新型正性肌力药左西孟旦的作用机制及临床应用

左西孟旦是一种新型正性肌力药--钙增敏剂,可通过钙敏作用增强心肌收缩力,激活K+通道使血管扩张,且并不增加心肌氧耗和心率,因而具有改善心功能和心肌保护等作用.可应用于治疗急性失代偿心力衰竭、心肌缺血后心脏收缩力异常、心肌顿抑以及用于心脏手术期间循环的调控等方面.     

Levosimendan, a new positive inotropic drug, decreases myocardial infarct size via activation of K(ATP) channels

We tested the hypothesis that levosimendan, a new positive inotropic drug that activates adenosine triphosphate-regulated potassium (K(ATP)) channels in vitro, decreases myocardial infarct size in vivo. Myocardial infarct size was measured after a 60-min left anterior descending coronary artery occlusion and 3 h of reperfusion in dogs receiving either IV vehicle (0.9% saline) or levosimendan (24 microg/kg bolus followed by an infusion of 0.4 microg x kg(-1) x min(-1)) in the presence or absence of glyburide (a K(ATP) channel antagonist) pretreatment (100 microg/kg). Levosimendan increased (P < 0.05) the maximal rate of increase of left ventricular pressure and decreased myocardial infarct size from 24%+/-2% (control experiments) to 11%+/-2% of the left ventricular area at risk for infarction. Glyburide did not alter the hemodynamic effects of levosimendan but blocked levosimendan-induced reductions of infarct size. Subendocardial collateral blood flow was similar among groups. However, levosimendan increased subepicardial and midmyocardial collateral perfusion in the absence, but not in the presence, of glyburide. Levosimendan exerts cardioprotective effects via activation of K(ATP) channels at a dose that simultaneously enhances myocardial contractility. IMPLICATIONS: Levosimendan may be advantageous in patients requiring inotropic support who are also at risk of myocardial ischemia. Activation of adenosine triphosphate-regulated potassium channels during infusion of levosimendan may produce cardioprotective effects while simultaneously enhancing ventricular contractile function.     

Levosimendan, a new inotropic and vasodilator agent

Several clinical studies suggest substantial limitations of currently available positive inotropic substances, including beta1-adrenoceptor agonists and phosphodiesterase III inhibitors in the short- and long-term treatment of heart failure. The reasons for these detrimental effects are related to the mechanism of action of these drugs, including increases in intracellular Ca2+ with subsequent increases in myocardial oxygen demand and arrhythmogenesis. Levosimendan, a myofilament Ca2+ sensitizer with inotropic effects, increases myocardial performance without substantial changes in oxygen consumption and with neutral effects on heart rhythm. In addition, levosimendan has vasodilatory effects that are achieved by stimulation of adenosine triphosphate-dependent potassium channels. This action may be of specific interest in the setting of myocardial ischemia. To date, levosimendan is approved in 31 countries worldwide, and more patients with heart failure have participated in randomized controlled trials with levosimendan than with any other intravenous inotropic agent.     

Is levosimendan an inoprotective drug in patients with acute coronary syndrome undergoing surgical revascularization?

Levosimendan, is a new calcium sensitiser with 2 major effects. First, levosimendan acts as a positive inotropic agent by binding calcium dependently to cardiac troponin C. Second, levosimendan activates adenosine triphosphate-regulated potassium (K (ATP)) channels. Thus it has vasodilatory properties and cardioprotective effects at a dose enhancing myocardial contractility. These unique properties of levosimendan might be of great advantage in patients with myocardial ischemia simultaneously requiring inotropic support. The concept of perioperative inoprotection is presented in 6 patients with acute ischemia undergoing emergent cardiac surgery.     

Isoflurane and coronary heart disease

Early studies indicated that isoflurane caused coronary steal and should therefore be avoided in patients with coronary heart disease. Subsequently, more detailed trials have disputed this and have shown that as long as coronary perfusion pressure is maintained, isoflurane does not cause coronary steal or myocardial ischaemia. There is now growing evidence, initially in animal work but more recently in human studies, that isoflurane has myocardial protective properties, limiting infarct size and improving functional recovery from myocardial ischaemia. The mechanism for this protection mimics ischaemic preconditioning and involves the opening of adenosine triphosphate-dependent potassium channels. The few studies comparing the myocardial protection offered by individual anaesthetic agents indicate that isoflurane represents the anaesthetic agent of choice for patients with coronary heart disease.     

