Background: Further to their beneficial effects in established heart failure (HF), mineralocorticoid receptor antagonists may act upstream on mechanisms preventing incident HF. In people at risk for developing HF, the "Heart OMics in Aging" (HOMAGE) trial showed that spironolactone treatment could provide antifibrotic and anti-remodelling effects, potentially slowing the progression to HF.Objectives: To further understand the mechanisms underlying spironolactone effect, we assessed its impact on multiple plasma protein biomarkers and respective underlying biological pathways.Methods: Baseline, 1-month and 9-months (or last visit), plasma samples of HOMAGE participants were measured for protein biomarkers (n=276) using Olink®Proseek-Multiplex cardiovascular and inflammation panels. Spironolactone effect on biomarkers was assessed by analysis of covariance (ANCOVA) and explored by knowledge-based network analysis.Results: 527 participants were enrolled, 265 were randomized to spironolactone (25-50 mg/day) and 262 to standard care ("control"). The median (percentile 25-75 ) age was 73 (69-79) years and 26% were female. Spironolactone reduced biomarkers of collagen metabolism (e.g., COL1A1, MMP2), BNP, biomarkers related to metabolic processes (e.g., PAPPA), inflammation and thrombosis (e.g., IL17A, VEGF and urokinase). Spironolactone increased biomarkers that reflect the blockade of the mineralocorticoid receptor (e.g., renin), increased the levels of adipokines involved in anti-inflammatory response (e.g., RARRES2), biomarkers of haemostasis maintenance (e.g., tPA, UPAR), myelosuppressive activity (e.g., CCL16), insulin suppression (e.g., RETN), and inflammatory regulation (e.g., IL12B).
Conclusion:Proteomic analyses suggest that spironolactone exerts pleiotropic effects including reduction in fibrosis, inflammation, thrombosis, congestion and vascular function