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Stressed brain, stressed heart?..... Relation between resting amygdalar activity and
cardiovascular events: a longitudinal and cohort study
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Download the PDF here
Download the PDF here
Comment
Jan 2017
"Emotional stress is associated with increased risk of cardiovascular disease.... Perceived stress was associated with amygdalar activity (r=0⋅56; p=0⋅0485), arterial inflammation (r=0⋅59; p=0⋅0345), and C-reactive protein (r=0⋅83; p=0⋅0210)..... Individuals with increased stress perception have a substantially higher prevalence of myocardial infarction."
"Our study shows, for the first time, a relation between neural tissue activity and subsequent cardiovascular events 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. Furthermore, our findings raise the possibility that efforts to attenuate psychosocial stress could produce benefits that extend beyond an improved sense of psychological wellbeing, and could beneficially impact the atherosclerotic milieu. Future studies of this neural-haemopoietic-arterial axis might lead to insights into how to further reduce the burden of cardiovascular disease.
Perceived stress was associated with amygdalar activity (r=0⋅56; p=0⋅0485), arterial inflammation (r=0⋅59; p=0⋅0345), and C-reactive protein......Individuals with increased stress perception have a substantially higher prevalence of myocardial infarction than controls....Our results clearly identify the amygdala as a key neural structure associated with future cardiovascular disease events...Previous human imaging studies demonstrated that amygdalar activity is correlated with the inflammatory response to stress........Stress prompts activation of both the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis, leading to increases in circulating catecholamines, glucocorticoids, and (eventually) inflammatory cytokines....Furthermore, by demonstrating a significant pathway of increased amygdalar activity leading to increased bone-marrow activity leading to increased arterial inflammation leading to cardiovascular disease event (figure 6), our findings are a key addition to the literature. Increased amygdalar activity and its downstream consequences of upregulated haemopoietic and inflammatory activity could also be implicated in other medical conditions in which inflammation has an important role......Additionally, stress can increase heart rate and blood pressure via the autonomic nervous system, all of which can contribute to endothelial dysfunction.....However, these mechanisms do not entirely explain the link between stress and cardiovascular disease. Work in animals has yielded important new insights into another (and potentially more important) mechanism by which stress might induce cardiovascular disease. Murine studies show that stress leads to mobilisation and release of neutrophils and monocytes, and increases activity of haemopoietic progenitor cells in the bone marrow.13 Haemopoietic progenitors might accumulate in the circulation and the spleen and are thus poised to potentiate leucocyte supply by establishing extramedullary haemopoiesis.34, 35, 36 In mice, bone-marrow-derived monocytes released in response to variable stress or to stressful events (such as myocardial infarction) migrate to the arterial wall, where they instigate atherosclerotic inflammation.11, 13, 37 Results from animal studies38 point to increased haemopoiesis and arterial inflammation as important mechanisms in stress. They also prompt two crucial questions that were addressed by our study: is this mechanism relevant to human beings, and how does the brain participate?."
Lancet Jan 2017and at ESC Bacelona now - *Ilze Bot, Johan Kuiper
Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden,
Netherlands
Emotional stress is associated with increased risk of cardiovascular disease. We imaged the amygdala, a brain region involved in stress, to determine whether its resting metabolic activity predicts risk of subsequent cardiovascular events.....293 patients (median age 55 years [IQR 45⋅0-65⋅5]) were included in the longitudinal study, 22 of whom had a cardiovascular disease event during median follow-up of 3⋅7 years (IQR 2⋅7-4⋅8). 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 (standardised hazard ratio 1⋅59, 95% CI 1⋅27-1⋅98; p<0⋅0001), a finding that remained significant after multivariate adjustments. The association between amygdalar activity and cardiovascular disease events seemed to be mediated by increased bone-marrow activity and arterial inflammation in series. In the separate cross-sectional study of patients who underwent psychometric analysis (n=13), amygdalar activity was 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 C-reactive protein (r=0⋅83; p=0⋅0210).
