Indium-111-labeled monoclonal antimyosin Fab has been used to image myocardial infarction, myocarditis and cardiac transplant rejection with localization in myocytes that have suffered irreversible loss of cell membrane integrity. Technical factors potentially limiting clinical usefulness of 111In antimyosin include dosimetry (72 hr half-life of 111In), slow blood clearance of antibody proteins delaying optimal imaging to 24 to 48 hr postinjection and nontarget organ uptake. Therefore, two new antimyosin imaging agents experimentally shown to potentially improve dosimetry, shorten time from injection to imaging or decrease nonspecific cell binding were evaluated in a primate cardiac transplant model. The two agents evaluated were polylysine 111In-antimyosin (0.023 mg Fab modified with a 3.3 kd polymer of polylysine and labeled with 111In) and 99mTc-antimyosin (0.5 mg Fab' antimyosin labeled using the RP-1 ligand technique). A total of eight baboons were studied: three with heterotopic (cervical) xenographs, three with orthotopic allographs and two control animals. Each animal was injected first with 12-23 mCi of 99mTc-RP-1 antimyosin and 5-16 hr after completion of imaging, was injected with 0.72-1.88 mCi of 111In-polylysine antimyosin (PIs) and reimaged 12-48 hr later. The imaging results were compared to the histology of the animals. Biexponential curves were fit to the blood sample data and rate constants were determined and expressed as T1/2 values. There were no significant differences between the two agents in either the early fast components or the late slow components. On planar imaging, there was blood-pool activity at 10-12 hr postinjection of both agents, but by 16-24 hr postinjection, blood pool was negligible on the 111In-PIs scans. Both agents were concentrated in the rejected cardiac tissue. The slow blood-pool clearance combined with the 6 hr half-life of 99mTc-RP-1 AMA make this agent less promising for detection of diffuse myocardial uptake than 111In Fab modified with polylysine.

To test the hypothesis that a small field of view portable multicrystal scintillation camera can perform stress/rest combined LV function by first-pass and perfusion studies using 99mTc-teboroxime, 26 patients with positive stress thallium studies within 2 wk and 8 healthy volunteers were studied. A 241Am point source marker over the sternum was used for motion correction. Dynamic dual-isotope (99mTc/241Am) acquisition was performed following injection of 15.6 +/- 2.3 mCi of 99mTc-teboroxime at peak treadmill exercise. Two minutes later (blood-pool clearance), while still standing on the flat treadmill, 3-4 40-sec planar images were acquired. One hour later patients were reinjected with 22.7 +/- 3.4 mCi of 99mTc-teboroxime while standing in front of the camera and the same dynamic/static acquisition protocol repeated. The planar images were interpolated from a 20 x 20 matrix to a 160 x 160 matrix, a sharpening filter and an interpolative background subtraction algorithm applied. The scans were divided into segments, each scored as normal, reversible and fixed. The agreement with thallium imaging for identifying an abnormal scan was 24/26 (92%) and for identifying abnormal vascular territories was 43/52, (83%). Fourteen patients had exercise LVEF less than 50% and all had either prior myocardial infarction, myocardial infarction plus ischemia or LAD ischemia. Diagnostic planar perfusion images and exercise LVEF can be acquired in less than 4 min using 99mTc-teboroxime and a portable multicrystal scintillation camera.

To assess the diagnostic value of indium-111 antimyosin for detecting right ventricular (RV) wall acute infarction, 30 patients with electrocardiographic-documented left ventricular inferior (posterior) wall acute myocardial infarction underwent simultaneous dual isotope indium-111 antimyosin and thallium-201 single-photon emission computed tomography (SPECT) within 2 days of admission. RV necrosis was defined as uptake of indium-111 antimyosin anterior and to the right of septal thallium uptake. Twenty-nine of the 30 patients (97%) had indium-111 antimyosin uptake in the inferior, posterior or lateral walls of the left ventricle and 14 of 30 (47%) had additional RV antimyosin uptake. Three different patterns of RV uptake of indium-111 antimyosin were observed: crescent-shaped, focal and apical. Twenty-seven patients underwent gated blood pool scanning before hospital discharge. Twelve of the 14 patients with RV antimyosin uptake had gated blood pool scintigraphy and 7 of 12 had RV dysfunction; 5 had normal RV function. Except for 1 patient who had questionable RV antimyosin uptake and had RV dysfunction, no patient without RV antimyosin uptake had RV dysfunction. In summary, right and left ventricular necrosis can be detected on tomographic images of indium-111 antimyosin uptake in patients with inferior infarctions when simultaneous uptake of a perfusion tracer, thallium-201, is imaged and used as an aid to reconstruction and anatomic localization.

