Selye, as a young contemporary of Cannon, developed the concept of the “General Adaptation Syndrome (GAS)” or the “Biologic Stress Syndrome” ₃ . The GAS articulates stress as an event, which elicits three stages of reaction. Selye compared these stages with developmental stages of life that are characterized by low resistance and exaggerated responses to stressors as a child, enhanced coping and adaptation to stressors as an adult, and eventual diminished ability to adapt to stressors in old age leading to death. The three stages of the GAS inculde ₃,₅ .

Alarm Stage – In the initial ALARM stage, the classic fight or flight reaction ensues. A stressor (physical or emotional) disrupts homeostasis of the subjects. Adrenal catecholamine secretion and other biologic responses occur and the individual experiences heightened arousal, increased heart rate and blood pressure, and the psychological urge to attack or flee from the stressor event. As the Alarm stage continues, and assuming that the individual survives, the body's natural inclination toward homeostasis yields the Stage of Resistance.

Stage of Resistance – In this stage, the body attempts to calm and better control the changes started in the alarm reaction. The individual settles into a psychological mode of coping and possibly co-existing with the stressor, if the stressor cannot be eliminated. The individual then enters what Selye termed the Stage of Exhaustion.

Stage of Exhaustion – In this stage, a stressor persists despite attempts to either remove exposure to it, or to peacefully coexist with it. The individual basically “gives in” due to resource /energy depletion. Diminished functional capacity, sleep, rest, or even death, are forced upon the person.

Hypothalamus–Pituitary–Adernal Axis and Other Hormonal Changes vis-à-vis stress:

The hypothalamic-pituitary-adernal axis is activated by corticotropin-releasing hormone from the paraventricular nucleus of the hypothalamus, which prompts the release of corticotropin from the pituitary, stimulating the production of glucorticoids (especially cortisol) from the adrenal cortex and to a lesser extent, mineralocorticoids and adrenal androgens ₆ . Cortisol has central energy-conserving effects, including inhibition of the release of gonadotropins, growth hormone, and thyroid stimulating hormone, but is better known for its somatic effects, including inhibition of inflammatory and immune responses, central redistribution of adiposity, reduced insulin sensitivity, and pressor effects ₇ .

The peripheral sympathetic nervous system, the other effector limb of the stress response, innervates tissues throughout the body, especially the heart, vasculature, and adrenal medulla. It is the means by which the brain effects body organs in response to acute stress. The adrenal medulla responds with systemic catecholamine release (predominantly epinephrine), whereas the sympathetic nerve terminals that line the vasculature release norepinephrine, which accounts for most circulating norepinephrine. The sympathetic nervous system has not only direct cardiostimulatory effects (chrontropy and inotropy via 1-adrenergic receptors) and pressor effects (via 1-adernergic receptors), but also metabolic effects (insulin resistance and lipolysis) and varied immunological effects ₈ , including inhibition of mast-cell degranulation but stimulation of interleukin 6 release.

Evidence is compelling that acute mental stress triggers major autonomic cardiovascular responses and acute cardiac events. Evidence that chronic mental stress leads to or promotes chronic cardiovascular disease is highly controversial. Most mental-health professionals believe that healthy subjects can experience short-term, mild-to-moderate mental stress without developing mental illness, particularly if subjects have the coping skills to find relief. Injuries unavoidable, and uncontrollable mental stresses have the capacity to induce adverse cardiovascular responses ₉ .

At time we distinguish between fear and anxiety, and at other times we use the terms interchangeably because the body responds immediately in similar ways to these stimuli. Fear is the body's physical and mental response to external (known) danger. Anxiety is the body's physical and mental response to internal (unknown) danger (conflict). Also, we may conceptualize anxiety as the body's response to expected (future) loss and depression as a response to past loss. This model has anxiety and depression on a continuum. Finally, using “kindling” models, stimulus driven (“exogenous”) stress can become autonomous (“endogenous”) or stress (or mental illness) ₁₀ .

The exercise is different from stress. The body's response to isotonic (aerobic) exercise and to isometric (anaerobic) exercise is different clinically. During isotonic exercise, the large muscle groups move the body through space. Examples include jogging, bicycle riding, and swimming. In healthy subjects, reduced peripheral vascular resistance and a sharply increased cardiac output accompany isotonic exercise. During low levels of isotonic exercise, the body principally increases heart rate to increase cardiac output. During very high isotonic exercise levels, increased stroke volume also contributes to increased cardiac output.

The body moves large muscle groups against one another during isometric (sustained muscle contraction) exercise. Examples include weight lifting and snow shoveling. In healthy subjects during weight lifting the body withdraws vagal tone and within seconds, heart rate increase and blood pressure elevation follow. This reflex is so potent that it can override normally set baroreceptors. Increased myocardial wall tension, increased peripheral vascular resistance, and increased myocardial oxygen demands accompany the modest cardiac output increase associated with isometric exercise.

Blood pressure

Heart rate

Double product: Blood pressure and heart rate

Blood pressure

Heart rate

Left ventricular performance

Cardiac arrhythmias

Long QT syndrome

Subacute and chronic stressors associated with psychological and emotional adjustment are associated with an increased risk of cardiac events, similar to traditional cardiovascular risk factors. Parkern et al ₃₉ reported that mortality from all causes, particularly cardiovascular ones, is increased in the months after the death of a spouse. Similarly, the fear in the USA subsequent to the terrorist attacks on the World Trade Center in New York in 2001 resulted in a rate of defibrillator firings of two to three times normal during the month after the event ₄₀ . These defibrillator firings occurred in patients living far from the catastrophe and in those with both ischaemic and non-ischaemic cardiomyopathies. The distribution of arrhythmic events (not all occurring on the day of the attacks) suggests that psychological fallout of the event lasted for weeks ₄₁ .

