Montserrat Estorch

I-123-mIBG myocardial imaging for assessment of risk for a major cardiac event in heart failure patients: insights from a retrospective European multicenter study

PurposeSingle-center experiences have shown that myocardial meta-iodobenzylguanidine (mIBG) uptake has prognostic value in heart failure (HF) patients. To verify these observations using a rigorous clinical trial methodology, a retrospective review and prospective quantitative reanalysis was performed on a series of cardiac 123I-mIBG scans acquired during a 10-year period at six centers in Europe.Methods123I-mIBG scans obtained on 290 HF patients [(262 with left ventricular ejection fraction (LVEF) < 50%)] from 1993 to 2002 were reanalyzed using a standardized methodology to determine the heart-to-mediastinum ratio (H/M) on delayed planar images. All image results were verified by three independent reviewers. Major cardiac events [MCEs; cardiac death, cardiac transplant, potentially fatal arrhythmia (including implantable cardioverter-defibrillator discharge)] during 24-month follow-up were confirmed by an adjudication committee.ResultsMCEs occurred in 67 patients (26%): mean H/M ratio was 1.51 ± 0.30 for the MCE group and 1.97 ± 0.54 for the non-MCE group (p < 0.001). Two-year event-free survival using an optimum H/M ratio threshold of 1.75 was 62% for H/M ratio less than 1.75, 95% for H/M ratio greater than or equal to 1.75 (p < 0.0001). Logistic regression showed H/M ratio and LVEF as the only significant predictors of MCE. Using the lower and upper H/M quartiles of 1.45 and 2.17 as high- and very low-risk thresholds, 2-year event-free survival rates were 52% and 98%, respectively. Among patients with LVEF ≤ 35% and H/M ≥ 1.75 (n = 73), there were nine MCEs because of progressive HF and only one because of an arrhythmia.ConclusionApplication of a clinical trial methodology via the retrospective reanalysis of 123I-mIBG images confirms the previously reported prognostic value of this method in HF patients, including potential identification of a quantitative threshold for low risk for cardiac mortality and potentially fatal ventricular arrhythmias.

SPECT mapping of cerebral activity changes induced by repetitive transcranial magnetic stimulation in depressed patients. A pilot study

Repetitive transcranial magnetic stimulation (rTMS) is being investigated as an alternative treatment for depression. However, little is known about the clinical role and the neurophysiological mechanisms of the action of rTMS in these patients. In this study, 99mTc-HMPAO single photon emission computed tomography (SPECT) was used to map the effects of left dorsolateral prefrontal rTMS on prefrontal activity in seven patients who met DSM-IV criteria for major depression resistant to pharmacological treatment. rTMS consisted of 30 trains of 2-s duration stimuli (20 Hz, 90% of motor threshold), separated by 30-s pauses. Each patient underwent three SPECTs: at baseline; during the first rTMS; and 1 week after 10 daily sessions of rTMS. Regional cerebral blood flow (rCBF) of each cerebral region was normalized to the rCBF value in the cerebellum and relative changes in normalized rCBF were addressed using a region-of-interest analysis. The Hamilton Depression Rating Scale (HDRS) was used for clinical evaluation before and after rTMS. A significant rCBF increase after the 10 sessions of rTMS was found in the left prefrontal region (MANOVA F=5.29, d.f.=2,10, P=0.027), but no significant rCBF changes were found during the first rTMS session. The remaining cerebral regions showed no significant rCBF changes at any time. Only two patients showed a clinical improvement after rTMS, with 50% reduction of the initial HDRS score. The study was repeated under placebo conditions (identical design but addressing coil discharges to the air) in these two patients, who failed to show any rCBF increase during sham-rTMS. No relationship was found between the percentage of left prefrontal rCBF change and the clinical findings. In conclusion, rTMS of the left prefrontal cortex induces a significant rCBF increase in this region, despite the limited clinical effect in our sample of depressed patients. Cerebral perfusion SPECT is a useful tool to map cerebral activity changes induced by rTMS.

Noninvasive localization of human atherosclerotic lesions with indium 111-labeled monoclonal Z2D3 antibody specific for proliferating smooth muscle cells.

