Abstract
Cardiovascular disease is the global leading cause of death. One route to address this problem is using biomedical imaging to measure the molecules and structures that surround cardiac cells. This cellular microenvironment, known as the cardiac extracellular matrix, changes in composition and organization during most cardiac diseases and in response to many cardiac treatments. Measuring these changes with biomedical imaging can aid in understanding, diagnosing, and treating heart disease. This chapter supports those efforts by reviewing representative methods for imaging the cardiac extracellular matrix. It first describes the major biological targets of ECM imaging, including the primary imaging target of fibrillar collagen. Then it discusses the imaging methods, describing their current capabilities and limitations. It categorizes the imaging methods into two main categories: organ-scale noninvasive methods and cellular-scale invasive methods. Noninvasive methods can be used on patients, but only a few are clinically available, and others require further development to be used in the clinic. Invasive methods are the most established and can measure a variety of properties, but they cannot be used on live patients. Finally, the chapter concludes with a perspective on future directions and applications of biomedical imaging technologies.
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References
Abe M, Takahashi M, Horiuchi K, Nagano A. The changes in crosslink contents in tissues after formalin fixation. Anal Biochem. 2003;318:118–23. https://doi.org/10.1016/S0003-2697(03)00194-5
Aelst LNLV, Voss S, Carai P, Leeuwen RV, Vanhoutte D, Wijk SS, Eurlings L, Swinnen M, Verheyen FK, Verbeken E, Nef H, Troidl C, Cook SA, Rocca H-PB-L, Möllmann H, Papageorgiou A-P, Heymans S. Osteoglycin Prevents Cardiac Dilatation and Dysfunction After Myocardial Infarction Through Infarct Collagen StrengtheningNovelty and Significance. Circ Res. 2015;116:425–36. https://doi.org/10.1161/CIRCRESAHA.116.304599
Al-Janabi S, Huisman A, Van Diest PJ. Digital pathology: current status and future perspectives. Histopathology. 2012;61:1–9. https://doi.org/10.1111/j.1365-2559.2011.03814.x
Bao H, Boussioutas A, Jeremy R, Russell S, Gu M. Second harmonic generation imaging via nonlinear endomicroscopy. Opt Express. 2010;18:1255. https://doi.org/10.1364/OE.18.001255
Bashey RI, Martinez-Hernandez A, Jimenez SA. Isolation, characterization, and localization of cardiac collagen type VI Associations with other extracellular matrix components. Circ Res. 1992;70:1006–17.
Becker W. Fluorescence lifetime imaging – techniques and applications. J Microsc. 2012;247:119–36. https://doi.org/10.1111/j.1365-2818.2012.03618.x
Bull S, White SK, Piechnik SK, Flett AS, Ferreira VM, Loudon M, Francis JM, Karamitsos TD, Prendergast BD, Robson MD, Neubauer S, Moon JC, Myerson SG. Human non-contrast T1 values and correlation with histology in diffuse fibrosis. Heart. 2013;99:932–7. https://doi.org/10.1136/heartjnl-2012-303052
Büttner P, Galli R, Jannasch A, Schnabel C, Waldow T, Koch E. Heart valve stenosis in laser spotlights: Insights into a complex disease. Clin Hemorheol Microcirc. 2014;58:65–75. https://doi.org/10.3233/CH-141882
Campagnola P. Second harmonic generation imaging microscopy: applications to diseases diagnostics. Anal Chem. 2011;83:3224–31. https://doi.org/10.1021/ac1032325
