Myocardial Kinetics of a Putative Hypoxic Tissue Marker, 99m Tc-Labeled Nitroimidazole (BMS-181321), After Regional Ischemia and Reperfusion

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Abstract
Background A new nitroimidazole complex, 99m Tc-propylene amine oxime-1,2-nitroimidazole (BMS-181321), has been developed to allow the positive imaging of hypoxic myocardium by standard gamma camera techniques. Methods and Results To determine the myocardial kinetics of BMS-181321 during myocardial ischemia and reperfusion, seven open-chest swine were prepared according to a model of extracorporeal coronary perfusion in which left ventricular wall thickening (percent end-diastolic thickness) and substrate use in the left anterior descending (LAD) region ([ 14 C]palmitate and [ 3 H]glucose infusions) were determined. Measurements were obtained at baseline, during 40 minutes of ischemia produced by reducing flow in the LAD distribution by 60%, and during 70 minutes of reperfusion. Three aerobic control hearts were also studied in which LAD blood flow was not reduced. Regional coronary circulation was further assessed in all hearts by use of radiolabeled microspheres injected during ischemia. BMS-181321 (20 to 30 mCi) was injected after 30 minutes of ischemia, and its myocardial uptake was assessed by dynamic planar gamma imaging. Ischemia was associated with declines in fatty acid metabolism (15±11 μmol · h −1 · g dry wt −1 , mean±SEM), systolic wall thickening (20±6%), and myocardial oxygen consumption (3±1 mL · min −1 · 100 g −1 ) and an increase in exogenous glucose utilization (75±13 μmol · h −1 · g dry wt −1 ). Systolic wall thickening recovered by only 8±3% with reperfusion. Initial distribution of BMS-181321 in the aerobic hearts appeared homogeneous. Washout from the ischemic and reperfused LAD bed was slower than the aerobically perfused LAD bed in the control group (t 1/2 =136±1 versus 80±1 minutes, P <.05), allowing visualization of the LAD region during reperfusion. Tissue activity of BMS-181321 was inversely related to LAD blood flow during ischemia ( r =−.68±.05), and the ratio of BMS-181321 in the LAD region versus normal myocardium was 1.7±0.2. Control swine lacked regional deposition of the tracer in the normally perfused LAD distribution. Conclusions Thus, acute regional ischemia in these studies was visualized as an increase in retention of BMS-181321, suggesting its applicability in the imaging of clinical conditions of myocardial hypoperfusion.