This project will examine the effects of hemodilution, transfusion therapy, and human recombinant hemoglobin on global cardiac and regional myocardial function in the setting of significant experimental coronary artery stenosis. We will test the central hypothesis that hemodilution has significantly different effects on the ischemic right ventricle as compared to the ischemic left ventricle. Two models of laboratory coronary stenosis using a canine preparation will be employed: critical left anterior descending coronary artery stenosis, and critical right coronary artery stenosis. Global hemodynamic function will be examined (systemic, pulmonary and ventricular pressures, cardiac output, time constant of isovolemic left and right ventricular relaxation (tau), first derivative of left and right ventricular pressures with respect to time [LV dP.dt and RV dP.dt, respectively], coronary blood flow); regional myocardial function sonomicrometry) will be used to characterize the response of different regions (normal and flow-compromised) of the right and left ventricle to hemodilution. The effects of hemodilution on right and left ventricle function will be described in a series of experiments designed to elucidate 1) Characterization of the global hemodynamic and regional function response of flow compromised myocardium to hemodilution: tolerable hematocrit range; 2) Tolerance of flow compromised myocardium to hemodilution - induced mild ischemia over time; 3) Tolerance to acute hemodilution: effects of human recombinant hemoglobin; 4) Reversal of ischemia, with transfusion therapy for hemodilution-induced ischemia, and with hemodilution to reverse flow compromised ischemia. Characterization of the tolerance of the right and left ventricles, with normal and compromised regional blood flow, to mild and severe hemodilution, and delineation of the appropriateness of transfusion therapy to prevent or alleviate hemodilution-induced ischemia, may result in decreased homologous blood transfusions. Blood replacement therapy with an oxygen-carrying blood substitute has been long sought, particularly in fluid replacement therapy for patient with coronary artery disease. Human recombinant hemoglobin is a new, genetically engineered hemoglobin analog which has physical properties similar to Dextran, yet is capable of oxygen delivery to peripheral tissues, and thus may have significant advantages as compared to conventional fluid therapy in the setting of coronary insufficiency. We will examine and compare the effects of human recombinant hemoglobin with Dextran in models of left and right ventricular ischemia to assess the potential benefit of blood replacement therapy with genetically engineered artificial blood.
