Skip to main content

Advertisement

SpringerLink
Log in

Recent Advances in Imaging Inflammation Post-Myocardial Infarction Using Positron Emission Tomography

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

Abstract

Purpose of Review

Despite advances in medical and surgical therapy, some patients after a myocardial infarction still develop heart failure, a devastating disease that has a high rate of morbidity and mortality. Differences in the immune response to the myocardial damage may affect the healing process. Molecular imaging enables the interrogation of immune cell subsets that can aid or impair left ventricular recovery post-myocardial infarction. Visualization of patient-specific differences in the cellular and molecular process among patients post-myocardial infarction may lead to the development of personalized therapy to prevent remodeling and promote myocardial recovery.

Recent Findings

Positron emission tomography (PET) has emerged as a commonly used modality for imaging myocardial inflammation in both pre-clinical and clinical studies. While 18F-FDG continues to be investigated for its ability to track inflammation in small clinical trials, its relative short half-life and nonspecific uptake have prompted investigation into other PET tracers, including agents that image amino acid metabolism, mitochondrial transport proteins, cell surface receptors, and integrins. Two of the most innovative approaches include the use of reporter gene imaging and nanoparticles. Of these, the latter offers the added advantage of delivering a therapeutic payload. Finally, recent advances in PET instrumentation such as total-body imaging can allow the study of multi-organ dysfunction simultaneously (e.g., cardiac and brain inflammation after a heart attack) with high sensitivity. Moreover, with multi-isotope PET scanners, simultaneous observation of multiple positron emitting isotopes has enabled the examination of different biological processes with distinct molecular probes in a single scan setting.

Summary

The development of advanced PET tracers for the visualization of the inflammatory cascade post-myocardial infarction may enable the development of immune modulating agents to promote left ventricular recovery.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Writing Group M, Mozaffarian D, Benjamin EJ, et al. Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation. 2016;133(4):e38–360.

  2. Benjamin EJ, Muntner P, Alonso A, et al. Heart disease and stroke statistics-2019 update: a report from the American Heart Association. Circulation. 2019(10):139, e56–e528.

  3. • Westman PC, Lipinski MJ, Luger D, et al. Inflammation as a driver of adverse left ventricular remodeling after acute myocardial infarction. J Am Coll Cardiol. 2016;67(17):2050–60. This is a good review of how immune cells affect recovery and remodeling after myocardial infarction.

  4. Ono K, Matsumori A, Shioi T, Furukawa Y, Sasayama S. Cytokine gene expression after myocardial infarction in rat hearts: possible implication in left ventricular remodeling. Circulation. 1998;98(2):149–56.

  5. Bujak M, Dobaczewski M, Chatila K, Mendoza LH, Li N, Reddy A, et al. Interleukin-1 receptor type I signaling critically regulates infarct healing and cardiac remodeling. Am J Pathol. Jul 2008;173(1):57–67.

  6. Abbate A, Salloum FN, Vecile E, et al. Anakinra, a recombinant human interleukin-1 receptor antagonist, inhibits apoptosis in experimental acute myocardial infarction. Circulation. 2008;117(20):2670–83.

  7. Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT. Anti-TNF Therapy Against Congestive Heart Failure Investigators.. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation. 2003;107(25):3133–40.

  8. Mann DL, McMurray JJ, Packer M, et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized etanercept worldwide evaluation (RENEWAL). Circulation. 2004;109(13):1594–602.

  9. Mann DL. Innate immunity and the failing heart: the cytokine hypothesis revisited. Circ Res. 2015;116(7):1254–68.

  10. Frangogiannis NG. The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol. 2014;11(5):255–65.

  11. Heusch G, Libby P, Gersh B, et al. Cardiovascular remodelling in coronary artery disease and heart failure. Lancet. 2014;383(9932):1933–43.

  12. • Tourki B, Halade G. Leukocyte diversity in resolving and nonresolving mechanisms of cardiac remodeling. FASEB J. 2017;31(10):4226–39. This is another good review of how the immune system plays an active role in repair and injury after myocardial infarction.

  13. Jung K, Kim P, Leuschner F, et al. Endoscopic time-lapse imaging of immune cells in infarcted mouse hearts. Circ Res. 2013;112(6):891–9.