Caorsi V, Toepfer C, Sikkel MB, Lyon AR, MacLeod K, Ferenczi MA. Non-Linear Optical Microscopy Sheds Light on Cardiovascular Disease. PLoS One. 2013;8:e56136. https://doi.org/10.1371/journal.pone.0056136
Chan JKC. The Wonderful Colors of the Hematoxylin–Eosin Stain in Diagnostic Surgical Pathology. Int J Surg Pathol. 2014;22:12–32. https://doi.org/10.1177/1066896913517939
Chatterjee S. Artefacts in histopathology. J Oral Maxillofac Pathol JOMFP. 2014;18:S111–6. https://doi.org/10.4103/0973-029X.141346
Dave JK, Mc Donald ME, Mehrotra P, Kohut AR, Eisenbrey JR, Forsberg F. Recent technological advancements in cardiac ultrasound imaging. Ultrasonics. 2018;84:329–40. https://doi.org/10.1016/j.ultras.2017.11.013
Désogère P, Tapias LF, Rietz TA, Rotile N, Blasi F, Day H, Elliot J, Fuchs BC, Lanuti M, Caravan P. Optimization of a collagen-targeted positron emission tomography probe for molecular imaging of pulmonary fibrosis. J Nucl Med jnumed. 2017;117:193532. https://doi.org/10.2967/jnumed.117.193532
Drobizhev M, Makarov NS, Tillo SE, Hughes TE, Rebane A. Two-photon absorption properties of fluorescent proteins. Nat Methods. 2011;8:393–9. https://doi.org/10.1038/nmeth.1596
Echegaray K, Andreu I, Lazkano A, Villanueva I, Sáenz A, Elizalde MR, EcheverrÃa T, López B, Garro A, González A, Zubillaga E, Solla I, Sanz I, González J, Elósegui-Artola A, Roca-Cusachs P, DÃez J, Ravassa S, Querejeta R. Role of Myocardial Collagen in Severe Aortic Stenosis With Preserved Ejection Fraction and Symptoms of Heart Failure. Rev Esp Cardiol Engl Ed. 2017;70:832–40. https://doi.org/10.1016/j.rec.2016.12.038
Eghiaian F, Rico F, Colom A, Casuso I, Scheuring S. High-speed atomic force microscopy: Imaging and force spectroscopy. FEBS Lett. 2014;588:3631–8. https://doi.org/10.1016/j.febslet.2014.06.028
Fernandez-Leiro R, Scheres SH. Unravelling biological macromolecules with cryo-electron microscopy., Unravelling the structures of biological macromolecules by cryo-EM. Nature. 2016;537:339–46. https://doi.org/10.1038/nature19948. https://doi.org/10.1038/nature19948.
Fornasiero EF, Opazo F. Super-resolution imaging for cell biologists. Bioessays. 2015;37:436–51. https://doi.org/10.1002/bies.201400170
Frangogiannis NG. The extracellular matrix in myocardial injury, repair, and remodeling. J Clin Invest. 2017;127:1600–12. https://doi.org/10.1172/JCI87491
Galetta F, Franzoni F, Bernini G, Poupak F, Carpi A, Cini G, Tocchini L, Antonelli A, Santoro G. Cardiovascular complications in patients with pheochromocytoma: A mini-review. Biomed Pharmacother. 2010;64:505–9. https://doi.org/10.1016/j.biopha.2009.09.014
Gao L, Kupfer ME, Jung JP, Yang L, Zhang P, Da Sie Y, Tran Q, Ajeti V, Freeman BT, Fast VG, Campagnola PJ, Ogle BM, Zhang J. Myocardial Tissue Engineering With Cells Derived From Human-Induced Pluripotent Stem Cells and a Native-Like, High-Resolution, 3-Dimensionally Printed Scaffold. Circ Res. 2017;120:1318–25. https://doi.org/10.1161/CIRCRESAHA.116.310277
Goergen CJ, Chen HH, Sakadžić S, Srinivasan VJ, Sosnovik DE. Microstructural characterization of myocardial infarction with optical coherence tractography and two-photon microscopy. Physiol Rep. 2016;4:e12894. https://doi.org/10.14814/phy2.12894