Biodistribution of monoclonal antibody T43 and its F(ab′)2111In-DTPA conjugates were determined in nu/nu mice bearing human breast tumor and rat pituitary tumor xenografts. T43 localized in the target tumor with tumorblood ratios of 3.9 (P < 0.01) and 4.5 (P < 0.05) at 48 and 72 h, respectively. T43 F(ab′)2 fragments localized with tumorblood ratio of 14.2 (P <0.1) at 72 h. Tumors as small as 4mm were detected without computer subtraction technique. These studies suggest that T43 and T43 F(ab′)2 might be useful reagents in radioimaging.

To evaluate the effect of infarct size on left ventricular volumes and geometric remodeling, 26 patients with a first acute Q wave myocardial infarction (anterior in 14, inferior in 12) had the infarct sized from single-photon emission computed tomographic (SPECT) imaging of indium-111 antimyosin. All patients underwent gated blood pool scintigraphy before hospital discharge for determination of ejection fraction and end-diastolic and end-systolic volume indexes. Infarct size was quantitated from indium-111 antimyosin uptake in coronal slices with use of a threshold technique for edge detection. Nineteen of 26 patients had additional simultaneous acquisitions of indium-111 and thallium-201 uptake and the infarct was expressed as a percent of the total left ventricle. Infarct size was larger (59 +/- 16 vs. 33 +/- 16 g), predischarge ejection fraction lower (35 +/- 5% vs. 60 +/- 9%) and end-systolic volume index higher (57 +/- 13 vs. 36 +/- 10 ml/m2) in the group with anterior infarction. Despite these differences, predischarge end-diastolic volume index was not significantly different between the group with anterior (88 +/- 17 ml/m2) versus inferior (89 +/- 14 ml/m2) infarction. There was a significant inverse correlation between percent infarct size and ejection fraction for patients with dual isotope imaging (r = -0.90) and a significant direct correlation between infarct size and end-systolic volume index (r = 0.79, p less than 0.01). Fourteen patients without subsequent myocardial infarction or coronary artery bypass grafting had a repeat gated blood pool study late (26 +/- 15 months) after infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

The clinical significance of silent ischemia is not fully known. The purpose of this study was to determine whether the presence or absence of angina during a thallium stress test positive for ischemia was independently predictive of an adverse outcome. Two hundred thirty-four consecutive patients with ischemia on a thallium stress test were identified. Ischemia was defined as the presence of defect(s) on the immediate postexercise scans not in the distribution of prior infarctions that redistributed on 4-hour scans. During the test 129 patients had angina, defined as characteristic neck, jaw, arm, back or chest discomfort, while the remaining 105 patients had no angina. Follow-up ranged from 2 to 8.2 years (mean 5.2 ± 2.1) and was successfully obtained in 156 patients. Eighty-two of the 156 patients had angina (group A) and 74 had silent ischemia (group S). Group A patients were significantly older (62 ± 8 vs 59 ± 8 years, p < 0.05). There was no significant difference between the 2 groups in terms of sex, history of prior infarction or presence of left main/3-vessel disease. A larger percentage of patients in group A were receiving β blockers (60 vs 41%, p < 0.05) and nitrates (52 vs 36%, 0.05 < p < 0.10). There was a large number of cardiac events (myocardial infarction, revascularization and death) in both groups (37 of 82 [45%] in group A; 28 of 72 [38%] in group S) but no statistically significant difference between the groups. Similarly, life-table analysis revealed no difference in mortality between the 2 groups. Thus, patients who show symptoms of angina during exercise-induced ischemia do not have a significantly different risk than those without pain.

