Mineralocorticoid receptor activation and cardiac fibrosis

MR (mineralocorticoid receptor) activation by either administration of exogenous mineralocorticoids or by allowing endogenous glucocorticoids to activate the MR has been shown to produce oxidative stress and vascular inflammation at the earliest stages of the development of cardiac fibrosis in experimental animals. These studies suggest potential mechanisms for the benefits observed in recent large scale clinical trials investigating the cardioprotective effects of MR antagonists given in conjunction with current best practice therapy for moderate-to-severe heart failure and heart failure post-myocardial infarction. Given that few patients had elevated plasma aldosterone, novel mechanisms involved in activating the MR in the failing heart are now being investigated.     

Targeting the aldosterone pathway in cardiovascular disease

Accumulated evidence has demonstrated that aldosterone is a key player in the pathogenesis of cardiovascular (CV) disease. Multiple clinical trials have documented that intervention in the aldosterone pathway can reduce blood pressure and lower albuminuria and improve outcome in patients with heart failure or myocardial infarction. Recent studies have unraveled details about the role of aldosterone at the cellular level in CV disease. The relative importance of glucocorticoids and aldosterone in terms of mineralocorticoid receptor activation is currently being debated. Also, studies are addressing which aldosterone modulator to use, which timing of treatment to aim for, and in which population to intervene. This review provides an overview of recent developments in the understanding of the role of aldosterone in CV disease, with particular reference to mechanisms and potential targets of intervention. Finally, ongoing or desirable clinical trials in the field are highlighted. The review is partly based on discussions between basic scientists and clinical trialists at the Cardiovascular Clinical Trials Forum 2009 and subsequently updated to encompass the most recent developments.     

Aldosterone and end-organ damage

Aldosterone concentrations are inappropriately high in many patients with hypertension, as well as in an increasing number of individuals with metabolic syndrome and sleep apnoea. A growing body of evidence suggests that aldosterone and/or activation of the MR (mineralocorticoid receptor) contributes to cardiovascular remodelling and renal injury in these conditions. In addition to causing sodium retention and increased blood pressure, MR activation induces oxidative stress, endothelial dysfunction, inflammation and subsequent fibrosis. The MR may be activated by aldosterone and cortisol or via transactivation by the AT(1) (angiotenin II type 1) receptor through a mechanism involving the EGFR (epidermal growth factor receptor) and MAPK (mitogen-activated protein kinase) pathway. In addition, aldosterone can generate rapid non-genomic effects in the heart and vasculature. MR antagonism reduces mortality in patients with CHF (congestive heart failure) and following myocardial infarction. MR antagonism improves endothelial function in patients with CHF, reduces circulating biomarkers of cardiac fibrosis in CHF or following myocardial infarction, reduces blood pressure in resistant hypertension and decreases albuminuria in hypertensive and diabetic patients. In contrast, whereas adrenalectomy improves glucose homoeostasis in hyperaldosteronism, MR antagonism may worsen glucose homoeostasis and impairs endothelial function in diabetes, suggesting a possible detrimental effect of aldosterone via non-genomic pathways.     

Renin-angiotensin system as a potential target for the treatment with heart failure: ACE inhibitors,angiotensin-II receptor blockers and aldosterone antagonists

Recent experimental studies and clinical trials have revealed that the modulation of either systemic or regional(cardiovascular) renin-angiotensin systems(RAS) is one of the potential targets to prevent the progression of heart failure. Either ACE inhibitor, angiotensin-II receptor blocker or aldosterone antagonist differently block RAS. Many clinical trials told us that each of them improves heart failure and might promise the better prognosis. Now, some experimental studies are encouraging us to test the comparative effects or the effects in combination of them. Here we will summarize the current outcomes from the experimental and clinical studies, and discuss the future direction.     

Aldosterone

Nonepithelial effect of aldosterone has been recognized as a cardiovascular risk factor independent of elevation of blood pressure. Pro-inflammatory effect of aldosterone in vasculature appears to be an initiating event for the target organ injuries. Recent clinical trials of aldosterone receptor blockers in congestive heart failure indicate the efficacy of aldosterone antagonism to prevent cardiac death. In addition to elevated plasma levels of aldosterone, mineralocorticoid receptor expression in cardiovascular tissues may contribute to the progression of heart failure. In this review, emerging role of aldosterone as a cardiovascular risk is highlighted.     

