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      β2-adrenergic stress evaluation of coronary endothelial-dependent vasodilator function in mice using 11C-acetate micro-PET imaging of myocardial blood flow and oxidative metabolism

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          Abstract

          Background

          Endothelial dysfunction is associated with vascular risk factors such as dyslipidemia, hypertension, and diabetes, leading to coronary atherosclerosis. Sympathetic stress using cold-pressor testing (CPT) has been used to measure coronary endothelial function in humans with positron emission tomography (PET) myocardial blood flow (MBF) imaging, but is not practical in small animal models. This study characterized coronary vasomotor function in mice with [ 11C]acetate micro-PET measurements of nitric-oxide-mediated endothelial flow reserve (EFR NOM) (adrenergic-stress/rest MBF) and myocardial oxygen consumption (MVO 2) using salbutamol β 2-adrenergic-activation.

          Methods

          [ 11C]acetate PET MBF was performed at rest + salbutamol (SB 0.2, 1.0 μg/kg/min) and norepinephrine (NE 3.2 μg/kg/min) stress to measure an index of MBF response. β-adrenergic specificity of NE was evaluated by pretreatment with α-adrenergic-antagonist phentolamine (PHE), and β 2-selectivity was assessed using SB.

          Results

          Adjusting for changes in heart rate × systolic blood pressure product (RPP), the same stress/rest MBF ratio of 1.4 was measured using low-dose SB and NE in normal mice (equivalent to human CPT response). The MBF response was correlated with changes in MVO 2 ( p = 0.02). Nitric oxide synthase (NOS)-inhibited mice (N g-nitro-L-arginine methyl ester (L-NAME) pretreatment and endothelial nitric oxide synthase (eNOS) knockout) were used to assess the EFR NOM, in which the low-dose SB- and NE-stress MBF responses were completely blocked ( p = 0.02). With high-dose SB-stress, the MBF ratio was reduced by 0.4 following NOS inhibition ( p = 0.03).

          Conclusions

          Low-dose salbutamol β 2-adrenergic-stress [ 11C]acetate micro-PET imaging can be used to measure coronary-specific EFR NOM in mice and may be suitable for assessment of endothelial dysfunction in small animal models of disease and evaluation of new therapies.

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          Most cited references 38

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          Quantification of myocardial blood flow with 82Rb dynamic PET imaging.

          The PET tracer (82)Rb is commonly used to evaluate regional perfusion defects for the diagnosis of coronary artery disease. There is limited information on the quantification of myocardial blood flow and flow reserve with this tracer. The goal of this study was to investigate the use of a one-compartment model of (82)Rb kinetics for the quantification of myocardial blood flow. Fourteen healthy volunteers underwent rest and dipyridamole stress imaging with both (13)N-ammonia and (82)Rb within a 2-week interval. Myocardial blood flow was estimated from the time-activity curves measured with (13)N-ammonia using a standard two-compartment model. The uptake parameter of the one-compartment model was estimated from the time-activity curves measured with (82)Rb. To describe the relationship between myocardial blood flow and the uptake parameter, a nonlinear extraction function was fitted to the data. This function was then used to convert estimates of the uptake parameter to flow estimates. The extraction function was validated with an independent data set obtained from 13 subjects with documented evidence of coronary artery disease (CAD). The one-compartment model described (82)Rb kinetics very well (median R-square = 0.98). The flow estimates obtained with (82)Rb were well correlated with those obtained with (13)N-ammonia (r = 0.85), and the best-fit line did not differ significantly from the identity line. Data obtained from the subjects with CAD confirmed the validity of the estimated extraction function. It is possible to obtain accurate estimates of myocardial blood flow and flow reserve with a one-compartment model of (82)Rb kinetics and a nonlinear extraction function.
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            Endothelial dysfunction: from molecular mechanisms to measurement, clinical implications, and therapeutic opportunities.

            Endothelial dysfunction has been implicated as a key factor in the development of a wide range of cardiovascular diseases, but its definition and mechanisms vary greatly between different disease processes. This review combines evidence from cell-culture experiments, in vitro and in vivo animal models, and clinical studies to identify the variety of mechanisms involved in endothelial dysfunction in its broadest sense. Several prominent disease states, including hypertension, heart failure, and atherosclerosis, are used to illustrate the different manifestations of endothelial dysfunction and to establish its clinical implications in the context of the range of mechanisms involved in its development. The size of the literature relating to this subject precludes a comprehensive survey; this review aims to cover the key elements of endothelial dysfunction in cardiovascular disease and to highlight the importance of the process across many different conditions.
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              Noninvasive quantification of the cerebral metabolic rate for glucose using positron emission tomography, 18F-fluoro-2-deoxyglucose, the Patlak method, and an image-derived input function.

              The authors developed and tested a method for the noninvasive quantification of the cerebral metabolic rate for glucose (CMRglc) using positron emission tomography (PET), 18F-fluoro-2-deoxyglucose, the Patlak method, and an image-derived input function. Dynamic PET data acquired 12 to 48 seconds after rapid tracer injection were summed to identify carotid artery regions of interest (ROIs). The input function then was generated from the carotid artery ROIs. To correct spillover, the early summed image was superimposed over the last PET frame, a tissue ROI was drawn around the carotid arteries, and a tissue time activity curve (TAC) was generated. Three venous samples were drawn from the tracer injection site at a later time and used for the spillover and partial volume correction by non-negative least squares method. Twenty-six patient data sets were studied. It was found that the image-derived input function was comparable in shape and magnitude to the one obtained by arterial blood sampling. Moreover, no significant difference was found between CMRglc estimated by the Patlak method using either the arterial blood sampling data or the image-derived input function.
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                Author and article information

                Affiliations
                National Cardiac PET Centre, Department of Medicine, Division of Cardiology, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, K1Y 4W7 ON Canada
                Contributors
                ecroteau@ottawaheart.ca
                JRenaud@ottawaheart.ca
                CArcher@uottawa.ca
                RKlein@ottawaheart.ca
                JDaSilva@ottawaheart.ca
                TRuddy@ottawaheart.ca
                RBeanlands@ottawaheart.ca
                RAdeKemp@ottawaheart.ca
                Journal
                EJNMMI Res
                EJNMMI Res
                EJNMMI Research
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                2191-219X
                16 December 2014
                16 December 2014
                December 2014
                : 4
                : 1
                4293492 68 10.1186/s13550-014-0068-9
                © Croteau et al.; licensee Springer. 2014

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.

                Categories
                Original Research
                Custom metadata
                © The Author(s) 2014

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