Assessment of myocardial perfusion by myocardial contrast echocardiography using harmonic power and the transvenous contrast agent SHU 563A in acute coronary occlusion and after reperfusion.

BACKGROUND: Harmonic power Doppler imaging is a novel technique for the assessment of myocardial perfusion by contrast echocardiography. In this study, we examined whether myocardial contrast echocardiography using harmonic power Doppler and the new transvenous contrast agent SHU 563A can identify myocardial perfusion defects during coronary occlusion and reperfusion. METHODS: To assess the potential of this technique, we occluded either the left anterior descending coronary artery or the circumflex coronary artery for 2 to 3 h followed by 1 h reperfusion in 10 dogs in an open chest model. After transvenous administration of SHU 563A, an air-filled, polymeric contrast agent, myocardial contrast echocardiography was performed in short and long axis views with triggered harmonic power Doppler imaging after coronary occlusion and reperfusion. Post-mortem triphenyl tetrazolium chloride staining was performed to verify infarction. Harmonic power Doppler and anatomic data were analyzed by independent observers. RESULTS: During coronary occlusion, harmonic power Doppler showed perfusion defects in all 10 dogs. The defect size in the short axis view at papillary muscle level ranged 4-51% (14+/-13%) and 3-43% (16+/-10%) in the long axis view (% total LV slice area). After reperfusion (1 h) and infusion of dipyridamole (0.56 mg/kg), power Doppler demonstrated perfusion defects in seven dogs: 0-20% (9+/-8%) (short axis view) and 0-48% (13+/-14%) (long axis view). Five dogs showed anatomic infarction. The anatomic infarct area was 0-18% (6+/-8%) (slices corresponding to the echocardiographic short axis images). Perfusion defect size by harmonic power Doppler correlated well with residual infarct size (r=0.82, P<0.01). CONCLUSIONS: Myocardial contrast echocardiography using harmonic power Doppler and the new contrast agent SHU 563A accurately displays perfusion defects during acute coronary occlusion and after reperfusion. The site and size of residual myocardial infarction is reliably identified on line, in color. This approach has excellent potential for clinical application.

[Myocardial contrast echocardiography with harmonic power Doppler and lung traversing SHU 563A ultrasound contrast medium for imaging myocardial perfusion disorders]. / Myokardiale Kontrastechokardiografie mit harmonischem Power Doppler Verfahren und dem lungengängigen Ultraschallkontrastmittel SHU 563A zur Darstellung von myokardialen Perfusionsstörungen. Tierexperimentelle Untersuchungen bei akuter Ischämie und nach Reperfusion.

The current approach for the assessment of myocardial perfusion using contrast echocardiography involves black-and-white gray scale imaging in b-mode. For better appreciation of perfusion abnormalities, off-line postprocessing techniques including color encoding are used. In this study, we examined whether we could exploit the contrast microbubble response to high ultrasound amplitude--the phenomenon of stimulated acoustic emission--that could be recorded with harmonic power Doppler (HPD) in color to identify myocardial perfusion defects. To assess the potential of HPD, we occluded branches of the left coronary artery for 2-3 h followed by 1 h reperfusion in 10 dogs. After transvenous administration of the new air-filled contrast agent SHU 563A, echocardiographic imaging was performed with ECG-triggered harmonic b-mode (HBM) and the harmonic power Doppler (HPD) approach in different short (SAX) and long axis (LAX) views. Post-mortem TTC staining was performed to verify infarction. HBM, HPD and TTC data were analyzed by independent observers. During coronary occlusion, HPD with SHU 563A showed perfusion defects in 10 dogs in all SAX and LAX views. HBM demonstrated perfusion defects in all dogs in SAX and in 8 dogs in LAX. The correlation of perfusion defect size between HPD and HBM images was good (SAX: r = 0.9, p < 0.001, LAX: r = 0.7, p < 0.01). One hour after reperfusion, both HPD and HBM showed perfusion defects with SHU 563A in 7 dogs. Five dogs showed TTC evidence of infarction. Perfusion defect size by HPD correlated well with residual infarct size (r = 0.8, p < 0.01), while defect size by HBM showed poor correlation (r = 0.3, p = ns). Myocardial contrast echocardiography with HPD and contrast agent SHU 563A identifies perfusion defects in acute coronary occlusion as reliably as HBM. After reperfusion HPD and SHU 563A accurately portray the site and size of residual myocardial infarction on line, in color. This approach has excellent potential for clinical application.

