Sergey V. Nesterov

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.

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 [18F]fluorodeoxyglucose (for brain glucose metabolism) and [15O]H2O (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.

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.

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 athletes 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 A2AR 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−2versus 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.

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.

Radical products of γ-radiolysis of 12-crown-4 at 77 K

Paramagnetic products of γ-radiolysis of 12-crown-4 and its solutions in CFCl3 and CFCl2CF2Cl at 77 K were studied by ESR spectroscopy. It was found that the ESR spectra of 12-crown-4 irradiated with γ-rays at 77 K contained superimposing signals of at least two species, the radicals resulting from macrocycle opening -ĊH-C(H) = O and macrocyclic radicals -O-ĊH-CH2-, which are formed with nearly equal yields. It was shown that -O-ĊH-CH2-radicals rapidly decayed at temperatures above 140 K. However, the -ĊH-C(H)=O radicals are stable almost up to the matrix softening temperature. The radical cations of 12-crown-4 are not stabilized in the matrices of Freon 11 and Freon 113, since they undergo transformation to macrocyclic radicals -O-ĊH-CH2-via the deprotonation reaction.

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.

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 × 106 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 [11C]-HED defect size (−4.9 ± 4.0 vs. −1.6 ± 2.2%, p = 0.08) and an increase in [18F]-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/m2, 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.

ICA Based Automatic Segmentation of Dynamic 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.

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.