Low-Dose Erythropoietin in Patients With ST-Segment Elevation Myocardial Infarction (EPO-AMI-II)　- A Randomized Controlled Clinical Trial.

BACKGROUND: Erythropoietin (EPO) has antiapoptotic and tissue-protective effects, but previous clinical studies using high-dose EPO have not shown cardioprotective effects, probably because of platelet activation and a lack of knowledge regarding the optimal dose. In contrast, a small pilot study using low-dose EPO has shown improvement in left ventricular function without adverse cardiovascular events.Methods and Results:We performed a multicenter (25 hospitals), prospective, randomized, double-blind, placebo-controlled, dose-finding study to clarify the efficacy and safety of low-dose EPO in patients with ST-segment elevation myocardial infarction (STEMI) under the Evaluation System of Investigational Medical Care of the Ministry of Health, Labor and Welfare of Japan. In total, 198 STEMI patients with low left ventricular ejection fraction (LVEF <50%) were randomly assigned to receive intravenous administration of EPO (6,000 or 12,000 IU) or placebo within 6 h of successful percutaneous coronary intervention. At 6 months, there was no significant dose-response relationship in LVEF improvement among the 3 groups tested (EPO 12,000 IU: 5.4±9.3%, EPO 6,000 IU: 7.3±7.7%, Placebo: 8.1±8.3%, P=0.862). Low-dose EPO also did not improve cardiac function, as evaluated by 99 mTc-MIBI SPECT or NT-proBNP at 6 months and did not increase adverse events. CONCLUSIONS: Administration of low-dose EPO did not improve LVEF at 6 months in STEMI patients (UMIN000005721).

Angioscopic assessment of peri-stent contrast staining following drug-eluting stent implantation.

BACKGROUND: Peri-stent contrast staining (PSS) has been recognized as a predictor of late stent thrombosis following drug-eluting stent (DES) implantation. However, the intravascular conditions at PSS sites remain unclear. METHODS AND RESULTS: We evaluated 10 patients (median age 72 years, 80% male) with stable angina pectoris by coronary angioscopy. The patients had a total of 11 DES implantations (5 sirolimus-eluting stents; 4 paclitaxel-eluting stents; 2 everolimus-eluting stents) that showed PSS. Neointimal coverage (NIC), presence of thrombus, and yellow plaques underneath the stent were compared between PSS and non-PSS sites for each stent. NIC was graded as: grade 0, struts exposed; grade 1, struts bulging into the lumen, although covered; grade 2, struts embedded by neointima, but translucent; grade 3, struts fully embedded and invisible. Mean follow-up was 394±206 days (median: 289). NIC grade was lower at PSS sites (P=0.021) with 8 out of 11 stents (73%) having grade 0. Angioscopy detected a thrombus more frequently at PSS sites than at non-PSS sites (64% vs. 9%, P=0.012). Yellow plaques tended to be more significant at PSS sites than at non-PSS sites (82% vs. 45%, P=0.091). CONCLUSIONS: The angioscopic findings suggest high thrombogenicity at PSS sites.

Arterial repair 4 months after zotarolimus-eluting stent implantation observed on angioscopy.

BACKGROUND: Arterial repair in the early phase following implantation of a zotarolimus-eluting stent (ZES) remains unknown. METHODS AND RESULTS: Following implantation of 49 Endeavor ZES in 33 patients, follow-up angioscopy was performed in 13 patients (26 ZES) in the early phase (EP; 123±24 days) and in 20 patients (23 ZES) in the middle phase (MP; 247±17 days). Neointimal coverage (NIC) was graded as follows: grade 0, stent struts exposed; grade 1, struts bulging into the lumen, although covered; grade 2, struts were embedded by the neointima but were seen translucently; grade 3, struts fully embedded and invisible. NIC was defined as heterogeneous for NIC grade variation≥1. The presence of thrombus and yellow plaque was also investigated. Although NIC heterogeneity tended to be more frequent in EP than in MP (50% vs. 22%, P=0.070), and yellow plaque significantly more frequent (58% vs. 13%, P=0.0025), the majority of stents were dominant NIC grade 3 at both follow-up periods (73% in EP vs. 78% in MP, P=0.75). There was no significant difference in thrombus (23% in EP vs. 4% in MP, P=0.10) between the follow-ups. CONCLUSIONS: Sufficient arterial repair may have occurred by 4 months after ZES implantation.

