The Endothelium as a Target for Chronic Stress

Nontraditional factors might play an important role in the pathogenesis of ischemic heart disease. As it has been shown in the INTERHEART study, the risk for myocardial infarction was 2- to 3-fold in individuals with a high psychosocial index, considered as a combined index of depression, work- and financial-related stress.1 It is well known that acute activation of hypothalamic–pituitary–adrenal axis and sympathetic nervous system plays a key role in the physiological process for maintaining biological homoeostasis during environmental or physiological challenges, the so-called allostasis.2 In the short-term, these alterations aim at restoring homeostasis and increase the individual chances of surviving. However, the parallel increase in blood pressure, decrease in insulin sensitivity and endothelial dysfunction are potentially harmful for the cardiovascular system. Indeed, both mental (anger, anxiety, frustration) and physical (intense physical exercise) acute stress increases the risk of plaque rupture, fatal arrhythmias, and eventually cardiovascular events, particularly in individuals with preexisting coronary disease. These negative acute effects might be mediated by an acute decrease in endothelial function,3 a crucial early step for development of atherosclerosis.4 Evidence is accumulating in support of the hypothesis that chronic activation of the hypothalamic–pituitary–adrenal axis and the sympathetic nervous system has negative consequences on cardiovascular health and might lead to endothelial dysfunction, arterial hypertension, development of early atherosclerosis and then to adverse cardiovascular events, but data are contradictory.2,5 For instance, endogenous (Cushing’s syndrome) and exogenous (drug-induced) glucocorticoid excess is associated with hypertension, development of abdominal obesity and insulin resistance and dyslipidemia and with an increased risk of cardiovascular events. Furthermore, chronic sympathetic activation is involved in the physiopathology of a number of cardiovascular conditions, including hypertension, heart failure, obesity, and chronic kidney disease.6 Thus, it is not surprising that chronic psychological conditions such as major depression, anxiety, work-related stress, and insomnia have been related to a worse cardiovascular prognosis. In this issue of AJH, Kershaw et al.7 explored the cross-sectional association between an index of chronic stress burden and endothelial function (evaluated as flow-mediated dilation of the brachial artery9 and activation (intercellular adhesion molecule-1 and E-selectin) in a sample of adults from the baseline examination of Multi-Ethnic Study of Atherosclerosis (MESA). They found that higher scores of chronic stress, calculated as the cumulative impact of problem related to work, family, financial aspects, and health, might directly worsen endothelial function (flow-mediated dilation) and activation (intercellular adhesion molecule-1), independently of known confounding factors such as socioeconomic status, lifestyle, including physical activity and smoking, and depression.8 The authors use a rather simplified approach to assess stress burden, which however proved to be effective. It is interesting to note that in the same population a more complex approach to the evaluation of work-related stress, that is job strain, was not associated to flow-mediated dilation.9 It is conceivable that a simpler but more comprehensive score, including different sources of chronic stress, might better depict overall cardiovascular burden of stress. Unfortunately, in this analysis7 the authors did not evaluate coping, an emerging modulator of the relationship between stress and cardiovascular disease. Coping refers to a process following stress occurrence and appraisal, representing how the individual responds to the stressor, employing particular strategies in attempt to self-regulate and reduce stress. Some coping strategies may be beneficial (or “adaptive”), while others may inadvertently result in subsequent adverse outcomes, therefore being defined “maladaptive”.10 An approach-oriented coping strategy (planning, consulting someone, or positive reappraisal), actively dealing with sources of stress, was inversely associated with the incidence of stroke and mortality for cardiovascular diseases in a large cohort of Japanese individuals without a history of cardiovascular disease.11 To date, whether adaptive coping strategies might mitigate the negative effects of stress on endothelial function or activations has not been yet studied. A limitation of the study of Kershaw et al.7 is also the lack of evaluation of possible pathophysiological mechanisms relating chronic stress and impaired endothelial function. As already commented, chronic stress induces sympathetic nervous system and hypothalamus–pituitary–adrenal axis activation and proinflammatory responses. Since heart rate variability,12 salivary cortisol,13 and inflammatory markers14 have been assessed in the MESA study, a more in-depth analysis of the available data might have provided crucial information for the interpretation of the results obtained. Finally, some methodological aspects of the study7 should be commented. Although it has been acknowledged as a limitation by the authors themselves, the reproducibility of flow-mediated dilation in the MESA study was worse as compared to reference standards,15,16 thus possibly affecting the strength of the associations found in the study.7 Furthermore, important data on the effect of chronic stress burden on brachial artery diameter, shear rate, and endothelium-independent vasodilation are not reported and/or tested, as recommended by current methodological guidelines.17 Therefore, it cannot be excluded that the observed association is related to differences in structural characteristics such as vascular remodeling, altered hyperemic stimulus for the endothelial response or impaired smooth muscle cell function.18 Future longitudinal studies are needed to verify the cause–effect relationship between chronic stress burden and endothelial dysfunction, including specific analysis on different sources of stress, pathophysiological mechanisms and possible modulators of the impact of stress on cardiovascular outcomes.