Delineation of experimental liver tumors in rabbits by a new ultrasound contrast agent and stimulated acoustic emission.

RATIONALE AND OBJECTIVES: A new ultrasound contrast agent (SH U 563 A), consisting of hollow biodegradable polymeric microparticles, and a new imaging technique (stimulated acoustic emission) were used for delineation of experimental liver tumors. After intravenous injection, these microparticles are phagocytosed by cells of the reticuloendothelial system (RES) and create a color-coded signal using color Doppler. Because of the different distribution of phagocytic cells in healthy liver tissue and tumors, the delineation of focal lesions was to be tested. METHODS: Sixteen rabbits with VX2 liver tumors received doses of 0.15-mL SH U 563 A per kilogram of body weight intravenously. Liver investigations (UM9, HD1, L10.5, ATL, Bothell, USA) were performed in vivo before and after SH U 563 A application in B and color Doppler modes. Additionally, the liver and spleen of these rabbits were examined ex vivo in color Doppler. The sonographic diagnosis was confirmed by pathology. RESULTS: After application of SH U 563 A, the healthy liver tissue of all rabbits was characterized by a typical mosaic color pattern in vivo and ex vivo, using color Doppler. Entire VX2 liver tumors were detectable exclusively in color Doppler after SH U 563 A application. This was possible in 14 of 16 rabbits in vivo and in all 16 livers ex vivo. Furthermore, all ex vivo investigated spleens were color enhanced homogeneously. Sonographic diagnoses were in accordance with pathologic findings. CONCLUSIONS: SH U 563 A, combined with stimulated acoustic emission, provides potential for delineation of small isoechogenic liver lesions by sonography.

[Contrast medium supported imaging of tumorous vessels by color Doppler and power Doppler mode in animal experiments]. / Kontrastmittelgestützte Darstellung von Tumorgefässen in Farb-Doppler- und Power-Doppler-Mode im Tierexperiment.

PURPOSE: The purpose was to determine tumor neovascularisation via colour-coded Doppler (duplex) sonography and the "power mode", both visually and quantitatively, by means of videodensitometry. MATERIAL AND METHODS: 6 VX2 tumours of 4 to 11 mm size were implanted in 4 rabbits at various sites. The colour-coded duplex sonography and the new sonographic power technique were tested before and after having injected a new contrast medium (SH U 616A). RESULTS: If no contrast medium was injected, tumour neovascularisation was identified in only 50% of the cases. Injection of contrast medium increased signal intensity three to fourfold with all examined tumors. Combined use of the sonographic method by the power technique with injection of contrast medium is outstandingly suitable for tumor vessel imaging even of small tumors, as these initial results seem to show. CONCLUSION: If these results are corroborated by further studies, contrast-medium supported sonographic technique may possibly become established as an alternative method to other imaging procedures.

[Extended diagnosis of color-coded Duplex sonography by ultrasound contrast media. Imaging of movements of the urinary tract and tubes in animal experiment]. / Erweiterung der Diagnostik der farbkodierten Duplexsonographie durch Ultraschallkontrastmittel. Darstellung von Bewegungen in den Harnwegen und Tuben im Tierexperiment.

In colour-coded Duplex sonography, ultrasound contrast agents produce a significant enhancement of Doppler signals from the blood. Animal experiments were performed to examine whether a combination of colour-coded Duplex sonography and ultrasound contrast agents can also visualise movements from hollow spaces which do not normally contain scatteres (or an insufficient number of them). The animal experiments showed that the method can visualise both movements in the tubae and a vesicoureteral reflux. This opens up new diagnostic possibilities for ultrasound, which, however, still require rechecking by means of clinical studies.

[Color-coded duplex sonography and ultrasound contrast media--detection of renal perfusion defects in experimental animals]. / Farbkodierte Duplexsonographie und Ultraschallkontrastmittel--Nachweis von renalen Perfusionsdefekten im Tierexperiment.

