{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T23:14:51Z","timestamp":1774307691208,"version":"3.50.1"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,6,10]],"date-time":"2016-06-10T00:00:00Z","timestamp":1465516800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,6,10]],"date-time":"2016-06-10T00:00:00Z","timestamp":1465516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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 \u03b1<jats:sub>v<\/jats:sub>\u03b2<jats:sub>3<\/jats:sub>. Here, we describe the capability of an \u03b1<jats:sub>v<\/jats:sub>\u03b2<jats:sub>3<\/jats:sub> integrin-targeting SPECT agent, <jats:sup>99m<\/jats:sup>Tc-IDA-D-[c(RGDfK)]<jats:sub>2<\/jats:sub>, 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. <jats:italic>In vivo<\/jats:italic> SPECT imaging of rat models with transient coronary occlusion showed significantly high uptake of <jats:sup>99m<\/jats:sup>Tc-IDA-D-[c(RGDfK)]<jats:sub>2<\/jats:sub> in the ischemic region. Comparative measurements with <jats:sup>201<\/jats:sup>Tl SPECT and <jats:sup>18<\/jats:sup>F-FDG PET, then, proved that such prominent uptake of <jats:sup>99m<\/jats:sup>Tc-IDA-D-[c(RGDfK)]<jats:sub>2<\/jats:sub> exactly matched the hallmark of hibernation, i.e., the perfusion-metabolism mismatch pattern. The uptake of <jats:sup>99m<\/jats:sup>Tc-IDA-D-[c(RGDfK)]<jats:sub>2<\/jats:sub> was non-inferior to that of <jats:sup>18<\/jats:sup>F-FDG, confirmed by time-course variation analysis. Immunohistochemical characterization revealed that an intense signal of <jats:sup>99m<\/jats:sup>Tc-IDA-D-[c(RGDfK)]<jats:sub>2<\/jats:sub> corresponded to the vibrant angiogenic events with elevated expression of \u03b1<jats:sub>v<\/jats:sub>\u03b2<jats:sub>3<\/jats:sub> integrin. Together, these results establish that <jats:sup>99m<\/jats:sup>Tc-IDA-D-[c(RGDfK)]<jats:sub>2<\/jats:sub> SPECT can serve as a sensitive clinical measure for myocardial salvage to identify the patients who might benefit most from revascularization.<\/jats:p>","DOI":"10.1038\/srep27520","type":"journal-article","created":{"date-parts":[[2016,6,10]],"date-time":"2016-06-10T09:36:06Z","timestamp":1465551366000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Identification of Angiogenesis Rich-Viable Myocardium using RGD Dimer based SPECT after Myocardial Infarction"],"prefix":"10.1038","volume":"6","author":[{"given":"Min Su","family":"Lee","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyun Soo","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Byung Chul","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jae Ho","family":"Jung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jung Sun","family":"Yoo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sang Eun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,6,10]]},"reference":[{"key":"BFsrep27520_CR1","doi-asserted-by":"crossref","first-page":"e29","DOI":"10.1161\/circ.131.suppl_2.o29","volume":"131","author":"D Mozaffarian","year":"2015","unstructured":"Mozaffarian, D. et al. Heart disease and stroke statistics\u20132015 update: a report from the American Heart Association. Circulation 131, e29\u2013322 (2015).","journal-title":"Circulation"},{"key":"BFsrep27520_CR2","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1007\/s00259-003-1344-5","volume":"31","author":"SR Underwood","year":"2004","unstructured":"Underwood, S. R. et al. Myocardial perfusion scintigraphy: the evidence. Eur J Nucl Med Mol Imaging 31, 261\u2013291 (2004).","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"BFsrep27520_CR3","doi-asserted-by":"publisher","first-page":"CR140","DOI":"10.12659\/MSM.881447","volume":"17","author":"YJ Akashi","year":"2011","unstructured":"Akashi, Y. J. et al. Significance of 99mTc-sestamibi myocardial scintigraphy after percutaneous coronary intervention in patients with acute myocardial infarction. Med Sci Monit 17, CR140\u2013145 (2011).","journal-title":"Med Sci Monit"},{"key":"BFsrep27520_CR4","doi-asserted-by":"publisher","first-page":"2984","DOI":"10.1093\/eurheartj\/ehq361","volume":"31","author":"N Ghosh","year":"2010","unstructured":"Ghosh, N., Rimoldi, O. E., Beanlands, R. S. & Camici, P. G. Assessment of myocardial ischaemia and viability: role of positron emission tomography. Eur Heart J 31, 2984\u20132995 (2010).","journal-title":"Eur Heart J"},{"key":"BFsrep27520_CR5","unstructured":"Lin, Y. D. et al. Instructive nanofiber scaffolds with VEGF create a microenvironment for arteriogenesis and cardiac repair. Sci Transl Med 4, 146ra109, 110.1126\/scitranslmed.3003841 (2012)."