Rolle von Levosimendan in der intensivmedizinischen Behandlung des myokardialen Pumpversagens

Levosimendan is a calcium sensitizer that is currently in the focus of intensive care medicine because it may be superior to standard inotropic agents in the treatment of acute myocardial insufficiency. The effects of levosimendan mainly depend on three predominant mechanisms: 1) positive inotropic effect by increasing the sensitivity of cardiac myofilaments to calcium ions, 2) vasodilatory effect by stimulation of adenosine triphosphate-sensitive potassium channels and 3) inhibition of phosphodiesterase-III. In a large number of experimental and clinical studies further possible indications for levosimendan have been described, e.g. cardioprotection during ischemia, cardiogenic shock, septic myocardial insufficiency and pulmonary hypertension. This review article critically summarizes the current scientific and clinical knowledge about levosimendan, its pharmacologic characteristics, mechanisms of action as well as indications and potential risks.     

Levosimendan compared with dobutamine in low output patients

There are 2 studies which have investigated the hemodynamic efficacy of levosimendan compared to dobutamine in congestive heart failure patients. The first is a dose finding comparative 24-h infusion trial which included 95 NYHA II-III patients to different doses of levosimendan and 20 patients to dobutamine administered as a continuous, open-label infusion of 6 microg/kg/min. Efficacy and safety of levosimendan in severe low-output heart failure a randomized, double-blind comparison to dobutamine study compared the short- and long-term efficacy and safety of a single 24-hour infusion of levosimendan (n=103) with dobutamine (n=100) in hospitalised patients in acute heart failure. This double-blind, parallel-group, randomised trial showed that, irrespective of the aetiology of the heart failure, levosimendan produced significantly greater improvement in major determinants of cardiac function in heart failure patients compared to dobutamine. Levosimendan produced significantly greater haemodynamic improvements than dobutamine by significantly reduced mortality at 31 days compared with dobutamine; this reduction was maintained at 180 days. Levosimendan significantly increased the number of days alive and out of hospital, compared with dobutamine. It was better tolerated than dobutamine and fewer patients receiving levosimendan experienced arrhythmias and myocardial ischaemia, compared with dobutamine. Levosimendan produced haemodynamic responses that were unaffected by concomitant use of beta blockers.     

Levosimendan: current status and future prospects

PURPOSE OF REVIEW: While patients with acute heart failure typically receive diuretics and vasodilators, contractile dysfunction and peripheral hypoperfusion also leads to a widespread use of inotropic agents despite the lack of evidence for efficacy or safety. Levosimendan, a calcium sensitizer and vasodilator, has been proposed to be superior to standard inotropes. In addition, further possible indications for levosimendan have been described, such as perioperative use, cardioprotection, cardiogenic shock, sepsis, and right ventricular dysfunction. RECENT FINDINGS: The mortality benefit of levosimendan has not been confirmed in two recent trials but the substance improves symptoms, decreases brain natriuretic peptide and is effective during beta-blocker treatment. The use of levosimendan as an add-on therapy in acute heart failure has been encouraged as well as its perioperative use. Levosimendan may also be useful during right ventricular dysfunction and septic shock due to its favorable effects on splanchnic perfusion. SUMMARY: Levosimendan is an established substance in the treatment of acute heart failure in several countries despite disappointing findings concerning a possible survival benefit in two recent clinical trials. Owing to its alternative mechanisms of action as compared with traditional cardiotonic agents, several promising clinical applications have arisen. Available evidence for the use of levosimendan in settings other than decompensated heart failure is currently limited.     

