Rationale and Protocol of the Multimodality Evaluation of Antibody-Mediated Injury in Heart Transplantation (LEONE-HT) Observational Cross-Sectional Study

Jorge Nuche, Javier de la Cruz Bertolo, Irene Marco Clement, Violeta Sánchez Sánchez, Fernando Sarnago Cebada, Esther Mancebo, Ana Belén Enguita, Marina Alonso-Riaño, Gema Ruiz-Hurtado, Juan Carlos López-Azor, Francisco José Hernández-Pérez, Javier Castrodeza, Javier Sánchez González, Fernando Arribas Ynsaurriaga, María Dolores García-Cosío Carmena, Juan F Delgado, Jorge Nuche, Javier de la Cruz Bertolo, Irene Marco Clement, Violeta Sánchez Sánchez, Fernando Sarnago Cebada, Esther Mancebo, Ana Belén Enguita, Marina Alonso-Riaño, Gema Ruiz-Hurtado, Juan Carlos López-Azor, Francisco José Hernández-Pérez, Javier Castrodeza, Javier Sánchez González, Fernando Arribas Ynsaurriaga, María Dolores García-Cosío Carmena, Juan F Delgado

Abstract

Introduction: Heart transplant (HT) survival has barely improved in the last decades, which is unsatisfactory for many HT recipients. The development of anti-human leukocyte antigen (anti-HLA) antibodies in HT patients is associated with a cardiac allograft dysfunction. The mechanisms leading to this damage are unclear. The Multimodality Evaluation Of Antibody-Mediated Injury In Heart Transplantation (LEONE-HT) study aimed to thoroughly describe the damage inflicted on the myocardium by anti-HLA antibodies.

Methods and analysis: The LEONE-HT study is a cohort study with a cross-sectional approach in which HT patients with positive anti-HLA antibodies are compared with coetaneous HT patients with negative anti-HLA antibodies. All patients will undergo a state-of-the-art multimodal assessment, including imaging techniques, coronary anatomy and physiology evaluations and histological and immunological analyses. The individual and combined primary outcomes of structural graft injuries and longitudinal secondary outcomes are to be compared between the exposed and non-exposed groups with univariate and multivariable descriptive analyses.

Ethics and dissemination: The LEONE-HT study is carried out in accordance with the principles set out in the Declaration of Helsinki and the International Conference on Harmonization guidelines for good clinical practice and following national laws and regulations. The study design, objectives and participant centers have been communicated to clinicaltrials.gov (NCT05184426). The LEONE-HT study counts on the support of patient associations to disseminate the objectives and results of the research. This study was funded by the Spanish Ministry of Science and Innovation and the Spanish Society of Cardiology.

Keywords: anti-HLA antibodies; heart transplant; rejection.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Working hypothesis and expected outcomes. CFR: coronary flow reserve; ECV: extracellular volume; FFR: fractional flow reserve; FGF: fibroblast growth factor; IMR: index of microvascular resistance; STIR: short tau inversion recovery.
Figure 2
Figure 2
Study design and patient workflow.
Figure 3
Figure 3
Study timeline and milestones.

