Very Late Heart Transplant Rejection Is Associated with Microvascular Injury, Complement Deposition and Progression to Cardiac Allograft Vasculopathy

Authors

  • A. Loupy,

    1. Service de Transplantation Rénale et de Soins Intensifs, Hôpital Necker, APHP, Paris, F-75015, France
    2. Université Paris Descartes, Paris, France
    3. INSERM UMR 970, Biostatistics and Histopathology Platform, PARCC Cardiovascular Research Institute, Paris, France
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    • AL and JPDVH are members of the Centaure group.

  • A. Cazes,

    1. Université Paris Descartes, Paris, France
    2. Laboratoire d’Anatomie Pathologique, Hôpital Européen Georges Pompidou, APHP, Paris, F-75015, France
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  • R. Guillemain,

    1. Service de Chirurgie Cardiaque, Hôpital Européen Georges Pompidou, APHP, Paris, F-75015, France
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  • C. Amrein,

    1. Service de Chirurgie Cardiaque, Hôpital Européen Georges Pompidou, APHP, Paris, F-75015, France
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  • A. Hedjoudje,

    1. Laboratoire d’Anatomie Pathologique, Hôpital Européen Georges Pompidou, APHP, Paris, F-75015, France
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  • M. Tible,

    1. Laboratoire d’Anatomie Pathologique, Hôpital Européen Georges Pompidou, APHP, Paris, F-75015, France
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  • V. Pezzella,

    1. Service de Chirurgie Cardiaque, Hôpital Européen Georges Pompidou, APHP, Paris, F-75015, France
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  • J. N. Fabiani,

    1. Service de Chirurgie Cardiaque, Hôpital Européen Georges Pompidou, APHP, Paris, F-75015, France
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  • C. Suberbielle,

    1. Laboratoire d’Histocompatibilité Hôpital Saint Louis, APHP, Paris, F-75011, France
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  • D. Nochy,

    1. Laboratoire d’Anatomie Pathologique, Hôpital Européen Georges Pompidou, APHP, Paris, F-75015, France
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  • G. S. Hill,

    1. Laboratoire d’Anatomie Pathologique, Hôpital Européen Georges Pompidou, APHP, Paris, F-75015, France
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  • J. P. Empana,

    1. Université Paris Descartes, Paris, France
    2. INSERM UMR 970, Biostatistics and Histopathology Platform, PARCC Cardiovascular Research Institute, Paris, France
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  • X. Jouven,

    1. Université Paris Descartes, Paris, France
    2. INSERM UMR 970, Biostatistics and Histopathology Platform, PARCC Cardiovascular Research Institute, Paris, France
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  • P. Bruneval,

    1. Université Paris Descartes, Paris, France
    2. INSERM UMR 970, Biostatistics and Histopathology Platform, PARCC Cardiovascular Research Institute, Paris, France
    3. Laboratoire d’Anatomie Pathologique, Hôpital Européen Georges Pompidou, APHP, Paris, F-75015, France
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  • J. P. Duong Van Huyen

    Corresponding author
    1. Université Paris Descartes, Paris, France
    2. INSERM UMR 970, Biostatistics and Histopathology Platform, PARCC Cardiovascular Research Institute, Paris, France
    3. Laboratoire d’Anatomie Pathologique, Hôpital Européen Georges Pompidou, APHP, Paris, F-75015, France
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    • AL and JPDVH are members of the Centaure group.


Jean-Paul Duong Van Huyen, jp.dvh@wanadoo.fr

Abstract

In heart transplants, the significance of very late rejection (after 7 years post-transplant, VLR) detected by routine endomyocardial biopsies (EMB) remains uncertain. Here, we assessed the prevalence, histopathological and immunological phenotype, and outcome of VLR in clinically stable patients. Between 1985 and 2009, 10 662 protocol EMB were performed at our institution in 398 consecutive heart transplants recipients. Among the 196 patients with >7-year follow-up, 20 (10.2%) presented subclinical ≥3A/2R-ISHLT rejection. The VLR group was compared to a matched control group of patients without rejection. All biopsies were stained for C4d/C3d/CD68 with sera screened for the presence of donor-specific antibodies (DSAs). In addition to cellular infiltrates with myocyte damage, 60% of VLR patients had evidence of intravascular macrophages. C4d and/or C3d-capillary deposition was found in 55% VLR EMB. All cases of VLR associated with microcirculation injury had DSAs (mean DSAmax−MFI = 1751 ± 583). This entity was absent from the control group (p < 0.0001). Finally, after a similar follow-up postreference EMB of 6.4 ± 1 years, the mean of CAV grade was 0.76 ± 0.18 in the control group compared to 2.06 ± 0.26 in the VLR group respectively, p = 0.001). There was no difference in patient survival between study and control groups. In conclusion, VLR is frequently associated with complement-cascade activation, microvascular injury and DSA, suggesting an antibody-mediated process. VLR is associated with a dramatic progression to severe CAV in long-term follow-up.

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