Angioscopic assessment of arterial repair following biodegradable polymer-coated biolimus A9-eluting stent implantation. - Comparison with durable polymer-coated sirolimus-eluting stent-.

BACKGROUND: Second-generation drug-eluting stents (DES) are expected to show better arterial repair than older DES. We angioscopically compared the biodegradable polymer-coated biolimus A9-eluting stent (BES) and durable polymer-coated sirolimus-eluting stent (SES) to explore differences in arterial repair. METHODS AND RESULTS: Angioscopy was performed 9 ± 1 months after 15 BES and 16 SES were implanted initially in the native coronary artery. Heterogeneity of neointimal coverage (NIC) as well as the dominant NIC grade was examined. NIC was defined as: grade 0 = fully visible struts; grade 1 = struts bulging into the lumen, but covered; grade 2 = embedded, but translucent struts; grade 3 = invisible struts. Heterogeneity was judged when the NIC grade varied ≥ 1. In-stent late loss (0.06 ± 0.23 vs. 0.07 ± 0.18 mm, P = 0.80), and dominant NIC grade (1.5 ± 0.8 vs. 1.3 ± 0.7, P = 0.45) were similar for BES and SES. Within the stents, NIC was more heterogeneous in SES than in BES (P = 0.035). 80% of BES showed homogeneous NIC, while 56% of SES had heterogeneous NIC. CONCLUSIONS: BES showed limited late loss similar to that for SES. Nonetheless, the NIC with BES was more homogeneous than that with SES. Biodegradable polymer-coated BES may have an advantage in homogeneous NIC.

Prediction of functional recovery after revascularization using quantitative gated myocardial perfusion SPECT: a multi-center cohort study in Japan.

BACKGROUND: Prediction of left ventricular functional recovery is important after myocardial infarction. The impact of quantitative perfusion and motion analyses with gated single-photon emission computed tomography (SPECT) on predictive ability has not been clearly defined in multi-center studies. METHODS: A total of 252 patients with recent myocardial infarction (n = 74) and old myocardial infarction (n = 175) were registered from 25 institutions. All patients underwent resting gated SPECT using (99m)Tc-hexakis-2-methoxy-isobutyl isonitrile (MIBI) and repeated the study after revascularization after an average follow-up period of 132 +/- 81 days. Visual and quantitative assessment of perfusion and wall motion were performed in 5,040 segments. RESULTS: Non-gated segmental percent uptake and end-systolic (ES) percent uptake were good predictors of wall motion recovery and significantly differed between improved and non-improved groups (66 +/- 17% and 55 +/- 18%, p < 0.0001 for non-gated; 64 +/- 16% and 51 +/- 17% for ES percent uptake, p < 0.0001). The area under the curve of receiver operating characteristics curve for non-gated percent uptake, ES percent uptake, end-diastolic percent uptake and visual perfusion defect score was 0.70, 0.71, 0.61, and 0.56, respectively. Sensitivity and specificity of percent uptake were 68% and 64% for non-gated map and 80% and 52% for ES percent uptake map. An optimal threshold for predicting segmental improvement was 63% for non-gated and 52% for ES percent uptake values. CONCLUSION: Segmental (99m)Tc-MIBI uptake provided a useful predictor of wall motion improvement. Application of quantitative approach with non-gated and ES percent uptake enhanced predictive accuracy over visual analysis particularly in a multi-center study.

Myocardial scintigraphy after pacemaker implantation for congenital complete atrioventricular block.

Patients with isolated congenital complete atrioventricular block (CCAVB) occasionally develop dilated cardiomyopathy (DCM), despite early pacemaker implantation. However, the etiology of the DCM and its relationship to permanent ventricular pacing are not fully understood. Twenty-five patients with CCAVB underwent (99m) technetium (Tc) myocardial perfusion scintigraphy. Five patients were studied before and after pacing, providing a total of 30 image sets, which were divided into three groups; group 1: CCAVB before pacemaker implantation (PMI) (n = 11); group 2: CCAVB after PMI who did not subsequently develop DCM (n = 13); group 3: CCAVB after PMI who subsequently developed DCM (n = 6). Perfusion defects on single-photon-emission computed tomography (SPECT) were identified in group 1, 0 of 11 patients; group 2, 85% of patients; and group 3, 100% of patients. In groups 2 and 3, in patients with right ventricular pacing, the perfusion defects were mainly in the septum or between the apex and septum. On 20 segments' polar maps, the distribution of %uptake showed a similar pattern in groups 2 and 3, the degree of decreased %uptake and the number of segments with decreased %uptake being more severe in group 3. "Artificial" left bundle branch block (LBBB) pattern myocardial contraction induced by right ventricular pacing decreased myocardial perfusion around the apex and septum. Some patients with CCAVB will develop left ventricular dysfunction caused by artificial LBBB-induced interventricular asynchrony.

