Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The clinician's primary objective in treating a patient with decompensated heart failure is rapid and effective stabilization. This goal often is achieved through the use of inotropic support. Classic inotropic agents (beta-adrenergic agonists and phosphodiesterase III inhibitors) can provide short-term hemodynamic benefits, but their long-term use has been correlated with poor survival rates. Calcium sensitizers comprise a new drug class that offers hemodynamic and symptomatic improvements without increasing cAMP and intracellular calcium concentrations. These agents enhance contractility without a concurrent increase in the risk of cardiac events and thus represent a significant improvement over classic positive inotropic agents. Levosimendan is the most potent calcium sensitizer to date, exhibiting a unique dual mechanism of action that combines a positive inotropic action mediated via calcium sensitization and a vasodilator property via ATP-dependent potassium channels. Available clinical data suggest that calcium sensitizer agents represent a promising class of inotropic agents in a field that has seen few advances in recent decades.
 ...
PMID:Calcium sensitizer agents: a new class of inotropic agents in the treatment of decompensated heart failure. 1630 57

Levosimendan is a calcium sensitizer that demonstrates enhanced myocardial contractility. There is little information concerning the effect of levosimendan on left ventricular tissue parameters and exercise capacity. We evaluated the effects of a 24-h course of levosimendan therapy on cardiac tissue parameters in 30 patients, aged 48 - 70 years, admitted to our hospital for the management of decompensated heart failure. All patients underwent echocardiographic examination using tissue Doppler imaging (TDI) and a 6-min walk test. Systolic myocardial velocity of the mitral annulus (Sm) was significantly increased in levosimendan-treated patients compared with placebo-treated patients. There was a positive correlation between Sm and exercise capacity. Levosimendan might be expected to increase cardiac contractile force, especially Sm velocity, in parallel with exercise tolerance. The study has also shown that the progress of ventricular function after levosimendan treatment in patients with exercise intolerance could be monitored effectively by Sm velocity measurements using TDI.
 ...
PMID:Effects of levosimendan on left ventricular functional remodelling and exercise intolerance: a tissue Doppler study. 1610 43

To-date positive inotropic therapy in the treatment of congestive heart failure has resulted in adverse effects on long term survival. These agents increase calcium cycling through beta-adrenergic stimulation or phosphodiesterase inhibition. An alternative method of producing positive inotropy is to increase the myofilament sensitivity to calcium. This can occur at several levels within the myofilament, and has potential benefits with respect to avoiding increased calcium cycling and producing a more favourable energy efficient positive inotropy. A potential adverse effect of increasing calcium sensitivity is slowed relaxation and diastolic dysfunction. We have learnt a considerable amount about the function of specific sites within the myofilament by the use of genetically engineered mouse models, which have shown diverse effects of various myofilament sites on global left ventricular function. Levosimendan is a novel inotropic agent that has several mechanisms of action including calcium sensitization, and is undergoing clinical trials at present. This review article will provide a comprehensive molecular, biophysical and physiological insight into the concepts underlying the myofilament force-calcium relationship and its potential as a target for positive inotropic therapy in heart failure.
 ...
PMID:The myofilament force-calcium relationship as a target for positive inotropic therapy in congestive heart failure. 1614 98

The management of acute heart failure syndromes (AHFS) focuses primarily on improving hemodynamic function and alleviating symptoms. Emerging evidence has raised the possibility that patients with AHFS may be susceptible to progressive myocardial failure because of the accelerated loss of cardiac myocytes. Although there are circumstantial data to suggest that the choice of therapeutic agent may affect long-term outcomes in such patients, the responsible mechanism is not known. Activation of mitochondrial adenosine triphosphate-dependent potassium (K(ATP)) channels in cardiac myocytes is a potent cardioprotective mechanism. We studied cardiac myocytes in culture to determine whether levosimendan can protect against apoptotic cell death in response to oxidative stress, a stimulus that appears to mediate myocyte loss in response to hemodynamic overload and beta-adrenergic stimulation, conditions commonly encountered in acute HF. Levosimendan, at concentrations below the therapeutic range in humans, protected myocytes from hydrogen peroxide-induced apoptosis. This effect was prevented by K(ATP) channel inhibitors. The demonstration that levosimendan can oppose myocyte apoptosis via the activation of mitochondrial K(ATP) channels provides a potential mechanism by which this agent might protect cardiac myocytes during episodes of acute HF. Although the alleviation of symptoms should remain an important goal of therapy in acute HF, a therapeutic approach that includes a cardioprotective strategy may be able to exert a clinically meaningful benefit on disease progression. This speculation, if proved true, would mandate a fundamental paradigm shift in the acute management of acute HF.
 ...
PMID:Cardioprotection: a new paradigm in the management of acute heart failure syndromes. 1618 20

