Heightened activity in the region of the brain that plays a key role in emotional reactions was found to be associated with an elevated risk for heart attack, stroke, and other major cardiovascular events in a new imaging study. The report, published in The Lancet, is the first to link regional brain activity with cardiovascular disease, and the first to suggest a possible mechanism to explain the relationship between chronic stress and myocardial infarction and stroke.
Ahmed Tawakol, MD, co-director of the Cardiac MR PET CT Program at Massachusetts General Hospital in Boston, and colleagues, followed a group of patients who did not have cardiovascular disease for an average of 3.7 years after baseline PET/CT diagnostic imaging. Higher resting metabolic activity within the amygdala — part of the brain’s salience network that drives stress — was found to be a significant predictor of cardiovascular disease, independent of other cardiovascular risk factors. Amygdalar activity was also shown to be associated with increased hematopoietic activity and increased arterial inflammation. Tawakol told MedPage Today that while previous observational research has repeatedly linked chronic stress to cardiovascular disease risk, the mechanism driving this link has not been known.
“There is no doubt that there is an association between stress and cardiovascular disease. In fact, the association is as strong as that for diabetes, hypertension, smoking, and other major risk factors. But the mechanism has not been clear.” The current research builds on animal studies reported within the last 5 or 6 years showing stress to be associated with increased activity in the bone marrow, he said. “The bone marrow starts pumping out inflammatory cells, and they traffic to the artery walls where they set up shop. This causes the kind of pathological changes that we associate with heart disease risk.”
Studies in mice suggest that sympathetic fibers from the amygdala signal the bone marrow to release these immune cells, but it has not been known if a similar pathway exists in humans, he said. While amygdalar reactivity is known to be increased in patients with atherosclerosis, “neither human nor animal studies have yet shown whether amygdalar activation precedes and predisposes to the subsequent development of cardiovascular events,” the researchers wrote. In an effort to show this, they recruited patients undergoing PET/CT scanning for screening or diagnostic purposes who were age 30 or older and did not have any known cardiovascular disease or cancer. All participants underwent ¹⁸F-fluorodeoxyglucose PET/CT over a 3-year period (2005-2008) and were followed for an average of 3.7 years.
Amygdalar activity, bone-marrow activity, and arterial inflammation were all assessed using validated methods. In a separate cross-sectional study, the researchers analyzed the relationship between perceived stress, amygdalar activity, arterial inflammation, and C-reactive protein (CRP). Image analyses and cardiovascular disease event adjudication were done by mutually blinded researchers. Relations between amygdalar activity and cardiovascular disease events were assessed using Cox models, log-rank tests, and mediation (path) analyses. The median age of the 293 participants included in the longitudinal analysis was 55 [IQR 45·0-65·5]); 22 of the participants had a cardiovascular disease event during follow-up.
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 (standardized hazard ratio 1·59, 95% CI 1·27–1·98; P<0·0001), and this finding remained significant after multivariate adjustments. The association between amygdalar activity and cardiovascular disease events appeared to be mediated by increased bone-marrow activity and arterial inflammation. In the separate cross-sectional study of patients who underwent psychometric analysis (n=13), amygdalar activity was found to be 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 CRP (r=0·83; P=0·0210).
“Our study shows, for the first time, a relation between neural tissue activity and subsequent cardiovascular event and suggests that the brain’s salience network, bone marrow, and arterial inflammation together form an axis that could accelerate the development of cardiovascular disease,” the researchers wrote. They said that study limitations included the reliance on patients undergoing imaging procedures for clinical indications (mostly cancer screening), which may have limited the generalizability of the findings. In addition, the vast majority (93%) of the participants in the outcome study, but not the cross-sectional substudy, were white.
The amygdala-bone marrow-arterial wall pathway may represent a significant target for cardiovascular disease prevention therapies, the team concluded. In the interview, Tawakol cited brain imaging studies showing a reduction in amygdala size and activity associated with stress-reduction strategies like meditation. “We don’t yet have large, randomized studies showing that reducing stress leads to lower cardiovascular disease risk, but studies like this one showing a potential mechanism and those showing a benefit to altering this mechanism make a strong case for screening patients for stress,” he said.