Short-term effects of sacubitril/valsartan therapy on myocardial oxygen consumption and energetic efficiency of cardiac work in heart failure with reduced ejection fraction: A randomized controlled study.

AIMS: We sought to evaluate the mechanism of angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan therapy and compare it with a valsartan-only control group in patients with heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: The study was a phase IV, prospective, randomized, double-blind, parallel-group study in patients with New York Heart Association class II-III heart failure and left ventricular ejection fraction (LVEF) ≤35%. During a 6-week run-in period, all patients received valsartan therapy, which was up-titrated to the highest tolerated dose level (80 mg bid or 160 mg bid) and then randomized to either valsartan or sacubitril/valsartan. Myocardial oxygen consumption, energetic efficiency of cardiac work, cardiac and systemic haemodynamics were quantified using echocardiography and 11 C-acetate positron emission tomography before and after 6 weeks of therapy (on stable dose) in 55 patients (ARNI group: n = 27, mean age 63 ± 10 years, LVEF 29.2 ± 10.4%; and valsartan-only control group: n = 28, mean age 64 ± 8 years, LVEF 29.0 ± 7.3%; all p = NS). The energetic efficiency of cardiac work remained unchanged in both treatment arms. However, both diastolic (-4.5 mmHg; p = 0.026) and systolic blood pressure (-9.8 mmHg; p = 0.0007), myocardial perfusion (-0.054 ml/g/min; p = 0.045), and left ventricular mechanical work (-296; p = 0.038) decreased significantly in the ARNI group compared to the control group. Although myocardial oxygen consumption decreased in the ARNI group (-5.4%) compared with the run-in period and remained unchanged in the control group (+0.5%), the between-treatment group difference was not significant (p = 0.088). CONCLUSIONS: We found no differences in the energetic efficiency of cardiac work between ARNI and valsartan-only groups in HFrEF patients. However, ARNI appears to have haemodynamic and cardiac mechanical effects over valsartan in heart failure patients.

Quantitative Perfusion Imaging with Total-Body PET.

Recently, PET systems with a long axial field of view have become the current state of the art. Total-body PET scanners enable unique possibilities for scientific research and clinical diagnostics, but this new technology also raises numerous challenges. A key advantage of total-body imaging is that having all the organs in the field of view allows studying biologic interaction of all organs simultaneously. One of the new, promising imaging techniques is total-body quantitative perfusion imaging. Currently, 15O-labeled water provides a feasible option for quantitation of tissue perfusion at the total-body level. This review summarizes the status of the methodology and the analysis and provides examples of preliminary findings on applications of quantitative parametric perfusion images for research and clinical work. We also describe the opportunities and challenges arising from moving from single-organ studies to modeling of a multisystem approach with total-body PET, and we discuss future directions for total-body imaging.

Carimas: An Extensive Medical Imaging Data Processing Tool for Research.

Carimas is a multi-purpose medical imaging data processing tool, which can be used to visualize, analyze, and model different medical images in research. Originally, it was developed only for positron emission tomography data in 2009, but the use of this software has extended to many other tomography imaging modalities, such as computed tomography and magnetic resonance imaging. Carimas is especially well-suited for analysis of three- and four-dimensional image data and creating polar maps in modeling of cardiac perfusion. This article explores various parts of Carimas, including its key features, program structure, and application possibilities.

Myocardial perfusion quantification with Rb-82 PET: good interobserver agreement of Carimas software on global, regional, and segmental levels.

PURPOSE: To estimate the interobserver agreement of the Carimas software package (SP) on global, regional, and segmental levels for the most widely used myocardial perfusion PET tracer-Rb-82. MATERIALS AND METHODS: Rest and stress Rb-82 PET scans of 48 patients with suspected or known coronary artery disease (CAD) were analyzed in four centers using the Carimas SP. We considered values to agree if they simultaneously had an intraclass correlation coefficient (ICC) > 0.75 and a difference < 20% of the median across all observers. RESULTS: The median values on the segmental level were 1.08 mL/min/g for rest myocardial blood flow (MBF), 2.24 mL/min/g for stress MBF, and 2.17 for myocardial flow reserve (MFR). For the rest MBF and MFR, all the values at all the levels fulfilled were in excellent agreement. For stress MBF, at the global and regional levels, all the 24 comparisons showed excellent agreement. Only 1 out of 102 segmental comparisons (seg. 14) was over the adequate agreement limit-23.5% of the median value (ICC = 0.95). CONCLUSION: Interobserver agreement for Rb-82 PET myocardial perfusion quantification analyzed with Carimas is good at any LV segmentation level-global, regional, and segmental. It is good for all the estimates-rest MBF, stress MBF, and MFR.