The diagnostic use of microbubble consisting transpulmonary ultrasound contrast media in combination with color-coded duplex sonography (CCDS) has not been evaluated. Perfusion of the orthotopic kidney was therefore examined in an animal experiment with CCDS and transpulmonary echocontrast agent. The contrast agent consists of tiny stabilized air bubbles which survive the lung passage after peripheral venous injection and cause echo-enhancement of the arterial blood. The combination of CCDS and this contrast agent permits demonstration of the renal perfusion including the peripheral parenchyma. Even small experimental perfusion defects can be identified by this method. The use of this contrast agent in combination with CCDS might contribute significantly to the diagnostic potential of ultrasound.

Successful opacification of the left heart chambers on echocardiographic examination after intravenous injection of a new saccharide based contrast agent.

A new monosaccharide microparticle based echocardiographic contrast agent (SH U 508) was injected intravenously into five healthy male volunteers following which the heart was imaged in an apical four-chamber view. Volumes of 2, 4, 8, and 16 mL of SH U 508 were incrementally injected into each volunteer. Concentrations of 50, 100, 200, 300, and 400 mg microparticles per mL of suspension were used in five successive examinations. Left heart opacification of diagnostic value was obtained during the whole cardiac cycle with concentrations of 300 and 400 mg/mL. There was no interference in imaging of the left ventricular walls due to increased attenuation. SH U 508 showed a good tolerance. No side effect was observed and no clinical relevant changes were observed in the heart rate, blood pressure, ECG, blood chemistry, hematology or urinalysis findings. This new agent may greatly extend the role of cardiac ultrasound and may also permit the examination of the arterial circulation in other organs.

Preclinical and clinical results with an ultrasonic contrast agent.

In comparison to diagnostic radiology, ultrasound diagnostics has had no real contrast media. Theoretical considerations indicate that gas liquid systems seem to be favorable. The echocontrast agent SH U 454 is a system that releases minute gas bubbles that provide the contrast properties. Preclinical and clinical trials in more than 500 patients with right-heart lesions proved the efficacy and tolerance of the agent. Initial investigations showed that SH U 454 also may be useful in fields (eg, urology, gynecology) other than cardiology.

Myocardial perfusion defects in contrast echocardiography: spatial and temporal localisation.

The position and size of experimental myocardial perfusion defects can be detected by using the echocardiographic contrast-medium Echoson together with digital image processing techniques. Video tapes showing the important sequences before, during and after cardial inflow of echo-enhancing agents are fed in total length into a digital image processing unit. The myocardial circumferences are then chosen interactively. All the frames are analysed and a synthetic picture is compiled, and shows the myocardial echo densities in a single, highly condensed form. Digital subtraction of blank values (condensed sequences before injection of contrast medium) greatly improves readability. Further concentration of the remaining information yields the following diagrams: flow/circumferential position (time summation); flow/time (position summation), which contain the desired information on homogeneity or defects of echo density against time and myocardial position.

Quantification of myocardial perfusion by contrast echocardiography.

Two-dimensional echocardiography allows identification of myocardial perfusion defects due to coronary artery occlusion by detection of regional wall motion abnormalities and absence of myocardial echocontrast enhancement after injection of echocontrast agents into the aortic root. In the current study twelve anesthetized closed chest dogs were examined before and after balloon occlusion of a coronary vessel. Size of perfusion defects was determined morphologically by Evans blue staining, while the circumferential extent of regional wall motion abnormality was calculated using radial wall motion analysis of the two-dimensional echocardiogram. Four mL of SH U 454 were injected into the aortic root for echocontrast studies. Perfusion defects in the echocardiogram were determined planimetrically in the analog two-dimensional echocardiographic image. In addition, perfusion defects in the contrast echocardiogram were estimated by a digital image processing technique along a circumferential mid-wall line. Along this line the time-intensity curves of the myocardial echocontrast were also calculated. There was a linear correlation between morphological determination of perfusion defects and their planimetric estimate in the contrast echocardiogram. The linear regression equation was y = 0.98x + 4.63, r = 0.92, and the standard error of estimate for the echocardiographic examination was SEE = 4.4%. Digital image processing did not increase accuracy in determining the size of perfusion defects (r = 0.88; y = 1.01x + 3.33; SEE = 5.7%). By comparing the extent of regional wall motion abnormalities with the size of anatomic perfusion defects there was a correlation of r = 0.85; SEE = 6.2%; y = 0.71x + 10.50.(ABSTRACT TRUNCATED AT 250 WORDS)

Right-heart echocontrast in the anesthetized dog after i.v. administration of a new standardized sonographic contrast agent. 1st communication: dose-response relationship.

