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Toll-like receptor 4 (TLR4) expression is correlated with T2* iron deposition in response to doxorubicin treatment: cardiotoxicity risk assessment

Although doxorubicin (Dox) is an effective antitumor antibiotic in the anthracycline class, it often induces the undesirable side effect of cardiomyopathy leading to congestive heart failure, which limits its clinical use. The primary goal of this study is to evaluate a reliable translational method...

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Autores principales: Trofenciuc, Nelu-Mihai, Bordejevic, Aurora Diana, Tomescu, Mirela Cleopatra, Petrescu, Lucian, Crisan, Simina, Geavlete, Oliviana, Mischie, Alexandru, Onel, Alexandru Fica Mircea, Sasu, Alciona, Pop-Moldovan, Adina Ligia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552385/
https://www.ncbi.nlm.nih.gov/pubmed/33046755
http://dx.doi.org/10.1038/s41598-020-73946-9
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author Trofenciuc, Nelu-Mihai
Bordejevic, Aurora Diana
Tomescu, Mirela Cleopatra
Petrescu, Lucian
Crisan, Simina
Geavlete, Oliviana
Mischie, Alexandru
Onel, Alexandru Fica Mircea
Sasu, Alciona
Pop-Moldovan, Adina Ligia
author_facet Trofenciuc, Nelu-Mihai
Bordejevic, Aurora Diana
Tomescu, Mirela Cleopatra
Petrescu, Lucian
Crisan, Simina
Geavlete, Oliviana
Mischie, Alexandru
Onel, Alexandru Fica Mircea
Sasu, Alciona
Pop-Moldovan, Adina Ligia
author_sort Trofenciuc, Nelu-Mihai
collection PubMed
description Although doxorubicin (Dox) is an effective antitumor antibiotic in the anthracycline class, it often induces the undesirable side effect of cardiomyopathy leading to congestive heart failure, which limits its clinical use. The primary goal of this study is to evaluate a reliable translational method for Dox-induced cardiotoxicity (CTX) screening, aiming to identify a high-risk population and to discover new strategies to predict and investigate this phenomenon. Early identification of the presence of iron deposits and genetic and environmental triggers that predispose individuals to increased risk of Dox-induced CTX (e.g., overexpression of Toll-like receptor 4 (TLR4)) will enable the early implementation of countermeasure therapy, which will improve the patient’s chance of survival. Our cohort consisted of 25 consecutive patients with pathologically confirmed cancer undergoing Dox chemotherapy and 12 control patients. The following parameters were measured: serum TLR4 (baseline), serum transferrin (baseline and 6-week follow-up) and iron deposition (baseline and 6-week follow-up). The average number of gene expression units was 0.121 for TLR4 (range 0.051–0.801). We subsequently correlated serum TLR4 levels in our cohort with myocardial iron overload using the cardiac magnetic resonance (CMR) T2* technique, the ventricular function (% ejection fraction, %EF) and serum transferrin levels. There is a strong negative linear relationship between serum TLR4 and CMR T2* values (r =  − 0.9106, ****P < 0.0001). There is also a linear correlation (either positive or negative) with EF and transferrin; no established relationship related to the sex of the patients was found. Patients with elevated serum TLR4 at baseline also exhibited an increase in serum transferrin levels and Dox-induced left ventricular dysfunction with a decreased EF (< 50%); this phenomenon was observed in 7 of 25 patients (28%) at the 6-week follow-up. There were no significant differences or correlations based on sex. We concluded that there is a direct relationship between Dox-induced CTX (indicated by elevated serum TLR4) and the times (ms) for T2* (decreases in which correspond to immediate and rapid iron overload).
