ReviewStress, inflammation and cardiovascular disease
Introduction
A large body of evidence, which indicates that psychosocial factors play some role in the etiology and progression of certain cardiovascular diseases such as atherosclerosis [1], [2], [3], [4], [5], has now been obtained. Accumulating evidence also indicates that atherosclerosis is the result of a prolonged and excessive inflammatory process in the vascular wall [6], [7], [8], [9]. It is, therefore, important to inquire whether stressful psychosocial factors can initiate or participate in the inflammatory events that culminate in atherosclerosis. In this paper, we shall consider the evidence that stress alone may evoke many, if not all, of these pathophysiologic events. If true, it may provide an explanation for the approximately 40% of patients with atherosclerosis who have no other known risk factors [5], [10], [11], [12].
Stress is a state of threatened homeostasis provoked by a psychological, environmental, or physiologic stressor [13], [14], [15], [16], [17]. One can also define stress as a stimulus, either internal or external, that activates the hypothalamic–pituitary–adrenal axis (HPA) and the sympathetic nervous system (SNS), resulting in a physiological change or adaptation so that the organism can deal with the threat [17]. In addition to these aspects, stress is now construed more broadly to include personality and socioenvironmental factors that are pertinent to individual adaptation [18], [19].
Section snippets
Neurobiology of stress
Psychological and emotional stress commence with impulses arising from high cortical centers of the brain that are relayed through the limbic system to the hypothalamus. Chemical mediators, including norepinephrine (NE), serotonin, and acetylcholine, are released and activate cells of the paraventricular nucleus of the hypothalamus to produce corticotropin-releasing factor (CRF), the coordinator of the stress response (see [15], [16] for reviews). CRF enters the portal venous system of the
Inflammation and the stress response
Inflammatory stimuli may also lead to activation of aspects of the stress response. The inflammatory response is the most primitive of protective mechanisms; rudiments of it existed before the development of the nervous system. The stress response evolved from and is intricately linked to the inflammatory response. Both are very primitive and are highly conserved over time and species [17], [20]. An important inflammatory stimulus is lipopolysaccharide (LPS), a component of Gram-negative
Association of nerves with an inflammatory process
In Inflammatory Mediators Contained Within Nerves, Participation of Nerves in an Inflammatory Process, and The Brain Modulates Inflammation, we present a brief review of the evidence for neurogenic inflammation, i.e., inflammation mediated by nerves. Nerves, both somatic and autonomic, are intimately associated with inflammatory cells; this is especially true of mast cells that resemble nerve cells in many respects [21], [22]. Indeed, the embryologic development of the SNS parallels the
Inflammatory mediators contained within nerves
Prostaglandins, especially PGE2, a potent inflammatory mediator, may be synthesized at sympathetic nerve endings in response to adrenergic stimulation [31], [32]. In addition, a number of other inflammatory mediators such as certain neuropeptides (e.g., neuropeptide Y (NPY) and CRF) are also present in sympathetic nerve endings and contribute to neurogenic inflammation [33], [34].
