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Background —We hypothesized that the persistence of albumin microbubbles within the myocardium during crystalloid cardioplegia (CP) infusion and ischemia-reperfusion (I-R) occurs because of endothelial injury. Methods and Results —The myocardial transit rate of albumin microbubbles was measured in 18 dogs perfused with different CP solutions and in 12 dogs undergoing I-R. Electron microscopy with cationized ferritin labeling of the glycocalyx was performed in 9 additional dogs after CP perfusion and in 3 additional dogs undergoing I-R. Microbubble transit was markedly prolonged during crystalloid CP perfusion. The addition of whole blood to the CP solution accelerated the transit rate in a dose-dependent fashion ( P P P + content, pH, P o 2 , osmolality, viscosity, and flow rate of the perfusate. Similarly, a proportion of microbubbles persisted in the myocardium after I-R, which was related to the duration of ischemia ( P Conclusions —Sonicated albumin microbubbles persist within the myocardium in situations in which the endothelial glycocalyx is damaged. The measurement of the myocardial transit rate of albumin microbubbles may provide an in vivo assessment of endothelial glycocalyx damage.

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 − 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 − 1 ·min − 1 dobutamine in the absence of a stenosis). There was a fair correlation between infarct size and perfusion defect size on myocardial contrast echocardiography after reperfusion ( r =.82), with the defect size underestimating infarct size by approximately 20%. This relationship improved ( P r =.99) and dobutamine ( r =.94) in the absence of a stenosis. The correlations between infarct size and perfusion defect on myocardial contrast echocardiography also remained good in the presence of a stenosis ( r =.95 and .81 for adenosine and dobutamine, respectively; P =NS compared with stenosis). Conclusions Microvascular reserve is superior to contractile reserve for definition of the spatial topography of necrosis and hence the extent of viable myocardium within the infarct bed after reperfusion, particularly when a residual stenosis is present in the infarct-related artery.

Background We have previously shown that the intravascular rheology of sonicated air-filled albumin microbubbles is similar to that of red blood cells (RBCs) and that their myocardial transit rate is also similar to that of RBCs in the beating canine heart. In the present study, we tested the hypothesis that the myocardial transit rates of these microbubbles reflect those of RBCs in humans at different coronary flow rates. Methods and Results RBC and microbubble transit rates were measured in 17 patients undergoing coronary angiography: in 8, measurements were made only at rest, whereas in 9, they were performed both at rest and during a pacing-induced increase in coronary blood flow. A γ-variate function was used to derive mean RBC and microbubble transit rates from the time-activity and time-intensity plots after the left main injection of RBCs and microbubbles, respectively. There was linear correlation between the myocardial transit rates with both tracers with the slope of the correlation determined by the specific echocardiographic system that was used. Microbubble transit rate consistently overestimated RBC transit rate due to artificial narrowing of the time-intensity curves caused by chest wall attenuation of the echocardiographic signal, which was confirmed through in vitro experiments. Conclusions There is close correlation between air-filled albumin microbubbles and RBC rheology in the human myocardium. The use of these microbubbles in the cardiac catheterization laboratory could, therefore, provide further insights into myocardial blood flow/myocardial blood volume relations in humans.

The number of cardiac catheterizations performed yearly is growing with correspondingly increasing amounts of morbidity, complications, and hospital costs. This study suggests that fibrin sealant instillation via an arterial sheath at the completion of femoral catheterization may improve hemostasis. Results using fibrin sealant in 12 unheparinized dogs documented significant reductions (McNemar's exact test) versus control for groin ecchymoses (1 versus 8, P = .008) and radiolabeled hematoma formation (0 versus 7, P = .016). Also swelling was less in the fibrin sealant treated groins when compared to control groins (1 versus 6, P = .125), but failed to reach statistical significance. Results in eight heparinized dogs (activated clotting time 374 +/- 22, mean +/- SEM) revealed a statistically significant reduction in signs of gross bleeding in the fibrin sealant-treated groins (1 versus 8, P = .016). This method may contribute to reduced morbidity, complications, and length of hospitalization. It may also allow for earlier patient mobilization after cardiac catheterization.

