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Bioprofiles and mechanistic pathways associated with Cheyne-Stokes respiration: insights from the SERVE-HF trial

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Abstract

Introduction

The SERVE-HF trial included patients with heart failure and reduced ejection fraction (HFrEF) with sleep-disordered breathing, randomly assigned to treatment with Adaptive-Servo Ventilation (ASV) or control. The primary outcome was the first event of death from any cause, lifesaving cardiovascular intervention, or unplanned hospitalization for worsening heart failure. A subgroup analysis of the SERVE-HF trial suggested that patients with Cheyne-Stokes respiration (CSR) < 20% (low CSR) experienced a beneficial effect from ASV, whereas in patients with CSR ≥ 20% ASV might have been harmful. Identifying the proteomic signatures and the underlying mechanistic pathways expressed in patients with CSR could help generating hypothesis for future research.

Methods

Using a large set of circulating protein-biomarkers (n = 276, available in 749 patients; 57% of the SERVE-HF population) we sought to investigate the proteins associated with CSR and to study the underlying mechanisms that these circulating proteins might represent.

Results

The mean age was 69 ± 10 years and > 90% were male. Patients with CSR < 20% (n = 139) had less apnoea-hypopnea index (AHI) events per hour and less oxygen desaturation. Patients with CSR < 20% might have experienced a beneficial effect of ASV treatment (primary outcome HR [95% CI] = 0.55 [0.34–0.88]; p = 0.012), whereas those with CSR ≥ 20% might have experienced a detrimental effect of ASV treatment (primary outcome HR [95% CI] = 1.39 [1.09–1.76]; p = 0.008); p for interaction = 0.001. Of the 276 studied biomarkers, 8 were associated with CSR (after adjustment and with a FDR1%-corrected p value). For example, higher PAR-1 and ITGB2 levels were associated with higher odds of having CSR < 20%, whereas higher LOX-1 levels were associated with higher odds of CSR ≥ 20%. Signalling, metabolic, haemostatic and immunologic pathways underlie the expression of these biomarkers.

Conclusion

We identified proteomic signatures that may represent underlying mechanistic pathways associated with patterns of CSR in HFrEF. These hypothesis-generating findings require further investigation towards better understanding of CSR in HFrEF.

Graphic abstract

Summary of the findings. PAR-1 proteinase-activated receptor 1, ADM adrenomedullin, HSP-27 heat shock protein-27, ITGB2 integrin beta 2, GLO1 glyoxalase 1, ENRAGE/S100A12 S100 calcium-binding protein A12, LOX-1 lectin-like LDL receptor 1, ADAM-TS13 disintegrin and metalloproteinase with a thrombospondin type 1 motif, member13 also known as von Willebrand factor-cleaving protease.

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Acknowledgements

JPF, PR, FZ are supported by a public grant overseen by the French National Research Agency (ANR) as part of the second “Investissements d’Avenir” program FIGHT-HF (reference: ANR-15-RHU-0004) and by the French PIA project “Lorraine Université d’Excellence”, reference ANR-15-IDEX-04-LUE. And by Contrat de Plan Etat-Lorraine and FEDER Lorraine.

Author information

Author notes

  1. João Pedro Ferreira and Kévin Duarte co-first authors.

  2. Wolfgang Koenig and Faiez Zannad co-last authors.

Authors and Affiliations

  1. Centre d’Investigation Clinique Inserm, CHU, Institut Lorrain du Coeur et des Vaisseaux, Université de Lorraine, INSERM CIC-P 1433, CHRU de Nancy, INSERM U1116, FCRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), 4, rue du Morvan, 54500, Vandoeuvre-les-Nancy, France

    João Pedro Ferreira, Kévin Duarte, Patrick Rossignol & Faiez Zannad

  2. ResMed Science Center, ResMed Germany Inc, Martinsried, Germany

    Holger Woehrle

  3. Imperial College London, London, UK

    Martin R. Cowie

  4. Department of Medicine and Comprehensive Heart Failure Center, University Hospital and University of Würzburg, Würzburg, Germany

    Christiane Angermann

  5. University Paris Diderot, Sorbonne Paris Cité, Hôpital Bichat, Explorations Fonctionnelles, DHU FIRE, AP-HP, Paris, France

    Marie-Pia d’Ortho

  6. Heart Center, University of Cologne, Cologne, Germany

    Erland Erdmann

  7. University of Grenoble Alpes, Inserm, HP2 lab, Grenoble, France

    Patrick Levy

  8. Royal Brompton Hospital, London, UK

    Anita K. Simonds

  9. Mayo Clinic and Mayo Foundation, Rochester, MN, USA

    Virend K. Somers

  10. Department of Pneumology, Ruhrlandklinik, West German Lung Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany

    Helmut Teschler

  11. Department of Medical Biometry and Epidemiology, University Medical Center Eppendorf, Hamburg, Germany

    Karl Wegscheider

  12. Université de Lorraine, CNRS, Inria, LORIA, Nancy, 54500, France

    Emmanuel Bresso & Marie Dominique-Devignes

  13. Deutsches Herzzentrum München, Technische Universität München, Munich, Germany

    Wolfgang Koenig

  14. DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany

    Wolfgang Koenig

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  1. João Pedro Ferreira
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Correspondence to Faiez Zannad.

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Ferreira, J.P., Duarte, K., Woehrle, H. et al. Bioprofiles and mechanistic pathways associated with Cheyne-Stokes respiration: insights from the SERVE-HF trial. Clin Res Cardiol 109, 881–891 (2020). https://doi.org/10.1007/s00392-019-01578-9

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  • DOI: https://doi.org/10.1007/s00392-019-01578-9

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