Impact of Mineralocorticoid Receptor Antagonists on Changes in Cardiac Structure and Function of Left Ventricular Dysfunction

Li, Xiaobo; Qi, Yue; Li, Yuqiong; Zhang, Shanshan; Guo, Songfeng; Chu, Shaoli; Gao, Pingjin; Zhu, Dingliang; Wu, Zhijun; Lü, Lin; Shi, Weifeng; Nan, Jun; Niu, Wenquan

doi:10.1161/circheartfailure.112.000074

Cited by 34 publications

(26 citation statements)

References 43 publications

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“…A recent meta‐analysis of trials on use of MRA in HFREF showed favorable reverse LV remodeling along with improvements in systolic and diastolic function 38. We observe a similar effect of MRA on biomarkers of collagen turnover and cardiac fibrosis in the current study.…”

Section: Discussionsupporting

confidence: 86%

Effect of Mineralocorticoid Receptor Antagonists on Cardiac Structure and Function in Patients With Diastolic Dysfunction and Heart Failure With Preserved Ejection Fraction: A Meta‐Analysis and Systematic Review

Pandey

Garg

Matulevicius

et al. 2015

JAHA

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BackgroundThere has been an increasing interest in use of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure with preserved ejection fraction (HFPEF). However, a comprehensive evaluation of MRA effects on left ventricular (LV) structure and function in these patients is lacking. In this meta‐analysis, we evaluated the effects of MRAs on LV structure and function among patients with diastolic dysfunction or HFPEF.Methods & ResultsRandomized, controlled clinical trials evaluating the efficacy of MRAs in patients with diastolic dysfunction or HFPEF were included. The primary outcome was change in E/e’, a specific measure of diastolic function. Secondary outcomes included changes in other measures of diastolic function, LV structure, surrogate markers for myocardial fibrosis (carboxy‐terminal peptide of procollagen type I [PICP] and amino‐terminal peptide of pro‐collagen type‐II [PIIINP]), blood pressure, and exercise tolerance. In the pooled analysis, MRA use was associated with significant reduction in E/e’ (weighted mean difference [WMD] [95% confidence interval {CI}]: −1.68 [−2.03 to −1.33]; P<0.0001) and deceleration time (WMD [95% CI]: −12.0 ms [−23.3 to −0.7]; P=0.04) as compared with control, suggesting and improvement in diastolic function. Furthermore, blood pressure and levels of PIIINP and PICP were also significantly reduced with MRA therapy with no significant change in LV mass or dimensions.Conclusion MRA therapy in patients with asymptomatic diastolic dysfunction or HFPEF is associated with significant improvement in diastolic function and markers of cardiac fibrosis without a significant change in LV mass or dimensions.

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Section: Discussionsupporting

confidence: 86%

Effect of Mineralocorticoid Receptor Antagonists on Cardiac Structure and Function in Patients With Diastolic Dysfunction and Heart Failure With Preserved Ejection Fraction: A Meta‐Analysis and Systematic Review

Pandey

Garg

Matulevicius

et al. 2015

JAHA

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“…25 Because heart failure in patients with Duchenne muscular dystrophy typically occurs only after ejection fraction has dropped significantly, the positive effect of mineralocorticoid receptor antagonists in previous trials in patients with symptomatic heart failure with reduced ejection fraction and in patients with acute myocardial infarction and reduced ejection fraction is encouraging and relevant for Duchenne muscular dystrophy cardiomyopathy. No previous trial of mineralocorticoid receptor antagonism has taken into account baseline extent of myocardial damage, 26 which significantly modified therapeutic response in our study. This finding parallels the results of our preclinical studies in which earlier treatment in a dystrophic mouse model resulted in significantly more attenuation of cardiac pathology compared with later treatment.…”