  14. Swirski FK, Nahrendorf M. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science. 2013;339(6116):161–6.

  15. Nahrendorf M, Swirski FK, Aikawa E, et al. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med. 2007;204(12):3037–47.

  16. Ma Y, Halade GV, Zhang J, et al. Matrix metalloproteinase-28 deletion exacerbates cardiac dysfunction and rupture after myocardial infarction in mice by inhibiting M2 macrophage activation. Circ Res. 2013;112(4):675–88.

  17. Bansal SS, Ismahil MA, Goel M, et al. Dysfunctional and proinflammatory regulatory T-Lymphocytes are essential for adverse cardiac remodeling in ischemic cardiomyopathy. Circulation. 2019;139(2):206–21.

  18. Thackeray JT, Bengel FM. Gauging cardiac repair and regeneration with new molecular probes. J Nucl Med. Apr 2018;59(4):549–50.

  19. Thackeray JT, Bengel FM. Molecular imaging of myocardial inflammation with positron emission tomography post-ischemia: a determinant of subsequent remodeling or recovery. J Am Coll Cardiol Img. 2018;11(9):1340–55.

  20. van Dongen GA, Visser GW, Lub-de Hooge MN, de Vries EG, Perk LR. Immuno-PET: a navigator in monoclonal antibody development and applications. Oncologist. Dec 2007;12(12):1379–89.

  21. Satomi T, Ogawa M, Mori I, Ishino S, Kubo K, Magata Y, et al. Comparison of contrast agents for atherosclerosis imaging using cultured macrophages: FDG versus ultrasmall superparamagnetic iron oxide. J Nucl Med. Jun 2013;54(6):999–1004.

  22. 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. Apr 2015;42(5):771–80.

  23. Wollenweber T, Roentgen P, Schafer A, et al. Characterizing the inflammatory tissue response to acute myocardial infarction by clinical multimodality noninvasive imaging. Circ Cardiovasc Imaging. 2014;7(5):811–8.

  24. 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(4):e004316.

  25. Tahara N, Mukherjee J, de Haas HJ, Petrov AD, Tawakol A, Haider N, et al. 2-deoxy-2-[18F]fluoro-D-mannose positron emission tomography imaging in atherosclerosis. Nat Med. Feb 2014;20(2):215–9.

  26. Blykers A, Schoonooghe S, Xavier C, D'hoe K, Laoui D, D'Huyvetter M, et al. PET imaging of macrophage mannose receptor-expressing macrophages in tumor stroma using 18F-radiolabeled camelid single-domain antibody fragments. J Nucl Med. Aug 2015;56(8):1265–71.

  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(11):1768–79.

  28. Taki J, Wakabayashi H, Inaki A, Imanaka-Yoshida K, Hiroe M, Ogawa K, et al. 14C-methionine uptake as a potential marker of inflammatory processes after myocardial ischemia and reperfusion. J Nucl Med. 2013;54(3):431–6.

  29. Morooka M, Kubota K, Kadowaki H, Ito K, Okazaki O, Kashida M, et al. 11C-methionine PET of acute myocardial infarction. J Nucl Med. 2009;50(8):1283–7.

  30. 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(15):1902–10.

  31. • Thackeray JT, Hupe HC, Wang Y, et al. Myocardial inflammation predicts remodeling and neuroinflammation after myocardial infarction. J Am Coll Cardiol. 2018;71(3):263–75. This is the first paper that details how inflammation in the heart and brain can occur together after myocardial injury.

  32. Fan Z, Calsolaro V, Atkinson RA, Femminella GD, Waldman A, Buckley C, et al. Flutriciclamide (18F-GE180) PET: first-in-human PET study of novel third-generation in vivo marker of human translocator protein. J Nucl Med. Nov 2016;57(11):1753–9.

  33. Hofman MS, Kong G, Neels OC, Eu P, Hong E, Hicks RJ. High management impact of Ga-68 DOTATATE (GaTate) PET/CT for imaging neuroendocrine and other somatostatin expressing tumours. J Med Imaging Radiat Oncol. Feb 2012;56(1):40–7.

