Only strongly enhanced residual FDG uptake in early response PET (Deauville 5 or qPET ≥ 2) is prognostic in pediatric Hodgkin lymphoma: Results of the GPOH-HD2002 trial.

PURPOSE: In 2014, we published the qPET method to quantify fluorodeoxyglucose positron emission tomography (FDG-PET) responses. Analysis of the distribution of the quantified signals suggested that a clearly abnormal FDG-PET response corresponds to a visual Deauville score (vDS) of 5 and high qPET values ≥ 2. Evaluation in long-term outcome data is still pending. Therefore, we analyzed progression-free survival (PFS) by early FDG-PET response in a subset of the GPOH-HD2002 trial for pediatric Hodgkin lymphoma (PHL). PATIENTS/METHODS: Pairwise FDG-PET scans for initial staging and early response assessment after two cycles of chemotherapy were available in 93 PHL patients. vDS and qPET measurement were performed and related to PFS. RESULTS: Patients with a qPET value ≥ 2.0 or vDS of 5 had 5-year PFS rates of 44%, respectively 50%. Those with qPET values < 2.0 or vDS 1 to 4 had 5-year PFS rates of 90%, respectively 80%. The positive predictive value of FDG-PET response assessment increased from 18% (9%; 33%) using a qPET threshold of 0.95 (vDS ≤ 3) to 30% (13%; 54%) for a qPET threshold of 1.3 (vDS ≤ 4) and to 56% (23%; 85%) when the qPET threshold was ≥ 2.0 (vDS 5). The negative predictive values remained stable at ≥92% (CI: 82%; 98%). CONCLUSION: Only strongly enhanced residual FDG uptake in early response PET (vDS 5 or qPET ≥ 2, respectively) seems to be markedly prognostic in PHL when treatment according to the GPOH-HD-2002 protocol is given.

Use of myocardial perfusion imaging and estimation of associated radiation doses in Germany from 2005 to 2012.

PURPOSE: For several years the Working Group Cardiovascular Nuclear Medicine of the German Society of Nuclear Medicine has been performing a regular survey to obtain information on technique, utilization and development of myocardial perfusion scintigraphy (MPS). Currently, data of six surveys from 2005 to 2012 are available. The aim of this paper is to deliver a general and comprehensive overview of all surveys documenting the course of patient doses over time and the development of the method. METHODS: A one-page questionnaire with number of MPS patients, number of stress and rest MPS, referral structure and several technical issues was sent to all centres performing MPS in Germany and evaluated. With the data on protocol utilization, effective MPS patient doses were estimated. RESULTS: MPS per million population (pmp) varied between 2,380 and 2,770. In 2012, MPS pmp showed a slight increase for the first time. From 2005 to 2009 the angiography to MPS ratio increased from 3.4 to 4.4, and the revascularization to MPS ratio decreased from 0.66 to 0.53. In 2012, both indices demonstrated an opposite trend for the first time (4.1 and 0.55). A total of 108 centres participated in all surveys. They showed an increase in MPS patients of 4.0 % over the reporting period. In 2012, more than 50 % of the centres experienced no change or an increase in MPS numbers. The leading single competitor was MRI, followed by angiography and stress echocardiography. (201)Tl studies have decreased since 2005 from 20 to 5 %. (99m)Tc MPS studies showed a mild increase in 2-day protocols. In 2012, the average effective dose per patient was estimated at 7.4 mSv. Due to the decreasing use of (201)Tl, a mild decline over the observation period can be documented. Dynamic exercise stress was the most common stress test and adenosine the leading pharmacological stress agent, with a growing percentage. In 2012, the regadenoson percentage was 9 %. Gated single photon emission computed tomography (SPECT) noted an increasing acceptance with >70 % in 2012. The segmental scoring of perfusion studies had a low acceptance. Ambulatory care cardiologists represented the major referral group. CONCLUSION: Germany has a moderate to moderate-high MPS utilization rate. Nevertheless, coronary artery disease (CAD) diagnosis and disease management are dominated by angiography. The survey data reveal a positive trend in MPS and a decrease in average patient dose reflecting good practice with guideline adherence, the implementation of technical improvements and success in training.

Circulating soluble fibroblast activation protein (FAP) levels are independent of cardiac and extra-cardiac FAP expression determined by targeted molecular imaging in patients with myocardial FAP activation.

