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Molecular Imaging of Atherosclerosis: a Clinical Focus

  • Molecular Imaging (J Wu and P Nguyen, Section Editors)
  • Published:
Current Cardiovascular Imaging Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Molecular imaging of cardiovascular disease is a powerful clinical and experimental approach that can inform our understanding of atherosclerosis biology. Complementing cross-sectional imaging techniques that provide detailed anatomical information, molecular imaging can further detect important biological changes occurring within atheroma and refine the prediction of vascular complications.

Recent Findings

Molecular imaging of atherosclerosis can illuminate underlying pathophysiology and serve as a surrogate endpoint in clinical trials of new drugs.

Summary

This review showcases promising molecular approaches for imaging atherosclerosis, with a focus on positron emission tomography (PET), magnetic resonance imaging (MRI), and intravascular near-infrared fluorescence (NIRF) imaging methods that are in the clinic or close-to-clinical usage.

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References

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  1. GBD 2013 Mortality and Causes of Death Collaborators, Naghavi M, Wang H, Lozano R, et al. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385:117–71.

    Article  Google Scholar 

  2. Chen W, Dilsizian V. PET assessment of vascular inflammation and atherosclerotic plaques: SUV or TBR? J Nucl Med. 2015;56:503–4.

    Article  CAS  PubMed  Google Scholar 

  3. Tarkin JM, Joshi FR, Rudd JH. PET imaging of inflammation in atherosclerosis. Nat Rev Cardiol. 2014;11:443–57.

    Article  CAS  PubMed  Google Scholar 

  4. Folco EJ, Sheikine Y, Rocha VZ, et al. Hypoxia but not inflammation augments glucose uptake in human macrophages: implications for imaging atherosclerosis with 18flourine-labeled 2-deoxy-D-glucose positron emission tomography. J Am Coll Cardiol. 2011;58:603–14.

    Article  CAS  PubMed  Google Scholar 

  5. Rudd JH, Warburton EA, Fryer TD, et al. Imaging atherosclerotic plaque inflammation with [18F]-fluorodeoxyglucose positron emission tomography. Circulation. 2002;105:2708–11.

    Article  CAS  PubMed  Google Scholar 

  6. Tawakol A, Migrino RQ, Bashian GG, et al. In vivo 18F-fluorodeoxyglucose positron emission tomography imaging provides a noninvasive measure of carotid plaque inflammation in patients. J Am Coll Cardiol. 2006;48:1818–24.

    Article  PubMed  Google Scholar 

  7. Taqueti VR, Di Carli MF, Jerosch-Herold M, et al. Increased microvascularisation and vessel permeability associate with active inflammation in human atheromata. Circ Cardiovasc Imaging. 2014;7:920–9.

    Article  PubMed  PubMed Central  Google Scholar 

  8. • Tawakol A, Singh P, Mojena M, et al. HIF-1alpha and PFKFB3 mediate a tight relationship between proinflammatory activation and anaerobic metabolism in atherosclerotic macrophages. Arterioscler Thromb Vasc Biol. 2015;35:1463–71. Findings in human, murine, and animal models verify that hypoxia potentiates macrophage glycolytic flux, with an upregulation of proinflammatory activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Moustafa RR, Izguierdo-Garcia D, Fryer TD, et al. Carotid plaque inflammation is associated with cerebral microembolism in patients with recent transient ischaemic attack or stroke: a pilot study. Circ Cardiovasc Imaging. 2010;3:536–41.

    Article  PubMed  Google Scholar 

  10. Marnane M, Merwick A, Sheehan OC, et al. Carotid plaque inflammation on 18F-fluorodeoxyglucose positron emission tomography predicts early stroke recurrence. Ann Neurol. 2012;71:709–18.

    Article  PubMed  Google Scholar 

  11. Rogers IS, Nasir K, Figueroa AL, et al. Feasibility of FDG imaging of the coronary arteries: comparison between acute coronary syndrome and stable angina. JACC Cardiovasc Imaging. 2010;3:388–97.

    Article  PubMed  Google Scholar 

  12. Abdelbaky A, Corsini E, Figueroa AL. Focal arterial inflammation precedes subsequent calcification in the same location: a longitudinal FDG-PET/CT study. Circ Cardiovasc Imaging; 2013: 747–754.

  13. Joseph P, Ishai A, Mani V, et al. Short-term changes in arterial inflammation predict long-term changes in atherosclerosis progression. Eur J Nucl Med Mol Imaging. 2016.