NPY is a cotransmitter of sympathetic nervous innervation and potentiates the actions of NE. It is considered a
Participation of nerves in an inflammatory process
Nervous transmission antidromically in a sensory nerve may result in an inflammatory reaction. For example, upon emotional arousal, autonomic nerves convey these stimuli to primary afferent sensory nerves that transmit the impulses antidromically, resulting in the release of various neuropeptides from the sensory nerve endings with resultant mast cell degranulation; mast cells have receptors for SP and/or other neuropeptides [41], [42]. That the brain can cause mast cell degranulation is
The brain modulates inflammation
The brain can also influence the inflammatory process. Downregulation of the inflammatory process occurs by synthesizing and secreting α-MSH, an antiinflammatory molecule that is produced by proteolytic cleavage of POMC in the pituitary gland (see above) [47], [48], [49] (see [50], [51] for reviews). α-MSH is regarded as an anticytokine since it inhibits proinflammatory cytokine production/function as well as pain in the periphery when inoculated intracerebrally. It also modulates other
Atherosclerosis process
The atherosclerotic process is the culmination of a number of events: endothelial injury; induction of adhesion molecules; adherence of platelets; recruitment of monocytes and lymphocytes which adhere to and permeate the arterial wall; appearance of proinflammatory cytokines; infiltration and oxidation of low-density lipoprotein (LDL); deposition of fibrous tissue and glycosaminoglycans in the intima; activation, movement, and hyperplasia of myocytes; formation of foam cells from macrophages
Hypothesis: stress and cardiovascular disease
Our hypothesis is that repeated episodes of acute stress or chronic stress, in a susceptible or at-risk person, can initiate and promote the atherosclerotic process. Stress induces cytokines, which, together with the major stress hormones corticosteroids and catecholamines, induce acute phase proteins (APPs) in the liver. Recurrent stress or chronic stress, with changes in blood flow and blood pressure, causes endothelial damage and adhesion of platelets. Cytokines, corticosteroids, and other
Psychosocial stress as a risk factor in cardiovascular disease
A considerable literature has accumulated indicating that various psychosocial stressors are risk factors for development of atherosclerosis [2], [55] (see Ref. [5] for review). Men with certain personality profiles such as type A are more at risk for development of cardiovascular disease; however, the hostility component or related aspects of anger seem to be most relevant [18], [56], [57], [58], [59], [60]. Men with type A personality who are characterized as high hostile tend to have higher
Psychological stress: an animal model relating stress to atherosclerosis
A revealing animal model utilizing cynomolgus monkeys in studies of the relationship between psychosocial stress and the development of coronary artery disease will illustrate how stress may be the predominant, if only, risk factor for atherosclerotic disease. These monkeys establish a social organization with one dominant and several submissive monkeys. Several psychosocial variables involving social instability (e.g., periodic changing of the dominant male, or periodic changing of the
Stress and endothelial damage
We have considered the evidence that psychosocial stress has been correlated with structural changes in arteries and that atherosclerotic blood vessels have an exaggerated response to sympathetic stimuli, which, if chronic, may lead to further endothelial injury [66], [92], [99], [100]. Activating the SNS increases blood pressure and heart rate; such increases in the pressure within blood vessels would contribute to the shear forces imposed by blood flow under pressure. Specific sites cause
Adhesion molecules
Injured endothelium, by releasing chemotactic molecules, attracts monocytes and lymphocytes [102] After arrest and rolling, these cells adhere to adhesion molecules (see [103], [104] for reviews). Adhesion molecules may be induced on damaged endothelium by diminished shear forces of the blood as mentioned, by cytokines bound to their respective receptors [105] subsequent to their induction by corticosteroids, by corticosteroids themselves, or by oxidized LDL [72] (see below). ICAM-1 and
Stress and glucocorticoids
Glucocorticoids, released during the stress response, are often identified with their powerful antiinflammatory and immunosuppressive effects, which they promote at certain doses. However, corticosteroids are now known to take part in many of the early and essential reactions of the organism to stress, including the inflammatory reaction (i.e., to have permissive as well as suppressive effects on inflammation and/or immunity) [72], [118], [119].
Corticosteroids are bound to a carrier molecule,
Stress induces cytokine production
Many studies indicate that various psychological stressors alone can induce proinflammatory (IL-1, IL-6, TNF-γ) cytokine secretion [133], [134]. This may be manifested by a cytokinemia and may vary according to the type of stress. For example, restraint (immobilization) stress experiments in animals have revealed elevations in three proinflammatory cytokines (i.e., IL-1 or IL-6, or TNF-α) [135], [136], [137], whereas other stresses (i.e., isolation or open field) have resulted in increased
Stress and the induction of the APR
The body responds to any type of tissue damage and infection with a series of specific physiological reactions in order to repair the damage, contain the offending organisms, promote wound healing, or recruit host defense mechanisms; this is called the APR. A number of proteins, called the APPs, are induced in the liver. These may be positive APPs (upregulated) or negative APPs (downregulated) in response to injury or infection. The former play a role in the inflammatory process, while the
Stress and lipoproteins: lipoproteins and the APR
Psychological stress is associated with increases in lipids including cholesterol, lipoproteins, triglyceride, and free fatty acids [68], [119], [230], [231], [232], [233]. These changes in lipid metabolism are part of the APR. Such changes induced by stress would act to protect the host from toxic components of microorganisms (e.g., LPS). Lipoproteins, as well as their apoproteins, bind to the inner or hydrophobic core of LPS, thereby neutralizing its toxic effect(s) [234], [235], including
Homocysteine
Homocysteine is an amino acid that has been implicated in the development of vascular disease (see [229], [253], [254], [255] for reviews). The inability to metabolize homocysteine in individuals, due to various inborn errors of metabolism, results in elevated levels of homocysteine and premature atherosclerosis. Homocysteine may also be elevated due to dietary, hormonal, or toxic factors.