Gyöngyösi M, Winkler J, Ramos I, Do Q-T, Firat H, McDonald K, González A, Thum T, DÃez J, Jaisser F, Pizard A, Zannad F. Myocardial fibrosis: biomedical research from bench to bedside. Eur J Heart Fail. 2017;19:177–91. https://doi.org/10.1002/ejhf.696
de Haas HJ, Arbustini E, Fuster V, Kramer CM, Narula J. Molecular Imaging of the Cardiac Extracellular Matrix. Circ Res. 2014;114:903–15. https://doi.org/10.1161/CIRCRESAHA.113.302680
Hanson KP, Jung JP, Tran QA, Hsu S-PP, Iida R, Ajeti V, Campagnola PJ, Eliceiri KW, Squirrell JM, Lyons GE, Ogle BM. Spatial and Temporal Analysis of Extracellular Matrix Proteins in the Developing Murine Heart: A Blueprint for Regeneration. Tissue Eng Part A. 2013;19:1132–43. https://doi.org/10.1089/ten.tea.2012.0316
Hurle JM, Kitten GT, Sakai LY, Volpin D, Solursh M. Elastic extracellular matrix of the embryonic chick heart: an immunohistological study using laser confocal microscopy. Dev Dyn. 1994;200:321–32. https://doi.org/10.1002/aja.1002000407
Hutson HN, Marohl T, Anderson M, Eliceiri K, Campagnola P, Masters KS. Calcific Aortic Valve Disease Is Associated with Layer-Specific Alterations in Collagen Architecture. PLoS One. 2016;11:e0163858. https://doi.org/10.1371/journal.pone.0163858
Icardo JM. Collagen and elastin histochemistry of the teleost bulbus arteriosus: False positives. Acta Histochem. 2013;115:185–9. https://doi.org/10.1016/j.acthis.2012.03.002
Jo JA, Park J, Pande P, Shrestha S, Serafino MJ, Jimenez Jde J R, Clubb F, Walton B, Buja LM, Phipps JE, Feldman MD, Adame J, Applegate BE. Simultaneous morphological and biochemical endogenous optical imaging of atherosclerosis. Eur Heart J Cardiovasc Imaging. 2015;16:910–8. https://doi.org/10.1093/ehjci/jev018
Jung JP, Sprangers AJ, Byce JR, Su J, Squirrell JM, Messersmith PB, Eliceiri KW, Ogle BM. ECM-incorporated hydrogels cross-linked via native chemical ligation to engineer stem cell microenvironments. Biomacromolecules. 2013;14:3102–11. https://doi.org/10.1021/bm400728e
Khan Z, Boughner DR, Lacefield JC. Anisotropy of High-Frequency Integrated Backscatter from Aortic Valve Cusps. Ultrasound Med Biol. 2008;34:1504–12. https://doi.org/10.1016/j.ultrasmedbio.2008.02.001
Kim H, Lee S-J, Kim JS, Davies-Venn C, Cho H-J, Won SJ, Dejene E, Yao Z, Kim I, Paik CH, Bluemke DA. Pharmacokinetics and microbiodistribution of 64Cu-labeled collagen binding peptides in chronic myocardial infarction. Nucl Med Commun. 2016;37:1306–17. https://doi.org/10.1097/MNM.0000000000000590
Kirk S e, Skepper J n, Donald A m. Application of environmental scanning electron microscopy to determine biological surface structure. J Microsc. 2009;233:205–24. https://doi.org/10.1111/j.1365-2818.2009.03111.x
Krafft C. Modern trends in biophotonics for clinical diagnosis and therapy to solve unmet clinical needs. J Biophotonics. 2016;9:1362–75. https://doi.org/10.1002/jbio.201600290
Lattouf R, Younes R, Lutomski D, Naaman N, Godeau G, Senni K, Changotade S. Picrosirius Red Staining: A Useful Tool to Appraise Collagen Networks in Normal and Pathological Tissues. J Histochem Cytochem. 2014;62:751–8. https://doi.org/10.1369/0022155414545787
Le TT, Langohr IM, Locker MJ, Sturek M, Cheng J-X. Label-free molecular imaging of atherosclerotic lesions using multimodal nonlinear optical microscopy. J Biomed Opt. 2007;12:054007. https://doi.org/10.1117/1.2795437