The mean transit rate of microbubbles of air obtained from time-intensity curves during contrast echocardiography can be used to evaluate flow through a vascular system, provided the volume of distribution of the system remains constant. We hypothesized that attenuation commonly associated with contrast echocardiography distorts the time-intensity curves, producing an error in the estimation of the mean transit rate of the microbubbles. The purpose of this study was to characterize this distortion with computer simulations and to study the effect of attenuation on the estimation of mean transit rate in an in vitro experiment. We also sought to determine if removing the data points from the time-intensity plots that visually can be attributed to attenuation before curve fitting can minimize the error in the estimation of mean microbubble transit rate. In both computer simulations and experimentally acquired in vitro data, attenuation distorted the time-intensity curves, producing an underestimation of mean microbubble transit rates. The mean microbubble transit rate decreased with an: increase in microbubble concentration. Removing the points that visually were attributed to attenuation before curve fitting did not correct this error completely in the computer-simulated data and failed to correct it at all in the experimental data. These results have major practical implications in assessing mean microbubble transit rates during contrast echocardiography.

BACKGROUND Although dobutamine echocardiography is being increasingly used to determine the presence of viable myocardium in patients who have undergone successful reperfusion therapy, the physiological basis for such a use has not been clearly defined. Because postischemic myocardium has contractile reserve, we hypothesized that the absolute degree of wall thickening induced by dobutamine during reflow would be directly related to the amount of myocardium that has escaped necrosis. METHODS AND RESULTS Three groups of 12 dogs each were studied at baseline and during 2 to 6 hours of coronary artery occlusion and 15 minutes of reperfusion. In group 1 dogs, which did not receive dobutamine during any of these stages, percent wall thickening at these stages was 32 +/- 6%, -2 +/- 6%, and 5 +/- 6%, respectively, and there was no relation between infarct size and percent wall thickening during reflow (r = .20, P = .51). In group 2 dogs, which received 15 micrograms/kg per minute of dobutamine at all stages, wall thickening at these stages was 40 +/- 8%, 0 +/- 8%, and 19 +/- 10%, respectively, and a good inverse correlation was noted between infarct size and percent wall thickening during reflow (r = -.81, P = .001). In group 3 dogs, in which wall thickening during reflow was measured both before and during infusion of 15 micrograms/kg per minute of dobutamine, it was 5 +/- 8% and 18 +/- 14%, respectively, at these stages. Although the correlation between infarct size and percent wall thickening was poor in the absence of dobutamine (r = .36, P = .26), an excellent inverse correlation was noted between the two in the presence of dobutamine (r = -.93, P < .001). A fair inverse correlation was also noted between infarct size and the absolute change in wall thickening induced by dobutamine (r = -.72, P < .01). Maximal wall thickening was noted at a dobutamine dose of 15 micrograms/kg per minute, and lower doses did not elicit thickening in the presence of larger infarcts despite the presence of viable myocardium. CONCLUSIONS When myocardial necrosis coexists with post-ischemic myocardial dysfunction and no residual coronary stenosis, the absolute degree of wall thickening during dobutamine can be used to determine the extent of myocardium that has escaped necrosis. The dose of dobutamine needed to elicit maximal thickening of the postischemic myocardium is related to the amount of myocardial necrosis.

BACKGROUND The purpose of this study was to determine whether myocardial perfusion can be quantified with myocardial contrast echocardiography using left atrial (LA) injection of contrast. METHODS AND RESULTS Based on a series of in vitro and in vivo experiments, the optimal dose of sonicated albumin microbubbles injected into the LA for establishing a linear relation between video intensity and blood volume in the anterior myocardium was determined. In 10 open-chest dogs, myocardial blood flow (MBF) was augmented by increasing myocardial blood volume (MBV) with an intravenous infusion of phenylephrine HCl. In the presence of this drug, left anterior descending artery stenosis was produced, followed by release of stenosis, to change MBF within the anterior myocardium. MBV was calculated by dividing radiolabeled microsphere-derived MBF by microbubble transit rate. There was close coupling between MBF and MBV in the anterior myocardium during LA injection of contrast (y = 1.0x-0.03, SEE = 1.07, r = .92, P < .001). An excellent correlation was also noted between background-subtracted peak video intensity and MBV (y = 0.24x + 0.73, SEE = 0.36, r = .88, P < .001). On multivariate analysis, background-subtracted peak video intensity correlated best with MBV. CONCLUSIONS Myocardial perfusion can be quantified from time-intensity curves derived from the anterior myocardium after LA injection of contrast. Background-subtracted peak video intensity in this situation correlates closely with MBV. When MBV and MBF are closely coupled, such as during inotropic stimulation of the heart, background-subtracted peak video intensity also correlates closely with MBF. Since there are similarities in the models of LA and venous injections, these data indicate that it may be feasible to quantify myocardial perfusion with myocardial contrast echocardiography after venous injection of contrast.