Acute heart failure syndromes (AHFS) are among the most frequent causes of hospitalizations in the United States and Europe. Despite current therapies, patients with AHFS have high readmission and mortality rates. The randomized, controlled clinical trial is the standard by which contemporary therapies are evaluated, yet this tool of clinical science only recently has been rigorously applied to the development of novel therapies for patients with AHFS. This review briefly discusses some of the challenges presented in designing a clinical trial of therapies for AHFS and to describe some of the recent trials with respect to these issues in established drugs (such as milrinone, dobutamine, nitroglycerin, nitroprusside, and nesiritide) that have been approved by the US Food and Drug Administration (FDA). Recent trials of current investigational agents, such as levosimendan (the Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy Versus Placebo in the Short-Term Treatment of Decompensated Heart Failure [REVIVE], the Calcium Sensitizer or Inotrope or None in Low-Output Heart Failure [CASINO] study, and the Survival of Patients with Acute Heart Failure in Need of Intravenous Inotropic Support [SURVIVE] trial), tezosentan (the Randomized Intravenous Tezosentan [RITZ] study and the Value of Endothelin Receptor Inhibition with Tezosentan in Acute Heart Failure Studies [VERITAS]), and tolvaptan (the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure [ACTIV-CHF] study), are also discussed.
 ...
PMID:Overview of randomized clinical trials in acute heart failure syndromes. 1618 24

Current therapies for acute heart failure syndromes (AHFS) target hemodynamics by decreasing congestion or increasing myocardial contraction. Several new agents for AHFS use novel mechanisms of action that focus on new treatment targets, such as those providing anti-ischemic and anti-stunning effects, blocking vasopressin receptors, or blocking endothelin-1 receptors. For example, levosimendan acts as a calcium sensitizer and adenosine triphosphate-dependent potassium (K(ATP)) channel opener that increases contraction, causes vasodilation, and provides cardioprotective effects. This is accomplished by its dual mechanism of action. Levosimendan binds to cardiac troponin C, thereby enhancing calcium myofilament responsiveness and increasing myocardial contraction without increasing intracellular calcium levels. Thus, contraction is increased with no significant increase in myocardial oxygen consumption. The opening of K(ATP) channels by levosimendan causes vasodilation and exerts anti-ischemic and anti-stunning effects on the myocardium. Other new agents target neurohormonal pathways. Tezosentan is an antagonist of endothelin-1 receptors A and B. By inhibiting endothelin-1 receptors, tezosentan may counteract the activities of endothelin-1, which include vasoconstriction, proarrhythmic activities, potentiation of other neurohormones, and mediation of increased vascular permeability. Tolvaptan is a vasopressin V2-receptor antagonist that functions as an aquaretic (ie, it increases urine volume and serum sodium with little or no sodium loss). Therefore, by using novel mechanisms of action, these agents may provide new opportunities for helping patients with AHFS.
 ...
PMID:Pharmacology of new agents for acute heart failure syndromes. 1618 25