BackgroundTargeting exclusive antigens in atherosclerotic plaques with antibodies may provide a noninvasive means to detect rapidly proliferative atherosclerotic lesions. 111In-labeled negative charge-modified Z2D3 F(ab′)2 (Z2D3) specific for an antigen expressed exclusively by proliferating smooth muscle cells has been shown to accumulate in rabbit atherosclerotic plaques.MethodsThe safety, biodistribution, accumulation, and elimination of Z2D3 were assessed in 11 patients who were candidates for carotid endarterectomy. The presence of atheromas in these patients was confirmed by angiography and Doppler ultrasound. Z2D3 (250 μg) labeled with 5 mCi of 111In was administered by slow intravenous injection. Planar and single photon emission computed tomography (SPECT) images were obtained 4, 24, 48, and 72 hours later. Carotid endarterectomy was performed and the surgical specimens were imaged, weighed, gamma-counted, and analyzed by immunostaining.ResultsUptake of Z2D3 at the site of the carotid plaques was observed in the planar and SPECT views at 4 hours in all subjects. In addition, antibody uptake was noted in the contralateral vessel in 5 subjects. SPECT images identified the atherosclerotic plaques with focal uptake. The antibody uptake corresponded with the angiographic location of the disease. Immunohistochemical studies of the endarterectomy specimens confirmed the localization of Z2D3 into the plaque areas containing smooth muscle cells. Adverse drug reactions were not observed.ConclusionThis study demonstrates the feasibility of targeting atherosclerotic lesions with negative charge-modified antibody. It also proposes the possibility of selective identification of various components of atherosclerotic plaque, which may contribute to determining strategies of intervention in future.

DMSA study performed during febrile urinary tract infection: a predictor of patient outcome?

Technetium-99m dimercaptosuccinic acid (DMSA) study has been advocated as a method for the assessment of renal sequelae after acute febrile urinary tract infection (UTI). However, it is not known whether DMSA scintigraphy performed during acute UTI has any prognostic value for outcome assessment. The objective of this study was to evaluate the usefulness of DMSA scintigraphy performed during UTI as a predictor of patient outcome, to identify children at risk of events [vesico-ureteral reflux (VUR) or recurrent UTI] that may lead to the development of progressive renal damage. One hundred and fifty-two children (including 78 girls) with a mean age of 20 months (range 1 month to 12 years) with first febrile UTI were evaluated by DMSA scintigraphy during acute UTI. After acute UTI, children were explored by voiding cysto-urethrography. Children who presented an abnormal DMSA study, or a normal DMSA study but VUR or recurrent UTI, underwent a DMSA control study 6 months after UTI. Children with VUR were followed up by direct radionuclide cystography. DMSA scintigraphy performed during acute UTI was normal in 112 children (74%). In 95 of these children, follow-up DMSA scintigraphy was not performed owing to a good clinical outcome. In the remaining 17 children, follow-up scintigraphy was normal. Forty children (26%) presented abnormal DMSA study during acute UTI. Twenty-five of them presented a normal follow-up DMSA, and 15 presented cortical lesions. Children with abnormal DMSA had a higher frequency of VUR than children with normal DMSA (48% vs 12%). It is concluded that children with normal DMSA during acute UTI have a low risk of renal damage. Children with normal follow-up DMSA and low-grade VUR have more frequent spontaneous resolution of VUR.

Myocardial iodine-labeled metaiodobenzylguanidine 123 uptake relates to age

Background123I-labeled metaiodobenzylguanidine (123I-MIBG) is used increasingly to assess cardiac adrenergic neuron function. Few studies have reported data on myocardial MIBG uptake in relation to age, with contradictory results. This study reports the results of myocardial MIBG studies in untreated patients with cancer to assess the influence of age on myocardial MIBG uptake.Methods and ResultsThirty-nine patients with cancer enrolled in a study to assess the effect of doxorubicin administration on adrenergic neuron function underwent baseline studies with 123I-MIBG before chemotherapy. None of the patients had a history of neuropathy, previous cardiac disease, or previous chemotherapy or mediastinal radiotherapy. Myocardial MIBG uptake was quantified by a heart/mediastinal ratio (HMR) 4 hours after intravenous administration of 5 mCi, 123I-MIBG. The mean age of patients was 38 years, ranging from 16 to 75 years. Ten patients were below 20 years, 13 patients were between 20 and 40 years, six patients were between 40 and 60 years, and 10 patients were greater than 60 years of age. Myocardial 123I-MIBG uptake was observed in all patients, with a mean HMR of 1.85±0.29 (range 1.31 to 2.62). HMR correlated with age (r=−0.6264; p<0.001). A decrease in 123I-MIBG uptake with aging was observed. The mean HMR of patients of less than 20 years was 2.07, of patients between 20 and 40 years 1.89, of patients between 40 and 60 years 1.83, and of patients greater than 60 years 1.56. The best separation was observed comparing patients who were greater than 60 years (mean HMR 1.56 ± 0.16; range 1.31 to 1.78) with patients who were less than 60 years of age (mean HMR 1.95 ±0.;24; range 1.56 to 2.62; p=0.003).ConclusionsMyocardial 123I-MIBG uptake relates to age. A decrease in myocardial MIBG uptake is observed with aging, especially in those patients over 60 years of age. The influence of age on myocardial MIBG uptake has to be taken into account when studies are designed to assess cardiac adrenergic neuron function with 123I-MIBG.

