Abstract
BackgroundThe novel nonsteroidal mineralocorticoid receptor (MR) antagonist finerenone holds promise to be safe and efficient in the treatment of patients with heart failure and/or chronic kidney disease. However, its effects on vascular function remain elusive.PurposeThe aim of this study was to determine the functional effect of selective MR antagonism by finerenone in vascular cells in vitro and the effect on vascular remodeling following acute vascular injury in vivo.Methods and resultsIn vitro, finerenone dose-dependently reduced aldosterone-induced smooth muscle cell (SMC) proliferation, as quantified by BrdU incorporation, and prevented aldosterone-induced endothelial cell (EC) apoptosis, as measured with a flow cytometry based caspase 3/7 activity assay.In vivo, oral application of finerenone resulted in an accelerated re-endothelialization 3 days following electric injury of the murine carotid artery. Furthermore, finerenone treatment inhibited intimal and medial cell proliferation following wire-induced injury of the murine femoral artery 10 days following injury and attenuated neointimal lesion formation 21 days following injury.ConclusionFinerenone significantly reduces apoptosis of ECs and simultaneously attenuates SMC proliferation, resulting in accelerated endothelial healing and reduced neointima formation of the injured vessels. Thus, finerenone appears to provide favorable vascular effects through restoring vascular integrity and preventing adverse vascular remodeling.
Highlights
Whereas acute myocardial infarction incidence has decreased globally throughout the last two decades, the prevalence of ischemic heart failure and diabetes without or with kidney disease has steadily increased [1]
De Boer and colleagues showed that mineralocorticoid receptor antagonist (MRA) use markedly increased over the last 20 years among patients with diabetic kidney disease, who are at high risk for vascular complications [7]
A novel non-steroidal MRA, finerenone, has been developed in an effort to overcome these limitations by achieving high specificity for the mineralocorticoid receptor (MR) as well as a balanced and equal tissue distribution between cardiac and renal tissues which is in contrast to steroidal MRAs. [9, 10]
Summary
Whereas acute myocardial infarction incidence has decreased globally throughout the last two decades, the prevalence of ischemic heart failure and diabetes without or with kidney disease has steadily increased [1]. The available (steroidal) MR antagonists (MRAs) spironolactone, and its sole successor eplerenone, suffer from substantial drawbacks that limit their clinical use, e.g. hyperkalemia especially in patients with severe chronic kidney disease (CKD) [8]. The phase 2a MinerAlocorticoid Receptor antagonist Tolerability Study (ARTS) confirmed a reduced risk for developing hyperkalemia in patients hospitalized for worsening chronic heart failure treated with finerenone compared with those treated with spironolactone despite comparable reduction of efficacy parameters like the brain natriuretic peptide (BNP), NT-proBNP, and albuminuria [11]. In the phase 2b MinerAlocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF) the investigators found a lower incidence of the clinical composite endpoint (all-cause death, cardiovascular hospitalization or emergency presentation for worsening chronic heart failure) among patients treated with finerenone compared with eplerenone, even though the study was not powered for this observation [12]. The aim of this study was to determine the functional effect of selective MR antagonism by finerenone in vascular cells in vitro and the effect on vascular remodeling following acute vascular injury in vivo
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