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Ths experimental study described myocardial echo contrast enhancement through coronary venous injections. Retrograde administration of renografin was performed in 15 closed-chest dogs. Two-dimensional echocardiography was used to study myocardial echo contrast enhancement before and after coronary artery occlusion. Digital subtraction venography was used to assess delivery, drainage and shunting of the retrograde injectate. Systolic/diastolic blood pressure in the great cardiac vein measured 7 +/- 3/1 +/- 0.6 mm Hg and increased to 29 +/- 11/5 +/- 3 after coronary sinus occlusion and to 55 +/- 2.3/15 +/- 12 mm Hg during coronary sinus contrast injection. Myocardial contrast echo appearance in a midpapillary left ventricular short axis cross-section was limited to the anteroseptal region, extending to 28.4 +/- 11.3% of the section circumference after great cardiac vein injections and 35.3 +/- 17% after coronary sinus injections (difference NS). After occlusion of the left anterior descending coronary artery, great cardiac vein contrast injections resulted in opacification of 36.6 +/- 9.7% of the section circumference (N.S. vs preocclusion control) and opacified most, but not all asynergic segments. After occlusion of the circumflex coronary artery, myocardial echo contrast uptake was restricted to the septum and the anterior wall. The ischemic and asynergic posterolateral myocardial segments were not opacified. Digital subtraction coronary venography revealed rapid drainage of retrogradely injected contrast to the right atrium, in spite of coronary sinus balloon occlusion via venovenous anastomoses. Retrograde coronary venous contrast injections may help define myocardial regions which are accessible with retrograde coronary venous interventions.

Underlying principles of echocontrast effects are outlined in this section, which aims to reflect the recent advances and detailed reports presented in subsequent chapters. To place microbubble phenomena in context, it was deemed useful to consider parallel multidisciplinary efforts in such areas as hydrodynamic cavitation, diving physiology and bubbly flow processes. Although there are many applications of ultrasound contrast, one difficult but potentially realizable objective was singled out: the quantitation of myocardial perfusion with intravenously administered gaseous bubbles.

Other segments of this text report on the development and manifold applications of contrast echocardiography. In view of recent emphasis on quantitation, this chapter will review a number of mechanisms believed to be associated with observed echo-contrast effects. Emphasis will be on miscellaneous illustrative theoretical and experimental studies of gaseous microbubble dynamics in fluids and interactions of such bubbles with an ultrasound field.

So far, application of MC-2DE for detection and delineation of regional perfusion defects involved primarily intracoronary or aortic root injection of the contrast agent, a procedure which can serve as a diagnostic adjunct in the catheterization laboratory. Thus, a left main coronary artery administration of sonicated renografin, during an LAD or left circumflex coronary artery occlusion, significantly enhances myocardial echo intensities in normal zones of a 2DE left ventricular short axis cross section, while the perfusion deficient risk zone remains essentially unenhanced. To evaluate the magnitude of risk zone residual perfusion (e.g. from collaterals), corresponding regional myocardial echo contrast appearance-disappearance dynamics might be studied with computerized MC-2DE videodensitometry. But for such MC-2DE study of an acutely ischemic zone to be effective, supplemental echo contrast would probably have to be injected distal to the coronary artery occlusion (e.g. via the center lumen of an intracoronary balloon catheter). It is uncertain how well a collateral blood supply from normal to ischemic myocardium, or an antegrade delivery via a severely stenosed coronary artery, can be quantitated with a microbubble-containing echo contrast agent.

To determine alterations in myocardial metabolism and and hemodynamics that occur within the first 30 minutes after coronary arterial occlusion, before the onset of ventricular fibrillation, measurements were compared in two series of dogs. Series A, 90 dogs that did not manifest ventricular fibrillation after coronary occlusion, were considered a control group. Series B consisted of 28 dogs that had ventricular fibrillation within 30 minutes after occlusion. All had similar comprehensive measurements completed preceding the onset of ventricular fibrillation. The animals in series B (subseuqnt fibrillation) had significantly higher heart rates before and after coronary occlusion. In this series cardiac metabolism of the occluded segment judged by transmyocardial lactate extraction, potassium balance, sodium/potassium ratio and blood pH because grossly more abnormal after coronary occlusion than in series A. In 5 animals whose measurements were obtained within 5 minutes of the onset of ventricular fibrillation, a sudden massive lactate production, potassium loss and increased acidosis of the occluded portion supervened minutes before the onset of the fatal arrhythmia. Animals with ventricular fibrillation had higher intracoronary S-T segment elevation that persisted until the onset of ventricular fibrillation. Measurements of abnormal hemodynamic function (left ventricular end-diastolic pressure, peak systolic pressure and first derivative of left ventricular pressure [DP/dt]) were not associated with an increased incidence of ventricular fibrillation. The study indicates that animals that manifest ventricular fibrillation within 30 minutes after coronary occlusion have higher preocclusion heart rates, a more severe metabolic disorder of the coronary occluded segment and more persistent intracoronary S-T segment elevation compared with animals that do not manifest ventricular fibrillation.

Two dimensional echocardiographic analysis of global and regional left ventricular function was applied in seven closed chest dogs to study the effects of nitroprusslde In ischemic heart failure. Simultaneous hemodynamic and two dimensional echocardiographic measurements were obtained sequentially: (1) in the control period, (2) after proximal occlusion of the left anterior descending coronary artery, (3) after volume loading, which increased left ventricular end-diastollc pressure to 30.3 ± 9.1 mm Hg (mean ± siandard deviation), (4) during nltroprusside infusion at 33.8 ± 29.4 jug/min and (5) after discontinuation of infusion of nitroprusside. A Simpson reconstruction using five echocardiographic short axis cross sections was used for assessment of left ventricular volumes. Regional function in short axis cross sections at different levels of the left ventricle was expressed as sectional systolic fractional area of change. Furthermore, each short axis section was subdivided into eight 45 ° segments and segmental fractional area change was automatically calculated by computer. Nitroprusside reduced global end-diastolic and end-systolic volumes (p

The consequences of sublingual and intravenous nitroglycerin treatment after acute coronary occlusion were studied in 18 closed chest dogs. Intravenous (0.1 mg/min) or sublingual (0.4 mg/15 min) nitroglycerin therapy was instituted 1 hour after occlusion and the effects were observed over a period of 2 hours. Hemodynamics and global and regional cardiac function were measured in both the coronary occluded and nonoccluded segments of the left ventricle before and during coronary occlusion, and after administration of nitroglycerin. A similar nine dog control series was used to establish the significance of the measured effects of nitroglycerin. Intravenous nitroglycerin therapy after 1 hour of occlusion resulted in a marked increase in heart rate (37 ± 12 [mean ± standard error of the mean] percent), reduction of systolic blood pressure (9 ± 3 percent), decrease in left ventricular end-diastolic and end-systolic volumes (32 ± 5 percent and 34 ± 5 percent), increase in coronary sinus flow (64 ± 24 percent) and decrease in left ventricular stroke work (29 ± 8 percent). Sublingually administered nitroglycerin produced similar trends but much less pronounced effects. However, intravenous or sublingual administration of nitroglycerin provided no improvement or caused further deterioration in ischemic region lactate extraction and potassium loss. The left ventricular ejection fraction, which was severely depressed after 1 hour of occlusion, changed minimally after administration of nitroglycerin, and there was no evidence of any correction of regional left ventricular akinesia or dyskinesia. Whereas mean systemic vascular resistance changed minimally as a result of nitroglycerin therapy, it increased 19 ± 8 percent during a corresponding period of an untreated coronary occlusion series suggesting that nitroglycerin prevented an anticipated increase. Postocclusion S-T segment elevation in the electrocardiogram persisted after treatment. Our data corroborated that nitroglycerin reduced left ventricular volumes and increased coronary sinus flow; however, these improvements were accompanied by persisting metabolic and mechanical derangements in the ischemic region.