The newly developed standardized sonographic contrast agent SH U 454, which consists of pure galactose microparticles, was examined for opacification of the right heart by 2 D echocardiography in 10 anesthetized female beagle dogs (6.8-12.7 kg) following i.v. administration. The right ventricular contrast of SH U 454 was investigated in 4 concentrations: 100, 150, 200 and 300 mg microparticles/ml suspension. With a 5-min interval between injections each animal was given 3 injections of 2 ml of each formulation in random order using an injection speed of approximately 2 ml/s. The echocardiographic pictures were recorded on videotape and the contrast assessed blind, using a visual score system (ratings 0-5), by two investigators working independently and also by a videodensitometer which measured 3 additional parameters. The contrast obtainable with SH U 454 is dose-dependent. SH U 454 containing 300 mg microparticles/ml was in every case significantly superior (p less than 0.05) to the suspension containing 100 mg/ml. All the videodensitometer values revealed a significant difference (p less than 0.05) between the 200 and 100 mg/ml concentrations. Only the concentration containing 300 mg/ml yielded contrast adequate for diagnostic purposes in respect of every parameters after every injection and in every dog.

Right-heart echocontrast in the anesthetized dog after i.v. administration of a new standardized sonographic contrast agent. 2nd communication: dependence of the intensity of contrast on the interval between preparation of the suspension and its injection.

The right-ventricular echocontrast provided by 5 different concentrations of the new standardized sonographic contrast agent SH U 454 (100, 150, 200, 300 and 400 mg microparticles/ml), which consists of pure galactose microparticles, was examined in 3 anesthetized female beagle dogs (8.6-9.3 kg) in order to assess the influence of the period of time which elapsed between preparation of the suspension and its injection. Each animal was given 2 ml of an SH U 454 concentration by intravenous injection at a speed of approximately 2 ml/s immediately after preparation of the suspension and 1, 2, 3 and 5 min thereafter. Evaluation of the intensity of contrast was performed blind by two investigators working independently and using a visual scoring system (ratings 0-5) and also by a videodensitometer. The videodensitometer provided a quantitative evaluation of the maximum intensity of contrast, the duration of contrast and the area under the videodensitometer curve. The intensity of the contrast of the prepared suspension subsided at a constant rate over a period of 5 min for all the concentrations tested. However, the difference between the starting value t0min and the terminal value t5min was small. On the whole, very little difference was found over the 5-min period in the intensity of the contrast provided by any of the SH U 454 concentrations examined. Thus, for the injection the examiner has a timeframe of at least 5 min after preparation of the suspension.

Right-heart echocontrast in the anesthetized dog after i.v. administration of a new standardized sonographic contrast agent. 3rd communication: comparison of various contrast agents employed in contrast echocardiography.

Right-ventricular contrast provided by the new standardized sonographic contrast agent SH U 454, which consists of pure galactose microparticles, with 300 mg microparticles/ml and by 5 other currently employed ultrasonic contrast media was examined by 2 D echocardiography in 10 anesthetized female beagle dogs (6.8-12.7 kg) following i.v. administration. With a 5-min interval between injections each animal was given 3 injections of 2 ml of each formulation in random order using an injection speed of approximately 2 ml/s. The echocardiographic investigation was recorded on videotape and the contrast assessed blind using a visual score system (rating 0-5) by two investigators working independently and also by a videodensitometer. Only SH U 454 caused an intense, homogeneous and reproducible opacification of the right heart chambers. By comparison with other formulations for right-heart echocontrast, SH U 454 was significantly superior (p less than 0.05) in every parameter assessed.

[Improved reproducibility of contrast echocardiography by SH U 454. Experimental studies using digital subtraction echocardiography]. / Verbesserte Reproduzierbarkeit der Kontrastechokardiographie durch SH U 454. Experimentelle Untersuchungen mittels digitaler Subtraktionsechokardiographie.

