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Identification of LTBP-2 as a plasma biomarker for right ventricular dysfunction in human pulmonary arterial hypertension

Nature Cardiovascular Research volume 1, pages 748–760 (2022)Cite this article

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Abstract

Although right ventricular (RV) function is the primary determinant of morbidity and mortality in pulmonary arterial hypertension (PAH), the molecular mechanisms of RV remodeling and the circulating factors reflecting its function remain largely elusive. In this context, the identification of new molecular players implicated in maladaptive RV remodeling along with the optimization of risk stratification approaches in PAH are key priorities. Through combination of transcriptomic and proteomic profiling of RV tissues with plasma proteome profiling, we identified a panel of proteins, mainly related to cardiac fibrosis, similarly upregulated in the RV and plasma of patients with PAH with decompensated RV. Among these, we demonstrated that plasma latent transforming growth factor beta binding protein 2 (LTBP-2) level correlates with RV function in human PAH and adds incremental value to current risk stratification models to predict long-term survival in two independent PAH cohorts.

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Fig. 1: Transcriptome profiling of human RV homogenates derived from CTRL, cRV and dRV patients with PAH.
Fig. 2: Proteome profiling of human RV homogenates derived from CTRL, cRV and dRV patients with PAH.
Fig. 3: Alteration of the plasma proteome in patients with PAH.
Fig. 4: Expression of LTBP-2 in human patients with RV failure and animal models.
Fig. 5: Expression levels (NPX) of LTBP-2, COL6A3, COL18A1, TNC and CA1 in plasma from patients with PAH of the two cohorts and correlation with prognosis.
Fig. 6: Univariate (unadjusted, red) and multivariate Cox proportional hazard analyses for death or lung transplantation in the combined cohort of all patients with PAH (n = 121).
Fig. 7: Performance of the logistic regression models with 2015 ERS/ESC risk score, REVEAL 2.0 risk score and the refined four-strata risk assessment method in patients with PAH of combined cohorts for death and lung transplantation (n = 121).

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Data availability

Gene expression profiling data were deposited in National Center of Biotechnology Information’s Gene Expression Omnibus (GEO) and are accessible through GEO Series accession number GSE198618. The clinical information of subjects for human RV tissues and plasma is provided in main and supplementary tables. Proteins (nano LC–MS/MS) were retrieved by searching the UniProt database (http://www.uniprot.org/). Data supporting the findings of this study are available within the article and its Supplementary Information files or are available from the corresponding author upon reasonable request.

Code availability

R scripts and methods used in processing RNA-seq analysis can be found in the Supplementary Information.

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Acknowledgements

We thank the clinical team from Sheffield for its support, especially D. G. Kiely, R. Condliffe, C. A. Elliot, I. Sabroe, A. Athanasiou, A. A. R. Thompson, A. M. K. Rothman, A. G. Hameed and I. Armstrong. O.B. holds a junior scholar award from the Fonds de Recherche du Québec: Santé (FRQS). S.B. holds a distinguished research scholar from FRQS.

Author information

Author notes

  1. These authors jointly supervised this work: Steeve Provencher, Sebastien Bonnet.

Authors and Affiliations

  1. Pulmonary Hypertension Research Group, Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec City, Québec, Canada

    Olivier Boucherat, Tetsuro Yokokawa, Sandra Martineau, Sandra Breuils-Bonnet, François Potus, Steeve Provencher & Sebastien Bonnet

  2. Department of Medicine, Université Laval, Québec City, Québec, Canada

    Olivier Boucherat, Steeve Provencher & Sebastien Bonnet

  3. Janssen Research & Development, Spring House, PA, USA

    Vinod Krishna, Shanker Kalyana-Sundaram, Nabil Azhar, Fany Bonilla, David Gutstein & Jey Jeyaseelan

  4. Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK & Insigneo institute for in silico medicine, Sheffield, UK

    Allan Lawrie

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Contributions

All authors made substantial contributions to the conception and design and data acquisition of the work. O.B., T.Y., V.K., S.K.-S., S.M., S.B.-B., N.A., F.B., F.P., D.G., J.J., S.P. and S.B. performed the analysis and/or interpretation of data. A.L. provided blood samples. O.B., S.P. and S.B. wrote the original draft. O.B., T.Y., S.P., S.B., D.G., A.L. and J.J. reviewed and edited the final paper. O.B., J.J., S.P. and S.B. supervised the project.

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Correspondence to Sebastien Bonnet.

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Extended data

Extended Data Fig. 1 Schematic representation of the experimental design implemented in this study.

cRV, compensated right ventricle; dRV, decompensated right ventricle; PAH, pulmonary arterial hypertension; RV, right ventricle.

Extended Data Fig. 2 Comparison of the transcriptome and the proteome in human RV failure.

(A and B) Principal component analysis (PCA) plots of the transcripts (A) and proteins (B). Each dot represents a sample. Green: control patients. Red: cRV patients. Blue: dRV PAH patients. (C) Circo plot and venn diagram showing the overlapping differentially expressed coding genes (DEG) and proteins (DEP) between dRV and CTRL.

Extended Data Fig. 3 Relationship between plasma protein levels.

(A) Correlation matrix (Pearson) illustrating mutual correlation amongst all plasma proteins differentially expressed (fold change ≥ 1.4 and FDR-corrected p-value ≤0.05) between PAH patients with dRV and controls. Red and blue denote statistically significant positive and negative correlations, respectively. Clusters of variables with high degree of correlation are shown as squares on the correlation matrix. (B) Plasma protein NPX level of TNNI3 in control (n = 28) and PAH patients (n = 60) classified as cRV or dRV based on hemodynamic data. Data are presented as mean ± SEM. Statistical analyses were performed using one-way ANOVA followed by Tukey post-hoc test.