Homocysteine promotes many processes that play a role in atherosclerosis. These include oxidative
Stress and mast cell degranulation
The presence of an inordinate number of mast cells within atherosclerotic lesions and fatty streaks suggests that they may play an important role in the atherosclerotic inflammatory process [258], [259], [260], [261], [262] (see above). We have reviewed the evidence that stress can cause neurogenic inflammation by mast cell degranulation; the contents of mast cell granules would contribute to augmentation of foam cell formation, and also would enhance the proteolytic process.
Acute and chronic stress and cardiac events
The hypothesis presented herein holds that repeated stresses evoke similar inflammatory responses and that the effects of stress are cumulative and progressive, both pathophysiologically and clinically. This would imply that most of the inflammatory responses, while leaving their imprint on the vasculature, remain largely asymptomatic. We might inquire whether chronic stress results in an attenuated response to stress. The capacity to adapt to stress generally declines with age. Levels of
Depression and coronary atherosclerosis
Much evidence has accumulated linking major depression and coronary artery disease [267], [268], [269], [270], [271], [272]. Seasonal mood changes (i.e., seasonal affective depression) have also been correlated with seasonal variation in coronary heart disease [287]. Major depression has been shown to be an independent risk factor for coronary artery disease; as such, it precedes and heightens the risk for subsequent coronary artery disease [267], [271]. Major depression may also potentiate
Atherosclerosis and an infectious agent
Since atherosclerosis is a chronic inflammatory process and the APR to stress is similar to the host's reaction to an infectious agent, there have been numerous studies seeking the presence of an infectious agent linked to the progression of atherosclerosis. A number of reports have documented the presence of numerous agents, including viruses (the herpes viruses, including cytomegaloinclusion disease virus (CMV)), bacteria (Helicobacter pylori, Porphyomonas gingivalis, and other gingival
Conclusions
The hypothesis presented is that the inflammatory response is linked to the stress response and that repeated episodes of acute stress or chronic stress via the stress hormones and stress-induced cytokines, in a susceptible or at risk person, can induce an APR and which, together with elevated homocysteine, can evoke the pathogenic events that culminate in atherosclerosis. Repeated or chronic stress causes injury to the endothelium at certain loci, the production of adhesion molecules, and
Acknowledgements
The authors wish to express their gratitude to Dr. Ari Berman whose work was instrumental in the formulation of this hypothesis [132], and to Michelle Villarta for her invaluable help in the preparation of the manuscript.
References (287)
Emotions and health in occupational life: new scientific findings and policy implications
Patient Educ Couns
(1995)- et al.
Psychosocial factors: role in cardiac risk and treatment strategies
Cardiol Clin
(1996) Atherosclerosis, serum cholesterol and the homocysteine theory: a study of 194 consecutive autopsies
Am J Med Sci
(1990)- et al.
Corticotropin-releasing factor in antinociception and inflammation
Eur J Pharmacol
(1997) - et al.
Postnatal development of neurogenic inflammation in the rat
Neurosci Lett
(1991) - et al.
The interaction between mast cells and nerves in the gastrointestinal tract
Immunol Today
(1994) Neurogenic inflammation in skin and airways
J Invest Dermatol Symp Proc
(1997)- et al.
Contribution of the nervous system to the pathophysiology of rheumatoid arthritis and other polyarthritides
Rheum Dis Clin North Am
(1987) - et al.
Further substantiation of a significant role for the sympathetic nervous system in inflammation
Neuroscience
(1993) - et al.
Modulation by adrenergic transmitters of the efferent function of capsaicin-sensitive nerves in cardiac tissue
Neuropeptides
(1991)