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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Looking at the clinical report of a single patients admitted with severely decompensated heart failure and successfully managed with levosimendan, the authors review the current knowledge about this new drug. The treatment of severely decompensated heart failure is currently based on classical catecholamines (dopamine and dobutamine). The various new positive inotropics investigated in the past have failed to improve survival. In spite of some symptomatic improvement an increase in long-term mortality was noticed in different trials testing different drugs. More recently a new concept has been introduced regarding a new way to improve myocardial contractility and vasodilation based on calcium-sensitizing properties with additional action on adenosine triphosphate-sensitive potassium channels. Levosimendan is a representative of this new class recently launched in the Portuguese market.
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PMID:Levosimendan: a new approach for the treatment of patients with severe heart failure. A brief summary based on a clinical case. 1458 61

The finely-tuned increases and decreases in the intracellular calcium levels in myocytes ultimately regulate the contraction and relaxation of the heart. Therapeutic agents can improve or interfere with this delicate balance. Calcium sensitizers enhance cardiac contraction by improving the use of calcium that is available, rather than by inundating the cell with excessive calcium, as is the case with traditional inotropes. With the sensitizing mechanism, the energy cost of contraction is maintained at a near-normal level, and the threat of arrhythmias and sudden death is low. Levosimendan is the first calcium sensitizer to become available for the treatment of patients with acute heart failure. In recent clinical studies, levosimendan increased cardiac output and stroke volume without significantly increasing oxygen demand. By its additional action as a vasodilator (via potassium channel opening), levosimendan also corrects the hemodynamic decompensation, thus lowering the pulmonary capillary wedge pressure and systemic vascular resistance. Furthermore, levosimendan increases the coronary circulation thus leading to an improved function of the stunned myocardium and lessened ischemia. Taken together, levosimendan's primary calcium-sensitizing action, along with its complementary vasodilator properties, make this new drug a highly promising agent for the treatment of patients with acute heart failure.
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PMID:Is calcium sensitization the best strategy to improve myocardial contractility in acute heart failure? 1463 67

The novel calcium sensitizer levosimendan improves myocardial contractility without causing an increase in intracellular calcium and cyclic adenosine monophosphate concentrations. It also has a vasodilator action due to an opening of the adenosine triphosphate-sensitive potassium channels. In a double-blind clinical trial levosimendan was compared with dobutamine in 203 patients with severe low-output congestive heart failure. A 24-hour infusion of these inotropic drugs was administered to increase the cardiac output by at least 30% together with a decrease in the pulmonary capillary wedge pressure by > or = 25%. The pre-defined hemodynamic improvement was achieved in 28% of patients receiving levosimendan compared to only 15% with dobutamine (p = 0.022). Levosimendan also reduced the 1- and 6-month mortality more than dobutamine (7.8 vs 17%, p = 0.045 and 26 vs 38%, p = 0.029, respectively). Levosimendan produced less myocardial ischemia and cardiac arrhythmias than dobutamine. Calcium sensitizers offer a new therapeutic possibility in patients with decompensated low-output heart failure.
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PMID:Levosimendan in patients with low-output heart failure: lessons from the LIDO trial. 1463 68

Levosimendan is a new vasodilator agent with properties which improve cardiac contractility by calcium sensitization. Its dose-related efficacy and prolonged action have been documented in several major studies both against placebo and dobutamine. Out of 997 patients, 837 (84%) had acute or stable heart failure due to coronary heart disease. Therefore, it would be most interesting to analyze the efficacy and safety of levosimendan in heart failure due to ischemic heart disease. The dose-finding study included 98 patients who were given intravenous levosimendan at different doses and 20 patients treated with dobutamine. All patients had heart failure due to coronary heart disease. The other major trial included 500 acute myocardial infarction patients with heart failure and was placebo-controlled. In other levosimendan vs placebo or dobutamine comparative trials 50-60% of patients had ischemic heart disease and severe heart failure. Levosimendan significantly improves the cardiac index by 30-39% at bolus doses of 6-24 micrograms/kg/min followed by infusion doses of 0.05-0.2 microgram/kg/min and reduces the wedge pressure by 20-25% to optimal levels (from 15-20 mmHg). There is a lesser blood pressure reduction and some heart rate increase. However in patients with an acute myocardial infarction the rate of ischemia or hypotension were similar in levosimendan- and placebo-treated patients and in the dobutamine controlled trials no major adverse effects were seen or they were more frequent in dobutamine patients. There is no increase in mortality either compared to placebo or to dobutamine. Rather, the opposite seems to be true. No increase in arrhythmias is seen. The hemodynamic effects of levosimendan are dose-dependent and the current recommended doses are safe. No increase in mortality or any life-threatening arrhythmias have been observed.
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PMID:Considerations on the efficacy and safety of levosimendan in ischemic heart failure. 1463 69

