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Proteomic profiling identifies CLEC4C expression as a novel biomarker of primary graft dysfunction after heart transplantation.

Publication ,  Journal Article
Truby, LK; Kwee, LC; Agarwal, R; Grass, E; DeVore, AD; Patel, CB; Chen, D; Schroder, JN; Bowles, D; Milano, CA; Shah, SH; Holley, CL
Published in: J Heart Lung Transplant
December 2021

PURPOSE: Clinical models to identify patients at high risk of primary graft dysfunction (PGD) after heart transplantation (HT) are limited, and the underlying pathophysiology of this common post-transplant complication remains poorly understood. We sought to identify whether pre-transplant levels of circulating proteins reporting on immune activation and inflammation are associated with incident PGD. METHODS: The study population consisted of 219 adult heart transplant recipients identified between 2016 and 2020 at Duke University Medical Center, randomly divided into derivation (n = 131) and validation (n = 88) sets. PGD was defined using modified ISHLT criteria. Proteomic profiling was performed using Olink panels (n = 354 proteins) with serum samples collected immediately prior to transplantation. Association between normalized relative protein expression and PGD was tested using univariate and multivariable (recipient age, creatinine, mechanical circulatory support, and sex; donor age; ischemic time) models. Significant proteins identified in the derivation set (p < 0.05 in univariate models), were then tested in the validation set. Pathway enrichment analysis was used to test candidate biological processes. The predictive performance of proteins was compared to that of the RADIAL score. RESULTS: Nine proteins were associated with PGD in univariate models in the derivation set. Of these, only CLEC4C remained associated with PGD in the validation set after Bonferroni correction (OR [95% CI] = 3.04 [1.74,5.82], p = 2.8 × 10-4). Patterns of association were consistent for CLEC4C in analyses stratified by biventricular/left ventricular and isolated right ventricular PGD. Pathway analysis identified interferon-alpha response and C-type lectin signaling as significantly enriched biologic processes. The RADIAL score was a poor predictor of PGD (AUC = 0.55). CLEC4C alone (AUC = 0.66, p = 0.048) and in combination with the clinical covariates from the multivariable model (AUC = 0.69, p = 0.018) improved discrimination for the primary outcome. CONCLUSIONS: Pre-transplantation circulating levels of CLEC4C, a protein marker of plasmacytoid dendritic cells (pDCs), may identify HT recipients at risk for PGD. Further studies are needed to better understand the potential role pDCs and the innate immune response in PGD.

Duke Scholars

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Published In

J Heart Lung Transplant

DOI

EISSN

1557-3117

Publication Date

December 2021

Volume

40

Issue

12

Start / End Page

1589 / 1598

Location

United States

Related Subject Headings

  • Surgery
  • Sensitivity and Specificity
  • Receptors, Immunologic
  • Proteomics
  • Primary Graft Dysfunction
  • Postoperative Complications
  • Middle Aged
  • Membrane Glycoproteins
  • Male
  • Lectins, C-Type
 

Citation

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Truby, L. K., Kwee, L. C., Agarwal, R., Grass, E., DeVore, A. D., Patel, C. B., … Holley, C. L. (2021). Proteomic profiling identifies CLEC4C expression as a novel biomarker of primary graft dysfunction after heart transplantation. J Heart Lung Transplant, 40(12), 1589–1598. https://doi.org/10.1016/j.healun.2021.07.024
Truby, Lauren K., Lydia Coulter Kwee, Richa Agarwal, Elizabeth Grass, Adam D. DeVore, Chetan B. Patel, Dongfeng Chen, et al. “Proteomic profiling identifies CLEC4C expression as a novel biomarker of primary graft dysfunction after heart transplantation.J Heart Lung Transplant 40, no. 12 (December 2021): 1589–98. https://doi.org/10.1016/j.healun.2021.07.024.
Truby LK, Kwee LC, Agarwal R, Grass E, DeVore AD, Patel CB, et al. Proteomic profiling identifies CLEC4C expression as a novel biomarker of primary graft dysfunction after heart transplantation. J Heart Lung Transplant. 2021 Dec;40(12):1589–98.
Truby, Lauren K., et al. “Proteomic profiling identifies CLEC4C expression as a novel biomarker of primary graft dysfunction after heart transplantation.J Heart Lung Transplant, vol. 40, no. 12, Dec. 2021, pp. 1589–98. Pubmed, doi:10.1016/j.healun.2021.07.024.
Truby LK, Kwee LC, Agarwal R, Grass E, DeVore AD, Patel CB, Chen D, Schroder JN, Bowles D, Milano CA, Shah SH, Holley CL. Proteomic profiling identifies CLEC4C expression as a novel biomarker of primary graft dysfunction after heart transplantation. J Heart Lung Transplant. 2021 Dec;40(12):1589–1598.
Journal cover image

Published In

J Heart Lung Transplant

DOI

EISSN

1557-3117

Publication Date

December 2021

Volume

40

Issue

12

Start / End Page

1589 / 1598

Location

United States

Related Subject Headings

  • Surgery
  • Sensitivity and Specificity
  • Receptors, Immunologic
  • Proteomics
  • Primary Graft Dysfunction
  • Postoperative Complications
  • Middle Aged
  • Membrane Glycoproteins
  • Male
  • Lectins, C-Type