  14. Rominger A, Saam T, Wolpers S, et al. 18F-FDG PET/CT identifies patients at risk for future vascular events in an otherwise asymptomatic cohort with neoplastic disease. J Nucl Med. 2009;50:1611–20.

    Article  PubMed  Google Scholar 

  15. Figueroa AL, Abdelbaky A, Truong QA, et al. Measurements of arterial activity on routine FDG PET/CT images improves prediction of risk of future CV events. JACC Cardiovasc Imaging. 2013;6:1250–9.

    Article  PubMed  Google Scholar 

  16. Marnane M, Merwick A, Sheehan OC, et al. Carotid plaque inflammation on 18F-fluorodeoxyglucose positron emission tomography predicts early stroke recurrence. Ann Neurol. 2012;71:709–18.

    Article  PubMed  Google Scholar 

  17. Rudd JH, Myers KS, Bansilal S, et al. (18)Fluorodeoxyglucose positron emission tomography imaging of atherosclerotic plaque inflammation is highly reproducible: implications for atherosclerosis therapy trails. J Am Coll Cardiol. 2007;50:892–6.

    Article  PubMed  Google Scholar 

  18. Tahara N, Kai H, Ishibashi M, et al. Simvastatin attenuates plaque inflammation: evaluation by fluorodeoxyglucose positron emission tomography. J Am Coll Cardiol. 2006;48:1825–31.

    Article  CAS  PubMed  Google Scholar 

  19. Tawakol A, Fayad ZA, Mogg R, et al. Intensification of statin therapy results in a rapid reduction in atherosclerotic inflammation: results of a multicentre fluorodeoxyglucose-positron emission tomography/computed tomography feasibility study. J Am Coll Cardiol. 2013;62:909–17.

    Article  CAS  PubMed  Google Scholar 

  20. Cholesterol Treatment Trialists’ (CCT) Collaboration, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670–81.

    Article  Google Scholar 

  21. Mizoguchi M, Tahara N, Tahara A, et al. Pioglitazone attenuates atherosclerotic plaque inflammation in patients with impaired glucose tolerance or diabetes a prospective, randomized, comparator-controlled study using serial FDG PET/CT imaging study of carotid artery and ascending aorta. JACC Cardiovasc Imaging. 2011;4:1110–08.

    Article  PubMed  Google Scholar 

  22. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitazone Clinical Trial in macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279–89.

    Article  CAS  PubMed  Google Scholar 

  23. •• Fayad ZA, Mani V, Woodward M, et al. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. Lancet. 2011;378:1547–59. This landmark FDG PET/CT clinical study demonstrated that dalcetrapib did not reduce inflammation in human atheroma. The subsequent clinical outcomes study was neutral

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Schwartz GC, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367:2089–99.

    Article  CAS  PubMed  Google Scholar 

  25. Tawakol A, Singh P, Rudd JH, et al. Effect of treatment for 12 weeks with rilapladib, a lipoprotein-associated phospholipase A2 inhibitor, on arterial inflammation as assessed with 18F-fluorodeoxyglucose-positron emission tomography imaging. J Am Coll Cardiol. 2014;63:86–8.

    Article  CAS  PubMed  Google Scholar 

  26. Investigators STABILITY, White HD, Held C, et al. Darapladib for preventing ischemic events in stable coronary heart disease. N Engl J Med. 2014;370:1702–11.

    Article  Google Scholar 

  27. O’Donoghue ML, Braunwald E, White HD, et al. Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial. JAMA. 2014;312:1006–15.

    Article  PubMed  Google Scholar 

  28. Elkhawad M, Rudd JH, Sarov-Blat L, et al. Effects of p38 mitogen-activated protein kinase inhibition on vascular and systemic inflammation in patients with atherosclerosis. JACC Cardiovasc Imaging. 2012;5:911–22.

    Article  PubMed  Google Scholar 

  29. Emani H, Vucic E, Subramanian S, et al. The effect of BMS-582949, a p38 mitogen-activated protein kinase (p38 MAPK) inhibitor on arterial inflammation: a multicentre FDG-PET trial. Atherosclerosis. 2015;240:490–6.

    Article  Google Scholar 

  30. O’Donoghue ML, Glaser R, Cavender MA, et al. Effect of losmapimod on cardiovascular outcomes in patients hospitalized with acute myocardial infarction: a randomized clinical trial. JAMA. 2016;315:1591–9.