Two-dimensional echocardiography during agitated saline contrast injections into the left ventricle was applied in eight closed chest dogs to examine the degree of mitral valve regurgitation encountered with pacing from two sites: 1) at the right ventricular apex and 2) within the coronary sinus at the base of the left ventricle. Pacing was at a rate of 10 beats/min above the sinus rate, and ranged from 60 to 120 beats/min. Hemodynamic variables were monitored, and data on global and regional left ventricular function were derived from a series of short- and long-axis cross-sectional echographic images. The degree of valvular regurgitation was assessed independently by two observers, and systolic appearance of echo contrast in the left atrium was graded as 0 to +4. Although no mitral regurgitation was noted in sinus rhythm, regurgitation was severe with right ventricular apical pacing (3.2 +/- 0.7, mean +/- standard deviation) and relatively mild (0.9 +/- 0.7) with basal pacing (p less than 0.01 and 0.05, respectively). Relative to sinus rhythm, thermodilution stroke volume was significantly (p less than 0.05) depressed by both apical and basal pacing (from 32.6 +/- 14.6 to 25.0 +/- 7.9 and 26.0 +/- 7.6 cc, respectively), but there was no significant difference between the two pacing sites. Mapping of regional function at six levels of the left ventricle revealed significant heterogeneities, with maximal dysfunction noted in the vicinity of the pacing site. It is concluded that significant differences in mitral regurgitation exist depending on the site of pacing, with apical pacing causing severe regurgitation and abnormal regional contraction near the pacing site.

Pressure-controlled intermittent coronary sinus occlusion has been reported to reduce infarct size in dogs with coronary artery occlusion, possibly because of increased ischemic zone perfusion and washout of toxic metabolites. The influence of this intervention on regional myocardial function was investigated in open and closed chest dogs. In six open chest dogs with severe stenosis of the left anterior descending coronary artery and subsequent total occlusion, a 10 minute application of intermittent coronary sinus occlusion increased ischemic myocardial segment shortening from 5.5 ± 1.2 to 8.2 ± 2.6% (NS) and from −0.1 ± 2.1 to 2.3 ± 1.2% (NS), respectively.In eight closed chest anesthetized dogs, intermittent coronary sinus occlusion was applied for 2.5 hours between 30 minutes and 3 hours of intravascular balloon occlusion of the proximal left anterior descending coronary artery. Standardized two-dimensional echocardio-graphic measurements of left ventricular function were performed to derive systolic sectional and segmental fractional area changes in five short-axis cross sections of the left ventricle. Fractional area change in all the severely ischemic segments (< 5% systolic wall thickening) was −4.0 ± 4.7% at 30 minutes after occlusion, and increased with subsequent 60 and 150 minutes of treatment to 13.1 ± 3.3 and 7.0 ± 3.3%, respectively (p < 0.05). At the most extensively involved low papillary muscle level of the ventricle, regional ischemic fractional area change was increased by intermittent coronary sinus occlusion between 30 and 180 minutes of coronary occlusion from −0.4 ± 0.1 to 14.4 ± 4% (p < 0.05), whereas a further deterioration was noted in untreated dogs with coronary occlusion.Continuous arterial and coronary venous blood density measurements were performed in seven open chest dogs to determine the influence of pressure-controlled intermittent coronary sinus occlusion on ischemic myocardial washout. The arteriovenous density gradient was 0.16 ± 0.05 g/Iiter during coronary artery occlusion, and decreased to 0.05 ± 0.08 g/liter (p < 0.05) as a result of the intervention, suggesting a significant fluid washout from the myocardium. It is concluded that pressure-controlled intermittent coronary sinus occlusion provides recovery of cardiac function and that this benefit might be associated with enhanced ischemic zone washout.

The potential for the use of contrast echocardiography to study myocardial perfusion has generated efforts to develop standardized echo contrast agents. The two methods used in this laboratory to generate microbubbles in solutions serving as contrast agents included the widely used hand-agitation method and the newer ultrasonic microcavitation (sonication) method. The latter has been demonstrated to generate smaller and more uniform microbubbles in an in vitro system. The present study was designed to observe, by direct microscopic examination of a cat mesentery preparation, the behavior and fate of the microbubbles in an in vivo system. The in vivo mesentery observations confirm the critical role of microbubble size in its unhindered passage through the capillary vasculature. The smaller and more uniform sonicated microbubbles passed rapidly through the microcirculation along with the red blood cells, whereas the larger microbubbles were observed to coalesce and interrupt the flow of blood and subsequently collapse or shrink.

Regional differences in wall motion and wall thickening were quantitated in the normal left ventricle using two-dimensional echocardiography (2-D echo). Using a computer-aided system, the left ventricle was subdivided in a standardized manner into 40 segments of five 2-D echo short-axis cross sections from the mitral valve level to the low left ventricle or apex. Measurements of sectional and segmental cavity areas, muscle areas and endocardial as well as epicardial perimeters, allowed assessment of contractile function using such indexes as endocardial systolic fractional area change (FAC), wall thickening (WTh), and circumferential fiber shortening (shortening). In 50 normal anesthetized, closed-chest dogs (including 10 studies in the conscious state) and in 32 normal humans, left ventricular contractile function increased significantly from base to apex. Thus, in anesthetized dogs, sectional FAC, WTh and shortening increased from left ventricular base to apex as follows: 39.4 +/- 5.1% to 61.6 +/- 7.2%, 20.5 +/- 6.6% to 46.7 +/- 11.5% and 22.7 +/- 3.4% to 35.4 +/- 5.9%, respectively. Similar trends were noted in conscious dogs. In man, sectional FAC, WTh and shortening also increased from the mitral valve to the low left ventricular level: 38.8 +/- 3.3% to 60.7 +/- 4.5%, 23.9 +/- 5.6% to 28.9 +/- 7.6% and 21.4 +/- 5.0% to 30.6 +/- 5.6%, respectively. Detailed segmental analysis in individual cross sections also revealed regional differences in contraction. Generally, contraction was most vigorous in posterior regions of the left ventricle. The septal regions exhibited lowest contraction at the base, but also the greatest increase from base to apex, both in the canine and human. Lateral regions did not show significant changes along the length of the left ventricle. Diastolic wall thickness also varied. We conclude that contraction in the normal left ventricle cannot be assumed to be uniform or symmetrical. These normal regional differences in function should be taken into account when evaluating altered physiologic states and in studying effects of therapeutic interventions.

In the present model study on the closed mitral valve, tensile force in the chordae tendineae is related to transvalvular pressure using a mathematical model of mechanics of the closed mitral valve. Circumferential stress as well as bending stress in the valve leaflets were neglected. Without precisely knowing the mechanical properties of the leaflet material, geometry of the leaflets was estimated by applying Laplace's law, which relates leaflet stress to leaflet curvature. Independent of shape of the mitral valve orifice, under all circumstances tensile force in the chordae tendineae was calculated to be equal or greater than half the force exerted on the mitral valve orifice by the transvalvular pressure.

