Proteomic mechanistic profile of patients with diabetes at risk of developing heart failure: insights from the HOMAGE trial

Job A J Verdonschot, João Pedro Ferreira, Pierpaolo Pellicori, Hans-Peter Brunner-La Rocca, Andrew L Clark, Franco Cosmi, Joe Cuthbert, Nicolas Girerd, Beatrice Mariottoni, Johannes Petutschnigg, Patrick Rossignol, John G F Cleland, Faiez Zannad, Stephane R B Heymans, HOMAGE “Heart Omics in AGEing” consortium, Job A J Verdonschot, João Pedro Ferreira, Pierpaolo Pellicori, Hans-Peter Brunner-La Rocca, Andrew L Clark, Franco Cosmi, Joe Cuthbert, Nicolas Girerd, Beatrice Mariottoni, Johannes Petutschnigg, Patrick Rossignol, John G F Cleland, Faiez Zannad, Stephane R B Heymans, HOMAGE “Heart Omics in AGEing” consortium

Abstract

Background: Patients with diabetes mellitus (DM) are at increased risk of developing heart failure (HF). The "Heart OMics in AGEing" (HOMAGE) trial suggested that spironolactone had beneficial effect on fibrosis and cardiac remodelling in an at risk population, potentially slowing the progression towards HF. We compared the proteomic profile of patients with and without diabetes among patients at risk for HF in the HOMAGE trial.

Methods: Protein biomarkers (n = 276) from the Olink®Proseek-Multiplex cardiovascular and inflammation panels were measured in plasma collected at baseline and 9 months (or last visit) from HOMAGE trial participants including 217 patients with, and 310 without, diabetes.

Results: Twenty-one biomarkers were increased and five decreased in patients with diabetes compared to non-diabetics at baseline. The markers clustered mainly within inflammatory and proteolytic pathways, with granulin as the key-hub, as revealed by knowledge-induced network and subsequent gene enrichment analysis. Treatment with spironolactone in diabetic patients did not lead to large changes in biomarkers. The effects of spironolactone on NTproBNP, fibrosis biomarkers and echocardiographic measures of diastolic function were similar in patients with and without diabetes (all interaction analyses p > 0.05).

Conclusions: Amongst patients at risk for HF, those with diabetes have higher plasma concentrations of proteins involved in inflammation and proteolysis. Diabetes does not influence the effects of spironolactone on the proteomic profile, and spironolactone produced anti-fibrotic, anti-remodelling, blood pressure and natriuretic peptide lowering effects regardless of diabetes status. Trial registration NCT02556450.

Keywords: Biomarker; Diabetes; Fibrosis; Heart failure; Spironolactone.

Conflict of interest statement

The authors have no relevant conflicts of interest to disclose with regards to the content of this manuscript.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Network of protein biomarkers which were significant differentially detected in patients with diabetes compared to non-diabetics. Knowledge-based induced network with the plasma protein biomarkers which were significantly increased or decreased in diabetic patients (FDRq 

Fig. 2

Overrepresented pathways of protein biomarkers…

Fig. 2

Overrepresented pathways of protein biomarkers in diabetic patients when compared to non-diabetic patients.…

Fig. 2
Overrepresented pathways of protein biomarkers in diabetic patients when compared to non-diabetic patients. The gene ontology (GO) biological processes are used as reference. Additional file 1: Table S2 contains further details on the proteins in these pathways

Fig. 3

Summary of the study design…

Fig. 3

Summary of the study design and results

Fig. 3
Summary of the study design and results
Fig. 2
Fig. 2
Overrepresented pathways of protein biomarkers in diabetic patients when compared to non-diabetic patients. The gene ontology (GO) biological processes are used as reference. Additional file 1: Table S2 contains further details on the proteins in these pathways
Fig. 3
Fig. 3
Summary of the study design and results

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