Source data

Extended Data Fig. 4 Expression levels (NPX) of LTBP2, COL6A3, COL18A1, TNC and CA1 in plasma from PAH patients (Canada cohort) and correlation with prognosis.

(A) Expression levels (NPX) of LTBP2, COL6A3, COL18A1, TNC and CA1 in control (CTRL, n = 28) and PAH (n = 60) patients from Canada cohort. Data are presented as mean ± SEM. Statistical analyses were performed using the Student’s t-test or one-way ANOVA followed by Tukey post-hoc test. (B) Receiver operating curves (ROC) assessing the prognostic accuracy of LTBP2, COL6A3, COL18A1, TNC and CA1. (C) Kaplan-Meier survival curves according to ROC cut-off values for LTBP2, COL6A3, COL18A1, TNC and CA1. AUC, area under the curve; CTD-PAH, connective tissue disease associated with pulmonary arterial hypertension; IPAH, idiopathic pulmonary hypertension.

Source data

Extended Data Fig. 5 LTBP2, COL6A3, COL18A1, TNC, and CA1 and hemodynamic/biochemical parameters of PAH patients (Canada cohort).

Pearson correlation coefficient with associated P value is shown in each graph. eGFR, estimating glomerular filtration rate; MDRD, Modification of Diet in Renal Disease; mPAP, mean pulmonary artery pressure; PVR, pulmonary vascular resistance; SV, strove volume.

Source data

Extended Data Fig. 6 Information of NT-proBNP in the UK and the combined cohort.

(A) In the UK cohort (CTRL, n = 56; PAH, n = 61), plasma protein NPX level of NT-proBNP, and scatter plot showing the pairwise correlation between the expression levels generated with PEA and Flex Reagent Cartridge (Siemens) for NT-proBNP (clinical). According to contemporary CI measured by right heart catheterization at the time blood sample was drawn, PAH patients were categorized as cRV (CI > 2.2 L/[min·m2]) and dRV (CI ≤ 2.2 L/[min·m2]). Data are presented as mean ± SEM. Statistical analyses were performed using the Student’s t-test or one-way ANOVA followed by Tukey post-hoc test. Pearson correlation coefficient with associated P value is shown. (B) In the combined cohort (Canada and UK; CTRL, n = 84; PAH, n = 121), plasma protein NPX levels of NT-proBNP were shown. Data are presented as mean ± SEM. Statistical analyses were performed using the Student’s t-test or one-way ANOVA followed by Tukey post-hoc test.

Source data

Extended Data Fig. 7 Expression levels (NPX) of LTBP2, COL6A3, COL18A1, TNC and CA1 in plasma from PAH patients (UK cohort) and correlation with prognosis.

(A) Expression levels (NPX) of LTBP2, COL6A3, COL18A1, TNC and CA1 in control (CTRL, n = 56) and PAH (n = 61) patients from UK cohort. According to contemporary CI measured by right heart catheterization at the time blood sample was drawn, PAH patients were categorized as cRV (CI > 2.2 L/[min·m2] and dRV (CI ≤ 2.2 L/[min·m2]. Data are presented as mean ± SEM. Statistical analyses were performed using the Student’s t-test or one-way ANOVA followed by Tukey post-hoc test. (B) Receiver operating curves (ROC) assessing the prognostic accuracy of LTBP2, COL6A3, COL18A1, TNC and CA1. (C) Kaplan-Meier survival curves according to ROC cut-off values for LTBP2, COL6A3, COL18A1, TNC and CA1. AUC, area under the curve; CI, cardiac index; CTD-PAH, connective tissue disease associated with pulmonary arterial hypertension; IPAH, idiopathic pulmonary hypertension.

Source data

Extended Data Fig. 8 LTBP2, COL6A3, COL18A1, TNC and CA1 and hemodynamic/biochemical parameters of PAH patients (UK cohort).

Pearson correlation coefficient with associated P value is shown in each graph. CI, cardiac index; eGFR, estimating glomerular filtration rate; MDRD, Modification of Diet in Renal Disease;.mPAP, mean pulmonary artery pressure; PVR, pulmonary vascular resistance; SV, strove volume.

Source data

Extended Data Fig. 9 LTBP2, COL6A3, COL18A1, TNC and CA1 and hemodynamic/biochemical parameters of PAH patients in combined cohorts (Canada and UK).

Pearson correlation coefficient with associated P value is shown in each graph. CI, cardiac index; eGFR, estimating glomerular filtration rate; MDRD, Modification of Diet in Renal Disease;.mPAP, mean pulmonary artery pressure; PVR, pulmonary vascular resistance; SV, strove volume.

Source data

Extended Data Fig. 10 Receiver operating characteristic (ROC) analyses in PAH patients for death and lung transplantation in the combined cohort.

ROC analyses of logistic regression models of established prognostic risk scores and their combination with LTBP2.

Source data

Supplementary information

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Supplementary Methods, Supplementary References, Supplementary Figs. 1–11 and Supplementary Tables 1–10

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Boucherat, O., Yokokawa, T., Krishna, V. et al. Identification of LTBP-2 as a plasma biomarker for right ventricular dysfunction in human pulmonary arterial hypertension. Nat Cardiovasc Res 1, 748–760 (2022). https://doi.org/10.1038/s44161-022-00113-w

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