Advertisement

Journal of Nuclear Cardiology

, Volume 26, Issue 1, pp 208–216 | Cite as

Emerging imaging targets for infiltrative cardiomyopathy: Inflammation and fibrosis

  • Frank M. BengelEmail author
  • Tobias L. Ross
Review Article

Abstract

Molecular imaging in infiltrative cardiomyopathies is increasingly penetrating the clinical arena. Current approaches target the infiltrate directly, or its metabolic, physiologic, or functional consequences. Inflammation may not just play a role as the infiltrative mechanism itself. It is also thought to play a key role in the development and progression of heart failure in general, because it promotes the development of tissue fibrosis. The cascade leading from tissue damage to inflammation and further to fibrosis and loss of function has emerged as a therapeutic target. This review focuses (1) on novel tracers of inflammation, which are on the brink of clinical applicability and may be more specific than the gross metabolic marker F-18 deoxyglucose; and (2) on novel biologic imaging targets in fibrosis, which may be exploited for interrogation of the crosstalk between inflammation and loss of contractile function. Ultimately, the success of any novel molecular imaging assay will depend on whether it can be used for successful guidance of novel, targeted therapies aiming at tissue regeneration.

Keywords

Molecular imaging infiltrative cardiomyopathy inflammation fibrosis 

Notes

Acknowledgement

This work was supported by the cluster of excellence “Rebirth (From Regenerative Biology to Reconstructive Therapy)” and the clinical research group KFO 311 “Pre-Terminal Heart and Lung Failure: Unloading and Repair” of the Hannover Medical School, both funded by the German Research Foundation (DFG).

Disclosure

Frank M. Bengel and Tobias L. Ross do not have any conflicts of interest to disclose.