INTRODUCTION: Tissue Fibroblast Activation Protein alpha (FAP) is overexpressed in various types of acute and chronic cardiovascular disease. A soluble form of FAP has been detected in human plasma, and low circulating FAP concentrations are associated with increased risk of death in patients with acute coronary syndrome. However, little is known about the regulation and release of FAP from fibroblasts, and whether circulating FAP concentration is associated with tissue FAP expression. This study characterizes the release of FAP in human cardiac fibroblasts (CF) and analyzes the association of circulating FAP concentrations with in vivo tissue FAP expression in patients with acute (ST-segment elevation myocardial infarction, STEMI) and chronic (severe aortic stenosis, AS) myocardial FAP expression. METHODS AND RESULTS: FAP was released from CF in a time- and concentration-dependent manner. FAP concentration was higher in supernatant of TGFß-stimulated CF, and correlated with cellular FAP concentration. Inhibition of metallo- and serine-proteases diminished FAP release in vitro. Median FAP concentrations of patients with acute (77 ng/mL) and chronic (75 ng/mL, p = 0.50 vs. STEMI) myocardial FAP expression did not correlate with myocardial nor extra-myocardial nor total FAP volume (P ≥ 0.61 in all cases) measured by whole-body FAP-targeted positron emission tomography. CONCLUSION: We describe a time- and concentration dependent, protease-mediated release of FAP from cardiac fibroblasts. Circulating FAP concentrations were not associated with increased in vivo tissue FAP expression determined by molecular imaging in patients with both chronic and acute myocardial FAP expression. These data suggest that circulating FAP and tissue FAP expression provide complementary, non-interchangeable information.

[Myocardial perfusion scintigraphy 2008 in Germany - results of the fourth query]. / Myokard-Perfusions-Szintigraphie 2008 in Deutschland - Ergebnisse der vierten Erhebung.

AIM: The working group Cardiovascular Nuclear Medicine of the German Society of Nuclear Medicine in cooperation with the working group Nuclear Cardiology of the German Cardiac Society herewith present the results of the 4th survey on myocardial perfusion scintigraphy (MPS) of the year 2008. METHOD: 310 questionnaires (191 private practices (PP), 93 hospitals (HO), 31 university hospitals (UH)) were evaluated. RESULTS: MPS of 98947 patients were reported. 15% of them were younger than 50 y, 57% between 50 and 70 y and 28% older than 70 y. 88% [2007: 83%] of all were studied with Tc-99m perfusion tracers. The patient radiation exposure of a stress and rest protocol considering German standard recommended doses was 8.5 mSv, of a stress-only protocol 1.9 mSv. 77% [2007: 76%] of the MPS were performed in PP, 15% [2007: 15%] in HO and 8% [2007: 9%] in UH. From 2005 to 2008 there was a mild increase in the MPS numbers by 1.2% (PP +7.1%, HO -5.5%, UH -31.4%). The type of stress was pharmacological in 30% [2007: 27%]; 68% adenosine (of these 22% with exercise), 29% dipyridamole (of these 64% with exercise), and <1% dobutamine. Gated SPECT was performed in 46% [2007: 47%] of all rest and in 42% [2007: 44%] of all stress MPS. 62% [2007: 61%] of all institutions did not use perfusion scores. CONCLUSION: The MPS numbers from 2005 to 2008 in Germany can be regarded as stable. However, there are considerable shifts from HO and UH to PP. The well known potential of MPS considering risk stratification and functional analysis has not been tapped so far. Both gated SPECT and a quantitative perfusion analysis should be performed routinely in every patient.

GABAA Receptors in the Mongolian Gerbil: a PET Study Using [18F]Flumazenil to Determine Receptor Binding in Young and Old Animals.

PURPOSE: Plastic changes in the central auditory system involving the GABAergic system accompany age-related hearing loss. Such processes can be investigated with positron emission tomography (PET) imaging using [18F]flumazenil ([18F]FMZ). Here, [18F]FMZ PET-based modeling approaches allow a simple and reliable quantification of GABAA receptor binding capacity revealing regional differences and age-related changes. PROCEDURES: Sixty-minute list-mode PET acquisitions were performed in 9 young (range 5-6 months) and 11 old (range 39-42 months) gerbils, starting simultaneously with the injection of [18F]FMZ via femoral vein. Non-displaceable binding potentials (BPnd) with pons as reference region were calculated for auditory cortex (AC), inferior colliculus (IC), medial geniculate body (MGB), somatosensory cortex (SC), and cerebellum (CB) using (i) a two-tissue compartment model (2TCM), (ii) the Logan plot with image-derived blood-input (Logan (BI)), (iii) a simplified reference tissue model (SRTM), and (iv) the Logan reference model (Logan (RT)). Statistical parametric mapping analysis (SPM) comparing young and old gerbils was performed using 3D parametric images for BPnd based on SRTM. Results were verified with in vitro autoradiography from five additional young gerbils. Model assessment included the Akaike information criterion (AIC). Hearing was evaluated using auditory brainstem responses. RESULTS: BPnd differed significantly between models (p < 0.0005), showing the smallest mean difference between 2TCM as reference and SRTM as simplified procedure. SRTM revealed the lowest AIC values. Both volume of distribution (r2 = 0.8793, p = 0.018) and BPnd (r2 = 0.8216, p = 0.034) correlated with in vitro autoradiography data. A significant age-related decrease of receptor binding was observed in auditory (AC, IC, MGB) and other brain regions (SC and CB) (p < 0.0001, unpaired t test) being confirmed by SPM using pons as reference (p < 0.0001, uncorrected). CONCLUSION: Imaging of GABAA receptor binding capacity in gerbils using [18F]FMZ PET revealed SRTM as a simple and robust quantification method of GABAA receptors. Comparison of BPnd in young and old gerbils demonstrated an age-related decrease of GABAA receptor binding.

