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(99m)Tc-annexin V (ANX) allows scintigraphic detection of apoptotic cells via specific binding to exposed phosphatidylserine. In myocardial infarction, apoptosis of myocytes is variable and depends especially on the presence or absence of coronary reperfusion. In this study, ANX uptake in non-reperfused experimental myocardial infarcts was compared with uptake of a marker of myocyte necrosis ((111)In-antimyosin antibodies, AM) and an immunohistochemical marker of apoptosis (Apostain).The left anterior coronary artery was ligated in 47 Wistar rats, which were then injected with ANX (n=20), AM (n=21) or both (n=6). Myocardial uptake of ANX and AM was determined at 2 h (n=14), 4 h (n=14) and 24 h (n=19) after coronary ligation (CL), by quantitative autoradiography with (n=23) or without (n=24) gamma imaging. Heart-to-lung ratios (HLRs) and infarct-to-remote myocardium activity ratios (INRs) were calculated on the scintigrams and autoradiograms respectively. Cardiac sections were stained with haematoxylin-eosin and Apostain. The above studies were repeated in 12 normal rats.All rats with CL showed increased ANX and AM uptake in cardiac areas on scintigrams 24 h after CL, with HLRs higher than in controls: 3.1+/-0.6 versus 1.5+/-0.3 (p=0.001) for ANX and 1.99+/-0.44 versus 1.01+/-0.05 (p0.0005) for AM. Autoradiography showed intense ANX and AM uptake in infarcts, with comparable topography and INRs at 2 h, 4 h and 24 h after CL (4.6+/-0.9 versus 5.0+/-1.8 at 24 h), while Apostain staining was very low (0.06+/-0.06% of cells).In this model of persistent CL, we observed increased ANX uptake in injured myocardium, comparable in intensity, topography and kinetics to that of AM. There was only minimal Apostain staining in the same areas.

In a retrospective study, 121 children with Kawasaki disease (KD) were investigated to determine (i) the incidence of myocardial damage using the antimyosin antibody (AMA) titer; (ii) the differences in the electrocardiograms between the AMA-positive and -negative patients; and (iii) the effect of treatment with intravenous gamma globulin (IVGG) on the AMA. Comparisons were made with 117 normal children (controls). Patients with KD showed a significantly higher mean AMA titer and more patients were positive for AMA than the controls. The AMA titer in the KD group was not related to the presence of coronary artery lesions. Electrocardiograms obtained during the acute and the convalescent stage of KD revealed that patients positive for AMA had a significantly lower voltage of T wave in lead V6 at week four than at week two of illness, whereas patients negative for AMA showed no T wave change after week two. The group treated with IVGG showed a significantly lower AMA titer than that not given IVGG. These observations suggest that myocardial damage occurs in some patients with KD which is unrelated to the presence of coronary artery lesions and that the treatment with IVGG reduces the AMA titer in patients with KD.

111In-antimyosin imaging is a highly sensitive and specific technique for the detection of myocardial necrosis. Two new methods of labeling antimyosin with 99mTc have been developed, and were compared with the standard 111In-antimyosin imaging technique in 29 patients with acute myocardial infarction. Fourteen patients (group I) received directly labeled 99mTc-antimyosin, and 15 (group II) were given RP-1 conjugated 99mTc-antimyosin. 99mTc-antimyosin imaging was performed at 6, 12, and 24 hours, and 111In-antimyosin imaging was done at 24 and 48 hours following injection. The images were interpreted by three blinded observers. In group I, 99mTc-antimyosin uptake could be detected in 3, 6, and 12 cases at 6, 12, and 24 hours, respectively, compared with only 8 cases at 24 hours with 111In-antimyosin. At 48 hours all patients showed 111In-antimyosin uptake. In group II, 99mTc-antimyosin uptake could be detected in 2, 3, and 6 cases at 6, 12, and 24 hours, respectively, compared with 8 and 12 cases at 24 and 48 hours, respectively, with 111In-antimyosin. Gated blood pool studies could be obtained in all patients following 99mTc-antimyosin injection and could be used to identify regional wall motion abnormalities. The plasma half-lives of 99mTc-antimyosin in group I and group II were 2.67 ± 0.3 hours and 4.23 ± 0.3 hours, respectively, and the plasma half-life of 111In-antimyosin was 6.3 ± 0.4 hours. In this preliminary study, direct labeled 99mTc-antimyosin was at least as efficacious as earlier diagnostic techniques, had better imaging characteristics, and showed more rapid plasma clearance when compared with the standard 111In-antimyosin technique.