There are important unmet needs in the treatment of acute heart failure syndromes (AHFS). The unique dual mechanism of action of levosimendan suggests that this new agent may help fill some of these unmet needs. A review of randomized, controlled clinical trials with levosimendan demonstrated that it is well tolerated, and its use results in significantly reduced pulmonary capillary wedge pressure (PCWP) and increased cardiac output. Effects of levosimendan on PCWP and cardiac output are more pronounced than those observed with dobutamine. Levosimendan treatment is also associated with significantly improved clinical symptoms. Moreover, data from 3 trials indicate that levosimendan treatment was associated with improved 6-month survival compared with dobutamine treatment or placebo. Emerging data suggest that levosimendan is beneficial for patients with acute myocardial ischemia. Thus, early clinical indicators suggest that levosimendan may help prevent myocardial injury during hospitalization for AHFS and may be well suited for first-line therapy for AHFS.
 ...
PMID:Randomized clinical trials with levosimendan. 1618 26

In this study we sought to determine whether a calcium sensitizer, levosimendan, would have a more favorable effect on postresuscitation myocardial function and, consequently, postresuscitation survival than beta-adrenergic dobutamine. The extreme decrease in survival before hospital discharge of resuscitated victims is attributed, in part, to postresuscitation myocardial failure, and dobutamine has been recommended for the management of postresuscitation myocardial failure. We studied a total of 15 animals. Ventricular fibrillation was induced in Sprague-Dawley rats weighing 450 to 550 g. Cardiopulmonary resuscitation (CPR), including chest compressions and mechanical ventilation, was begun after 8 minutes of untreated cardiac arrest. Electrical defibrillation was attempted after 6 minutes of CPR. Each animal was resuscitated. Animals were randomized to undergo treatment with levosimendan, dobutamine, or saline-solution placebo. These agents were administered 10 minutes after the return of spontaneous circulation. Levosimendan was administered in a loading dose of 12 microg kg(-1) over a 10-minute period, followed by infusion of 0.3 microg kg(-1) min(-1) over the next 230 minutes. Dobutamine was continuously infused at a dosage of 3 microg kg(-1) min(-1). Saline-solution placebo was administered in the same volume and over the same amount of time as levosimendan. Levosimendan and dobutamine produced comparable increases in cardiac output and rate of left-ventricular pressure increase. However, administration of levosimendan resulted in lower heart rates and lesser increases in left ventricular diastolic pressure compared with both dobutamine and placebo. The duration of postresuscitation survival was significantly greater with levosimendan (16 +/- 2 hours), intermediate with dobutamine (11 +/- 2 hours) and least with saline-solution placebo (8 +/- 1 hour). Levosimendan and dobutamine both improved postresuscitation myocardial function. However, levosimendan produced more favorable postresuscitation myocardial function and increased the duration of postresuscitation survival.
 ...
PMID:Levosimendan improves postresuscitation outcomes in a rat model of CPR. 1624 24

Levosimendan is effective in the treatment of decompensated heart failure. The beneficial effects of a single dose of levosimendan last much longer than those of other inotropes. However, the exact duration of the beneficial effects is unknown. We prospectively determined the duration of the cardiac effects, as measured by echocardiography, of levosimendan (LS) following a 24-hour infusion regimen in patients with decompensated heart failure (DHF). The effects of LS on plasma B-type natriuretic peptide (BNP) were also examined. Twenty patients with DHF displaying (1) deteriorating symptoms despite optimal oral therapy, (2) left ventricular ejection fractions (LVEF) < 35%, and (3) cardiac indices of < 2.5 L/m/min received 24 hours of LS infusion. Echocardiography and BNP measurements were performed pre- and postinfusion and were reassessed on days 7, 30, and 90. Left ventricular systolic function indices (cardiac output and LVEF), LV filling pressure indices, and right ventricular systolic function indices all improved following LS treatment. Most of these improvements were sustained for at least 7 days (P < 0.05) and returned to baseline by day 30 postinfusion and remained so on day 90. Plasma BNP also displayed the same pattern of transient improvements. In conclusion, LS transiently improved the cardiac function, and the effects lasted for at least 7 days after discontinuation of infusion. Most effects, except LVEF, were not significantly different from baseline on day 30.
 ...
PMID:Duration of the beneficial effects of levosimendan in decompensated heart failure as measured by echocardiographic indices and B-type natriuretic peptide. 1630 9

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.
 ...
PMID:Levosimendan for the treatment of acute heart failure syndromes. 1631 12


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>