The concept of anaesthetic-induced cardioprotection: mechanisms of action

The mechanisms by which ischaemia reperfusion injury can be influenced have been the subject of extensive research in the last decades. Early restoration of arterial blood flow and surgical measures to improve the ischaemic tolerance of the tissue are the main therapeutic options currently in clinical use. In experimental settings ischaemic preconditioning has been described as protecting the heart, but the practical relevance of interventions by ischaemic preconditioning is strongly limited to these experimental situations. However, ischaemia reperfusion of the heart routinely occurs in a variety of clinical situations, such as during transplantations, coronary artery bypass grafting or vascular surgery. Moreover, ischaemia reperfusion injury occurs without any surgical intervention as a transient myocardial ischaemia during a stressful anaesthetic induction. Besides ischaemic preconditioning, another form of preconditioning was discovered over 10 years ago: the anaesthetic-induced preconditioning. There is increasing evidence that anaesthetic agents can interact with the underlying pathomechanisms of ischaemia reperfusion injury and protect the myocardium by a preconditioning mechanism. Hence, the anaesthetist himself can substantially influence the critical situation of ischaemia reperfusion during the operation by choosing the right anaesthetic. A better understanding of the underlying mechanisms of anaesthetic-induced cardioprotection not only reflects an important increase in scientific knowledge but may also offer the new perspective of using different anaesthetics for targeted intraoperative myocardial protection. There are three time windows when a substance may interact with the ischaemia reperfusion injury process: (1) during ischaemia, (2) after ischaemia (i.e. during reperfusion), and (3) before ischaemia (preconditioning).     

Levosimendan in acute pulmonary embolism

Levosimendan has been used successfully in the treatment of ischaemic cardiac failure and myocardial stunning. There is growing evidence from both human and animal experiments that levosimendan has particularly favourable effects on the right ventricle. We describe a case of life-threatening pulmonary embolus supported by the use of levosimendan.     

An analysis of responses to levosimendan in the pulmonary vascular bed of the cat

Calcium-sensitizing drugs, such as levosimendan, are a novel class of drug therapy for heart failure. We investigated the hypothesis that levosimendan is a pulmonary vasodepressor mediated through inhibition of phosphodiesterase, adenosine triphosphate (ATP)-dependent potassium channels, or both. We investigated responses to the calcium sensitizer levosimendan in the pulmonary vascular bed of the cat under conditions of controlled pulmonary blood flow and constant left atrial pressure when lobar arterial pressure was increased to a high steady level with the thromboxane A(2) analog U-46619. Under increased-tone conditions, levosimendan caused dose-related decreases in lobar arterial pressure without altering systemic arterial and left atrial pressure. Responses to levosimendan were significantly attenuated, although not completely, after the administration of U-37883A, a vascular selective nonsulfonylurea ATP-sensitive K(+)-channel-blocking drug. Responses to levosimendan were not significantly different after the administration of the nitric oxide synthase inhibitor L-N(5)-(1-iminoethyl)-ornithine or the cyclooxygenase inhibitor sodium meclofenamate or when lung ventilation was interrupted. These data show that levosimendan has significant vasodilator activity in the pulmonary vascular bed of the cat. They also suggest that pulmonary vasodilator responses to levosimendan are partially dependent on activation of ATP-sensitive K(+) channels and independent of the synthesis of nitric oxide, activation of cyclooxygenase enzyme, or changes in bronchomotor tone in the pulmonary vascular bed of the cat. IMPLICATIONS: Calcium-sensitizing drugs, such as levosimendan, are a novel class of drug therapy for heart-failure treatment. The lung circulation affects both right- and left-sided heart failure. Levosimendan decreased lobar arterial pressure via a partial K(+)(ATP) (potassium channel sensitive to intracellular adenosine triphosphate levels)-dependent mechanism. These data suggest that, in addition to calcium-sensitizing activity, levosimendan decreases pulmonary resistance, which may also aid in the treatment of heart failure.     

