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Low levels of circulating methylated IRX3 are related to worse outcome after transcatheter aortic valve implantation in patients with severe aortic stenosis

BACKGROUND: Aortic stenosis (AS) is one of the most common cardiac diseases and major cause of morbidity and mortality in the elderly. Transcatheter aortic valve implantation (TAVI) is performed in such patients with symptomatic severe AS and reduces mortality for the majority of these patients. How...

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Autores principales: Kanwischer, Leon, Xu, Xingbo, Saifuddin, Afifa Binta, Maamari, Sabine, Tan, Xiaoying, Alnour, Fouzi, Tampe, Björn, Meyer, Thomas, Zeisberg, Michael, Hasenfuss, Gerd, Puls, Miriam, Zeisberg, Elisabeth M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10496273/
https://www.ncbi.nlm.nih.gov/pubmed/37697352
http://dx.doi.org/10.1186/s13148-023-01561-2
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author Kanwischer, Leon
Xu, Xingbo
Saifuddin, Afifa Binta
Maamari, Sabine
Tan, Xiaoying
Alnour, Fouzi
Tampe, Björn
Meyer, Thomas
Zeisberg, Michael
Hasenfuss, Gerd
Puls, Miriam
Zeisberg, Elisabeth M.
author_facet Kanwischer, Leon
Xu, Xingbo
Saifuddin, Afifa Binta
Maamari, Sabine
Tan, Xiaoying
Alnour, Fouzi
Tampe, Björn
Meyer, Thomas
Zeisberg, Michael
Hasenfuss, Gerd
Puls, Miriam
Zeisberg, Elisabeth M.
author_sort Kanwischer, Leon
collection PubMed
description BACKGROUND: Aortic stenosis (AS) is one of the most common cardiac diseases and major cause of morbidity and mortality in the elderly. Transcatheter aortic valve implantation (TAVI) is performed in such patients with symptomatic severe AS and reduces mortality for the majority of these patients. However, a significant percentage dies within the first two years after TAVI, such that there is an interest to identify parameters, which predict outcome and could guide pre-TAVI patient selection. High levels of cardiac fibrosis have been identified as such independent predictor of cardiovascular mortality after TAVI. Promoter hypermethylation commonly leads to gene downregulation, and the Iroquois homeobox 3 (IRX3) gene was identified in a genome-wide transcriptome and methylome to be hypermethylated and downregulated in AS patients. In a well-described cohort of 100 TAVI patients in which cardiac fibrosis levels were quantified histologically in cardiac biopsies, and which had a follow-up of up to two years, we investigated if circulating methylated DNA of IRX3 in the peripheral blood is associated with cardiac fibrosis and/or mortality in AS patients undergoing TAVI and thus could serve as a biomarker to add information on outcome after TAVI. RESULTS: Patients with high levels of methylation in circulating IRX3 show a significantly increased survival as compared to patients with low levels of IRX3 methylation indicating that high peripheral IRX3 methylation is associated with an improved outcome. In the multivariable setting, peripheral IRX3 methylation acts as an independent predictor of all-cause mortality. While there is no significant correlation of levels of IRX3 methylation with cardiac death, there is a significant but very weak inverse correlation between circulating IRX3 promoter methylation level and the amount of cardiac fibrosis. Higher levels of peripheral IRX3 methylation further correlated with decreased cardiac IRX3 expression and vice versa. CONCLUSIONS: High levels of IRX3 methylation in the blood of AS patients at the time of TAVI are associated with better overall survival after TAVI and at least partially reflect myocardial IRX3 expression. Circulating methylated IRX3 might aid as a potential biomarker to help guide both pre-TAVI patient selection and post-TAVI monitoring. GRAPHICAL ABSTRACT: [Image: see text]
