Manel Ballester

High prevalence of myocardial monoclonal antimyosin antibody uptake in patients with chronic idiopathic dilated cardiomyopathy

Monoclonal antimyosin antibody studies were undertaken to assess the presence of myocardial uptake in patients with chronic idiopathic dilated cardiomyopathy. Three groups were studied: 17 patients with chronic (greater than 12 months) idiopathic dilated cardiomyopathy, 12 patients with a large, poorly contracting left ventricle not due to dilated cardiomyopathy (control patients) and 8 normal individuals. The patients in the cardiomyopathy and control groups showed a similar degree of clinical and functional impairment. Imaging was undertaken 48 h after antimyosin injection. The heart/lung ratio of antimyosin uptake was used to assess the results. The mean ratio in the cardiomyopathy group was 1.83 +/- 0.36 (range 1.40 to 2.80), a value significantly higher than that obtained in the control patients without cardiomyopathy (mean 1.46 +/- 0.04, range 1.38 to 1.50) or normal subjects (mean 1.46 +/- 0.13, range 1.31 to 1.6) (p less than 0.01). No difference in the ratio was noted between the normal subjects and control patients. Abnormal antimyosin uptake was seen in 12 (70%) of the 17 patients with cardiomyopathy and in only 1 (8%) of the 12 control patients. Positive monoclonal antimyosin antibody studies are highly prevalent in chronic idiopathic dilated cardiomyopathy.

Indium-111-monoclonal antimyosin antibody studies after the first year of heart transplantation. Identification of risk groups for developing rejection during long-term follow-up and clinical implications.

The long-term clinical course and results of biopsies in 21 patients studied with monoclonal antimyosin antibodies more than 12 months after heart transplantation according to the presence and degree of antimyosin-antibody uptake is described. Eighteen men and three women aged 20-52 years (39 +/- 9 years) were studied with antimyosin antibodies 12-40 months (mean, 22 +/- 9 months) after heart transplantation, and followed for a mean of 18 months (10-28 months). The number of biopsies performed during follow-up was 102. Results showed normal antimyosin-antibody studies in nine patients and abnormal studies in 12 patients. Myocyte damage was identified in 18 of the 102 biopsies (17.6%), one in the normal antimyosin-antibody group of patients and 17 in those patients with myocardial antimyosin-antibody uptake. Patients who developed rejection comprised 11% and 67% of each respective group; the mean number of rejection episodes per patient was 0.11 +/- 0.33 and 1.41 +/- 1.41, respectively (p less than 0.01). A trend was noted by which higher heart-to-lung ratios were associated with greater probability of rejection. Conclusively, 1) antimyosin-antibody studies performed after more than 1 year after heart transplantation indicate the presence and level of rejection activity, 2) groups of patients at risk for developing rejection at biopsy during long-term follow-up may be detected by antimyosin-antibody study, and 3) surveillance for rejection and the degree of immunosuppression should be tailored to meet individual patient needs.

Early postoperative reduction of monoclonal antimyosin antibody uptake is associated with absent rejection-related complications after heart transplantation.

BackgroundDetection and treatment for rejection after transplantation are based on the identification of myocyte damage upon endomyocardial biopsy. Noninvasive detection of such damage is possible with 111In-labeled monoclonal antimyosin antibodies (MAA). Although the presence and degree of MAA uptake parallels the rejection activity detected by biopsy, the relation between the degree of uptake and the occurrence of severe rejection-related complications has not been previously assessed. Methods and ResultsTwo hundred forty-seven MAA studies were performed coinciding with biopsies in 52 patients 1-71 months after transplantation. A heart-to-lung ratio (HLR) was used as a measure of relative MAA uptake, with an HLR of 1.55 discriminating normal from abnormal studies. Of the 247 antimyosin studies, 149 coincided with absent, 38 with mild, and 60 with moderate rejection at biopsy. HLR was 1.68±0.27, 1.79±0.22, and 1.91±0.33 in the three biopsy groups, respectively (p < 0.0001). Two hundred thirty-eight of 247 antimyosin studies coexisted with absent rejection-related complications; in nine of 247 patients, such complications were detected (five congestive heart failure episodes due to rejection and four episodes of vascular occlusion, which resulted in five deaths), and mean HLR was 1.74±0.3 and 2.1±0.16 in the two groups, respectively (p < 0.0001). No complications were noted in 193 studies of patients with HLR of less than 2.00, whereas in nine of 45 with HRL of 2.00 or greater, complications occurred (p < 0.0001). None of the 23 patients prospectively followed since surgery who had a gradual decrease in MAA uptake during the first 3 months showed rejection-related complications, whereas persistent uptake was associated with complications in five of nine patients (p < 0.001) ConclusionsNo rejection-related complications are seen coinciding with HLR of less than 2.00, whereas patients who have complications have an HLR of more than 2.00. The early 3-month pattern of decreasing MAA uptake is associated with a clinical course free of rejection-related complications, whereas a persistent pattern is a signal of the possibility of such complications.