One-tissue compartment model for myocardial perfusion quantification with N-13 ammonia PET provides matching results: A cross-comparison between Carimas, FlowQuant, and PMOD.

PURPOSE: To cross-compare three software packages (SPs)-Carimas, FlowQuant, and PMOD-to quantify myocardial perfusion at global, regional, and segmental levels. MATERIALS AND METHODS: Stress N-13 ammonia PET scans of 48 patients with HCM were analyzed in three centers using Carimas, FlowQuant, and PMOD. Values agreed if they had an ICC > 0.75 and a difference < 20% of the median across all observers. RESULTS: When using 1TCM on the global level, the agreement was good, and the maximum difference between 1TCM MBF values was 17.2% (ICC = 0.83). On the regional level, the agreement was acceptable except in the LCx region (25.5% difference, ICC = 0.74) between FlowQuant and PMOD. Carimas-1TCM agreed well with PMOD-1TCM and FlowQuant-1TCM. Values obtained with FlowQuant-1TCM had a somewhat lesser agreement with PMOD-1TCM, especially at the segmental level. CONCLUSIONS: The global and regional MBF values (with one exception) agree well between the different software packages. There is significant variability in segmental values, mainly located in the LCx region and segments. Out of the studied tools, Carimas can be used interchangeably with both PMOD and FlowQuant for 1TCM implementation on all levels-global, regional, and segmental.

Software reproducibility of myocardial blood flow and flow reserve quantification in ischemic heart disease: A 13N-ammonia PET study.

BACKGROUND: We explored agreement in the quantification of myocardial perfusion by cross-comparison of implemented software packages (SPs) in three distinguishable patient profile populations. METHODS: We studied 91 scans of patients divided into 3 subgroups based on their semi-quantitative perfusion findings: patients with normal perfusion, with reversible perfusion defects, and with fixed perfusion defects. Rest myocardial blood flow (MBF), stress MBF, and myocardial flow reserve (MFR) were obtained with QPET, SyngoMBF, and Carimas. Agreement between SPs was considered adequate when a pairwise standardized difference was found to be < 0.20 and its corresponding intraclass correlation coefficient was ≥ 0.75. RESULTS: In patients with normal perfusion, two out of three comparisons of global stress MBF quantifications were outside the limits of agreement. In ischemic patients, all comparisons of global stress MBF and MFR were outside the limits of established agreement. In patients with fixed perfusion defects, all SP comparisons of perfusion quantifications were within the limit of agreement. Regionally, agreement of these perfusion estimates was mostly found for the left anterior descending artery vascular territory. CONCLUSION: Reversible defects demonstrated the worst agreement in global stress MBF and MFR and discrepancies showed to be regional dependent. Reproducibility between SPs should not be assumed.

Evidence for Indirect Action of Ionizing Radiation in 18-Crown-6 Complexes with Halogenous Salts of Strontium: Simulation of Radiation-Induced Transformations in Ionic Liquid/Crown Ether Compositions.

Ionic liquid/crown ether compositions are an attractive alternative to traditional extractants in the processes for spent nuclear fuel and liquid radioactive wastes reprocessing. These compositions are exposed to ionizing radiation, and their radiation stability, especially in the presence of metal salts, is a crucial issue. In the present study, the macrocyclic 18C6·Sr(BF4)2 and 18C6·Sr(PF6)2 complexes simulating the components of metal loaded ionic liquid/crown ether extractants were synthesized and their structures were characterized by FTIR spectroscopy and single-crystal X-ray diffraction analysis. Inclusion of Sr2+ cation into the 18C6 cavity resulted in more symmetric D3d conformations of the macrocycle. The structural transformations of the crown ether were accompanied by an elongation of polyether C-O bonds that could increase the possibility of radiolytic cleavage of the macrocycle. However, EPR study of the synthesized compounds subjected to X-ray irradiation revealed predominant formation of macrocyclic -CH2-CH-O- radicals. This result demonstrated an evidence for indirect action of ionizing radiation on individual components of the complexes and was reasonably described by a positive "hole" transfer from primary macrocyclic radical cation to fluorous anion at the primary stages of radiolysis and a subsequent interaction of fluorine atom with 18C6 macrocycle in secondary radical reactions. The observed effects may be partially responsible for enhanced sensitivity of the ionic liquid/crown ether extractants to ionizing radiation due to chemical blocking of the crown ether with radiolytic HF, radiation-chemical degradation of the 18C6, and precipitation of a low-soluble SrF2.

