Coronary artery disease – stress and immunity
In this review Roger Ho and colleagues discuss how stress hormones through affecting different components of the immune/inflammatory reaction may in turn contribute to the development of coronary artery disease (CAD).
Recent evidence indicates that acute and chronic psychological stress, such as intense anger, low socioeconomic status, work stress, social isolation, depression, anxiety and hostility are associated with the development of CAD. For example, high levels of hostility have been found to be associated with increased cortisol responses to anger-inducing interpersonal challenge.
Chronic stress can be an extremely detrimental phenomenon, and it is not surprising to find proinflammatoryphenomena occurring during chronic stress since the system maintains excitability, including that of immune origin.
Recent evidence indicates that acute and chronic psychological stress, such as intense anger, low socioeconomic status, work stress, social isolation, depression, anxiety and hostility are associated with the development of CAD.
Ho et al. outline the following mechanisms that may play a significant role in the pathogenesis of CAD:
- Effect of stress hormones on leukocytes circulation and trafficking, chemotaxis, endothelial dysfunction and expression of cell adhesion molecules
- Effect of stress on the production of proinflammatory cytokines
- The link between depression, infection and coronary artery disease
Stress Leading to Chemotaxis via Changes in Endothelium Function
Thus, for example, under high psychological stress, L-selectin from NK cells do not contribute to mobilisation and CD62+ NK cells will be retained in the vascular marginating pool or in the extravascular tissue. Moreover, there is an increased concentration of adhesion molecules such as ICAM-1 and CD 11a. The increased concentration of adhesion molecules causes the CD62- NK cells to stop rolling and adhere to the site of increased adhesion molecules. Endothelial dysfunction also results in recruitment and adhesiveness of T lymphocytes and platelets.
Further down this road, Activated T cells, in turn, produce proinflammatory cytokines, such as tumour necrosis factor-alpha (TNF-α), interleukin (IL)-l and IL-6, which stimulate macrophages and vascular endothelial cells and amplify the downstream inflammatory process.
Stress and Coronary Artery Disease – the link to Changes in Monocytes and Cytokines
For example, Douglas L Mann suggested suggested that the short-term expression of stress-activated cytokines within the heart may be an adaptive response to stress, whereas long-term expression of these molecules may be frankly maladaptive by producing cardiac decompensation. Cesari et al. found that proinflammatory cytokines predicted cardiovascular events in older persons. For example, IL-6 is significantly associated with coronary artery disease (CAD), stroke and congestive heart failure (CHF) and is a strong independent predictor for increased mortality in unstable CAD.
The Link between Stress, Coagulation and Atherosclerosis
As per the literature cited in this review, adverse social circumstances and psychosocial factors in childhood increase the concentrations of acute phase proteins such as plasma fibrinogen in adulthood and this increases the subsequent risk of CAD.
Furthermore, lonely individuals also displayed greater fibrinogen response to stress. Chronic psychosocial stressors increase both haemostatic factors (e.g. Factor VII) and acute phase proteins (e.g. fibrinogen). Fibrinogen is thought to promote atherosclerosis by promoting platelet aggregation, enhancing release of endothelial-derived growth factors, stimulating smooth muscle cell proliferation and increasing plasma and whole blood viscosity. Acute and chronic stress may activate the coagulation cascade and lead to thrombus formation and myocardial infarction (MI).
And, in addition, there is robust evidence from epidemiological studies and meta-analyses that higher levels of acute phase proteins such as CRP and fibrinogen predict future cardiovascular death and are associated with low socioeconomic status.
The authors explore some future directions, such as the possibility of modulating immunity through coping with stress and reducing the psychosocial risk for cardiac conditions, or through interventions such as cognitive therapy, relaxation training and behavioral modifications.
This may also include C-reactive protein monitoring that may identify the depressed or anxious patients who would most benefit from a strategy of early prevention of cardiovascular disease, or the need for prospective studies of depressed patients, measuring a wide array of inflammatory markers in order to identify those which are superior to the others in predicting CAD.
SOURCE: Ann Acad Med Singapore 2010, 39(3): 191
Updates
A 2018 review by Saideh Masafi et al. describes how stress, depression and type D personality contribute to coronary artery disease (CAD). According to the authors, stress contributes to myocardial ischemia; depression involves in the transfer of stable atherosclerotic plaque to unstable, whereas type D personality is effective in the initial stages of the CAD.
Few important statements from this review: Psychological stress activates the SNS, which regulates heart rate and release of catecholamines, and the hypothalamic-pituitary-adrenal axis (HPA) axis, which regulates the release of corticosteroids from the adrenal glands. In acute psychological stress, catecholamines predominantly affect leucocytes (release of granulocytes via α-adrenergic receptors; and increase of monocytes via β2-adrenergic receptors). In chronic stress, the activity of the HPA axis may decrease, leading to fatigue and increased activation of immune-mediated inflammation.