Forty-two patients (28 men and 14 women) with acute myocardial infarction (35 Q, seven non-Q wave) were injected with 2.0 mCi indium 111-labeled antimyosin (AM) monoclonal antibody (111In AM) within 48 hours of the onset of chest pain. Forty-eight hours later (72-96 hours after onset of chest pain), patients were injected with 2.2 mCi thallium 201, and two sets of single-photon emission computed tomography (SPECT) images were obtained simultaneously using dual energy windows set for the 247 keV indium photopeak and the 70 keV thallium peak. Seventeen patients had repeat scans at 4 hours. 111In AM uptake and 201Tl defects were localized to one or more of 24 coronal and sagittal segments. Scans with only 201Tl defects and corresponding 111In AM uptake were classified as matches; scans with unmatched 201Tl defects in addition to matching regions corresponding to electrocardiographic infarct location were classified as mismatches; and scans with 201Tl and 111In AM uptake in the same segments were classified as overlap. Scan patterns were correlated with clinical evidence for residual ischemia occurring within 6 weeks of infarct and including infarct extension, recurrent angina, and positive predischarge low-level or 6-week symptom-limited stress tests and with coronary anatomy. Fourteen patients had only matching patterns (group 1), 23 had mismatches (group 2), and five had 201Tl-111In overlap as the predominant pattern. None of the patients in group 1 had previous myocardial infarction; in each, the matched area corresponded to the Q wave location on electrocardiogram, and none had further in-hospital ischemic events or positive stress tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Murine monoclonal antimyosin antibody has been shown experimentally to bind selectively to irreversibly damaged myocytes. To evaluate the safety and efficacy of monoclonal antimyosin for identifying acute transmural infarction, 50 patients with acute Q wave myocardial infarction were entered into a phase I/II multicenter trial involving three clinical sites. Indium-111 antimyosin was prepared from an instant kit formulation containing 0.5 mg of diethylene triamine pentaacetic acid (DTPA)-coupled Fab fragment (R11D10) and 1.2 to 2.4 mCi of indium-111. Average labeling efficiency was 92%. Antimyosin was injected 27 ± 16 h after the onset of chest pain.

Myocardial infarct size was measured by single photon emission computed tomography (SPECT) following injection of indium-111 antimyosin in 27 patients (18 male and 9 female; mean age 57.4 +/- 10.5 years, range 37 to 75) who had acute transmural myocardial infarction (MI). These 27 patients represent 27 of 35 (77%) consecutive patients with acute Q-wave infarctions who were injected with indium-111 antimyosin. In the remaining 8 patients either tracer uptake was too faint or the scans were technically inadequate to permit infarct sizing from SPECT reconstructions. In the 27 patients studied, infarct location by electrocardiogram was anterior in 15 and inferoposterior in 12. Nine patients had a history of prior infarction. Each patient received 2 mCi of indium-111 antimyosin followed by SPECT imaging 48 hours later. Infarct mass was determined from coronal slices using a threshold value obtained from a human torso/cardiac phantom. Infarct size ranged from 11 to 87 g mean 48.5 +/- 24). Anterior infarcts were significantly (p less than 0.01) larger (60 +/- 20 g) than inferoposterior infarcts (34 +/- 21 g). For patients without prior MI, there were significant inverse correlations between infarct size and ejection fraction (r = 0.71, p less than 0.01) and wall motion score (r = 0.58, p less than 0.01) obtained from predischarge gated blood pool scans. Peak creatine kinase-MB correlated significantly with infarct size for patients without either reperfusion or right ventricular infarction (r = 0.66). Seven patients without prior infarcts had additional simultaneous indium-111/thallium-201 SPECT studies using dual energy windows.(ABSTRACT TRUNCATED AT 250 WORDS)

