Levosimendan: a parenteral calcium-sensitising drug with additional vasodilatory properties

Levosimendan (Simdax) is a new inodilator developed specifically for the treatment of decompensated heart failure. Its inotropic mechanism is based on calcium sensitisation of myofilaments and its vasodilator actions are related to the opening of ATP-dependent K-channels in the vasculature. Since the inotropic action of levosimendan does not require an increase in cytosolic free calcium, it is less arrhythmogenic than the conventional parenteral beta-agonist inotropes or PDE III inhibiting drugs. Due to the calcium-dependent binding of the drug to troponin C, levosimendan, unlike some other calcium-sensitising drugs, does not prolong diastolic relaxation of the myocytes but acts in synergy with the intramyocellular calcium levels. Furthermore, due to the anti-ischaemic effects of the K-channel opening in myocytes, levosimendan can be used during myocardial ischaemia. In clinical trials, levosimendan has dose-dependently increased cardiac output and decreased pulmonary capillary wedge pressure in patients with heart failure. On the other hand, it also increases heart rate and decreases blood pressure in these patients. In major clinical trials, where patients with decompensated heart failure have been treated with levosimendan, a reduction of overall mortality in comparison to placebo or dobutamine has been seen. This interesting finding should be verified in prospective outcome trials. In any case, the safety of levosimendan during myocardial ischaemia makes this drug valuable in the short-term treatment of decompensated heart failure.     

Levosimendan for the treatment of acute heart failure syndromes

Levosimendan is a novel calcium-sensitising agent that has been shown to have beneficial inotropic, metabolic and vasodilatory effects in the treatment of acute and advanced chronic heart failure. Levosimendan binds to troponin-C in cardiomyocytes and, thereby, improves cardiac contractility without disturbing the metabolic status of the heart and increasing myocardial oxygen demand or provoking fatal cardiac arrhythmias. Levosimendan also opens ATP-sensitive potassium channels, causing peripheral arterial and venous dilatation, and increasing coronary flow reserve. When it is given as a short-term therapy, levosimendan enhances cardiac output, reduces systemic vascular resistance and lowers pulmonary capillary wedge pressure. Clinical outcomes were significantly reduced in decompensated or postmyocardial infarction heart failure patients who received levosimendan, compared with those on dobutamine or placebo. Recent investigations focusing on the anti-inflammatory and antiapoptotic actions of levosimendan in the failing heart indicate that improvement of cardiac contractile performance is closely related with the drug-induced reduction of circulating pro-inflammatory cytokines and apoptosis inducers. The most common adverse effects of levosimendan treatment are hypotension and headache. Overall, levosimendan represents an effective and safe option for the treatment of decompensated heart failure patients.     

左西孟旦与多巴酚丁胺对急性失代偿心力衰竭 的有效性和安全性分析

目的：探讨静脉用左西孟旦与多巴酚丁胺对急性失代偿心力衰竭患者有效性和安全性。 方法：选取2012年11月至2013年11月我院心血管内科收治的98例心力衰竭患者作为研究对象,按照治疗方法的不同将其分为对照组和治疗组,对照组患者给予单用多巴酚丁胺治疗,治疗组患者给予左西孟旦联合多巴酚丁胺进行治疗,并比较两组患者临床效果、脑钠肽变化、心脏功能指标以及不良反应等情况。 结果：经过有效治疗后,治疗组患者显效24例,有效21例,无效4例,总有效率为91.8%,对照组患者显效17例,有效17例,无效15例,总有效率为69.4%,两组患者治疗有效率比较差异具有统计学意义（P＜0.05）;与对照组患者比较,治疗组患者BNP水平显著降低,LVEF和SV值显著升高,两组比较差异具有统计学意义（P＜0.05）;同时治疗组患者不良反应发生率与对照组比较差异不明显（P＞0.05）。 结论：左西孟旦联合多巴酚丁胺在治疗急性失代偿性心力衰竭方面临床效果明显,且能明显改善患者心脏功能。     

Haemodynamic interactions of a new calcium sensitizing drug levosimendan and captopril

