Role of Mineralocorticoid Receptor Antagonists in Cardiovascular Disease

Ferrario, Carlos M.; Schiffrin, Ernesto L.

doi:10.1161/circresaha.116.302706

Cited by 79 publications

(54 citation statements)

References 115 publications

(111 reference statements)

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“…7,21 Its antagonists (spironolactone and eplerenone) are part of the standard therapeutic regimen for treating heart failure in clinical practice. 22 Although animal studies have shown promising data that these antagonists may be beneficial for restenosis after PCI, they have not been clinically proved.…”

Section: Discussionmentioning

confidence: 99%

Mineralocorticoid Receptor Deficiency in Macrophages Inhibits Neointimal Hyperplasia and Suppresses Macrophage Inflammation Through SGK1-AP1/NF-κB Pathways

Sun

Shen

et al. 2016

ATVB

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Objective-Restenosis after percutaneous coronary intervention remains to be a serious medical problem. Although mineralocorticoid receptor (MR) has been implicated as a potential target for treating restenosis, the cellular and molecular mechanisms are largely unknown. This study aims to explore the functions of macrophage MR in neointimal hyperplasia and to delineate the molecular mechanisms. Approach and Results-Myeloid MR knockout (MMRKO) mice and controls were subjected to femoral artery injury.MMRKO reduced intima area and intima/media ratio, Ki67-and BrdU-positive vascular smooth muscle cells, expression of proinflammatory molecules, and macrophage accumulation in injured arteries. MMRKO macrophages migrated less in culture. MMRKO decreased Ki67-and BrdU-positive macrophages in injured arteries. MMRKO macrophages were less Ki67-positive in culture. Conditioned media from MMRKO macrophages induced less migration, Ki67 positivity, and proinflammatory gene expression of vascular smooth muscle cells. After lipopolysaccharide treatment, MMRKO macrophages had decreased p-cFos and p-cJun compared with control macrophages, suggesting suppressed activation of activator protein-1 (AP1). Nuclear factor-κB (NF-κB) pathway was also inhibited by MMRKO, manifested by decreased p-IκB kinase-β and p-IκBα, increased IκBα expression, decreased nuclear translocation of p65 and p50, as welll as decreased phosphorylation and expression of p65. Finally, overexpression of serum-and-glucocorticoid-induciblekinase-1 (SGK1) attenuated the effects of MR deficiency in macrophages. This manuscript was sent to Kathryn Moore, Consulting Editor, for review by expert referees, editorial decision, and final disposition. *These authors contributed equally to this article. angioplasty of coronary arteries and neointima formation after stent implantation in coronary arteries of swine. 3,4 However, the effects of MR antagonists on restenosis in human patients are uncertain. Early study has shown that spironolactone, another antagonist of MR, does not change the incidence of restenosis at 6 months after stenting in a clinical trial. Conclusions-Selective5 More recent results, however, have demonstrated that spironolactone reduces the rate of repeat revascularization at 1 year after PCI.6 Different population, length of treatments, and end points between the 2 studies may have contributed to the differential results. More fundamental studies on the cellular and molecular mechanisms how MR is involved in restenosis are needed to provide new insights for ultimately using this target to treat restenosis.Recent studies using knockout mouse models have begun to reveal the cell type-specific influence of MR in the vasculature.7 MR in monocytes/macrophages may play important roles in neointimal hyperplasia. Myeloid MR knockout (MMRKO) mouse was established and used to study the functions of macrophage MR in the cardiovascular system. The data have illustrated the importance of macrophage MR in cardiac hypertrophy, fibrosis, and inflammation. [8][9][10]...

