Pharmacological stress myocardial perfusion imaging with the potent and selective A(2A) adenosine receptor agonists ATL193 and ATL146e administered by either intravenous infusion or bolus injection.

BACKGROUND: Adenosine (Ado) and dipyridamole are alternatives to exercise stress for myocardial perfusion imaging. Though generally safe, side effects frequently occur that cause patient discomfort and sometimes lead to premature termination of the study or require aminophylline administration. Recently, a new class of A(2A) Ado receptor agonists was synthesized. ATL193 and ATL146e are 2-propynylcyclohexyl-5'-N-ethylcarboxamido derivatives of Ado. The study goals were to evaluate the potency and selectivity of these new compounds on recombinant canine Ado receptors and to evaluate their hemodynamic properties in dogs to assess their usefulness as vasodilators for myocardial perfusion imaging. METHODS AND RESULTS: In assays of recombinant canine Ado receptors, ATL-193 and ATL-146e were highly selective for the A(2A) over the A(1) and A(3) receptors and were more potent than MRE-0470 and CGS-21680. In 16 anesthetized dogs, the agonists were administered by infusion (ATL-193; n=7 normal) or bolus injection (ATL-146e; n=9 critical left anterior descending coronary artery stenosis), and hemodynamic responses were compared with those of Ado. Both agonists produced dose-dependent coronary flow (CF) elevation without provoking the hypotension observed with Ado. After an ATL-146e bolus, the CF increase was sustained for several minutes, providing ample time for injection and myocardial uptake of (99m)Tc-sestamibi, and CF returned to baseline within 20 minutes. The CF increase was completely blocked by the selective A(2A) antagonist ZM241385 (3 microgram. kg(-1). min(-1)). CONCLUSIONS: ATL-193 and ATL-146e are highly potent and selective Ado A(2A) receptor agonists with excellent potential for use as vasodilators for myocardial perfusion imaging. An important advantage of ATL-146e is the ability to administer it by bolus injection.

Assessment of residual coronary stenoses using 99mTc-N-NOET vasodilator stress imaging to evaluate coronary flow reserve early after coronary reperfusion in a canine model of subendocardial infarction.

UNLABELLED: Reperfusion is often incomplete after recanalization therapy because of the presence of residual coronary stenoses. Detecting mild to moderate stenoses requires assessing coronary flow reserve with vasodilator stress. 99mTc-(N-ethoxy-N-ethyl-dithiocarbamato)nitrido (N-NOET) is a viability-independent flow tracer and thus may be well suited for assessing coronary flow reserve in the acute phase of reperfusion. METHODS: Twelve open-chest dogs underwent 60 min of total left anterior descending artery (LAD) occlusion followed by either full reperfusion (group 1; n = 4) or reperfusion through a residual critical stenosis (group 2; n = 8). 99mTc-N-NOET was given during peak vasodilator stress 165 min after reperfusion, and initial and 60-min delayed images were acquired. Regional blood flow was assessed with radiolabeled microspheres. RESULTS: Infarct size was similar in both groups (9% +/- 2% vs. 8% +/- 2% of left ventricle). Both initial (0.61 +/- 0.02 vs. 0.73 +/- 0.01; P < 0.01) and 60-min (0.67 +/- 0.02 vs. 0.80 +/- 0.01; P < 0.01) defect count ratios (LAD/left circumflex coronary artery [LCx]) differentiated between the 2 groups, reflecting the greater diminution in coronary flow reserve in group 2 dogs (LAD/LCx flow ratios = 0.37 +/- 0.04 vs. 0.57 +/- 0.09; P < 0.01). Interestingly, coronary flow reserve in the reperfused zone of group 1 was diminished despite the absence of a stenosis. Thus, the difference in 99mTc-N-NOET uptake between the 2 groups was less than expected. CONCLUSION: In this canine myocardial infarction model with some coronary flow reserve preservation, 99mTc-N-NOET imaging can detect residual coronary stenoses. However, with more prolonged occlusion resulting in more severe endothelial or microvascular dysfunction, it may be difficult to distinguish varying degrees of vessel patency using any coronary flow reserve technique.

Tc-99m sestamibi defect magnitude predicts the amount of viable myocardium after coronary reperfusion despite the presence of severe residual stenosis.