No beneficial effects of levosimendan in acute porcine endotoxaemia

Background: Levosimendan has been proposed as an attractive alternative to adrenergic agents for the treatment of sepsis‐induced heart failure and haemodynamic derangements. Its use in this setting is, however, still not well investigated. The aim of this study was to test the hypothesis that levosimendan is able to attenuate endotoxin‐induced pulmonary hypertension and improve myocardial function in a porcine model. The secondary aims were to investigate its effect on renal and liver function, and the plasma cytokine response. Methods: Endotoxaemia was induced in 18 pigs, randomized to placebo and Levosimendan groups. All pigs were fluid resuscitated and Noradrenalin infusion was given according to a predefined protocol. Systemic haemodynamics and myocardial function were measured using pulmonary artery catheterization and transthoracic echocardiography. Renal and liver function tests and cytokine concentrations were measured in plasma. Results: Levosimendan did not attenuate endotoxin‐induced pulmonary hypertension and did not improve myocardial function. There were no differences in renal or liver function. Increases in arterial lactate and decreases in base excess were observed in the Levosimendan group, as well as significant increases in plasma interleukin (IL)‐6 and IL‐8. Conclusions: Contrary to our hypothesis, levosimendan given in conjunction with a protocolized vasopressor and fluid resuscitation did not improve cardiac, renal or liver function in this model of acute porcine endotoxaemia. Hyperlactataemia, acidosis and increases in plasma pro‐inflammatory cytokines were observed, the mechanisms and implications of which remain unclear.     

Levosimendan cardioprotection reduces the metabolic response during temporary regional coronary occlusion in an open chest pig model

BACKGROUND: Inotropic and myocardial anti-ischemic effects have been demonstrated with levosimendan. The comparison of levosimendan started before an ischemia-reperfusion event as compared with levosimendan started during ischemia has not been studied. METHODS: In anesthetized pigs, a major branch of the circumflex artery was completely occluded for 30 min and then reperfused. The metabolism in the ischemic myocardium and in non-ischemic control myocardium was studied with microdialysis concomitantly with monitoring of global hemodynamics and coronary artery flow in the chosen artery. In the protection group (PRO, n= 6), a levosimendan infusion was started 30 min before coronary artery occlusion, and in the treatment group (TRE, n= 6), a levosimendan infusion was started 10 min after the coronary artery occlusion with a loading dose of 13.3 microg/kg followed by an infusion of 0.67 microg/kg/min. A two-way repeated measures ANOVA completed with Bonferroni's multiple comparison procedure was applied to the data. A P < 0.05 was considered significant. RESULTS: During the ischemic period, the cardiac output and contractility (dp/dt(max)) were higher in the PRO as compared with the TRE and the systemic vascular resistance was lower. The myocardial microdialysate glucose concentration in the ischemic area during ischemia was higher in the PRO as compared with the TRE, and the lactate/pyruvate ratio and the lactate concentration were lower. The differences in the metabolites persisted into the first 10 min of reperfusion. No differences were found for the non-ischemic areas. CONCLUSION: Levosimendan used throughout myocardial ischemia-reperfusion might have a cardioprotective affect on the response to myocardial ischemia as compared with levosimendan started during the ischemia.     

Ischaemic pre-conditioning means an increased adenosine metabolism with decreased glycolytic flow in ischaemic pig myocardium

Background: Ischaemic pre‐conditioning (IP) is a potent protective mechanism for limiting the myocardial damage due to ischaemia. It is not fully known as to how IP protects. The metabolism of adenosine may be an important mechanistic component. We study the role of adenosine turnover together with glycolytic flow in ischaemic myocardium subjected to IP. Methods: An acute myocardial ischaemia pig model was used, with microdialysis sampling of some metabolites (lactate, adenosine, glucose, glycerol, taurine) of ischaemic myocardium. An IP group was compared with a control group before and during a prolonged ischaemia. ¹⁴C‐labelled adenosine and glucose were infused through microdialysis probes, and lactate, ¹⁴C‐labelled lactate, glucose, taurine and glycerol were analysed in the effluent. The glycogen content in myocardial biopsies was determined. Results: The ¹⁴C‐adenosine metabolism was higher as there was a higher production of ¹⁴C‐lactate in IP animals compared with the controls. The glycolytic flow, measured as myocardial lactate formation, was retarded during prolonged ischaemia in IP animals. Myocardial free glucose and glycogen content decreased during the prolonged ischaemia in both groups, with higher free glucose in the IP group. We confirmed the protective effects of IP with lower myocardial concentrations of markers for cellular damage (glycerol). Conclusions: This association between increased adenosine turnover and decreased glycolytic flow during prolonged ischaemia in response to IP can possibly be explained by the competitive effect for the metabolites from both glucose and adenosine metabolism for entering glycolysis. We conclude that this study provides support for an energy‐metabolic explanation for the protective mechanisms of IP.     

