Elevated Risks of Cardiovascular Diseases Associated with Chronic Psychological Stress
Chronic psychological stress can be referred to the non-specific systemic reaction induced by the prolonged stimulation of internal or external negative factors. Constant exposure to intense stressful events is accompanied by biochemical and physiological changes in body. Increased levels of inflammatory biomarkers including the pro-inflammatory cytokine interleukin-6 (IL-6) and c-reactive protein (CRP) triggered by chronic stress may contribute to the inflammation in cardiovascular system, particularly in coronary artery1,2. Pathophysiological effects induced by sympathetic nervous system activation under psychological stress also elevate the risks of getting cardiovascular diseases3. In addition, higher amygdala activities of the individuals with long lasting emotional stress may positively correlate with cardiovascular events4, suggesting mental stress might be strongly associated with elevated risks of cardiovascular diseases.
Stress-induced Inflammatory Responses in Coronary Artery
Chronic psychological stress triggers several inflammatory responses which elevates the risk of getting coronary artery disease. The pro-inflammatory cytokine interleukin-6 (IL-6) is responsive to prolonged exposure of emotional stress and potentially plays a prominent role in the inflammation cascade. It is secreted by arterial macrophages or smooth muscle cells, and appears to be involved in the developments of atherosclerotic lesions1.
IL-6 level is related to the recovery time of reversible left ventricular wall motion abnormalities (WMAs). Compared with the baseline levels, a greater release of IL-6 has been observed at peak stress and recovery in patients with a greater extent of ischaemia5. Due to the negative inotropic action of IL-6 exerted on myocardium, elevated levels of IL-6 at peak stress and recovery period have also been found associated with increased duration of WMAs (Figure 1)5.
Figure 1. Levels of IL-6 at peak stress and recovery in patients with WMAs recovery for more than 5 minutes compared with those WMAs lasting shorter than 5 minutes. Box plots indicate median values5
By initiating the acute phase response, IL-6 is a primary determinant of the production of c-reactive protein (CRP), which promotes vascular inflammation by activating complement system and directly interacting with atherosclerotic vessels2. Apart from CRP, synthesis of fibrinogen is regulated by the level of IL-6 as well. Fibrinogen is an acute phase protein and coagulation component. Being a key determinant of plasma viscosity, fibrinogen plays an important role in coagulation cascade and platelet aggregation that drives the atherosclerosis progression3. Besides, syntheses of cell adhesion molecules including intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) are upregulated by IL-66. It has been suggested that IL-6, CRP and fibrinogen significantly associate with coronary artery disease by triggering inflammatory responses under chronic stressful conditions7.
Stress-induced Activation of Sympathetic Nervous System
As a result of chronic psychological stress, sympathetic nervous system continues to be activated. Catecholamines like adrenaline and the stress hormone cortisol are released in response to mental stress and that brings a number of physiological changes in body. Owing to the vasoconstriction induced by continuous sympathetic nervous system activation, blood pressure of people with prolonged psychological stress is higher compared with psychologically healthy individuals8.
Chronic psychological stress is also possible to impair autonomic modulation by decreasing heart rate variability, resulting in an abnormal autonomic control of heart rate3. A major cardioprotective autonomic reflex mechanism, cardiac baroreflex sensitivity (α-index), is also lowered under chronic stress condition, thus favouring stress-induced hypertension (Table 1)8. Furthermore, reduced sympathetic baroreflex sensitivity strongly correlates with arterial stiffness in vascular ageing9, whereas arterial stiffness is positively associated with various cardiovascular events including coronary artery disease, hypertension and stroke. Therefore, stress-induced physiological changes strongly correlate with the elevated risks of cardiovascular diseases (Figure 2)3.
Table 1. Levels of haemodynamic parameters and baroreflex sensitivity of controls and patients under resting conditions (mean ± SEM)8.
*p≤0.005 versus control. †p<0.05 versus control.
Figure 2. Schematic diagram of cardiovascular events triggered by physiological responses and pathophysiological effects of stress3
Stress-induced Atherogenic Dyslipidaemia
Similar to hypertension, atherogenic dyslipidaemia can be induced by chronic psychological stress condition. Atherogenic dyslipidaemia is characterised by elevated levels of triglyceride and small low density lipoprotein, whereas the concentration of high density lipoprotein (HDL)-cholesterol is low. A high level of cortisol secretion in prolonged emotional stress has been linked with the low level of HDL-cholesterol in body, and the level of HDL-cholesterol is inversely associated with the risk of atherosclerosis1,10.
Amygdala Activation as a Predictor of Cardiovascular Disease Risks
Apart from memory formation and processing, amygdala is also responsible for the control of behaviour and emotions. Former studies suggested that prolonged hyperactivity of amygdala is prevalent among the people with long term emotional stress11, whereas stress intensity is reported to positively correlate with the degree of amygdala activity4.
In a longitudinal study involved 293 individuals without cardiovascular disease or active cancer, higher amygdala activity as reflected by higher 18F-fluorodexoyglucose (FDG) uptake was observed in patients who developed cardiovascular event in the follow-up period (Figure 3)4. The results thus suggested that higher amygdala activity under emotional stress is associated with a higher risk of subsequent cardiovascular events and amygdala activity independently predicts the future cardiovascular events4.
Figure 3. Axial views of amygdala after PET/CT in a patient who experienced an ischaemic stroke during the follow-up period of the study (right) compared with the patient who did not (left). TBR: target-to-background ratio
Stress as a Risk Factor for Cardiovascular Diseases
In summary, individuals suffer from long term emotional stress are more prone to cardiovascular diseases due to inflammatory responses, continuous sympathetic nervous system activation, abnormal lipoprotein concentrations and increased amygdala activity. Several biomarkers including IL-6 and CRP possibly serve as the prognostic factors and help identifying patients with high risks of cardiovascular events. Attenuating psychological stress would likely improve physiological health, including cardiovascular health, and overall quality-of-life. Certainly, further researches on stress management and in turns lowering the risks of cardiovascular diseases are highly desirable4.
References
1. Linton MRF, et al. Endotext. South Dartmouth (MA): MDText.com, Inc.; January 3, 2019. 2. Lindahl B, et al. N Engl J Med. 2000;343(16):1139-1147. 3. Kivimäki M and Steptoe A. Nat Rev Cardiol. 2018;15(4):215-229. 4. Tawakol A, et al. Lancet. 2017;389(10071):834-845. 5. Ikonomidis I, et al. Circulation. 2005;112(21):3272-3279. 6. Scheller J, et al. Biochim Biophys Acta. 2011;1813(5):878-888. 7. Luc G, et al. Arterioscler Thromb Vasc Biol. 2003;23(7):1255-1261. 8. Lucini D, et al. Hypertension. 2005;46(5):1201-1206. 9. Nowak KL, et al. Hypertension. 2018;71(3):389-402. 10. Chandola T, et al. BMJ. 2006;332(7540):521-525. 11. Zhang X, et al. Front Neurosci. 2018;12:367.