Antimyosin is an Fab fragment of a monoclonal antibody that binds with human myosin exposed in myocytes irreversibly damaged by an ischemic event. Labeled with 111In, the antibody is taken up into acutely necrotic tissue and can be imaged by planar or single photon emission computed tomography (SPECT) techniques. A large, multicenter clinical trial has demonstrated a high degree of both sensitivity for detecting infarction and specificity for excluding a recent ischemic event in patients admitted with chest pain syndrome. No allergic reactions to antibody injection have occurred, nor have there been documented significant increases in human antimouse antibody titers postinjection. Due to relatively slow blood clearance, the optimal imaging time is 24 to 48 hours post-injection. Between 13% and 21% of 24-hour scans are nondiagnostic due to persistent blood pool activity. In two thirds of these patients, 48-hour scans confirm negative tracer uptake. Moderate to intense cardiac uptake occurs in greater than 80% of scans. Faint tracer uptake, which occurs in a small minority of patients, is associated with inferoposterior infarct location and an occluded infarct vessel. Potential clinical uses include both diagnostic and prognostic areas. A negative scan in a patient with chest pain syndrome and no ECG changes rules out a recent significant ischemic event. The extent of antimyosin uptake (infarct size), measured semiquantitatively from planar scans or quantitatively from SPECT reconstructions, has been shown to correlate with future cardiac events. Relative patterns of distribution of indium-antimyosin and 201TI on simultaneous dual isotope SPECT reconstructions may identify patients with residual myocardium at further ischemic risk.

Myocardial perfusion in ten normal volunteers and 20 patients with coronary artery disease documented by recent coronary arteriography was studied with 99mTc-labeled SQ30217 and 201TI. Plantar 201TI imaging followed standard treadmill exercise and planar SQ30217 imaging followed upright bicycle exercise, performed to angina, or the same double product achieved on the treadmill test. Upright anterior, 30 degrees left anterior oblique, and 60 degrees left anterior oblique images were obtained for 3, 6, and 9 min, respectively, starting 2 min after injection of 15 mCi of 99mTc SQ30217. A second 15-mCi dose was injected at rest approximately 2 hr later, and the same imaging protocol was followed. No adverse reactions or laboratory abnormalities attributable to SQ30217 were observed. All scans on the normal volunteers were interpreted as normal. Qualitative readings of both tests were equally sensitive for detecting patients with coronary disease (SQ30217 - 16/20, TI - 17/20, p = NS) and identifying abnormal vessels (SQ30217 - 19/45, TI - 21/45, p = NS). Both agents were falsely positive in 1/15 vessels. Ten vascular regions showed persistent abnormalities on resting SQ30217 scans; eight of these were distal to stenoses of at least 90% and three were also abnormal on thallium redistribution images. Hepatic uptake of SQ30217 obscured inferoapical segments in some views in 14/20 patients but did not interfere with abnormal vessel identification.

To determine the feasibility of using serial injections of monoclonal antibodies (MoAbs; 96.5 and ZME 018) to evaluate metastases of malignant melanoma, 11 patients were studied. Each patient received two injections of antibody 7 days apart and were imaged 7 days after injection. Serum for human antimouse antibody (HAMA) was obtained immediately prior to injection of MoAb and 7-10 days after the second injection. Six patients were evaluated with both planar and single photon emission computed tomography (SPECT) images. Planar imaging alone was compared with SPECT alone and with planar and SPECT imaging in combination. In seven patients with 19 lesions, 96.5 and ZME 018 each identified eight lesions. In no case did one antibody identify a lesion missed by the other. In the six patients on whom SPECT imaging was performed, 14 confirmed and six suspected lesions were identified. Using planar imaging alone, only 12 confirmed and one suspected lesion were identified. HAMA titers rose significantly (0.32 optical density (O.D.) units prior to injection to 1.28 O.D. units on day 14, P less than 0.001). Allergic reactions occurred during the second injection in two patients. One of these demonstrated elevated HAMA titers and one did not. The preliminary data suggest that monoclonal antibody imaging may be aided by SPECT and that a normal HAMA titer does not preclude an allergic reaction.

