Effects of Spironolactone on Long-term Mortality and Morbidity in Patients With Heart Failure and Mild or No Symptoms

Vizzardi, Enrico; Nodari, Savina; Caretta, Giorgio; D’Aloia, Antonio; Pezzali, Natalia; Faden, Giacomo; Lombardi, Carlo; Raddino, Riccardo; Metra, Marco; Dei, Livio

doi:10.1097/maj.0b013e31829dd6b1

Cited by 22 publications

(14 citation statements)

References 37 publications

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“…Recently, post hoc analysis of the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) trial also revealed a substantial benefit of the MR antagonist eplerenone on major cardiovascular events in the subset of patients with mild heart failure, over and above high doses of standard therapies [73]. Similar observations were made in another study that enrolled patients with NYHA classes I to II HF and treated them with spironolactone [74]. Spironolactone improved diastolic cardiac function in patients with heart failure with preserved ejection fraction [75].…”

Section: Mr and Diabetic Complications In Humansmentioning

confidence: 71%

Aldosterone and the Mineralocorticoid Receptor: Risk Factors for Cardiometabolic Disorders

Garg

Adler

2015

Curr Hypertens Rep

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Preclinical studies have convincingly demonstrated a role for the mineralocorticoid receptor (MR) in adipose tissue physiology. These studies show that increased MR activation causes adipocyte dysfunction leading to decreased production of insulin-sensitizing products and increased production of inflammatory factors, creating an environment conducive to metabolic and cardiovascular disease. Accumulating data also suggest that MR activation may be an important link between obesity and metabolic syndrome. Moreover, MR activation may mediate the pathogenic consequences of metabolic syndrome. Recent attempts at reversing cardiometabolic damage in patients with type 2 diabetes using MR antagonists have shown promising results. MR antagonists are already used to treat heart failure where their use decreases mortality and morbidity over and above the use of traditional therapies alone. However, more data are needed to establish the benefits of MR antagonists in diabetes, obesity, and metabolic syndrome.

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Section: Mr and Diabetic Complications In Humansmentioning

confidence: 71%

Aldosterone and the Mineralocorticoid Receptor: Risk Factors for Cardiometabolic Disorders

Garg

Adler

2015

Curr Hypertens Rep

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“…7,21–77 The majority were multicenter, double-blind, placebo-controlled trials, including between 28 and 8399 patients with a mean follow-up duration ranging from 8 weeks to 4 years. The treatment classes assessed included ACEI, BB, ARB, MRA, and ARNI.…”

Section: Resultsmentioning

confidence: 99%

Thirty Years of Evidence on the Efficacy of Drug Treatments for Chronic Heart Failure With Reduced Ejection Fraction

Burnett

Earley

Voors

et al. 2017

Circ: Heart Failure

198

152

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“…Whilst the established pro-calcification actions of dexamethasone on VSMCs [18], [29] are presumed to be mediated via GR, plausibly endogenous corticosteroids may modulate VSMC calcification via MR. This is therapeutically important to ascertain, as vascular calcification is independently correlated with adverse cardiac events [50], and MR antagonism is highly successful in reducing mortality in heart failure [45]; aldosterone antagonists such as spironolactone and eplerenone have been shown to improve cardiovascular outcomes and prevent ischaemic events in cardiovascular patients [32], [33]. Corticosterone has been shown to induce rapid MR signaling in VSMCs that involves mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)-dependent pathways, suggesting that glucocorticoids may contribute to vascular disease via MR receptor signaling [27].…”

Section: Introductionmentioning

confidence: 99%

A novel role for the mineralocorticoid receptor in glucocorticoid driven vascular calcification

Zhu

Rashdan

Chapman

et al. 2016

Vascular Pharmacology

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Vascular calcification, which is common in the elderly and in patients with atherosclerosis, diabetes and chronic renal disease, increases the risk of cardiovascular morbidity and mortality. It is a complex, active and highly regulated cellular process that resembles physiological bone formation. It has previously been established that pharmacological doses of glucocorticoids facilitate arterial calcification. However, the consequences for vascular calcification of endogenous glucocorticoid elevation have yet to be established. Glucocorticoids (cortisol, corticosterone) are released from the adrenal gland, but can also be generated within cells from 11-keto metabolites of glucocorticoids (cortisone, 11-dehydrocorticosterone [11-DHC]) by the enzyme, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). In the current study we hypothesized that endogenous glucocorticoids facilitate vascular smooth muscle cell (VSMC) calcification and investigated the receptor-mediated mechanism underpinning this process.In vitro studies revealed increased phosphate-induced calcification in mouse VSMCs following treatment for 7 days with corticosterone (100 nM; 7.98 fold; P < 0.01), 11-DHC (100 nM; 7.14 fold; P < 0.05) and dexamethasone (10 nM; 7.16 fold; P < 0.05), a synthetic glucocorticoid used as a positive control. Inhibition of 11β-HSD isoenzymes by 10 μM carbenoxolone reduced the calcification induced by 11-DHC (0.37 fold compared to treatment with 11-DHC alone; P < 0.05). The glucocorticoid receptor (GR) antagonist mifepristone (10 μM) had no effect on VSMC calcification in response to corticosterone or 11-DHC. In contrast, the mineralocorticoid receptor (MR) antagonist eplerenone (10 μM) significantly decreased corticosterone- (0.81 fold compared to treatment with corticosterone alone; P < 0.01) and 11-DHC-driven (0.64 fold compared to treatment with 11-DHC alone; P < 0.01) VSMC calcification, suggesting this glucocorticoid effect is MR-driven and not GR-driven. Neither corticosterone nor 11-DHC altered the mRNA levels of the osteogenic markers PiT-1, Osx and Bmp2. However, DAPI staining of pyknotic nuclei and flow cytometry analysis of surface Annexin V expression showed that corticosterone induced apoptosis in VSMCs.This study suggests that in mouse VSMCs, corticosterone acts through the MR to induce pro-calcification effects, and identifies 11β-HSD-inhibition as a novel potential treatment for vascular calcification.

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Effects of Spironolactone on Long-term Mortality and Morbidity in Patients With Heart Failure and Mild or No Symptoms

Cited by 22 publications

References 37 publications

Aldosterone and the Mineralocorticoid Receptor: Risk Factors for Cardiometabolic Disorders

Aldosterone and the Mineralocorticoid Receptor: Risk Factors for Cardiometabolic Disorders

Thirty Years of Evidence on the Efficacy of Drug Treatments for Chronic Heart Failure With Reduced Ejection Fraction

A novel role for the mineralocorticoid receptor in glucocorticoid driven vascular calcification

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