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.

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.

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.

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.

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.

[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.

[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.

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.

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).

[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.

Present and future of clinical cardiovascular PET imaging in Europe--a position statement by the European Council of Nuclear Cardiology (ECNC).

This position statement was prepared by the European Council of Nuclear Cardiology and summarises the current and future potential of PET as a clinical cardiovascular diagnostic imaging tool. The first section describes how methodological developments have positively influenced the transition of PET from a research tool towards a clinical diagnostic test. In the second section, evidence in support of its superior diagnostic accuracy, its value to guide decision making and to predict outcome and its cost effectiveness is summarised. The third section finally outlines new PET-based approaches and concepts, which will likely influence clinical cardiovascular medicine in the future. The notion that integration of cardiac PET into healthcare systems and disease management algorithms will advance quality of care is increasingly supported by the literature highlighted in this statement.

Positron emission tomography and molecular imaging.

The use of positron emission tomography (PET) in cardiology is growing rapidly. Technical features make PET a strong technology for the non-invasive evaluation of cardiac physiology. It is currently considered the most reliable tool for the identification of myocardial viability and also allows accurate assessment of myocardial perfusion and detection of coronary artery disease (CAD). The unique feature of PET is that myocardial perfusion can be measured in absolute terms, improving sensitivity in the detection of multivessel of disease and also allowing evaluation of very early changes in coronary vasoreactivity and the progression or regression of CAD. Use of the newest generation of PET systems with integrated multislice computed tomography (CT) is becoming a standard technique for cardiac imaging. Since the PET and CT techniques ideally complement each other the combination is particularly attractive for the non-invasive assessment of CAD but also has other functions. Finally, there are also promising future applications that involve molecular imaging of cardiac targets, which may further enhance the clinical utility of PET and hybrid imaging.

[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.

Myocardial scars determined by delayed-enhancement magnetic resonance imaging and positron emission tomography are not common in right ventricles with systemic function in long-term follow up.

OBJECTIVE: To test the hypothesis that myocardial scars are common in patients with systemic right ventricles. METHODS: 27 consecutive patients with systemic right ventricle were studied with delayed-enhancement magnetic resonance imaging and positron emission tomography. Of the 27 patients, 18 had had an atrial switch operation a mean of 21.8 (SD 4.5) years previously and were 23.4 (SD 5.3) years old. Nine patients without previous heart surgery had congenitally corrected transposition of the great arteries and were 35.3 (SD 15.6) years old. RESULTS: Only one patient had a subendocardial scar identified by delayed-enhancement magnetic resonance imaging. Positron emission tomography identified no myocardial scars. CONCLUSIONS: This study shows that the hypothesis that myocardial scars are common in patients with systemic right ventricles is not correct.

Effects of nateglinide on myocardial microvascular reactivity in Type 2 diabetes mellitus--a randomized study using positron emission tomography.

AIMS: To evaluate effects of the oral antidiabetic insulinotropic agent nateglinide on myocardial blood flow (MBF) and microvascular reactivity in Type 2 diabetic patients. METHODS: Forty-seven Type 2 diabetic patients were randomly assigned 2 : 1 to nateglinide 120 mg (t.i.d., n = 33) or placebo (n = 14). At baseline and after 16 weeks of treatment, MBF was quantified using positron emission tomography with N-13 ammonia at rest, during endothelial-dependent stimulation by cold pressor test and during adenosine-mediated vasodilation. Additional blood samples were taken to assess glycaemic control and lipid profile. RESULTS: MBF at rest and during adenosine did not change during the study. The percentage of flow increase from rest during cold pressor test did not improve significantly in the nateglinide group vs. placebo (from 26.1 +/- 37.2% to 29.1 +/- 27.8% between week 0 to week 16 for nateglinide vs. 14.9 +/- 37.1% to 18.1 +/- 28.4% for placebo; P = 0.07 for nateglinide when adjusted for higher baseline values). Nateglinide decreased HbA1c by 0.4% (from 7.6 +/- 0.9% to 7.2 +/- 1.3%) compared to an increase of 0.5% in the placebo group (from 7.9 +/- 0.8% to 8.4 +/- 1.7%; P = 0.02 for nateglinide). No differences between the two groups were observed in insulin levels and lipid status. CONCLUSIONS: Nateglinide neither improved, nor impaired myocardial blood flow in Type 2 diabetic patients. Potential effects on endothelial-dependent myocardial blood flow remain to be investigated further. Positron emission tomography is a sensitive approach to assess the effects of therapeutic agents on myocardial blood flow in patients with diabetes.