Leeming, D.J., Karsdal, M.A., 2016. Chap. .5 – Type V Collagen. In: Biochemistry of Collagens, Laminins and Elastin. Academic Press. p. 43–48. https://doi.org/10.1016/B978-0-12-809847-9.00005-2
Li Y, Ho D, Meng H, Chan TR, An B, Yu H, Brodsky B, Jun AS, Yu SM. Direct detection of collagenous proteins by fluorescently labeled collagen mimetic peptides. Bioconjug Chem. 2013;24:9–16. https://doi.org/10.1021/bc3005842
Little CD, Piquet DM, Davis LA, Walters L, Drake CJ. Distribution of laminin, collagen type IV, collagen type I, and fibronectin in chicken cardiac jelly/basement membrane. Anat Rec. 1989;224:417–25. https://doi.org/10.1002/ar.1092240310
Liu, J., Lim, K.C., Li, H., Seck, H.L., Yu, X., Kok, S.W., Zhang, Y., 2015. Low cost and compact nonlinear (SHG/TPE) laser scanning endoscope for bio-medical application. 93041 K–93041 K–6. https://doi.org/10.1117/12.2078809
López B, González A, DÃez J. Circulating Biomarkers of Collagen Metabolism in Cardiac Diseases. Circulation. 2010;121:1645–54. https://doi.org/10.1161/CIRCULATIONAHA.109.912774
Mayhew TM, Lucocq JM. Developments in cell biology for quantitative immunoelectron microscopy based on thin sections: a review. Histochem Cell Biol. 2008;130:299–313. https://doi.org/10.1007/s00418-008-0451-6
McDonald KL. Out with the old and in with the new: rapid specimen preparation procedures for electron microscopy of sectioned biological material. Protoplasma. 2014;251:429–48. https://doi.org/10.1007/s00709-013-0575-y
McGavin MD. Factors Affecting Visibility of a Target Tissue in Histologic Sections. Vet Pathol. 2014;51:9–27. https://doi.org/10.1177/0300985813506916
Mostaço-Guidolin L, Rosin NL, Hackett T-L. Imaging Collagen in Scar Tissue: Developments in Second Harmonic Generation Microscopy for Biomedical Applications. Int J Mol Sci. 2017;18:1772. https://doi.org/10.3390/ijms18081772
Muzard J, Sarda-Mantel L, Loyau S, Meulemans A, Louedec L, Bantsimba-Malanda C, Hervatin F, Marchal-Somme J, Michel JB, Le Guludec D, Billiald P, Jandrot-Perrus M. Non-Invasive Molecular Imaging of Fibrosis Using a Collagen-Targeted Peptidomimetic of the Platelet Collagen Receptor Glycoprotein VI. PLoS One. 2009;4:e5585. https://doi.org/10.1371/journal.pone.0005585
Pataridis S, Eckhardt A, MikulÃková K, Sedláková P, MikÅ¡Ãk I. Identification of collagen types in tissues using HPLC-MS/MS. J Sep Sci. 2008;31:3483–8. https://doi.org/10.1002/jssc.200800351
Pauschinger M, Knopf D, Petschauer S, Doerner A, Poller W, Schwimmbeck PL, Kühl U, Schultheiss H-P. Dilated Cardiomyopathy Is Associated With Significant Changes in Collagen Type I/III ratio. Circulation. 1999;99:2750–6. https://doi.org/10.1161/01.CIR.99.21.2750
Perrotta I, Davoli M. Collagen Mineralization in Human Aortic Valve Stenosis: A Field Emission Scanning Electron Microscopy and Energy Dispersive Spectroscopy Analysis. Ultrastruct Pathol. 2014;38:281–4. https://doi.org/10.3109/01913123.2014.901468
Phipps JE, Sun Y, Fishbein MC, Marcu L. A Fluorescence Lifetime Imaging Classification Method to Investigate the Collagen to Lipid Ratio in Fibrous Caps of Atherosclerotic Plaque. Lasers Surg Med. 2012;44:564–71. https://doi.org/10.1002/lsm.22059
Podlesnikar T, Delgado V, Bax JJ. Cardiovascular magnetic resonance imaging to assess myocardial fibrosis in valvular heart disease. Int J Cardiovasc Imaging. 2017:1–16. https://doi.org/10.1007/s10554-017-1195-y