The cardioprotective effects of mineralocorticoid receptor antagonists

Despite state-of-the-art reperfusion therapy, morbidity and mortality remain significant in patients with an acute myocardial infarction. Therefore, novel strategies to limit myocardial ischemia–reperfusion injury are urgently needed. Mineralocorticoid receptor (MR) antagonists are attractive candidates for this purpose, since several clinical trials in patients with heart failure have reported a survival benefit with MR antagonist treatment. MRs are expressed by several cells of the cardiovascular system, including cardiomyocytes, cardiac fibroblasts, vascular smooth muscle cells, and endothelial cells. Experiments in animal models of myocardial infarction have demonstrated that acute administration of MR antagonists, either before ischemia or immediately at the moment of coronary reperfusion, limits infarct size. This action appears to be independent of the presence of aldosterone and cortisol, which are the endogenous ligands for the MR. The cardioprotective effect is mediated by a nongenomic intracellular signaling pathway, including adenosine receptor stimulation, and activation of several components of the Reperfusion Injury Salvage Kinase (RISK) pathway. In addition to limiting infarct size, MR antagonists can improve scar healing when administered shortly after reperfusion and can reduce cardiac remodeling post myocardial infarction. Clinical trials are currently being performed studying whether early administration of MR antagonists can indeed improve prognosis in patients with an acute myocardial infarction, independent of the presence of heart failure.     

Is the mineralocorticoid receptor a potential target for stroke prevention?

In recent years, it has become increasingly clear that the extra-renal effects of aldosterone play an important role in the pathogenesis of cardiovascular disease. Stroke is one of the leading causes of death in the Western world, and MR (mineralocorticoid receptor) antagonism is a potential preventative therapy for patients at risk of both ischaemic and haemorrhagic strokes. This protective effect of MR antagonism appears to occur at the level of the cerebral vasculature and may be related to the expression and activation of the EGFR (epidermal growth factor receptor) and the degree of vessel wall collagen deposition.     

Neurohormones and heart failure: the importance of aldosterone

Heart failure is a major cause of cardiovascular morbidity and mortality and its incidence is on the increase. The pathophysiology of heart failure is multi-factorial but recent studies suggest that aldosterone plays an important and independent role in its progression. Emerging evidence now suggests that aldosterone exerts renal-independent effects. It binds to its mineralocorticoid receptor to produce direct effects on the myocardium and vasculature, leading to damaging processes such as hypertrophy, necrosis, fibrosis and endothelial dysfunction, factors known to contribute to the pathophysiology of heart failure. Mineralocorticoid receptor antagonists have thus emerged as a new paradigm for the treatment of heart failure. The benefits of these agents on both morbidity and mortality when used in patients with chronic symptomatic heart failure have been demonstrated by recent trials.     

运动想象对脊髓损伤患者大脑活动和脑网络重塑MR研究进展

运动想象（MI）及在此基础上的脑机接口已在脊髓损伤等运动功能障碍疾病的康复中取得良好效果，但其对运动功能康复的机制仍不十分明确。随着功能MR技术的发展，大脑激活和网络连接变化在MI中的作用被逐渐认识，为揭示MI康复机制及其临床应用提供了理论依据。     

Rapid actions of aldosterone in vascular health and disease--friend or foe?

The mineralocorticoid receptor (MR) and the enzyme 11betahydroxysteroid dehydrogenase type 2, which confers aldosterone specificity to the MR, are present in endothelium and vascular smooth muscle. In several pathological conditions aldosterone promotes vascular damage by formation of reactive oxygen species. The effect of aldosterone on vascular function, however, is far from clear. By rapid non-genomic mechanisms aldosterone may cause calcium mobilization and vasoconstriction, or may stimulate nitric oxide formation through the PI-3 kinase/Akt pathway and thereby counteract vasoconstriction. Vasoconstrictor, vasodilator or no effects of aldosterone have been reported from studies on human forearm blood flow. Inhibition of MR with spironolactone improves endothelial function in patients with heart failure but worsens endothelial function in type 2 diabetic patients. The aim of the present review is to reconcile some of the apparently conflicting data. A key observation is that reactive oxygen and nitrogen species serve as physiological signaling molecules at low concentrations, while they initiate pathological processes at higher concentrations. The net effect of aldosterone, which stimulates ROS production, therefore depends on the ambient level of oxidative stress. Thus, in situations with low levels of oxidative stress aldosterone may promote vasodilatation, while at higher oxidative stress (high NaCl intake, pre-existing vascular pathological conditions, high oxygen tension in vitro) aldosterone is likely to be associated with vasoconstriction and oxidative damage, and in this setting inhibition of the MR is likely to be beneficial.     

