Background— Angiogenesis is a critical determinant of tumor growth and metastasis. We hypothesized that contrast-enhanced ultrasound (CEU) with microbubbles targeted to α v -integrins expressed on the neovascular endothelium could be used to image angiogenesis. Methods and Results— Malignant gliomas were produced in 14 athymic rats by intracerebral implantation of U87MG human glioma cells. On day 14 or day 28 after implantation, CEU was performed with microbubbles targeted to α v β 3 by surface conjugation of echistatin. CEU perfusion imaging with nontargeted microbubbles was used to derive tumor microvascular blood volume and blood velocity. Vascular α v -integrin expression was assessed by immunohistochemistry, and microbubble adhesion was characterized by confocal microscopy. Mean tumor size increased markedly from 14 to 28 days (2±1 versus 35±14 mm 2 , P <0.001). Tumor blood volume increased by ≈35% from day 14 to day 28, whereas microvascular blood velocity decreased, especially at the central portions of the tumors. On confocal microscopy, α v β 3 -targeted but not control microbubbles were retained preferentially within the tumor microcirculation. CEU signal from α v β 3 -targeted microbubbles in tumors increased significantly from 14 to 28 days (1.7±0.4 versus 3.3±1.0 relative units, P <0.05). CEU signal from α v β 3 -targeted microbubbles was greatest at the periphery of tumors, where α v -integrin expression was most prominent, and correlated well with tumor microvascular blood volume ( r =0.86). Conclusions— CEU with microbubbles targeted to α v β 3 can noninvasively detect early tumor angiogenesis. This technique, when coupled with changes in blood volume and velocity, may provide insights into the biology of tumor angiogenesis and be used for diagnostic applications.

No abstract

Background We hypothesized that by detecting regions with adequate collateral-derived myocardial blood flow (MBF) within the risk area (RA), we could predict ultimate infarct size (IS) at the time of coronary occlusion. Methods and Results Group 1 dogs (n=15) underwent coronary occlusion without reperfusion, whereas group 2 dogs (n=6) underwent both occlusion and reperfusion. RA was measured with aortic root injections of microbubbles. Myocardial contrast echocardiography (MCE) was performed with high mechanical index intermittent harmonic imaging at pulsing intervals (PIs) of <1 to 30 cardiac cycles during an intravenous infusion of microbubbles (Sonozoid). MBF was measured with radiolabeled microspheres, and postmortem tissue staining was used to determine IS. Perfusion defect size (PDS) on MCE varied with the PI and was largest at a PI of 2.6±0.4 seconds, where it correlated well with RA ( r =0.82). PDS was smallest at a PI of ≥10.6±1.5 seconds, where it correlated closely with IS ( r ≥0.92). Areas that underwent necrosis could be identified early after coronary occlusion as having the lowest microvascular flow velocity (β) and MCE-derived MBF (A×β). The results were similar with or without reperfusion. Because of variability in collateral-derived MBF, there was no correlation between RA and ultimate IS ( P =0.37). The extent of regional dysfunction also correlated poorly with IS ( r =0.31). Conclusions MCE can be used immediately after coronary occlusion to define ultimate IS by measuring the magnitude and spatial extent of collateral-derived residual MBF within the RA. Thus, it could help individualize risk and management in acute myocardial infarction.

MCE revealed striking temporal heterogeneity in the spatial distribution of myocardial perfusion during postischemia reflow and either significantly underestimated or did not correlate with infarct size during reperfusion. Because of abnormalities in coronary vascular reserve specific to infarcted tissue, MCE in conjunction with intravenous dipyridamole depicted, in vivo, the actual topography of the infarct with remarkable accuracy.

minnier@ohsu.edu

Background-We hypothesized that by using our newly defined method of destroying microbubbles and measuring their rate of tissue replenishment, we could assess the transmural distribution of myocardial perfusion. Methods and Results-We studied 12 dogs before and after creation of left anterior descending coronary artery stenoses both at rest and during hyperemia (nϭ62 stages). Microbubbles were administered as a constant infusion, and myocardial contrast echocardiography (MCE) was performed with the use of different pulsing intervals. The video intensity versus pulsing interval plots derived from each myocardial pixel were fitted to an exponential function: yϭA(1Ϫe ␤t ), where A reflects microvascular cross-sectional area (or myocardial blood volume), and ␤ reflects mean myocardial microbubble velocity. The product A ⅐ ␤ represents myocardial blood flow (MBF). Average values for these parameters were derived from the endocardial and epicardial regions of interest placed over the left anterior descending coronary artery bed. Radiolabeled microsphere-derived MBF was also measured from the same regions. There was poor correlation between radiolabeled microsphere-derived MBF and A-endocardial/epicardial ratios (EER) (rϭ0.46). The correlation with ␤-EER was better (rϭ0.69, PϽ0.01). The best correlation with radiolabeled microsphere-derived MBF-EER was noted with A ⅐ ␤-EER (rϭ0.88, PϽ0.01). Conclusions-The transmural distribution of myocardial perfusion can be accurately assessed with MCE with the use of our newly described method of tissue replenishment of microbubbles after their ultrasound-induced destruction. In the model studied, an uncoupling of the transmural distribution of MBF and myocardial blood volume was observed during reversal of the MBF-EER. (Circulation. 1998;98:1912-1920.)

No abstract

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.