Reduction in myocardial infarct size at 48 hours after brief intravenous infusion of ATL-146e, a highly selective adenosine A2A receptor agonist.

This study was undertaken to determine whether the myocardial infarct-sparing effect of ATL-146e, a selective adenosine A(2A) receptor agonist, persists without a rebound effect for at least 48 h and to determine the optimal duration of ATL-146e treatment in anesthetized dogs. Reperfusion injury after myocardial infarction (MI) is associated with inflammation lasting 24-48 h that contributes to ongoing myocyte injury. We previously showed that an ATL-146e infusion, starting just before reperfusion, decreased inflammation and infarct size in dogs examined 2 h after MI without increasing coronary blood flow. In the present study, adult dogs underwent 90 min of left anterior descending coronary artery occlusion. Thirty minutes before reperfusion, ATL-146e (0.01 microg x kg(-1) x min(-1); n = 21) or vehicle (n = 12) was intravenously infused and continued for 2.5 h (protocol 1) or 24 h (protocol 2). At 48 h after reperfusion hearts were excised and assessed for histological risk area and infarct size. Infarct size based on triphenyltetrazolium chloride (TTC) staining as a percentage of risk area was significantly smaller in ATL-146e-treated vs. control dogs (16.7 +/- 3.7% vs. 33.3 +/- 6.2%, P < 0.05; protocol 1). ATL-146e reduced neutrophil accumulation into infarcted myocardium of ATL-146e-treated vs. control dogs (30 +/- 7 vs. 88 +/- 16 cells/high-power field, P < 0.002). ATL-146e infusion for 24 h (protocol 2) conferred no significant additional infarct size reduction compared with 2.5 h of infusion. A 2.5-h ATL-146e infusion initiated 30 min before reperfusion results in marked, persistent (48 h) reduction in infarct size as a percentage of risk area in dogs with a reduction in infarct zone neutrophil infiltration. No significant further benefit was seen with a 24-h infusion.

Transmyocardial revascularization ameliorates ischemia by attenuating paradoxical catecholamine-induced vasoconstriction.

BACKGROUND: The mechanism by which transmyocardial revascularization (TMR) offers clinical benefit is controversial. We hypothesized that TMR ameliorates ischemia by reversing paradoxical catecholamine-induced vasoconstriction. METHODS AND RESULTS: Chronic ischemic cardiomyopathy was created in 11 dogs by placing ameroid constrictors on the proximal coronary arteries and their major branches. Six weeks later, 35 channels were created percutaneously in the left circumflex artery region, with the left anterior descending artery region serving as control. At rest, wall thickening and myocardial blood flow did not change in the treated region, whereas they deteriorated in the control bed. Contractile and myocardial blood flow reserve increased in the treated region but deteriorated in the control region. There was diminished iodine 123 metaiodobenzylguanidine uptake and a significant reduction in noradrenergic nerves in the treated region compared with the control region, with a corresponding reduction in tissue tyrosine hydroxylase activity. CONCLUSIONS: We conclude that the absence of a catecholamine-induced reduction in MBF reserve and contractile reserve in the TMR-treated region with associated evidence of neuronal injury indicates that the relief of exercise-induced ischemia after TMR most likely results from reversal of paradoxical catecholamine-induced vasoconstriction. These findings may have implications in selecting patients who would benefit from TMR.

Cyclic variation in ultrasonic myocardial integrated backscatter is due to phasic changes in the number of patent myocardial microvessels.

