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      Factors associated with cardiac allograft vasculopathy after heart transplantation

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          Abstract

          Introduction

          Cardiac allograft vasculopathy (CAV) is a major threat to long-term survival after heart transplantation (HT).

          Aim

          To determine factors associated with CAV detection in patients after HT.

          Material and methods

          We analyzed 299 consecutive patients after HT who underwent routine visits at our institution between 2016 and 2018. Human interleukin 33 (IL-33) and suppression of tumorigenicity 2 (ST2) were measured by sandwich enzyme-linked immunosorbent assay with a commercially available kit (Human ST-2 and IL-33 ELISA, SunRedBio Technology Co, Ltd, Shanghai, China).

          Results

          The patients’ median age was 59.00 years, and 74.2% were men. The frequency of CAV was 47.5%. Multivariable logistic regression analysis showed that IL-33 (odds ratio (OR) = 1.044 (1.029–1.059), p < 0.001) and ST2 (OR = 1.061 (1.040–1.083), p < 0.001) serum concentrations, donor age (OR = 1.046 (1.009–1.085), p = 0.015), left ventricular diastolic dimension (LVDD) (OR = 1.081 (1.016–1.149), p = 0.013), and time from HT to blood collection (OR = 1.256 (1.151–1.371), p < 0.001) were independent risk factors for CAV. The area under the receiver operating characteristics curve (AUC) indicated good prognostic power of IL-33 and ST2 concentrations (AUC = 0.779 and AUC = 0.784, respectively) and excellent prognostic power of the IL-33/ST2 score (AUC = 0.863).

          Conclusions

          Lower IL-33 and higher ST2 serum concentrations, as well as older donor age, larger LVDD and longer time from HT to blood collection, are independently associated with CAV. IL-33 and ST2 have good discriminatory power and the IL-33/ST2 score has excellent strength for detecting CAV.

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          Most cited references36

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          Interleukin-33 in health and disease.

          Interleukin-33 (IL-33) - a member of the IL-1 family - was originally described as an inducer of type 2 immune responses, activating T helper 2 (TH2) cells and mast cells. Now, evidence is accumulating that IL-33 also potently stimulates group 2 innate lymphoid cells (ILC2s), regulatory T (Treg) cells, TH1 cells, CD8(+) T cells and natural killer (NK) cells. This pleiotropic nature is reflected in the role of IL-33 in tissue and metabolic homeostasis, infection, inflammation, cancer and diseases of the central nervous system. In this Review, we highlight the molecular and cellular characteristics of IL-33, together with its major role in health and disease and the potential therapeutic implications of these findings in humans.
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            IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system.

            ST2 is an IL-1 receptor family member with transmembrane (ST2L) and soluble (sST2) isoforms. sST2 is a mechanically induced cardiomyocyte protein, and serum sST2 levels predict outcome in patients with acute myocardial infarction or chronic heart failure. Recently, IL-33 was identified as a functional ligand of ST2L, allowing exploration of the role of ST2 in myocardium. We found that IL-33 was a biomechanically induced protein predominantly synthesized by cardiac fibroblasts. IL-33 markedly antagonized angiotensin II- and phenylephrine-induced cardiomyocyte hypertrophy. Although IL-33 activated NF-kappaB, it inhibited angiotensin II- and phenylephrine-induced phosphorylation of inhibitor of NF-kappa B alpha (I kappa B alpha) and NF-kappaB nuclear binding activity. sST2 blocked antihypertrophic effects of IL-33, indicating that sST2 functions in myocardium as a soluble decoy receptor. Following pressure overload by transverse aortic constriction (TAC), ST2(-/-) mice had more left ventricular hypertrophy, more chamber dilation, reduced fractional shortening, more fibrosis, and impaired survival compared with WT littermates. Furthermore, recombinant IL-33 treatment reduced hypertrophy and fibrosis and improved survival after TAC in WT mice, but not in ST2(-/-) littermates. Thus, IL-33/ST2 signaling is a mechanically activated, cardioprotective fibroblast-cardiomyocyte paracrine system, which we believe to be novel. IL-33 may have therapeutic potential for beneficially regulating the myocardial response to overload.
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              Interleukin-33 (IL-33): A nuclear cytokine from the IL-1 family.

              Interleukin-33 (IL-33) is a tissue-derived nuclear cytokine from the IL-1 family abundantly expressed in endothelial cells, epithelial cells and fibroblast-like cells, both during homeostasis and inflammation. It functions as an alarm signal (alarmin) released upon cell injury or tissue damage to alert immune cells expressing the ST2 receptor (IL-1RL1). The major targets of IL-33 in vivo are tissue-resident immune cells such as mast cells, group 2 innate lymphoid cells (ILC2s) and regulatory T cells (Tregs). Other cellular targets include T helper 2 (Th2) cells, eosinophils, basophils, dendritic cells, Th1 cells, CD8+T cells, NK cells, iNKT cells, B cells, neutrophils and macrophages. IL-33 is thus emerging as a crucial immune modulator with pleiotropic activities in type-2, type-1 and regulatory immune responses, and important roles in allergic, fibrotic, infectious, and chronic inflammatory diseases. The critical function of IL-33/ST2 signaling in allergic inflammation is illustrated by the fact that IL33 and IL1RL1 are among the most highly replicated susceptibility loci for asthma. In this review, we highlight 15 years of discoveries on IL-33 protein, including its molecular characteristics, nuclear localization, bioactive forms, cellular sources, mechanisms of release and regulation by proteases. Importantly, we emphasize data that have been validated using IL-33-deficient cells.
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                Author and article information

                Journal
                Postepy Kardiol Interwencyjnej
                Postepy Kardiol Interwencyjnej
                PWKI
                Postępy w Kardiologii Interwencyjnej = Advances in Interventional Cardiology
                Termedia Publishing House
                1734-9338
                1897-4295
                20 October 2022
                September 2022
                : 18
                : 3
                : 237-245
                Affiliations
                [1 ]Department of Heart and Vessels Diseases, Silesian Center for Heart Diseases, Zabrze, Poland
                [2 ]3 rd Department of Cardiology, School of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, Poland
                [3 ]Department of Biostatistics, School of Public Health in Bytom, Medical University of Silesia in Katowice, Poland
                [4 ]Department of Cardiac, Vascular and Endovascular Surgery and Transplantology in Zabrze, School of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, Poland
                [5 ]Student Scientific Society, 3 rd Department of Cardiology, School of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, Poland
                Author notes
                Corresponding author: Bożena Szyguła-Jurkiewicz, 3 rd Department of Cardiology, School of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, Poland.
                Article
                48013
                10.5114/aic.2022.120370
                9885235
                44546577-53a8-4b1d-8a00-28244ee20c83
                Copyright: © 2022 Termedia Sp. z o. o.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License, allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.

                History
                : 29 July 2022
                : 08 September 2022
                Categories
                Original Paper

                heart transplantation,factors,cardiac allograft vasculopathy

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