Jasper Tromp1, Adriaan A Voors2, Abhinav Sharma3, João P Ferreira4, Wouter Ouwerkerk5, Hans L Hillege6, Karla A Gomez6, Kenneth Dickstein7, Stefan D Anker8, Marco Metra9, Chim C Lang10, Leong L Ng11, Pim van der Harst6, Dirk J van Veldhuisen6, Peter van der Meer6, Carolyn S P Lam12, Faiez Zannad4, Iziah E Sama6. 1. Department of Cardiology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands; National Heart Centre Singapore, Singapore; Duke-NUS Medical School, Singapore. 2. Department of Cardiology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands. Electronic address: a.a.voors@umcg.nl. 3. Division of Cardiology, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada; Division of Cardiology, Stanford University, Palo Alto, California. 4. Université de Lorraine, Inserm, Centre d'Investigations Cliniques-Plurithématique 1433, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France. 5. National Heart Centre Singapore, Singapore. 6. Department of Cardiology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands. 7. University of Bergen, Stavanger University Hospital, Stavanger, Norway. 8. Division of Cardiology and Metabolism-Heart Failure, Cachexia & Sarcopenia, Department of Cardiology, Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine, Berlin, Germany. 9. Institute of Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy. 10. Division of Molecular & Clinical Medicine, University of Dundee, Dundee, United Kingdom. 11. Department of Cardiovascular Sciences, Cardiovascular Research Centre, University of Leicester, Leicester, United Kingdom. 12. Department of Cardiology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands; National Heart Centre Singapore, Singapore; Duke-NUS Medical School, Singapore; The George Institute for Global Health, Sydney, Australia.
Abstract
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.
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.
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