Prevention of remodeling in congestive heart failure due to myocardial infarction by blockade of the renin–angiotensin system

Ventricular remodeling subsequent to myocardial infarction (MI) is a complex process and is considered to be a major determinant of the clinical course of congestive heart failure (CHF). Emerging evidence suggests that activation of the renin–angiotensin system (RAS) plays an important role in post-MI ventricular remodeling; however, it is becoming clear that this is one of several neurohumoral systems that are activated in CHF. Blockade of RAS by angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor antagonists attenuates the ventricular dysfunction, but the effects of individual drugs in reducing the morbidity and mortality in CHF patients are variable. Furthermore, there is a difference of opinion as to the time of initiation of therapy with RAS blockers after the onset of MI. Since blockade of RAS partially improves cardiac function, it is suggested that a combination therapy involving RAS blockers (angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor antagonists) and agents that affect other neurohumoral systems may prove useful for improved treatment of CHF. Although activation of RAS has been shown to promote oxidative stress in experimental studies, the use of antioxidant therapy in CHF patients is controversial. Recent experimental studies have shown that ventricular remodeling in CHF is associated with remodeling of subcellular organelles such as sarcolemma, sarcoplasmic reticulum, myofibrils and extracellular matrix in terms of their molecular structure and composition. Since attenuation of remodeling in one and/or more subcellular organelles by different agents may prevent the progression of CHF, it is a challenge to develop specific drugs affecting molecular mechanisms associated with subcellular remodeling for the improved therapy of CHF.     

Prevention of remodeling in congestive heart failure due to myocardial infarction by blockade of the renin-angiotensin system

Ventricular remodeling subsequent to myocardial infarction (MI) is a complex process and is considered to be a major determinant of the clinical course of congestive heart failure (CHF). Emerging evidence suggests that activation of the renin-angiotensin system (RAS) plays an important role in post-MI ventricular remodeling; however, it is becoming clear that this is one of several neurohumoral systems that are activated in CHF. Blockade of RAS by angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor antagonists attenuates the ventricular dysfunction, but the effects of individual drugs in reducing the morbidity and mortality in CHF patients are variable. Furthermore, there is a difference of opinion as to the time of initiation of therapy with RAS blockers after the onset of MI. Since blockade of RAS partially improves cardiac function, it is suggested that a combination therapy involving RAS blockers (angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor antagonists) and agents that affect other neurohumoral systems may prove useful for improved treatment of CHF. Although activation of RAS has been shown to promote oxidative stress in experimental studies, the use of antioxidant therapy in CHF patients is controversial. Recent experimental studies have shown that ventricular remodeling in CHF is associated with remodeling of subcellular organelles such as sarcolemma, sarcoplasmic reticulum, myofibrils and extracellular matrix in terms of their molecular structure and composition. Since attenuation of remodeling in one and/or more subcellular organelles by different agents may prevent the progression of CHF, it is a challenge to develop specific drugs affecting molecular mechanisms associated with subcellular remodeling for the improved therapy of CHF.     

Eplerenone--a novel selective aldosterone blocker

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and safety of eplerenone, a new selective aldosterone blocker. DATA SOURCES: Primary literature and review articles were obtained via MEDLINE search (1966-April 2002). Additional studies and abstracts were identified from the bibliographies of reviewed literature. STUDY SELECTION AND DATA EXTRACTION: Studies and review articles related to eplerenone, aldosterone, aldosterone antagonist, and spironolactone were reviewed. Data pertinent to this article were included. DATA SYNTHESIS: Eplerenone is a selective aldosterone blocker. Recent data have demonstrated the deleterious effects of aldosterone in several chronic disease states including hypertension and heart failure. Animal studies using eplerenone have shown a positive role for aldosterone antagonism in the treatment of hypertension, heart failure, myocardial infarction, renal disease, and atherosclerosis. In humans, eplerenone appears to be effective for the treatment of hypertension. An ongoing study will examine the effect of eplerenone for heart failure. To date, the incidence of adverse effects with eplerenone has been slightly lower than with spironolactone. CONCLUSIONS: Eplerenone appears to be a promising drug in a new class of agents called selective aldosterone blockers. The drug may be approved for treatment of hypertension in 2002. Additional studies are ongoing that may provide information on other clinical uses for this medication.     

