Identifying Pathophysiological Mechanisms in Heart Failure With Reduced Versus Preserved Ejection Fraction

Jasper Tromp, B Daan Westenbrink, Wouter Ouwerkerk, Dirk J van Veldhuisen, Nilesh J Samani, Piotr Ponikowski, Marco Metra, Stefan D Anker, John G Cleland, Kenneth Dickstein, Gerasimos Filippatos, Pim van der Harst, Chim C Lang, Leong L Ng, Faiez Zannad, Aelko H Zwinderman, Hans L Hillege, Peter van der Meer, Adriaan A Voors

Research output: Contribution to journalArticleAcademicpeer-review


Background: Information on the pathophysiological differences between heart failure with reduced ejection fraction (HFrEF) versus heart failure with preserved ejection fraction (HFpEF) is needed Objectives: The purpose of this study was to establish biological pathways specifically related to HFrEF and HFpEF. Methods: The authors performed a network analysis to identify unique biomarker correlations in HFrEF and HFpEF using 92 biomarkers from different pathophysiological domains in a cohort of 1,544 heart failure (HF) patients. Data were independently validated in 804 patients with HF. Networks were enriched with existing knowledge on protein–protein interactions and translated into biological pathways uniquely related to HFrEF, HF with a midrange ejection fraction, and HFpEF. Results: In the index cohort (mean age 74 years; 34% female), 718 (47%) patients had HFrEF (left ventricular ejection fraction [LVEF] <40%) and 431 (27%) patients had HFpEF (LVEF ≥50%). A total of 8 (12%) correlations were unique for HFrEF and 6 (9%) were unique to HFpEF. Central proteins in HFrEF were N-terminal B-type natriuretic peptide, growth differentiation factor-15, interleukin-1 receptor type 1, and activating transcription factor 2, while central proteins in HFpEF were integrin subunit beta-2 and catenin beta-1. Biological pathways in HFrEF were related to DNA binding transcription factor activity, cellular protein metabolism, and regulation of nitric oxide biosynthesis. Unique pathways in patients with HFpEF were related to cytokine response, extracellular matrix organization, and inflammation. Biological pathways of patients with HF with a midrange ejection fraction were in between HFrEF and HFpEF. Conclusions: Network analysis showed that biomarker profiles specific for HFrEF are related to cellular proliferation and metabolism, whereas biomarker profiles specific for HFpEF are related to inflammation and extracellular matrix reorganization.

Original languageEnglish
Pages (from-to)1081-1090
Number of pages10
JournalJournal of the American College of Cardiology
Issue number10
Publication statusPublished - 4 Sept 2018
Externally publishedYes


  • Activating Transcription Factor 2/metabolism
  • Aged
  • Biomarkers/metabolism
  • CD18 Antigens/metabolism
  • Female
  • Growth Differentiation Factor 15/metabolism
  • Heart Failure/metabolism
  • Humans
  • Male
  • Natriuretic Peptide, Brain/metabolism
  • Receptors, Interleukin-1 Type I/metabolism
  • Stroke Volume/physiology
  • Transcriptional Activation/physiology
  • beta Catenin/metabolism


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