The right heart chambers of 10 animals were contrasted by conventional (NaCl, CO2, H2O2, indocyanine green (ICG), haemaccel) and a newly developed echo-contrast medium (SH U 454) and studied by 2-D echocardiography. By means of digital subtraction echocardiography (DSE) endocardial borders were defined automatically and the results were compared with the manual input of endocardial borders of original and contrast echocardiograms. The area enclosed by these borders served as basis for the calculation of reproducibility (in %) and correlations. The following correlation coefficients (r) and SEE were calculated between the areas defined by the different contrast media and DSE and manually derived borders: r = 0.85, 3.98 cm2 (ICG), and 0.89, 1.00 cm2 (haemaccel). The best calculations were found using SH U 454 in concentrations between 100 and 300 mg/ml. The correlation coefficients were in the range of r = 0.95 and 0.98 with an SEE of 0.21 to 0.56 cm2 between manually and automatically derived contours. Comparing the reproducibility of data between the different evaluation methods we found the following results: manual input of endocardial borders in original echocardiograms 12.3%-16.9%; manual definition of endocardial borders in contrast echocardiograms 2.0% (SH U 454) - 15.7% (CO2); automatic contour finding in original echocardiograms 8.6%-28.9% (mean 21.6%); automatic definition of endocardium by DSE in contrast echocardiograms 7.6% (ICG) - 0.9% (SH U 454, 300 mg/ml). Our results demonstrate that digital subtraction echocardiography is a simple an safe procedure to define endocardial contours if echo contrast media lead to a uniform and homogeneous opacification of the left and right cardiac cavities.(ABSTRACT TRUNCATED AT 250 WORDS)

[Sonographic imaging of the kidney cavity system using a ultrasonic contrast medium]. / Sonographische Darstellung des Nierenhohlsystems mit einem Ultraschallkontrastmittel.

The echo contrast solution SH U 454 was injected through an ureteral stent into the upper urinary tract ex vivo in human cadaver kidneys and in vivo in kidneys of pigs. Small amounts of this solution gave excellent echogenic contrast to demonstrate the renal pelvis and calices ultrasonographically in percutaneous examination and ex vivo sonography. This sonographic contrast agent promises to be useful for non-roentgenologic voiding cystograms and antegrade or retrograde pyelography.

Contrast echography of the eye and orbit.

SH U 454 is a new echocontrast agent which was developed primarily for echocardiography. It seems that there is a further potential in ophthalmic ultrasound diagnostics. SH U 454 produces contrast enhancement in the orbit, choroid and ciliary body, and permits determination of intraocular blood flow parameters in dogs' eyes. The effects are measured with digital picture processing techniques.

[Quantification of myocardial perfusion defects using 2-dimensional contrast echocardiography]. / Quantifizierung myokardialer Perfusionsdefekte mittels zweidimensionaler Kontrastechokardiographie.

Ten closed-chested beagles were employed to determine whether reproducible echocontrast imaging of the myocardium could be obtained following injection of the new ultrasonic contrast medium Echocon into the aortic root, and whether myocardial perfusion defects could be successfully diagnosed by this method. The change in intensity of contrast in the myocardium was measured by videodensitometry simultaneously in the supply areas of the left anterior descending and left circumflex branches of the left coronary artery before and during occlusion of the circumflex branch by means of a balloon catheter. Injection of Echocon into the aortic root led to reproducible echocontrast imaging of the entire myocardium. The occlusion of the circumflex branch caused a significant reduction (p less than 0.01) in intensity of contrast in the supply area of the circumflex branch, whereas no differences by comparison with the starting values were identifiable in the supply area of the left anterior descending branch. The correlation factor between the sizes of the perfusion defects ascertained by echocardiography and by planimetric measurement using a pathological anatomical approach was found to be r = 0.89. The injection of Echocon into the aortic root did not induce any significant changes in the aortic or pulmonary pressure, or in heart rate. Only slight flattening of the T-waves, which never lasted longer than 15 seconds, was observed in 50% of the animals. Contrast echocardiography of the myocardium could thus contribute to the diagnosis of coronary heart disease, i.e. perfusion defects.