},{"key":"BFsrep27520_CR6","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1146\/annurev.pathol.2.010506.092038","volume":"2","author":"MA Laflamme","year":"2007","unstructured":"Laflamme, M. A., Zbinden, S., Epstein, S. E. & Murry, C. E. Cell-based therapy for myocardial ischemia and infarction: pathophysiological mechanisms. Annu Rev Pathol 2, 307\u2013339 (2007).","journal-title":"Annu Rev Pathol"},{"key":"BFsrep27520_CR7","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1038\/nrd1226","volume":"2","author":"M Simons","year":"2003","unstructured":"Simons, M. & Ware, J. A. Therapeutic angiogenesis in cardiovascular disease. Nat Rev Drug Discov 2, 863\u2013871 (2003).","journal-title":"Nat Rev Drug Discov"},{"key":"BFsrep27520_CR8","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1161\/CIRCIMAGING.108.839092","volume":"2","author":"M Nahrendorf","year":"2009","unstructured":"Nahrendorf, M. et al. Multimodality cardiovascular molecular imaging, Part II. Circ Cardiovasc Imaging 2, 56\u201370 (2009).","journal-title":"Circ Cardiovasc Imaging"},{"key":"BFsrep27520_CR9","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1038\/nrcardio.2009.201","volume":"7","author":"LW Dobrucki","year":"2010","unstructured":"Dobrucki, L. W. & Sinusas, A. J. PET and SPECT in cardiovascular molecular imaging. Nat Rev Cardiol 7, 38\u201347 (2010).","journal-title":"Nat Rev Cardiol"},{"key":"BFsrep27520_CR10","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1093\/cvr\/cvn033","volume":"78","author":"T Higuchi","year":"2008","unstructured":"Higuchi, T. et al. Assessment of alphavbeta3 integrin expression after myocardial infarction by positron emission tomography. Cardiovasc Res 78, 395\u2013403 (2008).","journal-title":"Cardiovasc Res"},{"key":"BFsrep27520_CR11","doi-asserted-by":"publisher","first-page":"1684","DOI":"10.1172\/JCI200420352","volume":"113","author":"DF Meoli","year":"2004","unstructured":"Meoli, D. F. et al. Noninvasive imaging of myocardial angiogenesis following experimental myocardial infarction. J Clin Invest 113, 1684\u20131691 (2004).","journal-title":"J Clin Invest"},{"key":"BFsrep27520_CR12","doi-asserted-by":"publisher","first-page":"2017","DOI":"10.1016\/j.jacc.2008.07.067","volume":"52","author":"SW van den Borne","year":"2008","unstructured":"van den Borne, S. W. et al. Molecular imaging of interstitial alterations in remodeling myocardium after myocardial infarction. J Am Coll Cardiol 52, 2017\u20132028 (2008).","journal-title":"J Am Coll Cardiol"},{"key":"BFsrep27520_CR13","doi-asserted-by":"publisher","first-page":"318","DOI":"10.2967\/jnumed.111.091652","volume":"53","author":"HM Sherif","year":"2012","unstructured":"Sherif, H. M. et al. Molecular imaging of early alphavbeta3 integrin expression predicts long-term left-ventricle remodeling after myocardial infarction in rats. J Nucl Med 53, 318\u2013323 (2012).","journal-title":"J Nucl Med"},{"key":"BFsrep27520_CR14","doi-asserted-by":"publisher","first-page":"2201","DOI":"10.1093\/eurheartj\/ehn129","volume":"29","author":"MR Makowski","year":"2008","unstructured":"Makowski, M. R., Ebersberger, U., Nekolla, S. & Schwaiger, M. In vivo molecular imaging of angiogenesis, targeting alphavbeta3 integrin expression, in a patient after acute myocardial infarction. Eur Heart J 29, 2201 (2008).","journal-title":"Eur Heart J"},{"key":"BFsrep27520_CR15","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1016\/j.jcmg.2008.05.002","volume":"1","author":"LL Johnson","year":"2008","unstructured":"Johnson, L. L. et al. Radiolabeled arginine-glycine-aspartic acid peptides to image angiogenesis in swine model of hibernating myocardium. JACC Cardiovasc Imaging 1, 500\u2013510 (2008).","journal-title":"JACC Cardiovasc Imaging"},{"key":"BFsrep27520_CR16","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1007\/s12350-010-9191-9","volume":"17","author":"J