A commercial two-dimensional echo unit, modified to permit digital acquisition (2.2 MHz) of echo signals prior to time-gain-compensation (TGC), was ratiometrically calibrated. Simulating the TGC in software, we demonstrated improvements in image quality as compared to conventional video methods. A path-dependent attenuation correction (PDAC) algorithm, utilizing the gray level image statistics to assign one of three attenuation coefficients (for chest, myocardium or blood) to each image pixel, was then developed. Using it on left ventricular (LV) short axis images obtained in nine healthy closed chest dogs, we demonstrated that the backscatter intensity at end diastole (ED) was 2.0 ± 0.5 dB (mean ± SEM) higher (p>0.01) than at end systole (ES), in circumferential segments of the myocardium oriented anteriorly and posteriorly, relative to the transducer. In seven of the dogs, subsequently occluded for one hour in the anterior descending branch of the left coronary artery (LAD), this normal phasic myocardial backscatter (PMB) variation decreased or was reversed in ischemic segments, relative to preocclusion values, suggesting utility of the method for sequential study of myocardial ischemia and its treatment.

The effects of synchronized coronary venous retroperfusion of arterial blood on myocardial washout were studied with digital subtraction angiography in 10 closed chest dogs during balloon occlusion of the proximal left anterior descending coronary artery. The center lumen of the intracoronary balloon catheter was used for sequential injections of 1 ml (meglumine diatrizoate) Renografin-76, and contrast washout rate was determined by videodensitometry in myocardial regions subserved by the left anterior descending coronary artery. Before coronary artery occlusion, washout rate was 22.4 +/- 2.7 min-1 (mean +/- SEM). Five minutes after occlusion, and immediately before synchronized retroperfusion, washout rate dropped sharply to 2.0 +/- 0.7 min-1. Twenty-five minutes after occlusion, with 50 ml/min synchronized retroperfusion treatment applied for 5 minutes, washout rate was 5.0 +/- 1.5 min-1. Thus, synchronized retroperfusion significantly (p less than 0.05) accelerated contrast disappearance over that during presynchronized retroperfusion ischemia. To determine the effects of synchronized retroperfusion on retrograde delivery to the ischemic myocardium, monastral blue dye was retroinfused through the system into the great cardiac vein before the dog was killed. Transverse heart slices were then studied by light microscopy, and regional intravascular dye content was scored from 0 to 3 (0 = no dye, 3 = maximal dye). After great cardiac vein synchronized retroperfusion, blue dye content in capillaries of ischemic anterior and nonischemic posterior aspects of the left ventricle was 2.3 +/- 0.5 versus 0.7 +/- 0.3, respectively (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of methylprednisolone treatment on acute myocardial ischemia were studied in nine closed chest dogs. After 1 hour of proximal occlusion of the left anterior descending coronary artery, an intravenous bolus injection (50 mg/kg body weight) of methylprednisolone was administered and its effects studied during an additional 2 hours of occlusion. After 2 hours of treatment the following significant mean alterations from levels after 1 hour of occlusion were noted: an increase of 16.7 percent in heart rate and decreases of 23 percent in left ventricular end-diastolic pressure, 32 percent in stroke volume, 14 percent in cardiac output and 37 percent in stroke work. Peak systolic pressure, maximal rate of rise of left ventricular pressure (dP/dt), left ventricular end-diastolic volume, systemic vascular resistance and coronary sinus blood flow changed less than 10 percent. Ejection fraction and regional cardiac wall motion were not improved. Metabolic dysfunction of the coronary-occluded myocardium, revealed by regional lactate as well as potassium derangements, persisted throughout the 2 hour treatment period. Comparison of these results with equivalent data from an untreated series of nine dogs with 3 hours of occlusion demonstrated no improvement in the treated series. Methylprednisolone failed to restore regional cardiac metabolic and mechanical function, and treatment was associated with a further rise in S-T segment elevations. Administration of methylprednisolone after 1 hour of proximal left anterior descending coronary occlusion apparently does not reverse cardiac dysfunction in the first 2 hours of treatment.

Experimental coronary occlusions were carried out in 12 closed-chest dogs to investigate the functional anatomic characteristics of the mitral valve complex during acute myocardial ischemia. Two-dimensional echocardiography was used to assess left ventricular function, the mitral valve complex, and left atrial size. Presence of mitral regurgitation was assessed by left ventricular contrast echocardiography. Thirty-seven coronary occlusions of up to 10 min in duration were carried out in proximal or distal locations in the left anterior descending and the left circumflex coronary arteries. Mitral regurgitation, which was mild in severity as judged by a small rise in pulmonary artery wedge pressures, was observed in 15 of 37 brief coronary occlusion experiments. Mitral valve prolapse was noted in all 15 experiments, as well as in four additional studies in which mitral regurgitation was not seen. The development of experimental mitral valve prolapse was explained by measurements that demonstrated a relative displacement of the papillary muscle tips toward the mitral orifice. We conclude that mitral valve prolapse is a common sequela of short-term coronary occlusion and is often associated with mild mitral regurgitation. Relative displacement of ischemic papillary muscles toward the mitral orifice appears to be a likely mechanism of acute ischemic mitral valve prolapse.

Myocardial contrast two-dimensional echocardiography was used in 21 closed chest dogs to assess its ability to delineate the extent of underperfused acutely ischemic myocardium. An agitated saline-Renografin echocardiographic contrast agent was injected into the left main coronary artery after left anterior descending coronary artery occlusion, and the size of the contrast echo-free area characterizing the perfusion defect was outlined in short-axis cross sections of the left ventricle. In 13 dogs, monastral blue dye was injected after 45 minutes of coronary artery occlusion and before sacrifice to provide anatomic delineation of underperfused zones in equivalent sections. Perfusion defects assessed by contrast two-dimensional echocardiography correlated well with those delineated by monastral blue dye (r = 0.91). Contrast echocardiographic study was also performed in eight other dogs at 5 hours of occlusion, after which infarct size was measured with triphenyl-tetrazolium-chloride. Contrast echocardiographic outline of the perfusion deficiency correlated but slightly overestimated the extent of necrosis (r = 0.88). It is concluded that contrast two-dimensional echocardiography can detect and outline the underperfused “risk area” during acute coronary artery occlusion, and may also permit assessment of the extent of myocardial infarction.

Both segmental and global left ventricular performance were assessed simultaneously in 29 patients with acute myocardial infarction using two-dimensional echocardiography. Comparisons were made between left ventricular wall motion versus peak CK-MB, site of infarction, and occurrence of heart failure. Two-dimensional echocardiography identified areas of dyssynergy which corresponded to electrocardiographic areas of infarction in 89% of all cases. Patients with heart failure had more dyssynergic segments, and these segments manifested more severe dyssynergy than patients without heart failure. Patients with severe global dysfunction manifested higher peak CK-MB values, and those with anterior infarction had more global dyssynergy than did those patients with inferior infarction. These observations suggest that two-dimensional echocardiography is a useful technique for localization and assessment of segmental and global dyssynergy in acute myocardial infarction. Information so derived correlates with the clinical status of patients with acute myocardial infarction, and may offer important insights into both prognosis and treatment.

Two computer-aided videodensitometric methods that may be used in conjunction with two-dimensional contrast echocardiography were examined to quantify the time course of echographic opacification in the myocardium after experimental injections of contrast agents (hand-agitated Renografin-saline and sonicated sorbitol 70% solutions) into the left main coronary artery. Echographic studies of myocardial cross sections were digitized with an image processing computer using a 128 X 128 resolution matrix. Both stop frame and continuous cycle modes of acquisition were performed. A set of computer programs was developed to extract and analyze time-intensity curves from the digitized images. These included cardiac outline delineation, segmental division, regional intensity computation and exponential curve analysis. The stop frame method was applied to experimental studies in 17 closed chest dogs during control states and after coronary occlusions. Significant differences were found in the decay half-lives of echo intensity between normal (24 +/- 8 seconds) and acutely ischemic (293 +/- 165 seconds; p less than 0.001) myocardium for the Renografin-saline solution. Interobserver reproducibility of the measured half-lives was r = 0.91 and standard error of the estimate = 5 seconds. The continuous cycle method of analysis was examined in five closed chest dogs (with up to six injections per dog), applying the sonicated sorbitol 70% solution in only the control state. The mean half-life was 4.2 +/- 1.1 seconds. These computer-based videodensitometric methods might be applied to a wide variety of experimental studies in two-dimensional contrast echocardiography that attempt to quantify myocardial perfusion and function.

