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Quantification of myocardial interstitial fibrosis and extracellular volume for the detection of cardiac allograft vasculopathy

  • Ruud B. van HeeswijkEmail author
  • Jessica A. M. Bastiaansen
  • Juan F. Iglesias
  • Sophie Degrauwe
  • Samuel Rotman
  • Jean-Luc Barras
  • Julien Regamey
  • Nathalie Lauriers
  • Piergiorgio Tozzi
  • Jérôme Yerly
  • Giulia Ginami
  • Matthias Stuber
  • Roger Hullin
Original Article

Abstract

In search of a non-invasive alternative detection of early-stage cardiac allograft vasculopathy (CAV), in this preliminary study we tested the hypothesis that interstitial fibrosis quantified with cardiac magnetic resonance (CMR) can serve as a biomarker for the detection of CAV. Late-stage CAV was detected with routine X-ray coronary angiography (XRCA), while a coronary intima-media thickness ratio (IMTR) > 1 on optical coherence tomography (OCT) was used to detect early-stage CAV. Interstitial fibrosis was quantified in the endomyocardial biopsy (EMB) and indirectly with CMR as the T1 relaxation time and extracellular volume (ECV). CMR was performed within 48 h of a single invasive procedure with XRCA, OCT, and EMB procurement in stable HTx recipients (n = 27; age 54 ± 13 years, 5.4 ± 3.7 years post-transplant). XRCA-CAV and IMTR > 1 were present in 15% and 75% of study patients, respectively. The T1 relaxation times and ECV were increased in patients with XRCA-CAV (p = 0.03 each), while IMTR and EMB interstitial fibrosis were not significantly different (both p > 0.05). ECV (ρ = 0.46, p = 0.02) and IMTR (ρ = 0.58; p = 0.01) correlated with the histological quantity of interstitial fibrosis, while the T1 relaxation time (p = 0.06) did not. The correlation of the IMTR with the EMB interstitial fibrosis tentatively validates the hypothesis that interstitial fibrosis may serve as an early indicator of CAV. Moreover, the significant association of CMR-based ECV with the magnitude of interstitial fibrosis in the biopsy suggests ECV as a potential biomarker for interstitial fibrosis due to early-stage CAV. The measurement of ECV may therefore have a role for non-invasive detection and follow-up of early-stage CAV.

Keywords

Cardiac allograft vasculopathy Interstitial fibrosis Cardiovascular magnetic resonance Extracellular volume Optical coherence tomography Heart transplantation 

Notes

Acknowledgements

This work was supported by grants from the Swiss Heart Foundation to RH, JAMB and RBvH, and from the Swiss National Science Foundation to RBvH (PZ00P3_154719 and 32003B_182615), RH (320030_147121), JAMB (PZ00P3_167871) and MS (320030_143923, 326030_150828, and 320030_173129). MS received non-monetary research support from Siemens Healthineers.

Author contributions

RBvH, JAMB, JY, and GG acquired, analysed and interpreted the CMR data. JFI and SD acquired, analysed and interpreted the OCT and X-ray data. SR and JLB performed and analysed the histology and interpreted its results. MK and PT performed the transplantation surgery. MK, JR, NL, and PT recruited subjects and collected clinical data. RBvH, MS, and RH designed the study and integrated the various results. RBvH and RH drafted the initial manuscript. All authors read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interest.

Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (Cantonal Ethics Committee for Research in the Canton of Vaud—CER-VD, Protocol 2016-00635) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from all individual participants included in the study.

Supplementary material

10554_2019_1733_MOESM1_ESM.docx (14 kb)
Supplementary material 1 (DOCX 13 kb)