Objective: Levosimendan in a new inodilator drug that sensitises troponin C in heart muscle cells to calcium, thus improving contractility. In previous studies, a single 2 mg intravenous dose of levosimendan increased cardiac output (CO) in healthy volunteers by about 40% and decreased pulmonary capillary wedge pressure in heart failure patients by 40–50%.The aim of the present, double-blind study was to evaluate the safety of concomitant use of levosimendan and an ACE-inhibiting drug. Methods: The haemodynamic effects of levosimendan, given with or without captopril, were evaluated by using 2-dimensional echocardiography, repeated blood pressure measurements and by ambulatory ECG recordings. Twenty-four male patients with stable NYHA II-III heart failure (EF<40%) after a previous myocardial infarct were given, in randomised order, a single IV infusion of levosimendan or placebo. The infusions were repeated after 2 weeks treatment with upto 50 mg b.i.d. of captopril. Twelve patients received levosimendan 1 mg and twelve received 2 mg. Results: Mean CO was increased from 6.0 to 6.81·min^–1 in patients receiving 1 mg levosimendan compared to placebo, but only from 6.3 to 6.51·min^–1 in patients receiving 2 mg. The increase in CO was statistically significant when all levosimendan patients were compared to placebo. Heart rate did not change after either dose. Mean stroke volume increased significantly after 1 mg but not after 2 mg of levosimendan. The addition of captopril did not change the effects of levosimendan. No additional decrease in systolic or diastolic blood pressure was observed when levosimendan and captopril were given concomitantly. Conclusion: It seems that concomitant treatment with captopril does not change the haemodynamic effects of levosimendan. No adverse haemodynamic interactions were seen.     

Treatment of congestive heart failure

Abstract: The past decade has improved our understanding of the pathophysiological mechanisms underlying the congestive heart failure syndrome. The same decade has seen a considerable expansion in modes of therapy for this syndrome. A review of the present forms of treatment is given.     

The use of levosimendan in comparison and in combination with dobutamine in the treatment of decompensated heart failure

Levosimendan is a new calcium sensitizer with inotropic and vasodilatory actions mediated by the sensitization of contractile proteins to calcium, opening of potassium channels and inhibition of phosphodiesterase-3. Its alternative mechanisms of action to those of other traditional inotropes provide a new approach in the management of decompensated heart failure. In contrast to dobutamine, levosimendan does not increase myocardial oxygen demand and, therefore, it is thought to have a lower potential to induce increases in myocardial ischemia and cardiac arrhythmias. The commonly used inotropic agent dobutamine increases myocardial contractility at the expense of increased myocardial oxygen consumption and, therefore, it can result in poor outcomes. Although dobutamine may also have favorable hemodynamic and symptomatic effects, levosimendan has been shown to be superior to dobutamine in increasing cardiac output and decreasing pulmonary capillary wedge pressure in patients with decompensated heart failure. In the presence of concomitant β-blocker therapy, these favorable effects were present or even more pronounced during treatment with levosimendan, but not dobutamine. However, the mortality benefit of levosimendan observed in earlier trials has not been confirmed in recent, larger clinical trials. A distinct advantage of levosimendan over dobutamine is its prolonged hemodynamic effects, which last for up to 7 – 9 days. There are more data on the safety of levosimendan in ischemic patients than with any other inotropic drug and, therefore, levosimendan seems to be safe and effective in patients with ischemic heart disease when used at the recommended doses. Despite advances in heart failure therapy, many patients experience clinical deterioration, or do not respond to a single inotropic drug. Increasing evidence suggests the use of levosimendan in combination with dobutamine in patients with decompensated heart failure that is refractory to dobutamine alone.     

Author's reply: Managing the combination of non-alcoholic fatty liver disease and metabolic syndrome

In heart failure, positive inotropes that increase the heart’s energy requirements (digoxin, phosphodiesterase inhibitors and β-adrenoceptor agonists) either have no effect or increase mortality. Calcium sensitisers, including levosimendan, have minimal effects on myocardial energy requirements. In deteriorating severe heart failure, intravenous levosimendan and dobutamine (a β-adrenoceptor agonist) were compared and haemodynamic improvement (≥ 30% increase in cardiac output and ≥ 25% decrease in pulmonary-capillary wedge pressure) was more common with levosimendan than dobutamine. The effectiveness of dobutamine in some patients was probably limited by concurrent treatment with β-blockers. In the patients who were not receiving a β-blocker, 19 of 70 patients in the levosimendan group and 11 of 71 patients in the dobutamine group had haemodynamic improvement. Levosimendan may be more appropriate than dobutamine for the treatment of decompensated heart failure, especially given the growing use of β-blockers that may limit the effectiveness of dobutamine.     