Dimastromatteo","year":"2010","unstructured":"Dimastromatteo, J. et al. In vivo molecular imaging of myocardial angiogenesis using the alpha(v)beta3 integrin-targeted tracer 99mTc-RAFT-RGD. J Nucl Cardiol 17, 435\u2013443 (2010).","journal-title":"J Nucl Cardiol"},{"key":"BFsrep27520_CR17","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1007\/s00259-013-2432-9","volume":"40","author":"L Menichetti","year":"2013","unstructured":"Menichetti, L. et al. MicroPET\/CT imaging of alphavbeta(3) integrin via a novel (6)(8)Ga-NOTA-RGD peptidomimetic conjugate in rat myocardial infarction. Eur J Nucl Med Mol Imaging 40, 1265\u20131274 (2013).","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"BFsrep27520_CR18","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1097\/MCA.0b013e3283608c32","volume":"24","author":"JS Eo","year":"2013","unstructured":"Eo, J. S. et al. Angiogenesis imaging in myocardial infarction using 68Ga-NOTA-RGD PET: characterization and application to therapeutic efficacy monitoring in rats. Coron Artery Dis 24, 303\u2013311 (2013).","journal-title":"Coron Artery Dis"},{"key":"BFsrep27520_CR19","doi-asserted-by":"publisher","first-page":"683","DOI":"10.1007\/s00259-011-2052-1","volume":"39","author":"H Gao","year":"2012","unstructured":"Gao, H. et al. PET imaging of angiogenesis after myocardial infarction\/reperfusion using a one-step labeled integrin-targeted tracer 18F-AlF-NOTA-PRGD2. Eur J Nucl Med Mol Imaging 39, 683\u2013692 (2012).","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"BFsrep27520_CR20","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1186\/2191-219X-3-38","volume":"3","author":"I Laitinen","year":"2013","unstructured":"Laitinen, I. et al. Comparison of cyclic RGD peptides for alphavbeta3 integrin detection in a rat model of myocardial infarction. EJNMMI Res 3, 38 (2013).","journal-title":"EJNMMI Res"},{"key":"BFsrep27520_CR21","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1039\/C2RA22460G","volume":"3","author":"BC Lee","year":"2013","unstructured":"Lee, B. C. et al. Synthesis and biological evaluation of RGD peptides with the Tc-99m\/Re-188 chelated iminodiacetate core: highly enhanced uptake and excretion kinetics of theranostics against tumor angiogenesis. RSC Adv 3, 782\u2013792 (2013).","journal-title":"RSC Adv"},{"key":"BFsrep27520_CR22","doi-asserted-by":"publisher","first-page":"11752","DOI":"10.1038\/srep11752","volume":"5","author":"J Sun Yoo","year":"2015","unstructured":"Sun Yoo, J. et al. SPECT\/CT Imaging of High-Risk Atherosclerotic Plaques using Integrin-Binding RGD Dimer Peptides. Sci Rep 5, 11752 (2015).","journal-title":"Sci Rep"},{"key":"BFsrep27520_CR23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s12350-008-9037-x","volume":"16","author":"PL Tilkemeier","year":"2009","unstructured":"Tilkemeier, P. L. et al. Standardized reporting of radionuclide myocardial perfusion and function. J Nucl Cardiol 16, 1 (2009).","journal-title":"J Nucl Cardiol"},{"key":"BFsrep27520_CR24","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s12350-009-9094-9","volume":"16","author":"V Dilsizian","year":"2009","unstructured":"Dilsizian, V. et al. PET myocardial perfusion and metabolism clinical imaging. J Nucl Cardiol 16, 1 (2009).","journal-title":"J Nucl Cardiol"},{"key":"BFsrep27520_CR25","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1016\/j.cpcardiol.2007.04.001","volume":"32","author":"AF Schinkel","year":"2007","unstructured":"Schinkel, A. F. et al. Hibernating myocardium: diagnosis and patient outcomes. Curr Probl Cardiol 32, 375\u2013410 (2007).","journal-title":"Curr Probl Cardiol"},{"key":"BFsrep27520_CR26","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nrcardio.2014.137","volume":"11","author":"V Fuster","year":"2014","unstructured":"Fuster, V. Top 10 cardiovascular therapies and interventions for the next decade. Nat Rev Cardiol 11, 671\u2013683 (2014).","journal-title":"Nat Rev Cardiol"},{"key":"BFsrep27520_CR27","doi-asserted-by":"publisher","first-page":"122","DOI":"10.5114\/aoms.2015.49205","volume":"11","author":"M Podgorski","year":"2015","unstructured":"Podgorski, M. et al. Peripheral vascular stiffness, assessed with two-dimensional speckle tracking versus