Protti A, Lavin B, Dong X, Lorrio S, Robinson S, Onthank D, Shah AM, Botnar RM. Assessment of Myocardial Remodeling Using an Elastin/Tropoelastin Specific Agent with High Field Magnetic Resonance Imaging (MRI). J Am Heart Assoc. 2015;4:e001851. https://doi.org/10.1161/JAHA.115.001851
Qin X, Fei B. Measuring Myofiber Orientations from High-frequency Ultrasound Images Using Multiscale Decompositions. Phys Med Biol. 2014;59:3907–24. https://doi.org/10.1088/0031-9155/59/14/3907
Qin X, Riegler J, Tiburcy M, Zhao X, Chour T, Ndoye B, Nguyen M, Adams J, Ameen M, Denney TS, Yang PC, Nguyen P, Zimmermann WH, Wu JC. Magnetic Resonance Imaging of Cardiac Strain Pattern Following Transplantation of Human Tissue Engineered Heart Muscles. Circ Cardiovasc Imaging. 2016;9:e004731. https://doi.org/10.1161/CIRCIMAGING.116.004731
Ranjit S, Dvornikov A, Stakic M, Hong S-H, Levi M, Evans RM, Gratton E. Imaging Fibrosis and Separating Collagens using Second Harmonic Generation and Phasor Approach to Fluorescence Lifetime Imaging. Sci Rep. 2015;5:13378. https://doi.org/10.1038/srep13378
Reusch LM, Feltovich H, Carlson LC, Hall G, Campagnola PJ, Eliceiri KW, Hall TJ. Nonlinear optical microscopy and ultrasound imaging of human cervical structure. J Biomed Opt. 2013;18:031110. https://doi.org/10.1117/1.JBO.18.3.031110
Richardson W, Clarke S, Quinn T, Holmes J. Physiological Implications of Myocardial Scar Structure. Compr Physiol. 2015;5:1877–909. https://doi.org/10.1002/cphy.c140067
Romito E, Shazly T, Spinale FG. In vivo assessment of regional mechanics post-myocardial infarction: A focus on the road ahead. J Appl Physiol. 2017;123:728–45. https://doi.org/10.1152/japplphysiol.00589.2015
Salerno M, Kramer CM. Advances in Parametric Mapping With CMR Imaging. JACC Cardiovasc Imaging. 2013;6:806–22. https://doi.org/10.1016/j.jcmg.2013.05.005
Sands G, Goo S, Gerneke D, LeGrice I, Loiselle D. The collagenous microstructure of cardiac ventricular trabeculae carneae. J Struct Biol. 2011;173:110–6. https://doi.org/10.1016/j.jsb.2010.06.020
Schelbert EB, Fonarow GC, Bonow RO, Butler J, Gheorghiade M. Therapeutic Targets in Heart Failure: Refocusing on the Myocardial Interstitium. J Am Coll Cardiol. 2014;63:2188–98. https://doi.org/10.1016/j.jacc.2014.01.068
Schenke-Layland K, Stock UA, Nsair A, Xie J, Angelis E, Fonseca CG, Larbig R, Mahajan A, Shivkumar K, Fishbein MC, MacLellan WR. Cardiomyopathy is associated with structural remodelling of heart valve extracellular matrix. Eur Heart J. 2009;30:2254–65. https://doi.org/10.1093/eurheartj/ehp267
Schipke J, Brandenberger C, Rajces A, Manninger M, Alogna A, Post H, Mühlfeld C. Assessment of cardiac fibrosis: a morphometric method comparison for collagen quantification. J Appl Physiol. 2017;122:1019–30. https://doi.org/10.1152/japplphysiol.00987.2016
Srinivasan A, Sehgal PK. Characterization of Biocompatible Collagen Fibers—A Promising Candidate for Cardiac Patch. Tissue Eng Part C Methods. 2009;16:895–903. https://doi.org/10.1089/ten.tec.2009.0475
Sudarshan V, Acharya UR, Ng EYK, Meng CS, Tan RS, Ghista DN. Automated Identification of Infarcted Myocardium Tissue Characterization Using Ultrasound Images: A Review. IEEE Rev Biomed Eng. 2015;8:86–97. https://doi.org/10.1109/RBME.2014.2319854
