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

1. The haemodynamic effects of a novel cardiotonic drug, levosimendan, which has both calcium-sensitizing and phosphodiesterase III (PDE III) inhibitory properties, were studied in conscious dogs in which heart failure had been induced by prolonged cardiac pacing in the presence of aortic constriction. These effects were compared with those in sham-operated dogs with essentially normal cardiac function. 2. Eighteen mongrel dogs were instrumented for the measurement of left ventricular pressure (LVSP, LVEDP) and contractile function (dP/dt; dP/dt/P). In twelve dogs a balloon catheter, positioned in the thoracic aorta, was inflated producing an approximate 60% reduction in effective aortic diameter. Twenty min later rapid ventricular pacing (240 beats mean-1) was commenced and maintained for 48 h by means of a bipolar pacing electrode introduced into the right ventricle. This electrode served also for recording changes in the endocardial electrogram in the absence of pacing. Six of these dogs were used to evaluate the haemodynamic changes of pacing-induced heart failure; a further six of these dogs the haemodynamic changes elicited by levosimendan under these conditions. Six sham-operated dogs (group 2) served as controls. 3. In six dogs (group 1) the haemodynamic alterations were assessed after the development of heart failure. In the presence of aortic constriction, 48 h continuous rapid cardiac pacing resulted in a marked deterioration in left ventricular function which remained stable for at least 48 h after cessation of pacing. Thus, there was a marked reduction in LVSP (15%), +dP/dtmax (35%), -dP/dtmax (36%) and also in dP/dt/P (29%), whereas LVEDP was increased considerably (from 6.4 +/- 1.4 to 20.0 +/- 2.2 mmHg). A marked elevation occurred in endocardial ST-segment (138%), lasting for 20 min.4. Levosimendan was administered intravenously in doses of 0.005, 0.01 and 0.03 micromol kg-1 to 2 groups of conscious dogs. In the sham-operated dogs (group 2), only the higher dose (0.03 micromol kg-1)produced significant increases in LVSP (19%), + dP/dtmax (37%), and in dP/dt/P (32%). In dogs with heart failure (group 3) doses of 0.005, 0.01 and 0.03 micromol kg-1 levosimendan resulted in an improve mentin +dP/dtmax (26%, 38% and 49%), -dP/dtmax (20%, 25% and 38%) and in dP/dt/P (19%, 34%and 50%) and reduction in the elevated LVEDP (from 20 =/- 2.2 mmHg to 16 +/- 1.0, 10 +/- 1.3 and 9 +/- 1.0 mmHg, respectively).5. Levosimendan proved to be a potent cardiotonic drug at the doses used, and was approximately three times more effective under conditions of impaired left ventricular function than in normal hearts.
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PMID:Cardiovascular effects of the calcium sensitizer, levosimendan, in heart failure induced by rapid pacing in the presence of aortic constriction. 773 92

Simendan is a novel cardiotonic drug with mixed properties, including calcium sensitization. Simendan was given intravenously to eight healthy volunteers in doses from 0.1 to 10.0 mg to define its safety and dose-response effects. Its effects on myocardial function were recorded by echocardiography with simultaneous measurement of heart rate (HR) and blood pressure (BP). A linear dose response was observed in all echocardiographic indices. Fractional shortening increased from a basal value of 29.5% to 32.4% (p < 0.05), 34.7% (p < 0.001), and 39.4% (p < 0.001) 10 minutes after doses of 1.0, 2.0, and 5.0 mg of simendan, respectively. The mean velocity of maximal circumferential fiber shortening increased from the baseline of 2.22 lengths/sec to 2.7 lengths/sec after the 2.0 mg dose (p < 0.05) and to 3.31 lengths/sec after the 5.0 mg dose (p < 0.001). Mean BP decreased slightly and mean HR increased only by 5.2 beats/min after the 5.0 mg dose. Because of the potent effect seen on hemodynamic indices and due to two vasovagal reactions, 10 mg was given to two subjects only. These results revealed that simendan has hemodynamic effects that can be explained by positive inotropy as well as vasodilatation, in agreement with preclinical findings. Further studies with patients disabled by heart failure are warranted.
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PMID:Hemodynamic effects of the novel cardiotonic drug simendan: echocardiographic assessment in healthy volunteers. 791 39