References

  1. 1.
    Lund LH, Khush KK, Cherikh WS, Goldfarb S, Kucheryavaya AY, Levvey BJ, Meiser B, Rossano JW, Chambers DC, Yusen RD, Stehlik J, Lung T, International Society for H (2017) The Registry of the International Society for Heart and Lung Transplantation: thirty-fourth adult heart transplantation report-2017; focus theme: allograft ischemic time. J Heart Lung Transplant 36(10):1037–1046.  https://doi.org/10.1016/j.healun.2017.07.019 CrossRefPubMedGoogle Scholar
  2. 2.
    Schmauss D, Weis M (2008) Cardiac allograft vasculopathy: recent developments. Circulation 117(16):2131–2141.  https://doi.org/10.1161/CIRCULATIONAHA.107.711911 CrossRefPubMedGoogle Scholar
  3. 3.
    Rahmani M, Cruz RP, Granville DJ, McManus BM (2006) Allograft vasculopathy versus atherosclerosis. Circ Res 99(8):801–815.  https://doi.org/10.1161/01.RES.0000246086.93555.f3 CrossRefPubMedGoogle Scholar
  4. 4.
    Mehra MR, Crespo-Leiro MG, Dipchand A, Ensminger SM, Hiemann NE, Kobashigawa JA, Madsen J, Parameshwar J, Starling RC, Uber PA (2010) International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy 2010. J Heart Lung Transplant 29(7):717–727.  https://doi.org/10.1016/j.healun.2010.05.017 CrossRefPubMedGoogle Scholar
  5. 5.
    Yeung AC, Davis SF, Hauptman PJ, Kobashigawa JA, Miller LW, Valantine HA, Ventura HO, Wiedermann J, Wilensky R, Multicenter Intravascular Ultrasound Transplant Study Group (1995) Incidence and progression of transplant coronary artery disease over 1 year: results of a multicenter trial with use of intravascular ultrasound. J Heart Lung Transplant 14(6 Pt 2):S215–S220PubMedGoogle Scholar
  6. 6.
    Khandhar SJ, Yamamoto H, Teuteberg JJ, Shullo MA, Bezerra HG, Costa MA, Selzer F, Lee JS, Marroquin OC, McNamara DM, Mulukutla SR, Toma C (2013) Optical coherence tomography for characterization of cardiac allograft vasculopathy after heart transplantation (OCTCAV study). J Heart Lung Transplant 32(6):596–602.  https://doi.org/10.1016/j.healun.2013.02.005 CrossRefPubMedGoogle Scholar
  7. 7.
    Estep JD, Shah DJ, Nagueh SF, Mahmarian JJ, Torre-Amione G, Zoghbi WA (2009) The role of multimodality cardiac imaging in the transplanted heart. JACC Cardiovasc Imaging 2(9):1126–1140.  https://doi.org/10.1016/j.jcmg.2009.06.006 CrossRefPubMedGoogle Scholar
  8. 8.
    Gude E, Gullestad L, Andreassen AK (2017) Everolimus immunosuppression for renal protection, reduction of allograft vasculopathy and prevention of allograft rejection in de-novo heart transplant recipients: could we have it all? Curr Opin Organ Transplant 22(3):198–206.  https://doi.org/10.1097/MOT.0000000000000409 CrossRefPubMedGoogle Scholar
  9. 9.
    Tan CD, Baldwin WM 3rd, Rodriguez ER (2007) Update on cardiac transplantation pathology. Arch Pathol Lab Med 131(8):1169–1191.  https://doi.org/10.1043/1543-2165(2007)131%5b1169:uoctp%5d2.0.co;2 CrossRefPubMedGoogle Scholar
  10. 10.
    Hiemann NE, Meyer R, Wellnhofer E, Klimek WJ, Bocksch W, Hetzer R (2001) Correlation of angiographic and immunohistochemical findings in graft vessel disease after heart transplantation. Transplant Proc 33(1–2):1586–1590CrossRefGoogle Scholar
  11. 11.
    Broyd CJ, Hernandez-Perez F, Segovia J, Echavarria-Pinto M, Quiros-Carretero A, Salas C, Gonzalo N, Jimenez-Quevedo P, Nombela-Franco L, Salinas P, Nunez-Gil I, Del Trigo M, Goicolea J, Alonso-Pulpon L, Fernandez-Ortiz A, Parker K, Hughes A, Mayet J, Davies J, Escaned J (2018) Identification of capillary rarefaction using intracoronary wave intensity analysis with resultant prognostic implications for cardiac allograft patients. Eur Heart J 39(20):1807–1814.  https://doi.org/10.1093/eurheartj/ehx732 CrossRefPubMedGoogle Scholar
  12. 12.