Positive inotropic drugs have various mechanisms of action. Long-term use of cyclic adenosine monophosphate (cAMP)-dependent drugs has adverse effects on the prognosis of heart failure patients, whereas digoxin has neutral effect on mortality. There are, however, little data on the effects of intravenous inotropic drugs on the outcome of patients. Intravenous inotropic agents are used to treat cardiac emergencies and refractory heart failure. beta-Adrenergic agonists are rapid acting and easy to titrate, with short elimination half-life. However, they increase myocardial oxygen consumption and are thus hazardous during myocardial ischaemia. Furthermore they may promote myocyte apoptosis. Phosphodiesterase (PDE) III inhibiting drugs (amrinone, milrinone and enoximone) increase contractility by reducing the degradation of cAMP. In addition, they reduce both preload and afterload via vasodilation. Short-term use of intravenous milrinone is not associated with increased mortality, and some symptomatic benefit may be obtained when it is used in refractory heart failure. Furthermore, PDE III inhibitors facilitate weaning from the cardiopulmonary bypass machine after cardiac surgery. Levosimendan belongs to a new group of positive inotropic drugs, the calcium sensitisers. It has complex pharmacokinetics and long-lasting haemodynamic effects as a result of its active metabolites. In comparative trials, it has been better tolerated than the most widely used beta-agonist inotropic drug, dobutamine. The pharmacokinetics of the intravenous inotropic drugs might sometimes greatly modify and prolong the response to the therapy, for example because of long-acting active metabolites. These drugs display considerable differences in their pharmacokinetics and pharmacodynamics, and the selection of the most appropriate inotropic drug for each patient should be based on careful consideration of the clinical status of the patient and on the pharmacology of the drug.
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PMID:Pharmacokinetics and pharmacodynamics of intravenous inotropic agents. 1487 Nov 56

Levosimendan is a recently developed drug which is not yet approved for clinical routine use in Germany. The clinical use is limited to a few selected cases and it has been used as a salvage therapy in patients with severe heart insufficiency. As a potent inodilator it has been given to patients with severe heart failure, when all other therapeutic options have failed. However, in some European countries levosimendan is used in clinical routine situations and the European Society of Cardiologists has included the drug in their guidelines for treatment of acute heart failure. The following article describes the main pharmacological characteristics of levosimendan and summarises the indications for this new drug for physicians working in the field of anaesthesia or intensive care.
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PMID:[Levosimendan. Clinical indications of a new vasoactive substance]. 1499 Nov 94

Levosimendan (LS) is a new calcium sensitizer that exerts positive inotropic effects without increasing intracellular cAMP or Ca2+ at therapeutic doses and therefore may avoid major limitations of beta-adrenergic agents. LS also causes arteriolar and venous dilation by opening potassium channels on vascular smooth muscle cells. In addition, LS does not increase myocardial oxygen demand and may exert anti-stunning effects. LS itself has a short elimination half life but has shown to have active metabolites with elimination half lives up to 80 hours. Three hemodynamic studies show that at recommended doses LS increases cardiac output by 8-30% and reduces pulmonary capillary wedge pressure by 11-28% in heart failure patients. Systemic vascular resistance falls significantly and blood pressure tends to decline. The hemodynamic effects are not attenuated by concomitant beta-blocker medication. Two large randomized studies on patients with chronic and acute congestive heart failure found a decrease in mortality with LS. In the LIDO trial there was a 52.9% survival benefit at day 31 when compared with patients receiving dobutamine. In the RUSSLAN trial, the survival benefit approached 40% at day 14 after start of treatment compared to placebo. Experience in the ICU setting is limited but LS therapy in postoperative low output failure and cardiogenic shock seems to be feasible and LS is a promising agent in the inotropic armamentarium. LS has a favourable side effect profile and is approved for 24-hour use in congestive heart failure. It may cause hypotension due to vasodilation, and this effect may be aggravated by inadequate preload conditions. Further morbidity and mortality studies are required to confirm the encouraging data from the LIDO and RUSSLAN trial but already the existing data support LS as the inotropic agent of choice in patients with worsening heart failure and a systolic arterial blood pressure beyond 90 mmHg.
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PMID:[Levosimendan in cardiology and intensive care medicine]. 1503 Jan 17

