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CILP1 as a biomarker for right ventricular maladaptation in pulmonary hypertension

Stanislav Keranov, Oliver Dörr, Leili Jafari, Christian Troidl, Christoph Liebetrau, Steffen Kriechbaum, Till Keller, Sandra Voss, Timm Bauer, Jakob Lorenz, Manuel J. Richter, Khodr Tello, Henning Gall, Hossein A. Ghofrani, Eckhard Mayer, Christoph B. Wiedenroth, Stefan Guth, Holger Lörchner, Jochen Pöling, Prakash Chelladurai, Soni Savai Pullamsetti, Thomas Braun, Werner Seeger, Christian W. Hamm, Holger Nef
European Respiratory Journal 2021 57: 1901192; DOI: 10.1183/13993003.01192-2019
Stanislav Keranov
1University of Giessen, Dept of Cardiology and Angiology, Giessen, Germany
2DZHK (German Center for Cardiovascular Research), Partner Site RheinMain, Frankfurt am Main, Germany
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  • ORCID record for Stanislav Keranov
  • For correspondence: stanislav.keranov@innere.med.uni-giessen.de
Oliver Dörr
1University of Giessen, Dept of Cardiology and Angiology, Giessen, Germany
2DZHK (German Center for Cardiovascular Research), Partner Site RheinMain, Frankfurt am Main, Germany
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Leili Jafari
3Kerckhoff Heart and Lung Center, Dept of Cardiology, Bad Nauheim, Germany
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Christian Troidl
2DZHK (German Center for Cardiovascular Research), Partner Site RheinMain, Frankfurt am Main, Germany
3Kerckhoff Heart and Lung Center, Dept of Cardiology, Bad Nauheim, Germany
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Christoph Liebetrau
1University of Giessen, Dept of Cardiology and Angiology, Giessen, Germany
2DZHK (German Center for Cardiovascular Research), Partner Site RheinMain, Frankfurt am Main, Germany
3Kerckhoff Heart and Lung Center, Dept of Cardiology, Bad Nauheim, Germany
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Steffen Kriechbaum
3Kerckhoff Heart and Lung Center, Dept of Cardiology, Bad Nauheim, Germany
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  • ORCID record for Steffen Kriechbaum
Till Keller
2DZHK (German Center for Cardiovascular Research), Partner Site RheinMain, Frankfurt am Main, Germany
3Kerckhoff Heart and Lung Center, Dept of Cardiology, Bad Nauheim, Germany
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Sandra Voss
3Kerckhoff Heart and Lung Center, Dept of Cardiology, Bad Nauheim, Germany
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Timm Bauer
1University of Giessen, Dept of Cardiology and Angiology, Giessen, Germany
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Jakob Lorenz
1University of Giessen, Dept of Cardiology and Angiology, Giessen, Germany
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Manuel J. Richter
4Dept of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
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Khodr Tello
4Dept of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
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Henning Gall
4Dept of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
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Hossein A. Ghofrani
4Dept of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
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Eckhard Mayer
5Kerckhoff Heart and Lung Center, Dept of Thoracic Surgery, Bad Nauheim, Germany
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Christoph B. Wiedenroth
5Kerckhoff Heart and Lung Center, Dept of Thoracic Surgery, Bad Nauheim, Germany
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Stefan Guth
5Kerckhoff Heart and Lung Center, Dept of Thoracic Surgery, Bad Nauheim, Germany
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Holger Lörchner
6Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
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Jochen Pöling
6Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
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Prakash Chelladurai
6Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
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Soni Savai Pullamsetti
6Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
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Thomas Braun
6Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
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Werner Seeger
4Dept of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany
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Christian W. Hamm
1University of Giessen, Dept of Cardiology and Angiology, Giessen, Germany
2DZHK (German Center for Cardiovascular Research), Partner Site RheinMain, Frankfurt am Main, Germany
3Kerckhoff Heart and Lung Center, Dept of Cardiology, Bad Nauheim, Germany
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Holger Nef
1University of Giessen, Dept of Cardiology and Angiology, Giessen, Germany
2DZHK (German Center for Cardiovascular Research), Partner Site RheinMain, Frankfurt am Main, Germany
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Abstract

The aim of our study was to analyse the protein expression of cartilage intermediate layer protein (CILP)1 in a mouse model of right ventricular (RV) pressure overload and to evaluate CILP1 as a biomarker of cardiac remodelling and maladaptive RV function in patients with pulmonary hypertension (PH).

Pulmonary artery banding was performed in 14 mice; another nine mice underwent sham surgery. CILP1 protein expression was analysed in all hearts using Western blotting and immunostaining. CILP1 serum concentrations were measured in 161 patients (97 with adaptive and maladaptive RV pressure overload caused by PH; 25 with left ventricular (LV) hypertrophy; 20 with dilative cardiomyopathy (DCM); 19 controls without LV or RV abnormalities)

In mice, the amount of RV CILP1 was markedly higher after banding than after sham. Control patients had lower CILP1 serum levels than all other groups (p<0.001). CILP1 concentrations were higher in PH patients with maladaptive RV function than those with adaptive RV function (p<0.001), LV pressure overload (p<0.001) and DCM (p=0.003). CILP1 showed good predictive power for maladaptive RV in receiver operating characteristic analysis (area under the curve (AUC) 0.79). There was no significant difference between the AUCs of CILP1 and N-terminal pro-brain natriuretic peptide (NT-proBNP) (AUC 0.82). High CILP1 (cut-off value for maladaptive RV of ≥4373 pg·mL−1) was associated with lower tricuspid annular plane excursion/pulmonary artery systolic pressure ratios (p<0.001) and higher NT-proBNP levels (p<0.001).

