Amygdalar activity in response to stress predicts development of subsequent CV events
Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study
The mechanisms that translate chronic stress into increased risk of cardiovascular disease (CVD) are poorly understood. The brain’s salience network is thought to play a role. This is an ensemble of interconnected structures involved in complex functions such as cognition and emotion, with the amygdala as a central component. Activation of this network leads to hormonal, autonomic and behavioural changes typically associated with fear and stress . The amygdala projects to the brainstem and contributes to the sympathetic response to stress .
A proliferative effect of haemopoietic stem cells and progenitor cells in the bone marrow, an accelerated innate immune cell output and cytokine production and potentiation of atherosclerosis have been described in response to stress in mice [3-7]. To date, it is unknown whether similar processes occur in humans, and in particular whether amygdalar activity precedes and predisposes to development of CV events.
Activation of the neural circuitry underlying the perception of fear-related stimuli can be imaged with functional MRI (fMRI) and 18F-fluorodoxyglucose (18F-FDG) PET/CT. The latter technique can both quantify regional brain metabolism/activity, and haemopoietic tissue activity and large vessel arterial inflammation [6,8].
Thus, 18F-FDG PET/CT was used to test the hypothesis that amygdalar activity is associated with haemopoietic activity and arterial inflammation, and that it predicts the development of future CVD events. A longitudinal outcomes study was conducted, as well as a smaller, cross-sectional perceived stress study to assess the relation between psychometric measures of perceived stress, resting amygdalar metabolic activity and atherosclerotic inflammation. 293 Participants without a history of cancer and CV disease and inflammatory or autoimmune disease, of at least 30 years old undergoing 18F-FDG) PET/CT for clinical assessment (often for cancer screening) were included. Median follow-up of the longitudinal outcomes study was 3.7 years (IQR: 2.7-4.8), during which 22 individuals experienced 39 CVD events.
- Each increase of one SD in amygdalar activity signal was associated with a 1.6-times higher risk of a CVD event. Activity in cerebral or cerebellar or control extra-cranial tissue (subcutaneous fat) did not predict the risk of CVD.
- The predictive relation between amygdalar activity and CVD events remained statistically significant after multivariate adjustment for CV risk factors, Framingham risk scores, and pre-existing atherosclerotic disease burden, and after correction for coronary artery calcium (CAC) score or visceral adipose tissue volume.
- The association between amygdalar activity and CVD did not depend on pre-clinical evidence of atherosclerosis, presence or absence of a high burden of coronary atherosclerotic risk factors, and a history with or without cancer.
- Amygdalar activity seemed to be related to the timing of the CVD event, with events occurring sooner in those with higher resting activity.
- Amygdalar activity correlated with haemopoietic tissue activity and a measure of arterial inflammation.
- Bone-marrow activity, followed by arterial inflammation, was found to be a significant mediator of the relation between amygdalar activity and CVD events.
- In the cross-sectional study, amygdalar activity correlated with arterial inflammation (r=0.70, P=0.0083). Perceived stress correlated to amygdalar activity (r=0.56, P=0.0485), arterial inflammation (r=0.59, P=0.0345) and CRP (0.83, P=0.0210).
- Amygdalar activity was found to mediate most of the relation between perceived stress and arterial inflammation.
This is the first study in humans that demonstrates that resting metabolic activity within the amygdala, an important component in the brain’s network involved in stress, predicts the development of CVD, independent of traditional CV risk factors. Amygdalar activity, which was associated with perceived stress in the cross-sectional study, correlated with increased haemopoietic activity and increased arterial inflammation in the longitudinal study.
Thus, these findings suggest that the amygdala may be a key structure in the pathway that links stress to CV events, and upregulation of haemopoietic tissue activity and increased atherosclerotic inflammation also seem implicated in this neural-haemopoietic-arterial axis.
Bot and Kuiper  note in their editorial comment that, although the statistical mediation analyses that showed that bone-marrow activity, followed by vascular inflammation, significantly mediated the relation between amygdalar activity and the incidence of CV events, these analyses do not provide evidence of causality. The data are, however, in line with data from an animal study in which stress induced an inflammatory response via activation of the bone marrow.
Also the data of the perceived stress study are in line with data of other cohorts of patients with post-traumatic stress disorder (PTSD), depression and other disease associated with chronic stress, in which associations between stress and CRP concentrations were described. Indeed, these individuals with high perceived stress levels appear to be at higher risk of having a CVD event.
According to Bot and Kuiper, the study of Tawakol justifies further larger and longer studies into the CV risk in patients with PTSD. Analysis of interleukin-6, which is often increased in stress, in addition to CRP might shed more light on the underlying inflammatory mechanisms. Of note, the association between the incidence of amygdalar activity and CVD remained after correction for history of depression or anxiety, suggesting that the data are also applicable to individuals without a history of psychological disorders. “Together, these clinical data establish a connection between stress and cardiovascular disease, thus identifying chronic stress as a true risk factor for acute cardiovascular syndromes, which could, given the increasing number of individuals with chronic stress, be included in risk assessments of cardiovascular disease in daily clinical practice.”