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spelling pubmed-75523852020-10-14 Toll-like receptor 4 (TLR4) expression is correlated with T2* iron deposition in response to doxorubicin treatment: cardiotoxicity risk assessment Trofenciuc, Nelu-Mihai Bordejevic, Aurora Diana Tomescu, Mirela Cleopatra Petrescu, Lucian Crisan, Simina Geavlete, Oliviana Mischie, Alexandru Onel, Alexandru Fica Mircea Sasu, Alciona Pop-Moldovan, Adina Ligia Sci Rep Article Although doxorubicin (Dox) is an effective antitumor antibiotic in the anthracycline class, it often induces the undesirable side effect of cardiomyopathy leading to congestive heart failure, which limits its clinical use. The primary goal of this study is to evaluate a reliable translational method for Dox-induced cardiotoxicity (CTX) screening, aiming to identify a high-risk population and to discover new strategies to predict and investigate this phenomenon. Early identification of the presence of iron deposits and genetic and environmental triggers that predispose individuals to increased risk of Dox-induced CTX (e.g., overexpression of Toll-like receptor 4 (TLR4)) will enable the early implementation of countermeasure therapy, which will improve the patient’s chance of survival. Our cohort consisted of 25 consecutive patients with pathologically confirmed cancer undergoing Dox chemotherapy and 12 control patients. The following parameters were measured: serum TLR4 (baseline), serum transferrin (baseline and 6-week follow-up) and iron deposition (baseline and 6-week follow-up). The average number of gene expression units was 0.121 for TLR4 (range 0.051–0.801). We subsequently correlated serum TLR4 levels in our cohort with myocardial iron overload using the cardiac magnetic resonance (CMR) T2* technique, the ventricular function (% ejection fraction, %EF) and serum transferrin levels. There is a strong negative linear relationship between serum TLR4 and CMR T2* values (r =  − 0.9106, ****P < 0.0001). There is also a linear correlation (either positive or negative) with EF and transferrin; no established relationship related to the sex of the patients was found. Patients with elevated serum TLR4 at baseline also exhibited an increase in serum transferrin levels and Dox-induced left ventricular dysfunction with a decreased EF (< 50%); this phenomenon was observed in 7 of 25 patients (28%) at the 6-week follow-up. There were no significant differences or correlations based on sex. We concluded that there is a direct relationship between Dox-induced CTX (indicated by elevated serum TLR4) and the times (ms) for T2* (decreases in which correspond to immediate and rapid iron overload). Nature Publishing Group UK 2020-10-12 /pmc/articles/PMC7552385/ /pubmed/33046755 http://dx.doi.org/10.1038/s41598-020-73946-9 Text en © The Author(s) 2020 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/.
spellingShingle Article
Trofenciuc, Nelu-Mihai
Bordejevic, Aurora Diana
Tomescu, Mirela Cleopatra
Petrescu, Lucian
Crisan, Simina
Geavlete, Oliviana
Mischie, Alexandru
Onel, Alexandru Fica Mircea
Sasu, Alciona
Pop-Moldovan, Adina Ligia
Toll-like receptor 4 (TLR4) expression is correlated with T2* iron deposition in response to doxorubicin treatment: cardiotoxicity risk assessment
title Toll-like receptor 4 (TLR4) expression is correlated with T2* iron deposition in response to doxorubicin treatment: cardiotoxicity risk assessment
title_full Toll-like receptor 4 (TLR4) expression is correlated with T2* iron deposition in response to doxorubicin treatment: cardiotoxicity risk assessment
title_fullStr Toll-like receptor 4 (TLR4) expression is correlated with T2* iron deposition in response to doxorubicin treatment: cardiotoxicity risk assessment
title_full_unstemmed Toll-like receptor 4 (TLR4) expression is correlated with T2* iron deposition in response to doxorubicin treatment: cardiotoxicity risk assessment
title_short Toll-like receptor 4 (TLR4) expression is correlated with T2* iron deposition in response to doxorubicin treatment: cardiotoxicity risk assessment
title_sort toll-like receptor 4 (tlr4) expression is correlated with t2* iron deposition in response to doxorubicin treatment: cardiotoxicity risk assessment
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552385/
https://www.ncbi.nlm.nih.gov/pubmed/33046755
http://dx.doi.org/10.1038/s41598-020-73946-9
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