To establish whether quantitative 111In antimyosin uptake can be used to predict infarct age, we studied the heart-lung ratio in 107 images from 90 patients at various intervals following a Q-wave infarction. Imaging was performed 24 hours following 111In antimyosin injection. The HLR was measured as the ratio of the maximum counts in the infarcted myocardium to the adjacent lung background. The ratio ranged from 1.26 to 3.87, and declined with increasing infarct age. Infarcts were classified on the basis of age as type I (less than 3 days old), type II (less than 14 days), and type III (less than 90 days). True positive and false positive rates (TPR and FPR), and test-likelihood ratio calculations were performed for HLR thresholds ranging from 1 to 4, for the three infarct types. A FPR of 0% and likelihood ratio of infinity was obtained at a HLR threshold of 2.3 for type I infarcts (TPR 40.8%); at a HLR threshold of 2 for type II infarcts (TPR 50.6%), and a threshold of 1.8 for type III infarcts (TPR 52.6%). The likelihood of each infarct type can be estimated directly from the HLR for values below the above thresholds. These results show that quantitative 111In-antimyosin imaging may be used to predict infarct age.

The significance of indium-111 antimyosin antibody and thallium-201 dual nuclide single photon emission computed tomography (SPECT) was evaluated in 7 patients with acute myocardial infarction (AMI) who underwent emergency coronary angiography with successful revascularization by intracoronary thrombolysis. Indium-111 antimyosin antibody and thallium-201 dual nuclide SPECT was performed 11 to 36 days after the onset of AMI. Antimyosin SPECT images delineated areas of myocardial necrosis in all 7 patients (100%), but planar images detected necrotic areas in only 4 of 7 patients (57%). Peak CPK-MBs of the 3 patients in which no necrotic area was detected by indium-111 planar image showed a tendency to be smaller. Indium-111 antimyosin antibody/thallium-201 overlap was observed in all patients. The area of overlap was at the center of necrosis in 4 patients (2 anterior infarction, 1 inferior infarction, 1 inferolateral infarction) and at the peripheral portion in 3 patients (all 3 had inferior infarction). Indium-111 antimyosin antibody and thallium-201 dual nuclide SPECT is useful in identifying the localization of myocardial infarction and the overlap of these tracers might reflect the presence of salvaged myocardium adjacent to the necrotic myocardium.

Indium-111-antimyosin imaging has been shown to be a sensitive and specific method for detecting myocardial necrosis, but a quantitative method for interpretation of 111In-antimyosin planar images is lacking. A prospective study was performed in 114 patients with suspected acute myocardial infarction using planar 111In-antimyosin imaging. A ratio of maximum myocardial uptake counts (H) (9 X 9 pixels) over adjacent lung background (L), i.e. H/L ratio, was obtained from 24 and 48 h images. This value was compared with peak creatine kinase (CK) enzyme and left ventricular ejection fraction (LVEF). The patients were classified into groups based upon standard criteria for Q-wave acute myocardial infarction (Q-MI) (n = 50), non-Q-MI (n = 21), unstable angina (n = 15) and those with no evidence of MI or ischaemia (n = 28). The mean +/- S.D. H/L ratio in the Q-MI group was 2.28 +/- 0.50 (24 h, left anterior oblique, LAO, view) and was greater than the non-Q-MI group (1.98 +2- 0.30) (P less than 0.02). In patients with unstable angina (UA), seven had a high ratio (1.75 +/- 0.29) and eight had a lower ratio (1.29 +/- 0.07). In the group of patients without MI or UA, the ratio was 1.24 +/- 0.11 and this was significantly lower than the Q-MI and non-Q-MI groups and those patients with UA and positive 111In uptake (P less than 0.001, respectively). However, there was no significant difference between old MI and patients without evidence of MI or UA.(ABSTRACT TRUNCATED AT 250 WORDS)

