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.

[1]  K. Csapo,et al.  Pharmacological mechanisms contributing to the clinical efficacy of levosimendan. , 2006, Cardiovascular drug reviews.

[2]  J. Dernellis,et al.  Effects of levosimendan on restrictive left ventricular filling in severe heart failure: a combined hemodynamic and Doppler echocardiographic study. , 2005, Chest.

[3]  F. Follath,et al.  European experience on the practical use of levosimendan in patients with acute heart failure syndromes. , 2005, The American journal of cardiology.

[4]  A. Mebazaa,et al.  Randomized clinical trials with levosimendan. , 2005, The American journal of cardiology.

[5]  W. Colucci,et al.  Cardioprotection: a new paradigm in the management of acute heart failure syndromes. , 2005, The American journal of cardiology.

[6]  P. Caimmi,et al.  Hemodynamic Effect of Intracoronary Administration of Levosimendan in the Anesthetized Pig , 2005, Journal of cardiovascular pharmacology.

[7]  S. Perrone,et al.  Calcium sensitizer agents: a new class of inotropic agents in the treatment of decompensated heart failure. , 2005, International journal of cardiology.

[8]  F. Fedele,et al.  Levosimendan improves hemodynamics and coronary flow reserve after percutaneous coronary intervention in patients with acute myocardial infarction and left ventricular dysfunction. , 2005, American heart journal.

[9]  G. Filippatos,et al.  Effects of levosimendan on markers of left ventricular diastolic function and neurohormonal activation in patients with advanced heart failure. , 2005, The American journal of cardiology.

[10]  I. Kallikazaros,et al.  The Ca2+‐sensitizer levosimendan improves oxidative damage, BNP and pro‐inflammatory cytokine levels in patients with advanced decompensated heart failure in comparison to dobutamine , 2005, European journal of heart failure.

[11]  I. Paraskevaidis,et al.  Anti-inflammatory and anti-apoptotic effects of levosimendan in decompensated heart failure: a novel mechanism of drug-induced improvement in contractile performance of the failing heart. , 2005, Current medicinal chemistry. Cardiovascular and hematological agents.

[12]  L. Erhardt An emerging role for calcium sensitisation in the treatment of heart failure , 2005, Expert opinion on investigational drugs.

[13]  R. Suojaranta-Ylinen,et al.  Levosimendan in cardiac surgery. , 2005, Journal of cardiothoracic and vascular anesthesia.

[14]  D. Farmakis,et al.  Anti-inflammatory effects of levosimendan in decompensated heart failure: impact on weight loss and anemia. , 2005, The American journal of cardiology.

[15]  E. Foster,et al.  Effects of Intravenous Levosimendan on Human Coronary Vasomotor Regulation, Left Ventricular Wall Stress, and Myocardial Oxygen Uptake , 2005, Circulation.

[16]  W. Little,et al.  Levosimendan improves LV systolic and diastolic performance at rest and during exercise after heart failure. , 2005, American journal of physiology. Heart and circulatory physiology.

[17]  L. Lehtonen,et al.  Levosimendan: a new inodilatory drug for the treatment of decompensated heart failure. , 2005, Current pharmaceutical design.

[18]  A. Mebazaa,et al.  ATP-dependent potassium channels as a key target for the treatment of myocardial and vascular dysfunction , 2004, Current opinion in critical care.

[19]  M. Anastasiou-Nana,et al.  Hemodynamic effects of levosimendan added to dobutamine in patients with decompensated advanced heart failure refractory to dobutamine alone. , 2004, The American journal of cardiology.

[20]  J. Eha,et al.  Pharmacodynamics and Pharmacokinetics of Oral Levosimendan and Its Metabolites in Patients With Severe Congestive Heart Failure: A Dosing Interval Study , 2004, Journal of clinical pharmacology.

[21]  P. Pollesello,et al.  Potassium-specific effects of levosimendan on heart mitochondria. , 2004, Biochemical pharmacology.

[22]  C. O'connor,et al.  Relationship of serum digoxin concentration to mortality and morbidity in women in the digitalis investigation group trial: a retrospective analysis. , 2004, Journal of the American College of Cardiology.

[23]  N. Freemantle,et al.  Clinical trials update from the European Society of Cardiology Heart Failure meeting: SHAPE, BRING‐UP 2 VAS, COLA II, FOSIDIAL, BETACAR, CASINO and meta‐analysis of cardiac resynchronisation therapy , 2004, European journal of heart failure.

[24]  L. Lehtonen,et al.  The calcium sensitizer levosimendan improves the function of stunned myocardium after percutaneous transluminal coronary angioplasty in acute myocardial ischemia. , 2004, Journal of the American College of Cardiology.