[Myocardial perfusion scintigraphy 2007 in Germany--results of the query and current status]. / Myokardperfusionsszintigraphie 2007 in Deutschland--Ergebnisse der Erhebung und Standortbestimmung.

AIM: This third survey of the working group Cardiovascular Nuclear Medicine of the German Society of Nuclear Medicine in cooperation with the working group Nuclear Cardiology of the German Cardiac Society was to deliver information on the procedures and in particular on the development of myocardial perfusion scintigraphy (MPS) from 2005 to 2007. METHOD: 370 questionnaires (222 private practices (PP), 117 hospitals (HO), 31 university hospitals (UH)) were evaluated. RESULTS: MPS of 114,374 patients were reported, 83% were investigated with 99mTc-perfusion tracers. 76% [2006=74%] were performed in PP, 15% [2006=17%] in HO and 9% [2006=9%] in UH. Diabetics represented 21% of all MPS patients in 2007. Data of 215 institutions which participated all from 2005 to 2007 showed an increase in MPS of 2.3% (PP +6.8%, HO -4.5%, UH -18.2%). The type of stress was pharmacological in 27% [2006 = 27%]; 67% adenosine (of these 25% with exercise), 31% dipyridamole (of these 55% with exercise), and 2% dobutamine. Gated SPECT was performed in 47% [2006 = 42%] of all rest and in 44% [2006 = 39%] of all stress MPS. 61% [2006 = 83%] of all institutions did not apply perfusion scores. 20% [2006 = 24%] of the institutions reported changes in the use of MPS by competing methods. CONCLUSION: There is a small increase of MPS between 2005 and 2007 despite competing methods. Gated SPECT has experienced more acceptance, but is still underrepresented. As compared to the European average and general standards of MPS a considerable backlog accounts to pharmacological stress tests, gated SPECT and perfusion scores.

Analytic system matrix resolution modeling in PET: an application to Rb-82 cardiac imaging.

This work explores application of a novel resolution modeling technique based on analytic physical models which individually models the various resolution degrading effects in PET (positron range, photon non-collinearity, inter-crystal scattering and inter-crystal penetration) followed by their combination and incorporation within the image reconstruction task. In addition to phantom studies, the proposed technique was particularly applied to and studied in the task of clinical Rb-82 myocardial perfusion imaging, which presently suffers from poor statistics and resolution properties in the reconstructed images. Overall, the approach is able to produce considerable enhancements in image quality. The reconstructed FWHM for a Discovery RX PET/CT scanner was seen to improve from 5.1 mm to 7.7 mm across the field-of-view (FoV) to approximately 3.5 mm nearly uniformly across the FoV. Furthermore, extended-source phantom studies indicated clearly improved images in terms of contrast versus noise performance. Using Monte Carlo simulations of clinical Rb-82 imaging, the resolution modeling technique was seen to significantly outperform standard reconstructions qualitatively, and also quantitatively in terms of contrast versus noise (contrast between the myocardium and other organs, as well as between myocardial defects and the left ventricle).

Relationship of coronary calcium and myocardial perfusion in individuals with chest pain. Assessed by integrated rubidium-82 PET-CT.

