Effect of aldosterone antagonism in heart failure: pharmacotherapeutic options

Aldosterone escape during chronic angiotensin-converting enzyme (ACE) inhibition may contribute to the high mortality among patients with heart failure. Aldosterone exerts several detrimental effects in the pathophysiology of heart failure. Spironolactone, an aldosterone antagonist, has proved beneficial when added to ACE inhibitors in patients with severe heart failure. However, spironolactone has substantial side effects mostly due to anti-androgen and anti-progestagen actions. This may limit its use in less severe heart failure. Recently, more selective aldosterone antagonists have been developed, which appear to have the same potential as spironolactone with fewer side effects. Trials to assess efficacy of these drugs in hypertension and mild heart failure are now being started.     

Profibrotic effects of aldosterone

Animal studies have shown that during high sodium intake aldosterone induces cardiac fibrosis and renal nephrosclerosis through activation of mineralocorticoid receptors. In the human heart mineralocorticoid receptors and activity of the enzyme 11beta-hydroxysteroid-dehydrogenase type 2, which is required for the activation of mineralocorticoid receptors by aldosterone, are both present. In clinical medicine the profibrotic effect of aldosterone has been related to diastolic dysfunction, arrhythmia and progression of cardiac and renal failure. The addition of an aldosterone receptor antagonist to optimal treatment in patients with heart failure causes a decrease in serum markers of collagen turnover and a decline in cardiac morbidity and mortality. These findings are a strong indication of a profibrotic effect of aldosterone in cardiac failure. Studies concerning the profibrotic effect of aldosterone in patients with primary hyperaldosteronism are contradictory and at the moment no data are available about a potential antifibrotic effect of aldosterone receptor antagonists in patients with impaired renal function.     

The role of aldosterone-antagonists in the treatment of congestive heart failure

The role of aldosterone-antagonists in the treatment of congestive heart failure. Despite the advances of the treatment of congestive heart failure, nearly half of the patients diagnosed with this disease five years ago are alive today. Experimental and human studies have demonstrated, that under special pathologic condition, the heart extracts aldosterone, and aldosterone extraction in the heart stimulates increased collagen turnover culminating in ventricular remodeling. Aldosterone blockade has been shown to be effective in reducing total mortality and hospitalization for heart failure in patients with systolic left ventricular dysfunction due to chronic heart failure (RALES study with spironolactone) and in patients with systolic left ventricular dysfunction post acute myocardial infarction (EPHESUS study with eplerenone). These clinical studies have shown that mineralocorticoid receptor activation remains important despite the use of angiotensin converting enzyme inhibitor or angiotensin receptor blocking agent and a beta blocker. In the ACC/AHA (and in the European and Hungarian) guidelines for the evolution and management of chronic heart failure, the indication of spironolactone was defined of Class Ila, Level of Evidence: B in CHF of stage C. The eplerenone (in US: INSPRA) was approved for the management of CHF patients after myocardial infarction with ejection fraction < 40%. Eplerenone, compared with spironolactone, is associated with a lower incidence of gynecomastia and other sex hormone-related adverse effect (breast pain, menstrual abnormalities). The spironolactone should not be used in patients with a creatinine above 220 mikromol/l. Despite the guidelines recommendation, spironolactone has been widely used in patients without consideration of their functional class or ejection fraction, without optimization of background treatment with ACE inhibitors and beta-blockers.     

Anti-aldosterone therapy in severe heart failure]

The mortality rate among patients with severe heart failure is still very high despite treatment with loop diuretics and angiotensin-converting enzyme (ACE) inhibitors. The 'randomized aldactone evaluation study' (RALES) has shown that 25 mg spironolactone added to this treatment was safe and reduced all-cause mortality by 30% in patients with severe (previous New York Heart Association (NYHA) functional class IV) heart failure due to systolic left ventricular dysfunction. Blockade of aldosterone in these patients may be necessary to overcome so-called aldosterone escape during chronic ACE-inhibition. The beneficial effects of spironolactone may relate to enhanced diuresis, anti-arrhythmogenic properties and direct effects on the myocardium and blood vessels. At present, addition of spironolactone may be appropriate for patients with severe heart failure, whereas patients with moderate heart failure may benefit more from beta-blockade.     