Cardiac rehabilitation improves coronary endothelial function in patients with heart failure due to dilated cardiomyopathy: A positron emission tomography study.

BACKGROUND: Endothelial dysfunction is common in patients with heart failure and is associated with poor clinical outcome. Cardiac rehabilitation is able to enhance peripheral endothelial function but its impact on coronary vasomotion remains unknown. We aimed to evaluate the effect of cardiac rehabilitation on coronary vasomotion in patients with heart failure. METHOD: We prospectively enrolled 29 clinically stable heart failure patients from non-ischaemic dilated cardiomyopathy and without coronary risk factors. Myocardial blood flow was quantified using (15)-O water positron emission tomography at rest and during a cold pressor test, before and after 12 weeks of cardiac rehabilitation and optimization of medical therapy. RESULTS: Rest myocardial blood flow was significantly improved after the completion of rehabilitation compared to baseline (1.31 ± 0.38 mL/min/g vs. 1.16 ± 0.41 mL/min/g, p = 0.04). The endothelium-related change in myocardial blood flow from rest to cold pressor test and the percentage of myocardial blood flow increase during the cold pressor test were both significantly improved after cardiac rehabilitation (respectively from -0.03 ± 0.22 mL/min/g to 0.19 ± 0.22 mL/min/g, p < 0.001 and from 101.5 ± 16.5% to 118.3 ± 24.4%, p < 0.001). Left ventricular ejection fraction, plasma levels of brain natriuretic peptide, maximal oxygen consumption and the Minnesota Living with Heart Failure Questionnaire score were also significantly improved. The improvement was not related to uptitration of medical therapy. CONCLUSIONS: Coronary endothelial function is altered in patients with heart failure due to non-ischaemic dilated cardiomyopathy. In these patients, cardiac rehabilitation significantly improves coronary vasomotion.

C-11 acetate has excellent reproducibility for quantification of myocardial oxidative metabolism.

AIMS: C-11 acetate PET imaging allows quantification of myocardial oxidative metabolism. We sought to assess the reproducibility of such analysis with the Carimas software. METHODS AND RESULTS: The myocardial oxygen consumption rate was assessed via a kmono index--the clearance rate constant of a mono-exponential function fitted to a C-11 acetate clearance curve. Two observers of different experience levels--a novice and an expert--analysed 53 C-11 acetate PET studies--each study twice. These results were compared using Bland-Altman (BA) plots with the global kmono-s obtained earlier with a validated reference method. We also assessed intra- and interobserver reproducibility on global, regional, and segmental [17-segment model (AHA)] levels--a linear mixed model for the repeated measures was fitted to our data--using intraclass correlation coefficients (ICCs) and differences between repeats and the observers. Carimas kmono values were lower than the reference--by 10.7% in the novice and by 9.6% in the expert, and were in substantial agreement with it--R(2) values were 0.944 and 0.943 correspondingly; the coefficients of repeatability--1.96 SD of biases in BA plots--were 11.2% in both the observers. The intra- and interobserver ICCs were high on global and regional levels--above 0.99 in the novice and 0.96 in the expert. The intra- and interobserver differences were low on global and regional levels, the most pronounced being the left anterior descending artery (LAD) interobserver difference of 2.2%. CONCLUSION: The study showed extremely good reproducibility-both intra- and interobserver-for C-11 acetate PET analysis of myocardial oxidative metabolism.

Quantification of myocardial blood flow in absolute terms using (82)Rb PET imaging: the RUBY-10 Study.

OBJECTIVES: The purpose of this study was to compare myocardial blood flow (MBF) and myocardial flow reserve (MFR) estimates from rubidium-82 positron emission tomography ((82)Rb PET) data using 10 software packages (SPs) based on 8 tracer kinetic models. BACKGROUND: It is unknown how MBF and MFR values from existing SPs agree for (82)Rb PET. METHODS: Rest and stress (82)Rb PET scans of 48 patients with suspected or known coronary artery disease were analyzed in 10 centers. Each center used 1 of 10 SPs to analyze global and regional MBF using the different kinetic models implemented. Values were considered to agree if they simultaneously had an intraclass correlation coefficient >0.75 and a difference <20% of the median across all programs. RESULTS: The most common model evaluated was the Ottawa Heart Institute 1-tissue compartment model (OHI-1-TCM). MBF values from 7 of 8 SPs implementing this model agreed best. Values from 2 other models (alternative 1-TCM and Axially distributed) also agreed well, with occasional differences. The MBF results from other models (e.g., 2-TCM and retention) were less in agreement with values from OHI-1-TCM. CONCLUSIONS: SPs using the most common kinetic model-OHI-1-TCM-provided consistent results in measuring global and regional MBF values, suggesting that they may be used interchangeably to process data acquired with a common imaging protocol.