Tao W, Rubart M, Ryan J, Xiao X, Qiao C, Hato T, Davidson MW, Dunn KW, Day RN. A practical method for monitoring FRET-based biosensors in living animals using two-photon microscopy. Am J Physiol Cell Physiol. 2015;309:C724–35. https://doi.org/10.1152/ajpcell.00182.2015
Taylor AJ, Salerno M, Dharmakumar R, Jerosch-Herold M. T1 Mapping: Basic Techniques and Clinical Applications. JACC Cardiovasc Imaging. 2016;9:67–81. https://doi.org/10.1016/j.jcmg.2015.11.005
Thimm TN, Squirrell JM, Liu Y, Eliceiri KW, Ogle BM. Endogenous Optical Signals Reveal Changes of Elastin and Collagen Organization During Differentiation of Mouse Embryonic Stem Cells. Tissue Eng Part C Methods. 2015;21:995–1004. https://doi.org/10.1089/ten.TEC.2014.0699
Trivedi V, Truong TV, Trinh LA, Holland DB, Liebling M, Fraser SE. Dynamic structure and protein expression of the live embryonic heart captured by 2-photon light sheet microscopy and retrospective registration. Biomed Opt Express. 2015;6:2056–66. https://doi.org/10.1364/BOE.6.002056
Tsamis A, Krawiec JT, Vorp DA. Elastin and collagen fibre microstructure of the human aorta in ageing and disease: a review. J R Soc Interface. 2013;10:20121004. https://doi.org/10.1098/rsif.2012.1004
Wahyudi H, Reynolds AA, Li Y, Owen SC, Yu SM. Targeting collagen for diagnostic imaging and therapeutic delivery. J Control Release. 2016;240:323–31. https://doi.org/10.1016/j.jconrel.2016.01.007
White JF, Werkmeister JA, Hilbert SL, Ramshaw JAM. Heart valve collagens: cross-species comparison using immunohistological methods. J Heart Valve Dis. 2010;19:766–71.
White SK, Sado DM, Flett AS, Moon JC. Characterising the myocardial interstitial space: the clinical relevance of non-invasive imaging. Heart. 2012;98:773–9. https://doi.org/10.1136/heartjnl-2011-301515
WHO | Cardiovascular diseases (CVDs) [WWW Document], 2017. WHO. URL. http://www.who.int/mediacentre/factsheets/fs317/en/. (Accessed 6 Mar 2018).
Won S, Davies-venn C, Liu S, Bluemke DA. Noninvasive imaging of myocardial extracellular matrix for assessment of fibrosis. Curr Opin Cardiol. 2013;28:282–9. https://doi.org/10.1097/HCO.0b013e32835f5a2b
Wu X, Sun Z, Foskett A, Trzeciakowski JP, Meininger GA, Muthuchamy M. Cardiomyocyte contractile status is associated with differences in fibronectin and integrin interactions. Am J Physiol Heart Circ Physiol. 2010;298:H2071–81. https://doi.org/10.1152/ajpheart.01156.2009
Zheng L, Ding X, Liu K, Feng S, Tang B, Li Q, Huang D, Yang S. Molecular imaging of fibrosis using a novel collagen-binding peptide labelled with 99 m Tc on SPECT/CT. Amino Acids. 2017;49:89–101. https://doi.org/10.1007/s00726-016-2328-7
Acknowledgment
We thank Brenda Ogle and Ellen Arena for useful input. We also acknowledge funding from the Laboratory for Optical and Computational Instrumentation, the Morgridge Institute for Research, NIH R01 HL137204 (RAH), NIH R01 131017 (RAH), NIH T32 CA009206 (MAP), and the NIH T32 GM008349 (MAP). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the National Science Foundation.
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Pinkert, M.A., Hortensius, R.A., Ogle, B.M., Eliceiri, K.W. (2018). Imaging the Cardiac Extracellular Matrix. In: Schmuck, E., Hematti, P., Raval, A. (eds) Cardiac Extracellular Matrix. Advances in Experimental Medicine and Biology, vol 1098. Springer, Cham. https://doi.org/10.1007/978-3-319-97421-7_2
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