Positron emission tomography is a sensitive and specific noninvasive approach for delineating abnormalities of myocardial perfusion and for characterizing the efficacy of interventions designed to enhance nutritive flow. Nonetheless, the use of PET has been limited by the availability of cyclotron-produced flow tracers. Accordingly, development of generator- produced, positron-emitting flow tracers is highly desirable. In the initial two years of this award, we developed and implemented approaches to quantify regional myocardial perfusion with 82/RbCl and 62/Cu- pyruvaldehyde bis(N/4-methylthiosemicarbazone) (PTSM). We demonstrated however that 62/Cu-PTSM binds to human albumin limiting the ability to quantify flow after pharmacologically-induced hyperemia. In the proposed continuation we plan to evaluate the myocardial kinetics of two alternative 62/Cu flow tracers: n-propylglyoxal bis(thiosemicarbazone) (Cu-n-PrTS) and its ethylglyoxal congener (Cu-ETS) (tracers which we have demonstrated in preliminary studies permit quantification of regional myocardial perfusion over a wide range of flows and which do not exhibit avid binding to human albumin) is isolated perfused rabbit hearts in which flow can be altered precisely. We will then evaluate these tracers in intact dogs with PET during selected physiological and pathophysiological conditions including permanent and transient ischemia and coronary hyperemia and compare estimates of regional flow to those obtained with microspheres. Estimates of absolute regional flow with 82/Rbcl and PET, validated during the current grant interval in experimental studies, will be extended to evaluations in humans compared with estimates made with H/2/15/O. Since recent studies have suggested that the backward efflux of 82//RbCl initially trapped by the myocardium (k/2) may delineate viable myocardium (heart muscle that will improve function after revascularization procedures) from nonviable myocardium, an additional goal of the proposed continuation is to evaluate the ability of k/2 (estimated with a compartmental model) to predict viable myocardium in dogs with transient myocardial ischemia referenced to sequential echocardiographic measurements of regional function. The most promising approaches will be evaluated in normal human volunteers and in patients with coronary artery disease. Mathematical models will be evaluated with computer simulations and error analysis and modified as required. The results of this research will enable PET centers to use generator- produced, positron-emitting flow tracers to quantitatively estimate regional myocardial perfusion and, potentially, to delineate myocardial viability.
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