A computer algorithm was developed and applied to measure brightness decay rates of myocardial contrast opacification observed with two-dimensional echocardiography (2DE). An agitated mixture of diatrizoate meglumine and saline (Renografin-saline) was injected into the left main coronary artery of 17 closed-chest dogs during the control state as well as after placement of an intracoronary plug to induce 85% stenosis in the left anterior descending coronary artery (LAD) in five dogs. In 12 dogs, injections were also performed distally to complete intracoronary balloon occlusion of the LAD. For each injection, up to 35 electrocardiographic-gated, end-diastolic 2DE frames were digitized into an image-processing computer that determined mean pixel brightness of each of 12 myocardial segments per 2DE short-axis cross-section. Time-activity curves for each segment were generated, and contrast decay half-life (t 1/2) was calculated. Mean t 1/2 for control-state injections was found to be 24.1 +/- 7.7 sec, as opposed to 293.8 +/- 164.5 sec after complete coronary occlusion (p less than .001). In the five dogs in which 85% LAD stenosis was induced, prolongation of contrast t 1/2 from 18.3 +/- 8.9 sec during control to 44.3 +/- 21.0 sec (p less than .001) after plug insertion occurred in myocardial segments subserved by the stenosed vessel. No significant change occurred in segments that were not supplied by the stenosed vessel (21.9 +/- 9.1 sec during control vs 24.9 +/- 11.6 after plug insertion into the LAD). A reproducibility study of injection-to-injection t 1/2 in the control state indicated a correlation coefficient of r = .84 and a standard error of the estimate (SEE) equal to 5.86 sec, while interobserver t 1/2 reproducibility was r = .91 and SEE = 5.21 sec. The t 1/2 measurement derived by computer analysis of myocardial contrast 2DE may serve as an index for characterization of regional myocardial blood flow and may be applicable to evaluate interventions that alter perfusion.

To facilitate the passage of echo contrast agents through the microcirculation and the echocardiographic study of myocardial perfusion, ultrasonic energy (sonication) was employed to produce contrast agents consisting of relatively uniform, stable and small (less than 10 mu diameter) gaseous microbubbles suspended in liquid solutions. The size and persistence of the microbubbles was verified by light microscopy and an in vitro system were employed for comparative assessment of peak echo amplitude and echo persistence characteristics of various contrast agents. The study indicated that although a variety of hand-agitated and sonicated contrast agents provided satisfactory echo intensities, sonication was clearly superior to the hand-agitation method, because sonication produced smaller, more uniform and more stable microbubbles that may be suitable for myocardial contrast echocardiography. It is concluded that of the contrast agents examined, sonicated solutions of sorbitol (70%) and dextrose (70%) appeared to have particular potential because of the small sizes of the microbubbles (6 +/- 2 and 8 +/- 3 mu, respectively) and their prolonged in vitro persistence. The use of sonication to produce standardized, small and stable microbubbles should facilitate physiologic passage of the contrast agent through the capillary beds and allow two-dimensional imaging of the left heart myocardium during right-sided, aortic root, coronary sinus or intracoronary contrast injections.

Sudden and staged reperfusion after experimental coronary artery occlusion was studied in relation to recovery of cardiac function and postreperfusion arrhythmias. Eighteen closed chest dogs with 3 hour intracoronary balloon occlusion of the proximal left anterior descending coronary artery were studied using two-dimensional echocardiography over a period of 3 weeks after reperfusion. Nine dogs had sudden reperfusion by abrupt balloon deflation. In nine other dogs reperfusion was staged with partial reflow (20 ml/min) for 2 hours through the central lumen of the catheter during persisting intracoronary balloon inflation, followed by balloon deflation and full reperfusion.Within the first 30 minutes of sudden reperfusion, ischemic zone end-diastolic wall thickness increased significantly, from 6.8 ± 0.3 mm at 3 hours of occlusion to 10.2 ± 2.6 mm (p < 0.05). In contrast, at 30 minutes of partial reflow, wall thickness was 7.5 ± 0.7 versus 6.8 ± 0.7 mm at 3 hours of occlusion (NS). A small temporary increase in end-diastolic wall thickness was noted when full reflow was established after 2 hours of staged reperfusion. However, wall thickness was normal on the first day in the staged reperfusion series, while sudden reperfusion delayed recovery to 7 days. Function of the ischemic zone failed to improve substantially until day 3 after sudden reperfusion, whereas it improved consistently starting as early as 30 minutes after institution of the staged reperfusion. After day 3, ischemic zone systolic function was significantly improved in both groups, though a small difference in function between the groups with sudden and gradual reperfusion was apparent on day 7 (19.0 ± 8.8 versus 29.0 ± 4.3%, 0.05 > p > 0.1). Sudden reperfusion caused a much higher frequency of premature ventricular complexes than was the case with staged reperfusion (3 hours postreperfusion, 227 ± 167 versus 14 ± 23 premature complexes per 5 minutes, p < 0.01).Thus, compared with sudden reperfusion, staged reperfusion accelerated improvement in cardiac function and reduced arrhythmias in the early reperfusion period.

The relation between experimental coronary stenosis and myocardial contrast echo disappearance rate ("washout") was investigated in anesthetized closed chest dogs. Of 13 dogs, 8 had serial contrast echographic studies with two successive degrees of coronary stenosis (50 and 70%) produced by threading stenotic plugs into the proximal left circumflex coronary artery. Studies were repeated with complete coronary occlusion achieved by inflation of an intracoronary balloon immediately proximal to the plugs. Myocardial contrast echograms were recorded in short-axis cross sections of the left ventricle after intracoronary injection of 2 ml hand-agitated saline-Renografin solution through a catheter placed in the coronary artery. An echo contrast washout index (t 1/2) was measured by digital processing computer analysis of successive end-diastolic images obtained by two-dimensional echocardiography during myocardial contrast agent injection. The injection to injection correlation coefficient of these t 1/2 measurements was satisfactory (r = 0.87, standard error of estimate 4.8 seconds). Involved segment t 1/2 measurements were found to be significantly altered by intracoronary stenosis and occlusion, ranging from 23 +/- 6 seconds (mean +/- standard deviation) in the control state, 29 +/- 9 and 44 +/- 10 seconds for 50 and 70% stenosis, respectively, and 104 +/- 35 seconds for total occlusion. It was concluded that myocardial contrast two-dimensional echocardiographic measurement of t 1/2 appears to be a useful index of the degree of coronary stenosis.

Cross-sectional echocardiography was utilized for quantification of volume in 19 formalin-fixed left ventricles in the presence or absence of ventricular symmetry, defined by the ratio of septal-lateral to anterior-posterior diameter. In 10 symmetric ventricles this ratio was 1.23 ± 0.06 (mean ± SEM), whereas in nine asymmetric ventricles the ratio was 1.80 ± 0.07. Area, diameter, and length measurements were obtained from short- and long-axis cross-sectional images of the left ventricle and volume was calculated by five mathematical models previously described. To evaluate the reliability of each model, echocardiographic left ventricular volume was compared by linear regression and percent error analyses to directly measured fluid volume. In symmetric ventricles, excellent correlations (r = 0.996 to 0.967) and reasonable mean percent errors (6% to 31%) were observed for all models. In asymmetric ventricles, models utilizing short-axis area or two short-axis diameters retained high correlation coefficients (r = 0.985 to 0.956) and similar mean percent errors, but standard formulas previously used with M-mode echo and angiography showed lower correlations (r = 0.886 to 0.873) and higher mean percent errors (52% to 54%). Thus, in the presence of ventricular asymmetry, analysis of short-axis areas or diameters with cross-sectional echocardiography is well suited for quantification of left ventricular volumes.

