Non-survivors of traumatic injury frequently succumb to complications arising not directly from their injuries but rather from a syndrome of multisystem organ failure (MOF). A diverse pattern of circulatory states arise and these patterns are often indistinguishable from those observed in other shock states, in particular septic shock. Mechanical function and metabolic state of the heart are tightly coupled to the physiologic requirements of the body during periods of stress. Catecholamines, elevated in circulatory shock, bind to beta-adrenergic receptors to increase the ionotropic and chronotropic state of the heart. The ability of the myocardium to respond to catecholamines maintains the adequacy of cardiac function despite intrinsic myocardial depression in early shock. Over time, however, the heart becomes refractory not only to endogenous catecholamines but also to exogenous beta agonists leading to the terminal stages of shock. These pathophysiologic derangements associated with post-traumatic MOF, like septic shock appear to arise indirectly through the effects of endogenous inflammatory mediators elaborated by the host and may occur either in the presence or absence of bacterial endotoxins. Using a multidisciplinary approach employing enzymatic assays and an isolated, crystalloid perfused heart preparation, the direct effects of putative post-traumatic mediators on myocardial mechanical function, cellular energetics and redox balance will be evaluated. Specifically, the purpose of this study will be to examine the ex vivo effects of endotoxin, myristate (endotoxin fragment), and platelet activating factor (endotoxin induced mediator) on myocardial 1) intrinsic mechanical function, 2) coronary flow, 3) tissue energetics, 4) redox balance, and 5) beta-adrenergic receptor coupled function. Expected is elucidation of the mechanisms by which post-traumatic mediators may directly modulate myocardial function. An understanding of the relationship of alterations in metabolic state and signal trafficking to myocardial mechanical function may allow the development of directed therapies which preserve the beneficial effects and prevent the harmful effects of multisystem trauma.
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