BACKGROUND: Whether technetium-99m-labeled methoxyisobutyl isonitrile (Tc-99m sestamibi) imaging early after reperfusion can detect the amount of salvaged viable myocardium in the presence of a severe residual stenosis remains controversial. METHODS AND RESULTS: Nine dogs underwent total left anterior descending coronary artery (LAD) occlusion for 40 to 180 minutes followed by reperfusion through a flow-limiting stenosis. They were divided into 2 groups based on infarct size (group 1, <15% of risk area; group 2, > or =15%). Triphenyl tetrazolium chloride infarct size was measured by planimetry, and regional flow was quantified by radiolabeled microspheres. Mean infarct size was 9.3% +/- 3.0% of risk area in group 1 versus 51.1% +/- 4.8% in group 2 (P <.01). Tc-99m sestamibi was injected 30 minutes after reperfusion, when the LAD flows were comparable for group 1 (9 +/- 2 mL. min(-1)) and group 2 (9 +/- 1 mL. min(-1)). Left circumflex coronary artery flows were 33 +/- 5 and 32 +/- 9 mL. min(-1) for groups 1 and 2, respectively. Despite administration of Tc-99m sestamibi during diminished residual LAD flow after reperfusion, defect magnitude on ex vivo images in group 1 was significantly less severe than that in group 2, which had larger infarcts (0.71 +/- 0.02 vs 0.42 +/- 0.05, P <.01). This reflects greater salvage and more viability in group 1. CONCLUSION: Resting perfusion imaging with Tc-99m sestamibi accurately determined viability of the infarct zone despite reperfusion through a residual stenosis. Tc-99m sestamibi imaging may prove useful in the clinical setting for the prediction of the amount of salvaged myocardium.

Response to incremental doses of dobutamine early after reperfusion is predictive of the degree of myocardial salvage in dogs with experimental acute myocardial infarction.

OBJECTIVES: We sought to determine whether the inotropic response to dobutamine might be useful for estimating the extent of viable myocardium soon after reperfusion. BACKGROUND: Early identification of viable myocardium in the presence of severe left ventricular dysfunction after reperfusion is important for clinical decision making. METHODS: Nine open-chest dogs had left anterior descending coronary artery occlusion for 40 to 180 min, followed by gradual reperfusion. The systolic thickening response to incremental dobutamine doses was measured with ultrasonic crystals and regional flow by microspheres. RESULTS: Dogs were divided into two groups based on triphenyl tetralozium chloride infarct size (group 1: 9.3 +/- 3.0% risk area; group 2: 51.1 +/- 4.8%). In group 2 dogs with larger infarcts, regional flow during peak dobutamine was lower than it was in group 1 in endocardial (1.15 +/- 0.22 vs. 2.64 +/- 0.33 mL x min(-1) x g(-1)) and midwall (1.47 +/- 0.32 vs. 2.92 +/- 0.36 mL x min(-1) x g(-1)) layers, and endocardial flow in group 2 failed to increase from baseline (0.96 +/- 0.07 vs. 1.15 +/- 0.22 mL x min(-1) x g(-1)). Group 1 dogs demonstrated a dose dependent increase in systolic thickening with dobutamine versus a blunted response in group 2. The inotropic response to only 10 microg x kg(-1) x min(-1) of dobutamine was predictive of the degree of myocardial salvage. CONCLUSIONS: In the early postischemic stunning phase of reperfusion, the inotropic response to dobutamine is predictive of the degree of myocardial salvage and ultimate infarct size. The ability to distinguish between stunned versus necrotic myocardium early after reperfusion was most likely due to the presence of subendocardial flow reserve during dobutamine in dogs with predominantly salvaged myocardium.

Optimal timing for initial and redistribution technetium 99m-N-NOET image acquisition.

BACKGROUND: Bis (N-ethoxy, N-ethyl dithiocarbamato) nitrido technetium-99m (V) (Tc-99m-N-NOET) is a new Tc-99m-labeled myocardial perfusion imaging agent that redistributes. We sought to determine the optimal timing for acquiring initial and delayed images to maximize sensitivity for the detection of coronary stenoses. METHODS: Twelve anesthetized dogs with critical stenoses of the left anterior descending coronary artery were infused with adenosine (250 microg/kg/min) or MRE-0470, an adenosine A2a agonist (0.6 microg/kg/min x 10 minutes), and Tc-99m-N-NOET (8 mCi; 296 MBq) was injected intravenously at peak flow. Myocardial and lung Tc-99m-N-NOET activities were determined by serial quantitative imaging and arterial blood sampling was performed over 2 hours. RESULTS: Left anterior descending/left circumflex artery defect count ratios showed rapid redistribution during the first 10 minutes after Tc-99m-N-NOET injection (0.66 +/- 0.02 at 2 minutes to 0.73 +/- 0.01 at 10 minutes; P < .01). Redistribution was nearly complete by 120 minutes (defect ratio = 0.87 +/- 0.03; P < or = .01 vs 2 minutes). Lung activity fell significantly during the first 10 minutes from a heart/lung activity ratio of 1.07 +/- 0.05 (2 minutes) to 1.44 +/- 0.09 (10 minutes; P < or = .01). CONCLUSION: Initial stress Tc-99m-N-NOET images should be acquired within 10 minutes after injection, whereas delayed images can be obtained as early as 2 hours later. Lung activity clears rapidly, permitting acquisition of good-quality poststress cardiac images. These Tc-99m-N-NOET uptake and redistribution kinetics after vasodilator stress provide important information for designing clinical imaging protocols for optimal identification of inducible ischemia.