  34. Tarkin JM, Joshi FR, Evans NR, et al. Detection of atherosclerotic inflammation by 68Ga-DOTATATE PET compared to [18F]FDG PET Imaging. J Am Coll Cardiol. 2017;69(14):1774–91.

  35. Thackeray JT, Bankstahl JP, Wang Y, Korf-Klingebiel M, Walte A, Wittneben A, et al. Targeting post-infarct inflammation by PET imaging: comparison of 68Ga-citrate and 68Ga-DOTATATE with 18F-FDG in a mouse model. Eur J Nucl Med Mol Imaging. 2015;42(2):317–27.

  36. Thackeray JT, Derlin T, Haghikia A, Napp LC, Wang Y, Ross TL, et al. Molecular imaging of the chemokine receptor CXCR4 after acute myocardial infarction. J Am Coll Cardiol Img. 2015;8(12):1417–26.

  37. Bajpai G, Bredemeyer A, Li W, et al. Tissue resident CCR2- and CCR2+ cardiac macrophages differentially orchestrate monocyte recruitment and fate specification following myocardial injury. Circ Res. 2019;124(2):263–78.

  38. • Heo GS, Kopecky B, Sultan D, et al. Molecular imaging visualizes recruitment of inflammatory monocytes and macrophages to the injured heart. Circ Res. 2019;124(6):881–90. This paper highlights how PET can image CCR2+ macrophages.

  39. Gao H, Kiesewetter DO, Zhang X, Huang X, Guo N, Lang L, et al. PET of glucagonlike peptide receptor upregulation after myocardial ischemia or reperfusion injury. J Nucl Med. Dec 2012;53(12):1960–8.

  40. Stahle M, Kyto V, Kiugel M, et al. Glucagon-like peptide-1 receptor expression after myocardial infarction: Imaging study using (68)Ga-NODAGA-exendin-4 positron emission tomography. J Nucl Cardiol. Dec 13 2018.

  41. Meoli DF, Sadeghi MM, Krassilnikova S, Bourke BN, Giordano FJ, Dione DP, et al. Noninvasive imaging of myocardial angiogenesis following experimental myocardial infarction. J Clin Invest. Jun 2004;113(12):1684–91.

  42. Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin alpha v beta 3 for angiogenesis. Science. 1994;264(5158):569–71.

  43. Jenkins WS, Vesey AT, Stirrat C, et al. Cardiac alphaVbeta3 integrin expression following acute myocardial infarction in humans. Heart. 2017;103(8):607–15.

  44. Laitinen I, Notni J, Pohle K, et al. Comparison of cyclic RGD peptides for alphavbeta3 integrin detection in a rat model of myocardial infarction. EJNMMI Res. 2013;3(1):38.

  45. Charoenphun P, Meszaros LK, Chuamsaamarkkee K, Sharif-Paghaleh E, Ballinger JR, Ferris TJ, et al. [(89)Zr]oxinate4 for long-term in vivo cell tracking by positron emission tomography. Eur J Nucl Med Mol Imaging. 2015;42(2):278–87.

  46. • Thunemann M, Schorg BF, Feil S, et al. Cre/lox-assisted non-invasive in vivo tracking of specific cell populations by positron emission tomography. Nat Commun. 2017;8(1):444. This paper uses a novel reporter system to track immune subpopulations.

  47. Kojima Y, Volkmer JP, McKenna K, et al. CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis. Nature. 2016;536(7614):86–90.

  48. Kojima Y, Weissman IL, Leeper NJ. The role of efferocytosis in atherosclerosis. Circulation. 2017;135(5):476–89.

  49. Flores AM, Ye J, Jarr KU, Hosseini-Nassab N, Smith BR, Leeper NJ. Nanoparticle therapy for vascular diseases. Arterioscler Thromb Vasc Biol. 2019;39(4):635–46.

  50. Pfau D, Thorn SL, Zhang J, et al. Angiotensin receptor neprilysin inhibitor attenuates myocardial remodeling and improves infarct perfusion in experimental heart failure. Sci Rep. 2019;9(1):5791.