Earlier demonstrated cardio-protection by ATP-loaded liposomes (ATP-L) was further improved by attachment of cardiac myosin-specific monoclonal 2G4 antibody onto the surface of ATP-L. ATP-IL were infused for 1 min duration before starting the global ischemia for 25 min followed by reperfusion for 30 min in an isolated rat heart. The left ventricular developed pressure at the end of reperfusion in ATP-IL group significantly recovered to above 80% of the baseline compared to ca 25% in the Kreb's-Henseleit (KH) buffer, ca 60% in the IL, and ca 70% in the ATP-L treated groups. At the end of the reperfusion, left ventricular end diastolic pressure significantly reduced to 15 +/- 2 mmHg in ATP-IL group compared to 59 +/- 6 mmHg in the KH buffer, 31 +/- 4 mmHg in the IL and 23 +/- 3 mmHg in the ATP-L controls. The extent of preservation depended on the amount of the antibody present on the surface of the ATP-IL.

We have previously shown that left ventricular (LV) shape transformation (from ellipsoid toward spherical) may modulate abnormal myocardial wall stresses occurring as a result of chronic severe aortic regurgitation (AR). If so then the extent of spherical shape change in AR may be inversely related to myocyte injury. To test this hypothesis, we compared the endocardial/epicardial antimyosin antibody uptake ratio in hearts from rabbits with early-AR and late-AR and from controls. The endocardial/epicardial antimyosin antibody activity ratio was increased in ellipsoid shaped late-AR hearts (vs control, p

The rationale for targeting the pathological myocardium is to enable development of better diagnostic modalities or to enhance therapeutic interventions. Since the heart is an end-differentiated organ that has no substantial regenerative properties, any injury to the heart could potentially lead to high morbidity and mortality. The causes of myocardial injury are varied. Acute myocardial infarction results in oncotic myocardial cell death, whereas cardiomyopathies are now believed to be associated primarily with apoptotic myocardial cell death. If these myocardial disorders can be targeted specifically for early diagnosis, then morbidity and mortality may be reduced and novel therapeutic interventions may result in decreasing the injury to the heart. This chapter will focus primarily on targeting the oncotic myocardium. Targeting the apoptotic myocardium will not be considered in detail, but an introduction to the latest advances will be provided.

The aetiology of cardiac dysfunction caused by sarcoid granulomatous inflammation may be difficult to clarify, and the potential of imaging methods is limited. We report on a patient who presented with acute biventricular decompensation. Pulmonary sarcoidosis was confirmed after hospitalization. Four weeks after the initiation of corticosteroid treatment, scintigraphy with indium-111-labelled antimyosin antibody Fab fragments (AMAB) revealed distinct activity accumulation in major parts of the left ventricular wall (heart-lung ratio: 1.6) 72 h following injection. There may be a role for AMAB scintigraphy in the early detection of cardiac sarcoidosis.

