Aldosterone synthase inhibition improves cardiovascular function and structure in rats with heart failure: a comparison with spironolactone

Mulder, Paul; Mellin, Virginie; Favre, Julie; Vercauteren, Magali; Rémy-Jouet, Isabelle; Monteil, Christelle; Richard, Vincent; Renet, Sylvanie; Henry, J. P.; Jeng, Arco Y.; Webb, Randy L.; Thuillez, Christian

doi:10.1093/eurheartj/ehn277

Cited by 110 publications

(79 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…4,5 Moreover, a recent study demonstrates that the highest tertile of aldosterone in patients with systolic heart failure (with no differences in median aldosterone concentration between patients with systolic heart failure and those without systolic heart failure) is associated with an adverse outcome. 27 The control of aldosterone plasma concentration (through the development and the use of aldosterone-synthase inhibitors such as the FAD286, 28 which experimentally presents promising results in treatment of cardiac heart failure) in addition to MR blockers may thus be a complementary strategy to fully block the aldosterone/MR activated pathways in patients with elevated aldosteronemia.…”

Section: Discussionmentioning

confidence: 99%

Aldosterone-Specific Activation of Cardiomyocyte Mineralocorticoid Receptor In Vivo

Messaoudi

Gravez²,

Tarjus³

et al. 2013

Hypertension

View full text Add to dashboard Cite

Inappropriate mineralocorticoid receptor (MR) activation is involved in cardiac diseases. Whether and how aldosterone is involved in the deleterious effects of cardiac mineralocorticoid activation is still unclear. Mice overexpressing MR in cardiomyocytes and their controls were treated for 7 days with aldosterone, and cardiac transcriptome was analyzed. Aldosterone regulated 265 genes in cardiomyocyte-targeted MR overexpression mice. Forty three of these genes were also differentially expressed between untreated cardiomyocyte-targeted MR overexpression and controls mice, thus representing putative aldosterone-regulated genes in cardiomyocytes. Among these genes, we focused on connective tissue growth factor (CTGF). In vivo, in cardiomyocyte-targeted MR overexpression mice, aldosterone (but not corticosterone) induced CTGF expression (mRNA and protein) in cardiomyocytes. Ex vivo, aldosterone induced the binding of mineralocorticoid receptor to CTGF promoter and increased the expression of its transcript. Aldosterone induction of CTGF synthesis in cardiomyocytes seems pathologically relevant as the increase in CTGF observed in a model of heart failure (transverse aortic constriction) in rats was prevented by eplerenone, a mineralocorticoid receptor blocker. This study demonstrates that aldosterone specifically regulates gene expression in cardiomyocytes despite large prevalence of glucocorticoids in plasma.

show abstract

Section: Discussionmentioning

confidence: 99%

Aldosterone-Specific Activation of Cardiomyocyte Mineralocorticoid Receptor In Vivo

Messaoudi

Gravez²,

Tarjus³

et al. 2013

Hypertension

View full text Add to dashboard Cite

show abstract

“…9 Although spironolactone limits vascular dysfunction in the rat aorta 10 and mesenteric arteries 11 after MI, whether VSMC-MR is involved in the progressive aggravation of HF post MI is unknown, as well as its role in coronary dysfunction associated with MI.…”

Section: Hypertensionmentioning

confidence: 99%

Vascular Smooth Muscle Mineralocorticoid Receptor Contributes to Coronary and Left Ventricular Dysfunction After Myocardial Infarction

