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      Identification of Angiogenesis Rich-Viable Myocardium using RGD Dimer based SPECT after Myocardial Infarction

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          Abstract

          Cardiac healing after myocardial ischemia is a complex biological process. Advances in understanding of wound healing response have paved the way for clinical testing of novel molecular imaging to improve clinical outcomes. A key factor for assessing myocardial viability after ischemic injury is the evaluation of angiogenesis accompanying increased expression of integrin α vβ 3. Here, we describe the capability of an α vβ 3 integrin-targeting SPECT agent, 99mTc-IDA-D-[c(RGDfK)] 2, for identification of ischemic but viable myocardium, i.e., hibernating myocardium which is crucial to predict functional recovery after revascularization, the standard care of cardiovascular medicine. In vivo SPECT imaging of rat models with transient coronary occlusion showed significantly high uptake of 99mTc-IDA-D-[c(RGDfK)] 2 in the ischemic region. Comparative measurements with 201Tl SPECT and 18F-FDG PET, then, proved that such prominent uptake of 99mTc-IDA-D-[c(RGDfK)] 2 exactly matched the hallmark of hibernation, i.e., the perfusion-metabolism mismatch pattern. The uptake of 99mTc-IDA-D-[c(RGDfK)] 2 was non-inferior to that of 18F-FDG, confirmed by time-course variation analysis. Immunohistochemical characterization revealed that an intense signal of 99mTc-IDA-D-[c(RGDfK)] 2 corresponded to the vibrant angiogenic events with elevated expression of α vβ 3 integrin. Together, these results establish that 99mTc-IDA-D-[c(RGDfK)] 2 SPECT can serve as a sensitive clinical measure for myocardial salvage to identify the patients who might benefit most from revascularization.

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          Myocardial perfusion scintigraphy: the evidence

          This review summarises the evidence for the role of myocardial perfusion scintigraphy (MPS) in patients with known or suspected coronary artery disease. It is the product of a consensus conference organised by the British Cardiac Society, the British Nuclear Cardiology Society and the British Nuclear Medicine Society and is endorsed by the Royal College of Physicians of London and the Royal College of Radiologists. It was used to inform the UK National Institute of Clinical Excellence in their appraisal of MPS in patients with chest pain and myocardial infarction. MPS is a well-established, non-invasive imaging technique with a large body of evidence to support its effectiveness in the diagnosis and management of angina and myocardial infarction. It is more accurate than the exercise ECG in detecting myocardial ischaemia and it is the single most powerful technique for predicting future coronary events. The high diagnostic accuracy of MPS allows reliable risk stratification and guides the selection of patients for further interventions, such as revascularisation. This in turn allows more appropriate utilisation of resources, with the potential for both improved clinical outcomes and greater cost-effectiveness. Evidence from modelling and observational studies supports the enhanced cost-effectiveness associated with MPS use. In patients presenting with stable or acute chest pain, strategies of investigation involving MPS are more cost-effective than those not using the technique. MPS also has particular advantages over alternative techniques in the management of a number of patient subgroups, including women, the elderly and those with diabetes, and its use will have a favourable impact on cost-effectiveness in these groups. MPS is already an integral part of many clinical guidelines for the investigation and management of angina and myocardial infarction. However, the technique is underutilised in the UK, as judged by the inappropriately long waiting times and by comparison with the numbers of revascularisations and coronary angiograms performed. Furthermore, MPS activity levels in this country fall far short of those in comparable European countries, with about half as many scans being undertaken per year. Currently, the number of MPS studies performed annually in the UK is 1,200/million population/year. We estimate the real need to be 4,000/million/year. The current average waiting time is 20 weeks and we recommend that clinically appropriate upper limits of waiting time are 6 weeks for routine studies and 1 week for urgent studies.
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            Impact of statin therapy on coronary plaque composition: a systematic review and meta-analysis of virtual histology intravascular ultrasound studies

            Background Virtual histology intravascular ultrasound (VH-IVUS) imaging is an innovative tool for the morphological evaluation of coronary atherosclerosis. Evidence for the effects of statin therapy on VH-IVUS parameters have been inconclusive. Consequently, we performed a systematic review and meta-analysis to investigate the impact of statin therapy on plaque volume and its composition using VH-IVUS. Methods The search included PubMed, Cochrane Library, Scopus and Embase (through 30 November 2014) to identify prospective studies investigating the effects of statin therapy on plaque volume and its composition using VH-IVUS. Results We identified nine studies with 16 statin treatment arms and 830 participants. There was a significant effect of statin therapy in reducing plaque volume (standardized mean difference (SMD): −0.137, 95 % confidence interval (CI): −0.255, −0.019; P = 0.023), external elastic membrane volume (SMD: −0.097, 95 % CI: −0.183, −0.011; P = 0.027) but not lumen volume (SMD: −0.025, 95 % CI: −0.110, +0.061; P = 0.574). There was a significant reduction in fibrous plaque volume (SMD: −0.129, 95 % CI: −0.255, −0.003; P = 0.045) and an increase of dense calcium volume (SMD: +0.229, 95 % CI: +0.008, +0.450; P = 0.043), while changes in fibro-fatty (SMD: −0.247, 95 % CI: −0.592, +0.098; P = 0.16) and necrotic core (SMD: +0.011, 95 % CI: −0.144, +0.165; P = 0.892) tissue volumes were not statistically significant. Conclusions This meta-analysis indicates a significant effect of statin therapy on plaque and external elastic membrane volumes and fibrous and dense calcium volumes. There was no effect on lumen volume, fibro-fatty and necrotic tissue volumes.
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              Hibernating myocardium: diagnosis and patient outcomes.

              Approximately 50% of the patients with chronic obstructive coronary artery disease resulting in chronic contractile dysfunction have hibernating myocardium and may benefit from revascularization. This pooled analysis describes the relative merits of dobutamine echocardiography, thallium-201 and technetium-99m scintigraphy, positron emission tomography, and magnetic resonance imaging, for the diagnosis of hibernating myocardium and prediction of patient outcomes.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                10 June 2016
                2016
                : 6
                : 27520
                Affiliations
                [1 ]Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine , Seoul, Republic of Korea
                [2 ]Smart Humanity Convergence Center, Program in Biomedical Radiation Sciences, Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University , Seoul, Republic of Korea
                [3 ]Center for Nanomolecular Imaging and Innovative Drug Development, Advanced Institutes of Convergence Technology , Suwon, Republic of Korea
                Author notes
                Article
                srep27520
                10.1038/srep27520
                4901298
                27283041
                ef560bb4-d586-4332-95c4-8ea74513c693
                Copyright © 2016, Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 19 November 2015
                : 20 May 2016
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