An acute psychological stressor increases pro-inflammatory cytokines including mononuclear cell interleukin 1 (IL-1)-β gene expression and plasma interleukin-6 (IL-6). Moreover, increased numbers of monocytes in the blood, i.e. monocytosis of depressed patients were first reported by Maes et al. and recently confirmed by Seidel et al.
An important issue, raised by the authors: Monocytes migrate from the blood into solid tissues where they are transformed into macrophages. Macrophages never return to the blood. This means they are rarely evaluated in humans because almost all immune system analyses are done on blood. Nevertheless, in animal experiments, whenever there is monocytosis, there is macrophage activation somewhere in the body. Thus, the monocytosis exhibited by depressed patients indicates that macrophages are activated somewhere in their bodies.
Figure 1. Acute, episodic and chronic psychological risk factors model by the immune system parameters involved in coronary artery disease (CAD).
Importantly, the authors of this review summarize the major psychological factors (acute, episodic and chronic) and the immune system parameters, derived from Kop’s theory, which are related to CAD progression and progression stages of heart diseases. This includes the pathologic changes/lesions in coronary arteries, respectively from left to right. As it can be seen at the right edge of the figure, the initial stages of coronary arteriosclerosis are specified by monocytes deposition in the arterial wall and through this process adhesion molecules play an important role. In the next stages of CAD, cytokines are involved in the activation of T cells and the formation of macrophage foam cells. In this stage, the performance of endothelium will diminish and thereby its dilation, and contractile properties will be lowered to respond to blood flow and other arteries vasodilatation stimuli.
A 2018 review by Massimo Fioranelli et al. outlines the current view of coronary heart disease – atherosclerosis is no longer considered a simple lipid storage disorder but a systemic inflammatory disease. The review describes the immune and endocrine properties of the heart and their critical roles in acute ischaemic damage and in post-infarct myocardial remodeling. The importance of the central and autonomic regulation of cardiac functions, namely, the neuro-cardiac axis, is extensively explained, highlighting the roles of acute and chronic stress, circadian rhythms, emotions and the social environment in triggering acute cardiac events and worsening heart function and metabolism in chronic cardiovascular diseases.
According to the authors, all stages of the atherosclerotic process might be viewed as an inflammatory response to vascular injury (Figure 2).
Figure 2. Pathological conditions that include common cardiovascular risk factors (such as hypertension, hyperlipidaemia, hyperglycaemia, smoking) and stress-related conditions (i.e. depression, anxiety) can elicit immune responses that promote the secretion of leukocyte adhesion molecules and chemotactic factors, inducing monocyte adhesion to endothelial cells and transmigration into the subintimal space. Initial atherosclerotic lesions begin with the differentiation of monocytes into macrophages that engulf cholesterol-rich oxidized lipoproteins to become foam cells that organize into fatty streaks. The perpetuation of pro-inflammatory and oxidizing atherosclerotic stimuli results in the recruitment of further macrophages, mast cells, and activated T and B cells that increase vascular lesions, which, in turn, releasing cytokines (i.e., IL-1β, TNF-α), increases monocytes migration into the subintimal space. ICAM-1, Intercellular Adhesion Molecule 1; VCAM-1, Vascular cell adhesion protein 1; NLRP3, nucleotide-binding domain and leucine-rich repeat containing (NLR) family member pyrin domain-containing protein 3; IL-1β, Interleukin 1 beta; IL-6, Interleukin 6.
Pathological conditions that include common cardiovascular risk factors, such as hypertension, hyperlipidaemia, hyperglycaemia and smoking, can elicit immune responses that promote the secretion of leukocyte adhesion molecules and chemotactic factors, inducing monocyte adhesion to endothelial cells and transmigration into the subintimal space.
The authors of this review summarize recent data indicating that inflammation is a physiological response to physical, mutagenic, infective or psychologic injury; an altered or prolonged inflammatory response may inflict serious damage upon the host. Cytokines are the fundamental mediators involved in the immune response; the cytokines IL-1, IL- 6, and TNF-α enhance inflammation, whereas IL-10 acts as an anti-inflammatory cytokine that downregulates inflammatory pathways.
Indeed, cardiac tissue contains resident immune cells and is able to synthesize and release cytokines and hormones after acute myocardial infarction in the ischaemic area, influencing the healing phase. In recent years, chronic depression has ranked among the most important cardiovascular risk factors for poor prognosis in patients with myocardial infarction.
Current understanding of the central and autonomic regulation of cardiac functions, namely, the neuro-cardiac axis, provides a physiological explanation that links psycho-emotional stressors and social adversities to acute cardiac event. Psychological distress can precipitate heart function through a dysregulated neuroendocrine and autonomic response. The complex network that links the heart, brain and the main biological systems provides a new vision of cardiovascular science based on psychoneuroendocrineimmunology, a science that studies the reciprocal interconnections between the psyche and nervous, immune and endocrine systems.
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