AIM: The integrated value of coronary calcium scoring added to myocardial perfusion assessment in hybrid PET-CT imaging remains poorly defined. In the present study, we sought to determine the relationship between calcium burden, other risk factors, and tissue perfusion in a group of patients with chest pain and predominantly intermediate likelihood for coronary artery disease. PATIENTS, METHODS: In 70 patients, coronary calcium scores (CCS) were obtained in addition to rest/dipyridamole stress 82Rb perfusion images using a GE Discovery Rx hybrid PET-CT system. From static perfusion images, summed rest, stress and difference scores (SRS, SSS, SDS) were calculated using a 20-segment model. Absolute CCS was determined according to Agatston and age-, gender-, and ethnicity-matched CCS percentiles were calculated using the MESA database. RESULTS: SSS, SRS and SDS were abnormal (>or=4) in 25 (36%), 17 (24%), and 12 (17%) patients. Mean CCS according to Agatston was 180+/-446(range 0-2122), and CCS percentile was 42+/-43(range 0-99). Absolute CCS correlated mildly but significantly with SSS (r=0.31, p=0.01), while CCS percentile did not (r=0.11, p=0.36). Of 49 patients with normal perfusion, 25 (57%) had CCS=0, and 8 (18%) had a CCS percentile>or=75th. Of 35 patients with a CCS=0, 26 (74%) had normal perfusion. Individuals in whom review of patient records revealed events during follow-up (n=10) had significantly higher SSS than those where no events were recorded (6.0+/-7.2 versus 2.9+/-3.1, p=0.03), and there was a trend towards higher CCS percentiles (62+/-36 versus 35+/-43, p=0.06). CONCLUSION: Coronary calcifications and myocardial tissue perfusion, as interrogated in a single PET-CT imaging session, show only partial agreement in patients with chest pain. Both tests seem to reflect different pathophysiologic components, and may be complementary for definition of individual disease patterns.

[Myocardial perfusion scintigraphy 2006 in Germany. Results of the query and current status]. / Myokardperfusionsszintigraphie 2006 in Deutschland Ergebnisse der Erhebung und Standortbestimmung.

AIM: This second survey was to deliver further information on myocardial perfusion scintigraphy (MPS) in Germany in 2006. METHOD: 351 questionnaires were evaluated: 207 private practices (PP), 117 hospitals (HO), 27 from university hospitals (UH). RESULTS: MPS of 106 331 patients were reported, 85% were investigated with (99m)Tc-perfusion tracers. 74% [2005 = 72%] were performed in PP, 17% [2005 = 15%] in HO and 9% [2005 = 13%] in UH. PP, which participated in 2005 and 2006, demonstrated an increase by 3,9% (HO 0%, UH - 13,0%). The type of stress was pharmacological in 27% [2005 = 22%]; 54% adenosine (of these 29% with exercise), 37% dipyridamole (of these 56% with exercise), and 9% dobutamine. Gated SPECT was performed in 42% [2005 = 36%] of all rest- and in 39% [2005 = 32%] of all stress MPS. An attenuation correction was used by 69 [2005 = 78] institutions. 40% of all MPS were performed in patients suspected to have CAD. 24% of all institutions reported changes in the use of MPS by competing methods. CONCLUSION: There is a small increase of MPS between 2005 and 2006 despite competing methods. Gated SPECT has experienced more acceptance. Suspicion of CAD is an important indication of MPS. In order to tap the full potential of MPS a gated SPECT should be performed routinely.

Activation in the auditory pathway of the gerbil studied with 18F-FDG PET: effects of anesthesia.

Here, we present results from an 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) study in the Mongolian gerbil, a preferred animal model in auditory research. One major issue in preclinical nuclear imaging, as well as in most of the neurophysiological methods investigating auditory processing, is the need of anesthesia. We compared the usability of two types of anesthesia which are frequently employed in electrophysiology, ketamine/xylazine (KX), and fentanyl/midazolam/medetomidine (FMM), for valid measurements of auditory activation with 18F-FDG PET. Gerbils were placed in a sound-shielding box and injected with 18F-FDG. Two acoustic free-field conditions were used: (1) baseline (no stimulation, 25 dB background noise) and (2) 90 dB frequency-modulated tones (FM). After 40 min of 18F-FDG uptake, a 30 min acquisition was performed using a small animal PET/CT system. Blood glucose levels were measured after the uptake phase before scanning. Standardized uptake value ratios for relevant regions were determined after implementing image and volume of interest templates. Scans demonstrated a significantly higher uptake in the inferior colliculus with FM stimulation compared to baseline in awake subjects (+ 12%; p = 0.02) and with FMM anesthesia (+ 13%; p = 0.0012), but not with KX anesthesia. In non-auditory brain regions, no significant difference was detected. Blood glucose levels were significantly higher under KX compared to FMM anesthesia (17.29 ± 0.42 mmol/l vs. 14.30 ± 1.91 mmol/l; p = 0.024). These results suggest that valid 18F-FDG PET measurements of auditory activation comparable to electrophysiology can be obtained from gerbils during opioid-based anesthesia due to its limited effects on interfering blood glucose levels.

[Myocardial perfusion scintigraphy in Germany. Results of the 2005 query and current status]. / Myokardszintigraphie in Deutschland. Ergebnisse der Erhebung 2005 und Standortbestimmung.

