Jorge Cheirif

Safety and efficacy of a new transpulmonary ultrasound contrast agent: Initial multicenter clinical results

Myocardial contrast echocardiography has been found to be a safe and useful technique for evaluating relative changes in myocardial perfusion and delineating areas at risk. Although earlier contrast agents required direct delivery into the coronary arteries or aortic root, a new echocardiographic contrast agent, sonicated albumin microspheres (Albunex), has been found to cross the pulmonary circulation in experimental models. To determine the safety and preliminary efficacy of intravenous injections of Albunex in humans, 71 patients at three independent medical institutions underwent two-dimensional echocardiographic examination before, during and after the administration of three intravenous doses of Albunex, ranging from 0.01 to 0.12 ml/kg body weight. All patients provided a complete history and underwent physical and neurologic examination and laboratory and electrocardiographic evaluation before the injections; all evaluations (except for the history) were repeated at 2 h and 3 days after the injections of Albunex. The efficacy of the injections was qualitatively assessed by two independent blinded observers using a grading system of 0 to +3, with 0 indicating an absence of contrast effect and +3 indicating full opacification of the cavities examined. All injections were well tolerated and no serious side effects were noted in any of the patients. Irrespective of dose group, a cavity opacification greater than or equal to +2 was seen in the right ventricle in 212 (88%) of 240 injections and in the left ventricle in 151 (63%) of 240 injections as judged by the independent observers. The degree of ventricular cavity opacification appeared to be dose and concentration related.(ABSTRACT TRUNCATED AT 250 WORDS)

Improved left ventricular endocardial border delineation and opacification with OPTISON (FS069), a new echocardiographic contrast agent. Results of a phase III Multicenter Trial.

OBJECTIVES The echocardiographic contrast-enhancing effects and safety profile of ALBUNEX (a suspension of air-filled albumin microspheres) were compared with the new contrast agent OPTISON (formerly FS069: a suspension of albumin microspheres containing the gas perfluoropropane) in 203 patients with inadequate noncontrast echocardiograms. BACKGROUND The efficacy of ALBUNEX has been limited by its short duration of action. By using perfluoropropane instead of air within the microsphere, its duration of action is increased. METHODS Each patient received ALBUNEX (0.8 and 0.22 mL/kg) and OPTISON (0.2, 0.5, 3.0, and 5.0 mL) on separate days a minimum of 48 hours apart. Echocardiograms were evaluated for increase in left ventricular (LV) endocardial border length, degree of LV opacification, number of LV endocardial border segments visualized, conversion from a nondiagnostic to a diagnostic echocardiogram, and duration of contrast enhancement. A thorough safety evaluation was conducted. RESULTS Compared with ALBUNEX, OPTISON more significantly improved every measure of contrast enhancement. OPTISON increased well-visualized LV endocardial border length by 6.0+/-5.1, 6.9+/-5.4, 7.5+/-4.7, and 7.6+/-4.8 cm, respectively, for each of the four doses, compared with only 2.2+/-4.5 and 3.4+/-4.6 cm, respectively, for the two ALBUNEX doses (p < 0.001). 100% LV opacification was achieved in 61%, 73%, 87%, and 87% of the patients with the four doses of OPTISON, but in only 16% and 36% of the patients with the two ALBUNEX doses (p < 0.001). Conversion of nondiagnostic to diagnostic echocardiograms with contrast occurred in 74% of patients with the optimal dose of OPTISON (3.0 mL) compared with only 26% with the optimal dose of ALBUNEX (0.22 mL/kg) (p < 0.001). The duration of contrast effect was also significantly greater with OPTISON than with ALBUNEX. In a subset of patients with potentially poor transpulmonary transit of contrast (patients with chronic lung disease or dilated cardiomyopathy), OPTISON more significantly improved the same measures of contrast enhancement compared with ALBUNEX and did so to the same extent as in the overall population. Side effects were similar and transient with the two agents. CONCLUSION OPTISON appears to be a safe, well-tolerated echocardiographic contrast agent that is superior to ALBUNEX.

