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Activity in amygdala predicts CV events
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Researchers have linked activity in the amygdala to risk for subsequent CVD, according to findings published in The Lancet.
“While the link between stress and heart disease has long been established, the mechanism mediating that risk has not been clearly understood,” Ahmed Tawakol, MD, co-director of the Cardiac MR PET CT Program in the division of cardiology at Massachusetts General Hospital, said in a press release. “Animal studies have shown that stress activates bone marrow to produce white blood cells, leading to arterial inflammation, and this study suggests an analogous path exists in humans. Moreover, this study identifies, for the first time in animal models or humans, the region of the brain that links stress to the risk [for MI] and stroke.”
The researchers conducted a longitudinal study of 293 patients (median age, 55 years) to assess amygdalar activity, bone-marrow activity and arterial inflammation, and a cross-sectional study of 13 patients with PTSD undergoing psychometric analysis to assess the relationships between perceived stress, amygdalar activity, arterial inflammation and C-reactive protein.
Complex relationship
In the longitudinal study, 22 patients had a CV event during median follow-up of 3.7 years (interquartile range, 2.7-4.8).
When the researchers compared those who had a CV event with those who did not, they found amygdalar activity was associated with increased bone-marrow activity (r = 0.47; P < .0001), arterial inflammation (r = 0.49; P < .0001) and risk for CVD (standardized HR = 1.59; 95% CI, 1.27-1.98). Multivariable adjustment did not change the results.
Bone-marrow activity mediated the relationship between amygdalar activity and arterial inflammation, accounting for 46% of the total effect, whereas arterial inflammation mediated the relationship between amygdalar activity and CVD events, accounting for 39% of the total effect, the researchers wrote.
In the cross-sectional study, amygdalar activity was associated with arterial inflammation (r = 0.7; P = .0083), whereas perceived stress was associated with amygdalar activity (r = 0.56; P = .0485), arterial inflammation (r = 0.59; P = .0345) and CRP (r = 0.83; P = .021), according to the researchers.
“These findings suggest several potential opportunities to reduce [CV] risk attributable to stress,” Tawakol said in the release. “It would be reasonable to advise individuals with increased risk [for CVD] to consider employing stress-reduction approaches if they feel subjected to a high degree of psychosocial stress. However, larger trials are still needed to confirm that stress reduction improves [CVD] risk. Further, pharmacological manipulation of the amygdalar-bone marrow-arterial axis may provide new opportunities to reduce [CVD].”
Connection established
In a related editorial, Ilze Bot, PhD, and Johan Kuiper, PhD, from the division of biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, the Netherlands, wrote that since the associations remained after adjustment for history of depression or anxiety, “these data are not only applicable to patients with severe psychological disorders, but also to individuals without previous history of these conditions.”
“Together, these clinical data establish a connection between stress and [CVD], thus identifying chronic stress as a true risk factor for acute [CV] syndromes, which could, given the increasing number of individuals with chronic stress, be included in risk assessments of [CVD] in daily clinical practice,” they concluded. – by Erik Swain
Disclosure: Tawakol reports receiving grants from Genentech and Takeda, and personal fees from Actelion, Amgen, AstraZeneca and Takeda. Bot and Kuiper report no relevant financial disclosures.
Perspective
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Michael J. Blaha, MD, MPH
We have known from the epidemiology literature that stress is bad for the heart, but we have not fully understood the mechanistic connection between stress and response in terms of CVD. This is a very novel study. It measured stress in a novel way using PET imaging of the amygdala. It measured inflammation in a novel way, using PET to assess the bone marrow and the arterial wall. The statistical method, a sophisticated mediation analysis, which determines the degree that stress is mediated by other factors along the causal pathway, is also novel and helps to build a theoretical model. The findings indicate that stress is not just associated with heart disease via known mechanisms such as BP, but that there is biology that directly relates to inflammation potentially leading to atherosclerotic events.
At this time, the implications of the study mostly concern the basic science and translational area. We’re still understanding the mechanism. Of course, regardless of the mechanism by which stress causes CVD, we need to reduce stress. In the future, there is potential for novel therapies that reduce some of the mediators of stress and reduce inflammation caused by stress. But right now, the main implication is that stress has bad CV consequences independent of other routinely measured risk factors such as BP.
Such novel findings need to be replicated in a different population. This population was a convenience sample of people who underwent PET studies for other reasons. It would help to analyze high-risk primary prevention patients, and to compare people on and off traditional therapies such as statins. It will help to look at larger, more diverse populations with longer follow-up. And testing of evidence-based stress-reduction strategies that exist in the psychiatric literature will be useful, with imaging studies at the end of follow-up to determine if we have impacted these pathways.
It is healthy that cardiologists are looking beyond traditional risk factors to better understand CVD. A similar imaging-based approach to understanding the effect on CVD at a deeper level is needed in areas such as sleep and physical activity. These should be among the most significant advances of the next decade, and imaging strategies like the one seen here may drive them.
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