Impaired myocardial blood flow and coronary flow reserve of the anatomical right systemic ventricle in patients with congenitally corrected transposition of the great arteries.

OBJECTIVES: To investigate myocardial blood flow of the morphological right systemic ventricle in unoperated patients with congenitally corrected transposition of the great arteries (CCTGA) by positron emission tomography (PET). DESIGN: Prospective cross sectional clinical study. SETTING: Tertiary referral centre for paediatric cardiology. PATIENTS: 15 patients with CCTGA were investigated by PET with nitrogen-13 ammonia at rest and during adenosine vasodilatation. A subgroup of seven patients had isolated CCTGA (group A, mean (SD) age 30.3 (11.9) years) and the remaining eight patients had complex CCTGA associated with subpulmonary stenosis; four of this second group also had ventricular septal defect (group B, mean (SD) age 30.6 (16.4) years). Eleven healthy adults (mean (SD) age 26.2 (5.1) years) served as the control group. RESULTS: Resting myocardial blood flow was not different between both groups of patients with CCTGA and the controls. Hyperaemic blood flows were significantly lower in both groups of CCTGA than in the control group (mean (SD) 195 (21) ml/100g/min in group A, 201 (27) ml/100g/min in group B, 309 (74) ml/100g/min in the control group; p < 0.001). Thus, coronary flow reserve was significantly lower in both groups of CCTGA than in the control group (mean (SD) 2.5 (0.28) in group A, 2.6 (0.48) in group B, and 4.0 (0.73) in the control group; p < 0.001). CONCLUSION: Blood flow measurements suggest that coronary reserve is decreased in the absence of ischaemic symptoms in patients with CCTGA. The global impairment of stress flow dynamics may indicate altered global vasoreactivity, and quantitative changes in microcirculation suggest that their role in the pathogenesis of systemic right ventricular dysfunction is important.

Cardiac autonomic dysinnervation and myocardial blood flow in long-term Type 1 diabetic patients.

AIMS: The aim of the study was to assess scintigraphically the relationship between myocardial blood flow response and sympathetic dysinnervation in long-term Type 1 diabetic patients. Effects of the iron chelator deferoxamine on myocardial blood flow were studied and they were investigated according to the presence of cardiac sympathetic dysfunction. METHODS: Myocardial blood flow (MBF) was assessed with N-13 ammonia positron emission tomography in 13 long-term Type 1 diabetic patients and 13 control subjects at rest and in response to sympathetic stimulation (cold pressor test (CPT)). In diabetic patients, the study was repeated after preinfusion with deferoxamine. Furthermore, 123I metaiodobenzylguanidine (MIBG) scintigraphy was applied to assess regional cardiac sympathetic dysinnervation (uptake score 1 = normal, homogeneous uptake em leader 6 = no uptake). RESULTS: In diabetic patients, MBF increased in response to CPT from 78 +/- 18 ml/100 g/min to 84 +/- 26 ml/100 g (8%, P < 0.001). Control subjects demonstrated an increase from 63 +/- 17 ml/100 g to 84 +/- 26 ml/100 g (33%, P < 0.001), respectively. Resting MBF was higher in diabetic patients than in control subjects (P < 0.001). In diabetic patients, increase in MBF in response to CPT was significant in regions with a MIBG uptake score of 3 did not exhibit a significant increase in MBF in response to CPT. After administration of deferoxamine, the increase in MBF in response to CPT was 23% and the magnitude of increase was related to the MIBG uptake score (r = 0.40, P < 0.0001). CONCLUSIONS: Myocardial blood flow response to sympathetic stimulation is significantly impaired in long-term Type 1 diabetes. After preinfusion with deferoxamine the impairment is partially reversed and a relationship between myocardial blood flow and the extent of cardiac sympathetic dysfunction is observed.

Alterations of myocardial presynaptic sympathetic innervation in patients with multi-vessel coronary artery disease but without history of myocardial infarction.