UNLABELLED: The working group Cardiovascular Nuclear Medicine of the German Society of Nuclear Medicine (DGN), in cooperation with the working group Nuclear Cardiology of the German Cardiac Society (DGK), decided to conduct a national survey on myocardial perfusion scintigraphy (MPS). METHOD: A questionnaire to evaluate MPS for the year 2005 was sent. RESULTS: 346 completed questionnaires had been returned (213 private practices, 99 hospitals and 33 university hospitals). MPS of 112 707 patients were reported with 110 747 stress and 95 878 rest studies. The majority (>75%) was performed with (99m)Tc-MIBI or tetrofosmin. (201)Tl stress-redistribution was used in 22 637 patients (20%). The types of stress were exercise in 78%, vasodilation with adenosine or dipyridamol in 21% and dobutamine in 1%. 99.97% of all MPS were SPECT studies. Gated SPECT was performed in 36% of the stress and in 32% of the rest studies. An attenuation correction was used in 21%. 29 institutions (8%) performed gated SPECT (stress and rest) and attenuation correction. 47% of all MPS were requested by ambulatory care cardiologists, 17% by internists, 12% by primary care physicians, 21% by hospital departments and 2% by others. CONCLUSION: In Germany, MPS is predominantly performed with (99m)Tc-perfusion agents. The common type of stress is ergometry. Gated SPECT and attenuation correction do not yet represent standards of MPS practice in Germany, which indicates some potential of optimization.

Serial assessment of sympathetic reinnervation after orthotopic heart transplantation. A longitudinal study using PET and C-11 hydroxyephedrine.

BACKGROUND: Little is known about the progressiveness of sympathetic reinnervation late after cardiac transplantation (HTX). The aim of the present study was to describe individual growth of sympathetic terminals after HTX by a longitudinal quantitative assessment. METHODS AND RESULTS: In 20 patients after HTX, dynamic PET with C-11 hydroxyephedrine (HED) was performed twice within 3.0+/-0.5 years. According to the time interval between HTX and first PET, subgroups of patients early (group A, <1.5 years; n=7), intermediate (group B, 1.5 to 7 years; n=7) and late (group C, >7 years; n=6) after HTX were defined. At the time of first HED PET, 10 patients were completely denervated (7 in group A, 2 in group B, and 1 in group C). Only 3 remained denervated at second PET. A significant increase of reinnervated myocardium between first and second PET was found in all 3 groups (0% to 9+/-9% of left ventricle for group A, P<0.05; 13+/-12% to 23+/-17% for group B, P<0.05; 21+/-21% to 37+/-23% for group C, P<0.05). The magnitude of increase was similar between groups. Reinnervation was first surveyed in the basal anterior region, then toward apex, septal, and lateral wall. Inferior wall remained denervated. The largest reinnervated area surveyed in an individuum was 66% of the left ventricle. CONCLUSIONS: The present data confirm the low likelihood of sympathetic reinnervation within 18 months after HTX. Once the reinnervation process is initiated, a continuous growth is observed even late after HTX, suggesting a progressive nature of reinnervation. Reinnervation, however, remained regionally heterogeneous, and a complete restoration was not found until 15 years after HTX.

Myocardial efficiency and sympathetic reinnervation after orthotopic heart transplantation: a noninvasive study with positron emission tomography.

BACKGROUND: The lack of cardiac catecholamine uptake and storage caused by sympathetic denervation may influence performance of the transplanted heart. Reinnervation, occurring late after transplantation, may partially resolve these effects. In this study, oxidative metabolism and its relation to cardiac work were compared in allografts and normal and failing hearts, and the effects of sympathetic reinnervation were evaluated. METHODS AND RESULTS: Twenty-seven nonrejecting, symptom-free transplant recipients, 11 healthy control subjects, and 10 patients with severe dilated cardiomyopathy underwent PET with (11)C acetate for assessment of oxidative metabolism by the clearance constant k(mono) and radionuclide angiography or MRI for measurement of ventricular function, geometry, and work. Efficiency was estimated noninvasively by a work-metabolic index [WMI=(stroke volumexheart ratexsystolic pressure)/k(mono)]. In 14 of 27 transplants, presence of regional reinnervation was identified with PET and the catecholamine analogue (11)C hydroxyephedrine (extent, 24+/-14% of left ventricle). The WMI was comparable in normal subjects and reinnervated and denervated transplants (6.2+/-2.3 versus 4.9+/-2.0 versus 4.9+/-1.2. 10(6) mm Hg. mL; P=NS) and significantly lower in cardiomyopathy patients (3.0+/-1.3. 10(6) mm Hg. mL; P<0.001). For normal subjects and transplant recipients, the WMI was significantly correlated with afterload (peripheral vascular resistance; r=-0.65, P<0.01), preload (end-diastolic volume; r=0.78, P<0.01), and stroke volume (r=0.81, P<0.01) but not with hydroxyephedrine retention (transplants only; r=0.09, P=NS). CONCLUSIONS: After transplantation, cardiac efficiency is improved compared with failing hearts and comparable to normal hearts. Differences between denervated and reinnervated allografts were not surveyed. Additionally, the dependency on loading conditions and contractility was preserved, suggesting that normal regulatory interactions for efficiency are intact and that sympathetic tone does not play a role under resting conditions.