    Article  PubMed  Google Scholar 

  31. Sakalihasan N, Van Damme H, Gomez P, et al. Positron emission tomography (PET) evaluation of abdominal aortic aneurysm (AAA). Eur J Vasc Endovasc Surg. 2002;23:431–6.

    Article  CAS  PubMed  Google Scholar 

  32. Morel O, Mandry D, Micard E, Kauffmann C, Lamiral Z, Verger A, et al. Evidence of cyclic changes in the metabolism of abdominal aortic aneurysms during growth phases: a FDG-PET sequential observational study. J Nucl Med. 2015;19:114.

    Google Scholar 

  33. Rudd JH, Coughlin PA, Groves A. Predicting aortic aneurysm expansion by PET. J Nucl Med. 2015;23:115.

    Google Scholar 

  34. Stacy MR, Zhou W, Sinusas AJ. Radiotracer imaging of peripheral vascular disease. J Nucl Med. 2013;54:2104–10.

    CAS  PubMed  Google Scholar 

  35. Myers KS, Rudd JH, Haliman EP, et al. Correlation between arterial FDG uptake and biomarkers in peripheral artery disease. JACC Cardiovasc Imagining. 2012;5:38–45.

    Article  Google Scholar 

  36. Silvera SS, Aidi HE, Rudd JH, et al. Multimodality imaging of atherosclerotic plaque activity and composition using FDG-PET/CT and MRI in carotid and femoral plaques. Atherosclerosis. 2009;207:139–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Doherty TM, Asotra K, Fitzpatrick LA, et al. Calcification in atherosclerosis: bone biology and chronic inflammation at the arterial crossroads. Proc Natl Acad Sci U S A. 2003;100:11201–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Schenker MP, Dorbala S, Hong EC, et al. Interrelation of coronary calcification, myocardial ischemia, and outcomes in patients with intermediate likelihood of coronary artery disease: a combined positron emission tomography/computed tomography study. Circulation. 2008;117:1693–700.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Bos D, Leening MJ, Kavousi M, et al. Comparison of atherosclerotic in major vessel beds on the risk of all-cause and cause-specific mortality: The Rotterdam Study. Circ Cardiovasc Imaging. 2015;8:e003843.

    Article  PubMed  Google Scholar 

  40. Hawkins RA, Choi Y, Huang SC, et al. Evaluation of the skeletal kinetics of fluorine-18-fluoride ion with PET. J Nucl Med. 1992;33:633–42.

    CAS  PubMed  Google Scholar 

  41. Grant FD, Fahey FH, Packard AB, et al. Skeletal PET with 18F-fluoride: applying new technology to an old tracer. J Nucl Med. 2008;49:68–78.

    Article  PubMed  Google Scholar 

  42. Aikawa E, Nahrendrof M, Figueiredo JL, et al. Osteogenesis associates with inflammation in early-stage atherosclerosis evaluated by molecular imaging in-vivo. Circulation. 2007;116:2841–50.

    Article  CAS  PubMed  Google Scholar 

  43. Derlin T, Toth Z, Papp L, et al. Correlation of inflammation assessed by 18F-FDG PET, active mineral deposition assessed by 18F-fluoride PET, and vascular calcification in atherosclerotic plaque: a dual-tracer PET/CT study. J Nucl Med. 2011;52:1020–7.

    Article  PubMed  Google Scholar 

  44. Abdelbaky A, Corsini E, Figueroa AL, et al. Focal arterial inflammation precedes subsequent calcification in the same location: a longitudinal FDG-PET/CT study. Circ Cardiovasc Imaging. 2013;6:747–54.

    Article  PubMed  Google Scholar 

  45. Derlin T, Richter U, Bannas P, et al. Feasibility of 18F-sodium fluoride PET/CT for imaging of atherosclerotic plaque. J Nucl Med. 2010;51:862–5.

    Article  PubMed  Google Scholar 

  46. Dweck MR, Chow MM, Joshi NV, et al. Coronary arterial 18F-sodium fluoride uptake: a novel marker of plaque biology. J Am Coll Cardiol. 2012;59:1539–48.

    Article  CAS  PubMed  Google Scholar 

  47. •• Joshi NV, Vesey AT, Williams MC, et al. 18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: a prospective clinical trial. Lancet. 2014;383:705–13. 18 F-NaF PET can non-invasively identify and localize ruptured and high-risk coronary plaque compared to non-culprit areas (TBR 1.66 vs. 1.24, p < 0.001, respectively).

