Metabolic and toxicological considerations for diuretic therapy in patients with acute heart failure

INTRODUCTION: Diuretics are widely recommended in patients with acute heart failure (AHF). However, loop diuretics predispose patients to electrolyte imbalance and hypovolemia, which in turn leads to neurohormonal activation and worsening renal function (WRF). Unfortunately, despite their widespread use, limited data from randomized clinical trials are available to guide clinicians with the appropriate management of this diuretic therapy. AREAS COVERED: This review focuses on the current management of diuretic therapy and discusses data supporting the efficacy and safety of loop diuretics in patients with AHF. The authors consider the challenges in performing clinical trials of diuretics in AHF, and describe ongoing clinical trials designed to rigorously evaluate optimal diuretic use in this syndrome. The authors review the current evidence for diuretics and suggest hypothetical bases for their efficacy relying on the complex relationship among diuretics, neurohormonal activation, renal function, fluid and sodium management, and heart failure syndrome. EXPERT OPINION: Data from several large registries that evaluated diuretic therapy in hospitalized patients with AHF suggest that its efficacy is far from being universal. Further studies are warranted to determine whether high-dose diuretics are responsible for WRF and a higher rate of coexisting renal disease are instead markers of more severe heart failure. The authors believe that monitoring congestion during diuretic therapy in AHF would refine the current approach to AHF treatment. This would allow clinicians to identify high-risk patients and possibly reduce the incidence of complications secondary to fluid management strategies.     

Teaching heart failure treatment guidelines and assessing heart failure therapy

Objectives

To determine the effectiveness of the heart failure screening form in teaching heart failure treatment guidelines and prompting students to evaluate patients'' medications to initiate patient education and provider intervention.

Design

Between 2002 and 2009, 123 students used the heart failure screeing form during an elective cardiology advanced pharmacy practice experience (APPE). A subset of 41 students were also assessed for change in heart failure knowledge and confidence pre- and post-APPE.

Assessment

A total of 1,114 heart failure patients were screened and assessed using the tool with a mean age of 71.9 ± 12.9 years. Of those, 535 (48%) patients met screening criteria and participated in heart failure education. From 2008 through 2009, there were 45 heart failure interventions with a 60% provider acceptance rate. Significant improvements were made in heart failure knowledge and in all areas of confidence at the end of the APPE for the 41 students assessed.

Discussion

The heart failure screening form is an effective tool to teach evidence-based medicine and to prompt students to initiate provider intervention and patient education. Its use is associated with significant increases in knowledge and confidence in heart failure medication therapy management in fourth-year pharmacy students.     

Anti-inflammatory therapy for heart failure

Recently, inflammation has been shown to be an important aspect of cardiovascular diseases, and markers of inflammation predict risk of adverse cardiovascular events. Accumulating evidence shows that heart failure is an inflammatory disease, and anti-inflammatory therapy by various agents would be a promising future treatment for heart failure.     

心力衰竭的代谢治疗进展

心力衰竭时交感神经兴奋性增加,使血浆游离脂肪酸浓度增高,引起胰岛素抵抗、葡萄糖氧化减少、游离脂肪酸氧化增加,导致能量产生减少、氧自由基和炎症介质产生增加,均加剧心力衰竭。肾上腺素β受体拮抗药、曲美他嗪、雷诺嗪、哌克昔林、二甲双哌等是目前心力衰竭代谢治疗中研究最多的药物。     

Vasodilator therapy in chronic congestive heart failure

Vasodilator agents are relatively new additions to the armamentarium for the management of patients with congestive heart failure. Myocardial failure, irrespective of the aetiology, tends to create a vicious cycle characterised by reduced cardiac output and elevated systemic vascular resistance, which further decrease cardiac output by increasing left ventricular ejection impedance. The rationale for the use of vasodilators is to interrupt the vicious cycle by decreasing the left ventricular ejection impedance by peripheral vasodilatation. Although most vasodilator agents produce qualitatively similar haemodynamic responses, quantitatively their haemodynamic effects differ considerably. Knowledge of the haemodynamic effects of the various vasodilators helps in the selection of a particular drug for the management of such patients. This article reviews the mechanisms of action, haemodynamic effects, pharmacokinetics, clinical usage and adverse effects of non-parenteral vasodilator agents currently available for the management of patients with chronic heart failure.     