Levosimendan belongs to a new group of heart failure drugs, the calcium sensitizers. Because these compounds are not yet available for clinical use, the adverse drug events (ADEs) during levosimendan treatment cannot be predicted in detail. To evaluate the tolerability of levosimendan in human subjects, ADEs, safety laboratory values before and after treatment, and ambulatory ECG findings have been collected from several phase I and phase II clinical studies. By June 1994, approximately 200 subjects had received levosimendan. The most common ADE seen in healthy volunteers is headache, reported by some 40% of subjects in oral dosing but only 10% in i.v. dosing. The incidence of headache does not correlate well with the total daily dose of the drug. However, the controlled release formulations tested appear to cause vasodilatory symptoms more frequently than i.v. or rapid release oral formulations. The other typical vasodilatory ADEs seen in healthy volunteers are nausea, palpitation, and dizziness. Symptomatic hypotension is rarely encountered. It appears that heart failure patients tolerate the vasodilatory actions of the drug better than healthy volunteers. Only individual cases of headache, vertigo, and flushing have been reported, and injection site irritation has been the most commonly reported ADE (with an incidence <5%). However, because the longest administration of the i.v. infusion has been only 24 h, the duration of exposure to the drug is too short to allow any definitive conclusions to be drawn. All patients who have received levosimendan have been monitored with an ambulatory ECG. Even though some increase in heart rate is seen with high doses of the drug, there are thus far no signs of an increased incidence of ventricular tachyarrhythmias, nor have there been any noteworthy changes in the clinical laboratory safety tests. The experience with levosimendan is limited thus far and long-term data are lacking. It can be concluded, however, that at least in i.v. dosing the drug is devoid of ADEs with significant medical seriousness.
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PMID:Safety of levosimendan and other calcium sensitizers. 890 34

Parenterally administered positive inotropic agents remain an important component of the therapeutics of cardiac dysfunction and failure. Dobutamine, a catechol, remains the prototype of this drug group, but recently has been joined by the phosphodiesterase III inhibitor, milrinone. Compared with dobutamine, milrinone has greater vasodilating-unloading properties. The catecholamine, dopamine, is often used as a parenteral positive inotrope; but at moderate to high dose, it evokes considerable systemic vasoconstriction. At lower doses, dopamine appears to augment renal function. Levosimendan and toborinone, new compounds with several mechanisms of action, are under active clinical investigation and review for approval. Parenteral positive inotropic therapy is indicated for short-term (hours to days) treatment of cardiovascular decompensation secondary to ventricular systolic dysfunction, low-output heart failure. More prolonged or continuous infusion of one of these agents may be necessary as a "pharmacologic bridge" to cardiac transplantation, another definitive intervention, or more advanced, intense medical therapy. An occasional patient will require a continuous infusion via indwelling venous catheter and portable pump, simply to be able to be discharged from the hospital setting and function in the home environment. Intermittent parenteral inotropic therapy for chronic heart failure has provoked considerable controversy and passion among cardiologists and heart failure specialists; an attempt is made to present this topic in an objective manner.
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PMID:Parenteral inotropic support for advanced congestive heart failure. 987 7

Provocation of fatal cardiac arrhythmias has limited the use of inotropic agents as heart failure therapy. Calcium sensitization of the myofilaments might increase inotropy without influencing cardiac electrophysiology unless modified by ancillary properties of the drugs. Electrophysiologic effects of a calcium sensitizer inotrope levosimendan were examined in short-term intravenous administration in humans. Variables were determined in 10 patients with normal cardiac function during a preceding control phase and levosimendan infusion yielding a high therapeutic concentration of 110 (+/-22) microg/L. Levosimendan increased heart rate by 9 beats/min (p < 0.01) on average and shortened the sinus node recovery time and AH interval. At the tested cycle lengths, levosimendan shortened the effective refractory periods in the atrioventricular node by 40-63 ms (p < 0.05), in the atrium by 22-33 ms (p < 0.001), and in the ventricle by 5-9 ms (p < 0.005) on average. Levosimendan increased ventricular monophasic action potential duration by 9-17 ms at 50% (p < 0.001) and by 5-15 ms (p = 0.07) at 90% levels of repolarization on average. The QT interval during spontaneous rhythm and atrial pacing remained unchanged although increased slightly when corrected to sinus rate (p < 0.001). The observations indicate that levosimendan in short-term administration facilitates impulse formation and conduction in cardiac slow-response tissue, enhances recovery of excitability in the myocardium, and may delay ventricular repolarization. The effects on the ventricle were not substantial, and therefore the likelihood of provoking serious cardiac arrhythmias is not estimated to be high.
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PMID:Electrophysiologic effects of a calcium sensitizer inotrope levosimendan administered intravenously in patients with normal cardiac function. 1077 99

