CARDIAC FUNCTION AND PROTECTION IN CARDIOGENIC SHOCK

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The overall goal is to develop pharmacologic and metabolic strategies to improve cardiac function during acute ischemic failure (cariogenic shock), without increasing ischemic injury, to maintain function until revascularization can be done. The left ventricle in cariogenic shock is composed of a large region (40%) which is severely ischemic, infarcting, and non-contractile, and a non-occluded region which is acutely overloaded and undergoes progressive contractile failure leading to systemic hypotension. With hypotension coronary perfusion pressure decreases and this non-occluded region becomes moderately ischemic. The ischemia accelerates the failure creating a "vicious cycle," and a mortality rate 90%. The proposed research will develop strategies to maintain contractile function of over-loaded moderately ischemic myocardium which will serve as a model of the non-occluded region of the cariogenic shock ventricle after it has developed acute overload, progressive ischemia and failure. The isolated isovolumic (balloon in LV) blood perfused rabbit heart preparation will be used to model the myocardial perfusion and loading conditions in cariogenic shock. Isolated hearts will be subjected to either a ligation of the left main coronary artery or to global low flow ischemia (50% decrease in global coronary flow). Cardiac function and injury will be assessed by measures of systolic and diastolic function, coronary vasomotion, magnetization transfer, ATP, creatine phosphate and glycogen contents and loss of myocardial creatine kinase activity. Studies will be done in non- hypertrophied hearts and in hearts with hypertrophy secondary to chronic myocardial infarction since cariogenic shock often occurs in patients with a previous infarct and secondary hypertrophy. Interventions will be assessed for their efficacy in reversing or inhibiting the following components of ischemic pathophysiology: decreased contractile (systolic) function, increased diastolic dysfunction, high energy phosphate supple/demand mismatch, and inadequate coronary vasodilation. The goal will be to maximize active systolic tension generation while minimizing any increase myofilament sensitivity to calcium, and which block inorganic phosphate's effect to decrease active tension during ischemia. Inhibition of cardiac angiotensin converting enzyme and the protein kinase C system will be studied as interventions to reduce ischemic diastolic dysfunction. Increased levels of selected substrates will be provided to test the hypothesis that overloaded myocardium may become substrate limited during sustained low-flow ischemia and to attempt to improve the high energy phosphate supply/demand mismatch; their efficacy will be measured by 31-P NMR magnetization transfer to measure ATP turnover. The impaired intrinsic coronary vasodilator response to low- flow ischemia will be reversed with coronary vasodilator. The overall hypothesis is that the separate components of myocardial ischemic depression of function and injury need to be corrected in combination. Improved function of ischemic myocardium should reduce the high mortality rate of cariogenic shock.