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

  • João Pedro Ferreira
  • Kévin Duarte
  • Holger Woehrle
  • Martin R. Cowie
  • Christiane Angermann
  • Marie-Pia d’Ortho
  • Erland Erdmann
  • Patrick Levy
  • Anita K. Simonds
  • Virend K. Somers
  • Helmut Teschler
  • Karl Wegscheider
  • Emmanuel Bresso
  • Marie Dominique-Devignes
  • Patrick Rossignol
  • Wolfgang Koenig
  • Faiez ZannadEmail author
Original Paper



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.


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.


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.


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.


Heart failure Adaptive servo-ventilation Circulating biomarkers Cheyne-Stokes respiration 



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.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.

Supplementary material

392_2019_1578_MOESM1_ESM.docx (47 kb)
Supplementary material 1 (DOCX 46 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • João Pedro Ferreira
    • 1
  • Kévin Duarte
    • 1
  • Holger Woehrle
    • 2
  • Martin R. Cowie
    • 3
  • Christiane Angermann
    • 4
  • Marie-Pia d’Ortho
    • 5
  • Erland Erdmann
    • 6
  • Patrick Levy
    • 7
  • Anita K. Simonds
    • 8
  • Virend K. Somers
    • 9
  • Helmut Teschler
    • 10
  • Karl Wegscheider
    • 11
  • Emmanuel Bresso
    • 12
  • Marie Dominique-Devignes
    • 12
  • Patrick Rossignol
    • 1
  • Wolfgang Koenig
    • 13
    • 14
  • Faiez Zannad
    • 1
    Email author
  1. 1.Centre d’Investigation Clinique Inserm, CHU, Institut Lorrain du Coeur et des VaisseauxUniversité de Lorraine, INSERM CIC-P 1433, CHRU de Nancy, INSERM U1116, FCRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists)Vandoeuvre-les-NancyFrance
  2. 2.ResMed Science Center, ResMed Germany IncMartinsriedGermany
  3. 3.Imperial College LondonLondonUK
  4. 4.Department of Medicine and Comprehensive Heart Failure CenterUniversity Hospital and University of WürzburgWürzburgGermany
  5. 5.University Paris Diderot, Sorbonne Paris Cité, Hôpital Bichat, Explorations Fonctionnelles, DHU FIRE, AP-HPParisFrance
  6. 6.Heart CenterUniversity of CologneCologneGermany
  7. 7.University of Grenoble Alpes, Inserm, HP2 labGrenobleFrance
  8. 8.Royal Brompton HospitalLondonUK
  9. 9.Mayo Clinic and Mayo FoundationRochesterUSA
  10. 10.Department of Pneumology, Ruhrlandklinik, West German Lung Center, University Hospital EssenUniversity Duisburg-EssenEssenGermany
  11. 11.Department of Medical Biometry and EpidemiologyUniversity Medical Center EppendorfHamburgGermany
  12. 12.Université de Lorraine, CNRS, Inria, LORIANancyFrance
  13. 13.Deutsches Herzzentrum München, Technische Universität MünchenMunichGermany
  14. 14.DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart AllianceMunichGermany

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