Opacification and border delineation improvement in patients with suboptimal endocardial border definition in routine echocardiography : results of the phase III albunex multicenter trial

OBJECTIVES This study was designed to assess the safety and efficacy of intravenously administered sonicated human serum albumin for enhancing echocardiographic delineation of the left ventricular endocardium and improving assessment of wall motion in patients with incomplete depiction of noncontrast echocardiography. BACKGROUND Echocardiographic regional wall motion analysis is impaired by incomplete endocardial definition in as many as 10% of patients. Sonicated human serum albumin is a stable contrast material that, unlike other agents, opacifies the left ventricle when administered intravenously. METHODS One hundred seventy-five patients were enrolled at eight centers on the basis of incomplete echocardiographic endocardial depiction. Sonicated 5% human serum albumin, a stable preparation of air-filled microspheres (size range 1 to 10 microns), was administered intravenously in divided doses: 0.08 ml/kg body weight in all patients, followed by 0.14 and 0.08 ml/kg or a single dose of 0.22 ml/kg, depending on the result of the initial dose. Investigators and independent reviewers blinded to the protocol scored the echocardiograms for degree of left ventricular opacification and improvement of endocardial border depiction. RESULTS Overall, 81% of patients had at least moderate left ventricular chamber opacification with at least one contrast dose, and endocardial definition was improved in 83%. In the subgroup with inadequate left ventricular opacification from the initial dose, a second, larger dose (0.22 ml/kg) improved endocardial depiction in 64%. No significant side effects occurred. CONCLUSIONS In patients with incomplete echocardiographic endocardial definition, sonicated human serum albumin is a safe, effective contrast agent that, when administered intravenously, produces left ventricular chamber opacification, improves endocardial depiction and enhances regional wall motion analysis.

Assessment of myocardial perfusion in humans by contrast echocardiography. I: Evaluation of regional coronary reserve by peak contrast intensity

Myocardial contrast echocardiography was performed during coronary angiography with 2 ml of sonicated meglumine diatrizoate sodium 76% (meglumine) in 40 patients (ranging in age from 25 to 79 years) before and 10 to 15 s after intracoronary injection of papaverine, 8 mg into the right coronary artery (n = 43) and 10 mg into the left (n = 46). The same protocol was repeated in 17 patients 5 to 10 min after completion of coronary angioplasty. In 13 patients with normal coronary angiograms, peak contrast intensity corrected for background myocardial intensity was measured in 36 regions and was found to increase after papaverine from 36 +/- 16 to 55 +/- 22 U (p less than 0.001). In contrast, in the 27 patients with angiographic evidence of coronary artery disease, peak intensity in 64 regions remained unchanged after papaverine (35 +/- 22 versus 36 +/- 23 U). An increase in peak intensity greater than or equal to 10 U was 80% sensitive and 92% specific for coronary artery disease. After successful coronary angioplasty, peak intensity in the involved regions improved significantly (p less than 0.001) during baseline contrast injections (from 32 +/- 16 to 50 +/- 25 U) as well as in the postpapaverine contrast injections (from 30 +/- 12 to 60 +/- 26 U). In conclusion, measurement of peak contrast intensity after intracoronary injections of sonicated meglumine provides a relative index of myocardial perfusion that allows assessment of regional coronary reserve in patients with coronary artery disease. This may be of particular value in evaluating the immediate effects of coronary angioplasty on myocardial perfusion.

Diagnosis of ischemic heart disease with adenosine echocardiography

To assess the feasibility, safety and diagnostic accuracy of adenosine infusion combined with echocardiography, 73 patients with suspected or known coronary artery disease underwent echocardiography at baseline and during a maximal intravenous adenosine infusion of 140 micrograms/kg per min. Compared with baseline values, adenosine caused an increase in heart rate, a decrease in systolic and diastolic blood pressure and a slight but significant increase in rate-pressure product. The echocardiographic images were digitized and randomly assigned in a quad-screen format for nonbiased interpretation. An ischemic response, defined as a new or worsening wall motion abnormality, developed in 25 patients; a fixed wall motion abnormality was present in 27 and no abnormality in 21. All patients underwent coronary angiography. The sensitivity of adenosine echocardiography for greater than or equal to 75% coronary artery diameter stenosis was 85% (46 of 54), with a specificity of 92% in patients with normal coronary arteries. In the 35 patients with a normal baseline electrocardiogram the sensitivity was 60%; 9 (82%) of 11 patients with multivessel disease were correctly identified. The sensitivity for adenosine electrocardiography (greater than or equal to 1-mm ST depression) was 35% with a specificity of 100%. Side effects were transient and mild; aminophylline was used in two patients. Thus, ischemic changes can be induced in patients with coronary artery disease with intravenous adenosine that, combined with echocardiography, is sensitive for the assessment of ischemic heart disease, particularly in patients with multivessel disease.