Evaluation of Biopsy Classification for Rejection: Relation to Detection of Myocardial Damage by Monoclonal Antimyosin Antibody Imaging

OBJECTIVES This study sought to compare the histologic grades of rejection in endomyocardial biopsy specimens with the global estimate of myocardial transplant-related cardiac damage detected by myocardial uptake of monoclonal antimyosin antibodies. BACKGROUND The diagnosis and treatment of acute cardiac allograft rejection is based on the interpretation of endomyocardial biopsies. Because allograft rejection is a multifocal process and biopsy is obtained from a small area of the right ventricle, sampling error may occur. Global assessment of myocardial damage associated with graft rejection is now possible with the use of antimyosin scintigraphy. The present study was undertaken to compare the histologic grades of rejection in endomyocardial biopsy specimens with the global assessment of transplant-related myocardial damage detected by antimyosin scintigraphy. METHODS Biopsies (n=395) from 112 patients were independently interpreted by three pathologists in a blinded manner according to the original Stanford four-grade (normal, mild, moderate and severe) and the current International Society of Heart and Lung Transplantation (ISHLT) seven-grade (0, 1A, 1B, 2, 3A, 3B and 4) classifications. The results were correlated with 395 antimyosin studies performed at the time of the biopsies. The heart/lung ratio of antimyosin antibody uptake was used to assess the severity of myocardial damage. RESULTS In the Stanford biopsy grade classification, significantly higher antimyosin uptake, indicating increasing degrees of myocardial damage, were associated with normal (1.78+/-0.26), mild (1.88+/-0.31) and moderate (1.95+/-0.38) biopsy classifications for rejection (p < 0.01). In the ISHLT classification, significant differences were detected only for antimyosin uptake associated with grades 0 (1.77+/-0.26) and 3A (1.98+/-0.39) but not for intermediate scores (1A, 1B and 2). In view of the similar intensity of antibody uptake among the various grades, ISHLT biopsy scores were regrouped: normal biopsies in grade A; 1A and 1B as grade B; and 2 and 3A as grade C. Antimyosin uptake in grades A, B and C was 1.78+/-0.26, 1.88+/-0.31, 1.95+/-0.38, respectively (p < 0.01). CONCLUSIONS The current ISHLT seven-grade scoring system does not reflect the progressive severity of myocardial damage associated with heart transplant rejection. Because myocardial damage constitutes the basis of treatment for allograft rejection, there is a need to reevaluate the ISHLT grading system, given its importance for multicenter trials.

Efficacy of augmented immunosuppressive therapy for early vasculopathy in heart transplantation

OBJECTIVES The present study was undertaken to prospectively and comparatively evaluate the role of serial myocardial perfusion imaging and coronary angiography for the detection of early vasculopathy in a large patient population and also to determine the short- and long-term efficacy of augmented immunosuppressive therapy in the potential reversal of the early vasculopathy. BACKGROUND Allograft vasculopathy is the commonest cause of death after the first year of heart transplantation. Anecdotal studies have reported the efficacy of augmented immunosuppressive therapy after early detection of vascular involvement. However, no prospective study has evaluated the feasibility of early detection and treatment of allograft vasculopathy. METHODS In 76 cardiac allograft recipients, 230 coronary angiographic and 376 scintigraphic studies were performed in a follow-up period of 8 years. Angiography was performed at 1 month and every year after transplantation, and thallium-201 scintigraphy at 1, 3, 6 and 12 months after transplantation and twice a year thereafter. Prospective follow-up of 76 patients showed that 18 developed either angiographic or scintigraphic evidence of coronary vasculopathy. All episodes were treated with 3-day methylprednisolone pulse and antithymocyte globulin. RESULTS Twenty-two episodes of vasculopathy were diagnosed and treated in these 18 patients. Of these 22 episodes, two were detected only by angiography, seven by both angiography and scintigraphy, four by scintigraphy and histologic evidence of vasculitis and nine episodes only by thallium-201 scintigraphy studies. Angiographic and/or scintigraphic resolution was observed in 15 of the 22 episodes (68%) with augmented immunosuppression. The likelihood of regression was higher when treatment was instituted within the first year of transplantation (92%) than after the first year (40%) (p = 0.033). Eighty percent of patients who responded to follow-up. CONCLUSIONS The present study suggests that early detection of allograft coronary vasculopathy is feasible with surveillance myocardial perfusion or coronary angiographic studies. When identified early after transplantation, immunosuppressive treatment may result in regression of coronary disease.

