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 Zannad

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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.[Figure not available: see fulltext.].

Original languageEnglish (US)
JournalClinical Research in Cardiology
DOIs
StateAccepted/In press - Jan 1 2019

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Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Ferreira, J. P., Duarte, K., Woehrle, H., Cowie, M. R., Angermann, C., d’Ortho, M. P., Erdmann, E., Levy, P., Simonds, A. K., Somers, V. K., Teschler, H., Wegscheider, K., Bresso, E., Dominique-Devignes, M., Rossignol, P., Koenig, W., & Zannad, F. (Accepted/In press). Bioprofiles and mechanistic pathways associated with Cheyne-Stokes respiration: insights from the SERVE-HF trial. Clinical Research in Cardiology. https://doi.org/10.1007/s00392-019-01578-9