    Article  PubMed  Google Scholar 

  48. Fiz F, Morbelli S, Piccardo A, et al. 18F-NaF uptake by atherosclerotic plaque on PET/CT imaging: inverse correlation between calcification density and mineral metabolic activity. J Nucl Med. 2015;56:1019–23.

    Article  CAS  PubMed  Google Scholar 

  49. • Irkle A, Vesey AT, Lewis DY, et al. Identifying active vascular microcalcification by (18)F-sodium fluoride positron emission tomography. Nat Commun. 2015;6:7495. 18 F-NaF adsorbs to calcific deposits within plaque and has a high affinity, being both selective and specific, and can distinguish between macro- and microcalcification.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Rominger A, Saam T, Vogl E, et al. In vivo imaging of macrophage activity in the coronary arteries using 68Ga-DOTATATE PET/CT: correlation with coronary calcium burden and risk factors. J Nucl Med. 2010;51:193–7.

    Article  PubMed  Google Scholar 

  51. Li X, Samnick S, Lapa C, et al. 68Ga-DOTATATE PET/CT for the detection of inflammation of large arteries: correlation with 18F-FDG, calcium burden and risk factors. EJNMMI Res. 2012;2:52.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Pederson SF, Sandholt BV, Keller SH, et al. 64Cu-DOTATATE PET/MRI for detection of activated macrophages in carotid atherosclerotic plaques: studies in patients undergoing endarterectomy. Arterioscler Thromb Vasc Biol. 2015;35:1696–703.

    Article  Google Scholar 

  53. Malmberg C, Ripa RS, Johnbeck CB, et al. 64Cu-DOTATATE for noninvasive assessment of atherosclerosis in large arteries and its correlation with risk factors: head-to-head comparison with 68Ga-DOTATOC in 60 patients. J Nucl Med. 2015;56:1895–900.

    Article  CAS  PubMed  Google Scholar 

  54. Jl B, Izquierdo-Garcia D, Davies JR, et al. Evaluation of translocator protein quantification as a tool for characterising macrophage burden in human carotid atherosclerosis. Atherosclerosis. 2010;210:388–91.

    Article  Google Scholar 

  55. Gaemperli O, Shalhoub J, Owen DR, et al. Imaging intraplaque inflammation in carotid atherosclerosis with 11C-PK11195 positron emission tomography/computed tomography. Eur Heart J. 2010;33:1902–10.

    Article  Google Scholar 

  56. Tahara N, Mukherjee J, de Haas HJ, et al. 2-Deoxy-2-[18F]fluoro-D-mannose positron emission tomography imaging in atherosclerosis. Nat Med. 2014;20:215–9.

    Article  CAS  PubMed  Google Scholar 

  57. Kooi ME, Cappendjik VC, Cleutjens KB, et al. Accumulation of ultrasmall superparamagnetic particles of iron oxide in human atherosclerotic plaques can be detected by in vivo magnetic resonance imaging. Circulation. 2003;107:2453–8.

    Article  CAS  PubMed  Google Scholar 

  58. Tang TY, Howart SP, Miller SR, et al. The ATHEROMA (Atorvastatin Therapy: Effects on Reduction of Macrophage Activity) Study. Evaluation using ultrasmall superparamagnetic iron oxide enhanced magnetic resonance imaging in carotid disease. J Am Coll Cardiol. 2009;53:2039–50.

    Article  CAS  PubMed  Google Scholar 

  59. Alam SR, Shah AS, Ricahrds J, et al. Ultrasmall superparamagnetic particles of iron oxide in patients with acute myocardial infarction: early clinical experience. Circ Cardiovasc Imaging. 2012;5:559–65.

    Article  PubMed  Google Scholar 

  60. McBride OM, Joshi NV, Robson JM, et al. Positron emission tomography and magnetic resonance imaging of cellular inflammation in patients with abdominal aortic aneurysms. Eur J Vasc Endovasc Surg. 2016;51:518–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Mulder WJ, Jaffer FA, Fayad ZA, et al. Imaging and nanomedicine in inflammatory atherosclerosis. Sci Transl Med. 2014;6:239sr1.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Jaffer FA, Verjans JW. Molecular imaging of atherosclerosis: clinical state-of-the-art. Heart. 2014;100:1469–77.

    Article  PubMed  Google Scholar 

  63. Bourantas CV, Jaffer FA, Gijsen FJ, et al. Hybrid intravascular imaging: recent advances, technical considerations, and current applications in the study of plaque pathophysiology. Eur Heart J. 26 Apr 2016. [Epub ahead of print].

