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

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.

Galectin-4 levels in hospitalized versus non-hospitalized subjects with obesity: the Malmö Preventive Project

“…Furthermore, another study of women with gestational diabetes found an overexpression of Gal-4 in the placental syncytiotrophoblast cells, compared to healthy controls [ 35 ]. Thus, one proposed explanation for our main finding may be Gal-4’s involvement in the development of diabetes, which also has been suggested in a previous publication with a similar approach of proteomic exploration [ 36 ]. To elucidate this, we carried out a post-hoc analysis, suggesting that elevation in Gal-4 was associated with higher probability of being HO only in those with prevalent diabetes.…”

Mineralocorticoid receptor antagonists, heart failure and predictive biomarkers

“…As detailed earlier, the proteomic studies from the HOMAGE trial were able to show changes in proteomic biomarkers in response to MRA treatment in patients at risk of HF. Verdonschot et al used a similar approach to show differential expression of plasma proteins in patients at risk of HF with/without diabetes (Verdonschot et al 2021). In diabetic patients, the plasma concentration of COL1A1 and PICP decreased, and plasma concentration of MMP7 increased after 9 months of spironolactone treatment (Verdonschot et al 2021).…”

“…Verdonschot et al used a similar approach to show differential expression of plasma proteins in patients at risk of HF with/without diabetes (Verdonschot et al 2021). In diabetic patients, the plasma concentration of COL1A1 and PICP decreased, and plasma concentration of MMP7 increased after 9 months of spironolactone treatment (Verdonschot et al 2021). Another study to employ the use of high-throughput proteomic profiling is the ongoing MyoVasc study; a large, prospective, observational cohort study aiming to use multi-omics profiling to gain a better understanding of HF pathophysiology (Gobel et al 2021).…”

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