Endomyocardial biopsy remains the only reliable diagnostic tool to detect acute allograft rejection (see Chapters 9,13)1–2. Biopsies are performed serially after transplantation, especially during the initial months. Immunosuppressive treatment is augmented when myocyte damage is detected by biopsy. Biopsy-based patient management is widely used and has been associated with very good long-term survival.3 However, there are significant limitations of endomyocardial biopsy. These include high procedural cost, a small but definite morbidity, and dwindling yield in obtaining adequate myocardial samples after the first year of transplantation. In addition, sampling error of the biopsy to detect acute rejection remains a major problem since myocardial expression of acute rejection is not a diffuse but rather a patchy. Rarely, patients who die of acute rejection demonstrate foci of myocardial damage and inflammation which can be seen surrounded by large areas of apparently intact myocardium.4,5

Myocarditis constitutes an important component of rheumatic carditis. Antimyosin scintigraphy, which allows noninvasive assessment of myocyte damage, can be used for documentation of cardiac involvement in patients with rheumatic fever where clinical diagnosis is not unequivocal.

During the last 20 years there has been a large amount of investigation designed to determine what is the best way of imaging acute myocardial infarction (AMI) using radiopharmaceuticals. 99mTc pyrophosphate is ideal for cases where the clinical diagnosis cannot be made but it is insensitive to detect subendocardial AMI and is taken up by reversibly-injured myocytes. Antimyosin antibody imaging is specific for AMI but it is flow-dependent at low myocardial flows and it distributes in a nonuniform way in reperfused infarcts requiring high nuclear imaging (SPECT or PET) spatial resolution for proper measurement. 18F fluorodeoxyglucose (FDG) is taken up by viable cells but likely by macrophages too, in the core of AMI. 99mTc glucarate has not been investigated in detail but this sugar analog is more accurate than FDG in AMI. 99mTc sestamibi has been extensively used for AMI measurement but SPECT quantitation of transmural infarcts has not been achieved. Unresolved issue is imaging of AMI during reperfusion where there is widespread microvascular injury and capillary plugging.

10 patients suffering from myosarcomas have been studied with In-111 labeled antimyosin Fabs in our department until now. At all times the diagnosis was ascertained by histological examination of the primary tumor. All myosarcomas, ie rhabdomyosarcomas as well as leiomyosarcomas, and different histologically and histochemically identified subgroups were also detected by antimyosin radioimmunoscintigraphy except for one case of recurrent leiomyosarcoma. In some cases the tumors could be delineated more clearly than by means of MRT or other anatomical methods.

Successive measurements of cardiac myosin light chain I (MLC), creatine kinase isoenzyme MB (CKMB), and the titer of antimyosin antibody (AMA) were performed prospectively in 19 patients following open heart surgery. Seven of these patients showed the postpericardiotomy syndrome (PPS). No differences in serum concentrations of MLC or CKMB were observed between the patients with and without PPS, and all patients in both groups had abnormal MLC values after surgery. However, only patients with PPS had significantly elevated AMA titers. The maximum AMA titer was significantly correlated with the severity of the effusion. These data suggest that PPS is unrelated to the severity of myocardial injury during operation. Furthermore, the AMA titer may be useful as one of the indicators for determining the patient's clinical condition.

Myocardial accumulation of In-111-antimyosin (InAM) was evaluated in comparison with circulating serum myosin light chain I (LCI) level at the time of InAM injection. Seventeen consecutive patients were studied at various stages ranging from 6 days to 34 days after myocardial infarction (MI). The infarct area was positive for InAM uptake in all patients (100%), and significant myocardial uptake was observed in 14 patients (82.4%). The intensity of InAM uptake correlated with the infarct location shown by ECG and CAG. In contrast, 12 patients (70.6%) had normal or undetectable serum myosin LCI levels, with 5 being normal (0.42–2.5 ng/ml) and 7 undetectable (0.42 ng/ml or less). Only 5 patients (29.4%) had elevated serum myosin LCI levels at the time of InAM injection, and this elevation was slight, ranging from 3.4 to 4.5 ng/ml (mean: 3.75 ng/ml). Among patients with undetectable, normal, and elevated serum myosin LCI levels, there was no significant correlation between InAM uptake and the serum myosin LCI level. Thus, even after the serum myosin LCI level has decreased to normal, InAM can still bind to cardiac myosin in patients with MI, presumably until there is complete recovery from the hibernating myocardium due to ischemic damage.