Levosimendan is a new inodilator, whose mechanism of action includes calcium sensitization of contractile proteins and the opening of ATP-dependent potassium channels. The combination of positive inotropy with anti-ischemic effects of K-channel opening offers many potential benefits in comparison to currently available intravenous inotropes, that are more or less contraindicated in patients with ongoing myocardial ischemia. Levosimendan has been extensively studied in various animal models of heart failure, in which the drug has increased contractility without adverse effects on diastolic function. These results have been repeated in patients with heart failure, by whom levosimendan dose-dependently increases cardiac output and reduces pulmonary capillary wedge pressure. On higher doses, the drug can induce tachycardia and hypotension. In clinical trials, drug-induced ventricular arrhythmia have been rare. Recently, trials in patients with decompensated heart failure have suggested that short-term intravenous treatment with levosimendan might improve the survival of these critical patients. These results highlight the importance of adequate treatment of the acute heart failure patients for their long-term outcome.
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PMID:Levosimendan: A promising agent for the treatment of hospitalized patients with decompensated heart failure. 1098 Aug 98

Levosimendan, a novel calcium sensitizer developed for the treatment of acute heart failure, is an inodilator that increases coronary flow. Because it was recently shown that levosimendan stimulates potassium current through K(ATP) channels in isolated rat arterial cells, our aim was to assess whether the levosimendan-induced increase in coronary flow is due to the opening of the K(ATP) channels in coronary smooth muscle. The effect of levosimendan on the diastolic coronary flow velocity (DCFV) was measured in the Langendorff perfused spontaneously beating guinea-pig heart in the absence and presence of glibenclamide. Pinacidil was used as a reference compound, and the protein kinase C inhibitor bisindolylmaleimide was used to study the dilatory effect of levosimendan when the K(ATP) channels in smooth muscle are not inhibited by PKC-dependent phosphorylation. Levosimendan (0.01-1 microM) increased DCFV concentration-dependently and was noncompetitively antagonized by 0.1 microM glibenclamide, whereas pinacidil was inhibited competitively by glibenclamide. In the presence of glibenclamide the positive inotropic and chronotropic effects of levosimendan were unaltered. The effect of bisindolylmaleimide and levosimendan on DCFV was additive. The results indicate that levosimendan induced coronary vasodilation through the opening of the K(ATP) channels. Levosimendan and pinacidil probably have different binding sites on the K(ATP) channels. The additive effect of bisindolylmaleimide and levosimendan on the increase of DCFV suggests that the latter binds to the unphosphorylated form of the channel.
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PMID:Levosimendan increases diastolic coronary flow in isolated guinea-pig heart by opening ATP-sensitive potassium channels. 1130 Jun 49

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.
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PMID:Levosimendan: a parenteral calcium-sensitising drug with additional vasodilatory properties. 1132 69

Levosimendan, a pyridazinone-dinitrile derivative, is a calcium sensitiser with additional action on adenosine triphosphate (ATP)-sensitive potassium channels. It is used intravenously (IV) for the treatment of decompensated cardiac failure. At therapeutic doses, levosimendan exhibits enhanced contractility with no increase in oxygen demands. It also produces antistunning effects without increasing myocardial intracellular calcium concentrations or prolonging myocardial relaxation. Levosimendan also causes coronary and systemic vasodilation. In patients with decompensated congestive heart failure (CHF), IV levosimendan significantly reduced the incidence of worsening CHF or death. IV levosimendan significantly increased cardiac output or cardiac index and decreased filling pressure in the acute treatment of stable or decompensated CHF in large, double-blind, randomised trials and after cardiac surgery in smaller trials. Levosimendan is well tolerated, with the most common adverse events (headache, hypotension, nausea) being secondary to vasodilation. It has not been shown to be arrhythmogenic. Levosimendan has shown no clinically important pharmacokinetic interactions with captopril, felodipine, beta-blockers, digoxin, warfarin, isosorbide-5-mononitrate, carvedilol, alcohol (ethanol) or itraconazole.
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PMID:Levosimendan. 1136 86

Levosimendan, a new inodilator developed for the treatment of heart failure has been shown to have a vasodilatory effect via opening of K(ATP) channels in the plasma membrane of vascular smooth muscle cells. In this study, we investigated the effects of levosimendan on the mitochondrial K(ATP) channel. This compound did not influence mitochondrial transmembrane potential (DeltaPsi), and at up to 2.2 microM had no effect on the respiration rate of rat liver mitochondria, respiring on 5 mM succinate (+5 microM rotenone). A sensitive method was developed for assessing K(ATP) channel opening activity employing rat liver mitochondria, respiring only on endogenous substrates in the presence of 400 microM ATP and 1 microg oligomycin/mg mitochondrial protein. In this model, levosimendan (0.7-2.6 microM) decreased DeltaPsi by 6.5-40.4% (n=3, incubation time 15 min). This effect was dependent on the K+ concentration in the incubation medium and was abolished by the selective blocker of the mitochondrial K(ATP) channel-5-hydroxydecanoate (200 microM). Our results indicate that levosimendan opens mitochondrial K(ATP) channels.
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PMID:Levosimendan is a mitochondrial K(ATP) channel opener. 1168 88


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