OBJECTIVE: We tested the hypothesis that the cyclic variation in ultrasonic myocardial integrated backscatter (IBS) is due to cardiac contraction-induced changes in the number of patent myocardial microvessels. METHODS: We performed experiments in open-chest dogs in which we increased the number of patent myocardial microvessels without changing cardiac contraction. We achieved this either by direct intracoronary administration of adenosine (group 1; n = 10) or by producing a noncritical coronary stenosis (group 2; n = 7). RESULTS: At baseline, IBS was lowest in systole and highest in diastole. This cyclic variation in IBS was closely associated with the phasic changes in myocardial blood volume that were measured with myocardial contrast echocardiography. During adenosine administration, the diastolic IBS increased from -18.8 +/- 6.5 to -17.5 +/- 6.1 dB (P = .002), with an associated increase in the difference between the systolic and diastolic IBS from 3.8 +/- 1.1 to 4.6 +/- 1.0 dB (P = .009). After a noncritical stenosis was produced, diastolic IBS also increased from -26.6 +/- 8.3 to -25.2 +/- 7.3 dB (P = .001), with an associated increase in the difference between the systolic and diastolic IBS from 3.7 +/- 1.2 to 5.0 +/- 1.0 dB (P = .02). No change in IBS was noted in the bed that did not receive adenosine or the bed that had a stenosis. CONCLUSIONS: The variation in IBS during the cardiac cycle is closely associated with the phasic changes in myocardial blood volume seen during cardiac contraction. When the number of patent myocardial arterioles is increased via adenosine or placement of a noncritical stenosis, diastolic IBS increases with a concomitant increase in IBS cyclic variation. These results may have important clinical applications for the noninvasive diagnosis of noncritical coronary stenosis at rest.

Dobutamine versus dipyridamole for inducing reversible perfusion defects in chronic multivessel coronary artery stenosis.

OBJECTIVES: We hypothesized that, although the effects of dipyridamole and dobutamine on myocardial blood volume (MBV) and mean microbubble velocity (VEL) are different, the magnitude of perfusion deficit during both forms of stress is the same because both drugs unmask abnormal myocardial blood flow (MBF) reserve. BACKGROUND: Both dipyridamole and dobutamine are used clinically as pharmacologic stress agents to induce reversible perfusion defects in patients with chronic coronary artery disease (CAD), but the basis for doing so for dobutamine is not clear. METHODS: Eleven chronically instrumented closed-chest dogs with multivessel coronary stenosis were studied. Hemodynamics, radiolabeled microsphere-derived MBF, and myocardial contrast echocardiography (MCE)-derived myocardial perfusion were measured at rest, after dipyridamole infusion (0.56 mg x kg(-1)), and at peak dobutamine dose (either 30 or 40 microg x kg(-1) x min(-1)). Abnormal beds were defined as those demonstrating an MBF reserve <3 with dipyridamole. RESULTS: In the presence of either drug, MBV increased more in the normal bed than in the abnormal bed, but the increase was higher in both beds with dobutamine than with dipyridamole. The slope of the relationship between MBF reserve and MBV reserve was greater during dobutamine than dipyridamole (p < 0.05). The converse was true for VEL reserve (p < 0.05). Consequently, the relationship between the ratios of either variable, or the product of the two, between the abnormal bed and normal bed was similar for both drugs. CONCLUSIONS: Although the effects of dipyridamole and dobutamine on MBV and VEL are different, both are equally effective in detecting physiologically relevant coronary stenoses on MCE. Both can therefore be used interchangeably with myocardial perfusion imaging for the detection of CAD.

Detection of noncritical coronary stenosis at rest without recourse to exercise or pharmacological stress.

BACKGROUND: Currently, the detection of noncritical coronary stenoses requires some form of stress. We hypothesized that these stenoses can be detected at rest without recourse to stress by assessing adaptive changes that occur distally in the microcirculation. METHODS AND RESULTS: Phasic changes in myocardial video intensity (VI) were measured at rest with continuous high-mechanical-index (MI) contrast echocardiography in 15 open-chest dogs. Data were acquired at baseline and in the presence of different degrees of noncritical coronary stenosis. In 6 of these dogs, capillary blood volume was also measured at baseline using high-MI intermittent imaging with triggering performed separately at both end diastole and end systole. During continuous high-MI imaging, a significant increase in systolic VI was noted with coronary stenoses that resulted in progressive increases in the systolic/diastolic VI ratio with greater degrees of stenosis (P=0.003), with a mildly quadratic relation noted between the two: y=1.3. 10(-6). x(2)+0.01x+0.32, P<0.001, r=0.76, SEE=0.14. There was no difference in capillary blood volume between end diastole and end systole at baseline. CONCLUSIONS: Capillary blood volume does not change between diastole and systole in vivo. Phasic changes in VI are noted at baseline during high-MI continuous imaging. The systolic component is negligible at baseline but increases with increasing levels of noncritical coronary stenosis because of adaptive changes in the microcirculation distal to the stenosis. Thus, the measurement of phasic changes in myocardial VI has the potential to detect coronary stenosis at rest without recourse to any form of stress.