    Gyongyosi M, Winkler J, Ramos I, Do QT, Firat H, McDonald K, Gonzalez A, Thum T, Diez J, Jaisser F, Pizard A, Zannad F (2017) Myocardial fibrosis: biomedical research from bench to bedside. Eur J Heart Fail 19(2):177–191.  https://doi.org/10.1002/ejhf.696 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Gramley F, Lorenzen J, Pezzella F, Kettering K, Himmrich E, Plumhans C, Koellensperger E, Munzel T (2009) Hypoxia and myocardial remodeling in human cardiac allografts: a time-course study. J Heart Lung Transplant 28(11):1119–1126.  https://doi.org/10.1016/j.healun.2009.05.038 CrossRefPubMedGoogle Scholar
  14. 14.
    Studeli R, Jung S, Mohacsi P, Perruchoud S, Castiglioni P, Wenaweser P, Heimbeck G, Feller M, Hullin R (2006) Diastolic dysfunction in human cardiac allografts is related with reduced SERCA2a gene expression. Am J Transplant 6(4):775–782.  https://doi.org/10.1111/j.1600-6143.2006.01241.x CrossRefPubMedGoogle Scholar
  15. 15.
    Schelbert EB, Fonarow GC, Bonow RO, Butler J, Gheorghiade M (2014) Therapeutic targets in heart failure: refocusing on the myocardial interstitium. J Am Coll Cardiol 63(21):2188–2198.  https://doi.org/10.1016/j.jacc.2014.01.068 CrossRefGoogle Scholar
  16. 16.
    Messroghli DR, Moon JC, Ferreira VM, Grosse-Wortmann L, He T, Kellman P, Mascherbauer J, Nezafat R, Salerno M, Schelbert EB, Taylor AJ, Thompson R, Ugander M, van Heeswijk RB, Friedrich MG (2017) Clinical recommendations for cardiovascular magnetic resonance mapping of T1, T2, T2* and extracellular volume: a consensus statement by the Society for Cardiovascular Magnetic Resonance (SCMR) endorsed by the European Association for Cardiovascular Imaging (EACVI). J Cardiovasc Magn Reson 19(1):75.  https://doi.org/10.1186/s12968-017-0389-8 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    White SK, Sado DM, Fontana M, Banypersad SM, Maestrini V, Flett AS, Piechnik SK, Robson MD, Hausenloy DJ, Sheikh AM, Hawkins PN, Moon JC (2013) T1 mapping for myocardial extracellular volume measurement by CMR: bolus only versus primed infusion technique. JACC Cardiovasc Imaging 6(9):955–962.  https://doi.org/10.1016/j.jcmg.2013.01.011 CrossRefPubMedGoogle Scholar
  18. 18.
    Cui Y, Cao Y, Song J, Dong N, Kong X, Wang J, Yuan Y, Zhu X, Yan X, Greiser A, Shi H, Han P (2018) Association between myocardial extracellular volume and strain analysis through cardiovascular magnetic resonance with histological myocardial fibrosis in patients awaiting heart transplantation. J Cardiovasc Magn Reson 20(1):25.  https://doi.org/10.1186/s12968-018-0445-z CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Tearney GJ, Regar E, Akasaka T, Adriaenssens T, Barlis P, Bezerra HG, Bouma B, Bruining N, Cho JM, Chowdhary S, Costa MA, de Silva R, Dijkstra J, Di Mario C, Dudek D, Falk E, Feldman MD, Fitzgerald P, Garcia-Garcia HM, Gonzalo N, Granada JF, Guagliumi G, Holm NR, Honda Y, Ikeno F, Kawasaki M, Kochman J, Koltowski L, Kubo T, Kume T, Kyono H, Lam CC, Lamouche G, Lee DP, Leon MB, Maehara A, Manfrini O, Mintz GS, Mizuno K, Morel MA, Nadkarni S, Okura H, Otake H, Pietrasik A, Prati F, Raber L, Radu MD, Rieber J, Riga M, Rollins A, Rosenberg M, Sirbu V, Serruys PW, Shimada K, Shinke T, Shite J, Siegel E, Sonoda S, Suter M, Takarada S, Tanaka A, Terashima M, Thim T, Uemura S, Ughi GJ, van Beusekom HM, van der Steen AF, van Es GA, van Soest G, Virmani R, Waxman S, Weissman NJ, Weisz G, International Working Group for Intravascular Optical Coherence Tomography (2012) Consensus standards for acquisition, measurement, and reporting of intravascular optical coherence tomography studies: a report from the International Working Group for Intravascular Optical Coherence Tomography Standardization and Validation. J Am Coll Cardiol 59(12):1058–1072.  https://doi.org/10.1016/j.jacc.2011.09.079 CrossRefPubMedGoogle Scholar
  20. 20.
    Messroghli DR, Radjenovic A, Kozerke S, Higgins DM, Sivananthan MU, Ridgway JP (2004) Modified Look-Locker inversion recovery (MOLLI) for high-resolution T1 mapping of the heart. Magn Reson Med 52(1):141–146.  https://doi.org/10.1002/mrm.20110 CrossRefPubMedGoogle Scholar
  21. 21.
