Over 60 years ago, Selye1 recognized the paradox that the physiologic systems activated by stress can not only protect and restore but also damage the body. What links these seemingly contradictory roles? How does stress influence the pathogenesis of disease, and what accounts for the variation in vulnerability to stress-related diseases among people with similar life experiences? How can stress-induced damage be quantified? These and many other questions still challenge investigators. This article reviews the long-term effect of the physiologic response to stress, which I refer to as allostatic load.2 Allostasis — the ability to achieve stability through change3 — . . .

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Protective and Damaging Effects of Stress Mediators

The adolescent brain and age-related behavioral manifestations

Recent studies provide clear and convincing evidence that psychosocial factors contribute significantly to the pathogenesis and expression of coronary artery disease (CAD). This evidence is composed largely of data relating CAD risk to 5 specific psychosocial domains: (1) depression, (2) anxiety, (3) personality factors and character traits, (4) social isolation, and (5) chronic life stress. Pathophysiological mechanisms underlying the relationship between these entities and CAD can be divided into behavioral mechanisms, whereby psychosocial conditions contribute to a higher frequency of adverse health behaviors, such as poor diet and smoking, and direct pathophysiological mechanisms, such as neuroendocrine and platelet activation. An extensive body of evidence from animal models (especially the cynomolgus monkey, Macaca fascicularis) reveals that chronic psychosocial stress can lead, probably via a mechanism involving excessive sympathetic nervous system activation, to exacerbation of coronary artery atherosclerosis as well as to transient endothelial dysfunction and even necrosis. Evidence from monkeys also indicates that psychosocial stress reliably induces ovarian dysfunction, hypercortisolemia, and excessive adrenergic activation in premenopausal females, leading to accelerated atherosclerosis. Also reviewed are data relating CAD to acute stress and individual differences in sympathetic nervous system responsivity. New technologies and research from animal models demonstrate that acute stress triggers myocardial ischemia, promotes arrhythmogenesis, stimulates platelet function, and increases blood viscosity through hemoconcentration. In the presence of underlying atherosclerosis (eg, in CAD patients), acute stress also causes coronary vasoconstriction. Recent data indicate that the foregoing effects result, at least in part, from the endothelial dysfunction and injury induced by acute stress. Hyperresponsivity of the sympathetic nervous system, manifested by exaggerated heart rate and blood pressure responses to psychological stimuli, is an intrinsic characteristic among some individuals. Current data link sympathetic nervous system hyperresponsivity to accelerated development of carotid atherosclerosis in human subjects and to exacerbated coronary and carotid atherosclerosis in monkeys. Thus far, intervention trials designed to reduce psychosocial stress have been limited in size and number. Specific suggestions to improve the assessment of behavioral interventions include more complete delineation of the physiological mechanisms by which such interventions might work; increased use of new, more convenient "alternative" end points for behavioral intervention trials; development of specifically targeted behavioral interventions (based on profiling of patient factors); and evaluation of previously developed models of predicting behavioral change. The importance of maximizing the efficacy of behavioral interventions is underscored by the recognition that psychosocial stresses tend to cluster together. When they do so, the resultant risk for cardiac events is often substantially elevated, equaling that associated with previously established risk factors for CAD, such as hypertension and hypercholesterolemia.

Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy.

Risky families are characterized by conflict and aggression and by relationships that are cold, unsupportive, and neglectful. These family characteristics create vulnerabilities and/or interact with genetically based vulnerabilities in offspring that produce disruptions in psychosocial functioning (specifically emotion processing and social competence), disruptions in stress-responsive biological regulatory systems, including sympathetic-adrenomedullary and hypothalamic-pituitary-adrenocortical functioning, and poor health behaviors, especially substance abuse. This integrated biobehavioral profile leads to consequent accumulating risk for mental health disorders, major chronic diseases, and early mortality. We conclude that childhood family environments represent vital links for understanding mental and physical health across the life span.