Creation and characterization of Japanese standards for myocardial perfusion SPECT: database from the Japanese Society of Nuclear Medicine Working Group.

OBJECTIVE: Standards for myocardial single-photon emission computed tomography (SPECT) adapted for a Japanese population were not available. The purpose of this study was to create standard files approved by the Japanese Society of Nuclear Medicine and to make known the characteristics of the myocardial perfusion pattern of this population. METHODS: With the collaboration of nine hospitals, a total of 326 sets of exercise-rest myocardial perfusion images were accumulated from subjects with a low likelihood of cardiac diseases. The normal database included a (99m)Tc-MIBI/tetrofosmin myocardial perfusion study with 360 degrees (n = 80) and 180 degrees (n = 56) rotations, (201)Tl study with 360 degrees (n = 115) and 180 degrees rotations (n = 54) and a dual-isotope study with 360 degrees rotation (n = 27). The projection images were transferred by digital imaging and communications in medicine (DICOM) format and reconstructed and analyzed with polar maps. RESULTS: The projection data from multiple centers were successfully transferred to a common format for SPECT reconstruction. When the average values were analyzed using a 17-segment model, myocardial counts in the septal segment differed significantly between 180 degrees and 360 degrees rotation acquisitions. Regional differences were observed between men and women in the inferior and anterior regions. A tracer difference between (99m)Tc and (201)Tl was also observed in some segments. The attenuation patterns differed significantly between subjects from the United States and those from Japan. CONCLUSIONS: Myocardial perfusion data that were specific for the Japanese population were generated. The normal database can serve a standard for nuclear cardiology work conducted in Japan.

[Clinical evaluation of cellular pathophysiology in cardiovascular diseases with radionuclide biochemical imaging].

Myocardial imaging with radionuclide biochemical tracers has provided advanced diagnostic approaches for patients with coronary artery disease and heart failure. Since the biochemical information includes cellular events such as metabolism, inflammation, and sympathetic drive, it can be regarded as one of 'Molecular Imaging'. In this chapter, I introduce topics on clinical evaluation of cellular pathophysiology in cardiovascular diseases with radionuclide biochemical imaging: detection of coronary vulnerable plaque to predict the occurrence of acute coronary syndrome and estimation of altered myocardial metabolism and sympathetic drive to estimate the severity of myocardial failure.

Gated myocardial SPECT to predict response to beta-blocker therapy in patients with idiopathic dilated cardiomyopathy.

UNLABELLED: Because of the difficulty of predicting the response of patients with idiopathic dilated cardiomyopathy (IDC) to beta-blocker therapy, this study was performed to evaluate whether gated myocardial SPECT (gated SPECT) could be useful for predicting that response. METHODS: We performed gated SPECT with (99m)Tc-sestamibi on 38 patients with IDC before treatment with a beta-blocker and standard medication. Perfusion abnormalities, left ventricular (LV) function, and spheric distortion were assessed by a quantitative software program. RESULTS: We classified patients into 2 groups according to improvement in LV function after 4 mo of therapy. The groups consisted of 16 poor responders whose LV ejection fraction (LVEF) increased less than 10% and 22 good responders whose LVEF increased by 10% or more. The patient characteristics before therapy, including LV volume and LVEF, did not significantly differ between the 2 groups, but the size of the myocardial perfusion defect and spheric distortion were significantly greater in poor responders than in good responders. CONCLUSION: Gated SPECT, by allowing simultaneous assessment of perfusion, function and geometry, might be useful for predicting the response of patients with IDC to beta-blocker therapy.

Superimposed display of coronary artery on gated myocardial perfusion scintigraphy.