左西孟旦致心力衰竭患者不良反应原因分析及预防对策

目的：分析左西孟旦治疗心力衰竭时诱发不良反应的原因和特点,为临床安全用药提供参考。方法：对2017年1月至2019年1月临床应用左西孟旦治疗心力衰竭患者的107份病例进行回顾性统计分析。结果：107份病例中9例发生左西孟旦相关不良反应,不良反应发生率8.41%,其中男3例,女6例,年龄48~91岁,累及系统-器官主要为心血管系统和中枢神经系统。结论：应用左西孟旦治疗心力衰竭时可出现严重程度不同的药物不良反应,应根据患者的自身状况做到个体化用药,并加强用药期间的心电监护,保障患者用药安全。     

Population pharmacokinetics of levosimendan in patients with congestive heart failure

AIMS: The aim of this study was to characterize the population pharmacokinetics of levosimendan in patients with heart failure (NYHA grades III and IV) and its relationship to demographic factors, disease severity and concomitant use of digoxin and beta-blocking agents. METHODS: Data from two efficacy studies with levosimendan administered by intravenous infusion were combined (190 patients in total). The data were analysed using a nonlinear mixed-effects modelling approach as implemented in the NONMEM program. The model development was done in three sequential steps. First the best structural model was determined (e.g. a one-, two- or three-compartment pharmacokinetic model). This was followed by the identification and incorporation of important covariates into the model. Lastly the stochastic part of the model was refined. RESULTS: A two-compartment model best described levosimendan pharmacokinetics. Clearance and the central volume of distribution were found to increase linearly with bodyweight. No other covariates, including concomitant use of digoxin and beta-blocking agents, influenced the pharmacokinetics. In the final model, a 76-kg patient was estimated to have a clearance +/- s.e. of 13.3 +/- 0.4 l h-1 and a central volume of distribution of 16.8 +/- 0.79 l. The interindividual variability was estimated to be 39% and 60% for clearance and central volume of distribution, respectively. Weight changed clearance by 1.5% [95% confidence interval (CI) 0.9%, 2.1%] and the central volume of distribution by 0.9% (95% CI 0.5%, 1.3%) per kg. CONCLUSIONS: The population pharmacokinetics parameters of levosimendan in this patient group were comparable to those obtained by traditional methods in healthy volunteers and patients with mild heart failure. Bodyweight influenced the clearance and the central volume of distribution, which in practice is accounted for by weight adjusting doses. None of the other covariates, including digoxin and beta-blocking agents, significantly influenced the pharmacokinetics of levosimendan.     

新型抗心力衰竭药物钙离子敏感药

钙离子敏感药是一种新型的治疗心力衰竭的药物。它通过使钙离子诱导的心肌收缩所必需的心肌纤维蛋白的空间构型得以稳定 ,从而使心肌收缩力增加。本文对钙离子敏感药的作用机制、对心血管系统的影响、在心力衰竭治疗中的前景等作一综述     

Zebrafish as a New Model for Phenotype-based Screening of Positive Inotropic Agents

The zebrafish-based assay is a widely used animal model system for cardiovascular research. In this study, we investigated the cardiac defects caused by terfenadine and tested the pharmacological response of digoxin to zebrafish with cardiac defects. The study suggested that zebrafish could be a suitable model for phenotype-based screening and evaluation of positive inotropic agents. This phenotype-based heart failure zebrafish model system was then utilized in in-house library screen. Some positive inotropic compound was discovered, which could attenuate the cardiac defects by increasing the flow velocity of caudal artery blood.     

Dofetilide: a class III anti-arrhythmic drug for the treatment of atrial fibrillation

Dofetilide is a class III anti-arrhythmic drug that has been approved for the treatment of atrial fibrillation. Two clinical studies, which enrolled 996 patients, demonstrated pharmacological conversion to sinus rhythm to occur in 30% of patients. Following pharmacological or electrical conversion, median time to relapse exceeded one year. Two large clinical studies that enrolled 3028 patients have been performed in high-risk patients with severe heart failure and large myocardial infarctions. The outcomes of these studies were neutral with respect to survival and demonstrated the safety of dofetilide. After pharmacological or electrical conversion of atrial fibrillation to sinus rhythm in these studies, the probability of remaining in sinus rhythm during the following year was 75%. Dofetilide has a single significant side effect: risk of developing torsade de pointes ventricular tachycardia. Therefore, dosage must be carefully adjusted to the length of QTc interval, calculated creatinine clearance and the presence of heart failure or recent infarction. In addition, treatment must be initiated in hospital with three days of continuous telemetry. Dofetilide can be co-administered with digoxin and β-blockers. Other anti-arrhythmic drugs, as well as drugs that interfere with the renal elimination or the metabolism of dofetilide, must be avoided. Dofetilide is an option when persistent atrial fibrillation is a clinical problem. In the setting of severe heart failure and large myocardial infarctions, only amiodarone and dofetilide have proven safety and dofetilide is a strong candidate for first choice treatment when the aim is to achieve sinus rhythm.     

Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1994: NEW DRUGS IN THE TREATMENT OF HEART FAILURE

1. Current therapy of heart failure relies on diuretics, positive inotropic compounds and vasodilators. The short-term haemo-dynamic benefits, especially of the cAMP generators, may be compromised by long-term limitations leading to an increased mortality. In contrast, some vasodilators, especially angiotensin converting enzyme inhibitors, improve survival even in severe heart failure. 2. Modulation of Na⁺- or K⁺-channels and calcium sensitization are positive inotropic mechanisms whose promise in treatment of heart failure needs to be fully explored. 3. The introduction of vasodilator therapy has been a significant advance. Newer compounds act to inhibit the endogenous vasoconstrictors angiotensin II and endothelin, or to potentiate the endogenous vasodilators atrial natriuretic factor and nitric oxide. The full potential of these compounds is yet to be realised.     

Levosimendan improves calcium sensitivity of diaphragm muscle fibres from a rat model of heart failure

BACKGROUND AND PURPOSE

Diaphragm muscle weakness occurs in patients with heart failure (HF) and is associated with exercise intolerance and increased mortality. Reduced sensitivity of diaphragm fibres to calcium contributes to diaphragm weakness in HF. Here we have investigated the ability of the calcium sensitizer levosimendan to restore the reduced calcium sensitivity of diaphragm fibres from rats with HF.

EXPERIMENTAL APPROACH

Coronary artery ligation in rats was used as an animal model for HF. Sham-operated rats served as controls. Fifteen weeks after induction of HF or sham operations animals were killed and muscle fibres were isolated from the diaphragm. Diaphragm fibres were skinned and activated with solutions containing incremental calcium concentrations and 10 µM levosimendan or vehicle (0.02% DMSO). Developed force was measured at each calcium concentration, and force–calcium concentration relationships were plotted.

KEY RESULTS

Calcium sensitivity of force generation was reduced in diaphragm muscle fibres from HF rats, compared with fibres from control rats (P < 0.01). Maximal force generation was ∼25% lower in HF diaphragm fibres than in control fibres (P < 0.05). Levosimendan significantly increased calcium sensitivity of force generation in diaphragm fibres from HF and control rats, without affecting maximal force generation.

CONCLUSIONS AND IMPLICATIONS

Levosimendan enhanced the force generating capacity of diaphragm fibres from HF rats by increasing the sensitivity of force generation to calcium concentration. These results provide strong support for testing the effect of calcium sensitizers on diaphragm muscle weakness in patients with HF.     

Cardiovascular risks of COX inhibition: current perspectives

Background: NSAIDs are among the most commonly used pharmacotherapeutic agents worldwide. As the long-term use of these drugs is associated with serious gastrointestinal side effects, a new subgroup of COX-2 selective NSAIDs was developed. It was thought that the therapeutic strategy underlying the development of these newer compounds would enable them to provide the same analgesic and anti-inflammatory benefits as those of their traditional counterparts but perhaps offer a much safer gastrointestinal profile. Much scientific data has accumulated over the last few years, however, raising concerns regarding the increased cardiovascular complications associated with the use of COX-2 selective NSAIDs, and perhaps of the traditional NSAIDs as well. Objective: To review current and emerging evidence related to the cardiovascular effects of COX inhibitors and examine the clinical implications. Method: We studied data from basic clinical research, non-randomized analyses, and randomized trials of COX inhibitors that investigated their cardiovascular effects. Conclusion: Both COX-2 selective and traditional NSAIDs are associated with a moderately increased risk of cardiovascular events.     

罗格列酮和吡格列酮对65岁以上糖尿病患者心血管事件风险的meta分析

目的:系统评价罗格列酮和吡格列酮对65岁以上糖尿病患者心血管事件的风险。方法:以"罗格列酮","吡格列酮","心血管风险","心血管事件","老年患者","65岁以上",以及"队列研究"为关键词,分别检索Cochrane图书馆(1996—2010年)、PubMed(1966—2010年)、荷兰医学文摘(1966—2010年)、中国期刊全文数据库(1979—2010年)、中国生物医学文献数据库(1978—2010年)和中国科技期刊数据库(1989—2010年)。收集罗格列酮和吡格列酮治疗65岁以上糖尿病患者所致心血管事件风险比较的回顾性队列研究的文献。根据纳入标准对文献进行筛选和评估,采用RevMan 5.0软件对数据进行meta分析,计算65岁以上糖尿病患者应用罗格列酮或吡格列酮后心肌梗死、心力衰竭及全因死亡的相对危险系数(RR)和95%可信区间(CI)。结果:共获得相关文献74篇,经筛选最终纳入2008—2010年3项回顾性队列研究,共有患者295 668例,其中应用罗格列酮患者104 479例,应用吡格列酮患者191 189例。meta分析结果显示,与应用吡格列酮患者相比,应用罗格列酮患者心肌梗死、心力衰竭和全因死亡的发生率均高,其RR(95%CI)分别为1.05(0.98～1.13,P=0.17),1.22(1.05～1.40,P=0.007),1.14(1.08～1.21,P<0.000 01)。结论:老年2型糖尿病患者应用罗格列酮治疗,发生心力衰竭及全因死亡的风险较吡格列酮高。     

