New paradigm in graft rejection detection in heart transplantation recipients: diagnostic utility of synchrotron X-ray phase contrast imaging (GRAFT-XPCI) - a multi-centric, prospective, observational study protocol

    Authors

    Keywords

    heart transplantation, graft rejection, synchrotron imaging, histology

    DOI

    https://doi.org/10.15836/ccar2022.261

    Full Text

    **Background:** Graft rejection remains the most important complication after heart transplantation (HTx). Endomyocardial biopsy (EMB) is the gold standard in HTx follow-up, however, conventional histopathological (HP) analysis is limited by tissue damage during preparation, 2-dimensional (2D) analysis, and low inter-observer agreement in rejection grading. X-ray phase contrast imaging (X-PCI) has shown potential for non-destructive imaging of the myocardium, enabling high-resolution 3-dimensional (3D) analysis with fibrosis and fibre orientation quantification. (1) **Methods and Design:** GRAFT-XPCI is a multi-centric, prospective observational study aiming to prove non-inferiority of X-PCI in graft rejection diagnosis, vs. conventional HP **(****Figure 1****)**. It will include approximately 400 patients in standard post-HTx follow-up at 3 clinical centres: University Hospital Centre Zagreb, Dubrava University Hospital and Hospital Clinic Barcelona. Collected data will include EMB samples, patient history, laboratory, electrocardiogram (ECG), coronarography and echocardiographic data. EMB specimens will be initially imaged by X-PCI at the Paul Scherrer Institute (Villigen, Switzerland), producing digital 3D imaging datasets (at 0.65 um pixel resolution) for computational analysis, and then prepared for HP microscopy at the University of Zagreb School of Medicine. Three datasets will be generated for analysis - 2D X-PCI dataset, 3D X-PCI dataset, and 2D HP images. Acquired X-PCI images and HP slides will be diagnostically graded (ISHLT 2004. grading system) (2), comparatively assessed by at least two observers in a blinded fashion, further analysed in conjunction with gathered clinical data. Computer methods for the automatic and semi-automatic analysis of digital image datasets will be developed as an additional output. FIGURE 1. GRAFT- X-ray phase contrast imaging study. **Conclusion:** GRAFT-XPCI will: 1) compare X-PCI and conventional HP in graft rejection analysis, 2) enable insight into structural and pathophysiological processes in graft rejection after HTx, 3) extend the amount of information gained by EMB analysis. The development of new research tools and imaging protocols should widen future research of EMB analysis in various cardiac conditions. This study has been fully supported by the Croatian Science Foundation under the trial registration no. UIP-2020-02-5572.

    Literature

    1. Planinc I, Garcia-Canadilla P, Dejea H, Ilic I, Guasch E, Zamora M, et al. Comprehensive assessment of myocardial remodeling in ischemic heart disease by synchrotron propagation based X-ray phase contrast imaging. Sci Rep. 2021 July 7;11(1):14020. https://doi.org/10.1038/s41598-021-93054-6
    2. Stewart S, Winters GL, Fishbein MC, Tazelaar HD, Kobashigawa J, Abrams J, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant. 2005 November;24(11):1710–20. https://doi.org/10.1016/j.healun.2005.03.019
    Cardiologia Croatica
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    New paradigm in graft rejection detection in heart transplantation recipients: diagnostic utility of synchrotron X-ray phase contrast imaging (GRAFT-XPCI) - a multi-centric, prospective, observational study protocol

    Extended Abstract
    Issue9-10
    Published
    Pages261-262
    PDF via DOIhttps://doi.org/10.15836/ccar2022.261
    heart transplantation
    graft rejection
    synchrotron imaging
    histology