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Section: Discussionmentioning

confidence: 99%

Mineralocorticoid Receptor Deficiency in Macrophages Inhibits Neointimal Hyperplasia and Suppresses Macrophage Inflammation Through SGK1-AP1/NF-κB Pathways

Sun

Shen

et al. 2016

ATVB

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“…[236][237][238][239][240][241][242][243][244][245][246][247] Aldosterone blockade by spironolactone was shown to reduce all-cause mortality in adults with symptomatic HF by 35% when it was added to standard HF therapy in the RALES trial (Randomized Aldactone Evaluation Study). 248 Subsequently, eplerenone was found to provide a similar survival benefit in adults with HF caused by LV dysfunction 249,250 In addition to improving survival and hospitalization rates, canrenone and spironolactone have been associated with reverse remodeling in adults with HF.…”

Section: Mineralocorticoid Antagonistsmentioning

confidence: 99%

Management of Cardiac Involvement Associated With Neuromuscular Diseases: A Scientific Statement From the American Heart Association

Feingold¹,

Mahle²,

Auerbach³

et al. 2017

Circulation

223

195

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For many neuromuscular diseases (NMDs), cardiac disease represents a major cause of morbidity and mortality. The management of cardiac disease in NMDs is made challenging by the broad clinical heterogeneity that exists among many NMDs and by limited knowledge about disease-specific cardiovascular pathogenesis and course-modifying interventions. The overlay of compromise in peripheral muscle function and other organ systems, such as the lungs, also makes the simple application of endorsed adult or pediatric heart failure guidelines to the NMD population problematic. In this statement, we provide background on several NMDs in which there is cardiac involvement, highlighting unique features of NMD-associated myocardial disease that require clinicians to tailor their approach to prevention and treatment of heart failure. Undoubtedly, further investigations are required to best inform future guidelines on NMD-specific cardiovascular health risks, treatments, and outcomes. N euromuscular diseases (NMDs) encompass a broad spectrum of diagnoses with overlapping but distinct phenotypes. Common to many NMDs is cardiac involvement. Although the past 3 decades have seen marked advances in our understanding of many NMDs, significant gaps in knowledge remain on how best to approach cardiac care in these patients. For example, survival in Duchenne muscular dystrophy (DMD) has been extended through the use of glucocorticoid use and respiratory support, yet cardiac complications remain a significant cause of morbidity and mortality.1-3 To achieve further gains in care, we will need to improve our understanding of the pathophysiologies driving cardiac involvement in NMDs and advance treatments aimed at preventing the progression of heart failure (HF) and sudden death in NMDs. The recently published findings of an expert working group on cardiac involvement in DMD, which outlined key gaps in knowledge and made specific recommendations aimed at improving diagnosis and management, are a step toward this goal. 4 In this statement, we include a comprehensive overview of the major categories of NMDs with cardiac involvement. For each, a brief background of the gene defect(s), common clinical manifestations (particularly cardiac findings), and current therapies is summarized. Gaps in knowledge are highlighted, and where possible, clinical treatment suggestions are made by the expert writing group appointed by the American Heart Association to review the available literature. Selection of the writing group was performed in accordance with the American Heart Association's conflict-of-interest management policy. Participants volunteered to write sections relevant to their expertise and experience. CLINICAL STATEMENTS AND GUIDELINESconducted a general search of the literature, restricted to human subjects research published between 1980 and 2016. Drafts of each section were written and sent to the chair of the writing group for incorporation into a single document, which was then edited. The edited document was discussed electron...

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“…Alternative important mechanisms that are involved in the development of aldosterone-induced morbidity and mortality include inflammation, apoptosis, cell proliferation, matrix formation, collagen deposition, fibrosis, ROS generation, cell adhesion, baroreflex dysfunction, vasoconstriction, endothelial dysfunction, platelet activation and pro-arrhythmogenicity Ferrario and Schiffrin, 2015;Fuller and Young, 2005;Funder, 2009;Kontak et al, 2010;McCurley and Jaffe, 2012;Nguyen Dinh Cat and Jaisser, 2012;Rocha and Funder, 2002;van den Berg et al, 2014). These effects may all contribute to the aldosterone-associated premature pro-atherogenic and prothrombotic effects, being the pathogenic explanation for the increased risk of cardiovascular morbidity and mortality in patients with PA.…”

Section: Consequences Of Aldosterone Excessmentioning

confidence: 99%

“…Preclinical and clinical studies have shown that pathological effects of exposure to excess aldosterone can be attenuated and even prevented by antagonizing the aldosterone effects on the MR (Bauersachs et al, 2015;Ferrario and Schiffrin, 2015). In animal studies, spironolactone has well proven beneficial effects on many pathogenetic mechanism that are involved in the development of cardiovascular complications and these effects are independent from its hypotensive effect per se.…”

Section: Spironolactonementioning

confidence: 99%