References

  1. 1.
    Falk RH, Alexander KM, Liao R, Dorbala S. AL (light-chain) cardiac amyloidosis: a review of diagnosis and therapy. J Am Coll Cardiol. 2016;68:1323-41.Google Scholar
  2. 2.
    Narotsky DL, Castano A, Weinsaft JW, Bokhari S, Maurer MS (2016) Wild-type transthyretin cardiac amyloidosis: novel insights from advanced imaging. Can J Cardiol 32:1166 e1-1166 e10.Google Scholar
  3. 3.
    Chareonthaitawee P, Beanlands RS, Chen W, et al. Joint SNMMI-ASNC expert consensus document on the role of (18)F-FDG PET/CT in cardiac sarcoid detection and therapy monitoring. J Nucl Med. 2017;58:1341-53.Google Scholar
  4. 4.
    Schatka I, Bengel FM. Advanced imaging of cardiac sarcoidosis. J Nucl Med. 2014;55:99-106.Google Scholar
  5. 5.
    Dorbala S, Vangala D, Bruyere J Jr, et al. Coronary microvascular dysfunction is related to abnormalities in myocardial structure and function in cardiac amyloidosis. JACC Heart Fail. 2014;2:358-67.Google Scholar
  6. 6.
    Kruse MJ, Kovell L, Kasper EK, et al. Myocardial blood flow and inflammatory cardiac sarcoidosis. JACC Cardiovasc Imaging. 2017;10:157-67.Google Scholar
  7. 7.
    Coleman GC, Shaw PW, Balfour PC Jr, et al. Prognostic value of myocardial scarring on cmr in patients with cardiac sarcoidosis. JACC Cardiovasc Imaging. 2017;10:411-20.Google Scholar
  8. 8.
    Patel AR, Kramer CM. Role of cardiac magnetic resonance in the diagnosis and prognosis of nonischemic cardiomyopathy. JACC Cardiovasc Imaging. 2017;10:1180-93.Google Scholar
  9. 9.
    Sengupta PP, Krishnamoorthy VK, Abhayaratna WP, et al. Disparate patterns of left ventricular mechanics differentiate constrictive pericarditis from restrictive cardiomyopathy. JACC Cardiovasc Imaging. 2008;1:29-38.Google Scholar
  10. 10.
    Bengel FM, George RT, Schuleri KH, Lardo AC, Wollert KC. Image-guided therapies for myocardial repair: concepts and practical implementation. Eur Heart J Cardiovasc Imaging. 2013;14:741-51.Google Scholar
  11. 11.
    Nahrendorf M, Frantz S, Swirski FK, et al. Imaging systemic inflammatory networks in ischemic heart disease. J Am Coll Cardiol. 2015;65:1583-91.Google Scholar
  12. 12.
    Nahrendorf M (2018) Myeloid cell contributions to cardiovascular health and disease. Nat Med 24:711-720.Google Scholar
  13. 13.
    Trachtenberg BH, Hare JM. Inflammatory cardiomyopathic syndromes. Circ Res. 2017;121:803-18.Google Scholar
  14. 14.
    Kempf T, Zarbock A, Vestweber D, Wollert KC. Anti-inflammatory mechanisms and therapeutic opportunities in myocardial infarct healing. J Mol Med (Berl). 2012;90:361-9.Google Scholar
  15. 15.
    Lee WW, Marinelli B, van der Laan AM, et al. PET/MRI of inflammation in myocardial infarction. J Am Coll Cardiol. 2012;59:153-63.Google Scholar
  16. 16.
    Rischpler C, Dirschinger RJ, Nekolla SG, et al. Prospective evaluation of 18F-Fluorodeoxyglucose uptake in postischemic myocardium by simultaneous positron emission tomography/magnetic resonance imaging as a prognostic marker of functional outcome. Circ Cardiovasc Imaging. 2016;9:e004316.Google Scholar
  17. 17.
    Prabhu SD, Frangogiannis NG. The biological basis for cardiac repair after myocardial infarction: from inflammation to fibrosis. Circ Res. 2016;119:91-112.Google Scholar
  18. 18.
    Mann DL. Innate immunity and the failing heart: the cytokine hypothesis revisited. Circ Res. 2015;116:1254-68.Google Scholar
  19. 19.
    Mehta JL, Pothineni NV. Inflammation in heart failure: the holy grail? Hypertension. 2016;68:27-9.Google Scholar
  20. 20.
    Dick SA, Epelman S. Chronic heart failure and inflammation: what do we really know? Circ Res. 2016;119:159-76.Google Scholar
  21. 21.
    Travers JG, Kamal FA, Robbins J, Yutzey KE, Blaxall BC. Cardiac fibrosis: the fibroblast awakens. Circ Res. 2016;118:1021-40.Google Scholar