We postulated that the pulmonary transit rate of sonicated albumin microbubbles, which have an intravascular rheology similar to that of red blood cells, would be directly proportional to cardiac output (CO) and inversely proportional to pulmonary blood volume (PBV). Accordingly, 4 ml of Albunex ultrasound contrast agent (0.5 billion/ml of 4.3 mu bubbles) was injected into the right atrium of six dogs (Group I) during simultaneously performed two-dimensional echocardiography, and the time between the initial appearance of the bubbles in the right and left ventricle, respectively, was measured. CO was either increased (by intravenous infusion of 15 micrograms/kg/min of dobutamine) or decreased (by producing left ventricular ischemia or by administering 2 mg of intravenous propranolol) in a random order and microbubbles were injected again. At each stage, thermodilution CO was measured. There was a close linear relation between CO and pulmonary transit rate of Albunex in each dog with the correlation coefficient ranging from 0.79 to 0.99, with a mean of 0.92. Pulmonary blood volume was derived in each dog from the reciprocal of the slope of the regression between CO and pulmonary transit rate and varied from 106 to 261 ml in the six dogs with a mean value of 178 +/- 64 ml. There was excellent interobserver and intraobserver correlation (r = 0.99 each) for determining the pulmonary transit rate of Albunex. The reproducibility of pulmonary transit rate estimation from repeated contrast injections at the same hemodynamic state in another group of six dogs (Group II) was also good (r = 0.99). It is concluded that the pulmonary transit rate of Albunex ultrasound contrast agent can be used to assess directional changes in CO and to measure pulmonary blood volume. This method may have clinical applications.

A contrast echocardiography workstation was developed and used to determine whether the myocardial transit rate of microbubbles injected into the left atrium would also correlate with regional myocardial blood flow (RMBF). End diastolic images were analyzed and time intensity plots are automatically derived from the anterior myocardium. It has been found that there is a close linear correlation between myocardial microbubble transit rate and RMBF in the 7 dogs tested (r=0.83, SEE=0.14, p >

Background The aim of this study was to determine whether myocardial contrast echocardiography (MCE) during exogenous vasodilation can accurately delineate infarct size, and hence the extent of myocardial viability, both immediately (15 minutes) and late (3 hours) after reperfusion when postreflow coronary hyperemia is still present. Methods and Results Twenty-one open-chest anesthetized dogs underwent 3 to 6 hours of coronary occlusion followed by reperfusion. MCE was performed 15 minutes after reflow before and during infusion of 0.2 mg·kg −1 ·min −1 adenosine IV. In 12 dogs, infarct size was measured at this time. In the remaining 9 dogs, reperfusion was continued for 3 hours, when MCE was repeated before and after an infusion of 0.56 mg·kg −1 ·min −1 dipyridamole IV and infarct size was measured. In the absence of adenosine, MCE perfusion defect at 15 minutes underestimated infarct sizes at both 15 minutes and 3 hours, whereas in the presence of adenosine, the estimate of infarct size was more accurate. Similarly, in the absence of dipyridamole, although MCE perfusion defect underestimated infarct size (both measured 3 hours after reflow), in the presence of dipyridamole, the estimate of infarct size was more accurate. Conclusions By unmasking abnormalities in flow reserve within the infarct bed, MCE in conjunction with coronary vasodilators can accurately predict infarct size both 15 minutes and 3 hours after reperfusion. Thus, MCE can be used for assessing the extent of myocardial viability both immediately and late after reperfusion when postreflow coronary hyperemia is still present.

This study was designed to answer the question of whether, despite their theoretic superiority, integrated backscatter imaging (IBS) and digital data acquisition (DA) offer any advantage over conventional echocardiography (CE) during quantitative myocardial contrast echocardiography. In vitro experiments were performed (1) to determine the microbubble concentration versus videointensity relationships for CE and IBS and (2) to define the relationship between flow through and microbubble transit rates for CE and IBS. These data were stored on videotape. In vivo experiments were performed whereby microbubbles were injected into the left anterior descending artery at different flow rates in 14 dogs and IBS and CE data were stored both in difital format and on videotape. Although the level of compression did not affect the microbubble concentration versus videointensity plots during IBS compared with CE, in practical terms the mean transit rate, peak intensity, and area under the curve were not affected by the level of compression for both forms of imaging as long as the postprocessing used for CE imaging was linear and the microbubble dose was small. In addition, although DA resulted in higher peak intensity and area under the curve compared with storage on videotape because of its broader dynamic range, the correlation between these measurements was excellent with both forms of image storage. We conclude that, although differences exist between CE and IBS and between DA and analog acquisition, these differences do not significantly affect the derivation of parameters from time-intensity plots during myocardial contrast echocardiography when contrast material is injected into a coronary artery.