The adequacy of two-dimensional echocardiography during right atrial pacing for the detection and characterization of coronary artery stenosis was examined in 10 closed chest dogs. Pacing at successively higher rates up to 210 beats/min was carried out in the control state and again during a 70% left anterior descending coronary artery stenosis induced with intracoronary plugs. Left ventricular short-axis echographic cross sections were obtained at several levels of the left ventricle. After computer-aided standardized subdivision, contractile function of the global section and its subsegments was characterized by computed systolic fractional area change percent and wall thickening percent. Ventricular segments supplied from the site of the 70% coronary stenosis were delineated in a low papillary level cross section by a myocardial contrast echographic technique, and these segments demonstrated significant dysfunction during pacing at 150 to 210 beats/min. Echographic observation of the involved segments immediately after pacing revealed a maximal depression of function 5 seconds after pacing, equivalent to dysfunction at peak pacing, with function returning to control levels within about 2 minutes. Both maximal pacing and early postpacing studies facilitated satisfactory discrimination of ischemic from normally perfused myocardial segments. These experiments show that right atrial pacing study with quantitative two-dimensional echocardiography may serve to detect and assess a coronary stenosis associated with minor or no cardiac dysfunction in the rest state.

Left ventricular stroke volumes derived by two-dimensional echocardiography (2D echo) were compared with thermodilution and cineangiography measurements in closed-chest dogs before andone hour after proximal LAD occlusion. Stroke volume was calculated from end-diastolic and end-systolic volumes reconstructed by two models: 1) Simpson's rule employing left ventricular length and five short-axis cross-sectional areas; 2) a simplified volume formula (V = 5/6 area . length), utilizing a single short-axis area at either the mitral valve or midpapillary muscle level. The comprehensive Simpson reconstruction yielded a good correlation of 2D echo stroke volume against thermodilution (r = 0.89) over a range of normal (N = 14) and ischemic (N = 8) states. The simplified formula provided a satisfactory correlation (r = .90, N = 22) when using the midpapillary cross-section, which encompassed the induced ischemic dys-synergy. In contrast, when using the mitral valve level cross-section above the site of ventricular asymmetry, there was no significant statistical correlation. Comparison of cineangiography with 2D echo volume reconstruction based on the simplified formula with the midpapillary muscle level section yielded good correlations for stroke volume (r = 0.87) and ejection fraction (r = 0.97). Intraobserver and interobserver variability of duplicate echo stroke volume measurements was 8% and 10%, respectively. We conclude that 2D echocardiography in dogs permits quantitation of left ventricular stroke volume in normal and ischemic states.

Two-dimensional echocardiography was applied experimentally in a closed chest dog model with intact pericardium to determine the location, magnitude and extent of contractile response during pacing from discrete ventricular sites. Mid ventricular short-axis tomographic images obtained during regular sinus rhythm and subsequent premature ventricular beats provided comparative measurements of global and segmental systolic changes of cross-sectional luminal areas and myocardial wall thickness. Computer-assisted standardized analysis of segmental systolic fractional area change and wall thickening was used to map left ventricular contraction during normal rhythm and premature beats of 70% coupling interval, induced alternately from anterior and lateral aspects of the mid-left ventricular short-axis cross-sectional plane. A characteristic pattern consisting of early systolic contraction and wall thickening was followed by paradoxical motion and wall thinning in late systole in segments corresponding to the region of direct electrical stimulation. Statistical analysis of segment by segment function indicated a maximal amount of premature beat contractile derangement at the site of the stimuli. Pacing from a right ventricular wall site in the midventricular plane caused a similar premature beat response at the anterior aspect of the interventricular septum. It is concluded that two-dimensional echographic analysis of segmental ventricular function can identify the location of electrical stimuli, and thus might non-invasively characterize regional patterns of contraction associated with ectopic foci during arrhythmias.

The effects and reliability of a simple method of contrast two-dimensional echocardiographic delineation of myocardium after intracoronary injections were evaluated in closed-chest dogs. Multiple injections of an agitated saline-Renografin (meglumine diatrizoate) mixture (3:2 ratio, 2-ml bolus) into the left main coronary artery as well as at different sites of the left anterior descending and circumflex coronary arteries were studied in several short-axis and long-axis cross sections of the left ventricle. These contrast injections opacified specific regions of left ventricular myocardium depending on the site of injection. Contrast injection into the left main coronary artery provided a clear, echo-free outline (negative contrast) of underperfused myocardium distal to the coronary occlusion. Reproducibility studies of the extent of involved zones measured in echocardiographic cross sections indicated high intra- and interobserver correlation coefficients (r = 0.97 and 0.97). The effects of the intracoronary injection of contrast material appeared minor and brief. ECG ST-T changes lasted 49.4 +/- 36.7 seconds, aortic systolic pressure was reduced by 7.6 +/- 4.4% for 18.9 +/- 4.8 seconds, and the peak rate of left ventricular pressure rise decreased by 14.3 +/- 2.6%, but returned to control levels within 19.4 +/- 6.1 seconds. The zone of left ventricular asynergy after coronary occlusions was also delineated by cross-sectional echocardiography and corresponded to the contrast-outlined underperfused zone (negative contrast). This new intracoronary echocardiographic technique has only minor hemodynamic consequences and provides reliable quantitation of underperfused and dysfunctioning zones after experimental coronary occlusions. Further investigation and validation of this method may provide useful characterization of the extent and severity of myocardial ischemia and infarction.

This study examined whether an occlusive thrombus within a coronary artery can be lysed by streptokinase retroperfusion into the associated regional coronary vein. Experimental coronary artery thrombosis was induced in 15 closed chest dogs by placing a small copper coil at a proximal site of the left anterior descending coronary artery. Total thrombotic obstruction of this artery was verified within 10 to 60 minutes (38.0 +/- 15.8, mean +/- standard deviation) and streptokinase was administered within 94.0 +/- 17.4 minutes from coil insertion at an average rate of 42 IU/kg per minute by one of three modes: 1) intermittent 10 minute direct coronary venous retroinfusion (five dogs); 2) continuous infusion into the pumping circuit of synchronized phased retroperfusion of the great cardiac vein with arterial blood (five dogs); and 3) for comparison, streptokinase administered intravenously (five dogs). The intracoronary thrombus was fully lysed and anterograde reperfusion established within 51.0 +/- 18.7 minutes by intermittent streptokinase retroinfusion, and in 50.0 +/- 6.1 minutes by streptokinase supplemented synchronized retroperfusion (50.5 +/- 13.2 minutes for pooled retrograde coronary venous delivery). Lysis was also induced by systemic streptokinase, but the time to lysis was significantly longer and more variable (131.6 +/- 60.6 minutes) than with retrograde administration (p less than 0.01). The retroperfusion modality appears the preferable technique because it provides early thrombolysis and, at the same time, improves cardiac function and maintains myocardial viability of the jeopardized ischemic zone pending achievement of full reflow. Thus, streptokinase retroperfusion, if promptly instituted, may be a useful complemental nonsurgical treatment of evolving acute myocardial infarction after thrombotic coronary artery occlusion.