the degree of coronary artery calcification, evaluated by tomographic coronary artery calcification index. Arch Med Sci 11, 122\u2013129 (2015).","journal-title":"Arch Med Sci"},{"key":"BFsrep27520_CR28","doi-asserted-by":"publisher","first-page":"428","DOI":"10.5114\/aoms.2011.23407","volume":"7","author":"K Koyama","year":"2011","unstructured":"Koyama, K. et al. Relevance of I-BMIPP delayed scintigraphic imaging for patients with angina pectoris - a pilot study. Arch Med Sci 7, 428\u2013432 (2011).","journal-title":"Arch Med Sci"},{"key":"BFsrep27520_CR29","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1186\/s12916-015-0459-4","volume":"13","author":"M Banach","year":"2015","unstructured":"Banach, M. et al. Impact of statin therapy on coronary plaque composition: a systematic review and meta-analysis of virtual histology intravascular ultrasound studies. BMC Med 13, 229 (2015).","journal-title":"BMC Med"},{"key":"BFsrep27520_CR30","doi-asserted-by":"publisher","first-page":"1359","DOI":"10.1161\/01.CIR.0000061911.47710.8A","volume":"107","author":"TD Henry","year":"2003","unstructured":"Henry, T. D. et al. The VIVA trial: Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis. Circulation 107, 1359\u20131365 (2003).","journal-title":"Circulation"},{"key":"BFsrep27520_CR31","doi-asserted-by":"publisher","first-page":"1015","DOI":"10.1016\/j.jacc.2006.09.053","volume":"49","author":"S Yla-Herttuala","year":"2007","unstructured":"Yla-Herttuala, S., Rissanen, T. T., Vajanto, I. & Hartikainen, J. Vascular endothelial growth factors: biology and current status of clinical applications in cardiovascular medicine. J Am Coll Cardiol 49, 1015\u20131026 (2007).","journal-title":"J Am Coll Cardiol"},{"key":"BFsrep27520_CR32","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.jcmg.2013.12.003","volume":"7","author":"AJ Beer","year":"2014","unstructured":"Beer, A. J. et al. PET\/CT imaging of integrin alphavbeta3 expression in human carotid atherosclerosis. JACC Cardiovasc Imaging 7, 178\u2013187 (2014).","journal-title":"JACC Cardiovasc Imaging"},{"key":"BFsrep27520_CR33","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1161\/CIRCRESAHA.111.243162","volume":"110","author":"NG Frangogiannis","year":"2012","unstructured":"Frangogiannis, N. G. Regulation of the inflammatory response in cardiac repair. Circ Res 110, 159\u2013173 (2012).","journal-title":"Circ Res"},{"key":"BFsrep27520_CR34","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1038\/nrcardio.2009.199","volume":"7","author":"SW van den Borne","year":"2010","unstructured":"van den Borne, S. W. et al. Myocardial remodeling after infarction: the role of myofibroblasts. Nat Rev Cardiol 7, 30\u201337 (2010).","journal-title":"Nat Rev Cardiol"},{"key":"BFsrep27520_CR35","first-page":"288","volume":"48","author":"T Higuchi","year":"2007","unstructured":"Higuchi, T. et al. Characterization of normal and infarcted rat myocardium using a combination of small-animal PET and clinical MRI. J Nucl Med 48, 288\u2013294 (2007).","journal-title":"J Nucl Med"},{"key":"BFsrep27520_CR36","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/j.ccl.2008.12.003","volume":"27","author":"L Lalonde","year":"2009","unstructured":"Lalonde, L., Ziadi, M. C. & Beanlands, R. Cardiac positron emission tomography: current clinical practice. Cardiol Clin 27, 237\u2013255, Table of Contents (2009).","journal-title":"Cardiol Clin"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep27520.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep27520","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep27520.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T05:26:34Z","timestamp":1672896394000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep27520"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,6,10]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,6,20]]}},"alternative-id":["BFsrep27520"],"URL":"https:\/\/doi.org\/10.1038\/srep27520","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,6,10]]},"assertion":[{"value":"19 November 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 May 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 June 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"27520"}}