References

    1. McDonagh T.A., Metra M., Adamo M., Gardner R.S., Baumbach A., Böhm M., Burri H., Butler J., Čelutkienė J., Chioncel O., et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur. J. Heart. 2022;24:4–131. doi: 10.1002/ejhf.2333.
    1. Khush K.K., Cherikh W.S., Chambers D.C., Goldfarb S., Hayes D., Kucheryavaya A.Y., Levvey B.J., Meiser B., Rossano J.W., Stehlik J., et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-fifth Adult Heart Transplantation Report-2018; Focus Theme: Multiorgan Transplantation. J. Heart Lung Transplant. 2018;37:1155–1168. doi: 10.1016/j.healun.2018.07.022.
    1. López-Sainz Á., Barge-Caballero E., Barge-Caballero G., Couto-Mallón D., Paniagua-Martin M.J., Seoane-Quiroga L., Iglesias-Gil C., Herrera-Noreña J.M., Cuenca-Castillo J.J., Vázquez-Rodríguez J.M., et al. Late graft failure in heart transplant recipients: Incidence, risk factors and clinical outcomes. Eur. J. Heart. 2018;20:385–394. doi: 10.1002/ejhf.886.
    1. Loupy A., Toquet C., Rouvier P., Beuscart T., Bories M.C., Varnous S., Guillemain R., Pattier S., Suberbielle C., Leprince P., et al. Late Failing Heart Allografts: Pathology of Cardiac Allograft Vasculopathy and Association with Antibody-Mediated Rejection. Am. J. Transplant. 2016;16:111–120. doi: 10.1111/ajt.13529.
    1. Smith J.D., Banner N.R., Hamour I.M., Ozawa M., Goh A., Robinson D., Terasaki P.I., Rose M.L. De novo donor HLA-specific antibodies after heart transplantation are an independent predictor of poor patient survival. Am. J. Transplant. 2011;11:312–319. doi: 10.1111/j.1600-6143.2010.03383.x.
    1. Kobashigawa J., Colvin M., Potena L., Dragun D., Crespo-Leiro M.G., Delgado J.F., Olymbios M., Parameshwar J., Patel J., Reed E., et al. The management of antibodies in heart transplantation: An ISHLT consensus document. J. Heart Lung Transplant. 2018;37:537–547. doi: 10.1016/j.healun.2018.01.1291.
    1. Costanzo M.R., Dipchand A., Starling R., Anderson A., Chan M., Desai S., Fedson S., Fisher P., Gonzales-Stawinski G., Martinelli L., et al. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J. Heart Lung Transplant. 2010;29:914–956. doi: 10.1016/j.healun.2010.05.034.
    1. Terasaki P.I. Humoral theory of transplantation. Am. J. Transplant. 2003;3:665–673. doi: 10.1034/j.1600-6143.2003.00135.x.
    1. Tambur A.R., Pamboukian S.V., Costanzo M.R., Herrera N.D., Dunlap S., Montpetit M., Heroux A. The presence of HLA-directed antibodies after heart transplantation is associated with poor allograft outcome. Transplantation. 2005;80:1019–1025. doi: 10.1097/01.tp.0000180564.14050.49.
    1. Loupy A., Haas M., Roufosse C., Naesens M., Adam B., Afrouzian M., Akalin E., Alachkar N., Bagnasco S., Becker J.U., et al. The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection. Am. J. Transplant. 2020;20:2318–2331. doi: 10.1111/ajt.15898.
    1. Berry G.J., Burke M.M., Andersen C., Bruneval P., Fedrigo M., Fishbein M.C., Goddard M., Hammond E.H., Leone O., Marboe C., et al. The 2013 International Society for Heart and Lung Transplantation Working Formulation for the standardization of nomenclature in the pathologic diagnosis of antibody-mediated rejection in heart transplantation. J. Heart Lung Transplant. 2013;32:1147–1162. doi: 10.1016/j.healun.2013.08.011.
    1. Afzali B., Chapman E., Racapé M., Adam B., Bruneval P., Gil F., Kim D., Hidalgo L., Campbell P., Sis B., et al. Molecular Assessment of Microcirculation Injury in Formalin-Fixed Human Cardiac Allograft Biopsies with Antibody-Mediated Rejection. Am. J. Transplant. 2017;17:496–505. doi: 10.1111/ajt.13956.
    1. Yang H.M., Khush K., Luikart H., Okada K., Lim H.S., Kobayashi Y., Honda Y., Yeung A.C., Valantine H., Fearon W.F. Invasive Assessment of Coronary Physiology Predicts Late Mortality After Heart Transplantation. Circulation. 2016;133:1945–1950. doi: 10.1161/CIRCULATIONAHA.115.018741.
    1. López B., González A., Ravassa S., Beaumont J., Moreno M.U., San José G., Querejeta R., Díez J. Circulating Biomarkers of Myocardial Fibrosis: The Need for a Reappraisal. J. Am. Coll. Cardiol. 2015;65:2449–2456. doi: 10.1016/j.jacc.2015.04.026.
    1. Vázquez-Sánchez S., Poveda J., Navarro-García J.A., González-Lafuente L., Rodríguez-Sánchez E., Ruilope L.M., Ruiz-Hurtado G. An Overview of FGF-23 as a Novel Candidate Biomarker of Cardiovascular Risk. Front. Physiol. 2021;12:632260. doi: 10.3389/fphys.2021.632260.
    1. Dolan R.S., Rahsepar A.A., Blaisdell J., Suwa K., Ghafourian K., Wilcox J.E., Khan S.S., Vorovich E.E., Rich J.D., Anderson A.S., et al. Multiparametric Cardiac Magnetic Resonance Imaging Can Detect Acute Cardiac Allograft Rejection After Heart Transplantation. JACC Cardiovasc. Imaging. 2019;12:1632–1641. doi: 10.1016/j.jcmg.2019.01.026.
    1. Mingo-Santos S., Moñivas-Palomero V., Garcia-Lunar I., Mitroi C.D., Goirigolzarri-Artaza J., Rivero B., Oteo J.F., Castedo E., González-Mirelis J., Cavero M.A., et al. Usefulness of Two-Dimensional Strain Parameters to Diagnose Acute Rejection after Heart Transplantation. J. Am. Soc. Echocardiogr. 2015;28:1149–1156. doi: 10.1016/j.echo.2015.06.005.
    1. Kobashigawa J.A., Tobis J.M., Starling R.C., Tuzcu E.M., Smith A.L., Valantine H.A., Yeung A.C., Mehra M.R., Anzai H., Oeser B.T., et al. Multicenter intravascular ultrasound validation study among heart transplant recipients: Outcomes after five years. J. Am. Coll. Cardiol. 2005;45:1532–1537. doi: 10.1016/j.jacc.2005.02.035.
    1. Wavamunno M.D., O’Connell P.J., Vitalone M., Fung C.L., Allen R.D., Chapman J.R., Nankivell B.J. Transplant glomerulopathy: Ultrastructural abnormalities occur early in longitudinal analysis of protocol biopsies. Am. J. Transplant. 2007;7:2757–2768. doi: 10.1111/j.1600-6143.2007.01995.x.
    1. Harris P.A., Taylor R., Thielke R., Payne J., Gonzalez N., Conde J.G. Research electronic data capture (REDCap)—A metadata-driven methodology and workflow process for providing translational research informatics support. J. Biomed. Inform. 2009;42:377–381. doi: 10.1016/j.jbi.2008.08.010.
    1. Harris P.A., Taylor R., Minor B.L., Elliott V., Fernandez M., O’Neal L., McLeod L., Delacqua G., Delacqua F., Kirby J., et al. The REDCap consortium: Building an international community of software platform partners. J. Biomed. Inform. 2019;95:103208. doi: 10.1016/j.jbi.2019.103208.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi