The role of aldosterone in heart failure and the clinical benefits of aldosterone blockade

Aldosterone has a variety of detrimental effects on the heart and vasculature and is increasingly recognized as an important target in chronic heart failure, as illustrated by the Randomized Aldactone Evaluation Study. In this article, the evidence supporting the cardiovascular effects of aldosterone in humans and the proven benefits of aldosterone-receptor antagonists in heart failure shall be discussed.     

Eplerenone for the treatment of cardiovascular disorders

The clinical utility and ultimately guideline recommendations for aldosterone receptor-blocking agents in cardiovascular disorders is clearly mentioned by a number of major clinical outcome trials. This article reviews the pharmacology, clinical efficacy and safety of the two currently available receptor blocking agents: spironolactone and eplerenone. The potential utility of eplerenone and other mineralocorticoid receptor agents beyond current clinical indications will also be examined.     

Candesartan cilexetil in cardiovascular disease

Hypertension is a major cardiovascular risk factor, but most patients remain asymptomatic for many years. Successful therapy not only needs to be effective, it also needs to be well tolerated. Angiotensin receptor blockers have emerged as a major therapeutic class because they meet both of these requirements. Numerous studies indicate that all approved angiotensin receptor blockers are highly selective for angiotensin-1 receptors, lower blood pressure as monotherapies, and work well in combination with other drugs – particularly diuretics. The side-effect profile of angiotensin receptor blockers is similar to that of placebo and they have not been associated with known side effects of angiotensin-converting enzyme inhibitors such as cough and angioneurotic edema. Candesartan cilexetil is an angiotensin receptor blocker with insurmountable binding properties to the angiotensin-1 receptor, long duration of action and improved efficacy. In patients with hypertension, candesartan monotherapy has been shown to be safe and effective. Comparative data have shown similar or better results to other monotherapies in blood-pressure control, and in combination with hydrochlorothiazide it has been shown to have additive or synergistic effects. More recent data demonstrate that candesartan cilexetil is useful in the treatment of patients with heart failure and may protect against diabetic nephropathy. Studies have also shown protection from stroke, particularly in patients with isolated systolic hypertension.     

Eplerenone in the treatment of chronic heart failure

There has been a recent revival of interest in aldosterone receptor antagonists for the treatment of chronic heart failure. This was largely triggered by fresh insights into the role of aldosterone in a number of key pathophysiological processes, including fibrosis and remodeling, inflammation, and the potentiation of catecholamine effects. The therapeutic efficacy of spironolactone (Aldactone^®, Pfizer) in severe chronic heart failure was established by the Randomized Aldactone Evaluation Study, but hormonal side effects (gynecomastia) associated with the drug posed a problem. More recently, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study has provided firm support for the use of eplerenone (Inspra?, Pfizer) in heart failure following acute myocardial infarction in addition to neurohormonal blockade with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and β-blockers. This strategy can be expected to benefit both mortality and morbidity. Due to the fact that eplerenone is a selective aldosterone receptor antagonist, it does not cause troublesome hormonal side effects. This is an important feature of the drug that is likely to help maintain compliance.     

Adverse cardiorenal effects of aldosterone: is aldosterone antagonism beneficial?

Aldosterone has recently been recognized as an important factor in the development and progression of cardiorenal disease. Animal and human data suggest that aldosterone contributes importantly to several disease states. These include congestive heart failure, coronary heart disease and progression of kidney disease. Recently, the discovery that aldosterone antagonists decrease pathologic injury in the kidneys and nonepithelial tissues, such as the myocardium and endothelium, has generated great controversy regarding the actual mechanisms of benefit of these agents. The available data is reviewed and conclusions drawn regarding the relative benefits of modulating aldosterone effects in the cardiovascular system and the kidney. In particular, the authors review their effects on reductions in cardiovascular events and progression of chronic kidney disease, as well as the safety and tolerability of these agents.     

醛固酮拮抗剂螺内酯辅助治疗慢性心力衰竭的效果及对患者炎性细胞因子水平的影响

目的探讨醛固酮拮抗剂螺内酯治疗慢性心力衰竭(简称心衰)的临床效果。方法将本院收治的92例心衰患者按随机数字法分为对照组和观察组,每组46例。对照组行常规基础性抗心衰治疗,观察组在此基础上加用醛固酮拮抗剂螺内酯。比较两组的治疗效果。结果治疗后,观察组的血钾、肌酐水平均高于对照组(P<0.05);治疗后,两组患者的IL-1β、IL-6及TNF-α水平均明显降低,且观察组显著低于对照组(P<0.05);观察组的治疗总有效率显著高于对照组(P<0.05);治疗后,观察组的LVEDD、LVESD小于对照组,LVEF、CO大于对照组(P<0.05)。结论在常规治疗基础上加用醛固酮拮抗剂螺内酯治疗慢性心衰患者,可明显控制炎症反应,提高临床治疗总体效果。     

Role of carvedilol controlled-release in cardiovascular disease

Carvedilol is a β₁- and β₂-adrenergic receptor antagonist with additional vasodilatory α₁-blocking properties. Carvedilol was shown to be more efficacious than a traditional β-blocker for treating heart failure and improving myocardial function. Carvedilol is the only agent in its class to have been demonstrated to significantly reduce mortality and morbidity in post-myocardial-infarction patients with left ventricular dysfunction. Moreover, carvedilol does not exhibit the carbohydrate and lipid disturbances observed with other β-blockers. Originally available as a twice-daily formulation, a controlled-release, once-daily formulation of carvedilol is now available, which has equivalent efficacy and safety, as demonstrated by numerous studies. The convenience of once-daily dosing is expected to contribute to patient adherence, thereby potentially improving long-term clinical outcomes.     

The role of heart rate in the development of cardiovascular disease

Heart rate is an independent risk factor for patients with cardiovascular disease, in particular with arterial hypertension, myocardial infarction, coronary artery disease and heart failure. This relation is supported by a large number of animal studies as well as clinical trials which are summarized in this article. These studies demonstrated detrimental effects of increased heart rate on the function and structure of the cardiovascular system. Heart rate can be easily detected during physical examination of the patient and therefore allows a simple conclusion on prognosis and efficiency of therapy.     

Spironolactone use in patients with heart failure

BACKGROUND: The addition of spironolactone, an aldosterone antagonist, to standard therapy can reduce the risk of both morbidity and mortality in patients with severe heart failure. OBJECTIVE: To evaluate the use of spironolactone in class III and IV heart failure patients in four urban teaching hospitals. METHODS: We conducted a concurrent medical record review of 163 patients with documented heart failure admitted to a general medicine service over a 5-week period. Data retrieved included patient demographics, heart failure class, left ventricular ejection fraction, spironolactone contraindications, spironolactone use, dose and frequency, and other heart failure medication use, dose and frequency. All data reflected patients' baseline status. RESULTS: Our patient population was 80% white people, 61% male, with a mean age of 70 years (35-99). A total of 114 had class III or IV heart failure (70%). Angiotensin-converting enzyme inhibitors or appropriate alternative were prescribed in 117 (72%) patients, whereas beta-blockers were used in 121 (74%) patients. Fifty-seven patients met spironolactone ideal candidate criteria. Of these, eight (14%) were appropriately prescribed spironolactone. CONCLUSIONS: Three years after publication of the Randomized Aldactone Evaluation Study, spironolactone is underutilized in the treatment of heart failure. Results of this study indicated that the majority of patients in class III or IV heart failure were not prescribed spironolactone. Improvements in spironolactone prescribing are needed.     

肥胖与心血管疾病

肥胖是高血压、冠心病、脑卒中、2型糖尿病等疾病的重要危险因子。研究发现肥胖与心血管疾病密切相关。本文主要就常用的肥胖指标如皮褶厚度、体重指数（BMI）、腰臀比值(WHR)、腰围及体脂分布与冠心病、高血压和心脏结构与功能的关系进行综述;同时简单介绍了减肥对它们的影响。     

依那普利联合螺内酯治疗慢性心衰安全性观察

目的探讨依那普利联合螺内酯治疗慢性心衰的安全性。方法68例慢性心衰患者在常规抗心衰治疗的基础上随机分为两组（A组和B组）。A组患者不加用螺内酯。B组加用螺内酯40～120mg／d口服。随访6个月，监测血钾、钠、氯、肌酐、尿素氮、丙氨酸氨基转移酶水平。结果治疗前后A组和B组患者各项指标差异无统计学意义。两组患者治疗6个月无肿瘤发生，男性患者无乳腺发育，无肝、肾功能损害。结论依那普利联合螺内酯治疗慢性心衰是安全的。     

Clinical utility of sympathetic blockade in cardiovascular disease management

Introduction: A dysregulated sympathetic nervous system is a major factor in the development and progression of cardiovascular disease; thus, understanding the mechanism and function of the sympathetic nervous system and appropriately regulating sympathetic activity to treat various cardiovascular diseases are crucial.

Areas covered: This review focused on previous studies in managing hypertension, atrial fibrillation, coronary artery disease, heart failure, and perioperative management with sympathetic blockade. We reviewed both pharmacological and non-pharmacological management.

Expert commentary: Chronic sympathetic nervous system activation is related to several cardiovascular diseases mediated by various pathways. Advancement in measuring sympathetic activity makes visualizing noninvasively and evaluating the activation level even in single fibers possible. Evidence suggests that sympathetic blockade still has a role in managing hypertension and controlling the heart rate in atrial fibrillation. For ischemic heart disease, beta-adrenergic receptor antagonists have been considered a milestone drug to control symptoms and prevent long-term adverse effects, although its clinical implication has become less potent in the era of successful revascularization. Owing to pathologic involvement of sympathetic nervous system activation in heart failure progression, sympathetic blockade has proved its value in improving the clinical course of patients with heart failure.     

缬沙坦联合螺内脂对原发性高血压合并心力衰竭患者心功能及血清VEGF水平的影响

目的探讨缬沙坦联合螺内脂对原发性高血压合并心力衰竭患者心功能及血清血管内皮生长因子(VEGF)水平的影响。方法将90例原发性高血压合并心力衰竭患者按随机数字表法分为对照组与观察组,各45例。对照组给予螺内脂治疗,观察组在对照组基础上给予缬沙坦治疗。比较两组的治疗效果。结果治疗后,观察组的收缩压和舒张压均显著低于对照组(P<0.05)。治疗后,两组的LVEF与LVFS均提高,且观察组高于对照组(P<0.05)。治疗后,两组的血清VEGF水平均降低,且观察组低于对照组(P<0.05)。结论缬沙坦联合螺内脂治疗原发性高血压合并心力衰竭能改善患者的心功能,抑制血清VEGF表达水平,从而发挥持续降压效果。     

心血管系统疾病患者血浆神经肽Y检测的临床意义

目的：探讨神经肽Ｙ（ＮＰＹ）在心血管疾病发病中的病理生理作用。方法：用放免分析法对原发性高血压、冠状动脉粥样硬化性心脏病（冠心病）、充血性心力衰竭患者治疗前后血中ＮＰＹ的含量进行测定和对比研究。结果：３种疾病患者血浆中ＮＰＹ含量分别为（３０．７１±２．９７）ｐｍｏｌ／Ｌ,（３２．６２±１１．３１）ｐｍｏｌ／Ｌ和（３４．８３±８．２６）ｐｍｏｌ／Ｌ,明显高于正常对照组（１７．３７±５．０８）ｐｍｏｌ／Ｌ,Ｐ＜０．０１;原发性高血压、充血性心力衰竭组患者血浆中ＮＰＹ的含量与疾病的程度正相关（ｒ＝０．５７３,Ｐ＜０．０５;Ｆ＝９．１２,Ｐ＜０．０１）。结论：ＮＰＹ在心血管疾病发生、发展过程中发挥着重要的作用;ＮＰＹ作为一种监测指标对心血管系统疾病病情的评估可能具有重要的意义。     