  64. • Ughi GJ, Wang H, Gerbaud E, et al. Clinical characterisation of coronary atherosclerosis with dual-modality OCT and near infrared autofluorescence imaging. JACC Cardiovasc Imaging. Nov 2016;9(11):1304–1314. First-in-human study of intravascular OCT and near-infrared fluorescence imaging of coronary atherosclerosis.

  65. Jaffer FA, Vinegoni C, John MC, et al. Real-time catheter molecular sensing of inflammation in proteolytically active atherosclerosis. Circulation. 2008;118:1802–9.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Jaffer FA, Calfon MA, Rosenthal A, et al. Two-dimensional intravascular near-infrared fluorescence molecular imaging of inflammation in atherosclerosis and stent-induced vascular injury. J Am Coll Cardiol. 2011;57:2516–26.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Khamis RY, Wollard KJ, Hyde GD, et al. Near infrared fluorescence (NIRF) molecular imaging of oxidized LDL with an autoantibody in experimental atherosclerosis. Sci Rep. 2016;26:21785.

    Article  Google Scholar 

  68. Vinegoni C, Botnaru I, Aikawa E, et al. Indocyanine green enables near-infrared fluorescence imaging of lipid-rich, inflamed atherosclerotic plaques. Sci Transl Med. 2011;3:84ra45.

    Article  PubMed  PubMed Central  Google Scholar 

  69. • Verjans JW, Osborn EA, Ughi GJ, et al. Targeted near-infrared fluorescence imaging of atherosclerosis: clinical and intracoronary evaluation of indocyanine green. JACC Cardiovasc Imaging. Sep 2016;9(9):1087–95. Subsequent clinical study of indocyanine green NIRF imaging demonstrated that ICG targets human plaques in areas of impaired endothelial barrier function. ICG may accelerate first-in-human intravascular NIRF molecular imaging studies.

  70. • Yoo H, Kim JW, Shishkov M, et al. Intra-arterial catheter for simultaneous microstructural and molecular imaging in vivo. Nat Med. 2011;17:1680–4. First combined intravascular molecular-structural imaging system, using NIRF-OCT.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Hara T, Ughi GJ, McCarthy JR, et al. Intravascular fibrin molecular imaging improves the detection of unhealed stents assessed by optical coherence tomography in vivo. Eur Heart J. 18 Dec 2015. [Epub ahead of print].

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Authors and Affiliations

  1. Division of Vascular & Endovascular Surgery, Department of Surgery, University of Cambridge and Cambridge University Hospitals, Cambridge, UK

    Mohammed M. Chowdhury

  2. Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Ahmed Tawakol & Farouc A. Jaffer

  3. Cardiology Division, MGH Cardiovascular Research Center, 185 Cambridge Street, Simches 3206, Boston, MA, USA

    Farouc A. Jaffer

Authors
  1. Mohammed M. Chowdhury
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  2. Ahmed Tawakol
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  3. Farouc A. Jaffer
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Corresponding author

Correspondence to Farouc A. Jaffer.

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Conflict of Interest

A.T. reports grants and personal fees from Takeda, grants and personal fees from Actelion, grants from Genetech, and personal fees from Astra Zeneca, outside the submitted work.

F.A.J. reports grants from Canon, grants from Siemens, personal fees from Abbott Vascular, and personal fees from Boston Scientific, outside the submitted work. In addition, F.A.J. has a patent for Intravascular NIRF imaging with royalties paid to Canon.

M.M.C. declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Disclosures

F.A.J. has received research funding from Siemens and Canon, and has a consulting agreement with Boston Scientific and Abbott Vascular. Massachusetts General Hospital has a patent licensing arrangement with Canon Corporation. F.A.J. has the right to receive licensing royalties through this licensing arrangement. A.T. has received research funding from Actelion, Genetech, and Takeda, and has a consulting agreement with Actelion.

Support Sources

M.M.C. is supported by the Royal College of Surgeons of England Fellowship Programme and British Heart Foundation Research Fellowship award FS/16/29/31957. F.A.J. is supported by NIH R01HL122388 and the MGH Hassenfeld Research Scholar Fund. A.T. is supported by NIH R01HL122177.

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This article is part of the Topical Collection on Molecular Imaging

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Chowdhury, M.M., Tawakol, A. & Jaffer, F.A. Molecular Imaging of Atherosclerosis: a Clinical Focus. Curr Cardiovasc Imaging Rep 10, 2 (2017). https://doi.org/10.1007/s12410-017-9397-1

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