Uptake of radiolabeled 2'-fluoro-2'-deoxy-5-iodo-1-beta-D-arabinofuranosyluracil in cardiac cells after adenoviral transfer of the herpesvirus thymidine kinase gene: the cellular basis for cardiac gene imaging.

BACKGROUND: Gene therapy is a promising approach for the treatment of cardiac diseases. Coexpression of therapeutic genes with a suitable marker gene would allow for the noninvasive imaging of successful gene transfer and expression via radiolabeled marker substrates. In the present study, such an approach was first applied to cardiac tissue. METHODS AND RESULTS: The combination of the herpesvirus thymidine kinase reporter gene (HSV1-tk) and radiolabeled 2'-fluoro-2'-deoxy-5-iodo-1-beta-D-arabinofuranosyluracil (FIAU) was evaluated. H9c2 rat cardiomyoblasts were infected in vitro with a replication-defective HSV1-tk-containing adenovirus and a negative control virus. The intracellular uptake of [(14)C]FIAU increased with increasing multiplicity of infection and with time after infection. Uptake in negative controls remained <15% of positive controls. Additionally, vectors were applied intramyocardially in Wistar rats. The marker substrate [(125)I]FIAU was injected intravenously 3 days later, and animals were killed after 24 hours. Autoradiographically, regional transgene expression was clearly identified in animals receiving the adenovirus containing HSV1-tk (3. 4+/-2.2-fold increase of radioactivity at vector administration site compared with remote myocardium), whereas nonspecific uptake in negative controls was low (<10% of positive controls). CONCLUSIONS: Using an adenoviral vector, HSV1-tk can be successfully expressed in cardiac cells in vitro and in vivo, yielding high uptake of radiolabeled FIAU. The results suggest that imaging transgene expression in the heart is feasible and may be used to monitor gene therapy noninvasively.

Extent of cardiac sympathetic neuronal damage is determined by the area of ischemia in patients with acute coronary syndromes.

BACKGROUND: Prior studies have demonstrated that acute ischemic injury causes sympathetic neuronal damage exceeding the area of necrosis. The aim of this study was to test the hypothesis that sympathetic neuronal damage measured by (123)I-metaiodobenzylguanidine (MIBG) imaging would be determined by the area of ischemia as reflected by area at risk in patients undergoing reperfusion therapy for acute coronary syndromes. METHODS AND RESULTS: In 12 patients, the myocardium at risk was assessed by (99m)Tc-sestamibi SPECT before reperfusion, and infarct size was measured by follow-up (99m)Tc-sestamibi SPECT 1 week later. All patients also underwent (123)I-MIBG SPECT within a mean of 11 days after onset. The SPECT image analysis was based on a semiquantitative polar map approach. Defect size on the (123)I-MIBG or (99m)Tc-sestamibi SPECT was measured for the left ventricle (LV) with the use of a threshold of -2.5 SD from the mean value of a normal database and was expressed as %LV. The (123)I-MIBG defect size (47+/-18%LV) was larger than the infarct size (27+/-23%LV, P<0. 001) but was similar to the risk area (49+/-18%LV, P=NS). Furthermore, the (123)I-MIBG defect size was closely correlated with the risk area (r=0.905, P<0.001). CONCLUSIONS: Sympathetic neuronal damage measured by (123)I-MIBG SPECT is larger than infarct size and is closely related to risk area, suggesting high sensitivity of neuronal structures to ischemia compared with myocardial cells.

Myocardial blood flow and flow reserve after coronary reimplantation in patients after arterial switch and ross operation.

