Author + information
- Received August 7, 2019
- Revision received November 5, 2019
- Accepted November 6, 2019
- Published online February 24, 2020.
- Jasper Tromp, MD, PhDa,b,c,
- Adriaan A. Voors, MD, PhDa,∗ (, )
- Abhinav Sharma, MDd,e,f,
- João P. Ferreira, MD, PhDg,
- Wouter Ouwerkerk, PhDb,
- Hans L. Hillege, PhDa,
- Karla A. Gomez, MDa,
- Kenneth Dickstein, MDh,
- Stefan D. Anker, MD, PhDi,
- Marco Metra, MDj,
- Chim C. Lang, MDk,
- Leong L. Ng, MDl,
- Pim van der Harst, MD, PhDa,
- Dirk J. van Veldhuisen, MD, PhDa,
- Peter van der Meer, MD, PhDa,
- Carolyn S.P. Lam, MD, PhDa,b,c,m,
- Faiez Zannad, MDg and
- Iziah E. Sama, PhDa
- aDepartment of Cardiology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands
- bNational Heart Centre Singapore, Singapore
- cDuke-NUS Medical School, Singapore
- dDivision of Cardiology, McGill University Health Centre, McGill University, Montreal, Quebec, Canada
- eDivision of Cardiology, University of Alberta, Edmonton, Alberta, Canada
- fDivision of Cardiology, Stanford University, Palo Alto, California
- gUniversité de Lorraine, Inserm, Centre d’Investigations Cliniques-Plurithématique 1433, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France
- hUniversity of Bergen, Stavanger University Hospital, Stavanger, Norway
- iDivision of Cardiology and Metabolism-Heart Failure, Cachexia & Sarcopenia, Department of Cardiology, Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine, Berlin, Germany
- jInstitute of Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
- kDivision of Molecular & Clinical Medicine, University of Dundee, Dundee, United Kingdom
- lDepartment of Cardiovascular Sciences, Cardiovascular Research Centre, University of Leicester, Leicester, United Kingdom
- mThe George Institute for Global Health, Sydney, Australia
- ↵∗Address for correspondence:
Prof. Dr. Adriaan A. Voors, Department of Cardiology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
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.
BIOSTAT-CHF was funded by the European Commission (FP7-242209-BIOSTAT-CHF; and EudraCT 2010-020808-29). Additional funding was provided by Roche Diagnostics. Dr. Voors has received consultancy fees and/or research grants from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Myokardia, Novartis, Roche Diagnostics, and Servier. Dr. van Veldhuisen has received board membership fees and travel expenses from BioControl, Cardiorentis, Johnson & Johnson, Novartis, Vifor, and Zoll Medical. Dr. Dickstein has received honoraria and/or research support from Medtronic, Boston Scientific, St. Jude, Biotronik, Sorin, Merck, Novartis, Amgen, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer, GlaxoSmithKline, Roche, Sanofi, Abbott, Otsuka, Leo, Servier, and Bristol-Meyers Squibb. Dr. Lang has received consultancy fees and/or research grants from Amgen, AstraZeneca, Merck Sharpe & Dohme, Novartis, and Servier. Dr. Anker has received grants from Vifor and Abbott Vascular; and has received fees for consultancy from Vifor, Bayer, Boehringer Ingelheim, Brahms, Janssen, Novartis, Servier, Stealth Peptides, and ZS Pharma. Dr. Metra has received consulting honoraria from Amgen, AstraZeneca, Novartis, Relypsa, and Servier; and has received speaking fees from Abbott Vascular and Servier. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received August 7, 2019.
- Revision received November 5, 2019.
- Accepted November 6, 2019.
- 2020 American College of Cardiology Foundation
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