Introduction

Blocking the adverse effects of the renin–angiotensin system has been a major focus of drug development for the treatment of cardiovascular disease over the last 30 years. With the introduction of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and, more recently, direct renin inhibitors, the importance of blocking the action of aldosterone and the mineralocorticoid receptor (MR) has received less attention, in part because it was initially assumed that treatment with an ACE inhibitor would also suppress aldosterone. On the contrary, plasma aldosterone levels are only transiently suppressed after the initiation of ACE inhibitor treatment and aldosterone has been shown to exert adverse effects on the cardiovascular system independent of angiotensin II. Clinical interest in blocking aldosterone in patients treated with an ACE inhibitor or ARB was stimulated by the Randomized Aldactone Evaluation Study (RALES), which demonstrated that the MR antagonist spironolactone reduced the risk of all-cause mortality as well as hospitalizations for heart failure (HF) in patients with severe (New York Heart Association [NYHA] Class III–IV) HF with a reduced left ventricular ejection fraction (HFREF).1 Shortly thereafter, the Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) showed a benefit of the second-generation MR antagonist eplerenone on all-cause mortality as well as hospitalizations for HF in patients with HFREF early post-myocardial infarction (MI).2 Recently, the Eplerenone in Mild Patients Hospitalization And Survival Study in Heart Failure (EMPHASIS-HF) trial found a major reduction of all-cause death and all-cause hospitalizations among patients with HFREF and mild symptoms (NYHA Class II).3 These results have prompted intense research into the biology of aldosterone and the effects of blocking the MR. Increasing evidence suggests that MR antagonists affect a wide variety of signalling pathways and mechanisms involving vasculature, myocardial and electrical remodelling, as well as nitric oxide availability, oxygen-free radical production, and their cardiovascular consequences. Further alternative approaches to block aldosterone are being developed, including inhibitors of aldosterone synthase and non-steroidal MR antagonists, which might provide an attractive further step in the attempt to balance the benefits and risks of aldosterone blockade. To summarize the current knowledge on MR antagonists and, in particular, the second-generation MR antagonist eplerenone, we invited experts in the field of aldosterone research to contribute concise reviews about their area of expertise, resulting in a comprehensive overview of this exciting area of research. In the first part, which includes contributions by Messaoudi and Jaisser, Bauersachs and Fraccarollo, Yagi and Sata, as well as Sudano et al. pre-clinical data on the role of MR antagonists are outlined. Within this context Messaoudi and Jaisser point out the mechanisms associated with the emerging role of MR activation in the pathophysiology of ventricular and atrial arrhythmias, the critical role of macrophages in MR signalling, the importance of central nervous system MR activation, the evidence involving the role of glucocorticoids in activating the MR in addition to aldosterone, and the critical role of sodium and oxidative stress in MR activation, and emphasize the importance of blocking both the MR and the AT1 receptor to achieve optimum cardiovascular protection. Bauersachs and Fraccarollo review the benefits of eplerenone on accelerated macrophage infiltration into the area of MI, neovascularization, infarct healing, and ventricular remodelling. Their work on the effect of MR antagonists on endothelial progenitor function has important implications not only for infarct healing but also for endothelial cell repair, vasomotor tone, and possibly the treatment of atherosclerosis. Studies in animal models with over-expression of the human MR and in those lacking the MR on macrophages and cardiomyocytes provide a firm basis for an understanding of the role of MR activation and MR antagonism in HF post-MI. Sudano et al. summarize the evidence on the role of aldosterone blockade on endothelial function. They stress the importance of endothelial function for cardiovascular health and present evidence that aldosterone induces endothelial dysfunction by uncoupling endothelial nitrous oxide synthase as well as inactivation of nitrous oxide by reactive oxygen species produced in the presence of elevated plasma or tissue levels of aldosterone. They further conclude that the molecular mechanisms in endothelial dysfunction are modifiable by aldosterone blockade, offering therapeutic potential of this class of drugs in cardiovascular patients. Finally, Yagi and Sata emphasize the finding that, while angiotensin II and AT1 receptor stimulation are important for the adrenal production of aldosterone, activation of the MR is associated with an up-regulation of the ACE and the AT1 receptor, creating a vicious cycle that has implications for HF, diabetes mellitus, hypertension, and atherosclerosis, and possibly other cardiovascular diseases. They also provide important details regarding the role of MR activation and blockade on vascular inflammation and fibrosis and review the role and consequences of MR-induced oxidative stress and decreased nitric oxide availability. Struthers and Unger outline the pathophysiology and pharmacology of aldosterone blockers, emphasizing the importance of ‘aldosterone escape’, which may explain why MR antagonists are important despite the use of ACE inhibitors or ARBs. They review the new biology of aldosterone, pointing out its important effects on endothelial function, oxidative stress, inflammation, and fibrosis, as well as discussing its genomic and non-genomic effects. In