[25]  S. Adamopoulos,et al.  Effects of levosimendan on circulating pro-inflammatory cytokines and soluble apoptosis mediators in patients with decompensated advanced heart failure. , 2004, The American journal of cardiology.

[26]  S. Adamopoulos,et al.  Levosimendan reduces plasma B-type natriuretic peptide and interleukin 6, and improves central hemodynamics in severe heart failure patients. , 2004, International journal of cardiology.

[27]  B. Amantéa,et al.  Hemodynamic effects of levosimendan in patients with low-output heart failure after cardiac surgery. , 2004, International journal of clinical pharmacology and therapeutics.

[28]  L. Toivonen,et al.  The calcium sensitizer levosimendan and cardiac arrhythmias: an analysis of the safety database of heart failure treatment studies , 2004, Scandinavian cardiovascular journal : SCJ.

[29]  B. McBride,et al.  Levosimendan: Implications for Clinicians , 2003, Journal of clinical pharmacology.

[30]  M. Packer,et al.  Development of a comprehensive new endpoint for the evaluation of new treatments for acute decompensated heart failure: results with levosimendan in the REVIVE 1 study , 2003 .

[31]  J. Eha,et al.  Pharmacodynamic Interactions of Levosimendan and Felodipine in Patients with Coronary Heart Disease , 2003, Cardiovascular Drugs and Therapy.

[32]  J. Pataricza,et al.  Functional Role of Potassium Channels in the Vasodilating Mechanism of Levosimendan in Porcine Isolated Coronary Artery , 2003, Cardiovascular Drugs and Therapy.

[33]  B. Kobilka,et al.  Linkage of beta1-adrenergic stimulation to apoptotic heart cell death through protein kinase A-independent activation of Ca2+/calmodulin kinase II. , 2003, The Journal of clinical investigation.

[34]  D. Sawyer,et al.  &bgr;-Adrenergic Receptor–Stimulated Apoptosis in Cardiac Myocytes Is Mediated by Reactive Oxygen Species/c-Jun NH2-Terminal Kinase–Dependent Activation of the Mitochondrial Pathway , 2003, Circulation research.

[35]  P. Pentikäinen,et al.  Pharmacokinetics of levosimendan and its metabolites during and after a 24-hour continuous infusion in patients with severe heart failure. , 2002, International journal of clinical pharmacology and therapeutics.

[36]  R. Lange,et al.  Effect of the Calcium Sensitizer Levosimendan on the Performance of Ischaemic Myocardium in Anaesthetised Pigs , 2002, Cardiovascular Drugs and Therapy.

[37]  M. Nieminen,et al.  Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction. A randomized, placebo-controlled, double-blind study (RUSSLAN). , 2002, European heart journal.

[38]  L. Lehtonen,et al.  The contractility enhancing effect of the calcium sensitiser levosimendan is not attenuated by carvedilol in healthy subjects , 2002, European Journal of Clinical Pharmacology.

[39]  J. Cleland,et al.  Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial , 2002, The Lancet.

[40]  J. Cleland,et al.  Levosimendan: a new era for inodilator therapy for heart failure? , 2002, Current opinion in cardiology.

[41]  Marc A Pfeffer,et al.  New therapeutic options in congestive heart failure: Part I. , 2002, Circulation.

[42]  S. Adamopoulos,et al.  A glossary of circulating cytokines in chronic heart failure , 2001, European journal of heart failure.

[43]  E. D. du Toit,et al.  Effect of levosimendan on myocardial contractility, coronary and peripheral blood flow, and arrhythmias during coronary artery ligation and reperfusion in the in vivo pig model , 2001, Heart.

[44]  A. Annila,et al.  Binding of Levosimendan, a Calcium Sensitizer, to Cardiac Troponin C* , 2001, The Journal of Biological Chemistry.

[45]  M. Nieminen,et al.  Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure. , 2000, Journal of the American College of Cardiology.

[46]  S. Gottlieb,et al.  Acute Hemodynamic and Clinical Effects of Levosimendan in Patients With Severe Heart Failure , 2000, Circulation.

[47]  T. Honkanen,et al.  Pharmacokinetic and pharmacodynamic interactions between the novel calcium sensitiser levosimendan and warfarin , 2000, European Journal of Clinical Pharmacology.

[48]  P. Pollesello,et al.  Calcium sensitivity enhancers. , 2000, IDrugs : the investigational drugs journal.

[49]  G. Hasenfuss,et al.  Levosimendan improves diastolic and systolic function in failing human myocardium. , 2000, European journal of pharmacology.

[50]  M. Konstam Progress in heart failure Management? Lessons from the real world. , 2000, Circulation.

