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Consensus Transcriptional Landscape of Human End‐Stage Heart Failure
BACKGROUND: Transcriptomic studies have contributed to fundamental knowledge of myocardial remodeling in human heart failure (HF). However, the key HF genes reported are often inconsistent between studies, and systematic efforts to integrate evidence from multiple patient cohorts are lacking. Here,...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174362/ https://www.ncbi.nlm.nih.gov/pubmed/33787284 http://dx.doi.org/10.1161/JAHA.120.019667 |
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author | Ramirez Flores, Ricardo O. Lanzer, Jan D. Holland, Christian H. Leuschner, Florian Most, Patrick Schultz, Jobst‐Hendrik Levinson, Rebecca T. Saez‐Rodriguez, Julio |
author_facet | Ramirez Flores, Ricardo O. Lanzer, Jan D. Holland, Christian H. Leuschner, Florian Most, Patrick Schultz, Jobst‐Hendrik Levinson, Rebecca T. Saez‐Rodriguez, Julio |
author_sort | Ramirez Flores, Ricardo O. |
collection | PubMed |
description | BACKGROUND: Transcriptomic studies have contributed to fundamental knowledge of myocardial remodeling in human heart failure (HF). However, the key HF genes reported are often inconsistent between studies, and systematic efforts to integrate evidence from multiple patient cohorts are lacking. Here, we aimed to provide a framework for comprehensive comparison and analysis of publicly available data sets resulting in an unbiased consensus transcriptional signature of human end‐stage HF. METHODS AND RESULTS: We curated and uniformly processed 16 public transcriptomic studies of left ventricular samples from 263 healthy and 653 failing human hearts. First, we evaluated the degree of consistency between studies by using linear classifiers and overrepresentation analysis. Then, we meta‐analyzed the deregulation of 14 041 genes to extract a consensus signature of HF. Finally, to functionally characterize this signature, we estimated the activities of 343 transcription factors, 14 signaling pathways, and 182 micro RNAs, as well as the enrichment of 5998 biological processes. Machine learning approaches revealed conserved disease patterns across all studies independent of technical differences. These consistent molecular changes were prioritized with a meta‐analysis, functionally characterized and validated on external data. We provide all results in a free public resource (https://saezlab.shinyapps.io/reheat/) and exemplified usage by deciphering fetal gene reprogramming and tracing the potential myocardial origin of the plasma proteome markers in patients with HF. CONCLUSIONS: Even though technical and sampling variability confound the identification of differentially expressed genes in individual studies, we demonstrated that coordinated molecular responses during end‐stage HF are conserved. The presented resource is crucial to complement findings in independent studies and decipher fundamental changes in failing myocardium. |
format | Online Article Text |
id | pubmed-8174362 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-81743622021-06-11 Consensus Transcriptional Landscape of Human End‐Stage Heart Failure Ramirez Flores, Ricardo O. Lanzer, Jan D. Holland, Christian H. Leuschner, Florian Most, Patrick Schultz, Jobst‐Hendrik Levinson, Rebecca T. Saez‐Rodriguez, Julio J Am Heart Assoc Systematic Review and Meta‐analysis BACKGROUND: Transcriptomic studies have contributed to fundamental knowledge of myocardial remodeling in human heart failure (HF). However, the key HF genes reported are often inconsistent between studies, and systematic efforts to integrate evidence from multiple patient cohorts are lacking. Here, we aimed to provide a framework for comprehensive comparison and analysis of publicly available data sets resulting in an unbiased consensus transcriptional signature of human end‐stage HF. METHODS AND RESULTS: We curated and uniformly processed 16 public transcriptomic studies of left ventricular samples from 263 healthy and 653 failing human hearts. First, we evaluated the degree of consistency between studies by using linear classifiers and overrepresentation analysis. Then, we meta‐analyzed the deregulation of 14 041 genes to extract a consensus signature of HF. Finally, to functionally characterize this signature, we estimated the activities of 343 transcription factors, 14 signaling pathways, and 182 micro RNAs, as well as the enrichment of 5998 biological processes. Machine learning approaches revealed conserved disease patterns across all studies independent of technical differences. These consistent molecular changes were prioritized with a meta‐analysis, functionally characterized and validated on external data. We provide all results in a free public resource (https://saezlab.shinyapps.io/reheat/) and exemplified usage by deciphering fetal gene reprogramming and tracing the potential myocardial origin of the plasma proteome markers in patients with HF. CONCLUSIONS: Even though technical and sampling variability confound the identification of differentially expressed genes in individual studies, we demonstrated that coordinated molecular responses during end‐stage HF are conserved. The presented resource is crucial to complement findings in independent studies and decipher fundamental changes in failing myocardium. John Wiley and Sons Inc. 2021-03-31 /pmc/articles/PMC8174362/ /pubmed/33787284 http://dx.doi.org/10.1161/JAHA.120.019667 Text en © 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Systematic Review and Meta‐analysis Ramirez Flores, Ricardo O. Lanzer, Jan D. Holland, Christian H. Leuschner, Florian Most, Patrick Schultz, Jobst‐Hendrik Levinson, Rebecca T. Saez‐Rodriguez, Julio Consensus Transcriptional Landscape of Human End‐Stage Heart Failure |
title | Consensus Transcriptional Landscape of Human End‐Stage Heart Failure |
title_full | Consensus Transcriptional Landscape of Human End‐Stage Heart Failure |
title_fullStr | Consensus Transcriptional Landscape of Human End‐Stage Heart Failure |
title_full_unstemmed | Consensus Transcriptional Landscape of Human End‐Stage Heart Failure |
title_short | Consensus Transcriptional Landscape of Human End‐Stage Heart Failure |
title_sort | consensus transcriptional landscape of human end‐stage heart failure |
topic | Systematic Review and Meta‐analysis |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174362/ https://www.ncbi.nlm.nih.gov/pubmed/33787284 http://dx.doi.org/10.1161/JAHA.120.019667 |
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