A quantitative two dimensional echocardiographic study was conducted in 10 normal subjects performing bicycle exercise in a supine position. Standardized two dimensional echocardiographic short axis and apical views of the left ventricle were analyzed to derive left ventricular sectional areas and length. Over a range of exercise heart rates from 108 to 152 beats/min, satisfactory two dimensional echocardiographic views and measurements were obtained for quantitative assessment of sectional and global left ventricular function. Variability of left ventricular short axis area measurements ranged from 2.9 to 8.3 percent. Left ventricular volume reconstruction employed a simplified formula (volume = 5/6 area X length) with a single papillary muscle level short axis area and left ventricular length. Changes in left ventricular function from rest to exercise quantitated by two dimensional echocardiography indicated a significant reduction in end-systolic volume (from 28.1 +/- 5.6 to 20.8 +/- 4.3 cc/m2, p less than 0.001) and increased left ventricular ejection fraction (from 63.4 +/- 6.3 to 72.1 +/- 5.7 percent, p less than 0.001). The change in end-diastolic volume was not significant. It is concluded that standardized two dimensional echocardiographic study during supine bicycle exercise in normal subjects provides good reproducibility of measurement of sectional and global left ventricular function. Quantitative two dimensional echocardiographic exercise study of global as well as segmental left ventricular performance in patients may be feasible using standardized procedure and analysis.

Measurement errors that may interfere with quantitation by the new myocardial contrast two-dimensional echocardiographic technique were examined in a simplified in vitro model consisting of a 50 cc blood-filled balloon with supplemental controlled injection of 0.2 to 2.6 cc of sonicated dextrose 70%. The blood-contrast mixture in the balloon volume was imaged with two-dimensional echocardiography and discrete regions were studied for both magnitude and time course of echo intensities. Preliminary evidence indicates that a regional contrast echo intensity measurement is significantly modified by contrast-related ultrasound attenuation in intervening regions and by the amount and mode of contrast material injection. Thus, injection of 1.2 cc contrast material resulted in substantially higher peak echo intensity and a more rapid decay than injection of 0.8 or 0.6 cc. These measurements were also found to be influenced by the echographic system signal processing and time-gain compensation which contribute to nonlinear and unevenly compensated image distribution of echo amplitudes. Other factors are discussed, including transducer-related image resolution and image texture, contrast agent bubble size and persistence and computer methods for standardized selection of region of interest and analysis of the regional contrast intensity decay curve.

Two dimensional echocardiography was applied experimentally in the closed chest dog to quantitate left ventricular function during and immediately after single premature ventricular contractions induced through threshold stimulation at the apex. Coupling intervals were varied over a range from 35 to 85 percent of the R-R interval during normal sinus rhythm (920 to 980 ms). The quality of tomographic echocardiographic images during premature as well as postextrasystolic beats was found to be satisfactory for quantitating short axis section areas at end-diastole and end-systole. A systolic fractional area change was computed from two dimensional echocardiographic measurements to characterize mid ventricular cardiac function, which correlated significantly with peak left ventricular pressure and maximal first derivative of left ventricular pressure (dP/dt). Marked shortening of coupling intervals reduced fractional shortening during premature systole and enhanced the degree of potentiation during the postextrasystolic beat. By contrast, premature beats with relatively long coupling intervals caused less reduction in contraction and only minor postextrasystolic potentiation. Systolic shortening of left ventricular length as well as transverse diameters were studied in a two dimensional echocardiographic long axis cross section. During long coupling intervals contraction was normal except for distinct regional systolic outward “bulging” in the apical region. In contrast, short coupling intervals were associated with a more significant generalized derangement of ventricular wall motion during systole. It is concluded that the two dimensional echocardiographic method can be used to portray and quantitate global as well as regional left ventricular function during disturbances of cardiac rhythm.

Two-dimensional echocardiography was applied in 10 closed-chest dogs to evaluate, in several left ventricular (LV) short-axis cross sections and subsegments, the regional contractile response to right atrial pacing. Compared with sinus rhythm (81 +/- 10 beats/min), which exhibited a moderate 7.2 +/- 12.0% (mean +/- standard deviation) base-to-apex increment in function, this gradient was significantly augmented to 34 +/- 12% by pacing at a heart rate of 180 beats/min. Measurements of wall thickening and perimeter shortening exhibited similar trends. Differences also were observed in subsegments of individual cross sections: in sinus rhythm the base-to-apex difference in function was relatively minor in the anterior and lateral aspects of the left ventricle (-9.1 +/- 18% and -1.9 +/- 19%), whereas a significant increase was noted in posterior and midseptal zones (18 +/- 17% and 22 +/- 30%). In response to pacing, the anterior and lateral wall base-to-apex gradients were significantly augmented (25 +/- 8% and 35 +/- 34%), but there was no further change in the posterior or septal regions. In conclusion, apical regions of the canine left ventricle responded to right atrial pacing with significant augmentation of contractile function, whereas more basal levels showed little response. Circumferentially, response to atrial pacing was most pronounced in the anterior and lateral segments.

Gross histochemical delineation of myocardium which has lost dehydrogenase enzyme activity has been shown to facilitate macroscopic recognition of necrotic myocardium. The present study was undertaken to assess the accuracy of the triphenyl tetrazolium chloride (TTC) technique for quantitating myocardial infarct size very early after coronary occlusion. In 16 closed-chest dogs the left anterior descending coronary artery was occluded with an intra-arterial balloon. Twelve dogs were killed 6 hours after occlusion, their hearts excised, cut from apex to base into 1 cm thick slices, and incubated in TTC. Whole-mount histologic sections of each slice were prepared. Myocardial infarct size was measured by planimetry of photographs of each gross slice and histologic section using classical criteria of necrosis. Myocardial infarct size determined in 54 slices by the TTC technique and histologically was similar (25 ± 16% vs 27 ± 16% of the left ventricular mass, mean ± SD) with close correlation between the two methods ( r = 0.91). Four dogs were killed 3 hour after occlusion and TTC stained and unstained myocardium was studied by electron microscopy. When the TTC technique identified necrosis so did electron microscopy. Areas identified by the TTC technique as non-necrotic were either normal or only ischemic by electron microscopy. Thus, using TTC, necrosis can be quantitated reliably 6, and even 3 hours after coronary occlusion, before histologic changes are clearly diagnostic. This technique represents a reliable, practical means for quantitation of recent infarction and for studying the evolution of ischemic injury in its early phase.

Contrast echocardiography has achieved importance in the diagnosis of cardiac shunt lesions. The technique provides information about flow patterns and serves as an adjunct to identifying communications that may be too small to image, even with high resolution real time scanning. This report reviews clinical applications and experiences in the use of standard, peripherally injected echocardiographic contrast agents for the detection of atrial septal defect, ventricular septal defect and patent ductus arteriosus. The importance and development of transpulmonary contrast agents capable of crossing the pulmonary capillary bed to opacify the left ventricle are reviewed and experience with a variety of experimental

Cross-sectional echocardiography was used to quantify volume in 21 canine left ventricles that were fixed in formalin and immersed in mineral oil. Area, length and diameter measurements were obtained from short- and long-axis cross-sectional images of the left ventricle and volume was calculated by seven mathematic models. Calculated volume was then compared, by linear regression and percent error analyses, with fluid volume of the left ventricle, obtained by filling the chamber with a known amount of fluid. Volumes ranged from 13-146 ml. Mathematic models using short-axis area and long-axis length gave higher correlation coefficients (r = 0.982 and r = 0.969) and lower mean errors (10-20%) than standard formulas previously used for M-mode echo and angiography. Thus, short-axis area analysis with cross-sectional echocardiography is well-suited for quantifying left ventricular volumes in dogs.