UNLABELLED: Fusion of images of vascular anatomy and of myocardial perfusion images might be helpful for understanding the relationship between ischemia and the responsible vessels. The aim of this study was to develop a simple means of superimposing the images obtained from coronary angiography and gated myocardial perfusion SPECT. METHODS: Right and left oblique views from conventional coronary angiography and left ventriculography (LVG) were stored as 512 x 512 x 8-bit digital datasets and combined. We reconstructed images from routine gated myocardial perfusion imaging (MPI) by using (99m)Tc-tetrofosmin to match the oblique positions between the image from MPI and combined angiographic images. We then generated a 3-dimensional (3D) surface map by using the quantitative gated SPECT (QGS)/quantitative perfusion SPECT (QPS) program. Both the combined angiographic images and the 3D surface map were rescaled and unified by registering the internal landmarks between the 2 images. After subtraction of the LVG image, the coronary angiogram and the 3D surface map were fused into 1 image. All processes were performed with the QGS/QPS program and commercially available graphic software. We applied this method to datasets from a cardiac phantom and from several patients with coronary artery disease. RESULTS: In the phantom study, our technique could obtain a 3D surface map in which the oblique angle was identified as that of radiography and could realize image registration and superimposition of radiography on scintigraphy. The preliminary results from the patients indicated that the markedly stenotic vessels showed good coincidence with the regional myocardial perfusion abnormalities on the unified images. In addition, these images could show the relationship between the coronary artery and regional wall motion in the gated mode. CONCLUSION: We developed a simple method of superimposing the image of the coronary artery tree on images from gated MPI. The technique yielded useful information about myocardial perfusion and function as well as the supplying coronary artery.

Quantitative analysis of lung perfusion in patients with primary pulmonary hypertension.

UNLABELLED: The aim of this study was to evaluate quantitatively the heterogeneity of lung perfusion scans in patients with primary pulmonary hypertension (PPH) and to compare it with the severity of disease. METHODS: Lung perfusion scans were obtained on 22 patients with PPH and 12 age-matched control subjects. The perfused area rates (PARs) were calculated by dividing the lung area in each 10% threshold width from 10% to 100% of maximal counts by total lung area. The total absolute difference in the PAR between each patient and the mean control value was assumed as the perfusion index of the lung (P index). The P index was compared with hemodynamic parameters and the right ventricular ejection fraction (RVEF), including 7 patients who received long-term vasodilator therapy. RESULTS: The P index correlated significantly with mean pulmonary arterial pressure (P < 0.001) and RVEF (P < 0.05). In patients with vasodilator therapy, the P index was improved significantly after therapy (P < 0.05) and was associated with a reduction in pulmonary arterial pressure. CONCLUSION: Quantitative assessment of lung perfusion irregularity might provide useful information about the severity of disease and the effect of therapy in addition to the routine visual representation.

Visualization of interscapular brown adipose tissue using (99m)Tc-tetrofosmin in pediatric patients.

UNLABELLED: Brown adipose tissue (BAT) is a site of nonshivering thermogenesis in mammals. The mitochondria of BAT operate in an uncoupled mode and increase fatty acid oxidation to produce heat at birth. Thus, the BAT of human infants and children contains more active mitochondria than that of adults. We surmised that because (99m)Tc-tetrofosmin can be absorbed by functional mitochondria in the myocardium and in tumor cells, it could reveal mitochondrial function in BAT. METHODS: Between January 1999 and December 2002, we retrospectively analyzed 385 consecutive studies of (99m)Tc-tetrofosmin uptake in pediatric patients with cardiac disorders. All patients with symmetric (99m)Tc-tetrofosmin accumulation within the neck and shoulder region according to planar images were selected, and the features of the uptake were analyzed. RESULTS: Increased symmetric (99m)Tc-tetrofosmin uptake in the interscapular BAT was a typical profile of 65 of the 385 patients (17%). The frequency of (99m)Tc-tetrofosmin uptake was significantly higher in winter than in spring or summer (P < 0.05) and prominent in newborns. The frequency peaked between 0 and 2 y of age and then declined with age. CONCLUSION: Gamma-camera imaging with (99m)Tc-tetrofosmin can reveal interscapular BAT distribution in infants and children in terms of mitochondrial activity.

Evaluation of a commercial PET tomograph-based system for the quantitative assessment of rCBF, rOEF and rCMRO2 by using sequential administration of 15O-labeled compounds.