Short-Term Aggressive Disease Management Programs for Heart Failure

Cardiovascular disease is the leading cause of death in developed countries. It is estimated that about 15 million people worldwide die every year from heart disease, with a substantial proportion of these deaths occurring in developing nations. Congestive heart failure (CHF) is a condition that develops as a late complication from a variety of heart disease states. CHF remains a devastating disease. It exacts a high toll in terms of mortality and morbidity and carries a high price burden. As the population ages and treatments for conditions such as acute coronary syndrome and hypertension improve, the prevalence of heart failure can be expected to increase, because survivors of hypertension and myocardial infarction live long enough to develop complications such as congestive heart failure.Recent advances have clearly shown that treatment strategies including ACE inhibitors, β-adrenoceptor antagonists, and aldosterone inhibitors improve morbidity and survival. However, even among patients treated with recommended therapy at recommended doses, mortality remains high. Opportunities exist for further improvement of prognosis beyond current guidelines for heart failure. As new evidence emerges, it is evident that survival can be further improved by using other strategies such as angiotensin receptor antagonists as alternative or add-on therapy and ventricular resynchronization for qualifying candidates.The management of heart failure patients in the community presents unique challenges. Patients who are managed in community hospitals are often elderly and/or very ill, with several comorbidities and clinical characteristics that may be different from patients who qualify for clinical trials. Furthermore, there appears to be a delay in incorporating scientific evidence into practice and studies continue to show that many heart failure patients do not receive recommended medications at adequate doses.Disease management programs have evolved as a way of improving heart failure care. Different models have been established and some institutions have published the results of their specific programs. The consistent findings include reductions in hospitalization rates, improvements in quality of life, and reductions in cost. However, to date, such studies have not compared different models and until large prospective trials are available, the true benefits of these programs will continue to be debated.     

Management of Hypertension in Patients with Diabetes Mellitus

Hypertension and diabetes mellitus are significant and independent risk factors for cardiovascular disease.Antihypertensive therapy reduces cerebrovascular and cardiovascular morbidity and mortality in patients with hypertension. Tight blood pressure (BP) control [target diastolic BP (DBP) ≤80mm Hg] reduced the incidence of major cardiovascular events by 51% compared with less tight control (DBP ≤90mm Hg) in patients with diabetes mellitus in the Hypertension Optimal Treatment (HOT) study. Similarly, in the UK Prospective Diabetes Study (UKPDS), tight BP control [mean systolic BP (SBP)/DBP = 144/82mm Hg] with captopril or atenolol reduced diabetes mellitus-related morbidity and mortality by 24% compared with less tight control (mean SBP/DBP = 154/87mm Hg). Importantly, the frequency of microvascular disease (including retinopathy) was reduced by 37% among those randomised to tight BP control in the UKPDS.In the diabetic subgroup in the Heart Outcomes Prevention Evaluation (HOPE) study, there was a 25% reduction in the composite end-point of death due to cardiovascular causes, or myocardial infarction or stroke during 5 years of treatment with ramipril 10 mg/day relative to placebo.Lisinopril is an ACE inhibitor indicated for use in hypertension, heart failure and post-myocardial infarction. As an antihypertensive agent the drug is effective and generally well tolerated in patients with type 1 or 2 diabetes mellitus and in those with early or overt nephropathy.In the Swedish Treatment of Old People (STOP) Hypertension 2 trial, there was no difference in the relative risk of cardiovascular death between those assigned to ACE inhibitors (lisinopril or enalapril), calcium channel blockers (felodipine or isradipine) or ‘conventional’ antihypertensive therapy (thiazide diuretics or β blockers); treatment effects did not differ significantly between diabetic and nondiabetic patients (10.9% of the 6614 patients had diabetes mellitus). Importantly, lower frequencies of nonfatal or fatal myocardial infarction [relative risk (RR) 0.77; 95% confidence interval (CI) 0.61 to 0.96] and congestive heart failure (RR 0.78; CI 0.83 to 0.97) were detected during 4 years’ treatment with lisinopril or enalapril than felodipine or isradipine in this study.Lisinopril reduced albumin excretion rates in patients with type 1 or 2 diabetes mellitus. In the 2-year EURODIAB Controlled Trial of Lisinopril in IDDM (EUCLID) study, albumin excretion rates decreased by 49.7% relative to placebo in normotensive patients with type 1 diabetes mellitus and microalbuminuria during treatment with lisinopril 10 to 20 mg/day. Progression of retinopathy was attenuated in normotensive patients with type 1 diabetes mellitus during treatment with lisinopril in this study.In conclusion, lisinopril, like other ACE inhibitors should be considered a first-line agent for reducing BP and attenuating nephropathy in patients with type 1 or 2 diabetes mellitus.     

Heart failure in women

Congestive heart failure represents a growing health issue with significant morbidity, expense, and mortality. Unfortunately, despite heart failure affecting men and women equally, women historically have represented a minority in heart failure trials. Despite this disparity, treatment decisions rely heavily on these trials. Women with heart failure often have different clinical features than men, such as age of onset and comorbidities. Compared with men, women also demonstrate differences in remodeling and the response to injury, such as volume or pressure overload and myocardial infarction. We are only beginning to understand the clinical implications of these gender differences and their impact on pharmacologic treatments. After discussing these differences, a review of the agents useful in systolic failure is made, including angiotensin-converting enzyme inhibitors, b-blockers, digoxin, and aldosterone inhibition. Treatment of diastolic heart failure with empiric guidelines follows.     

Secondary prevention after myocardial infarction

The management of acute myocardial infarction has been revolutionized in the past decade. Advances in pharmacological and mechanical reperfusion therapy have improved the survival of patients who experience myocardial infarction. Although revascularisation techniques have been shown to reduce infarct size and in-hospital mortality, patients recovering from myocardial infarction are still at increased risk for reinfarction, congestive heart failure, and sudden death. Despite impressive technological advances, lifestyle modification and pharmacological interventions remain the key components of secondary prevention after myocardial infarction. Although the concept of secondary prevention of reinfarction and death has been investigated vigorously for several decades, preventive therapy has been seriously underused by physicians. The aim of this paper is to provide a comprehensive, evidence-based overview of secondary prevention postmyocardial infarction clinical trials, in the hope of improving the utilization of effective therapies in patients with coronary heart disease.     

Stem cell therapy in cardiovascular diseases

Myocardial infarction is the leading cause of congestive heart failure in the industrialized world. Current treatments fail to address the underlying scarring and cell loss, which are the causes of ischaemic heart failure. Recent interest has focused on stem cells, which are undifferentiated and pluripotent cells that can proliferate, potentially self-renew, and differentiate into cardiomyocytes and endothelial cells. Myocardial regeneration is the most widely studied and debated example of stem cell plasticity. Early reports from animal and clinical investigations disagree on the extent of myocardial renewal in adults, but evidence indicates that cardiomyocytes were generated in what was previously considered a postmitotic organ. So far, candidates for cardiac stem cell therapy have been limited to patients with acute myocardial infarction and chronic ischaemic heart failure. Currently, bone marrow stem cells seem to be the most attractive cell type for these patients. The cells may be delivered by means of direct surgical injection, intracoronary infusion, retrograde venous infusion, and transendocardial infusion. Stem cells may directly increase cardiac contractility or passively limit infarct expansion and remodeling. Early phase I clinical studies indicate that stem cell transplantation is feasible and may have beneficial effects on ventricular remodeling after myocardial infarction. Future randomized clinical trials will establish the magnitude of benefit and the effect on mortality after stem cell therapy.     

Selective aldosterone blockade reduces mortality after MI

Eplerenone, a selective mineralocorticoid receptor antagonist currently approved by the Food and Drug Administration for treatment of hypertension, reduces mortality following myocardial infarction in patients with left ventricular dysfunction and clinical signs of congestive heart failure. Previous research by the same group established that spironolactone does the same at lower cost than eplerenone.     

A critical review of anti-adrenergic therapy in patients with heart failure and diabetes mellitus

Anti-adrenergic therapy has been widely accepted as an important therapeutic intervention in patients with chronic heart failure. However, there has been continuing controversy regarding the risks and clinical significance of metabolic effects of different anti-adrenergic drugs. This review summarizes what has been learned from clinical trial evidence regarding the benefits of anti-adrenergic drugs in diabetic patients with chronic heart failure.     