  51. Ni NC, Jin CS, Cui L, Shao Z, Wu J, Li SH, et al. Non-invasive macrophage tracking using novel porphysome nanoparticles in the post-myocardial infarction murine heart. Mol Imaging Biol. Aug 2016;18(4):557–68.

  52. Keliher EJ, Ye YX, Wojtkiewicz GR, et al. Polyglucose nanoparticles with renal elimination and macrophage avidity facilitate PET imaging in ischaemic heart disease. Nat Commun. 2017;8:14064.

  53. Wang J, Hu X, Xiang D. Nanoparticle drug delivery systems: an excellent carrier for tumor peptide vaccines. Drug Delivery. 2018;25(1):1319–27.

  54. Posadas I, Monteagudo S, Cena V. Nanoparticles for brain-specific drug and genetic material delivery, imaging and diagnosis. Nanomedicine. 2016;11(7):833–49.

  55. Oliveira I, Vieira S, Oliveira JM, Reis RL. Nanoparticles-based systems for osteochondral tissue engineering. Adv Exp Med Biol. 2018;1059:209–17.

  56. Cherry SR, Badawi RD, Karp JS, Moses WW, Price P, Jones T. Total-body imaging: Transforming the role of positron emission tomography. Sci Transl Med. 2017;9(381).

  57. Cherry SR, Jones T, Karp JS, Qi J, Moses WW, Badawi RD. Total-body PET: maximizing sensitivity to create new opportunities for clinical research and patient care. J Nucl Med. 2018;59(1):3–12.

  58. Badawi RD, Shi H, Hu P, Chen S, Xu T, Price PM, et al. First human imaging studies with the EXPLORER total-body PET scanner. J Nucl Med. 2019;60(3):299–303.

  59. Huang SC, Carson RE, Hoffman EJ, Kuhl DE, Phelps ME. An investigation of a double-tracer technique for positron computerized tomography. J Nucl Med. 1982;23(9):816–22.

  60. Koeppe RA, Raffel DM, Snyder SE, Ficaro EP, Kilbourn MR, Kuhl DE. Dual-[11C]tracer single-acquisition positron emission tomography studies. J Cereb Blood Flow Metab. 2001;21(12):1480–92.

  61. Kadrmas DJ, Rust TC. Feasibility of rapid multitracer PET tumor imaging. IEEE Trans Nucl Sci. 2005;52:1341–7.

  62. Kadrmas DJ, Rust TC, Hoffman JM. Single-scan dual-tracer FLT+FDG PET tumor characterization. Phys Med Biol. 2013;58(3):429–49.

  63. Kadrmas DJ, Hoffman JM. Methodology for quantitative rapid multi-tracer PET tumor characterizations. Theranostics. 2013;3(10):757–73.

  64. Olcott PD, Levin C, Gambhir SS, Inventors. Dual-isotope position emitting tomography for disease evaluation, 2016.

  65. Fukuchi T, Okauchi T, Shigeta M, Yamamoto S, Watanabe Y, Enomoto S. Positron emission tomography with additional gamma-ray detectors for multiple-tracer imaging. Med Phys. 2017;44(6):2257–66.

Download references

Author information

Author notes

  1. Jessica D’Addabbo and Mirwais Wardak contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Division of Cardiovascular Medicine, Stanford University, 870 Quarry Rd Ext, Falk Research Building, Rm 187, Stanford, CA, USA

    Jessica D’Addabbo & Patricia K. Nguyen

  2. Department of Radiology, Stanford University, Stanford, CA, USA

    Mirwais Wardak

  3. Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA

    Mirwais Wardak & Patricia K. Nguyen

  4. Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA

    Patricia K. Nguyen

Authors
  1. Jessica D’Addabbo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mirwais Wardak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Patricia K. Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Patricia K. Nguyen.

Ethics declarations

Conflict of Interest

All authors declare 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.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Molecular Imaging

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

D’Addabbo, J., Wardak, M. & Nguyen, P.K. Recent Advances in Imaging Inflammation Post-Myocardial Infarction Using Positron Emission Tomography. Curr Cardiovasc Imaging Rep 12, 38 (2019). https://doi.org/10.1007/s12410-019-9515-3

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s12410-019-9515-3

Keywords

Search

Navigation