Background We hypothesized that the degree and spatial extent of blood flow mismatch in beds supplied by stenoses that are not flow-limiting at rest can be quantified with myocardial contrast echocardiography (MCE) using left atrial (LA) and right atrial (RA) injections of contrast during pharmacologically induced coronary hyperemia. Methods and Results In 12 open-chest dogs, MCE was performed and myocardial blood flow (MBF) was measured by use of radiolabeled microspheres at baseline and during phenylephrine-induced coronary hyperemia. In the presence of this drug, stenoses were placed during different stages on the left anterior descending (LAD) and left circumflex (LCx) coronary arteries, and MCE and MBF assessments were performed. LA injections of 2 mL of 0.5 billion/mL microbubbles (mean diameter, 4.3 μm) were performed at each stage in all 12 dogs, and RA injections of 10 mL of 6 billion/mL microbubbles (mean diameter, 3.7 to 5.3 μm) were administered in 7 dogs. MCE images in which the contrast disparity between the LAD and LCx beds was maximal were digitally subtracted from precontrast images, and mean videointensities in these beds were measured after the dynamic range of gray-scale intensities was increased in the subtracted image and the image was color coded. The region showing hypoperfusion during LAD stenosis was planimetered and expressed as a percentage of the myocardial area in the short-axis slice. There was an excellent correlation between the LAD/LCx bed videointensity ratio and LAD/LCx bed MBF ratio ( y =0.5 x +0.44, r =.91, P y =0.8 x +4.2, r =.90, P y =0.86 x +3.4, r =.93, P Conclusions Coronary stenoses, which are not flow limiting at rest, can be detected and the degree and spatial extent of blood flow mismatch during pharmacologically induced coronary hyperemia can be quantified with MCE using LA and RA injections of contrast. Thus, it is possible that the severity of coronary stenoses and the quantum of myocardium in jeopardy could be quantified in the future with MCE using venous injection of contrast.

This study was designed to identify a concentration of sonicated albumin microspheres that is safe, useful in determining graft patency, and provides an estimate of regional myocardial perfusion. The study included 8 patients between 50 and 72 years of age who were undergoing coronary artery bypass grafting. All patients were hemodynamically stable with left ventricular ejection fractions ≥ 0.35. None had congestive heart failure or myocardial infarction with in 4 months prior to the study. All had normal baseline neurologic and renal functions, and none had experienced allergic reactions to blood products or contrast dyes. A standard median sternotomy was performed for exposure of the heart at surgery, and saphenous veins were harvested and used for grafting. Intraoperative epicardial echocardiography (EE), always in the left ventricle short-axis at midpapillary level, was performed before and after grafting to determine regional myocardial wall motion. Sonicated albumin microspheres were prepared and injected into a single vein graft using an 18-gauge needle; 20 3 106, 100 3 106, and 200 3 106 microspheres were injected into the first graft sequentially. All other vein grafts were injected once with the dose that gave optimal contrast enhancement in the initial graft studied. In each patient, a minimum of 3 and maximum of 5 injections were performed, and graft perfusion was studied using EE. Graft flow, blood pressure, and electrocardiographic (ECG) measurements were continuously monitored, with a final EE performed after weaning the patient off cardiopulmonary bypass to assess wall motion. Preliminary results showed that no patient had adverse effects during or after the study and all remained hemodynamically stable. No significant arrhythmias or ECG changes were recorded up to 72 hours postoperatively. Although hyperemia occurred immediately after 13 injections, in all cases it was mild and graft flow returned rapidly to baseline. Graft pressure and wall motion remained unchanged. The best contrast perfusion images, as measured by time—intensity curves, were obtained with injecting 1 ml of the 100 3 106 microspheres/ml solution. We conclude that sonicated albumin microspheres are a safe and effective contrast agent to assess regional myocardial perfusion and vein graft patency using EE.