  22. 22.
    Thackeray JT, Bengel FM. Gauging cardiac repair and regeneration with new molecular probes. J Nucl Med. 2018;59:549-50.Google Scholar
  23. 23.
    Thackeray JT, Bankstahl JP, Wang Y, et al. Targeting post-infarct inflammation by PET imaging: comparison of (68)Ga-citrate and (68)Ga-DOTATATE with (18)F-FDG in a mouse model. Eur J Nucl Med Mol Imaging. 2015;42:317-27.Google Scholar
  24. 24.
    Thackeray JT, Bankstahl JP, Wang Y, Wollert KC, Bengel FM. Clinically relevant strategies for lowering cardiomyocyte glucose uptake for 18F-FDG imaging of myocardial inflammation in mice. Eur J Nucl Med Mol Imaging. 2015;42:771-80.Google Scholar
  25. 25.
    van der Valk FM, Kroon J, Potters WV, et al. In vivo imaging of enhanced leukocyte accumulation in atherosclerotic lesions in humans. J Am Coll Cardiol. 2014;64:1019-29.Google Scholar
  26. 26.
    Taki J, Wakabayashi H, Inaki A, et al. 14C-Methionine uptake as a potential marker of inflammatory processes after myocardial ischemia and reperfusion. J Nucl Med. 2013;54:431-6.Google Scholar
  27. 27.
    Thackeray JT, Bankstahl JP, Wang Y, Wollert KC, Bengel FM. Targeting Amino Acid Metabolism for Molecular Imaging of Inflammation Early After Myocardial Infarction. Theranostics. 2016;6:1768-79.Google Scholar
  28. 28.
    Yamada Y, Uchida Y, Tatsumi K, et al. Fluorine-18-fluorodeoxyglucose and carbon-11-methionine evaluation of lymphadenopathy in sarcoidosis. J Nucl Med. 1998;39:1160-6.Google Scholar
  29. 29.
    Thackeray JT, Derlin T, Haghikia A, et al. Molecular Imaging of the Chemokine Receptor CXCR4 After Acute Myocardial Infarction. JACC Cardiovasc Imaging. 2015;8:1417-26.Google Scholar
  30. 30.
    Jujo K, Ii M, Sekiguchi H, et al. CXC-chemokine receptor 4 antagonist AMD3100 promotes cardiac functional recovery after ischemia/reperfusion injury via endothelial nitric oxide synthase-dependent mechanism. Circulation. 2013;127:63-73.Google Scholar
  31. 31.
    Reiter T, Kircher M, Schirbel A, et al. Imaging of C-X-C motif chemokine receptor CXCR4 expression after myocardial infarction with [(68)Ga]Pentixafor-PET/CT in correlation with cardiac MRI. JACC Cardiovasc Imaging. 2018.  https://doi.org/10.1016/j.jcmg.2018.01.001.Google Scholar
  32. 32.
    Weiberg D, Thackeray JT, Daum G, et al. Clinical molecular imaging of chemokine receptor CXCR4 expression in atherosclerotic plaque using (68)Ga-Pentixafor PET: correlation with cardiovascular risk factors and calcified plaque burden. J Nucl Med. 2018;59:266-72.Google Scholar
  33. 33.
    Tarkin JM, Joshi FR, Evans NR, et al. Detection of Atherosclerotic Inflammation by (68)Ga-DOTATATE PET Compared to [(18)F]FDG PET Imaging. J Am Coll Cardiol. 2017;69:1774-91.Google Scholar
  34. 34.
    Schatka I, Wollenweber T, Haense C, Brunz F, Gratz KF, Bengel FM. Peptide receptor-targeted radionuclide therapy alters inflammation in atherosclerotic plaques. J Am Coll Cardiol. 2013;62:2344-5.Google Scholar
  35. 35.
    Lapa C, Reiter T, Kircher M, et al. Somatostatin receptor based PET/CT in patients with the suspicion of cardiac sarcoidosis: an initial comparison to cardiac MRI. Oncotarget. 2016;7:77807-14.Google Scholar
  36. 36.
    Lapa C, Reiter T, Li X, et al. Imaging of myocardial inflammation with somatostatin receptor based PET/CT - A comparison to cardiac MRI. Int J Cardiol. 2015;194:44-9.Google Scholar
  37. 37.
    Wan MYS, Endozo R, Michopoulou S, et al. PET/CT imaging of unstable carotid plaque with (68)Ga-Labeled somatostatin receptor ligand. J Nucl Med. 2017;58:774-80.Google Scholar
  38. 38.
    Albrecht DS, Granziera C, Hooker JM, Loggia ML. In Vivo Imaging of Human Neuroinflammation. ACS Chem Neurosci. 2016;7:470-83.Google Scholar
