N. Craig Goodman

Myocardial perfusion characteristics and hemodynamic profile of MRX-115, a venous echocardiographic contrast agent, during acute myocardial infarction.

We sought to determine whether MRX-115, a new venous echocardiographic contrast agent, could accurately assess risk area during coronary occlusion and infarct size after reperfusion by using novel imaging modalities meant to selectively enhance contrast signals. In 12 open-chest dogs, venous injections of 0.5 ml of MRX-115 were performed during baseline and coronary occlusion and after reperfusion in the presence of exogenous hyperemia. Ultrasound was transmitted at 2 MHz and received at both 2 MHz (fundamental) and 4 MHz (harmonic) frequencies during continuous and intermittent (end-systolic only) imaging. The risk area during coronary occlusion was compared with technetium autoradiography, and the infarct size after reperfusion was compared with postmortem tissue staining. MRX-115 produced no alterations in hemodynamic or pulmonary gas exchange at any stage. During continuous (both fundamental and harmonic) and intermittent fundamental imaging, measurements of perfusion defects were precluded in many dogs by either poor signal enhancement or posterior wall attenuation. By comparison, these measurements were possible during intermittent harmonic imaging in all dogs except one, which had a very small infarction during reflow. Correlation analysis between perfusion defect size on intermittent harmonic imaging and either autoradiographic risk area or postmortem infarct size gave r values of 0.83 and 0.92, respectively. We conclude that MRX-115 is hemodynamically well tolerated and, when imaging is performed after venous injection, can accurately assess regions of hypoperfusion when combined with intermittent harmonic imaging. These results are promising for the use of this approach in patients with acute myocardial infarction.

A canine model of chronic ischemic cardiomyopathy: characterization of regional flow-function relations

The controversy regarding the mechanism(s) of left ventricular (LV) dysfunction in chronic coronary artery disease is, in part, related to the lack of an appropriate animal model for this condition. We have developed such a model by placing Ameroid constrictors on proximal portions of coronary arteries in dogs who were euthanized (mean of 6 wk) after the development of severe global LV dysfunction noted on two-dimensional echocardiography. The LV end-systolic size nearly doubled ( P < 0.001) over the observation period, and the percent change in LV size from end diastole to end systole decreased by >50% ( P< 0.001). Regional dysfunction was noted in 23 of 24 myocardial beds analyzed within regions showing no gross evidence of infarction. In 10 of these beds, severe dysfunction was noted without a decrease in radiolabeled microsphere-derived myocardial blood flow (MBF). In 13 myocardial beds, decrease in function was associated with a decrease in MBF ( P < 0.001), with close coupling noted between percent wall thickening and MBF. In the beds that exhibited an ultimate decrease in MBF, the decrease in function preceded the decrease in MBF. In conclusion, we describe chronic LV dysfunction in a canine model of multivessel stenosis that closely mimics chronic ischemic LV dysfunction in humans. Whereas regional function is severely reduced in this model, MBF is varied in different segments and at different times during the observation period. These results provide new insights regarding flow-function relations in chronic ischemic LV dysfunction.The controversy regarding the mechanism(s) of left ventricular (LV) dysfunction in chronic coronary artery disease is, in part, related to the lack of an appropriate animal model for this condition. We have developed such a model by placing Ameroid constrictors on proximal portions of coronary arteries in dogs who were euthanized (mean of 6 wk) after the development of severe global LV dysfunction noted on two-dimensional echocardiography. The LV end-systolic size nearly doubled (P < 0.001) over the observation period, and the percent change in LV size from end diastole to end systole decreased by >50% (P < 0.001). Regional dysfunction was noted in 23 of 24 myocardial beds analyzed within regions showing no gross evidence of infarction. In 10 of these beds, severe dysfunction was noted without a decrease in radiolabeled microsphere-derived myocardial blood flow (MBF). In 13 myocardial beds, decrease in function was associated with a decrease in MBF (P < 0.001), with close coupling noted between percent wall thickening and MBF. In the beds that exhibited an ultimate decrease in MBF, the decrease in function preceded the decrease in MBF. In conclusion, we describe chronic LV dysfunction in a canine model of multivessel stenosis that closely mimics chronic ischemic LV dysfunction in humans. Whereas regional function is severely reduced in this model, MBF is varied in different segments and at different times during the observation period. These results provide new insights regarding flow-function relations in chronic ischemic LV dysfunction.