不同NYHA分级慢性心力衰竭患者NT-proBNP的变化及意义

目的探讨血浆NT-proBNP（氮端前体脑钠肽）浓度变化在慢性心衰患者中的意义。方法选择慢性心力衰竭患者65例,NYHA分级分为Ⅱ-Ⅳ级,正常对照组21例,测定NT-proBNP血浆浓度。结果各组间NT-proBNP差别有统计学意义（P〈0.01）,NT-proBNP与NYHA分级呈正相关（r=0.509,P〈0.01）,抗心衰治疗7天后,与入院时相比各心衰组NT-proBNP明显下降（P〈0.01）。结论监测NT-proBNP,对慢性心衰的诊断、严重程度的判断、疗效判定是一项快速简便的指标,值得广泛应用于临床心力衰竭患者。     

The nutritional and metabolic support of heart failure in the intensive care unit

PURPOSE OF REVIEW: Heart failure and cardiovascular disease are common causes of morbidity and mortality, contributing to many ICU admissions. Nutritional deficiencies have been associated with the development and worsening of chronic heart failure. Nutritional and metabolic support may improve outcomes in critically ill patients with heart failure. This review analyzes the role of this support in the acute care setting of the ICU. RECENT FINDINGS: Cardiac cachexia is a complex pathophysiologic process. It is characterized by inflammation and anabolic-catabolic imbalance. Nutritional supplements containing selenium, vitamins and antioxidants may provide needed support to the failing myocardium. Evidence shows that there is utility in intensive insulin therapy in the critically ill. Finally, there is an emerging metabolic role for HMG-CoA reductase inhibition, or statin therapy, in the treatment of heart failure. SUMMARY: Shifting the metabolic milieu from catabolic to anabolic, reducing free radicals, and quieting inflammation in addition to caloric supplementation may be the key to nutritional support in the heart failure patient. Tight glycemic control with intensive insulin therapy plays an expanding role in the care of the critically ill. Glucose-insulin-potassium therapy probably does not improve the condition of the patient with heart failure or acute myocardial infarction.     

Cardiac resynchronization therapy for patients with atrial fibrillation

Atrial fibrillation and chronic heart failure are two major and even growing cardiovascular conditions that often coexist. Cardiac resynchronization therapy is an important, device-based, non-pharmacological approach in a selected group of chronic heart failure patients that has been shown to improve left ventricular function and to reduce both morbidity and mortality in large randomized trials. The latest European and American guidelines have considered atrial fibrillation patients with heart failure eligible for cardiac resynchronization therapy. This review summarizes current literature concerning the following topics: prognostic relevance of atrial fibrillation in heart failure, effects of cardiac resynchronization therapy in atrial fibrillation, relevance and strategies of rhythm and rate control in this group of patients. Authors explain how atrial fibrillation may interfere with the delivery of adequate cardiac resynchronization therapy, how to reduce the burden of atrial tachyarrhythmias, and finally present a brief overview.     

Selection on atherosclerosis as an explanation of the attenuated cholesterol-mortality relation in coronary heart disease populations

Recent studies of patients with coronary heart disease (CHD) at baseline have shown that their cholesterol levels are much less predictive of subsequent mortality than in populations free of CHD (FCHD). One previously suggested explanation of this attenuation is that the impact of hyperlipidemia on atherosclerosis or of atherosclerosis on mortality is reduced for post-myocardial infarction patients. In this paper it is shown that an alternative explanation is selection of CHD populations from FCHD populations for higher atherosclerosis levels. Data from all known follow-up studies on patients with baseline coronary angiograms are assembled to yield relations between cholesterol, atherosclerosis and mortality in CHD and FCHD populations. These data show that the selection hypothesis is not only logically possible but is also consistent with presently available epidemiologic information on relations between these three variables. An ethically impracticable large prospective study of a FCHD population with baseline angiograms might, however, be needed to choose definitively between the selection and reduced impact hypotheses.     