  39. 39.
    Chung SJ, Yoon HJ, Youn H, et al. (18)F-FEDAC as a targeting agent for activated macrophages in DBA/1 Mice with collagen-induced arthritis: comparison with (18)F-FDG. J Nucl Med. 2018;59:839-45.Google Scholar
  40. 40.
    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. 2012;33:1902-10.Google Scholar
  41. 41.
    Pugliese F, Gaemperli O, Kinderlerer AR, et al. Imaging of vascular inflammation with [11C]-PK11195 and positron emission tomography/computed tomography angiography. J Am Coll Cardiol. 2010;56:653-61.Google Scholar
  42. 42.
    Thackeray JT, Hupe HC, Wang Y, et al. Myocardial inflammation predicts remodeling and neuroinflammation after myocardial infarction. J Am Coll Cardiol. 2018;71:263-75.Google Scholar
  43. 43.
    Grimaldi V, De Pascale MR, Zullo A, et al. Evidence of epigenetic tags in cardiac fibrosis. J Cardiol. 2017;69:401-8.Google Scholar
  44. 44.
    Beermann J, Piccoli MT, Viereck J, Thum T. Non-coding RNAs in development and disease: background, mechanisms, and therapeutic approaches. Physiol Rev. 2016;96:1297-325.Google Scholar
  45. 45.
    Liu C, Zhao W, Meng W, et al. Platelet-derived growth factor blockade on cardiac remodeling following infarction. Mol Cell Biochem. 2014;397:295-304.Google Scholar
  46. 46.
    Ellims AH, Taylor AJ, Mariani JA, et al. Evaluating the utility of circulating biomarkers of collagen synthesis in hypertrophic cardiomyopathy. Circ Heart Fail. 2014;7:271-8.Google Scholar
  47. 47.
    Zannad F. What is measured by cardiac fibrosis biomarkers and imaging? Circ Heart Fail. 2014;7:239-42.Google Scholar
  48. 48.
    van den Borne SW, Isobe S, Verjans JW, et al. Molecular imaging of interstitial alterations in remodeling myocardium after myocardial infarction. J Am Coll Cardiol. 2008;52:2017-28.Google Scholar
  49. 49.
    Chen J, Lee SK, Abd-Elgaliel WR, et al. Assessment of cardiovascular fibrosis using novel fluorescent probes. PLoS ONE. 2011;6:e19097.Google Scholar
  50. 50.
    Kim H, Lee SJ, Kim JS, et al. Pharmacokinetics and microbiodistribution of 64Cu-labeled collagen-binding peptides in chronic myocardial infarction. Nucl Med Commun. 2016;37:1306-17.Google Scholar
  51. 51.
    Muzard J, Sarda-Mantel L, Loyau S, et al. Non-invasive molecular imaging of fibrosis using a collagen-targeted peptidomimetic of the platelet collagen receptor glycoprotein VI. PLoS ONE. 2009;4:e5585.Google Scholar
  52. 52.
    Velikyan I, Rosenstrom U, Bulenga TN, Eriksson O, Antoni G. Feasibility of multiple examinations using (68)Ga-labelled collagelin analogues: organ distribution in rat for extrapolation to human organ and whole-body radiation dosimetry. Pharmaceuticals (Basel). 2016;9:31.Google Scholar
  53. 53.
    Velikyan I, Rosenstrom U, Estrada S, et al. Synthesis and preclinical evaluation of 68Ga-labeled collagelin analogs for imaging and quantification of fibrosis. Nucl Med Biol. 2014;41:728-36.Google Scholar
  54. 54.
    Debunne M, Portal C, Delest B, et al. In vitro and ex vivo evaluation of smart infra-red fluorescent caspase-3 probes for molecular imaging of cardiovascular apoptosis. Int J Mol Imaging. 2011;2011:413290.Google Scholar
  55. 55.
    Reed NI, Jo H, Chen C, et al. The alphavbeta1 integrin plays a critical in vivo role in tissue fibrosis. Sci Transl Med. 2015;7:288ra79.Google Scholar
  56. 56.
    Hu LY, Bauer N, Knight LM, et al. Characterization and evaluation of (64)Cu-labeled A20FMDV2 conjugates for imaging the integrin alphavbeta 6. Mol Imaging Biol. 2014;16:567-77.Google Scholar

Copyright information

© American Society of Nuclear Cardiology 2018

Authors and Affiliations

  1. 1.Klinik für Nuklearmedizin, Medizinische Hochschule HannoverHannoverGermany

Personalised recommendations