Pediatric heart failure therapy with beta-adrenoceptor antagonists

Management of chronic heart failure in pediatrics has been altered by the adult literature showing improvements in mortality and hospitalization rates with the use of beta-adrenoceptor antagonists (beta-blockers) for routine therapy of all classes of ischemic and non-ischemic heart failure. Many pediatric heart failure specialists have incorporated these agents into their routine management of pediatric heart failure related to dilated cardiomyopathy or ventricular dysfunction in association with congenital heart disease. Retrospective and small prospective case series have shown encouraging improvements in cardiac function and symptoms, but interpretation has been complicated by the high rate of spontaneous recovery in pediatric patients. A recently completed pediatric double-blind, randomized, placebo-controlled clinical trial showed no difference between placebo and two doses of carvedilol over a 6-month period of follow-up, with significant improvement of all three groups over the course of evaluation.Experience with adults has suggested that only certain beta-blockers, including carvedilol, bisoprolol, nebivolol, and metoprolol succinate, should be used in the treatment of heart failure and that patients with high-grade heart failure may derive the most benefit. Other studies surmise that early or prophylactic use of these medications may alter the risk of disease progression in some high-risk subsets, such as patients receiving anthracyclines or those with muscular dystrophy. This article reviews these topics using experience as well as data from all the recent pediatric studies on the use of beta-blockers to treat congestive heart failure, especially when related to systolic ventricular dysfunction.     

他汀类药物对非缺血性心力衰竭的有益作用

他汀类药物可能通过抗炎、改善内皮功能、减轻氧化应激与调节神经体液因素等机制产生对慢性心力衰竭的有益作用。对冠心病或心力衰竭研究的回顾性分析显示，他汀类药物可改善慢性心力衰竭患者预后，与是否为缺血性病因无关。现综述近年他汀类药物对非缺血性心力衰竭的作用机制、回顾性分析及前瞻临床研究，结果显示它可改善左室功能与炎症状态，但需要进一步的大规模随机双盲研究验证。     

收缩性心力衰竭的非药物治疗

收缩性心力衰竭的内科常用非药物治疗方法包括心脏再同步化(CRT)、植入心脏转复除颤器(ICD)和心脏收缩调节装置(CCM)。CRT主要适用于QRS波增宽(尤其是左束支传导阻滞)、左室射血分数(LVEF)≤35%和美国纽约心脏病协会(NYHA)心功能分级Ⅱ~Ⅳ级患者;ICD适用于LVEF≤35%和NYHAⅡ~Ⅲ级患者(均为IA类适应证)。已有大量研究证实CRT和ICD可降低适应证患者的总死亡率和猝死率。国内存在的主要问题是医生对适应证认识不够,使大多数适应证患者得不到治疗。CCM适用于不伴宽QRS波的心力衰竭患者,可改善生活质量和心功能,目前尚未在国内应用。     

Intravenous vasodilator therapy in congestive heart failure

The prevalence of congestive heart failure (CHF) is increasing in the US and worldwide, partly because patients are living longer. Treatment of CHF is mostly on an outpatient basis, but inpatient care is required for decompensated CHF, acute CHF or poor response to outpatient treatment. Control of symptoms is usually achieved by diuresis. Intravenous (IV) vasodilators are an important adjunct to the inpatient treatment of CHF. They work mainly by reducing the afterload on the myocardium although preload reduction also occurs. After clinical stabilisation, the goal is to switch to a maintenance oral regimen to be continued as outpatient therapy. The range of IV vasodilators available for inpatient treatment of CHF includes nitrates, phosphodiesterase inhibitors, dobutamine, morphine, ACE inhibitors, B-type natriuretic peptides and endothelin receptor antagonists. As each agent may have a different mechanism or site of action, each agent may affect preload, contractility or afterload to a different extent and it may be desirable to choose one over the other in a particular clinical setting. Examples of standard therapy include dobutamine, milrinone and nitroglycerin. Nesiritide, a B-type natriuretic peptide, is a newer vasodilator and US FDA approved for use in acute CHF. However, most studies with this agent have been in small numbers of patients with anecdotal findings. Larger studies are warranted to pinpoint the efficacy and adverse effects of this agent. It is primarily used to reduce the acuity of decompensated CHF on admission to hospital.Endothelin receptor antagonists show promise in the management of acute CHF, but continue to be investigational. Long-term data on their efficacy and safety are limited. None of the endothelin receptor antagonists are FDA approved for use in patients with CHF.     