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Risky Families: Family Social Environments and the Mental and Physical Health of Offspring

In this review, the authors examine the evidence linking social support to physiological processes and characterize the potential mechanisms responsible for these covariations. A review of 81 studies revealed that social support was reliably related to beneficial effects on aspects of the cardiovascular, endocrine, and immune systems. An analysis of potential mechanisms underlying these associations revealed that (a) potential health-related behaviors do not appear to be responsible for these associations; (b) stress-buffering effects operate in some studies; (c) familial sources of support may be important; and (d) emotional support appears to be at least 1 important dimension of social support. Recommendations and directions for future research include the importance of conceptualizing social support as a multidimensional construct, examination of potential mechanisms across levels of analyses, and attention to the physiological process of interest.

The relationship between social support and physiological processes: a review with emphasis on underlying mechanisms and implications for health.

Impedance cardiography was introduced over 20 years ago as a noninvasive and unobtrusive technique for measuring systolic time intervals and cardiac output. Although our understanding of the physiological events reflected in the impedance cardiogram has become more refined, the technique's theoretical basis remains somewhat controversial and acceptance of its validity has relied heavily upon empirical validation. Largely as a consequence of this status, there have been inadequate grounds on which to develop sound methodological standardization. Currently, the methodological approaches that have been most frequently adopted may be viewed as representing the standard. The various aspects of impedance methodology are discussed, and alternative approaches described, with the objective of providing an informed basis for choosing among these methodological alternatives. It is recommended that studies utilizing impedance cardiography should be reported with clear and detailed methodological description. This should help clarify the extent to which methodological differences may underlie any discrepant research observations, as well as facilitate the emergence of improved methodological standards.

Methodological Guidelines for Impedance Cardiography

Cardiovascular reactivity to stress may have a pathophysiological role in neurogenic hypertension. We studied the value of measuring blood pressure change during standardized mental and physical challenges to prediction of resting blood pressure status 6.5 years later among 206 middle-aged adults and their 164 children, with the latter group originally being tested while enrolled in elementary through high school. After adjustment for age, resting blood pressure, and body mass index at study entry, as well as length of follow-up, larger systolic and diastolic blood pressure responses to a combination of mental and physical challenges were associated with higher subsequent resting diastolic blood pressure 6.5 years later among adults. Among boys, but not among girls, larger systolic and diastolic blood pressure responses to challenge were associated with higher subsequent resting blood pressure. These data suggest that people who are at high risk for elevated blood pressure might have an exaggerated stress-induced cardiovascular response at a younger age.

Cardiovascular reactivity to stress predicts future blood pressure status.

Evaluation of beta-adrenergic influences on cardiovascular and metabolic adjustments to physical and psychological stress.

Exaggerated cardiovascular reactivity to psychological stress is a potential pathophysiological mechanism linking behavior and cardiovascular disease. Because of the recognized gender differences in incidence of cardiovascular disease, potential gender differences in cardiovascular reactivity to laboratory stressors have been evaluated. The current study examined the cardiovascular responses of a total of 42 young women (N = 22) and men (N = 20) undergoing a laboratory protocol including the following: a nonverbal math task, a mirror tracing task, the Stroop Color-Word interference task, and an isometric handgrip task. In addition to the assessment of heart rate and blood pressure, cardiac output, stroke volume, total peripheral resistance and preejection period were assessed by impedance cardiography. A number of personality characteristics that vary in prevalence by gender were also measured to evaluate their ability to explain potential gender differences in cardiovascular responses. Results indicated that men responded with greater total peripheral resistance and systolic and diastolic blood pressure responses than did women on a subset of tasks, whereas women exhibited larger increases in heart rate on a subset of tasks. Thus, men were more likely to be "vascular" reactors, with women being more likely to be "cardiac" reactors. Personality characteristics did differ between men and women, but did not explain significant variance in the gender differences in cardiovascular responses. We conclude that additional studies should focus on experimental manipulations of potential physiological mechanisms responsible for these differences, such as reproductive hormones.

Michael T. Allen

Papers

Methodological Guidelines for Impedance Cardiography

Cardiovascular reactivity to stress predicts future blood pressure status.

Evaluation of beta-adrenergic influences on cardiovascular and metabolic adjustments to physical and psychological stress.

Hemodynamic adjustments to laboratory stress: the influence of gender and personality.

Enhanced Cardiovascular and Catecholamine Responses in Women with Depressive Symptoms