Presence, evolving changes, and prognostic implications of myocardial damage detected in idiopathic and alcoholic dilated cardiomyopathy by 111In monoclonal antimyosin antibodies.

BACKGROUND The clinical relevance of myocardial cell damage in dilated cardiomyopathy is uncertain. Myocardial uptake of 111In monoclonal antimyosin antibodies (MAA) was used to study myocardial damage in patients with idiopathic (IDC) and alcoholic (ADC) dilated cardiomyopathy and to assess its prognostic implications. METHODS AND RESULTS MAA and echocardiographic studies were performed in 117 patients. Intensity of antibody uptake was measured by heart-to-lung ratio (HLR) (normal < 1.55). Studies were repeated in survivors and patients who did not receive a cardiac transplant. Follow-up extended up to 62 months (mean, 23 +/- 16 months). Eighty-eight patients with IDC showed a 77% prevalence of abnormal MAA. After acute-onset IDC, reduction of HLR (1.81 +/- 0.2 to 1.56 +/- 0.1) (P = .007) with improvement in ejection fraction (EF) (35 +/- 10% to 46 +/- 14%) (P = .018) was observed. No changes in HLR or EF were detected in patients with chronic stable IDC. Twenty-nine patients with ADC showed a lower prevalence (48%) of abnormal MAA studies than those with IDC (P = .003). HLR was higher in 13 active (1.78 +/- 0.3) than in 16 past consumers (1.49 +/- 0.2) (P = .019); in the former, HLR decreased to 1.44 +/- 0.2 (P = .012), and EF improved (35 +/- 14% to 53 +/- 18%) (P = .05) after abstention. Intensities of uptake HLR of > 1.87 were associated with increased risk of death or transplantation. CONCLUSIONS In patients with IDC, variations of MAA uptake are detected in patients who present acutely but not in those with chronic stable disease. In patients with ADC, MAA uptake mainly depends on alcohol consumption. In both situations, reduction of uptake correlates with improvement of ventricular function. Higher intensities of MAA uptake are associated with a worse outcome. The intensity of antibody uptake, along with other clinical and functional variables, may be helpful in risk stratification of patients with dilated cardiomyopathy.

Nitrate administration to enhance the detection of myocardial viability by technetium-99m tetrofosmin single-photon emission tomography

A comparison was performed between technetium-99m tetrofosmin myocardial perfusion tomography at baseline and after nitrate administration, using a 2-day protocol, and rest-reinjection thallium-201 single-photon emission tomography (SPET) studies in order to assess whether nitrates enhance the detection of viable myocardium with99mTc-tetrofosmin. Fifteen patients with coronary artery disease, previous myocardial infarction and a left ventricular ejection fraction <40% underwent201T1 rest-injection and99mTc-tetrofosmin. baseline-postnitroglycerin (0.4 mg sublingually) SPET studies, within 48 h. Tomograms based on the three spatial planes were divided into 15 segments and regional tracer uptake was quantitatively analysed. Viability was defined as presence of tracer uptake >50% of peak activity on baseline studies or after reversibility. The percentage of peak activity of99mTc-tetrofosmin at baseline correlated with that of 201T1 (r=0.82,P <0.001). On baseline99mTc-tetrofosmin studies, 73 of the 225 segments that were analysed had <50% of peal. activity. Fifteen percent of these segments showed reversibility after nitrate administration, with an increase in99mTc-tetrofosmin uptake from 40%±9% to 57%±9% of peak activity (P=0.003). All reversible segments after nitrate administration had viability criteria on201Tl studies, but 20 segments that were non-viable on99mTc-tetrofosmin. studies were viable on201Tl studies. Using a threshold value of >40% of peak activity, only seven segments remained non-viable on99mTc-tetrofosmin studies. Overall agreement between99mTc-tetrofosmin with nitrates and201Tl-reinjection regarding the presence of myocardial viability was 90%. Detection of myocardial viability with99mTc-tetrofosmin. was enhanced after nitrate administration, correlating with viability criteria observed on thallium studies.

Active myocardial damage without attending inflammatory response in dilated cardiomyopathy.