After median follow-up of 3⋅7 years, amygdalar activity was significantly associated with the incidence of cardiovascular events, including myocardial infarction, heart failure, and cerebrovascular events, even after multivariate adjustments.
perceived stress was associated with amygdalar activity, vascular inflammation, and circulating c-reactive protein (CRP) concentrations. .....interleukin 6 is repeatedly increased in stress in both human beings and rodents.....patients with a history of post-traumatic stress disorder (PTSD). In these patients, perceived stress was associated with amygdalar activity, vascular inflammation, and circulating c-reactive protein (CRP) concentrations......The association between stress and CRP concentrations is in line with data obtained from other cohorts containing patients with PTSD, depression, and other diseases that are associated with chronic stress, in whom increased circulating CRP, interleukin 6, and tumour necrosis factor α concentrations were noted......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.....
In the past decade, more and more individuals experience psychosocial stress on a daily basis. Heavy workloads, job insecurity, or living in poverty are circumstances that can result in chronically increased stress, which in turn can lead to chronic psychological disorders such as depression. Besides the heavy psychological burden, chronic stress is also associated with an increased risk of cardiovascular disease.1, 2Individuals with increased stress perception have a substantially higher prevalence of myocardial infarction than controls, as was reported by Rosengren and colleagues in 2004.2 However, these association studies have thus far not established whether increased stress is causally related to the incidence of cardiovascular disease, and neither have they provided mechanistic insight into the pathways involved. This lack of mechanistic insight might be at least partly due to difficulties measuring personal stress levels—which can vary between individuals as stress perception differs from person to person—at the time of the stressor. Experimental work in animal models has established that both acute and chronic stress contribute to the underlying cause of cardiovascular disease3—ie, development of atherosclerosis, which is generally mediated by an increased inflammatory response to a stressor. However, direct clinical evidence in human beings was lacking.
In The Lancet, Ahmed Tawakol and colleagues4 report that the activity of the amygdala, a key component of the brain involved in emotion and stress, is of predictive value for the incidence of acute cardiovascular events. Their main study included 293 individuals without previous history of cardiovascular disease who underwent 18F fluorodeoxyglucose (18F-FDG) PET or CT to visualise amygdalar activity as a measure for underlying stress. After median follow-up of 3⋅7 years, amygdalar activity was significantly associated with the incidence of cardiovascular events, including myocardial infarction, heart failure, and cerebrovascular events, even after multivariate adjustments. 18FDG PET or CT also allows visualisation of haemopoietic tissue activity and the activity of inflammatory cells within the vessel wall. Statistical mediation analysis showed that bone-marrow activity, followed by vascular inflammation, was a significant mediator in the association between amygdalar activity and the incidence of cardiovascular events. Although these mediation analyses do not provide evidence of causality, the data are in line with data from an animal study,5 in which stress induced an inflammatory response via activation of the bone marrow. Additionally, interleukin 6 derived from bone-marrow-derived leucocytes has been implicated as one of the causal mediators of the stress response in mice.6 How the reported increase in the inflammatory response directly relates to the rise in acute cardiovascular syndromes caused by atherosclerotic plaque rupture or erosion7 remains to be investigated.
Of clinical relevance is the perceived stress study that Takawol and colleagues also did,4 which included patients with a history of post-traumatic stress disorder (PTSD). In these patients, perceived stress was associated with amygdalar activity, vascular inflammation, and circulating c-reactive protein (CRP) concentrations. The association between stress and CRP concentrations is in line with data obtained from other cohorts containing patients with PTSD, depression, and other diseases that are associated with chronic stress, in whom increased circulating CRP, interleukin 6, and tumour necrosis factor α concentrations were noted.8, 9, 10 The findings of these studies8, 9, 10 suggest that individuals with high perceived stress levels—whether patients with PTSD, depression, or anxiety, or other individuals experiencing chronic stress—are at higher risk of having a cardiovascular disease event.
Although only 13 patients with PTSD were included in the perceived stress study (and no healthy controls with basal amygdalar activity), this study provides important evidence justifying the initiation of new studies of larger populations and with longer follow-up to assess cardiovascular disease risk directly in patients with PTSD. Because interleukin 6 is repeatedly increased in stress in both human beings and rodents, analysis of circulating interleukin 6 concentrations, next to CRP, might provide more insight into the underlying inflammatory mechanisms. In Takawol and colleagues' outcomes study,4 the association between amygdalar activity and the incidence of cardiovascular disease still remains after correction for history of depression or anxiety, which suggests that 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 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.
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