Assessment of regional myocardial perfusion by contrast echocardiography. II. Detection of changes in transmural and subendocardial perfusion during dipyridamole-induced hyperemia in a model of critical coronary stenosis☆

Measurements of myocardial contrast (sonicated meglumine diatrizoate) intensity were compared with myocardial flow by radioactive microspheres before and after administration of dipyridamole (0.5 mg/kg body weight intravenously) in 10 open chest dogs with a critical stenosis in the left circumflex coronary artery. Computer measurements of contrast time-intensity curves corrected for background myocardial intensity were made along 12 transmural segments of the left ventricle at mid-papillary level and for the subendocardial and subepicardial half of each segment. After administration of dipyridamole, transmural flow in the control region increased significantly (p less than 0.001), resulting in a dipyridamole/baseline flow ratio (i.e., coronary reserve ratio) of 2.54 +/- 0.95. Similar changes (p less than 0.001) were seen by contrast echocardiography; the coronary reserve ratio was 2.10 +/- 0.60 with use of peak intensity and 3.48 +/- 1.58 with use of area under the time-intensity curve. In contrast, no significant changes were observed in myocardial flow, peak contrast intensity or area under the curve in the ischemic region after dipyridamole. In the control region the ratio of subendocardial to subepicardial flow was similar at baseline and after dipyridamole administration as assessed by microspheres (1.08 +/- 0.24 versus 1.17 +/- 0.25) or by area under the time-intensity curve (1.11 +/- 0.45 versus 1.11 +/- 0.56). In the ischemic region, the subendocardial/subepicardial flow ratio decreased significantly after dipyridamole administration as measured by microspheres (1.15 +/- 0.19 to 0.82 +/- 0.25; p less than 0.001) or by area under the curve (1.10 +/- 0.28 to 0.70 +/- 0.47; p less than 0.01). Thus, myocardial contrast echocardiography appears to be a sensitive technique with which to detect changes in myocardial flow induced by dipyridamole in the various myocardial layers of normal segments as well as of segments supplied by a critically stenotic coronary artery.

Clinical variables affecting recovery of left atrial mechanical function after cardioversion from atrial fibrillation

OBJECTIVES We sought to evaluate the effect of clinical factors on recovery of atrial function after cardioversion for atrial fibrillation. BACKGROUND Lack of effective mechanical atrial function (EMAF) after cardioversion of atrial fibrillation predisposes to thromboembolic complications and delays improvement in functional capacity. METHODS Fifty-two patients underwent cardioversion (group I, electrical cardioversion, n = 40; group II, pharmacologic or spontaneous cardioversion, n = 12) for atrial fibrillation. Serial transmitral inflow Doppler variables were recorded after cardioversion until EMAF (atrial filling velocity > 0.50 m/s) was seen. Clinical variables (age, duration of atrial fibrillation, left ventricular ejection fraction, left atrial diameter, underlying cardiovascular disease, antiarrhythmic drug therapy and mode of cardioversion) were tested for an association with the outcomes of recovery of atrial function by day 3 and day 7. RESULTS Effective mechanical atrial function recovered in 68% of patients by day 3 and in 76% by day 7 after cardioversion. The mode of cardioversion was significantly associated with recovery of atrial function by day 3 in bivariate and multivariate analyses (odds ratio 0.12, 95% confidence interval 0.01 to 1.0, for electrical cardioversion). None of the variables had an association with recovery of atrial function by day 7. Group I patients took a longer time to recover atrial function than group II patients (p = 0.012). In addition, group I patients had a significantly lower peak atrial filling velocity (mean [+/-SD] 0.39 +/- 0.19 m/s vs. 0.56 +/- 0.16 m/s) and a higher early filling to atrial filling velocity ratio (2.5 +/- 1.2 vs. 1.5 +/- 0.5) after cardioversion. CONCLUSIONS A high proportion of patients recover EMAF within 1 week after cardioversion. Patients who undergo electrical cardioversion display a greater degree and a longer duration of mechanical atrial dysfunction than those who convert pharmacologically or spontaneously.

Mechanical dysfunction of the left atrium and the left atrial appendage following cardioversion of atrial fibrillation and its relation to total electrical energy used for cardioversion