addition, they discuss some of the important differences between the currently available MR antagonists spironolactone and eplerenone. The important differences in MR affinity, duration of action, and specificity of these two agents reviewed in this paper suggest caution in extrapolating the risk/benefit ratio of either agent in defined indications to the other. Ketelslegers and colleagues provide new insights on the role of aldosterone as a biomarker, the collagen biomarkers pro-collagen type I and type III, NT-pro-BNP, as well as newer biomarkers such as the heart-type fatty acid-binding protein and pentraxin 3 used alone and/or in combination, which provides a basis for a more targeted use of MR antagonists in the future and, therefore, potentially a greater benefit/risk ratio. In the last part of this supplement, Böhm et al. and Ruilope discuss the clinical efficacy and safety, respectively, of the available MR antagonists. There are also papers by van Veldhuisen and Swedberg discussing their role in clinical practice and by Montalescot and Turgonyi outlining current and future clinical research into MR antagonists. Böhm and colleagues provide a brief review of MR antagonist use in patients with severe HFREF, mild HFREF, HF with a preserved left ventricular ejection fraction (HFPEF), HF post-MI, and hypertension. They conclude that MR antagonists throughout the cardiovascular continuum are an effective means of preventing cardiovascular death and morbidity in patients with cardiovascular end-organ damage and in HF in particular, and emphasize their synergistic effect on halting the progression of cardiac remodelling and reducing cardiovascular events in patients with chronic HF. Ruilope, on the other hand, focuses on the safety of MR antagonists, particularly with regard to hyperkalaemia and its predisposing factors such as baseline serum potassium concentration, diabetes mellitus, prior use of anti-arrhythmic agents, renal dysfunction, and especially the concomitant use of non-steroidal anti-inflammatory drugs in elderly patients with renal dysfunction and osteoarthritis. There is, however, as pointed out in this article, an increased incidence of hyperkalaemia when an MR antagonist is added to an ACE inhibitor and/or ARB. It should also be stated that the addition of an MR antagonist is associated with a reduction in total mortality in patients with chronic HFREF and in patients with HFREF post-MI, and that in the large-scale randomized trials1–3 in which more than 5000 patients have received an MR antagonist, there has not been a single death attributable to hyperkalaemia. van Veldhuisen and Swedberg provide a brief overview of the current indications and guideline recommendations concerning the use of MR antagonists in chronic HFREF, HFREF post-MI, and hypertension, and point out their ongoing evaluation in patients with HFPEF. Finally, Bramlage, Turgonyi and Montalescot provide the basis for the use of MR antagonists in patients with an acute coronary syndrome without concomitant HF and describe the ongoing trials evaluating their use in patients with both ST elevation MI and non-ST elevation MI as well as the ongoing trials evaluating the role of MR antagonists in patients with atrial fibrillation. New aldosterone synthase inhibitors and non-steroidal MR antagonists hold the promise for an even more effective and possibly safer means of preventing the cardiovascular consequences of aldosterone and MR activation in the future. Despite the overwhelming evidence for the use of MR antagonists in HFREF, recent data have repeatedly shown their under-use in clinical practice.4–6 Albert and colleagues, for example, reported data of a recent observational analysis of more than 40 000 patients admitted with HF and discharged home in the Get With The Guidelines-HF quality improvement registry between January 2005 and December 2007.4 Among 12 565 patients eligible for aldosterone antagonist therapy, 4087 (32.5%) received an aldosterone antagonist at discharge, and treatment increased modestly from 28 to 34% over the study period. These data confirm prior data demonstrating that only 29% of eligible patients received aldosterone antagonists while being diagnosed with systolic HF.6 The hesitance to use aldosterone antagonists might plausibly be related to the side-effect profile of spironolactone, as Samuel and Delcayre pointed out in a recent comment on these unexpected findings.5 Spironolactone binds to the MR but also binds the androgen receptor and induces gynaecomastia in men and amenorrhoea in pre-menopausal women. In contrast, with the more selective MR antagonist eplerenone, these adverse effects were almost completely absent. Physicians’ opinions of aldosterone antagonists, however, are likely to have been marred by their classification as potassium-sparing diuretics for many years.5 Along with respective guidelines,7–9 it appears reasonable to assume that with an improvement in guideline adherence we can expect a further reduction in cardiovascular mortality and morbidity in the future. Beyond the well-established indication for the use of MR antagonists in patients with HFREF, it appears reasonable to predict that MR antagonists may gain a greater role in other selected cardiovascular diseases in the future. These will include their use in patients with NYHA Class II HFREF and HFPEF, but may also include patients with acute coronary syndromes, atrial fibrillation, and (diabetic) nephropathy as outlined by Montalescot and Turgonyi in this supplement. It is reasonable to predict that, in the next several years, advances in our understanding of the mechanisms involved in MR activation and antagonism reviewed in this supplement will continue, and that in the not too distant future MR antagonists will play an even more important role in cardiovascular disease.