Comparison of clinical non-commercial tools for automated quantification of myocardial blood flow using oxygen-15-labelled water PET/CT.

AIMS: Absolute quantification of myocardial blood flow (MBF) with (15)O-water cardiac positron emission tomography (PET)/CT has recently demonstrated to hold promising diagnostic value for the detection of coronary artery disease (CAD). However, methodological differences in utilized analysis software packages (SP) could affect generated MBF values, potentially prohibiting widespread clinical applicability of obtained normal thresholds. The aim of this study was to compare two validated non-commercial SP, Carimas and Cardiac VUer, for the quantification of MBF using (15)O-water PET. METHODS AND RESULTS: One hundred patients with intermediate likelihood of CAD and scanned in academic centres in Amsterdam (n = 50) and Turku (n = 50) were included in the study. Patients underwent a (15)O-water PET/CT scan during rest and vasodilator stress based on clinical indications. A single observer, blinded from clinical results and with no prior experience in either SP, analysed all patients twice with both SP. Reproducibility of each SP was assessed using intraclass correlation coefficients (ICC). Intersoftware agreement was assessed using paired t-tests and linear regression. ICC was excellent for each SP for both global and regional MBF (ICC >0.90). Global MBF was comparable between Carimas and Cardiac VUer during rest (1.02 ± 0.28 vs. 0.99 ± 0.23 mL min(-1)g(-1), respectively, P = 0.07), and slightly higher for Carimas during stress (2.73 ± 0.82 vs. 2.63 ± 0.84 mL min(-1)g(-1), respectively, P = 0.01). At a regional level, for resting conditions small (<10%) but significant discrepancies were noted in each vascular territory while for stress MBF, a significant difference was only observed for the LAD region. Differences between SP for the LAD territory were abolished after exclusion of the distal apical segment, which is susceptible to spillover artefacts. An excellent correlation between MBF values was found for global (r = 0.96) and regional MBF (r > 0.94 for all). CONCLUSION: For global and regional MBF, Carimas and Cardiac VUer showed excellent agreement and intra-observer reproducibility. These results confirm that, for patients with intermediate likelihood of CAD, these validated SP are interchangeable and can be utilized for routine clinical practice of (15)O-water cardiac PET.

PET: Is myocardial flow quantification a clinical reality?

Positron emission tomography (PET) enables quantitative measurements of myocardial blood flow (MBF) and myocardial flow reserve (MFR). Recent developments and improved availability of PET technology have resulted in growing interest in translation of quantitative flow analysis from mainly a research tool to routine clinical practice. Quantitative PET measurements of absolute MBF and MFR have potential to improve accuracy of myocardial perfusion imaging in diagnosis of multivessel coronary artery disease as well as definition of the extent and functional importance of stenoses. This article reviews recent advances and experience in the quantitative myocardial perfusion imaging together with issues that need to be resolved for quantitative analysis to become clinical reality.

Cardiac Function, Perfusion, Metabolism, and Innervation following Autologous Stem Cell Therapy for Acute ST-Elevation Myocardial Infarction. A FINCELL-INSIGHT Sub-Study with PET and MRI.