The purpose of this study was to develop a reliable and practical strategy that generates quantitative CBF and OEF maps accurately from PET data sets obtained with 15O-tracers. Sequential sinogram data sets were acquired after the administration of 15O-tracers, and combined single-frame images were obtained. The delay time between sampled input function and the brain was estimated from the H2(15)O study with the whole brain and the arterial time-activity curves (TACs). The whole-brain TACs were obtained from the reconstructed images (image-base method) and the sinogram data (sinogram-base method). Six methods were also evaluated for the dead-time and decay correction procedures in the process of generating a single-frame image from the dynamic sinogram. The estimated delay values were similar with both the sinogram-based and image-based methods. A lumped correction factor to a previously added single-frame sinogram caused an underestimation of CBF, OEF and CMRO2 by 16% at maximum, as compared with the correction procedure for a short sinogram. This suggested the need for a dynamic acquisition of a sinogram with a short interval. The proposed strategy provided an accurate quantification of CBF and OEF by PET with 15O-tracers.

[Significance of 99mTc-labeled perfusion agents in the simultaneous assessment of myocardial perfusion and cardiac function].

Simultaneous assessment of left ventricular myocardial perfusion and systolic function was accomplished by utilizing ECG-gated myocardial perfusion SPECT. This development in nuclear cardiology will be attributed to the recent advances in new 99mTc-labeled perfusion agents, multi-detector SPECT system and software for automatic edge-detection of the left ventricle. In this article, we described about the clinical utilities of this method in detecting "hibernating myocardium," severe coronary artery disease patients with exercise-induced LV dysfunction, in predicting functional recovery after reperfusion therapy for acute myocardial infarction patients and in diagnosing patients with right heart diseases.

Reconstruction of semiautomated cardiac regions of interest using iodine-123 metaiodobenzylguanidine myocardial scintigraphy.

INTRODUCTION: Analysis using cardiac iodine-123 metaiodobenzylguanidine (MIBG) scintigraphy with regions of interest (ROIs) is useful for assessing myocardial sympathetic activity. However, manual placement of the cardiac ROI is sometimes difficult because myocardial MIBG uptake is reduced in patients with heart failure. A new method was developed to reconstruct the semiautomated cardiac ROI in a sympathetic denervated heart. MATERIALS AND METHODS: Using dynamic planar data, a summed image was generated and the matrix size was changed. Then, the radial count profiles originating from the center of the left ventricle were generated to extract the myocardial count profiles. An asymmetric Gaussian distribution was fitted to each profile and the epicardial border was defined by the threshold method. This program was tested in 50 patients, and its reproducibility was validated when compared with the manual tracing method. RESULTS: The semiautomated method yielded a better quality image compared with the standard image with higher counts. Cardiac ROIs were generated successfully in each patient within normal limits. The intraobserver and interobserver agreements were excellent (P<0.0001 each). This approach showed a significantly higher consistency in measuring the heart-to-mediastinum ratio as compared with the manual tracing method (P<0.05). CONCLUSION: The semiautomated method is useful in generating cardiac ROIs with high reproducibility in myocardial MIBG imaging.

Usefulness of scintigraphy to predict electrical storms in severe idiopathic dilated cardiomyopathy.

BACKGROUND: Although several predictors of an electrical storm (ES) are indicated in patients with idiopathic dilated cardiomyopathy (IDCM), whether the severity of the myocardial tissue damage (SMTD) evaluated by myocardial perfusion SPECT (MPS) has an association with an ES remains unclear. The purpose of this study was to elucidate the clinical significance of SMTD for the prediction of ES in IDCM patients with an ICD. METHODS: Thirty-seven (27 men, mean age 58 ± 15 years) IDCM patients receiving ICD implantations for secondary prevention with preoperative MPS were enrolled in this study. The medical history, physical and laboratory findings, electrocardiograms, echocardiograms and MPS findings were evaluated. The SMTD was assessed by the summed scores of 17 segments using a 4-point system (0, normal ~3, severe defect). RESULTS: During a mean follow-up of 43.9 ± 30.7 months, an ES developed in 12/37 (32.4 %) patients. The SMTD score predicted an ES with a 92 % sensitivity and 56 % specificity, at a cut-off score of 10. In addition, a multivariate analysis showed that the SMTD score remained an independent predictor of an ES (HR 1.09/score 1 increase, 95 % CI 1.01-1.19, p = 0.02). The SMTD score was significantly associated with three indices of late potentials on the signal-averaged electrocardiograms, and was significantly higher in patients with positive late potentials (p = 0.0006). CONCLUSION: SMTD score assessed by MPS has a strong correlation to the late potentials and higher SMTD score may increase the risk of ES among patients with IDCM and an ICD.