阿替洛尔对充血性心力衰竭患者的疗效观察

目的 :观察阿替洛尔治疗充血性心力衰竭 (CHF)症状改善程度。方法 :将 5 6例CHF患者随机分为阿替洛尔组及常规治疗组 ,观察治疗前后患者左室射血分数、左室舒张末期容积、呼吸困难及运动耐量改善情况。结果 :阿替洛尔组明显增加左室射血分数 ,降低左室舒张末期容积 ,缓解呼吸困难 ,提高运动耐量 ,同常规治疗组相比有显著差异 (P <0 0 5 )。结论 :阿替洛尔对轻中度、甚至重度CHF患者均有明显的治疗结果。     

Beta-blocker therapy of heart failure: an update

The beneficial effects of beta-blocker therapy in patients with heart failure have been consistently shown by multi-center randomised trials. These agents are effective and also relatively well tolerated in the elderly and in patients with diabetes and advanced heart failure--traditionally considered as relative contraindications to their administration. However, the use of beta-blockers in clinical practice remains low. The difficulties in their initiation and up-titration may be overcome by patient and physician education, as well as by their initiation during hospitalisation and/or the involvement of non-physician providers (i.e., a nurse facilitator). Forthcoming advances in the pharmacokinetic and pharmacodynamic characteristics of some beta-blockers, and testing of novel methods for patient and drug selection may be based on genetic testing, and may allow further improvement of beta-blocker therapy in the next future.     

阿替洛尔对充血性心力衰竭患者的疗效观察

目的:观察阿替洛尔治疗充血性心力衰竭(CHF)症状改善程度.方法:将56例CHF患者随机分为阿替洛尔组及常规治疗组,观察治疗前后患者左室射血分数、左室舒张末期容积、呼吸困难及运动耐量改善情况.结果:阿替洛尔组明显增加左室射血分数,降低左室舒张末期容积,缓解呼吸困难,提高运动耐量,同常规治疗组相比有显著差异(P＜0.05).结论:阿替洛尔对轻中度、甚至重度CHF患者均有明显的治疗结果.     

急性心力衰竭药物治疗的研究近况

急性心力衰竭(AHF)是以心输出量降低、组织灌注减少及肺毛细血管楔压升高为特征的临床综合征.利尿剂为体液容量超载心力衰竭患者的首选治疗药物.AHF不伴低血压患者的一线治疗药物为血管扩张剂.上述干预未奏效的组织低灌注者,可按病情选用正性肌力药物治疗.本文简要介绍AHF的药物治疗及心脏肌球蛋白激活剂、istaroxine、利钠肽、腺苷受体拮抗剂以及血管加压素受体拮抗剂等新药的研究进展.     

心力衰竭患者高凝状态与抗栓治疗

心力衰竭(HF)患者脑卒中、肺栓塞及外周静脉血栓等血栓栓塞事件的发生率明显高于非HF患者。其抗栓治疗一直存在争议,主要权衡抗栓(抗凝和抗血小板)治疗、血栓栓塞风险降低的获益和出血的风险。多项研究已证实,有心房颤动或血栓栓塞史的HF患者需要进行常规抗凝治疗,但窦性心律HF患者是否需要进行预防性抗栓治疗目前还没有达成共识。     

Neuregulin1 as novel therapy for heart failure

Neuregulin1 proteins (NRG1s) are epidermal growth factor (EGF) family members which are ligands for the ErbB receptor tyrosine kinases (RTKs). A decade of research has revealed that the NRG1-ErbB signaling is essential for the cardiac development and pivotal for maintaining the physiological function of the adult heart. The first evidence regarding the protective effect of the ErbB2 signaling in the adult heart came from clinical trials in breast cancer patients using Trastuzumab, a monoclonal antibody that blocks the ErbB2 receptor. The incidence of the New York Heart Association (NYHA) class III/IV heart failure increased five-fold in patients treated concurrently with chemotherapy drug doxorubicin and Trastuzumab compared to those treated with doxorubicin alone. Subsequent studies further show that stimulation of the ErbB2 signaling by NRG1s improves cardiomyocyte survival, growth and proliferation, maintains cardiac myofibril structure, counterbalances excessive β-adrenergic signaling and promotes angiogenesis in the heart. Injections of recombinant NRG1s improve cardiac function in animal models with myocardial infarction, doxorubicin, viral infection or pacing-induced heart failure. Recent clinical trials show that NRG1s are effective for improving the cardiac function in heart failure patients. These results suggest that NRG1s may become a new drug for the treatment of heart failure. NRG1s stimulate RTKs. This is different from Beta-blockers, ACE inhibitors (Angiotensin-Converting Enzyme) and Angiotensin II receptor blockers which inhibit the excessive activation of G-protein coupled receptors (GPCRs). A clear understanding of how NRG1-ErbB signaling regulates cardiac function is essential for successful use of NRG1s for heart failure. Here, we review the current knowledge of the NRG1-ErbB signaling in the heart and discuss the potential use of NRG1s as novel therapy for heart failure.     