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.

Contractile Versus Microvascular Reserve for the Determination of the Extent of Myocardial Salvage After Reperfusion

Background We hypothesized that microvascular reserve is a better indicator of the extent of viable myocardium postinfarction than contractile reserve, especially in the presence of a residual stenosis of the infarct-related artery. Methods and Results Fifteen dogs with various infarct sizes were studied after reperfusion. Contractile reserve, studied by use of dobutamine echocardiography, and microvascular reserve, studied by use of myocardial contrast echocardiography, were measured both before and after creation of a stenosis. In the absence of a stenosis, the relation between infarct size, expressed as percent of risk area, and wall thickening improved with increasing doses of dobutamine (r=.41, .71, and .90 for 5, 10, and 15 μg·kg−1·min−1, respectively; P<.01 for dobutamine 15 μg·kg−1·min−1). In the presence of a stenosis, however, the relation was poor for all doses of dobutamine (r=.22, .57, and .32 for 5, 10, and 15 μg·kg−1·min−1, respectively; P<.01 for 15 μg·kg−1·min−1 dobutamine in the absence ...

Deoxygenated blood minimizes adherence of sonicated albumin microbubbles during cardioplegic arrest and after blood reperfusion: Experimental and clinical observations with myocardial contrast echocardiography

Both administration of cardioplegic solution and blood reperfusion result in endothelial dysfunction. The transit rate of albumin microbubbles during myocardial contrast echocardiography may reflect endothelial injury. Accordingly, we performed myocardial contrast echocardiography in 12 dogs undergoing cardiopulmonary bypass and measured the myocardial transit rate of microbubbles injected into the aortic root during delivery of cardioplegic solutions containing arterial and venous blood and delivery of pure crystalloid cardioplegic solution. The myocardial transit rate of 99mTc-labeled red blood cells was measured and perfusates were sampled for biochemical analysis at each stage. The microbubble transit rate was markedly prolonged during delivery of crystalloid cardioplegic solution and improved significantly during infusion of blood cardioplegic solution (p < 0.001); venous compared with arterial blood in the solution resulted in a greater rate (p < 0.001). The microbubble transit rate did not correlate with pH, oxygen tension or carbon dioxide tension values, or K+ concentration. The red blood cell transit rate remained constant regardless of the cardioplegic perfusate infused. Myocardial contrast echocardiography was also performed in 12 patients undergoing coronary artery bypass who underwent sequential arterial and venous reperfusion after cardioplegic arrest. The microbubble transit rate was faster with venous than arterial blood reperfusion (p = 0.01), although this gain was diminished when arterial blood reperfusion preceded venous blood reperfusion (p = 0.05). Our results indicate that endothelial dysfunction after cardioplegic arrest may be ameliorated by reperfusion with venous rather than arterial blood.

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.

Reduction of hemorrhage after knee arthroplasty using cryo-based fibrin sealant

The spray application of cryo-based fibrin sealant was evaluated for reducing hemorrhage in a complex, anticoagulated canine model of knee joint arthroplasty. Nine heparinized dogs underwent bilateral knee arthroplasty under tourniquet control with each animal having 3 mL of fibrin sealant sprayed onto one joint and the other joint serving as control. The fibrin sealant significantly reduced total and incremental bleeding as compared to the control side (P < .05). In addition, the hemostatic effectiveness of the fibrin sealant increased as bleeding propensity increased (P < .05). This study suggests that fibrin sealant may reduce bleeding from orthopedic joint replacement in human patients undergoing routine operations as well as those receiving forms of anticoagulation to reduce the incidence of deep venous thrombosis and pulmonary embolus.