The effect of intravenous nifedipine (5 micrograms/kg) on the recovery of myocardial function after occlusion of the left anterior descending coronary artery was studied in 18 closed chest dogs. Using computer-aided analysis of two-dimensional echocardiograms, systolic and diastolic function of ischemic segments in low papillary left ventricular cross sections were characterized, respectively, as holosystolic fractional area change and early diastolic velocity of luminal area change. The time required for systolic function to return to preocclusion values after a 1 minute untreated control occlusion (n = 12) was 5 to 10 minutes, and after a 2 minute occlusion (n = 6) it was 20 to 30 minutes. When nifedipine was administered during the occlusion, recovery after a 2 minute occlusion was accelerated slightly to 10 to 15 minutes. Recovery times of early diastolic function were substantially longer, and nifedipine effects were more pronounced. After a 1 or 2 minute control coronary occlusion, 60 to 75 minutes or 90 to 105 minutes were needed to return early diastolic function to normal levels. Nifedipine administered during a 1 or 2 minute coronary occlusion improved these recovery times to 10 to 15 minutes. When the dogs were treated with intravenous nifedipine before coronary occlusion, recovery after 1 or 2 minutes of acute ischemia was apparent as early as 2 minutes after reperfusion. Thus, intravenous nifedipine accelerates the recovery of myocardial function after brief periods of ischemia, and when administered before coronary occlusion, it assures very prompt recovery of function.

l -dopa was administered to 20 dogs in cardiogenic shock. Beneficial effects were noted three to five minutes after infusion began, but more significant effects were observed within 15 minutes, reaching a maximum 45 to 60 minutes after infusion. The principal changes observed were: (1) a significant increase in coronary flow, (2) a significant rise in left ventricular dp dt max , and (3) a decrease in total peripheral vascular resistance. Aortic and mesenteric flows increased significantly. Renal flow did not improve throughout the l -dopa infusion. l -dopa benefits were probably due to a stimulation of the beta-receptors.

Hemodynamic and regional metabolic measurements were obtained in seven closed chest dogs during a control period, 3 hours of coronary occlusion and 5 hours of reperfusion. Reperfusion resulted in intermittent ectopic arrhythmias in five dogs and severe shock in two. It usually caused increases in heart rate, coronary sinus flow and maximal isovolumetric rate of rise in left ventricular pressure (dP/dt), which were associated with a decrease in systemic pressure, left ventricular end-diastolic pressure, systemic vascular resistance and stroke work. A transitory increase in cardiac output occurred. Global myocardial oxygen consumption, which was reduced during occlusion, increased with reperfusion. Reperfusion induced abnormal lactate metabolism and myocardial potassium loss in the previously occluded area and often in the nonoccluded segment as well. Histopathologic changes of accelerated necrosis, reactive hyperemia and hemorrhage were often noted after reperfusion. These studies indicate that reperfusion after 3 hours of occlusion caused serious abnormalities in hemodynamic states, metabolic function and morphologic features of the heart.

A new closed chest animal technique permits selective intracoronary balloon occlusion and measurement of hemodynamic and regional metabolic function before and during occlusion and reperfusion. The distal end of the double lumen balloon catheter provides information about the nature and extent of flow distal to the occlusion and permits blood sampling or administration of pharmacologic agents directly into the ischemic zone. Independent blood sampling from the great cardiac vein by means of a specially designed balloon catheter and from the coronary sinus by cannula allows simultaneous biochemical and regional blood flow measurements from the occluded and nonoccluded segments of the heart. Simultaneous intracoronary epicardial electrocardiograms permit electrophysiologic correlation with regional hemodynamic and metabolic events. The administration of oxygen by tracheal airway can increase partial oxygen tension in the circulation distal to coronary occlusion. When intracoronary pressures distal to occlusion are markedly reduced, the frequency of ventricular fibrillation is much greater.

Venoarterial pulsatile partial bypass and intraaortic balloon counterpulse techniques produce (1) diastolic augmentation of aortic pressure which improves perfusion of the myocardium, and (2) a sink in presystolic and systolic pressures which lowers the workload of the left ventricle. Both techniques are effective in reversing the shock state in dogs and in man. Regional hemodynamic studies performed before, during and after counterpulsation explain benefits and drawbacks of each technique.

The effect of synchronized coronary venous retroper-fusion of arterial blood on cardiac function after experimental coronary occlusion was examined by two-dimensional echocardiography. In 18 closed chest anesthetized dogs, the proximal left anterior descending coronary artery was occluded for 6 hours with an intracoronary balloon catheter. Eight of these animals served as untreated controls. Ten were treated with synchronized retroperfusion initiated 30 minutes after occlusion, and treatment was interrupted for 5 minutes at 1 hour after occlusion for study of the rapidity of retroperfusion response. Quantitative echographic analysis yielded global ejection fraction and regional indexes of contraction in a low left ventricular short-axis section, including segmental systolic area change, systolic wall thickening and end-diastolic wall thickness.At 6 hours after occlusion, ejection fraction had decreased from 50.7 ± 4.9% to 28.1 ± 7.7% (mean ± standard deviation) in control dogs, but was significantly (p < 0.01) less depressed in treated dogs (from 55.9 ± 5.2 to 41.8 ± 9.3%). The ischemic zone fractional area change at 30 minutes of occlusion exhibited a marked depression in both groups, after which the dysfunction persisted in the control dogs, but was largely reversed with retroperfusion from 6.0 ± 6.5 to 35.9 ± 15.9% at 6 hours of occlusion (p < 0.01). Brief interruption of retroperfusion 1 hour after occlusion reduced ischemic zone fractional area change from 33.0 ± 14.9 to 12.2 ± 9.5% (p < 0.01). This depression was promptly reversed to 33.6 ± 12.2% when retroperfusion was resumed. Segmental wall thickening followed a similar trend.Compared with previously observed derangements of sudden reperfusion, retroperfusion did not result in increased diastolic wall thickness in the ischemic zone and was not associated with arrhythmias. Thus, synchronized retroperfusion rapidly restored regional as well as global cardiac function during acute coronary occlusion.

Two-dimensional echocardiographic measurements of regional left ventricular end-diastolic wall thickness and systolic wall thickening were studied during coronary artery occlusion and early after reperfusion and compared with measurements of regional myocardial infarct size. In 25 closed chest anesthetized dogs with left anterior descending coronary artery occlusion followed by reperfusion, the occlusion period was 3 minutes in group I (n = 4), 20 minutes in group II (n = 4), 60 minutes in group III (n = 5) and 180 minutes in group IV (n = 12). Infarct size in groups III and IV was quantitated using the triphenyltetrazolium chloride technique. After coronary occlusion, wall thickening was replaced by thinning in the center of the ischemic region at the midpapillary echographic short-axis section, and no improvement in function occurred up to 60 minutes after reperfusion, except in group I. Ischemic zone enddiastolic wall thickness did not change significantly from control to the end of the coronary occlusion period, except Group IV. At 60 minutes after reperfusion, enddiastolic wall thickness increased only slightly in groups I and II (by 7.2 and 0.24%, respectively), but a marked increase was observed in groups III and IV (by 41 and 50%, respectively). The percent change in ischemic zone end-diastolic wall thickness from before reperfusion to 60 minutes after reperfusion correlated well with the amount of myocardial necrosis in corresponding segments (r = 0.936, standard error of estimate = 11.4%); an increase in segmental end-diastolic wall thickness of more than 25% was generally associated with 20% or more segmental necrosis. It is concluded that significantly increased regional end-diastolic wall thickness early after reperfusion is associated with irreversibly damaged myocardium, and this might be used as an index of myocardial salvage.