    Authors

    Nikola Škreb*ORCIDUniversity of Zagreb School of Medicine, Zagreb, Croatia
    Filip LončarićORCIDUniversity Hospital Centre Zagreb, Zagreb, Croatia
    Bart BijnensORCIDInstitut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
    Anne BonninORCIDPaul Scherrer Institute, Villigen, Switzerland
    Hector DejeaORCIDLund University, Lund, Sweden
    Marta Farrero TorresORCIDHospital Clinic Barcelona, Barcelona, Spain
    Patricia Garcia CanadillaORCIDHospital Sant Joan de Déu Barcelona, Barcelona, Spain
    Sven LončarićORCIDUniversity of Zagreb, Zagreb, Croatia
    Angela López-SainzORCIDHospital Clinic Barcelona, Barcelona, Spain
    Hrvoje GašparovićORCIDUniversity of Zagreb School of Medicine, Zagreb, Croatia
    Ivana IlićORCIDUniversity of Zagreb School of Medicine, Zagreb, Croatia
    Davor MiličićORCIDUniversity of Zagreb School of Medicine, Zagreb, Croatia
    Igor RudežORCIDUniversity of Zagreb School of Medicine, Zagreb, Croatia
    Boško SkorićORCIDUniversity of Zagreb School of Medicine, Zagreb, Croatia
    Ivo PlanincORCIDUniversity of Zagreb School of Medicine, Zagreb, Croatia
    Maja ČikešORCIDUniversity of Zagreb School of Medicine, Zagreb, Croatia

    *Correspondence email: nikola.skreb7@gmail.com

    Full Text

    Background: Graft rejection remains the most important complication after heart transplantation (HTx). Endomyocardial biopsy (EMB) is the gold standard in HTx follow-up, however, conventional histopathological (HP) analysis is limited by tissue damage during preparation, 2-dimensional (2D) analysis, and low inter-observer agreement in rejection grading. X-ray phase contrast imaging (X-PCI) has shown potential for non-destructive imaging of the myocardium, enabling high-resolution 3-dimensional (3D) analysis with fibrosis and fibre orientation quantification. (1)

    Methods and Design: GRAFT-XPCI is a multi-centric, prospective observational study aiming to prove non-inferiority of X-PCI in graft rejection diagnosis, vs. conventional HP (Figure 1). It will include approximately 400 patients in standard post-HTx follow-up at 3 clinical centres: University Hospital Centre Zagreb, Dubrava University Hospital and Hospital Clinic Barcelona. Collected data will include EMB samples, patient history, laboratory, electrocardiogram (ECG), coronarography and echocardiographic data. EMB specimens will be initially imaged by X-PCI at the Paul Scherrer Institute (Villigen, Switzerland), producing digital 3D imaging datasets (at 0.65 um pixel resolution) for computational analysis, and then prepared for HP microscopy at the University of Zagreb School of Medicine. Three datasets will be generated for analysis - 2D X-PCI dataset, 3D X-PCI dataset, and 2D HP images. Acquired X-PCI images and HP slides will be diagnostically graded (ISHLT 2004. grading system) (2), comparatively assessed by at least two observers in a blinded fashion, further analysed in conjunction with gathered clinical data. Computer methods for the automatic and semi-automatic analysis of digital image datasets will be developed as an additional output.

    FIGURE 1. GRAFT- X-ray phase contrast imaging study.

    Conclusion: GRAFT-XPCI will: 1) compare X-PCI and conventional HP in graft rejection analysis, 2) enable insight into structural and pathophysiological processes in graft rejection after HTx, 3) extend the amount of information gained by EMB analysis. The development of new research tools and imaging protocols should widen future research of EMB analysis in various cardiac conditions. This study has been fully supported by the Croatian Science Foundation under the trial registration no. UIP-2020-02-5572.

    Literature

    1. 1.
      Planinc I, Garcia-Canadilla P, Dejea H, Ilic I, Guasch E, Zamora M, et al. Comprehensive assessment of myocardial remodeling in ischemic heart disease by synchrotron propagation based X-ray phase contrast imaging. Sci Rep. 2021 July 7;11(1):14020.DOI
    2. 2.
      Stewart S, Winters GL, Fishbein MC, Tazelaar HD, Kobashigawa J, Abrams J, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant. 2005 November;24(11):1710–20.DOI