The mechanisms by which [99mTc]pertechnetate becomes attached to stannous-primed red blood cells are not known in detail. To study the problem further, the effect of red cell surface charge on labeling efficiency was evaluated. Red cell surface charge was reduced by using the enzyme neuraminidase to remove the terminal charge-bearing sialic acid moiety of the membrane glycoprotein. Forty-five blood samples from six volunteers were treated with neuraminidase for varying lengths of time, resulting in the removal of from 11% to 99% of the normal negative surface charge, as determined from electrophoretic mobility measurements. There was excellent linear correlation between labeling efficiency and the remaining red cell surface charge for values down to 20% of normal (r = 0.89). When surface charge was less than 20% of normal, labeling efficiency was constant at 30%. Eleven blood samples from three donors were divided into two groups that were treated with neuraminidase either before or after they were labeled. The labeling efficiency was independent of the order in which the steps were performed. No evidence for shifting of the radiolabel from the cell membrane to hemoglobin was found. The results suggest that clinical conditions associated with a reduction of sialic acid on the erythrocyte membrane may be one cause of decreased red blood cell labeling efficiency, and that increased membrane permeability for reduced technetium species may be responsible for the decrease.

The acute rejection of cardiac allografts is currently diagnosed by the presence of myocyte necrosis on endomyocardial biopsy. We evaluated the efficacy of noninvasive scintigraphic imaging with indium-111-labeled anticardiac myosin Fab fragments (indium-111 antimyosin) to detect and quantify cardiac allograft rejection. Six dogs that had intrathoracic heterotopic cardiac allograft transplantation were injected with indium-111 antimyosin and planar and single photon emission computed tomographic (SPECT) images were obtained in various stages of acute and subacute rejection. Four dogs had an allograft older than 8 months and had been on long-term immunosuppressive therapy; two dogs had an allograft less than 2 weeks old and were not on immunosuppressive therapy. Count ratios comparing heterotopic with native hearts were calculated from both SPECT images and in vitro scans of excised and sectioned hearts and were compared with the degree of rejection scored by an independent histopathologic review. Indium-111 antimyosin uptake was not visible in planar or SPECT images of native hearts. Faint diffuse uptake was apparent in cardiac allografts during long-term immunosuppression and intense radioactivity was present in hearts with electrocardiographic evidence of rejection. The heterotopic to native heart count ratios in SPECT images correlated significantly with the count ratios in the excised hearts (r = 0.93) and with the histopathologic rejection score (r = 0.97). The distribution of indium-111 antimyosin activity in right and left ventricles corresponded to areas of histopathologic abnormalities. Immunoperoxidase studies showed deposition of indium-111 antimyosin only in areas of myocyte necrosis. The results demonstrate that indium-111 antimyosin imaging can noninvasively detect the presence, location and severity of canine cardiac allograft rejection.

Single photon-emission tomography (SPECT) and indium 111-labeled monoclonal antimyosin Fab fragments were used to measure myocardial infarct size in 12 dogs, six subjected to balloon catheter-induced coronary artery occlusion for 6 hr (late reperfusion) and six subjected to occlusion with reperfusion at 2 hr (early reperfusion). Tomographic imaging was performed 24 hr after the intravenous injection of labeled Fab fragments with the use of a dual-head SPECT camera with medium-energy collimators. Immediately after the first tomographic scan, thallium-201 was injected into nine of 12 dogs and imaging was repeated. Estimated infarct size in grams was calculated from transaxially reconstructed, normalized, and background-corrected indium SPECT images with the use of a threshold technique for edge detection. Estimated noninfarcted myocardium in grams was calculated from obliquely reconstructed thallium SPECT images by a similar method. The animals were killed and infarct size in grams and true infarct size as a percentage of total left ventricular myocardial volume were measured by triphenyl tetrazolium chloride staining. Estimated infarct size from indium SPECT images showed an excellent correlation with true infarct size (r = .95, SEE = 4.1 g). Estimated percentage myocardium infarcted was calculated by dividing estimated infarct size from indium images by the sum of estimated infarct size plus estimated noninfarcted myocardium obtained from thallium images. Correlation between the estimated percentage of myocardium infarcted and true percentage of myocardium infarcted was excellent (r = .93, SEE = 4.4%). We conclude that dual-isotope SPECT with indium 111-monoclonal antimyosin antibodies and thallium-201 can accurately estimate infarct size and percentage myocardium infarcted.