European Heart Journal (2002) 23, 1727–1728 doi:10.1053/euhj.2002.3283, available online at http://www.idealibrary.com on Editorials How socioeconomic status may ‘‘get under the skin’’ and affect the heart See doi:10.1053/euhj.2001.3233 for the article to which this Editorial refers. How do experiences of inequality and of lower socioeconomic position ‘get under the skin’ and aﬀect health? Cardiovascular disease varies according to socioeconomic status (SES). This association, which exists across the full range of SES, is not eliminated when negative health behaviour practices, such as smoking, are taken into account, leading to the hypothesis that pathophysiological mechanisms are accelerated by the experiences and lifestyles associated with lower SES[1,2]. The cardiovascular system is particularly sensitive to stress and to lifestyle factors, and elevated, prolonged and disregulated cardiovascular activity and atherosclerosis are well-known pathophysiological consequences that reflect a gradual progression towards disease. The concept of allostasis provides a framework for looking at the protective and damaging aspects of the physiological response to stress and lifestyle[3,4]. Allostasis, meaning ‘achieving stability (homeostasis) through change’, relates the reactive responses to challenge of the autonomic and endocrine system, as well as neurotransmitters and immune system mediators, to both short-term adaptation, as well as to cumulative wear and tear, termed allostatic load. Allostatic load is accelerated when the systems that normally mediate adaptation are either not turned oﬀ eﬃciently after the challenge or are not turned on in adequate amounts when needed. The article by Steptoe and colleagues in the current issue provides important new information that supports a dynamic and cumulative mechanism whereby delayed recovery of cardiovascular function after mental stress in lower SES individuals is postulated to be a contributor to accelerated cardiovascular disease. They studied participants in the Whitehall II study, a prospective study of British civil servants in which a gradient of cardiovascular disease across employment grades has been well-documented. They measured blood pressure and heart rate variability during and for 45 min following two mental stress tests. They report that lower SES was associated with 0195-668X/02/$35.00/0 delayed recovery of the cardiovascular responses after mental stress. They also found reduced heart rate variability, reflecting disregulated autonomic control that predicts a poor prognosis after myocardial infarction. It is noteworthy that both the low and middle employment grades showed slow recovery of blood pressure and heart rate variability after the mental stress tests, which is consistent with the linearity of the gradient of cardiovascular disease reported in the Whitehall studies and indicative of the fact that the SES eﬀects are manifested throughout the social hierarchy and not just at the lowest end. How does cardiovascular reactivity aﬀect cardiovascular health over time and thereby ‘get under the skin’? Steptoe and co-workers note that abnormal blood pressure responses are known to predict a variety of pathophysiological changes in the cardiovascular system, including hypertension, increased left ventricular mass and atherosclerosis. Indeed, systolic blood pressure reactivity in individuals with low SES accelerates carotid atherosclerosis. Furthermore, social hierarchies in infrahuman primates are known to accelerate atherosclerosis, working synergistically with dietary factors by a process that is attenuated by beta adrenergic antagonists. Steptoe and colleagues suggest that probable mediators of this type of allostatic load include impairment in endothelial function that may result, at least in part, from elevations in inflammatory cytokines. Inflammatory cytokine production is elevated by psychological stressors[7,8]. Their production is also increased by dietary factors and sleep deprivation[9,10], and the elevation of inflammatory cytokines is closely tied to oxidative stress, which stimulates transcription factors such as Nf-kB that damage endothelial function. Thus, although inflammatory cytokines are only one factor in a complex network of biological interactions, their regulation and actions upon endothelial cells illustrate the convergence of systemic, cellular and transcriptional regulatory mechanisms around the consequences of psychological stressors and lifestyle factors such as diet and sleep. Such convergence in biological mechanisms provides a target for further exploration of psychosocial influences on health that 2002 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved 1728 Editorials may well be able to elucidate how the eﬀects of SES on cardiovascular reactivity and recovery seen by Steptoe and colleagues ultimately exert their influence on cardiovascular health. B. S. MCEWEN A. E. MIRSKY Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY, U.S.A.      