Distinct Pathological Pathways in Patients With Heart Failure and Diabetes

Jasper Tromp, Adriaan A Voors, Abhinav Sharma, João P Ferreira, Wouter Ouwerkerk, Hans L Hillege, Karla A Gomez, Kenneth Dickstein, Stefan D Anker, Marco Metra, Chim C Lang, Leong L Ng, Pim van der Harst, Dirk J van Veldhuisen, Peter van der Meer, Carolyn S P Lam, Faiez Zannad, Iziah E Sama

Research output: Contribution to journalArticleAcademicpeer-review


Objectives: The aims of this study were to compare the characteristics of patients with and without diabetes and to use network analyses to compare biomarker profiles and associated pathways in patients with diabetes compared with those without diabetes, which might offer new avenues for potential therapeutic targets. Background: Diabetes adversely affects clinical outcomes and complicates treatment in patients with heart failure (HF). A clear understanding of the pathophysiological processes associated with type 2 diabetes in HF is lacking. Methods: Network and pathway over-representation analyses were performed to identify unique pathological pathways in patients with and without diabetes using 92 biomarkers from different pathophysiological domains measured in plasma samples from 1,572 patients with HF (31% with diabetes) with reduced ejection fraction (left ventricular ejection fraction <40%). The results were validated in an independent cohort of 729 patients (30% with diabetes). Results: Biomarker profiles were first compared between patients with HF with and without diabetes. Patients with diabetes showed higher levels of galectin-4, growth differentiation factor 15, and fatty acid binding protein 4 and lower levels of paraoxonase 3. Network analyses were then performed, revealing that epidermal growth factor receptor and galectin-3 were the most prominent connecting proteins. Translation of these networks to biologic pathways revealed that diabetes was associated with inflammatory response and neutrophil degranulation. Diabetes conferred worse outcomes after correction for an established risk model (hazard ratio: 1.20; 95% confidence interval: 1.01 to 1.42). Conclusions: Concomitant diabetes in patients with HF with reduced ejection fraction is associated with distinct pathophysiological pathways related to inflammation, protein phosphorylation, and neutrophil degranulation. These data support the evaluation of anti-inflammatory therapeutic approaches, epidermal growth factor receptor in particular, for patients with HF and diabetes.

Original languageEnglish
Pages (from-to)234-242
Number of pages9
JournalJACC. Heart failure
Issue number3
Publication statusPublished - Mar 2020
Externally publishedYes


  • Aged
  • Biomarkers/metabolism
  • Diabetes Mellitus, Type 2/complications
  • Female
  • Heart Failure/complications
  • Humans
  • Male
  • Prognosis
  • Prospective Studies
  • Stroke Volume/physiology
  • Ventricular Function, Left/physiology


Dive into the research topics of 'Distinct Pathological Pathways in Patients With Heart Failure and Diabetes'. Together they form a unique fingerprint.

Cite this