Beneficial Effects of Eplerenone<i>Versus</i>Hydrochlorothiazide on Coronary Circulatory Function in Patients with Diabetes Mellitus

Joffe, Hylton V.; Kwong, Raymond Y.; Gerhard‐Herman, Marie; Rice, Caitlin; Feldman, Kathryn; Adler, Gail K.

doi:10.1210/jc.2007-0393

Cited by 71 publications

(65 citation statements)

References 39 publications

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Section: Discussionmentioning

confidence: 99%

“…Of note, in patients with diabetes mellitus without clinical cardiovascular disease, receiving an angiotensin-converting enzyme inhibitor and a calcium channel antagonist, adenosine-stimulated coronary reserve is higher after 6 weeks of treatment with eplerenone in comparison with a thiazidic diuretic. 25 This suggests an important role for MR in the regulation of the coronary reserve in different pathological contexts.In conclusion, VSMC-MR is involved in the progression of HF post MI, at least through its direct role in oxidative stress-induced coronary endothelial dysfunction and in decreased coronary reserve. Treatment of infarcted mice with the nonsteroidal MRA finerenone 12 is associated with cardiac functional benefits, including improvements of endothelial function and maintenance of a coronary reserve.…”

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confidence: 99%

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

et al. 2016

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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...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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

et al. 2016

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“…Two studies used additional potassium supplementation or potassium binders. 24,27 Exclusion of these two studies made little difference to the result (0. …”

Section: End Of Study Serum Potassium and Hyperkalemia Events (K + > mentioning

confidence: 99%

Cardiovascular actions of mineralocorticoid receptor antagonists in patients with chronic kidney disease: A systematic review and meta-analysis of randomized trials

Arnold

Sharif

et al. 2015

J Renin Angiotensin Aldosterone Syst

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Introduction: The safety and actions of mineralocorticoid receptor antagonists on surrogate markers of cardiovascular disease as well as major patient level cardiovascular end-points in patients with chronic kidney disease are unclear. Methods: MEDLINE, EMBASE, Trip Database, Cochrane Central Register of Controlled Trials, Cochrane Renal Group specialized register, Current Controlled Trials and clinicaltrials.gov were searched for relevant trials. Results: Twenty-nine trials (1581 patients) were included. Overall, mineralocorticoid receptor antagonists lowered both systolic and diastolic blood pressure (–5.24, 95% confidence interval (CI) –8.65, −1.82 mmHg; p=0.003 and −1.96, 95% CI −3.22, –0.69 mmHg; p=0.002 respectively). There were insufficient data to perform a meta-analysis of other cardiovascular effects. However, a systematic review of the studies included suggested a consistent improvement in surrogate markers of cardiovascular disease. Overall, the use of mineralocorticoid receptor antagonists was associated with an increased serum potassium (0.23, 95% CI 0.13, 0.33 mmol/l; p<0.0001) and higher risk ratio (1.76, 95% CI 1.20, 2.57; p=0.001) of hyperkalemia. Data on long-term cardiovascular outcomes and mortality were not available in any of the trials. Conclusions: The long-term effects of mineralocorticoid receptor antagonists on cardiovascular events, mortality and safety need to be established.

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“…This is a distinct possibility, as both heart failure and diabetes are strongly characterised by high levels of oxidative stress while mineralocorticoid blockade is thought to produce many of its benefits by reducing oxidative stress. Also of interest is a recent proof-of-concept, pilot study [7] showing that short-term treatment with an aldosterone antagonist was better than hydrochlorthiazide in improving coronary circulatory function in diabetic patients on ACE inhibitors, again suggesting a major role for mineralocorticoid receptor in diabetes. It seems a sensible first approach to see whether aldosterone blockade favourably effects the same factors in diabetes that are thought to contribute to the favourable effects on mortality rates in heart failure.…”

Section: Introductionmentioning

confidence: 99%

Spironolactone for poorly controlled hypertension in type 2 diabetes: conflicting effects on blood pressure, endothelial function, glycaemic control and hormonal profiles

et al. 2008

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Aims/hypothesis Aldosterone antagonism improves endothelial function (and reduces deaths) in chronic heart failure. It is not known whether similar effects occur in other high-risk groups such as patients with diabetes and hypertension. We therefore assessed the full effects of aldosterone blockade in poorly controlled hypertensive patients with type 2 diabetes, focussing on blood pressure, endothelial function, glycaemic control and key hormones. Methods We performed a randomised, placebo-controlled, double-blind, crossover study on 50 patients with type 2 diabetes and treated but poorly controlled hypertension, comparing spironolactone versus placebo. Patients had their endothelial function assessed by standard forearm venous occlusion plethysmography. Results There was no significant improvement in endotheliumdependent vasodilatation in response to acetylcholine, despite highly significant reductions in systolic and diastolic blood pressure. However, spironolactone significantly worsened glycaemic control, plasma angiotensin II and cortisol. Conclusions/interpretation Spironolactone is highly effective in lowering blood pressure in patients with type 2 diabetes and poorly controlled hypertension on standard treatment, but does not improve vascular endothelial function in this group. We speculate that any tendency for the spironolactoneinduced lowering of blood pressure to improve endothelial function is offset by its tendency to worsen glycaemic control and increase the levels of angiotensin II and even possibly cortisol.Trials Registry no.: ISRCTN 76558770

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Beneficial Effects of EplerenoneVersusHydrochlorothiazide on Coronary Circulatory Function in Patients with Diabetes Mellitus

Abstract: Mineralocorticoid receptor blockade improves coronary circulatory function compared with hydrochlorothiazide in patients with diabetes already receiving ACE inhibitor therapy.

Cited by 71 publications

References 39 publications

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

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

Cardiovascular actions of mineralocorticoid receptor antagonists in patients with chronic kidney disease: A systematic review and meta-analysis of randomized trials

Spironolactone for poorly controlled hypertension in type 2 diabetes: conflicting effects on blood pressure, endothelial function, glycaemic control and hormonal profiles

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