    Fontana M, White SK, Banypersad SM, Sado DM, Maestrini V, Flett AS, Piechnik SK, Neubauer S, Roberts N, Moon JC (2012) Comparison of T1 mapping techniques for ECV quantification. Histological validation and reproducibility of ShMOLLI versus multibreath-hold T1 quantification equilibrium contrast CMR. J Cardiovasc Magn Reson 14:88.  https://doi.org/10.1186/1532-429x-14-88 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Nakamori S, Dohi K, Ishida M, Goto Y, Imanaka-Yoshida K, Omori T, Goto I, Kumagai N, Fujimoto N, Ichikawa Y, Kitagawa K, Yamada N, Sakuma H, Ito M (2017) Native T1 mapping and extracellular volume mapping for the assessment of diffuse myocardial fibrosis in dilated cardiomyopathy. JACC Cardiovasc Imaging.  https://doi.org/10.1016/j.jcmg.2017.04.006 CrossRefPubMedGoogle Scholar
  23. 23.
    Asleh R, Briasoulis A, Kremers WK, Adigun R, Boilson BA, Pereira NL, Edwards BS, Clavell AL, Schirger JA, Rodeheffer RJ, Frantz RP, Joyce LD, Maltais S, Stulak JM, Daly RC, Tilford J, Choi WG, Lerman A, Kushwaha SS (2018) Long-term sirolimus for primary immunosuppression in heart transplant recipients. J Am Coll Cardiol 71(6):636–650.  https://doi.org/10.1016/j.jacc.2017.12.005 CrossRefPubMedGoogle Scholar
  24. 24.
    Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, von Kaeppler HAV, Starling RC, Sorensen K, Hummel M, Lind JM, Abeywickrama KH, Bernhardt P, Group RBS (2003) Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med 349(9):847–858.  https://doi.org/10.1056/nejmoa022171 CrossRefPubMedGoogle Scholar
  25. 25.
    Clemmensen TS, Holm NR, Eiskjaer H, Jakobsen L, Berg K, Neghabat O, Logstrup BB, Christiansen EH, Dijkstra J, Terkelsen CJ, Maeng M, Poulsen SH (2018) Detection of early changes in the coronary artery microstructure after heart transplantation: a prospective optical coherence tomography study. J Heart Lung Transplant 37(4):486–495.  https://doi.org/10.1016/j.healun.2017.10.014 CrossRefPubMedGoogle Scholar
  26. 26.
    Yamani MH, Haji SA, Starling RC, Tuzcu EM, Ratliff NB, Cook DJ, Abdo A, Crowe T, Secic M, McCarthy P, Young JB (2002) Myocardial ischemic-fibrotic injury after human heart transplantation is associated with increased progression of vasculopathy, decreased cellular rejection and poor long-term outcome. J Am Coll Cardiol 39(6):970–977CrossRefGoogle Scholar
  27. 27.
    Armstrong AT, Binkley PF, Baker PB, Myerowitz PD, Leier CV (1998) Quantitative investigation of cardiomyocyte hypertrophy and myocardial fibrosis over 6 years after cardiac transplantation. J Am Coll Cardiol 32(3):704–710CrossRefGoogle Scholar
  28. 28.
    Cassar A, Matsuo Y, Herrmann J, Li J, Lennon RJ, Gulati R, Lerman LO, Kushwaha SS, Lerman A (2013) Coronary atherosclerosis with vulnerable plaque and complicated lesions in transplant recipients: new insight into cardiac allograft vasculopathy by optical coherence tomography. Eur Heart J 34(33):2610–2617.  https://doi.org/10.1093/eurheartj/eht236 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Clemmensen TS, Holm NR, Eiskjaer H, Logstrup BB, Christiansen EH, Dijkstra J, Barkholt TO, Terkelsen CJ, Maeng M, Poulsen SH (2017) Layered fibrotic plaques are the predominant component in cardiac allograft vasculopathy: systematic findings and risk stratification by OCT. JACC Cardiovasc Imaging 10(7):773–784.  https://doi.org/10.1016/j.jcmg.2016.10.021 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.RadiologyLausanne University Hospital (CHUV) and University of Lausanne (UNIL)LausanneSwitzerland
  2. 2.Cardiology and Cardiac SurgeryLausanne University Hospital (CHUV) and University of Lausanne (UNIL)LausanneSwitzerland
  3. 3.Clinical PathologyLausanne University Hospital (CHUV) and University of Lausanne (UNIL)LausanneSwitzerland
  4. 4.Center for Biomedical ImagingLausanneSwitzerland
  5. 5.CardiologyUniversity Hospital of Geneva (HUG)GenevaSwitzerland
  6. 6.Siemens Healthcare GmbH, Siemens AGErlangenGermany

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