Natriuretic peptides in therapy for decompensated heart failure

Congestive heart failure (CHF) is the most frequent cause of hospitalization for patients >65 years of age and continues to be a major public health burden among the ageing population. Unlike therapy for chronic CHF, there has been only modest progress in medical treatment for acutely decompensated CHF over the past several decades. Moreover, current treatment—consisting generally of diuretic, inotropic, and vasodilatory agents–is associated with many limitations in clinical practice. Natriuretic peptides provide a promising mechanism of action in the pathophysiologic background for CHF treatment based on their vasodilatory and diuretic properties and effective inhibition of the renin–angiotensin–aldosterone system, which is activated early in the course of CHF. Nesiritide (Natrecor® or Noratak®) is a recombinant natriuretic peptide that has the same 32 amino-acid sequence as human B-type natriuretic peptide. Nesiritide has been shown to improve dyspnea and hemodynamic parameters in patients with decompensated heart failure. Ularitide is a synthetic form of urodilatin, a natriuretic peptide hormone secreted by the kidney. Recent clinical studies suggest that ularitide may play a role in managing decompensated heart failure. This review provides an update on natriuretic peptides and their therapeutic potential in advanced CHF.     

Growth hormone and testosterone in heart failure therapy

Importance of the field: Heart failure is a progressive disease affecting millions of people worldwide. The disease carries a significantly high morbidity and mortality risk. There are multiple pharmaceutical options to decrease this risk and prolong survival; however, despite optimization of medical management, several patients still await heart transplant, the only definitive cure for heart failure. To slow the progression of disease preventing need for transplantation, improve clinical symptoms, and improve heart failure outcomes, there is a persistent need to discover new therapeutic strategies. Of interest, low growth hormone and testosterone levels have been associated with a worsening degree of heart failure. Many studies have begun to show a clinical improvement in heart failure symptoms when these levels are corrected with hormonal therapy. These findings, although mixed, are promising and indicate that both testosterone and growth hormone therapy should be considered as adjunctive therapy in advanced heart failure patients.

Areas covered in this review: This review discusses the physiology of both of these natural hormones, their therapeutic effects in heart failure and data from the published literature on studies using growth hormone or testosterone in patients with chronic heart failure. An extensive search of PubMed was conducted for topics on heart failure, growth hormone, insulin-like growth factor, testosterone, their physiology and pathophysiology, and trials in which they have been used as therapeutic interventions between 1989 and 2009.

What the reader will gain: The reader will gain an understanding of the intricate balance of both of these hormones in the disease state of heart failure. In addition, the trials conducted using these hormones in pharmacotherapy for heart failure are discussed along with proposed theories for interstudy variability.

Take home message: Testosterone deficiency and growth hormone resistance are positively associated with a poor state of heart failure. Treatment of deficiency improves outcomes in heart failure; however, there is a significant paucity of data with regard to testosterone and heart failure as well as a significant amount of study variability with growth hormone and heart failure.     

中药辅助治疗冠心病慢性心力衰竭41例

目的观察丹参酮ⅡA磺酸钠针（诺新康）辅助治疗心力衰竭的临床疗效及安全性。方法将51例患者随机分2组,治疗组41例,静脉滴注丹参酮ⅡA磺酸钠针,联合利尿剂、ACEI、地高辛、β-受体阻滞剂;对照组10例,与治疗组所用西药治疗方法相同。结果2组临床疗效比较,治疗组疗效优于对照组（P〈0．01）。结论在患者常规西药治疗基础上,丹参酮ⅡA磺酸钠针可进一步改善患者的临床症状、心功能及生活质量,而且安全有效,未出现不良反应。