PURPOSE: Beneficial mechanisms of bone marrow cell (BMC) therapy for acute ST-segment elevation myocardial infarct (STEMI) are largely unknown in humans. Therefore, we evaluated the feasibility of serial positron emission tomography (PET) and MRI studies to provide insight into the effects of BMCs on the healing process of ischemic myocardial damage. METHODS: Nineteen patients with successful primary reteplase thrombolysis (mean 2.4 h after symptoms) for STEMI were randomized for BMC therapy (2.9 × 10(6) CD34+ cells) or placebo after bone marrow aspiration in a double-blind, multi-center study. Three days post-MI, coronary angioplasty, and paclitaxel eluting stent implantation preceded either BMC or placebo therapy. Cardiac PET and MRI studies were performed 7-12 days after therapies and repeated after 6 months, and images were analyzed at a central core laboratory. RESULTS: In BMC-treated patients, there was a decrease in [(11)C]-HED defect size (-4.9 ± 4.0 vs. -1.6 ± 2.2%, p = 0.08) and an increase in [(18)F]-FDG uptake in the infarct area at risk (0.06 ± 0.09 vs. -0.05 ± 0.16, p = 0.07) compared to controls, as well as less left ventricular dilatation (-4.4 ± 13.3 vs. 8.0 ± 16.7 mL/m(2), p = 0.12) at 6 months follow-up. However, BMC treatment was inferior to placebo in terms of changes in rest perfusion in the area at risk (-0.09 ± 0.17 vs. 0.10 ± 0.17, p = 0.03) and infarct size (0.4 ± 4.2 vs. -5.1 ± 5.9 g, p = 0.047), and no effect was observed on ejection fraction (p = 0.37). CONCLUSION: After the acute phase of STEMI, BMC therapy showed only minor trends of long-term benefit in patients with rapid successful thrombolysis. There was a trend of more decrease in innervation defect size and enhanced glucose metabolism in the infarct-related myocardium and also a trend of less ventricular dilatation in the BMC-treated group compared to placebo. However, no consistently better outcome was observed in the BMC-treated group compared to placebo.

Increasing exercise intensity reduces heterogeneity of glucose uptake in human skeletal muscles.

Proper muscle activation is a key feature of survival in different tasks in daily life as well as sports performance, but can be impaired in elderly and in diseases. Therefore it is also clinically important to better understand the phenomenon that can be elucidated in humans non-invasively by positron emission tomography (PET) with measurements of spatial heterogeneity of glucose uptake within and among muscles during exercise. We studied six healthy young men during 35 minutes of cycling at relative intensities of 30% (low), 55% (moderate), and 75% (high) of maximal oxygen consumption on three separate days. Glucose uptake in the quadriceps femoris muscle group (QF), the main force producing muscle group in recreational cycling, and its four individual muscles, was directly measured using PET and 18F-fluoro-deoxy-glucose. Within-muscle heterogeneity was determined by calculating the coefficient of variance (CV) of glucose uptake in PET image voxels within the muscle of interest, and among-muscles heterogeneity of glucose uptake in QF was expressed as CV of the mean glucose uptake values of its separate muscles. With increasing intensity, within-muscle heterogeneity decreased in the entire QF as well as within its all four individual parts. Among-muscles glucose uptake heterogeneity also decreased with increasing intensity. However, mean glucose uptake was consistently lower and heterogeneity higher in rectus femoris muscle that is known to consist of the highest percentage of fast twitch type II fibers, compared to the other three QF muscles. In conclusion, these results show that in addition to increased contribution of distinct muscle parts, with increases in exercise intensity there is also an enhanced recruitment of muscle fibers within all of the four heads of QF, despite established differences in muscle-part specific fiber type distributions. Glucose uptake heterogeneity may serve as a useful non-invasive tool to elucidate muscle activation in aging and diseased populations.

Effects of insulin on brain glucose metabolism in impaired glucose tolerance.

OBJECTIVE: Insulin stimulates brain glucose metabolism, but this effect of insulin is already maximal at fasting concentrations in healthy subjects. It is not known whether insulin is able to stimulate glucose metabolism above fasting concentrations in patients with impaired glucose tolerance. RESEARCH DESIGN AND METHODS: We studied the effects of insulin on brain glucose metabolism and cerebral blood flow in 13 patients with impaired glucose tolerance and nine healthy subjects using positron emission tomography (PET). All subjects underwent PET with both [(18)F]fluorodeoxyglucose (for brain glucose metabolism) and [(15)O]H(2)O (for cerebral blood flow) in two separate conditions (in the fasting state and during a euglycemic-hyperinsulinemic clamp). Arterial blood samples were acquired during the PET scans to allow fully quantitative modeling. RESULTS: The hyperinsulinemic clamp increased brain glucose metabolism only in patients with impaired glucose tolerance (whole brain: +18%, P = 0.001) but not in healthy subjects (whole brain: +3.9%, P = 0.373). The hyperinsulinemic clamp did not alter cerebral blood flow in either group. CONCLUSIONS: We found that insulin stimulates brain glucose metabolism at physiological postprandial levels in patients with impaired glucose tolerance but not in healthy subjects. These results suggest that insulin stimulation of brain glucose metabolism is maximal at fasting concentrations in healthy subjects but not in patients with impaired glucose tolerance.