References   Adler NE, Boyce T, Chesney MA et al. Socioeconomic status and health: the challenge of the gradient. Am Psychol 1994; 49: 15–24.  Adler NE, Marmot M, McEwen BS, Stewart JE. Socioeconomic Status and Health in Industrial Nations: Social, psychological, and biological pathways, Vol. 896. New York: The New York Academy of Sciences, 1999.  Sterling P, Eyer J. Allostasis: A New Paradigm to Explain Arousal Pathology. In: Fisher S, Reason J, eds. Handbook of   Life Stress, Cognition and Health. New York: John Wiley & Sons, 1988: 629–49. McEwen BS, Stellar E. Stress and the individual: mechanisms leading to disease. Arch Int Med 1993; 153: 2093–101. McEwen BS. Protective and damaging eﬀects of stress mediators. N Engl J Med 1998; 338: 171–9. Manuck SB, Kaplan JR, Muldoon MF, Adams MR, Clarkson TB. The behavioral exacerbation of atherosclerosis and its inhibition by propranolol. In: McCabe PM, Schneiderman N, Field TM, Skyler JS, eds. Stress, Coping and Disease. Hove and London: Lawrence Erlbaum Associates, 1991: 51–72. Altemus M, Rao B, Dhabhar FS, Ding W, Granstein RD. Stress-induced changes in skin barrier function in healthy women. J Invest Dermatol 2001; 117: 309–17. Steptoe A, Willemsen G, Owen N, Flower L, Mohamed-Ali V. Acute mental stress elicits delayed increases in circulating inflammatory cytokine levels. Clin Sci 2001; 101: 185–92. Obal F Jr, Krueger JM. Hormones, cytokines, and sleep. In: Coping with the Environment: Neural and Endocrine Mechanisms, Vol. IV. New York: Oxford University Press, 2000: 331–49. Bierhaus A, Schiekofer S, Schwaninger M et al. Diabetesassociated sustained activation of the transcription factor nuclear factor-B. Diabetes 2001; 50: 2792–808. Barnes PJ, Karin M. Nuclear factor-B — a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997; 336: 1066–71. European Heart Journal (2002) 23, 1728–1730 doi:10.1053/euhj.2002.3310, available online at http://www.idealibrary.com on Is measuring endothelial function a good idea for prediction of coronary heart disease complications? See doi:10.1053/euhj.2001.3237 for the article to which this Editorial refers Endothelial cells play an essential role in almost all basic biological functions, in health and disease. The endothelial cell presents a selectively permeable barrier and has the ability to respond to haemodynamic shear forces; it mediates vasorelaxation and vasocontraction; it is antithrombogenic by maintaining a nonadhesive surface for leukocytes, has anticoagulant (glycosaminglycans, thrombomodulin), and fibrinolytic properties (tissue plasminogen activator); but also produces the most important antagonist of the fibrinolytic system, plasminogenactivator-inhibitor 1, and other coagulation factors (tissue factor; von Willebrand factor) upon activation; it mediates cell growth and proliferation and angiogenesis; it is involved in inflammatory (and antiinflammatory activities via nitric oxide) and immune mechanisms in the vessel wall, and plays a role in extracellular matrix reorganization. Activated endothelial cells express various cellular adhesion molecules (CAMs; VCAM-1, ICAM-1, E-selectin), cytokines (interleukin (IL)-1; tumour necrosis factor-), and chemokines (monocyte chemoattractant factor 1, IL-8). Selectins from activated endothelial cells mediate leukocyte ‘rolling’ that leads to low-aﬃnity interaction with endothelial CAMs. Firm adhesion and extravasation of leukocytes is mediated by chemokine-induced activated leukocyte integrin interaction. Thus, endothelial dysfunction implies an imbalance between relaxation and contraction, between antiand prothrombogenicity, and between antiproliferation and proliferation, favouring the latter. Several studies have shown that it is closely correlated with the number of cardiovascular risk factors and according to our current understanding, dysfunction of activated endothelial cells represents the initial step in atherogenesis. Direct assessment of endothelial dysfunction by invasive procedures has been shown to be a strong 2002 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved.