醛固酮受体拮抗剂治疗慢性心力衰竭的研究进展

近些年来人们对慢性心力衰竭(chronic heartfailure,CHF)发生机理有了新的理解,认识到 CHF发生的本质是心室重塑,神经内分泌的过度激活则参与了心室重塑的过程,因而 CHF 的治疗模式发生了根本性的变化,从以往的"改善血流动力学"模式转变为"阻断神经内分泌的过度激活和心脏重塑,提高生活质量和延长其寿命的治疗"模式[1-3].     

慢性心力衰竭治疗中醛固酮拮抗剂的应用

慢性心力衰竭(CHF)是心血管疾病的终末阶段,其预后同恶性肿瘤相似或更差。尽管血管紧张素转换酶(ACE)抑制剂的应用使其病死率明显下降,但其病死率仍较高。部分原因是由于长期应用ACE抑制剂后出现醛固酮逃逸现象。故而,醛固酮拮抗剂在心力衰竭患者中的应用又成为研究的热点且颇具希望。     

Eplerenone: a selective aldosterone receptor antagonist for hypertension and heart failure

Aldosterone has been implicated for many years as an important substance in the pathogenesis of heart disease. Elevated aldosterone concentrations have been documented in patients with hypertension and heart failure, leading to the use of aldosterone antagonists for the treatment of these conditions. Spironolactone has been used for nearly 2 decades for the treatment of hypertension, and more recently, has become a standard agent for the treatment of systolic heart failure. Spironolactone, however, is a nonselective antagonist of the aldosterone receptor, binding also to other steroid receptors and causing a significant percentage of patients to have sex hormone-related adverse effects such as gynecomastia. Eplerenone is the first of a new class of drugs known as selective aldosterone receptor antagonists, which selectively block the aldosterone receptor with minimal effect at other steroid receptors, thereby minimizing many of the hormonal side effects seen with spironolactone. Eplerenone has been shown to be beneficial both as monotherapy and combination therapy for lowering elevated blood pressure in patients with hypertension. The antihypertensive efficacy of eplerenone is roughly similar to that of other antihypertensive agents, although in 1 study black patients responded better with eplerenone than losartan. In addition, eplerenone has demonstrated some renoprotective effects in diabetic patients with hypertension. Recently, eplerenone was shown to significantly reduce mortality and cardiovascular morbidity in post-myocardial infarction patients with systolic heart failure currently taking standard heart failure medications. Eplerenone is generally well tolerated, although hyperkalemia with this agent is of some concern. Eplerenone is metabolized by CYP3A4 and administration with potent inhibitors of this enzyme is contraindicated because of the risk of hyperkalemia. In summary, eplerenone has proven to be beneficial in treating hypertension and post-myocardial infarction heart failure. Its exact place in therapy will in large part be determined by its cost and whether or not future studies will be able to demonstrate a clinical benefit of this agent over spironolactone or other currently available treatments.     

Pharmacotherapy in congestive heart failure: aldosterone receptor antagonism: interface with hyperkalemia in heart failure

Aldosterone receptor antagonism (ARA) is an increasingly well-accepted element of heart failure therapy. The experimental underpinnings for the use of ARA in heart failure are strong being linked to a variety of tissue-based cardiac effects characteristic of drugs in this class. However, the benefits of ARA therapy do not come without some risk since drugs in this class are potent inhibitors of renal potassium (K+) elimination. Thus, some increment in serum K+, up to and including the development of overt hyperkalemia (typically defined as a serum K+ value in excess of 6.0 mEq/L), is to be expected whenever they are used. Hyperkalemia attributable to ARA relates to several factors including ARA dose, patient predisposition to hyperkalemia, as in the case of renal failure, and dietary intake of K+. The risk of some change in serum K+ with ARA should not be a deterrent to use of drugs in this class but, rather should prompt careful surveillance for the onset of this potentially life-threatening electrolyte disturbance. The frequency of such scrutiny should be patient-specific and based on the constellation of risk factors for hyperkalemia.     

醛固酮拮抗剂对老年慢性心力衰竭患者的疗效

目的：探讨长期应用醛固酮拮抗剂（螺内酯）的老年慢性心力衰竭（CHF）患者的左室重构、左室功能与脑钠肽（BNP）水平的关系和临床评价治疗效果。方法：在常规治疗心力衰竭药物治疗的基础上,120例CHF患者采用双盲法随机分为：螺内酯组（66例,螺内酯20mg／d）,CHF常规治疗对照组（54例）;检测治疗前、治疗3个月后左室重量指数（LVMI）、左心室射血分数（LVEF）、脑钠肽（BNP）水平的变化并进行比较分析。结果：螺内酯组心功能改善的总有效率80％,明显高于CHF常规治疗对照组的9．25％,P〈0.05;与CHF常规治疗对照组比较,螺内酯组治疗3月后LVMI[（340．7±68．3）g／m2比（179．6±33．3）g／m2]、BNP[（366．15±23．36）pg／ml比（330．38±11．56）pg／ml]水平显著降低,LVEF[（34．11±2．71）％比（46．2±3．9）％]显著升高（P均〈0．05）。结论：醛固酮拮抗剂在常规治疗心力衰竭的药物治疗的基础上,可降低BNP水平,改善心功能,抑制心室重构。     

Optimizing outcomes in the patient with acute decompensated heart failure

Heart failure (HF) and episodes of acute decompensated HF (ADHF) continue to pose a substantial clinical challenge in the United States and represent a significant source of morbidity, mortality, and health care resource use. Recent therapeutic advances have shifted ADHF treatment paradigms from diuretic management with or without inotrope use to therapy where intravenous vasodilators are the central component, above a background of diuretics. This shift in treatment has resulted in more rapid symptomatic improvements as well as in decreases in overall morbidity and mortality. Elevated left ventricular filling pressure has become an important clinical target for resolution during ADHF, as this parameter most closely correlates with degree of symptoms, extent of ischemic complications, and the deleterious neurohormonal activation in response to ADHF. Therapies that lead to rapid improvements in left ventricular filling pressure, including the use of nesiritide, a recombinant analog of B-type natriuretic peptide, have been shown to provide rapid symptomatic relief, but effects on long-term morbidity and mortality are as yet unclear. In addition to new treatments, new technologies--including assays based on cardiac biomarkers and techniques such as impedance cardiography for noninvasive monitoring of hemodynamic parameters--are contributing to improvements in care that will ultimately reduce the sizeable clinical and economic burden that HF represents.     

Hyperkalemia,congestive heart failure,and aldosterone receptor antagonism

Hyperkalemia is a common occurrence in patients with congestive heart failure, particularly when renal failure coexists. The level of renal function in congestive heart failure is often difficult to ascertain because good measurement tools for estimation of renal function are not available. Serum creatinine values have often been offered as a good gauge of renal function, although in most cases true renal function is appreciably lower than the estimate derived from a specific serum creatinine value. Thus, patients with congestive heart failure very commonly, particularly in the advanced stages of the disease, have moderate renal insufficiency, either due to specific heart failure-related renal perfusion changes or as the result of renal involvement from the same processes having caused the heart failure, as is the case with diabetes. It is in this setting of mild-to-moderate levels of renal failure that therapies, such as angiotensin-converting inhibitors, angiotensin-receptor blockers, and aldosterone-receptor antagonists, are administered either individually or collectively. Each of these drug classes reduces the homeostatic ability to eliminate ingested potassium loads by the renal route and increase the tendency to evolve into a hyperkalemic state. This is noteworthy because aldosterone-receptor antagonists are increasingly considered as important therapies in the long-term management of heart failure. Spironolactone has been employed in this capacity and a new aldosterone-receptor antagonist, eplerenone, will become available in the near future, which further increases the importance of evaluating and treating the hyperkalemia risk in a timely manner.     

Addition of the selective aldosterone receptor antagonist eplerenone to ACE inhibition in heart failure: effect on endothelial dysfunction

OBJECTIVES: To investigate the effects of adding the selective aldosterone receptor antagonist eplerenone to ACE inhibition on endothelium-dependent vasodilation in rats with chronic heart failure (CHF). BACKGROUND: Addition of the non-selective aldosterone antagonist spironolactone to ACE-inhibitors reduces mortality and morbidity in CHF and improves endothelial vasomotor dysfunction, but is associated with considerable side-effects. METHODS: Starting 10 days after extensive myocardial infarction (MI) or sham-operation, Wistar rats were treated either with placebo, the ACE inhibitor trandolapril (TR, 0.3 mg/kg body weight per day), the selective aldosterone receptor antagonist eplerenone (EPL, 100 mg/kg per day) or a combination of both for 9 weeks. RESULTS: Maximum acetylcholine-induced, nitric oxide-dependent relaxation was significantly attenuated in aortic rings from rats with CHF compared with sham-operated animals (R(max) 55% vs. 87%). EPL alone slightly and TR significantly improved NO-mediated relaxation (CHF-EPL 66%; CHF-TR: 78%), while treatment with both EPL and TR completely restored endothelium-dependent vasorelaxation (CHF-EPL-TR: 83%). Aortic superoxide formation was significantly increased in rats with CHF compared with sham-operated animals, but was normalised by treatment with EPL or TR-EPL. Expression of the endothelial nitric oxide synthase was decreased in CHF and normalised in all treatment groups. CONCLUSIONS: In experimental CHF, the selective aldosterone antagonist EPL reduced the increased vascular superoxide formation. Although a combination of TR and EPL normalised endothelium-dependent relaxation, ACE inhibition as a monotherapy was almost equally effective.     

Efficacy of aldosterone receptor antagonism in heart failure: Potential mechanisms

Results of the Randomized Aldactone Evaluation Study and the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study indicate aldosterone receptor antagonism, together with angiotensin-converting enzyme inhibition and loop diuretics, is a most effective strategy in reducing risk for all-cause and cardiovascularrelated mortality and morbidity in patients with symptomatic heart failure. Responsible mechanisms are likely multifactoral. As a circulating hormone, aldosterone has well-known endocrine properties that contribute to the pathophysiology of congestive heart failure. This includes Na⁺ resorption at the expense of K⁺ excretion in such tissues as kidneys, colon, sweat, and salivary glands. Mg²⁺ excretion at these sites is likewise enhanced by aldosterone, whereas adrenal aldosterone secretion is regulated by extracellular Mg²⁺. Other endocrine actions of aldosterone receptor-ligand binding include: a reduction in biologically active cytosolic-free Mg²⁺, with intracellular Ca²⁺ loading in nonepithelial cells such as peripheral blood mononuclear cells; its influence on endothelial cell function; and its central actions, including the choroid plexus, activity of the hypothalamic paraventricular nucleus, and autonomic nervous system. De novo generation of aldosterone within the cardiovasculature is recognized and findings suggest its auto/paracrine properties contribute to tissue repair. Each of these actions is interrupted by aldosterone receptor antagonism and therefore may contribute to its salutary response in heart failure.     

Value of aldosterone receptor blockade in diuretic therapy of patients with chronic heart failure

PATHOGENESIS: All forms of chronic heart failure (high-output and low-output failure) are accompanied by an "arterial underfilling" inducing the activation of various neurohumoral systems (renin-angiotensin-aldosterone system, sympathic nervous system, non-osmotic stimulation of vasopressin). Elevated levels of those neurohormones detrimentally modulate renal function. Subsequently, renal salt and volume retention occurs leading to the main symptoms of heart failure, edema formation and dyspnea. DIURETIC THERAPY: Diuretics, which have been discovered more than 40 years ago, beneficially influence renal salt- and volume retention by their effects on tubular sodium reabsorption. While thiazides are recommended in mild forms, loop diuretics are used in severe stages of congestive heart failure. The clinician has to consider the changed pharmacokinetic and -dynamic properties during the application of diuretics in patients with chronic heart failure. In addition, increased sodium reabsorption occurs immediately after cessation of diuretic action often nullifying the preceding diuresis. Thus, salt- and volume restriction should be guaranteed, and a regular application of loop diuretics during the day should be preferred due to the short-acting nature of currently available loop diuretics. Sometimes, diuresis does not longer occur during the treatment with one substance (diuretic resistance), although the therapeutic goals of water excretion have not been achieved. After ruling out factors reducing the actions of diuretics (non-compliance, hyponatremia, etc.), a sequential nephron blockade should be initiated (combination of loop diuretics and a thiazide or an aldosterone-receptor antagonist) to increase diuresis and to elevate symptoms of volume overload. SIDE EFFECTS: Loop diuretics and thiazides often induce mild hypokalemia, which has been demonstrated to be not as benign as thought before. Chronic treatment with oral potassium supplements has several drawbacks, as urine excretion of potassium is subsequently increased and supplementation is not as effective as believed. Diuretic-induced hypokalemia seems to be aldosterone dependent. As aldosterone levels increase during diuretic therapy even during chronic treatment with an angiotensin-converting enzyme (aldosterone-escape) a combined treatment including an aldosterone-receptor antagonist has been suggested. Beneficial effects of aldosterone-receptor blockade on mortality (RALES trial) appear to be mediated be extrarenal and renal mechanisms. The suggested beneficial renal mechanisms of aldosterone receptor blockade are discussed in detail in the review. CONCLUSION: In conclusion, diuretic therapy of patients with congestive heart failure is effective to relieve symptoms and, presumably, to prolong life. As renal function and pharmacokinetics and -dynamics of diuretics are changed in heart failure, diuretic treatment has to be adapted to provide optimal treatment. Increased levels of aldosterone appear to play an important role in diuretic-induced hypokalemia, and in the progression of heart and renal failure. Thus, aldosterone receptor antagonists should be used in the treatment of heart failure more frequently.     

Effects of aldosterone receptor blockade in patients with mild-moderate heart failure taking a beta-blocker

AIMS: Spironolactone improves prognosis in severe heart failure (HF). We investigated its effects in patients with mild-moderate HF treated with an ACE inhibitor and beta-blocker. METHODS AND RESULTS: Randomised, double-blind, parallel-group, 3-month comparison of placebo and spironolactone (25 mg daily) in 40 patients in New York Heart Association (NYHA) class I (20%), II (70%) or III (10%), with a left ventricular ejection fraction of <40%. The mean (standard error) changes from baseline in the spironolactone and placebo groups were, respectively: i) B-type natriuretic peptide (BNP) -53.4(22.2) pg/mL and +3.3(12.1) pg/mL, P=0.04, ii) pro-collagen type III N-terminal amino peptide (PIIINP) -0.6(0.2) micromol/L and +0.02(0.2) micromol/L, P=0.02 and iii) creatinine +10.7(3.2) micromol/L and -0.3(2.6) micromol/L, P=0.01. Compared with placebo, spironolactone therapy was associated with a reduction in self-reported health-related quality of life: change in visual analog score: -6 (3) vs. +6 (4); P=0.01. No differences were observed on other biochemical, neurohumoral, exercise and autonomic function assessments. CONCLUSION: In patients with mild-moderate HF, spironolactone reduced neurohumoral activation (BNP) and a marker of collagen turnover (PIIINP) but impaired renal function and quality of life. The benefit-risk ratio of aldosterone blockade in mild HF is uncertain and requires clarification in a large randomised trial.     

Angiotensin receptor blockers and aldosterone antagonists in chronic heart failure.

Prognosis in congestive heart failure is directly linked to neurohormonal activation. Angiotensin II through the activation of the renin angiotensin aldosterone system has been the principal focus therapy over the last 2 decades. New agents that target selective blockade of the angiotensin II receptor have been introduced in clinical trials for the treatment of heart failure. Aldosterone has been identified as a critically important neurohormone with direct detrimental effects on the myocardium. Aldosterone antagonists have been used in clinical trials to improve mortality in patients with chronic heart failure.     

Selection of a mineralocorticoid receptor antagonist for patients with hypertension or heart failure

Clinical trials have demonstrated morbidity and mortality benefits of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure. These studies have used either spironolactone or eplerenone as the MRA. It is generally believed that these two agents have the same effects, and the data from studies using one drug could be extrapolated for the other. National and international guidelines do not generally discriminate between spironolactone and eplerenone, but strongly recommend using an MRA for patients with heart failure due to LV systolic dysfunction and post‐infarct LV systolic dysfunction. There are no major clinical trials directly comparing the efficacy of these two drugs. This article aims to compare the pharmacokinetics and pharmacodynamics of spironolactone and eplerenone, and to analyse the available data for their cardiovascular indications and adverse effects. We have also addressed the role of special circumstances including co‐morbidities, concomitant drug therapy, cost, and licensing restrictions in choosing an appropriate MRA for a particular patient, thus combining an evidence‐based approach with personalized medicine.