ICA based automatic segmentation of dynamic H(2)(15)O cardiac PET images.

In this study, we applied an iterative independent component analysis (ICA) method for the separation of cardiac tissue components (myocardium, right, and left ventricle) from dynamic positron emission tomography (PET) images. Previous phantom and animal studies have shown that ICA separation extracts the cardiac structures accurately. Our goal in this study was to investigate the methodology with human studies. The ICA separated cardiac structures were used to calculate the myocardial perfusion in two different cases: 1) the regions of interest were drawn manually on the ICA separated component images and 2) the volumes of interest (VOI) were automatically segmented from the component images. For the whole myocardium, the perfusion values of 25 rest and six drug-induced stress studies obtained with these methods were compared to the values from the manually drawn regions of interest on differential images. The separation of the rest and stress studies using ICA-based methods was successful in all cases. The visualization of the cardiac structures from H (2) (15) O PET studies was improved with the ICA separation. Also, the automatic segmentation of the VOI seemed to be feasible.

Myocardial perfusion quantitation with 15O-labelled water PET: high reproducibility of the new cardiac analysis software (Carimas).

PURPOSE: Carimas (Cardiac Image Analysis System) is a new software package developed at the Turku PET Centre for the quantitation of PET studies of the heart with a broad range of tracers. The goal of this study was to assess the reproducibility of results the package provides for myocardial perfusion (MP) quantitation using (15)O-labelled water. METHODS: Four observers with various levels of experience in nuclear medicine independently analysed 20 MP studies (10 rest flow: "rest", 10 adenosine-induced hyperaemia: "stress"). Each study was analysed twice. The linear mixed model for repeated measures was fitted to the data to calculate intraclass correlation coefficients (ICC), differences between the repeats (the intraobserver differences) and differences between the observers (the interobserver differences). Also, Pearson correlation coefficients (r) were calculated and Bland-Altman plots were drawn. The reproducibility of MP was assessed on global, regional and segmental levels. Thereafter, this analysis was applied in 48 consecutive clinical patients with suspected coronary heart disease (CHD). RESULTS: For the experienced observer the Pearson r for all segments was 0.974 at rest and 0.978 at stress (p < 0.0001), and the repeatability coefficients were 0.145 ml/g per min (15.5% of the average) and 0.389 ml/g per min (14.9%), correspondingly. The ICC reflected very good overall reproducibility. The intraobserver and interobserver differences were small, and the difference between the most and the least experienced observers at stress was 8.5% for the global MP. The clinical accuracy of the perfusion in the detection of CHD was excellent (positive predictive value 91% and negative predictive value 88%) against invasive angiography. CONCLUSION: The results demonstrate high reproducibility of myocardial perfusion quantitation with (15)O-labelled water PET using Carimas. The results support the feasibility of robust analysis and good clinical accuracy.

Myocardial blood flow and adenosine A2A receptor density in endurance athletes and untrained men.

Previous human studies have shown divergent results concerning the effects of exercise training on myocardial blood flow (MBF) at rest or during adenosine-induced hyperaemia in humans. We studied whether these responses are related to alterations in adenosine A2A receptor (A2AR) density in the left-ventricular (LV) myocardium, size and work output of the athlete's heart, or to fitness level. MBF at baseline and during intravenous adenosine infusion, and A2AR density at baseline were measured using positron emission tomography, and by a novel A(2A)R tracer in 10 healthy male endurance athletes (ET) and 10 healthy untrained (UT) men. Structural LV parameters were measured with echocardiography. LV mass index was 71% higher in ET than UT (193 +/- 18 g m(-2) versus 114 +/- 13 g m(-2), respectively). MBF per gram of tissue was significantly lower in the ET than UT at baseline, but this was only partly explained by reduced LV work load since MBF corrected for LV work was higher in ET than UT, as well as total MBF. The MBF during adenosine-induced hyperaemia was reduced in ET compared to UT, and the fitter the athlete was, the lower was adenosine-induced MBF. A2AR density was not different between the groups and was not coupled to resting or adenosine-mediated MBF. The novel findings of the present study show that the adaptations in the heart of highly trained endurance athletes lead to relative myocardial 'overperfusion' at rest. On the other hand hyperaemic perfusion is reduced, but is not explained by A2AR density.