Heart failure is the most common malignant disease in the developed world. Levosimendan (Simdax) is a novel intravenous agent that exerts inotropic effects through sensitization of myofilaments to calcium and vasodilator effects by opening ATP-dependent potassium channels on vascular smooth muscle. Infusion of levosimendan increases cardiac output due to an increase in stroke volume and heart rate, with a fall in pulmonary capillary wedge pressure. It has an active metabolite with a half-life of about 80 h, therefore infusions of 6 to 24 h result in hemodynamic effects that persist for 7 to 10 days. Preliminary observations suggest that a single infusion of levosimendan lasting 6 to 24 h in patients with severe heart failure due to left ventricular systolic dysfunction results in hemodynamic changes, symptomatic benefit and a reduction in morbidity and mortality over the following 2 to 4 weeks compared with placebo in one study and with dobutamine in another. Long-term follow-up suggests no loss of this early benefit over 6 months. Levosimendan is licensed for the treatment of decompensated heart failure in many countries but not in North America. Further large trials are being conducted comparing levosimendan with placebo and with dobutamine in patients with severe heart failure and left ventricular systolic dysfunction. If these studies confirm the benefits of levosimendan, then it may become routine therapy for the management of severe heart failure.
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PMID:Levosimendan: first in a new class of inodilator for acute and chronic severe heart failure. 1503 9

Following cardiac surgery, low-output syndrome is relatively common. Since this condition can lead to serious consequences, this postsurgical, low-output state should be reversed whenever possible. Patients with low-output syndrome need drug and fluid management aimed at enhancing cardiac contractility and at facilitating optimal myocardial loading. The objective of this pilot study was to evaluate whether benefits of levosimendan, a new calcium-sensitizing agent approved for treatment of patients with acute exacerbation of chronic heart failure, could be extended to patients with low-output syndrome following cardiac surgery. For this study, each patient was given levosimendan as a loading dose of 12 microg/kg over 10 minutes, followed by a continuous infusion of 0.1 microg/kg/min for 12 hours. Of 11 postsurgical patients with severely impaired cardiac output and hemodynamic compromise, 8 patients (73%) showed evidence of combined hemodynamic improvement (> 30% increase in cardiac index and PCWP corrected to < 18 mmHg) within 3 h after the start of levosimendan infusion. Specifically, cardiac index and stroke volume were significantly increased, while mean arterial pressure, indexed systemic vascular resistance, mean pulmonary pressure, right arterial pressure, and pulmonary capillary wedge pressure were all significantly lowered. Taken together, such changes showed enhanced cardiac output along with significantly decreased preload and afterload--conditions associated with recovery of cardiac function. Levosimendan is thus highly favorable for short-term treatment of patients with low cardiac output following cardiac surgery.
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PMID:Hemodynamic effects of levosimendan in patients with low-output heart failure after cardiac surgery. 1512 78

In this study, we evaluated levosimendan, a new drug developed for the treatment of acute and decompensated heart failure, as a potential activator of ATP-sensitive potassium flux to the matrix of cardiac mitochondria. We estimated the KATP channel openers-induced increase in mitochondrial inner membrane permeability for potassium by registering changes in membrane potential of heart mitochondria, oxidizing endogenous substrates. We compared the effect of levosimendan with the effects of the known KATP channel openers diazoxide and pinacidil. Levosimendan (1 microM) accelerated potassium-specific DeltaPsi decrease by 0.15%/s, whereas 50 microM diazoxide by 0.10%/s, and 50 microM pinacidil by 0.08%/s, respectively. These results were confirmed by swelling experiments of non-respiring mitochondria in potassium nitrate medium. We found that levosimendan with an EC50 of 0.83 +/- 0.24 microM activates potassium flux to the mitochondrial matrix. This effect is discussed as a possible explanation of the anti-ischemic action of levosimendan.
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PMID:Potassium-specific effects of levosimendan on heart mitochondria. 1529 43


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