Study Links Stress-Related Amygdala Activity to Future CVD Events

Marlene Busko

January 13, 2017

BOSTON, MA — Previous studies have shown that stress ups metabolic activity in a certain brain area and is a risk factor for CVD, but now a new longitudinal study connects the dots and shows for the first time in humans that "amygdalar activity independently and robustly predicted CVD events," researchers report[1].

The research was composed of two parts. In a study of 293 patients who were injected with 18F fluorodeoxyglucose (18F-FDG) and had full-body PET/CT scans, researchers at Massachusetts General Hospital in Boston, MA, identified that increased resting metabolic activity in the amygdala, bone marrow, and arterial wall correlated with increased risk of stroke, MI, or angina during follow-up.

In a second study of 13 patients with posttraumatic stress disorder (PTSD) who had 18F-FDG PET scans and also replied to a 10-item Perceived Stress Scale (PSS-10) questionnaire, researchers at Icahn School of Medicine in New York identified that high levels of perceived stress correlated with increased amygdalar activity, arterial inflammation, and C-reactive protein.

Thus, the researchers, led by Dr Ahmed Tawakol (Massachusetts General Hospital and Harvard Medical School, Boston), in a study published online January 11, 2017 in the Lancet, propose a model to explain the mechanism that links stress to eventual CVD events.

"The amygdala could be a key structure in the mechanism linking stress to cardiovascular disease events, and upregulation of hemopoietic tissue activity and increased atherosclerotic inflammation are additionally implicated in a neural-hemopoietic-arterial axis," they write.

The implications are that "eventually, chronic stress could be treated as an important risk factor for cardiovascular disease, one that is routinely screened for and effectively managed, similar to other major cardiovascular disease risk factors," they conclude.

However, the study shows only associations, Tawakol cautioned to heartwire from Medscape. "To better understand causation we'll need to conduct prospective studies in large numbers of patients to see whether modulating the system results in a reduction in CVD events."

In the meantime, "stress . . . is as strong a risk factor as any other, so we should routinely be screening for [it]," which can easily be done using the PSS-10 questionnaire, for example. It is also reasonable, "when [stress is] found, to consider advising patient to pay attention to stress and consider also whether or not they should follow some stress-reduction approach."

A recent study in 151 patients showed that adding stress management to cardiac rehab lowered the risk of 5-year CV-related events by 50%[2], he noted.

"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," Drs Ilze and Johan Kuiper (Leiden University, the Netherlands) agree in an accompanying editorial[3].

Clues From the Brain, Spleen, and Artery Walls

The researchers used ¹⁸F-FDG PET/CT imaging to test the hypothesis that stress-related amygdalar activity is associated with hemopoietic activity and arterial inflammation and predicts the development of future cardiovascular disease events.

The larger study included 293 patients aged 30 and older (median age 55) who had full body ¹⁸F-FDG PET/CT scans during 2005–2008 for cancer but were free of cancer and CVD. ¹⁸F-FDG uptake was measured in the amygdala, bone marrow, spleen, and aortic and carotid walls.

During a mean follow-up of 3.7 years, 22 patients experienced 39 CVD events. The 22 index events were eight MIs, three unstable angina cases, two peripheral arterial diseases, six strokes, one heart failure, and two new-onset angina cases.

Amygdalar activity was associated with increased bone-marrow activity (r=0.47; P<0.0001) and arterial inflammation (r=0.49; P<0.0001).

The patients had a 1.6-fold increased risk of a CVD event for each one standard deviation in amygdalar signal (hazard ratio 1.59, 95% CI 1.27–1.98; P<0.001) after multivariable adjustment.

Serial two-mediator analysis supported the hypothesized indirect path of increased amygdalar activity leading to increased bone-marrow activity, leading to increased arterial inflammation, leading to cardiovascular disease events.

In the 13 patients with PTSD who had ¹⁸F-FDG-PET scans and replied to stress questionnaires, perceived stress was associated with amygdalar activity (r=0.56; P=0.05), arterial inflammation (r=0.59; P=0.03), and C-reactive protein (r=0.83; P=0.02).

"The study provides additional insights into the mechanism linking stress physiologically to the downstream activities leading to CVD, and by enhancing our understanding of this mechanism it expands our opportunities to further study and potentially interrupt the mechanism leading to heart attacks and strokes," Tawakol summarized.

"Our findings raise the hypothesis that the benefits noted in [a recent] stress-reduction study[2] could partly have been due to a therapeutic action on the neural-hemopoietic-arterial axis," the researchers suggest.

Although further research is needed, added together, these studies provide "compelling evidence to suggest that stress reduction might eventually be a fruitful intervention," Tawakol said.

In the meantime, "when encountering a patient with a stress syndrome, clinicians could reasonably consider the possibility that alleviation of stress might result in benefits to the cardiovascular system," the researchers write.

The study was supported by grants from the US National institutes of Health. Tawakol reports receiving grants from Genentech and Takeda and personal fees from Takeda, Actelion, AstraZeneca, and Amgen during this study for research outside the submitted work. Disclosures for the coauthors are listed in the paper. The editorialists declared they have no relevant financial relationships.

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