Cardioprotection by anesthetics

Perioperative myocardial ischemia is one of the most important complications associated with significant risk of perioperative cardiac event. Ischemic preconditioning is a phenomenon in which single or multiple brief periods of ischemia have been shown to protect the myocardium against a more prolonged ischemic insult, the result of which is a marked reduction in myocardial infarct size, severity of myocardial stunning, or incidence of cardiac arrhythmias. Myocardial stunning is a clinically important ischemia-reperfusion injury described as a prolonged postischemic contractile dysfunction of myocardium salvaged by reperfusion. Experimental data indicate that general anesthetics protect the myocardium against ischemia-reperfusion injury, as shown by decreased infarct size and a more rapid recovery of contractile function on myocardial stunning. This phenomenon is called anesthetic preconditioning. Volatile anesthetics and morphine have a strong preconditioning like effect. The cardioprotective effect of volatile anesthetics has been supported by some clinical studies. Although the cellular mechanism of anesthetic preconditioning is not fully investigated, possible mechanism involves adenosine, adenosine receptors, the ATP-dependent potassium (K(ATP)) channels, protein kinase C, reactive oxygen species and other mediators or substances. Further, mitochondrial K(ATP) channels play the central role in anesthetic preconditioning.     

Adenosine and cardioprotection during ischaemia and reperfusion--an overview

Adenosine is a local hormone, with numerous tissue-specific biological functions. In the myocardium, adenosine is released in small amounts at constant basal rate during normoxia. During ischaemia the production of adenosine increases several fold due to breakdown of adenosine triphosphate (ATP). Increased production of adenosine causes coronary vasodilatation. Thus, adenosine couples myocardial metabolism and flow during ischaemia and is called a homeostatic or "retaliatory metabolite". Furthermore, adenosine has electrophysiological effects in supraventricular tissue, causing a decrease in heart rate. In 1985 it was discovered that adenosine also exerts cardioprotective effects directly on cardiomyocytes. The aim of this review is to give an overview of the role of adenosine as a directly cytoprotective agent during myocardial ischaemia and reperfusion. We will focus on its effects on the myocytes, elicited by stimulation of adenosine receptors in sarcolemma, which triggers intracellular signalling systems. We will also address the new aspect that adenosine can influence regulation of gene expression. There is evidence that the myocardium is capable of endogenous adaptation in response to ischaemia, namely "hibernation" and early and late phases of "preconditioning". Endogenous substances produced during ischaemia probably trigger these responses. We will discuss the role of adenosine in these different settings. Adenosine can be given exogenously through intravasal routes; however, this review will also focus on the effects of endogenously produced adenosine. We will discuss pharmacological ways to increase endogenous levels of adenosine, and the effects of such interventions during ischaemia and reperfusion. Finally, we will review results from studies in humans together with relevant experimental studies, and indicate potential therapeutic implications of adenosine.     

Levosimendan cardioprotection in acutely β-1 adrenergic receptor blocked open chest pigs

Background: Levosimendan and volatile anesthetics have myocardial pre-conditioning effects. β-1 adrenergic receptor antagonists may inhibit the protective effect of volatile anesthetics. No information exists as to whether this also applies to the pre-conditioning effect of levosimendan. We therefore investigated whether levosimendan added to metoprolol would demonstrate a cardioprotective effect.
Methods: Three groups of anesthetized open chest pigs underwent 30 min of myocardial ischemia and 90 min of reperfusion by temporary occlusion of the largest side branch from the circumflex artery or the left anterior descending artery. One group (CTRL) served as a control, in another group (BETA), a metoprolol-loading dose was intravenously injected 30 min before ischemia, and in a third group (BETA+L), a levosimendan infusion was added to metoprolol. Myocardial tissue concentrations of glucose, glycerol, and lactate/pyruvate ratio as the primary end-points were investigated with microdialysis in ischemic and non-ischemic tissues.
Results: At the end of the ischemic period, statistically significant differences were only found between CTRL and BETA+L in the ischemic myocardium, with a lower lactate/pyruvate ratio, lower glycerol, and higher glucose concentrations in BETA+L as compared with CTRL. There were no differences in non-ischemic myocardium. From 10 to 90 min of reperfusion, no more differences were found between groups.
Conclusion: The cardioprotective effect of levosimendan on ischemic metabolism with a reduction in the myocardial lactate/pyruvate ratio, less glycerol accumulation, and better preserved glucose concentration does not seem to be prevented by β-1 adrenergic receptor antagonism with metoprolol.     

