Proteomic and Mechanistic Analysis of Spironolactone in Patients at Risk for HF

Abstract

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

Plasma Biomarker Profiling in Heart Failure Patients with Preserved Ejection Fraction before and after Spironolactone Treatment: Results from the Aldo-DHF Trial

“…It may therefore be speculated that spironolactone mediates distinct beneficial effects in HFpEF by enhancing ADM and GH expression. The increase in MMP7 plasma levels observed in our study is consistent with recent findings demonstrating a similar regulation through spironolactone in a cohort of patients at risk of developing HF (HOMAGE trial) [12]. Interestingly, plasma levels of MMP7 were also reported to be increased in patients with diastolic HF [45].…”

“…The analysis of large panels of plasma or serum biomarkers in distinct patient cohorts is a common approach in cardiovascular science [11][12][13]. It can be used to identify underlying mechanisms of the disease of interest, or to analyse downstream effects of an administered drug.…”

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

“…Spironolactone did not significantly change the proteomic profiles of patients with diabetes, but yielded the same clinical benefits as in the complete HOMAGE cohort. The four proteins which were significantly modified in diabetic patients after 9 months of spironolactone treatment (COL1A1, PICP, SELE and MMP7) are altered in the same direction as in the complete population, indicating that the effects are not specific for diabetic patients [ 9 ]. These proteins are implicated in extracellular matrix metabolism (COL1A1, PICP), cell-cell adhesion (SELE) and proteolysis (MMP7).…”

“…As spironolactone is a steroidal mineralocorticoid receptor antagonist (MRA) that is not specific for the mineralocorticoid receptor, it may exert other effects (e.g., cortisol elevation) on glucose and insulin metabolism. In a previous analysis we showed the influence of spironolactone on the proteome in the total HOMAGE trial population [ 9 ]. It remains unknown to what extent DM influences the effects of spironolactone on clinical and proteomic variables.…”

Effect On Cardiac Function Among Patients With Type 2 Diabetes Following High-Dose Mineralocorticoid Receptor Antagonist Using Echocardiography; Data From The MIRAD Randomized Clinical Trial

“…Experimental studies investigating the potential underlying mechanisms of MRA therapy in HF, demonstrated receptormediated effects in cardiomyocytes and vascular endothelial cells, which was independent of simple diuretic effects mediated by mineralocorticoid receptor activation in the kidneys [8][9][10]. An exploratory analysis from the HOMAGE trial using targeted proteomics has found evidence of the spironolactone exerting pleiotropic effects across multiple mechanistic pathways, spanning the mitigation of fibrosis, thrombosis, congestion, vascular function and inflammation [27].…”