The non-infarcted region within the reperfused myocardium has both contractile and microvascular reserve, which form the basis for the assessment of myocardial viability: the former for dobutamine echocardiography (DE) and the latter for myocardial contrast echocardiography (MCE), The purpose of this study was to evaluate which of the two, DE or MCE, is better for the assessment of myocardial viability after reperfusion, Accordingly, 15 openchest dogs underwent 3–6 hr of coronary occlusion followed by reperfusion, DE (using 15 μg/kg/min of dobutamine) and MCE (using an aortic root injection of 1–5 ml of Albunex®) were performed during reperfusion both in the absence and presence of a critical stenosis supplying the reperfused myocardium, Infarct size was measured using triphenyltetrazolium chloride (TTC). During reperfusion, in the absence of dobutamine, there was a poor correlation between infarct size and percent wall thickening (r = -0.49, P = 0.07). However, the relation between infarct size and size of perfusion defect on MCE was good (r = 0.82, P l 0.01). When no coronary stenosis was present, a close inverse relation between infarct size and percent wall thickening was observed in the presence of 15 μg/kg/min of dobutamine (r = -0.92, P l 0.01). In the presence of a critical stenosis, however, when 15 μg/kg/min of dobutamine was infused, although the relation between infarct size and perfusion defect on MCE remained good (r = 0.80, P l 0.01), that between infarct size and wall thickening deteriorated significantly (r = 0.22, P = 0.49). We conclude that both contractile and microvascular reserve provide an excellent assessment of the extent of myocardial viability after reperfusion as long as there is no residual coronary stenosis. In the presence of a residual critical coronary stenosis, whereas contractile reserve may be exhausted, the spatial extent of perfusion abnormality still predicts the extent of myocardial salvage.

We hypothesized that coronary stenoses, which are not flow-limiting at rest, can be detected and the degree and spatial extent of blood flow mismatch can be quantified during pharmacologically-induced coronary hyperemia using FS-069, a new intravenous contrast agent. In 15 open-chest dogs, myocardial contrast echo (MCE) was performed using 1-2 ml of FS-069 injected intravenously and myocardial blood flow (MBF) was measured using radiolabeled microspheres at baseline and during dipyridamole (0.56 mg/kg) induced coronary hyperemia. In the presence of this drug, a stenosis was placed either on the left anterior descending (LAD) (n = 9) or the left circumflex (LC) (n = 6) coronary arteries and MCE and MBF assessment were repeated at each stage. MCE images, where contrast disparity between LAD and LC beds was maximal, were digitally-subtracted from pre-contrast images and mean videointensities in the LAD and LC beds were measured. There was a good correlation between the LAD/LC bed videointensity ratio and LAD/LC bed MBF ratio (y = 0.2x + 0.71, r = 0.77, p = 0.0001, SEE = 0.16, n = 45). In addition, the region showing hypoperfusion during LAD or LC stenosis was planimetered and expressed as a percent of the myocardial area in the short-axis slice. There was also a fair correlation between the hypoperfused bed size on MCE and the hypoperfused myocardium as determined by radiolabeled microspheres during LAD or LC stenosis (y = 0.8x + 3.3, r = 0.65, p l 0.001, SEE = 4.2, n = 15). We conclude that it is possible to detect coronary stenoses that are not flow limiting at rest with MCE using intravenous injection of FS-069 during pharmacologically-induced coronary vasodilation. The magnitude of blood flow mismatch and the spatial extent of relative hypoperfusion can also be quantified using this approach. Thus it is possible not only to detect the presence of coronary stenoses, but also to quantify their severity and the quantum of myocardium they supply using MCE from venous injection of 1-2 ml of this new contrast agent.

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. (J Therac Cardiovasc Surg 1997;113:1100-8)

The transit rate of sonicated albumin microbubbles (Albunex ® , mean size = 4.3 μ) has been shown to correlate with that of radiolabelled red blood cells in the blood perfused beating heart. We have previously demonstrated that the transit rate of these microbubbles is decreased during hyperthermia-induced microvascular injury In this study, we hypothesized that microbubble transit rate could be used as a marker of reversible endothelial injury during myocardial contrast echocardiography (MCE). We produced endothelial injury by inducing different degrees of myocardial hypoxia. This was accomplished by perfusing an arrested heart with either arterial blood, venous blood, or blood diluted to different degrees with a crystalloid cardioplegia solution. The flow rate into the cross-clamped aorta was held constant in each dog (mean = 170 mi), as was the perfusate temperature (mean = 27°C). Perfusate hematocrit varied from 0–27%, while perfusate pO 2 ranged from 15–600 mmHg. MCE was performed by injecting 2 ml of a 1:1 dilution of Albunex ® into the perfusate line and images were acquired at a sampling rate of 30 Hz. The mean transit rate of Albunex ® through the myocardium was derived by fitting a λ-variate function to the background-subtracted time-intensity plots. The mean transit rate of Albunex ® decreased as the hematocrit decreased. On multivariate analysis, the hematocrit and the pO 2 were the best correlates of mean microbubble transit rate (y = 0.06 hematocrit - 0.002 pO 2 + 0.72, r = 0.72, p l 0.001). We conclude that MCE, can be used to assess reversible microvascular injury. This technique, therefore, has great potential for understanding dynamic changes in microvascular function in-vivo, particularly those modulated by the endothelium.