A method using contrast two-dimensional echocardiography for left ventricular chamber and myocardial opacification from a right-sided pulmonary capillary wedge position is described. A total of 152 studies were carried out in nine mongrel dogs. Four different catheters with different catheter tip cross-sectional areas (varying from 0.75 to 2.3 mm2) were used. In addition, catheter position (six different positions in the pulmonary circulation), pressure of injection and type of echo contrast agent (hand-agitated and sonicated) were studied.In all 152 studies, two independent observers agreed that echo contrast was seen in the left ventricular chamber after a pulmonary capillary wedge injection of 8 cc of echo contrast agent followed by a flush injection of 8 cc saline solution. In 71% of the studies, the two independent observers agreed about the degree of opacification on a qualitative scale of 0 to 3 +.Time from injection from the catheter tip to the appearance of echo contrast in the left atrium was 6.2 ± 4.8 seconds for sonicated Renografin-76 and 2.8 ± 0.6 seconds for sonicated sorbitol 70% (p < 0.05). Correlation for the disappearance rate of echo contrast as determined for the region in the mid left ventricular chamber and thermodilution cardiac output was fair (r = -0.78; n = 14). In 24 studies, it was not possible to demonstrate the appearance of echo contrast in the myocardium.Peak videointensity of 10 duplicate injections showed a mean percent error of 10.4 ± 2.1% for sonicated Renografin-76 and 1.4 ± 0.8% for sonicated sorbitol 70%. For both agents, peak video intensity decreased by 15.1 ± 2.3% after 12 consecutive injections. In contrast, the hand-agitated agents showed a striking decrease of 50% of peak video intensity after a minimum of three consecutive injections. Echo contrast extravasation was noted in 3 of the 152 studies by fluoroscopy and confirmed by microscopic analysis; however, hemodynamic and electrocardiographic changes were not seen.Thus, transpulmonary opacification of the left ventricular chamber and to a lesser degree of the left ventricular myocardium is feasible. Furthermore, the procedure causes no serious side effects, is reproducible and repeatable. The ultimate success is highly dependent on the echo contrast agent and catheter used.

The efficacy of retrograde coronary venous delivery of procainamide for the management of spontaneous and inducible sustained ventricular tachycardia was evaluated and compared with systemic intravenous procainamide administration in 22 conscious dogs with permanent left anterior descending coronary artery occlusion. Selective retrograde injection of procainamide was achieved through an autoinflatable balloon catheter placed in the great cardiac vein, with the tip positioned in the vicinity of the site of left anterior descending coronary occlusion. Great cardiac vein retroinfusion of procainamide was significantly (p less than 0.05) more effective than systemic intravenous injection against spontaneous ventricular tachycardia 1 day after coronary artery occlusion (13 dogs) and against electrically induced sustained ventricular tachycardia in the 3 to 12 day postocclusion period (9 dogs). Significantly lower doses of procainamide were used with retroinfusion as compared with systemic administration, that is, 19.6 +/- 8.8 versus 35 +/- 0 mg/kg body weight during spontaneous tachycardia and 13.4 +/- 4.1 versus 32.1 +/- 2 mg/kg during induced tachycardia (p less than 0.01). Retroinfusion of saline solution through the great cardiac vein had no effect on either type of tachycardia. Myocardial tissue procainamide levels measured in infarcted and ischemic zones of the left anterior ventricular wall were 9 to 100 times higher after great cardiac vein retroinfusion than after systemic injection. Great cardiac vein dye injection studies demonstrated a preferential distribution in left ventricular regions supplied by the occluded coronary artery. It is concluded that regional coronary venous procainamide retroinfusion in dogs with myocardial infarction is more effective than systemic intravenous injection against both spontaneous and inducible sustained ventricular tachycardia. The greater efficacy of great cardiac vein treatment appears to be primarily related to selectively increased delivery of procainamide to ischemic myocardial sites.

The safety and efficacy of a new clinical synchronized diastolic retroperfusion mechanical pump and autoinflatable balloon catheter was studied in 10 dogs during and after 6 hours of left anterior descending coronary artery occlusion. Eight other dogs served as the untreated control group. Infarct size measured by triphenyltetrazolium chloride, and expressed as a percent of area at risk, was significantly reduced by retroperfusion treatment (19 +/- 18 versus 58 +/- 36, p less than 0.01). Morphologic examination of the coronary sinus and cardiac veins did not demonstrate evidence of damage from synchronized retroperfusion. There was also no evidence of excess myocardial edema in either the jeopardized ischemic or normally perfused zones. There was no evidence of significant red cell hemolysis or platelet destruction from the treatment. Thus, it appears that synchronized diastolic retroperfusion is a safe and effective treatment of acute myocardial ischemia in experimental animals and warrants clinical testing.

Several intracoronary echo contrast agents that provided satisfactory regional myocardial delineation with two-dimensional echocardiography were compared in 15 dogs and their effects on coronary blood flow were examined. Reproducible delineation of myocardium subserved from the intracoronary echo contrast injection site was achieved with hand-agitated agents containing greater than or equal to 30% Renografin, greater than or equal to 30% glucose, greater than or equal to 30% sucrose or 6% dextran. After a 2 cc injection of the echo contrast agent, peak hyperemic augmentation of coronary flow was 56.7 +/- 54.4% for 6% dextran, 116.0 +/- 71.1% for 30% Renografin, 119.3 +/- 47.8% for 30% sucrose, 173.8 +/- 38.3% for 30% glucose. Although, 6% dextran resulted in the lowest and shortest hyperemic response of the four agents, computer-derived echo contrast appearance-disappearance analysis indicated a prolonged myocardial contrast decay half-life (21.0 seconds). On the other hand, 30% Renografin had a more rapid myocardial echo contrast washout (T 1/2 = 15.5 seconds), but a significantly greater hyperemic effect was observed. It is concluded that development of echo contrast agents for myocardial contrast two-dimensional echocardiographic assessment of myocardial perfusion will require consideration of alterations in coronary flow due to contrast-induced hyperemia.

Regional myocardial echo contrast appearance-disappearance after intracoronary contrast agent injection was examined with computerized two-dimensional contrast echocardiography in eight open chest dogs during successive variation of the coronary blood supply. A new sonication method applied to dextrose 50% produced an echo contrast agent with a microbubble size of 12 ± 6 μ (mean ± standard deviation), and 1 cc of this agent was injected into a coronary artery during the echocar-diographic study of the left ventricle. Left anterior descending or circumflex coronary artery flow, measured by electromagnetic flowmeter, was successively reduced up to 90% with an extravascular hydraulic occluder, or else increased 40 to 60% through intravenous dipyridamole infusion (7 to 10 μg/kg per min). The corresponding myocardial echo time-intensity curves were analyzed for each of 12 segments of a midventricular short-axis cross section.Several potential indexes of myocardial perfusion were derived: peak echo contrast intensity, time from echo contrast appearance to peak intensity, half-life of echo contrast decay phase (T½ and total duration of contrast appearance-disappearance. Except for peak intensity, all of these indexes provided significant (p < 0.05) differentiation between control coronary flow (66 ± 17 nil/min) and greater than 50% flow reductions (26 ± 6 nil/min) or hyperemia (115 ± 17 ml/min). Half-life values were 5.2 ± 0.3 seconds for the control state, 9 ± 2 seconds for the reduced coronary flow and 2 ± 2 seconds for dipyridamole hyperemia. Compared with an echo contrast-delineated circumferential extent of 5.6 ±1.4 myocardial segments subserved from the site of the coronary occluder, greater than 50% flow reduction significantly decreased contrast disappearance T½ in 3.7 ± 1.7 segments versus decreased systolic wall thickening in 6.6 ±1.4 segments. T½ for the central ischemic zone correlated moderately with coronary flow (r = 0.56, p < 0.05).It is concluded that myocardial contrast two-dimensional echocardiography, using small microbubbles as the agent, can identify a primary perfusion defect and may permit characterization of myocardial blood supply.