intensification of statin therapy results in a rapid reduction in atherosclerotic inflammation: results of a multicenter fluorodeoxyglucose-positron emission tomography/computed tomography feasibility study. , 2013, Journal of the American College of Cardiology.

[22]  M. Kivimäki,et al.  Increased risk of coronary heart disease among individuals reporting adverse impact of stress on their health: the Whitehall II prospective cohort study. , 2013, European heart journal.

[23]  J. Min,et al.  Splenic metabolic activity predicts risk of future cardiovascular events: demonstration of a cardiosplenic axis in humans. , 2015, JACC. Cardiovascular imaging.

[24]  Ahmad R. Hariri,et al.  Preclinical Atherosclerosis Covaries with Individual Differences in Reactivity and Functional Connectivity of the Amygdala , 2009, Biological Psychiatry.

[25]  Charles P. Lin,et al.  Myocardial infarction accelerates atherosclerosis , 2012, Nature.

[26]  S. Shelton,et al.  Central amygdala nucleus (Ce) gene expression linked to increased trait-like Ce metabolism and anxious temperament in young primates , 2012, Proceedings of the National Academy of Sciences.

[27]  V. Gerbaudo,et al.  Improved Discrimination of Benign and Malignant Lesions on FDG PET/CT, Using Comparative Activity Ratios to Brain, Basal Ganglia, or Cerebellum , 2008, Clinical nuclear medicine.

[28]  Hugo D. Critchley,et al.  Central autonomic network mediates cardiovascular responses to acute inflammation: Relevance to increased cardiovascular risk in depression? , 2013, Brain, Behavior, and Immunity.

[29]  Ahmed Tawakol,et al.  In vivo 18F-fluorodeoxyglucose positron emission tomography imaging provides a noninvasive measure of carotid plaque inflammation in patients. , 2006, Journal of the American College of Cardiology.

[30]  R. Cahill,et al.  Prediction of calculated future cardiovascular disease by monocyte count in an asymptomatic population , 2008, Vascular health and risk management.

[31]  M. Pencina,et al.  General Cardiovascular Risk Profile for Use in Primary Care: The Framingham Heart Study , 2008, Circulation.

[32]  D. Fliser,et al.  CD14 CD16 Monocytes Independently Predict Cardiovascular Events , 2012 .

[33]  Christian Grillon,et al.  Positron emission tomographic imaging of neural correlates of a fear acquisition and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder , 2004, Psychological Medicine.

[34]  M. Irwin,et al.  Greater amygdala activity and dorsomedial prefrontal–amygdala coupling are associated with enhanced inflammatory responses to stress , 2015, Brain, Behavior, and Immunity.

[35]  H. Scheerer,et al.  Neural correlates of mindful self-awareness in mindfulness meditators and meditation-naïve subjects revisited , 2016, Biological Psychology.

[36]  N. Volkow,et al.  Evidence of gender differences in the ability to inhibit brain activation elicited by food stimulation , 2009, Proceedings of the National Academy of Sciences.

[37]  Richard J. Davidson,et al.  Amygdalar and hippocampal substrates of anxious temperament differ in their heritability , 2010, Nature.

[38]  M. Hofman,et al.  Increased expression level of corticotropin-releasing hormone in the amygdala and in the hypothalamus in rats exposed to chronic unpredictable mild stress , 2010, Neuroscience Bulletin.

[39]  J. Slattery,et al.  Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). 1994. , 1994, Atherosclerosis. Supplements.

[40]  Darin D Dougherty,et al.  Regional cerebral blood flow in the amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD. , 2004, Archives of general psychiatry.

[41]  M. Nahrendorf,et al.  Leukocyte Behavior in Atherosclerosis, Myocardial Infarction, and Heart Failure , 2013, Science.

[42]  P. Libby.  Inflammation in Atherosclerosis , 2012, Arteriosclerosis, thrombosis, and vascular biology.