左西孟旦对右心室衰竭大鼠右心功能、心肌能量代谢和心肌代谢的影响

目的：探究左西孟旦对右心室（RV）肥厚和衰竭者右心功能,心肌耗氧量,心肌能量代谢（MEE）和心肌代谢的影响。方法：右心室衰竭（right ventricular heart-failure,RVF）大鼠肥大和衰竭是由肺部躯干条带诱导的。将大鼠随机（数字表法）分配到安慰剂组（n=16）或左西孟旦组（3 mg·kg^-1·d^-1）（n=13）进行7周干预。通过超声心动图,¹¹C-乙酸正电子发射断层扫描（PET）,¹⁸F-FDG PET和有创压力测量来评估RV MEE和RV代谢。结果：左西孟旦在不影响RV心肌耗氧量的情况下,通过增加右室外径[（0.62±0.06） vs.（0.30±0.03） mm,P<0.001],可改善RV MEE[（26±3）% vs. （14±1）%,P<0.01]。RV MEE的改善与RV心肌葡萄糖摄取的变化无关[（1.3±0.1） vs. （1.0±0.1） μmol·g^-1·min^-1,P=0.44]。在大鼠的肥大和衰竭RV中,左西孟旦改善RV功能而不增加心肌耗氧量,从而改善MEE。结论：左西孟旦对右心衰竭具有潜在的治疗价值,可扩展左西孟旦的临床应用范围。     

Current concepts and animal models of sudden cardiac death for drug development

Sudden cardiac death (SCD) or sudden coronary death, occurring in patients with unstable angina (angina at rest), myocardial ischemia with or without myocardial infarction (MI), and congestive heart failure (CHF), emerges as one of the most important challenges in cardiovascular medicine at present. Of the 1.5 million cases of myocardial infarction that occur each year in the U.S., about 540,000 patients will die and more than 300,000 of these will die before they reach a hospital, mostly due to ventricular fibrillation (VF) and/or SCD. About 4.8 million people alive in the U.S. have a history of myocardial infarction, angina pectoris, or both and are prime candidates for SCD. About 3 million people in the U.S. have congestive heart failure (CHF) and about 400,000 new cases are reported each year. One year mortality due to CHF is 33–58% and about 45% of the deaths are sudden. These patients were not those who had deleterious hemodynamic parameters whose demise could be predicted; they were those that died suddenly and unexpectedly of VF. Current pharmacological intervention in patients with a documented myocardial infarction with marketed antiarrhythmic agents has not reduced the overall mortality of SCD significantly. This suggests that an efficacious antiarrhythmic/antifibrillatory agent for the prevention of SCD does not exist at present and that there is an urgent need for such an agent.     

Pharmacokinetic drug evaluation of bucindolol for the treatment of atrial fibrillation in heart failure patients

Introduction: Atrial fibrillation (AF) and heart failure (HF) often coexist. When AF and HF are both present, they are associated with negative outcomes, increased hospitalizations and mortality. As β-blockade is effective inF and may be useful in presence of AF, bucindolol, a non-selective β-blocker with α-1 vasodilatory effect, may be used.

Area covered: This review evaluates the efficacy and safety of bucindolol in HF patients with AF. The largest amount of data comes from BEST trial which evaluated the efficacy of bucindolol in HF patients. Since bucindolol’s effects are genetically modulated by β1 and α2c-adrenergic receptor polymorphisms BEST genetic substudy arose.

Expert opinion: In the BEST Trial, bucindolol demonstrated efficacy in HF patients showing a 74% reduction in new-onset atrial fibrillation events particularly in β1 389 Arg/Arg homozygous. GENETIC-AF study was designed to determine whether bucindolol therapy is superior to metoprolol in preventing recurrent AF in a genetically targeted population of HF patients. Furthermore, this drug is safe, but presents the same side effects as all β-blockers and has showed no clear benefits in African-Americans and in class IV NYHA patients. Further studies are needed to confirm and validate the role of bucindolol and its economic implications.