The intensity of 111In antimyosin uptake is related to the type (Q wave or non-Q wave), size, and location of an acute myocardial infarction. To determine whether the uptake intensity is also related to the infarct age, and to establish the time frame during which 111In antimyosin uptake occurs postinfarction, we studied a quantitative measure of uptake intensity, the heart-lung (HL) ratio, in 90 consecutive patients at various intervals following a Q wave infarction. Imaging was performed 24 hours following 111In antimyosin injection. Uptake of antimyosin could be demonstrated up to 154 days postinfarction. The HL ratio was measured as the ratio of the maximum counts in the infarcted myocardium to the adjacent lung background, and was 1.93 +/- 0.51 (mean +/- SD) overall. The ratio declined exponentially with increasing age of infarct. Using nonlinear regression analysis, 47% of the total variance of the HL ratio could be attributed to age alone (p less than 0.001). Sequential antimyosin imaging was performed in nine patients, with the first study between 4 and 15 days, the second between 50 to 100 days, and the third between 125 to 270 days after the onset of chest pain. The HL ratios were (mean +/- SD) 1.77 +/- 0.25 for scans between 4 and 15 days, 1.54 +/- 0.12 for scans between 50 and 100 days (p less than 0.02), and 1.42 +/- 0.16 (p less than 0.05) for scans between 125 to 270 days, further establishing the progressive reduction in 111In antimyosin uptake with age of myocardial infarction.

MATSUNAGA, K., KAWAI, T., KATO, K., TANI, K. and OHKUBO, T. Antimyosin Antibodies in CNS-Lupus. Tohoku J. Exp. Med., 1991, 163 (3), 211-218 -Anti-myosin antibodies (AMA) in the sera of patients with systemic lupus erythematosus (SLE) and healthy subjects were measured by ELISA. AMA were IgM dominant. The titers of AMA were significantly higher in active SLE than in inactive SLE and healthy subjects. AMA negative SLE patients have significantly lower serum IgM than that in AMA positive subjects. Frequency analysis of HLA antigens in SLE revealed that AMA positivity was associated with HLA-A11, AMA negativity with HLA-B40 and DR2, and those with central nervous system involvement (CNS-SLE) were associated with HLA-B40. The patients with CNS-SLE have low serum IgM, low titer of AMA and HLA-B40.

Antimyosin (Myoscint ™ Centocor Inc. Malvern PA) is a Fab fragment of a specific antibody to myosin heavy chains that binds to necrotic cardiac myocytes. Planar or single photon emission computed tomography (SPECT) techniques using Indium- 111 labelled antibody have been used for the clinical detection of myocardial necrosis, both in acute myocardial infarction, and in myocarditis. This article reviews the role of antimyosin (AM) imaging in myocardial infarction diagnosis and risk stratification.

A method for labeling monoclonal antimyosin antibodies with 66Ga is described. The radionuclide is a positron emitter (t1/2: 9.4h) produced by means of the 63Cu (4He, n) 66Ga reaction. Purification of the 66Ga from the copper target is described in detail. Monoclonal antimyosin antibodies are labeled with 66Ga at a high yield (99%) by transcomplexation from an acetate buffer with the diethylenetriamine pentaacetic acid (DTPA)-labeled antibody and preliminary evaluated in two dogs for imaging of myocardial necrosis by positron emission tomography.

111In-AMA scintigraphy coupled with rest 201Tl imaging may be useful for the positive diagnosis of subacute myocardial necrosis in patients with angina, aortic stenosis, and normal coronary arteries. The present observation suggests that diffuse myocyte necrosis, histologically confirmed in this case, can be identified with 111In-AMA and may be a cause of cardiac complications in such patients.