CILP1 is a novel biomarker of RV and LV pathological remodelling that is associated with RV maladaptation and ventriculoarterial uncoupling in patients with PH.

Abstract

CILP1 is a novel biomarker of RV and LV pathological remodelling that is associated with RV maladaptation and ventriculoarterial uncoupling in patients with pulmonary hypertension https://bit.ly/33HwLtN

Footnotes

  • This article has an editorial commentary: https://doi.org/10.1183/13993003.04277-2020

  • This article has supplementary material available from erj.ersjournals.com

  • Conflict of interest: S. Keranov reports grants from German Research Foundation (Project B07, Collaborative Research Center 1213-Pulmonary Hypertension and Cor Pulmonale), during the conduct of the study.

  • Conflict of interest: O. Dörr reports grants from German Research Foundation (Project B07, Collaborative Research Center 1213-Pulmonary Hypertension and Cor Pulmonale), during the conduct of the study.

  • Conflict of interest: L. Jafari has nothing to disclose.

  • Conflict of interest: C. Troidl has nothing to disclose.

  • Conflict of interest: C. Liebetrau reports grants from German Research Foundation (Project B07, Collaborative Research Center 1213-Pulmonary Hypertension and Cor Pulmonale), during the conduct of the study.

  • Conflict of interest: S. Kriechbaum reports grants from German Research Foundation (Project B07, Collaborative Research Center 1213-Pulmonary Hypertension and Cor Pulmonale), during the conduct of the study.

  • Conflict of interest: T. Keller has nothing to disclose.

  • Conflict of interest: S. Voss has nothing to disclose.

  • Conflict of interest: T. Bauer has nothing to disclose.

  • Conflict of interest: J. Lorenz has nothing to disclose.

  • Conflict of interest: M.J. Richter has nothing to disclose.

  • Conflict of interest: K. Tello has nothing to disclose.

  • Conflict of interest: H. Gall has nothing to disclose.

  • Conflict of interest: H.A. Ghofrani has nothing to disclose.

  • Conflict of interest: E. Mayer has nothing to disclose.

  • Conflict of interest: C.B. Wiedenroth has nothing to disclose.

  • Conflict of interest: S. Guth has nothing to disclose.

  • Conflict of interest: H. Lörchner has nothing to disclose.

  • Conflict of interest: J. Pöling has nothing to disclose.

  • Conflict of interest: P. Chelladurai has nothing to disclose.

  • Conflict of interest: S.S. Pullamsetti has nothing to disclose.

  • Conflict of interest: T. Braun has nothing to disclose.

  • Conflict of interest: W. Seeger has nothing to disclose.

  • Conflict of interest: C.W. Hamm reports grants from German Research Foundation (Project B07, Collaborative Research Center 1213-Pulmonary Hypertension and Cor Pulmonale), during the conduct of the study.

  • Conflict of interest: H. Nef reports grants from German Research Foundation (Project B07, Collaborative Research Center 1213-Pulmonary Hypertension and Cor Pulmonale), during the conduct of the study.

  • Support statement: This work was supported by Project B07, Collaborative Research Center 1213-Pulmonary Hypertension and Cor Pulmonale, German Research Foundation (DFG).

  • Received June 17, 2019.
  • Accepted October 3, 2020.
  • Copyright ©ERS 2021
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CILP1 as a biomarker for right ventricular maladaptation in pulmonary hypertension
Stanislav Keranov, Oliver Dörr, Leili Jafari, Christian Troidl, Christoph Liebetrau, Steffen Kriechbaum, Till Keller, Sandra Voss, Timm Bauer, Jakob Lorenz, Manuel J. Richter, Khodr Tello, Henning Gall, Hossein A. Ghofrani, Eckhard Mayer, Christoph B. Wiedenroth, Stefan Guth, Holger Lörchner, Jochen Pöling, Prakash Chelladurai, Soni Savai Pullamsetti, Thomas Braun, Werner Seeger, Christian W. Hamm, Holger Nef
European Respiratory Journal Apr 2021, 57 (4) 1901192; DOI: 10.1183/13993003.01192-2019

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CILP1 as a biomarker for right ventricular maladaptation in pulmonary hypertension
Stanislav Keranov, Oliver Dörr, Leili Jafari, Christian Troidl, Christoph Liebetrau, Steffen Kriechbaum, Till Keller, Sandra Voss, Timm Bauer, Jakob Lorenz, Manuel J. Richter, Khodr Tello, Henning Gall, Hossein A. Ghofrani, Eckhard Mayer, Christoph B. Wiedenroth, Stefan Guth, Holger Lörchner, Jochen Pöling, Prakash Chelladurai, Soni Savai Pullamsetti, Thomas Braun, Werner Seeger, Christian W. Hamm, Holger Nef
European Respiratory Journal Apr 2021, 57 (4) 1901192; DOI: 10.1183/13993003.01192-2019
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