Myocardial depression associated with pneumococcal septic shock reversed by levosimendan

Levosimendan is a myocardial calcium sensitiser and potassium-ATP channel opener Levosimendan has been used in critically ill patients in various conditions to support myocardial function as an inotrope, lusitrope and vasodilator. We report the use of levosimendan in a patient with invasive streptococcal septic shock.     

The use of the novel calcium sensitizer levosimendan in critically ill patients

Levosimendan, a novel calcium sensitizer, enhances cardiac contractility by increasing myocyte sensitivity to calcium, and induces vasodilation. In this prospective observational study the haemodynamic effects of levosimendan in postoperative critically ill patients are reported. Twelve patients with the need for inotropic support were studied. One dose of levosimendan (12.5 mg) was administered at a rate of 0.1-0.2 microg kg(-1).min(-1), either alone or in addition to pre-existing inotropic therapy. Haemodynamic measurements were obtained at baseline, and at 3 h, 6 h, 12 h, and 24 h after the start of the levosimendan infusion. Levosimendan significantly increased cardiac output from (mean+/-SD) 4.3+/-0.91.min(-1) to 5.2+/-1.51 min(-1) after 24h (P=0.013), by increases in stroke volume (baseline 47+/-15 ml, after 24h 57+/-25 ml, P=0.05), as heart rate remained unchanged. Systemic vascular resistance decreased from 1239+/-430 dyn.sec.cm(-5) at baseline to 963+/-322 dyn.sec. cm(-5) at 24h (P<0.001). Pre-existing inotropic therapy present in ten patients remained unchanged or was reduced. In postoperative critically ill patients, infusion of levosimendan exerted favourable haemodynamic responses. Levosimendan increased cardiac output by increasing stroke volume, which might be attributed primarily to its inotropic properties. Due to its cyclic adenosine monophosphate independent positive inotropic effects, levosimendan may be of value as adjunctive therapy to other inotropic drugs in critically ill patients.     

Preconditioning the human heart.

The phenomenon of ischaemic preconditioning protects the myocardium by limiting infarct size in animal models of ischaemia and reperfusion. Ischaemic preconditioning may be induced by short periods of ischaemia and reperfusion. We investigated whether the human heart can be ischaemically preconditioned during coronary artery bypass grafting (CABG). Patients were enrolled into two separate studies. In the first study myocardial adenosine triphosphate (ATP) was used as the measured endpoint, assayed from myocardial biopsies taken at onset of cardiopulmonary bypass (CPB), at the end of the preconditioning stimulus, and at the end of a 10 min sustained ischaemic insult. In the second study the release of myocardial troponin T was used as the endpoint; taken at pre-CPB, and at 1, 6, 24, and 72 h after CPB. In both studies, patients were randomised into either the preconditioning group or the control group. Preconditioning was induced, after the onset of CPB, with two 3 min periods of crossclamping and an intervening 2 min of reperfusion, followed by 10 min sustained ischaemia. The control group only received 10 min of sustained ischaemia. Ischaemic preconditioning resulted in a slower rate of ATP (mumol/g dry weight) depletion in the preconditioned hearts at the end of the 10 min of sustained ischaemia (preconditioned: 11.5 +/- 0.8 vs control: 7.2 +/- 0.3; P < 0.005). Also, preconditioning resulted in a slower rate of troponin T release which was significantly different at 72 h after CPB in the preconditioned group (0.3 milligram) when compared with the control group (1.4 milligrams; P < 0.05). In addition, more patients in the preconditioned group had troponin T levels lower than 0.5 milligram at 72 h than in the control group (10 vs 3 patients). Both groups of patients received the same number of grafts, and underwent the same length of ischaemia during the procedure. We conclude that in patients undergoing CABG surgery, ischaemic preconditioning may reduce myocardial injury as shown by the favourable changes in myocardial ATP, and serum troponin T levels.