BACKGROUND: Coronary reimplantation is used in therapy for congenital heart disease, such as in the arterial switch (ASO) and Ross operations. The adequacy of myocardial perfusion may remain a matter of concern. The aim of the present study was to stratify the effect of coronary reimplantation on myocardial perfusion and to highlight the clinical relevance of any attenuation in myocardial perfusion. METHODS AND RESULTS: A total of 21 children with transposition of the great arteries at a mean interval of 11.2+/-2.9 years after ASO and 9 adolescents at a mean interval of 4.2+/-2.1 years after the Ross procedure were investigated. All patients were asymptomatic and had a normal exercise capacity. On stress echocardiography, 2 of the ASO patients had dyskinetic areas within the left ventricular myocardium, and 5 had adenosine-induced perfusion defects on positron emission tomography. No coronary obstruction was detected on coronary angiography in any patient, but a common finding was right coronary dominance and a small caliber of the distal part of the left anterior descending artery. Coronary flow reserve (CFR) was significantly reduced in all patients after ASO when compared with 10 normal healthy volunteers (age, 25.6+/-5.3 years). CFR was normal in the 9 patients who had the Ross operation (age, 19.2+/-7.6 years); exercise-induced perfusion defects were not detected in the Ross patients. CONCLUSIONS: Children after ASO are asymptomatic, without clinical signs of coronary dysfunction. In contrast to patients who had the Ross operation, stress-induced perfusion defects and an attenuated CFR were documented. The prognostic implications of these findings and the clinical consequences are unclear; nevertheless, close clinical follow-up of ASO patients is mandatory.

Myocardial blood flow and coronary flow reserve late after anatomical correction of transposition of the great arteries.

OBJECTIVES: Myocardial blood flow (MBF) in children late after arterial switch operation (ASO) was investigated quantitatively by positron emission tomography (PET). BACKGROUND: In children with transposition of the great arteries (TGA), ASO is widely accepted as the management of choice. The long-term patency of coronary arteries after surgical transfer to the neo-aorta, however, remains a concern. METHODS: Twenty-two normally developed, symptom-free children were investigated by PET with nitrogen-13 ammonia at rest and during adenosine vasodilation 10+/-1 years after ASO. A subgroup of 15 children (9+/-1 years; group A) had simple TGA and underwent ASO within 20 days after birth while 7 (13+/-3 years; group B) had complex TGA and underwent ASO and correction of associated anomalies later after birth. Ten young, healthy adults (26+/-6 years) served as the control group. RESULTS: Resting MBF was not different between groups. After correction for the rate-pressure product as an index of cardiac work, younger children of group A had significantly higher MBF at rest compared to healthy adults (102+/-29 vs. 77+/-6 ml/100 g/min; p = 0.012) while flow in group B was not different from the other groups (85+/-22 ml/100 g/min; p = NS). Hyperemic blood flows were significantly lower in both groups after ASO compared to normals (290+/-42 ml/100 g/min for group A, 240+/-28 for group B, 340+/-57 for normals; p < 0.01); thus, coronary flow reserve was significantly lower in both groups after ASO compared to healthy adults (3.0+/-0.6 for group A, 2.9+/-0.6 for group B, 4.6+/-0.9 for normals; p < 0.01). CONCLUSIONS: Blood flow measurements suggest decreased coronary reserve in the absence of ischemic symptoms in children late after arterial switch repair of TGA. The global impairment of stress flow dynamics may indicate altered vasoreactivity; however, the prognostic significance of these findings needs to be determined.

Effect of thyroid hormones on cardiac function, geometry, and oxidative metabolism assessed noninvasively by positron emission tomography and magnetic resonance imaging.

Thyroid hormones influence cardiac performance directly and indirectly via changes in peripheral circulation. Little, however, is known about the effect on myocardial oxidative metabolism and its relation to cardiac function and geometry. Patients with a history of thyroidectomy for thyroid cancer present a unique model to investigate the cardiac effects of hypothyroidism. Ten patients without heart disease were investigated in the hypothyroid state and again 4-6 weeks later under euthyroid conditions. Myocardial oxidative metabolism was measured by positron emission tomography with [11C]acetate and the clearance constant k(mono). Cine magnetic resonance imaging was applied to determine left ventricular geometry. A stroke work index (SWI = stroke volume x systolic blood pressure/ventricular mass) was calculated. Then, to estimate myocardial efficiency, a work metabolic index [WMI = SWI x heart rate/k(mono)] was obtained. Compared to hormone replacement, systemic vascular resistance and left ventricular mass were significantly higher in hypothyroidism. Ejection fraction and SWI were significantly lower. Despite an additional reduction of k(mono), the WMI was significantly lower, too. In summary, cardiac oxygen consumption is reduced in hypothyroidism. This reduction is associated with increased peripheral resistance and reduced contractility. Estimates of cardiac work are more severely suppressed than those of oxidative metabolism, suggesting decreased efficiency. These findings may provide an explanation for development or worsening of heart failure in hypothyroid patients with preexisting heart disease.