Probrain Natriuretic Peptide for assessment of efficacy in heart failure treatment

N-terminal probrain natriuretic peptide (NT-proBNP) is elevated in patients with heart failure. Numerous clinical trials have evaluated the efficacy of spironolactone in heart failure; however, no studies have directly examined the effects of spironolactone treatment on NT-proBNP level. This study investigated whether NT-proBNP levels decrease with daily spironolactone treatment. The study consisted of 117 adult patients with heart failure. All participants were divided into 3 groups, class I, class II, and class III, according to the New York Heart Association classification system. Patients were randomly assigned to receive spironolactone or were treated with another drug, other than spironolactone, as placebo. NT-proBNP plasma samples were taken at baseline and after 6 mo of treatment. A total of 62 patients were treated with daily spironolactone; 55 patients were followed with available treatment without spironolactone. The baseline demographic and laboratory parameters were similar for patients in all groups. At the end of 6 mo, spironolactonetreated patients had significantly lower NT-proBNP levels and significantly better ejection fractions than did patients in all New York Heart Association classes who were not treated with spironolactone. Results suggest that spironolactone decreases plasma NT-proBNP concentrations, and that the measurement of plasma NT-proBNP levels may be helpful in assessing therapeutic efficacy in patients who are treated for heart failure.     

Comprehensive review of cardiovascular toxicity of drugs and related agents

Cardiovascular diseases are a leading cause of morbidity and mortality in most developed countries of the world. Pharmaceuticals, illicit drugs, and toxins can significantly contribute to the overall cardiovascular burden and thus deserve attention. The present article is a systematic overview of drugs that may induce distinct cardiovascular toxicity. The compounds are classified into agents that have significant effects on the heart, blood vessels, or both. The mechanism(s) of toxic action are discussed and treatment modalities are briefly mentioned in relevant cases. Due to the large number of clinically relevant compounds discussed, this article could be of interest to a broad audience including pharmacologists and toxicologists, pharmacists, physicians, and medicinal chemists. Particular emphasis is given to clinically relevant topics including the cardiovascular toxicity of illicit sympathomimetic drugs (e.g., cocaine, amphetamines, cathinones), drugs that prolong the QT interval, antidysrhythmic drugs, digoxin and other cardioactive steroids, beta‐blockers, calcium channel blockers, female hormones, nonsteroidal anti‐inflammatory, and anticancer compounds encompassing anthracyclines and novel targeted therapy interfering with the HER2 or the vascular endothelial growth factor pathway.     

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.     

Mineralocorticoid receptor activation in myocardial infarction and failure: recent advances

Eur J Clin Invest 2012; 42 (10): 1112-1120 The classical view of aldosterone actions via the mineralocorticoid receptor (MR) limited to control of fluid balance and blood pressure homoeostasis has been progressively overcome by clinical and experimental evidence emphasizing the pleiotropic role of MR activation in the pathogenesis of cardiovascular disease. Clinical studies have shown the benefit of MR blockade in patients with left ventricular dysfunction and heart failure after myocardial infarction (MI), hypertension or diabetic nephropathy. Deleterious effects of MR activation include cardiac structural and electrical remodelling, cardiovascular fibrosis, inflammation and oxidative stress. Complexity of pathophysiological role of MR derives from the presence of circulating glucocorticoids at higher concentrations than aldosterone and the equal affinity of the MR for aldosterone, cortisol and corticosterone. Recent experimental studies using different animal models and genetic tools have deeply explored the cell-specific functional role of MR in cardiovascular pathology. This review addresses emerging preclinical studies as well as ongoing clinical trials regarding MR activation in MI and failure.