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spelling pubmed-104962732023-09-13 Low levels of circulating methylated IRX3 are related to worse outcome after transcatheter aortic valve implantation in patients with severe aortic stenosis Kanwischer, Leon Xu, Xingbo Saifuddin, Afifa Binta Maamari, Sabine Tan, Xiaoying Alnour, Fouzi Tampe, Björn Meyer, Thomas Zeisberg, Michael Hasenfuss, Gerd Puls, Miriam Zeisberg, Elisabeth M. Clin Epigenetics Research BACKGROUND: Aortic stenosis (AS) is one of the most common cardiac diseases and major cause of morbidity and mortality in the elderly. Transcatheter aortic valve implantation (TAVI) is performed in such patients with symptomatic severe AS and reduces mortality for the majority of these patients. However, a significant percentage dies within the first two years after TAVI, such that there is an interest to identify parameters, which predict outcome and could guide pre-TAVI patient selection. High levels of cardiac fibrosis have been identified as such independent predictor of cardiovascular mortality after TAVI. Promoter hypermethylation commonly leads to gene downregulation, and the Iroquois homeobox 3 (IRX3) gene was identified in a genome-wide transcriptome and methylome to be hypermethylated and downregulated in AS patients. In a well-described cohort of 100 TAVI patients in which cardiac fibrosis levels were quantified histologically in cardiac biopsies, and which had a follow-up of up to two years, we investigated if circulating methylated DNA of IRX3 in the peripheral blood is associated with cardiac fibrosis and/or mortality in AS patients undergoing TAVI and thus could serve as a biomarker to add information on outcome after TAVI. RESULTS: Patients with high levels of methylation in circulating IRX3 show a significantly increased survival as compared to patients with low levels of IRX3 methylation indicating that high peripheral IRX3 methylation is associated with an improved outcome. In the multivariable setting, peripheral IRX3 methylation acts as an independent predictor of all-cause mortality. While there is no significant correlation of levels of IRX3 methylation with cardiac death, there is a significant but very weak inverse correlation between circulating IRX3 promoter methylation level and the amount of cardiac fibrosis. Higher levels of peripheral IRX3 methylation further correlated with decreased cardiac IRX3 expression and vice versa. CONCLUSIONS: High levels of IRX3 methylation in the blood of AS patients at the time of TAVI are associated with better overall survival after TAVI and at least partially reflect myocardial IRX3 expression. Circulating methylated IRX3 might aid as a potential biomarker to help guide both pre-TAVI patient selection and post-TAVI monitoring. GRAPHICAL ABSTRACT: [Image: see text] BioMed Central 2023-09-11 /pmc/articles/PMC10496273/ /pubmed/37697352 http://dx.doi.org/10.1186/s13148-023-01561-2 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Kanwischer, Leon
Xu, Xingbo
Saifuddin, Afifa Binta
Maamari, Sabine
Tan, Xiaoying
Alnour, Fouzi
Tampe, Björn
Meyer, Thomas
Zeisberg, Michael
Hasenfuss, Gerd
Puls, Miriam
Zeisberg, Elisabeth M.
Low levels of circulating methylated IRX3 are related to worse outcome after transcatheter aortic valve implantation in patients with severe aortic stenosis
title Low levels of circulating methylated IRX3 are related to worse outcome after transcatheter aortic valve implantation in patients with severe aortic stenosis
title_full Low levels of circulating methylated IRX3 are related to worse outcome after transcatheter aortic valve implantation in patients with severe aortic stenosis
title_fullStr Low levels of circulating methylated IRX3 are related to worse outcome after transcatheter aortic valve implantation in patients with severe aortic stenosis
title_full_unstemmed Low levels of circulating methylated IRX3 are related to worse outcome after transcatheter aortic valve implantation in patients with severe aortic stenosis
title_short Low levels of circulating methylated IRX3 are related to worse outcome after transcatheter aortic valve implantation in patients with severe aortic stenosis
title_sort low levels of circulating methylated irx3 are related to worse outcome after transcatheter aortic valve implantation in patients with severe aortic stenosis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10496273/
https://www.ncbi.nlm.nih.gov/pubmed/37697352
http://dx.doi.org/10.1186/s13148-023-01561-2
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