In patients with myocardial infarction, left ventricular sympathetic denervation exceeds the size of the scar tissue. However, little is known about the regional innervation in patients with coronary artery disease (CAD) but no myocardial infarction. Using positron emission tomography (PET) with N-ammonia and C-hydroxyephedrine (HED), resting perfusion and presynaptic sympathetic innervation were studied in eight patients (seven males, one female; 58+/-9 years) with multi-vessel CAD and no history of myocardial infarction. Using polar map analysis of the PET data, the results were regionally compared with normal databases. The mean HED retention was 8.0%+/-2.0% x min(-1). Myocardial resting perfusion was normal in 23 of 24 vascular territories. Despite normal resting perfusion, significantly reduced HED retention, indicating dysinnervation, was found in 14 of 23 (61%) vascular territories (six of eight patients). Of the dysinnervated territories, 11 (79%) showed angiographically severe stenosis (>or=90% of native vessel/coronary artery bypass graft), eight (57%) showed ischaemia (myocardial perfusion scintigraphy/stress-electrocardiogram) and 12 (86%) had been revascularized. Of the nine segments with normal innervation, two (22%) revealed severe stenosis, two (22%) showed ischaemia and seven (78%) had been revascularized. It can be concluded that, in patients with advanced CAD and normal left ventricular function, dysinnervation can occur in the absence of myocardial infarction. This is consistent with the hypothesis that sympathetic neurones are more susceptible than myocytes to ischaemic damage.

Myocardial perfusion and coronary flow reserve assessed by positron emission tomography in patients after Fontan-like operations.

Ventricular dysfunction in patients after Fontan-like operations (FLOs) is a serious complication that might contribute to poor long-term results. Ischemic heart disease will have debilitating consequences on a Fontan heart. Ten patients (15.8 +/- 5.01 years) after FLO had transesophageal echocardiography and cardiac catheterization 9.3 +/- 4.2 years after surgery. Myocardial perfusion was assessed by NH3-positron emission tomography (rest/adenosine) and compared with that of 10 healthy adults (26.1 +/- 6.3 years). Ventricular function was normal in 4 and reduced in 6 patients; end systolic and end diastolic meridional wall stress was significantly elevated in the FLO group. Coronary angiography revealed no stenosis of the coronaries. Compared to normals, myocardial blood flow (MBF) at rest was higher in the FLO group (0.99 +/- 0.25 vs 0.77 +/- 0.17 ml/g/min, p <0.05), whereas MBF after vasodilatation (2.12 +/- 0.78 vs 3.10 +/- 0.85 ml/g/min, p <0.05) and coronary flow reserve (CFR) was reduced (2.5 +/- 0.88 vs 4.1 +/- 1.01, p <0.05), especially in those with impaired ventricular function. Coronary vascular resistance after vasodilatation was elevated in the FLO group (38.2 +/- 17.4 vs 24.5 +/- 8.3 mmHg/ml/g/min, p <0.05). Altered MBF, increased meridional wall stress, and impaired CFR are common findings in FLO. Attenuated CFR and reduced ventricular function are significantly correlated and may be risk factors for the long-term outcome.

Effect of sympathetic reinnervation on cardiac performance after heart transplantation.

BACKGROUND: Late after cardiac transplantation, limited reinnervation of the transplanted heart may occur, but little is known about the effect of reinnervation on cardiac function and exercise performance. METHODS: We quantified the extent of myocardial reinnervation noninvasively in 29 cardiac-transplant recipients, using positron-emission tomography and the catecholamine analogue [11C]hydroxyephedrine. Global and regional ventricular function at rest and during standardized exercise testing were measured with the use of radionuclide angiography, and the results were compared with those in 10 healthy controls. RESULTS: Sympathetic reinnervation, mainly in the anteroseptal wall, was present in 16 of the 29 transplant recipients. At rest, hemodynamic differences were not observed between the patients with reinnervation and those with denervation. However, the latter group had a shorter mean (+/-SD) exercise time (6.1+/-1.5, minutes vs. 8.2+/-1.2 in the group with reinnervation; P<0.01) and a lower peak heart rate (121+/-13 vs. 143+/-15 beats per minute, P<0.01). The contractile response to exercise was significantly enchanced in transplant recipients with reinnervation and similar to that of normal controls. In a multivariate analysis, hydroxyephedrine retention was the only independent determinant of the exercise-induced increase in the ejection fraction. CONCLUSIONS: In heart-transplant recipients, the restoration of sympathetic innervation is associated with improved responses of the heart rate and contractile function to exercise. These results support the functional importance of reinnervation in transplanted hearts.