Current possibilities of ACE inhibitor and ARB combination in arterial hypertension and its complications

The renin–angiotensin–aldosterone system (RAAS) plays a crucial role in blood pressure regulation and hypertension-related complications. Angiotensin-converting enzyme inhibitors (ACEIs) were the first to be used to block the RAAS and now have many compelling indications in the treatment of hypertension and its cardiovascular and renal complications. Angiotensin II receptor blockers (ARBs), introduced 20 years later, have been shown to be equally as effective as antihypertensive treatment and are also associated with a lower number of side effects. Furthermore, in clinical trials ARBs and ACEIs were associated with comparable benefits for their most typical indications. This was confirmed in the 2007 New European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines for the management of hypertension by comparable specific recommendations for ARB and ACEI treatment. There is sufficient theoretical background and, in some cases, also clinical evidence that combination therapy with ACEIs and ARBs may be more beneficial than monotherapy with either of the groups alone, both in uncomplicated hypertension and with concomitant heart failure or renal dysfunction. However, the combination of ACEI and ARB was not recommended in the ESH/ESC 2007 Guidelines. This may change after the publication of the Ongoing Telmisartan Alone and in Combination with Ramipril Global End point Trial (ONTARGET) study, the preliminary results of which have just been presented. In heart failure, recent studies have shown that the combination of ACEI and ARB decreases cardiovascular mortality and the number of hospitalizations due to aggravation of heart failure. These results have been reflected in the newest ESC guidelines of the heart failure treatment. Nephroprotective properties of the combination of ACEs and ARBs have been proved both in studies on nondiabetic and diabetic nephropathy. The potential benefits, indications in prespecified groups of patients, the most recent data from clinical trials and latest research regarding dual blockade of RAAS will be reviewed in this article.     

Preventing sudden cardiac death in post myocardial infarction patients with left ventricular dysfunction

Cardiovascular nurses play a key role in caring for the post myocardial infarction (MI) patient. That role includes reducing the risk of MI recurrence and the progression to heart failure. Equally important is evaluating for the risk of sudden cardiac death (SCD). Although drugs such as beta blockers and angiotensin converting enzyme (ACE) inhibitors are typically indicated to help reduce the risk of SCD, data continue to show that using implantable cardioverter defibrillators (ICDs) saves lives compared with using medications alone. This article focuses on the problem of SCD, the findings of recent clinical trials, the implant criteria for defibrillators, new Centers for Medicare & Medicaid Services (CMS) decisions regarding reimbursement, and postoperative care for the defibrillator patient. Included are 2 case studies demonstrating the nurses' role in identifying asymptomatic patients who are indicated for ICD therapy. It is critical that cardiovascular nurses be aware of the latest scientific evidence showing improved outcomes for post-MI patients, particularly those with left ventricular dysfunction.     

Clinical and instrumental evaluation of the myocardial reserve in patients with prior myocardial infarction

The clinical manifestations of heart failure (HF), myocardial systolic and diastolic functions and the indices of remodeling of the left ventricle (L V) were compared to define the most informative characteristics of the myocardial reserve (MR) in patients with prior myocardial infarction (MI). Examination of 220 patients with MI indicated that the low LV ejection fraction reliably determined only a high functional class (FC) of HF. Myocardial diastolic dysfunction (DD) was equally characteristic of any FCs of HF and the restrictive type of blood filling was most commonly associated with FC III-IV of HF. LV concentric hypertrophy, as well as DD, occurred in all FCs of HF. The detection rate of LV eccentric remodeling significantly increased from 5.1% in FC I to 98.7% in FC IV, which characterized this process as the most characteristic while grading the decrease in MR in patients with MI.     

Angiotensin receptor blockers versus ACE inhibitors: prevention of death and myocardial infarction in high-risk populations

OBJECTIVE: To determine, through a review of the medical literature, whether there is adequate evidence to support the use of angiotensin receptor blockers (ARBs) in place of angiotensin-converting enzyme (ACE) inhibitors in high-risk populations, focusing on the prevention of death and myocardial infarction (MI). DATA SOURCES: Original investigations, reviews, and meta-analyses were identified from the biomedical literature via a MEDLINE search (1966-August 2004). Published articles were also cross-referenced for pertinent citations, and recent meeting abstracts were searched for relevant data. STUDY SELECTION AND DATA EXTRACTION: All articles identified during the search were evaluated. Preference was given to prospective, randomized, controlled trials that evaluated major cardiovascular endpoints and compared ARBs with ACE inhibitors, active controls, or placebo. DATA SYNTHESIS: The renin-angiotensin system plays a pivotal role in the continuum of cardiovascular disease and represents a major therapeutic target in the treatment of patients at risk for vascular events. While ACE inhibitors have been definitively shown to prevent death and MI, studies with ARBs in similar populations have not reduced these endpoints. In clinical trials that enrolled patients with heart failure, post-MI, diabetes, and hypertension, ARBs did not prevent MI or prolong survival compared with ACE inhibitors, other antihypertensives, or placebo. CONCLUSIONS: ACE inhibitors and ARBs should not be considered interchangeable, even among patients with a documented history of ACE inhibitor intolerance. ARBs can be considered a second-line alternative in such patients with the realization that they have not been shown to prevent MI or prolong survival.