Stress of daily living can also increase risk of cardiovascular events. In one study of work-related stressors ₄₂ , upcoming deadlines were associated with a six folds increase in myocardial infarction. Kivimaki M et al ₄₃ reported that chronic work-related stress could carry a two to three times higher risk of cardiac events, especially when employees perceive little control over their work environment. Likewise, in women with established coronary disease, marital stress was associated with a risk of recurrent events three times higher than in women with no marital stress ₄₄ .

Frequent anger and hostility also predict incident coronary events ₄₅ . In the Atherosclerosis Risk in Communities Study ₄₆ , normotensive patients with high anger temperament scores (characterized by frequent or long-lasting anger reactions with little or no provocation) had a hazard ratio of 2.3 for fatal or non-fatal cardiac events after adjustment for traditional cardiovascular risk factors. Chronic anxiety also is a predictor of cardiovascular events, both ischaemic heart disease events and sudden death. Severe phobic anxiety, in particular, has been associated with increases in cardiac events of 1.3 to 3.0 times, perhaps via frequent paroxysms of fear ₄₇ .

Personality types – both type A and type D – lead to unhealthy responses to daily psychological stressors. The type D (distressed) personality is characterized by a combination of pessimistic emotions and introversion, which prevents sharing emotions with others. Type D individuals are gloomy, anxious and socially inept worriers ₄₈ . By contrast, in the type A personality, anxiety and hypervigilance are directed outward as competitive, aggressive, irritable, and sometimes hostile behaviours. Type A personality has received attention as a potential cardiovascular risk factor for two decades, but results have been mixed as to whether this personality type is truly associated with cardiovascular events ₄₉ .

Acute stress, can tigger acute thrombotic, arrhythmic, or mechanical cardiovascular events, chronic stress seems to affect cardiovascular risk mainly by acceleration of the atherosclerotic process. Although physiological pathways exist through which chronic stress could potentiate cardiovascular disease (such as increased blood pressure), behavioural changes (such as medical non-compliance, smoking, or sedentary lifestyle) might also accompany chronic psychological stressors ₅₀ . There is a consistent relation between chronic emotional or psychosocial stress and coronary atherosclerosis (and atherosclerotic risk factors), and these relations persist after adjustment for confounding variables, including lifestyle variables. This association suggests, that stress itself contributes to cardiovascular morbidity in the general population. Acute stress elicits rapid increases in circulating catecholamine and cortisol concentrations, different forms of chronic stress might lead to different neuroendocrine response. Some forms of chronic stress, such as post-traumatic stress disorder, can be associated with a blunted amplitude of cortisol secretion and diminished responsiveness to acute stressors, perhaps due to a repetitive over stimulation of the hypothalamic-pituitary-adrenal stress response (analogous to -cell failure in patients with insulin resistance) with compensatory activation of the sympathetic nervous system ₅₁ .

The likelihood of developing myocardial arrhythmia is also subject to genetic variation. The ryanodine receptor affects the clinical manifestations of circulating catecholamines. Mutations in the gene for this receptor render individuals susceptible to ventricular tachycardia during catecholamine challenges, whether induced by exercise or by emotional triggers ₅₂ . Similarly patients with congenital long QT syndromes due to mutations in genes for sodium or potassium channels are also at risk of sudden death after catecholamine surges ₅₃ .

Activity of (hypothalamic-pituitary-adrenal) axis, and the sympathetic nervous system, show sstriking diurnal variation. Peak corticotropin and cortisol concentrations occur in the early morning, and peak cortisol concentrations can be ten times higher than at trough ₅₄ . Circulating norepinephrine and epinephrine concentrations shows large diurnal variation with increases throughout the day and decreases at night.

Proposed mechanisms to explain why ischaemic heart events and cerebrovascular events are more common in the early morning than at other times include increasing morning catecholamine concentrations, highest cortisol concentrations, hypercoagulability, and endothelial dysfunction ₅₅,₅₆ . Not surprisingly, in view of the association between the stress systems and the sleep-wake cycle, disruption of sleep pattern interferes with autonomic balance and function of the hypothalamic-pituitary-adrenal axis. Sleep deprivation blunts the normal trough in circadian cortisol concentrations and also increases sympathetic nervous system activity at the expense of parasympathetic tone ₅₇ . Via stress system activation and perhaps via other hormone and immune mechanisms as well, sleep disruption is associated with several metabolic disorders, including obesity and insulin resistance ₅₈ .

There are evidences that relaxation techniques or methods such as meditation, yoga, and prayer can modify indices of autonomic activation at beneficial in relieving stress ₅₉,₆₀ .

Drug therapies have been studied to a limited extent. Bernardi L et al ₆₀ In the SADHART study reported that the treatment with sertaline was not powered to detect differences in clinical end point. (In this study 369 depressed patients who had recently had myocardial infarction were randomly assigned sertaline or placebo for 24 weeks).

In the ENRICHD study that enrolled nearly 2500 myocardial infarction patients with depression or low social support, or both, to cognitive behaviours therapy versus usual care and recorded no effect on event – free survival with modest improvement in depression and social isolation score ₆₁ . Taylor CB et al ₆₂ reported a relative reduction in death or recurrent myocardial infarction of about 40% in patients with major depression who were prescribed selective serotonin reuptake inhibitor.

JoAnn Difede et al ₆₃ reported that Virtual Reality (VR) is an effective treatment tool for enhancing exposure therapy for both civilians and disaster workers with Post Traumatic Stress Disorder and may be especially useful for those patients who cannot engage in imaginal exposure therapy.