In 39 patients undergoing electrical cardioversion for atrial fibrillation (AF), we examined the effect of total electrical energy used for cardioversion on postcardioversion peak left atrial (LA) rapid filling velocity (A) and the atrial emptying fraction, and recovery of LA effective mechanical atrial function (defined as peak A velocity > or = 0.50 m/s), as assessed by transthoracic echocardiography. In a subset of 27 patients who underwent pre- and postcardioversion transesophageal echocardiography, we assessed the relation between total electrical energy and LA appendage filling and emptying velocities and spontaneous echo contrast. Patients were randomized to receive an initial shock of 1.5 J/kg based on body weight, or 2.5, 3.5, 5 J/kg, or 360 J, followed sequentially by higher shock intensities until sinus rhythm was achieved. Patients were classified into 4 groups based on quartiles of total energy delivered for cardioversion. Conversion to sinus rhythm was associated with a significant decrease in the LA appendage filling velocities (0.42 +/- 0.20 m/s vs 0.29 +/- 0.14 m/s; p = 0.002) and LA appendage emptying velocities (0.40 +/- 0.22 m/s vs 0.29 +/- 0.18 m/s; p = 0.03), but no change in the incidence of spontaneous echo contrast (61% vs 70%, p = 0.08). The 4 groups of patients did not differ with respect to postcardioversion LA appendage filling velocities, LA appendage emptying velocities, incidence of spontaneous echo contrast, or worsening of spontaneous echo contrast. Similarly, the change in LA appendage filling and emptying velocities associated with cardioversion was not different between the groups. Furthermore, postcardioversion peak A velocity and atrial emptying fraction and recovery of effective mechanical atrial function were similar between the 4 groups. These results suggest that in patients undergoing electrical cardioversion for AF, the total electrical energy used for cardioversion has no effect on the mechanical function of the left atrium or LA appendage following cardioversion.

Assessment of regional myocardial perfusion with myocardial contrast echocardiography in a canine model of varying degrees of coronary stenosis

Previous studies showed that myocardial contrast echocardiography can be used to detect relative regional underperfusion in a canine model of critical coronary stenoses. The aim of this study was to determine if myocardial contrast echocardiography performed with a sterile sonicated human serum albumin preparation (Albunex, Molecular Biosystems, San Diego, Calif.) could detect the presence of coronary stenoses of variable degrees of severity. The results were compared with myocardial blood flow as assessed by radiolabeled microspheres in 16 open-chest dogs during baseline, following the creation of a coronary stenosis of variable severity and at the peak of dipyridamole-induced hyperemia. When flow ratios (that is, flow in the control area/ischemic area) were examined, a good correlation was observed between the area under the time-intensity curve and radioactive microsphere blood flow (r = 0.94, p < 0.0001), which allowed distinction of mild from severe stenosis. However, a consistent underestimation of the dipyridamole-induced hyperemia by myocardial contrast echo was seen in the control zone. This could be partially explained by a simultaneous increase in coronary blood flow and blood volume with dipyridamole and by attenuation of the ultrasound signal because of the high concentration of microbubbles at high flows. Myocardial contrast echocardiography can quantitate the amount of jeopardized myocardium during various degrees of coronary stenoses.

Myocardial contrast echocardiography: relation of collateral perfusion to extent of injury and severity of contractile dysfunction in a canine model of coronary thrombosis and reperfusion.

OBJECTIVES This study sought to determine whether myocardial contrast echocardiography could be used to detect and quantitate collateral blood flow capable of limiting the effects of ischemia in an experimental model of coronary thrombosis and reperfusion. BACKGROUND Myocardial contrast echocardiography has been used to assess collateral blood flow in humans, but this technique has not been extensively validated in the experimental laboratory. METHODS Myocardial ischemia occurred after electrically induced left circumflex coronary artery thrombosis in a canine model. Ischemia was intensified by administration of vasodilators. Reperfusion was induced with recombinant tissue-type plasminogen activator. Myocardial perfusion was assessed with contrast echocardiography and radiolabeled microspheres. Infarct size was determined by histochemical staining methods. Myocardial samples were evaluated histologically. RESULTS The dogs were classified into two groups on the basis of contrast echocardiographic detection of perfusion in the ischemic region: those with (n = 13) and without collateral flow (n = 10). Collateral perfusion detected by contrast echocardiography paralleled changes detected by radiolabeled microspheres during thrombosis and vasodilator administration. A 91% agreement was observed between the two techniques in detecting collateral flow > 0.3 ml/min per g (p < 0.0001). Collateral perfusion correlated directly with radial shortening fractions of the ischemic myocardium (p < 0.01). Recovery of function after reperfusion was faster, infarct size was smaller (mean [+/- SD] 4 +/- 1% vs. 11 +/- 3%, p = 0.05), and histopathologic injury was less in dogs with than without collateral flow, respectively (p < 0.05). CONCLUSIONS Myocardial contrast echocardiography can identify physiologically significant collateral vessels capable of limiting the degree of ischemic damage during coronary thrombosis. The magnitude of collateral flow and the change in flow induced by vasodilators can be assessed and compares favorably with the microsphere standard.