Impact of Stress Reduction on Inflammation and Atherosclerosis

Awardee Recipient

  • Ahmed Tawakol, MD

    Ahmed Tawakol, MD

    Co-Director of Cardiovascular MR-PET-CT Program and Director of Nuclear Cardiology, and Associate Professor of Medicine

    Massachusetts General Hospital and Harvard Medical School

    Ahmed Tawakol is Director of Nuclear Cardiology and Co-Director of the Cardiac MR PET CT Program at the Massachusetts General Hospital (MGH). He is Associate Professor of Medicine at Harvard Medical School.  He obtained his medical degree from...


  • 2018 - Pilot Grant

Background and Significance

Cardiovascular Disease (CVD) remains a significant cause of morbidity and mortality in the United States and worldwide.(1,2) Psychosocial stress has long been linked with increased risk for atherosclerosis and CVD events.(3-5) Moreover, after correcting for risk factors, stress has an attributable risk that is on par with that of other major cardiovascular risk factors, including smoking and diabetes (3,4). However, until relatively recently, the mechanistic link between chronic stress and CVD was not well-characterized in humans.

Inflammation is an important feature of both stress and atherosclerosis. Atherosclerosis is driven by active inflammation that results in monocyte migration to the vessel wall.(6,7) Animal studies suggest that stress, through stimulation of sympathetic nerves that terminate in the bone marrow, prompts increased production and release of inflammatory cells that subsequently increase arterial inflammation, a key pathobiological stimulus for progression of CVD. (8-10) Likewise, human studies repeatedly linked stress to increased levels of inflammatory markers (11-14). However, an observation of a neural-hematopoietic-arterial link was only recently observed in humans.

Our group recently employed advanced imaging techniques to gain insights into the link between stress and CVD in humans. The amygdala links higher-level processing of anxiety and stress with physiologic responses in the body. High resting amygdalar metabolic activity, which associates with self- reported stress and anxiety (15), can be assessed by amygdalar uptake of radiolabeled glucose [18fluorodeoxy-glucose (FDG)] detected using positron emission tomography (PET). In a landmark study of 293 individuals, published recently in the Lancet (15), we demonstrated that resting amygdalar activity (by FDG-PET/CT) robustly predicts future CVD risk; each standard deviation increase in the amygdalar signal independently associated with a 60% increase in future CVD risk. Further, we observed that the link between amygdalar activity and CVD was mediated by upregulated bone marrow activity and increased arterial inflammation in series (figure 1). Accordingly, the recent work suggests that stress may link to CVD through upregulation of an amygdalar-hematopoietic-arterial axis.

Stress reduction (SR), reduces perceived stress,1(6,17) systemic inflammatory biomarkers (e.g., CRP, IL-6, etc.),(18-21) gene expression related to the inflammatory response,(18,22) and parameters of metabolic health.(23) Furthermore, meditation and stress reduction may reduce carotid intimal medial thickness and clinical events in individuals with CVD when implemented with usual care.(24,25) Moreover, SR has been shown to alter brain structure and function, including reductions in amygdalar grey matter density and amygdalar activation in response to emotional stimuli in a non-meditative

state. (26,27) However, a key knowledge gap remains: whether reduction of chronic stress will attenuate amygdalar-hematopoietic-arterial activity. Indeed, the question of a possible beneficial effect of stress reduction on CVD (and the mechanism mediating that benefit) were recently highlighted as key questions in a recent American Heart Association (AHA) consensus statement.(28) Accordingly, herein, we propose to take the natural next step to study these gaps. Our central hypothesis is that stress reduction reduces stress- associated neural activity and systemic inflammation, resulting in reduced arterial inflammation. We propose a pilot study to test the hypotheses that SR results in a reduction in arterial inflammation (compared to usual care) and that the reduced arterial inflammation is the result of a reduction in amygdalar-hematopoietic activity, in series. To test these hypotheses, we will leverage an NIH program project grant investigating associations between stress-related neural activity, immune system activation, and arterial inflammation, in 240 individuals who will be undergoing PET/magnetic resonance (PET/MR) imaging. Subjects will undergo full psychometric analysis, along with cutting- edge body and brain PET/MRI, brain functional MRI, and inflammatory biomarkers. The current proposal represents a longitudinal extension of that project, wherein individuals with moderate baseline stress and evidence of increased arterial inflammation (N=21) will be randomized to an 8-week stress reduction program (vs. usual care).


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