Potential Impact of Non-Steroidal Mineralocorticoid Receptor Antagonists in Cardiovascular Disease

Abstract

Inappropriate mineralocorticoid receptor (MR) activation in different cardiovascular cell types has deleterious effects on cardiac remodeling and function. Therefore, MR inhibition is a crucial pharmacological strategy to overcome cardiovascular dysfunction. Despite efficient blockade of MR with steroidal MR antagonists (MRAs), their clinical application is unsatisfactory due to the adverse effects. Newer non-steroidal MRAs with greater potency could be suitable for clinical application, especially in patients with type 2 diabetes mellitus and chronic kidney disease. Although clinical evidence has shown the beneficial effects of non-steroidal MRAs on cardiovascular outcomes in patients with heart failure with reduced ejection fraction, clinical trials are ongoing to evaluate the efficacy of heart failure with preserved ejection fraction. Therefore, comparative pharmacological characterization of non-steroidal MRAs over classic steroidal MRAs is crucial. Here, we summarize the pre-clinical evidence of non-steroidal MRAs, which suggests an improvement in cardiac dysfunction, as well as the underlying molecular mechanisms in animal models mimicking different clinical conditions. In addition, we discuss up-to-date information from clinical trials regarding the beneficial effects of non-steroidal MRAs on meaningful cardiovascular outcomes. Both pre-clinical and clinical evidence support treatment with non-steroidal MRAs in patients with cardiovascular disease.

Additive Effects of Esaxerenone, a Nonsteroidal Mineralocorticoid Receptor Blocker, on Cardioplegic Arrest in Rat Hearts

“…Chai et al suggested that aldosterone was still present in the isolated perfused rat Langendorff heart. 13) Steroidal MRBs, such as spironolactone and eplerenone, reduce mortality 5) ; however, steroidal MRBs are not prescribed routinely in clinical settings owing to concerns regarding the risk of hyperkalemia and hormonal side effects.…”

“…The discovery of non-steroidal MRBs has opened an avenue in cardiorenal disease therapy. 6) Rahman et al revealed that animals fed a high-salt diet (HSD) developed cardiac dysfunction, as evidenced by the reduction in stroke volume, ejection fraction, and cardiac output. 14) In addition, the administration of esaxerenone decreased the worsening of cardiac dysfunction and induced a significant reduction in systolic blood pressure.…”

“…Esaxerenone, a potent and selective non-steroidal MRB, has pharmacological properties distinct from those of steroidal MRBs. 6) When used for the treatment of hypertension, esaxerenone induces reverse remodeling in patients with heart failure who have a preserved ejection fraction. 7) Moreover, esaxerenone may be effective in reducing brain natriuretic peptide levels in patients with heart failure who have a reduced ejection fraction.…”

Efficacy of Pfizer vaccine on IL-12/IFN-γ pathway with related to COVID-19 infection

“…IL-12 expression regulates the innate immune response during infection and is ultimately responsible for determining the length and type of the following adaptive immune response. Similarly, IL-12 promotes differentiation in naive CD4+ helper T cells into the Th1 phenotype that go on to produce IFN-γ and facilitate cell-mediated immunity [29]. IL-12 can drive interferon-γ (IFN-γ) production in dendritic cells (DCs), NK cells, macrophages, and T cells [30].…”

Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone Improves Diastolic Dysfunction in Preclinical Nondiabetic Chronic Kidney Disease

“…The mineralocorticoid receptor (MR) is expressed not only by epithelial renal cells but also by other cell types, including cardiomyocytes, endothelial cells, and cardiac fibroblasts. 9 MR overactivation in the heart is proposed to play an important role in the progression of cardiovascular disease in the context of CKD by promoting inflammation and fibrosis. 10 Several preclinical studies have shown that the use of MR antagonists (MRAs) has a beneficial effect by delaying the progression of the disease in both kidney and cardiovascular disease models.…”