et al. 2016

View full text Add to dashboard Cite

C hronic heart failure (HF) after myocardial infarction (MI) is steadily increasing worldwide and remains a major cause of death. Mineralocorticoid receptor (MR) antagonists (MRAs) improve survival in patients with HF as illustrated by spironolactone in the RALES (Randomized Aldactone Evaluation Study) 1 trial and by eplerenone in the EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) trial, 2 which only included patients with post-MI. Recently, the EMPHASIS (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) study even showed that eplerenone is effective in slowing down the progression of mild-to-moderate HF. 3 However, MRAs are associated with side effects, such as hyperkalemia or gynecomastia; the latter is caused by the antiandrogenic properties of their steroidal structure. These adverse effects are responsible for the underuse of MRAs. 4 Understanding of the cell-specific contribution of MR to HF and of the effects of MRA on various cell subtypes will be useful for the future development of tissue-selective MR targeting approaches that would improve the benefit/risk ratio. 5A crucial role of cardiomyocyte MR has been demonstrated in mice with cardiomyocyte-specific MR deletion, which allows improving left ventricular (LV) function after either MI 6 or pressure overload induced by transverse aortic constriction. 7 The deletion of MR specifically in fibroblasts does not affect cardiac failure after aortic constriction. 7 The role of vascular MR has been underlined recently: the MR expressed in vascular smooth muscle cells (VSMCs) is involved in age-related Abstract-Mineralocorticoid receptor (MR) antagonists slow down the progression of heart failure after myocardial infarction (MI), but the cell-specific role of MR in these benefits is unclear. In this study, the role of MR expressed in vascular smooth muscle cells (VSMCs) was investigated. Two months after coronary artery ligation causing MI, mice with VSMC-specific MR deletion (MI-MR SMKO ) and mice treated with the MR antagonist finerenone (MI-fine) had improved left ventricular compliance and elastance when compared with infarcted control mice (MI-CTL), as well as reduced interstitial fibrosis. Importantly, the coronary reserve assessed by magnetic resonance imaging was preserved (difference in myocardial perfusion before and after induction of vasodilatation, mL mg . The endothelial function, tested on isolated septal coronary arteries by analyzing the acetylcholine-induced nitric oxide-dependent relaxation, was also improved by MR deletion in VSMCs or by finerenone treatment (relaxation %: MI-CTL: 36±5, MI-MR SMKO : 54±3, and MI-fine: 76±4; P<0.05). Such impairment of the coronary endothelial function on MI involved an oxidative stress that was reduced when MR was deleted in VSMCs or by finerenone treatment. Moreover, short-term incubation of coronary arteries isolated from noninfarcted animals with low-dose angiotensin-II (10 −9 mol/L) induced oxidative stress and impaired...

show abstract

“…In a rat model of CHF, FAD286 improved cardiac hemodynamic parameters, as well as function, and prevented LV remodeling. 34 …”

Section: Novel Targets Within Existing Systemsmentioning

confidence: 99%

The Future of Pharmacological Therapy for Heart Failure

Sata

Krum

2010

Circ J

View full text Add to dashboard Cite

Current pharmacological therapy for heart failure (HF) is based on improved understanding of the pathophysiological mechanisms of HF progression. In particular, inhibition of key activated neurohormonal systems (eg, the renin-angiotensin-aldosterone system) and the sympathetic nervous system has been the cornerstone of drug therapy for this condition. However, despite these major advances, many HF patients still only marginally respond to these therapies. Novel therapeutic approaches have been tested. Several recent phase III studies have failed, however, despite intriguing pathophysiological concepts and promising pilot data. In other studies, significant benefits have been observed in certain subgroups only, suggesting the need for a more tailored approach to individual risk and comorbidity. This review will focus on recent and potential future pharmacological HF therapies and where drug treatment may be in the next few years. In discussing future pharmacological therapy for HF, 3 key strategies will be considered: (1) optimization of conventional therapies, (2) a focus on new drug development within areas not yet adequately represented by major clinical data and (3) new drugs affecting novel therapeutic targets. (Circ J 2010; 74: 809 - 817)

show abstract

Aldosterone synthase inhibition improves cardiovascular function and structure in rats with heart failure: a comparison with spironolactone

Abstract: In experimental CHF, FAD286 and spironolactone improve LV haemodynamics, remodelling, and function, but only FAD286 persistently normalizes LV 'redox status'. These results suggest that aldosterone synthase inhibition is a potential therapeutic strategy for the treatment of CHF.

Cited by 110 publications

References 43 publications

Aldosterone-Specific Activation of Cardiomyocyte Mineralocorticoid Receptor In Vivo

Aldosterone-Specific Activation of Cardiomyocyte Mineralocorticoid Receptor In Vivo

Vascular Smooth Muscle Mineralocorticoid Receptor Contributes to Coronary and Left Ventricular Dysfunction After Myocardial Infarction

The Future of Pharmacological Therapy for Heart Failure

Contact Info

Product

Resources

About