An enduring state of exhaustion as opposed to chronic hostility - a long-term risk factor - has been found to be a more proximal precursor of myocardial infarction. The strength of the association with exhaustion suggests that this behavioral factor reflects not only a breakdown in adaptation to chronic stressors but also the disease process itself. Recent research on the pathogenesis of myocardial infarction lends credence to a role for immunological factors. Herein, we outline a two-stage theoretical model, postulating a feedback relationship between behavior, associated neuroendocrine changes, immunological responses, and the pathogenesis of this disease. We propose a long-term first stage consisting of chronic hostility, prolonged occupational over-exertion, and exposure to other life stressors, terminating eventually in a much shorter second stage of 'vital exhaustion'. Stressor-associated neuroendocrine changes result in immunosuppression leading to reactivation of latent, systemic infections (such as cytomegalovirus) and potentially to autoimmune reactions as well. The consequent release of pro-inflammatory cytokines exacerbates fatigue and induces a stimulus for cytokine production in brain. This cytokine production stimulates a chronically activated, over-compensated limbic-hypothalamic-pituitary-adrenal axis, resulting in a dampened response, continued exhaustion, and a potential 'reverberating circuit' between behavior, neuroendocrine change, cytokine release and coronary artery occlusion, culminating in myocardial infarction.
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