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.

Assessment of anthracycline-induced myocardial damage by quantitative indium 111 myosin-specific monoclonal antibody studies

To assess chemotherapeutically induced myocardial damage, myosin-specific antibody scans and ejection fraction measurements were performed in 32 patients with breast cancer and in 9 patients with other tumours. All patients had received chemotherapy including anthracyclines. The ejection fraction decreased by ≥ 10% in 14 of 41 (34%) patients after chemotherapy. Antimyosin uptake in the myocardium was observed in 38 of 41 (92%) patients after chemotherapy. Antimyosin uptake was quantified by means of a heart-to-lung ratio, revealing a correlation between the degree of antimyosin uptake in the myocardium and the cumulative dose of anthracycline. Patients with a decreased ejection fraction showed more intense antimyosin uptake, indicating more severe myocardial damage. A higher degree of antimyosin uptake was found in 17 breast cancer patients treated with doxorubicin compared with 15 patients treated with mitoxantrone. We conclude that antimyosin studies provide a sensitive, non-invasive method to monitor myocardial damage in patients treated with anthracyclines. Antimyosin uptake in the myocardium precedes ejection fraction deterioration. This technique may be helpful in the early identification of patients at risk of congestive heart failure during chemotherapy including anthracyclines.

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.

Technetium-99m human polyclonal immunoglobulin G studies and conventional bone scans to detect active joint inflammation in chronic rheumatoid arthritis.

Rheumatoid arthritis is a chronic polyarthritis in which active inflammed joints coexist with joints in remission. We performed bone scans (99mTc-DPD) and 99mTc human polyclonal immunoglobulin G scans (99mTc-IgG) in 18 patients with rheumatoid arthritis to assess the uptake in actively inflamed joints and in joints in which remission after inflammation had occurred. A quantitative analysis of tracer uptake in each joint was performed on both scans. In 123 joints without current active inflammation, an increased 99mTc-DPD uptake was observed (2.31 ± 1.27), whereas no 99mTc-IgG uptake was noted (1.18±0.32). Some 78 joints with mild pain or swelling exhibited increased 99mTc-DPD uptake (2.48 ± 1.14) and increased 99mTc-IgG uptake (1.76 ± 0.50; P <0.001), while 21 joints with moderate to severe pain or swelling exhibited increased 99mTc-DPD uptake (2.39±0.93) and increased 99mTc-IgG uptake (1.79±0.51; P <0.001). In conclusion, 99mTc-IgG scans distinguish between joints with and without active inflammation in chronic rheumatoid arthritis, whereas bone scans do not. Thus, 99mTc-IgG scans may be useful in identifying joints with current active inflammation in rheumatoid arthritis.

Myocyte cell damage after administration of doxorubicin or mitoxantrone in breast cancer patients assessed by indium 111 antimyosin monoclonal antibody studies.

PURPOSE To compare myocyte cell damage induced by doxorubicin or mitoxantrone, we performed left ventricular ejection fraction (LVEF) measurements and indium 111 antimyosin antibody studies in a group of patients with advanced breast cancer who had been treated with these anthracycline derivatives. PATIENTS AND METHODS We studied 35 patients eligible to receive chemotherapy including the anthracyclines: doxorubicin or mitoxantrone (cumulative dose of doxorubicin, 500 mg/m2; or mitoxantrone, 120 mg/m2). LVEF was measured before and after 10 cycles of chemotherapy. Antimyosin uptake in the myocardium was quantified by means of a heart-to-lung ratio (HLR). RESULTS Patients treated with doxorubicin presented with a significant decrease in LVEF after chemotherapy (before, 60.4% +/- 8.92%; after, 49.8% +/- 9.71%; P = .001). Antimyosin uptake was observed in all patients with a HLR of 2.03 +/- 0.25. Seven of eight patients with a HLR greater than 2.03 had a greater than 10% decrease in LVEF. Patients treated with mitoxantrone did not present with a decrease in LVEF after chemotherapy (before, 55.4% +/- 6.25%; after, 55.8% +/- 7.25%; not significant). Antimyosin uptake was observed in 14 of 17 patients with a HLR of 1.77 +/- 0.18 (P < .05). CONCLUSION 111In antimyosin monoclonal antibodies defect myocardial cell damage produced by doxorubicin and mitoxantrone. In patients with advanced breast cancer, cumulative doses of 120 mg/m2 of mitoxantrone produce less myocardial cell damage than cumulative doses of 500 mg/m2 of doxorubicin. 111In antimyosin uptake without decrease in LVEF after treatment with mitoxantrone indicates the presence of myocyte cell damage, but not to the extent necessary to deteriorate function. These results indicate that 111In antimyosin antibody studies are useful in the noninvasive comparative assessment of cardiotoxicity produced by different anthracycline derivatives.