LBODP028 Identifying Biomarkers For Predicting Response To Mineralocorticoid Receptor Antagonist Treatment In Heart Failure

Abstract

Abstract Despite significant improvements to patient care, heart failure (HF) remains a major public health burden. Mineralocorticoid receptor antagonists (MRAs) reduce hospitalisation and improve survival in patients with HF with reduced ejection fraction (HFrEF) but the widespread use of MRAs is limited by adverse effects including hyperkalaemia. The use of biomarkers to guide therapy may enable earlier treatment or minimise side effects from unnecessary therapies. We have previously described mineralocorticoid receptor responsive genes in monocytes/macrophages and hypothesised that response to MRAs can be detected in this cell population. Therefore, we aimed to identify biomarkers for predicting response to MRAs to facilitate personalised treatment of HF. Microarray-based transcriptome profiling was performed on monocytes obtained from six patients with HFrEF, before and after three months of MRA treatment. Three patients demonstrated improvement in left ventricular ejection fraction (LVEF) after 12 months of MRA treatment (Group 1), whereas the other three patients exhibited minimal functional response to MRAs (Group 2). To visualise sample similarity, multidimensional scaling (MDS) was employed which revealed distinct separation of males from females. To understand the changes in monocyte gene expression following MRA treatment, differential expression analysis was performed. Paired analysis of Group 1 samples (before vs after MRA treatment) identified 319 unique differentially expressed genes (DEGs) with an estimated fold-change ≥ 2 and q-value < 0. 05; 1 upregulated, 318 downregulated, and paired analysis of Group 2 identified 1 unique DEG. RT-qPCR was used validate top DEGs implicated in cardiovascular pathophysiology which confirmed downregulation of 12 of the top DEGs in Group 1. Additionally, cluster of differentiation (CD) encoding genes CD14, CD163, and CD68 were upregulated in Group 1 but downregulated in Group 2. Additional differential expression analyses were also performed by stratifying patients according to additional metrics of functional response including change in B-type natriuretic peptide (BNP). However, these analyses did not identify statistically significant DEGs. Our results indicate MRA treatment can significantly alter the human monocyte transcriptomic profile. Further research is needed to establish the utility of these DEGs as biomarkers for early prediction of MRA treatment-response in patients with HF, and to define sex-specific differences. Presentation: No date and time listed