[51]  R. Takahashi,et al.  Effects of OR-1896, an active metabolite of levosimendan, on contractile force and aequorin light transients in intact rabbit ventricular myocardium. , 2000, Journal of cardiovascular pharmacology.

[52]  M. Viitasalo,et al.  Electrophysiologic effects of a calcium sensitizer inotrope levosimendan administered intravenously in patients with normal cardiac function. , 2000, Journal of cardiovascular pharmacology.

[53]  A. Annila,et al.  Further evidence for the cardiac troponin C mediated calcium sensitization by levosimendan: structure-response and binding analysis with analogs of levosimendan. , 2000, Journal of molecular and cellular cardiology.

[54]  P. Pagel,et al.  Levosimendan, a New Positive Inotropic Drug, Decreases Myocardial Infarct Size via Activation of KATP Channels , 2000, Anesthesia and analgesia.

[55]  H. Kanerva,et al.  Site dependent bioavailability and metabolism of levosimendan in dogs. , 1999, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[56]  M. Nieminen,et al.  Oral levosimendan improves cardiac function and hemodynamics in patients with severe congestive heart failure , 1999 .

[57]  D. Pimentel,et al.  Norepinephrine stimulates apoptosis in adult rat ventricular myocytes by activation of the beta-adrenergic pathway. , 1998, Circulation.

[58]  M. Nieminen,et al.  Effects of a new calcium sensitizer, levosimendan, on haemodynamics, coronary blood flow and myocardial substrate utilization early after coronary artery bypass grafting. , 1998, European heart journal.

[59]  M. Sunagawa,et al.  Levosimendan, a novel Ca2+ sensitizer, activates the glibenclamide-sensitive K+ channel in rat arterial myocytes. , 1997, European journal of pharmacology.

[60]  P. Kaheinen,et al.  The role of cAMP- and cGMP-dependent protein kinases in the cardiac actions of the new calcium sensitizer, levosimendan. , 1997, Cardiovascular research.

[61]  P. Pagel,et al.  Levosimendan enhances left ventricular systolic and diastolic function in conscious dogs with pacing-induced cardiomyopathy. , 1997, Journal of cardiovascular pharmacology.

[62]  J. Levijoki,et al.  Cardiac troponin C as a target protein for a novel calcium sensitizing drug, levosimendan. , 1995, Journal of molecular and cellular cardiology.

[63]  J. Levijoki,et al.  Troponin C–Mediated Calcium Sensitization Induced by Levosimendan Does Not Impair Relaxation , 1995, Journal of cardiovascular pharmacology.

[64]  N. Kalkkinen,et al.  Binding of a new Ca2+ sensitizer, levosimendan, to recombinant human cardiac troponin C. A molecular modelling, fluorescence probe, and proton nuclear magnetic resonance study. , 1994, The Journal of biological chemistry.

[65]  T. DeMarco,et al.  Nonglycoside inotropes in congestive heart failure. Are they beneficial or harmful? , 1994, Cardiology clinics.

[66]  M. Packer,et al.  The search for the ideal positive inotropic agent. , 1993, The New England journal of medicine.

[67]  M. Packer,et al.  Vasodilator and inotropic therapy for severe chronic heart failure: passion and skepticism. , 1983, Journal of the American College of Cardiology.

[68]  S. Silver,et al.  Heart Failure , 1937, The New England journal of medicine.

[69]  B. O’Rourke,et al.  Evidence for Mitochondrial K Channels and Their Role in Cardioprotection , 2004 .

[70]  R. Schwinger,et al.  Beneficial effects of the Ca(2+) sensitizer levosimendan in human myocardium. , 2002, American journal of physiology. Heart and circulatory physiology.

[71]  J. Papp,et al.  STEERING COMMITTEE AND INVESTIGATORS OF THE LEVOSIMENDAN INFUSION VERSUS DOBUTAMINE (LIDO) STUDY. EFFICACY AND SAFETY OF INTRAVENOUS LEVOSIMENDAN COMPARED WITH DOBUTAMINE IN SEVERE LOWOUTPUT HEART FAILURE (THE LIDO STUDY): A RANDOMISED DOUBLEBLIND TRIAL , 2002 .

[72]  N. Alpert,et al.  Effects of calcium sensitizers on intracellular calcium handling and myocardial energetics. , 1995, Journal of cardiovascular pharmacology.

[73]  H. Haikala,et al.  Mechanisms of action of calcium-sensitizing drugs. , 1995, Journal of cardiovascular pharmacology.

[74]  P. Heikkinen,et al.  Pharmacokinetics of levosimendan in healthy volunteers and patients with congestive heart failure. , 1995, Journal of cardiovascular pharmacology.