Kinetics of 123I-MIBG after acute myocardial infarction and reperfusion therapy.

UNLABELLED: Metaiodobenzylguanidine (MIBG) washout from the myocardium has been thought to reflect sympathetic nerve tone. After acute myocardial infarction, however, little is known about this parameter. The aim of this study was to determine the significance of cardiac washout after myocardial infarction and early reperfusion by investigating MIBG kinetics and correlating those kinetics to clinical parameters. METHODS: Sixty patients with acute myocardial infarction underwent planar MIBG and thallium imaging within 14 d of early reperfusion therapy. Global uptake and washout in myocardium, lungs and liver were calculated from early and delayed images. A regional analysis of myocardial kinetics in normal and infarcted myocardium and in an infarct border zone was also performed. Scintigraphic data were correlated with heart-rate variability as an electrophysiologic marker for autonomic tone and prevalence of arrhythmia in 52 patients. Heart-rate variability was described by time-domain indices from long-term electrocardiogram recordings. An age-matched normal control group for MIBG consisted of 10 individuals without heart disease. RESULTS: The infarct patients had preserved left-ventricular ejection fraction (LVEF) (56% +/- 17%). Although late myocardial uptake was expectedly lower in infarct patients compared with healthy volunteers (2.36 +/- 0.66 versus 2.80 +/- 0.55; P = 0.04), global myocardial MIBG washout was faster (11.6% +/- 7.9% versus 0.2% +/- 10.2%, respectively; P = 0.002). Lung and liver kinetics did not differ in patients and healthy volunteers. Global MIBG washout showed a weak but significant positive correlation with the baseline heart rate (r = 0.28, P = 0.03) and an inverse correlation with LVEF (r = -0.28, P = 0.04). Washout was faster in a subgroup of 8 patients with reduced heart-rate variability (16.5% +/- 9.9% versus 10.3% +/- 8.3%; P = 0.04). Regional analysis revealed similar degrees of enhanced MIBG washout for infarcted (low perfusion, low MIBG uptake) and remote myocardium (normal perfusion, high MIBG uptake), whereas the border zone (normal perfusion, low MIBG uptake) showed a nonsignificant trend toward higher washout. CONCLUSION: After myocardial infarction, changes in MIBG kinetics occur specifically in the myocardium, whereas kinetics in lung and liver remain unchanged. Even in patients with left-ventricular function preserved by reperfusion therapy, MIBG washout is abnormal and globally increased. Enhanced washout may reflect increased sympathetic nerve tone and represent increased catecholamine turnover or impaired reuptake in the subacute phase of myocardial infarction.

Coronary microvascular reactivity to sympathetic stimulation in patients with idiopathic dilated cardiomyopathy.

UNLABELLED: The objective of this study was to assess noninvasively the microvascular reactivity to sympathetic stimulation in patients with idiopathic dilated cardiomyopathy (IDC) and in healthy volunteers, who underwent cardiac catheterization for exclusion of coronary artery disease. METHODS: Myocardial flow was quantified with 13N-ammonia PET and tracer kinetic modeling at rest and in response to cold pressor testing (CPT). Ten healthy volunteers (8 men, 2 women; mean age +/- SD, 50.7 +/- 15 y) and 10 matched patients (8 men, 2 women; mean age, 52.5 +/- 14 y) with IDC (mean left ventricular ejection fraction, 0.30 +/- 0.12) were included in the study. RESULTS: Myocardial perfusion at rest was not significantly different between the groups. However, myocardial vascular resistance (MVR) was significantly lower in IDC patients at rest than in healthy volunteers. In response to CPT a significant decrease in MVR was found in healthy volunteers (1.9 +/- 0.4 to 1.5 +/- 0.4 mm Hg x 100 g/mL; 22% decrease) but not in IDC patients (1.5 +/- 0.4 to 1.4 +/- 0.3 mm Hg x 100 g/mL; 9% decrease). Consequently, the increase of the myocardial blood flow in response to CPT was significantly lower (P < 0.008) in IDC patients (56 +/- 17 to 66 +/- 18 mL/100g/min; 20% increase) compared with healthy volunteers (52 +/- 12 to 80 +/- 30 mL/100 g/min; 52% increase), whereas both showed comparable hemodynamic reactions. CONCLUSION: The data indicate that CPT in combination with 13N PET imaging is a valuable noninvasive tool for assessment of coronary microvascular reaction to sympathetic stimulation in IDC patients. Lower coronary vascular resistance was found in IDC patients at rest compared with healthy volunteers, suggesting possible exhaustion of sympathetically induced dilation of the coronary microvasculature in IDC patients at rest. This mechanism may explain the impaired flow response to cold in IDC patients in the present study.