OBJECTIVES This study aimed to compare indium-111 (111In)-monoclonal antimyosin antibody uptake in patients with dilated cardiomyopathy before heart transplantation with the histologic findings in the explanted hearts. BACKGROUND A high prevalence of 111In-monoclonal antimyosin antibody uptake has been described in patients with dilated cardiomyopathy, suggesting the presence of active, ongoing myocyte damage; however, no correlation between monoclonal antimyosin antibodies and histologic findings is available in these patients. METHODS A consecutive series of 21 patients with dilated cardiomyopathy awaiting heart transplantation were studied with monoclonal antimyosin antibodies before the operation, and the results were compared with the histologic analysis of the explanted hearts. The interval between monoclonal antimyosin antibody studies and transplantation was 1 to 90 days (mean 58 +/- 31). RESULTS Using a semiquantitative method (heart/lung ratio), monoclonal antimyosin antibody uptake was present in 15 (71%) of 21 patients, but active myocarditis in the explanted hearts was detected in only 7. In 11 patients, intense monoclonal antimyosin antibody uptake coexisting with absent myocyte damage or cellular infiltration of explanted hearts was noted. One patient who showed preoperative monoclonal antimyosin antibody uptake underwent transplantation 11 h later, and ex vivo diffuse myocardial antimyosin uptake was detected, but active myocarditis was seen only at cardiectomy in only a small area of the heart; the rest of the myocardium showed no signs of myocyte damage. CONCLUSIONS In dilated cardiomyopathy, monoclonal antimyosin antibody uptake cannot be equated with the presence of an inflammatory response detected in the myocardium of the explanted heart.

Early transient multivalvular regurgitation detected by pulsed Doppler in cardiac transplantation

Abstract Use of pulsed Doppler to detect and evaluate cardiac valvular regurgitation is an accepted noninvasive diagnostic method. 1 Since the cardiac transplantation program started at our institution, 8 consecutive patients have been prospectively studied by pulsed Doppler. This report provides the first description of valvular function in the transplanted heart.

Burden of myocardial damage in cardiac allograft rejection: Scintigraphic evidence of myocardial injury and histologic evidence of myocyte necrosis and apoptosis

BackgroundBecause myocardial damage determines morbidity and outcomes in heart transplant rejection, assessment of total burden of myocardial damage is highly desirable. In addition to myocyte necrosis, programmed cell death, or apoptosis, has recently been shown to contribute to cardiac allograft rejection. In the present study, we noninvasively determined myocardial damage by antimyosin scintigraphy and compared it with necrotic and apoptotic myocardial damage in endomyocardial biopsy (EMB) specimens.Methods and ResultsForty scintigraphic and histologic studies were simultaneously performed. Of these, 19 patients had no EMB evidence of allograft rejection (group I, International Society of Heart and Lung Transplantation [ISHLT] grade 0/4), 12 had mild rejection (group II, ISHLT grades 1A and 1B), and 9 had evidence of moderate allograft rejection (group III, ISHLT grades 2, 3A, and 3B). None of the biopsies demonstrated severe allograft rejection (ISHLT grade 4/4). The severity of global myocyte damage in 40 patients was assessed by antimyosin scintigraphy. Endomyocardial biopsies were performed in these patients within 48 hours of imaging study; biopsy specimens were characterized for presence of myocyte necrosis and apoptosis. Evidence of myocyte necrosis was observed in 9 (23%) of 40 EMB specimens. Nineteen EMB specimens of group I had no inflammation and no myocyte necrosis, 12 of group II specimens showed interstitial mononuclear cell infiltration (only) but no myocyte necrosis, and all 9 of group III specimens had evidence of cellular infiltration and myocyte damage. Myocyte necrosis was assessed by hematoxylin-eosin and trichrome staining of EMB specimens. On the other hand, apoptosis of myocytes, as assessed by TUNEL staining of DNA fragments, was seen in 22 (55%) of the 40 biopsy specimens: 47%, 58%, and 67% in groups I, II and III, respectively. Abnormal antimyosin scan findings, indicating presence of myocardial damage, were observed in 9 of the 19 patients in group I and in all patients in groups II and III. Although positive antimyosin scan results in group III patients are concordant with the presence of histologic myocardial necrosis, myocardial uptake of antimyosin antibodies in groups I and II (no apparent myocyte damage at light microscopic examination) could reflect either sampling error of the biopsy or ongoing apoptotic myocyte damage.ConclusionsApoptosis of myocytes is frequently observed during cardiac allograft rejection. The presence of apoptotic myocytes in the absence of histologic rejection activity in patients with antimyosin uptake suggests that apoptosis could be an additional mechanism of transplant-associated myocardial damage.