Section: Discussionmentioning

confidence: 86%

Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-controlled trial

Raman

Hor

Mazur

et al. 2015

The Lancet Neurology

194

180

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Summary Background Cardiomyopathy is a leading cause of death in patients with Duchenne muscular dystrophy and myocardial damage precedes decline in left ventricular systolic function. We tested the efficacy of eplerenone on top of background therapy in patients with Duchenne muscular dystrophy with early myocardial disease. Methods In this randomised, double-blind, placebo-controlled trial, boys from three centres in the USA aged 7 years or older with Duchenne muscular dystrophy, myocardial damage by late gadolinium enhancement cardiac MRI and preserved ejection fraction received either eplerenone 25 mg or placebo orally, every other day for the first month and once daily thereafter, in addition to background clinician-directed therapy with either angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Computer-generated randomisation was done centrally using block sizes of four and six, and only the study statistician and the investigational pharmacy had the preset randomisation assignments. The primary outcome was change in left ventricular circumferential strain (Ecc) at 12 months, a measure of contractile dysfunction. Safety was established through serial serum potassium levels and measurement of cystatin C, a non-creatinine measure of kidney function. This trial is registered with ClinicalTrials.gov, number NCT01521546. Findings Between Jan 26, 2012, and July 3, 2013, 188 boys were screened and 42 were enrolled. 20 were randomly assigned to receive eplerenone and 22 to receive placebo, of whom 20 in the eplerenone group and 20 in the placebo group completed baseline, 6-month, and 12-month visits. After 12 months, decline in left ventricular circumferential strain was less in those who received eplerenone than in those who received placebo (median ΔEcc 1.0 [IQR 0.3–2.2]vs2.2 [1.3–3.1]; p=0.020). Cystatin C concentrations remained normal in both groups, and all non-haemolysed blood samples showed normal potassium concentrations. One 23-year-old patient in the placebo group died of fat embolism, and another patient in the placebo group withdrew from the trial to address long-standing digestive issues. All other adverse events were mild: short-lived headaches coincident with seasonal allergies occurred in one patient given eplerenone, flushing occurred in one patient given placebo, and anxiety occurred in another patient given placebo. Interpretation In boys with Duchenne muscular dystrophy and preserved ejection fraction, addition of eplerenone to background ACEI or ARB therapy attenuates the progressive decline in left ventricular systolic function. Early use of available drugs warrants consideration in this population at high risk of cardiac death, but further studies are needed to determine the effect of combination cardioprotective therapy on event-free survival in Duchenne muscular dystrophy. Funding BallouSkies, Parent Project for Muscular Dystrophy, US National Center for Advancing Translational Sciences, and US National Institutes of Health.

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“…A meta‐analysis of randomized clinical trials revealed that pharmacological blockade of MR has beneficial effects on cardiac remodeling and improves parameters of LV function in HFrEF patients (Li et al. 2013). Delineating the precise tissues through which MR modulates these effects has been an area of active investigation and overall suggests that MR signaling in different cell types plays distinct roles.…”

Section: Discussionmentioning

confidence: 99%

Endothelial mineralocorticoid receptor contributes to systolic dysfunction induced by pressure overload without modulating cardiac hypertrophy or inflammation

et al. 2017

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Heart Failure (HF) is associated with increased circulating levels of aldosterone and systemic inflammation. Mineralocorticoid receptor (MR) antagonists block aldosterone action and decrease mortality in patients with congestive HF. However, the molecular mechanisms underlying the therapeutic benefits of MR antagonists remain unclear. MR is expressed in all cell types in the heart, including the endothelial cells (EC), in which aldosterone induces the expression of intercellular adhesion molecule 1 (ICAM‐1). Recently, we reported that ICAM‐1 regulates cardiac inflammation and cardiac function in mice subjected to transverse aortic constriction (TAC). Whether MR specifically in endothelial cells (EC) contributes to the several mechanisms of pathological cardiac remodeling and cardiac dysfunction remains unclear. Basal cardiac function and LV dimensions were comparable in mice with MR selectively deleted from ECs (EC‐MR −/−) and wild‐type littermate controls (EC‐MR +/+). MR was specifically deleted in heart EC, and in EC‐containing tissues, but not in leukocytes of TAC EC‐MR −/− mice. While EC‐MR −/− TAC mice showed preserved systolic function and some alterations in the expression of fetal genes, the proinflammatory cytokine TNF α and the endothelin receptors in the LV as compared to EC‐MR +/+ TAC mice, no difference was observed between both TAC groups in overall cardiac hypertrophy, ICAM‐1 LV expression and leukocyte infiltration, cardiac fibrosis or capillary rarefaction, all hallmarks of pathological cardiac remodeling. Our data indicate that EC‐MR contributes to the transition of cardiac hypertrophy to systolic dysfunction independently of other maladaptive changes induced by LV pressure overload.

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Impact of Mineralocorticoid Receptor Antagonists on Changes in Cardiac Structure and Function of Left Ventricular Dysfunction

Cited by 34 publications

References 43 publications

Effect of Mineralocorticoid Receptor Antagonists on Cardiac Structure and Function in Patients With Diastolic Dysfunction and Heart Failure With Preserved Ejection Fraction: A Meta‐Analysis and Systematic Review

Effect of Mineralocorticoid Receptor Antagonists on Cardiac Structure and Function in Patients With Diastolic Dysfunction and Heart Failure With Preserved Ejection Fraction: A Meta‐Analysis and Systematic Review

Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-controlled trial

Endothelial mineralocorticoid receptor contributes to systolic dysfunction induced by pressure overload without modulating cardiac hypertrophy or inflammation

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