Transcriptional profiling unveils molecular subgroups of adaptive and maladaptive right ventricular remodeling in pulmonary hypertension

Abstract

Right ventricular (RV) function is critical to prognosis in all forms of pulmonary hypertension. Here we perform molecular phenotyping of RV remodeling by transcriptome analysis of RV tissue obtained from 40 individuals, and two animal models of RV dysfunction of both sexes. Our unsupervised clustering analysis identified ‘early’ and ‘late’ subgroups within compensated and decompensated states, characterized by the expression of distinct signaling pathways, while fatty acid metabolism and estrogen response appeared to underlie sex-specific differences in RV adaptation. The circulating levels of several extracellular matrix proteins deregulated in decompensated RV subgroups were assessed in two independent cohorts of individuals with pulmonary arterial hypertension, revealing that NID1, C1QTNF1 and CRTAC1 predicted the development of a maladaptive RV state, as defined by magnetic resonance imaging parameters, and were associated with worse clinical outcomes. Our study provides a resource for subphenotyping RV states, identifying state-specific biomarkers, and potential therapeutic targets for RV dysfunction.

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Item Type:	Article
Authors/Creators:	Khassafi, F. Chelladurai, P. https://orcid.org/0000-0002-8258-5115 Valasarajan, C. Nayakanti, S.R. Martineau, S. Sommer, N. Yokokawa, T. Boucherat, O. Kamal, A. Kiely, D.G. https://orcid.org/0000-0003-0184-6502 Swift, A.J. Alabed, S. https://orcid.org/0000-0002-9960-7587 Omura, J. Breuils-Bonnet, S. Kuenne, C. https://orcid.org/0000-0001-8013-5906 Potus, F. Günther, S. Savai, R. Seeger, W. https://orcid.org/0000-0003-1946-0894 Looso, M. https://orcid.org/0000-0003-1495-9530 Lawrie, A. https://orcid.org/0000-0003-4192-9505 Zaugg, J.B. Tello, K. Provencher, S. Bonnet, S. https://orcid.org/0000-0001-5753-1900 Pullamsetti, S.S. https://orcid.org/0000-0003-0440-8831
Copyright, Publisher and Additional Information:	© 2023 The Authors. 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.
Keywords:	Lung; Heart Disease; Cardiovascular; Cardiovascular
Dates:	Published: October 2023 Published (online): 28 September 2023 Accepted: 25 August 2023
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health
Funding Information:	Funder Grant number WELLCOME TRUST (THE) 205188/Z/16/Z British Heart Foundation PG/11/116/29288
Depositing User:	Symplectic Sheffield
Date Deposited:	16 Oct 2023 11:13
Last Modified:	16 Oct 2023 11:13
Published Version:	http://dx.doi.org/10.1038/s44161-023-00338-3
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s44161-023-00338-3
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:204279

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Transcriptional profiling unveils molecular subgroups of adaptive and maladaptive right ventricular remodeling in pulmonary hypertension

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