电风暴患者临床特点和病因分析

目的研究电风暴患者临床特点及其相关危险因素。方法选取2006年1月1日~2010年12月31日在解放军总医院住院,24h内因室性心动过速、心室颤动接受电除颤≥3次或置入型心律转复除颤器置入后放电次数≥3次患者81例,分析该人群血钾、血清钠、血清氯、血清镁、血清肌酐清除率、心脏功能、原发病因、患者除颤前治疗情况和抢救时用药情况。结果急性心肌梗死、陈旧性心肌梗死和心功能不全患者易发生电风暴,多数患者合并肾功能不全,低钾血症可能为电风暴的诱发因素。结论冠心病、心功能不全为电风暴患者的主要基础疾病。     

干细胞移植治疗缺血性心脏病现状与进展

医学科学快速发展的今天，药物治疗各种缺血性心脏病还不能解决晚期心衰及心梗等医学难题。干细胞移植能否弥补这些缺憾，临床医生已经展开了这一领域的科学研究及临床实践。故本研究将干细胞移植国际国内现状及进展综述如下。     

早期积极溶栓治疗急性心肌梗死83例疗效观察

目的 探讨早期积极溶栓治疗急性心肌梗死的临床疗效.方法 选择笔者所在医院2005年6月至2009年6月收治的83例急性心肌梗死患者,根据以上患者溶栓治疗时间分为观察组和对照组,观察组实施早期溶栓（发病到溶栓治疗时间小于4 h）治疗,对照组实施非早期（从发病到溶栓治疗时间在4～12 h内）溶栓治疗.结果 观察组心绞痛发生率、心力衰竭发生率与对照组比较,差异有统计学意义（P〈0.05）.结论 早期溶栓治疗可以显著降低急性心肌梗死患者心绞痛和心力衰竭发生率,临床治疗效果显著,值得借鉴.     

Valsartan in the treatment of heart failure or left ventricular dysfunction after myocardial infarction

The physiological role of the renin angiotensin aldosterone system (RAAS) is to maintain the integrity of the cardiovascular system. The effect of angiotensin II is mediated via the angiotensin type I receptor (AT1 ) resulting in vasoconstriction, sodium retention and myocyte growth changes. This causes myocardial remodeling which eventually leads to left ventricular hypertrophy, dilation and dysfunction. Inhibition of the RAAS with angiotensin converting enzyme (ACE) inhibitors after acute myocardial infarction has been shown to reduce cardiovascular morbidity and mortality. Angiotensin receptor blockers (ARBs) specifically inhibit the AT1 receptor. It has not been known until the performance of the VALIANT (valsartan in acute myocardial infarction trial) whether blockade of the angiotensin receptor with an ARB or combination of an ACE inhibitor and ARB leads to similar outcomes as an ACE inhibitor. The VALIANT trial demonstrated equal efficacy and non-inferiority of the ARB valsartan 160 mg bid compared with captopril 50 mg tds, when administered to high risk patients with left ventricular dysfunction or heart failure in the immediate post myocardial infarction period. The combination therapy showed no incremental benefit over ACE inhibition or an ARB alone and resulted in increased adverse effects. This review examines the role of valsartan in left ventricular dysfunction post myocardial infarction. We also discuss pharmacokinetics, dosing, side effects, and usage in the elderly.     

Addition of beta blockers in chronic heart failure

Chronic heart failure is an increasing cause of hospital admission in the Netherlands and Belgium. Despite numerous medical treatment modalities, the mortality remains high. Recent placebo-controlled randomized studies suggest that the addition of beta-blockers in stabilized, optimally pretreated patients with chronic heart failure using angiotensin converting enzyme (ACE) inhibitors, diuretics and digitalis, is accompanied by an additional absolute decrease in mortality by about 5% and a relative decrease in mortality by about 35%. Also the number hospitalization frequency decreases. Initially, the beneficial effects of beta-blockers on symptoms are only minor or absent. During the initiation period some clinical deterioration may occur which has to be treated accordingly; these patients are, however, difficult to identify. Initiation has to be done using low doses and should be restricted to stabilized, optimally treated patients. Doses should only be increased every 2 to 4 weeks until target doses are reached. These findings must not be extrapolated automatically to all cases of heart failure, since patients in the trials may differ considerably from those encountered in general practice.