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ABSTRACT: In the latest years, several studies described the impact of repetitive/intermittent i.v. levosimendan treatment in the management of advanced heart failure. For this updated review, we systematically searched the literature for clinical trials, registries , and real-world data and identified 31 studies that we commented in a narrative review: 3814 patients were described, of whom 1744 were treated repetitively with levosimendan. On the basis of the nature of the study protocols and of the end points, out of those studies, we further selected 9 that had characteristics, making them suitable for a meta-analysis on mortality. This short list describes data from 680 patients (of whom 399 received repeated doses of levosimendan) and 110 death events (of which 50 occurred in the levosimendan cohort). In the meta-analysis, repetitive/intermittent therapy with i.v. levosimendan was associated with a significant reduction in mortality at the longest time point available: 50 of 399 (12.5%) versus 60 of 281 (21.4%) in the control arms, with a risk ratio of 0.62 (95% confidence interval, 0.42-0.90; P < 0.01). In a sensitivity analysis, removing each trial and reanalyzing the remaining data set did not change the trend, magnitude, or significance of the results. A visual inspection of the funnel plot did not suggest publication bias. The results provide a very strong rationale for continuing to investigate the repetitive use of levosimendan in patients with advanced heart failure by properly powered regulatory clinical trials. Meanwhile, it seems that the use of repetitive/intermittent i.v. levosimendan infusions has become one of the few effective options for preserving the hemodynamic and symptomatic balance in such patients.
Assuntos
Insuficiência Cardíaca , Piridazinas , Humanos , Simendana/uso terapêutico , Cardiotônicos/uso terapêutico , Hidrazonas/uso terapêutico , Piridazinas/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológicoRESUMO
ABSTRACT: OR-1855 and OR-1896 are 2 hemodynamically active metabolites of the inodilator levosimendan, with calcium sensitizing activity, but their mechanism of action is still not fully understood. It has been previously reported that the positive inotropic effect of levosimendan is not potentiated by the adenylate cyclase activator forskolin, whereas forskolin does potentiate the effects of the phosphodiesterase (PDE) inhibitor milrinone. To ascertain whether the active metabolites follow the same pattern of levosimendan, the positive inotropic effects of OR- 1855 and OR-1896 were studied in guinea-pig-isolated papillary muscle in the presence and absence of forskolin. OR-1855 and OR-1896 were also tested as inhibitors of PDE-III and PDE-IV. Our results show that 0.1 µM forskolin did not potentiate the positive inotropic effect of OR-1855 or OR-1896, as in the case of the parent compound levosimendan. As in previous studies, the positive inotropic effect of milrinone was markedly potentiated in the presence of forskolin. From these data, we propose an explanation for the divergent behavior of the calcium sensitizing drugs and PDE inhibitors.
Assuntos
Milrinona , Inibidores de Fosfodiesterase , Adenilil Ciclases , Animais , Cálcio/metabolismo , Cardiotônicos/farmacologia , Colforsina/farmacologia , Cobaias , Milrinona/farmacologia , Contração Miocárdica , Inibidores de Fosfodiesterase/farmacologia , Simendana/farmacologiaRESUMO
ABSTRACT: Infusions of levosimendan delivered in ambulatory/outpatient settings have been shown to improve quality of life and reduce hospitalizations in patients with advanced heart failure (HF). The aim of this pilot study was to evaluate the effects of ambulatory infusion of levosimendan on echocardiographic markers of perfusion, congestion, and cardiovascular efficiency. Thirty patients with diagnosed advanced HF underwent ambulatorial infusion of levosimendan at a total dose of 6.25 mg as a part of a repetitive biweekly treatment strategy with the inotrope. Standardized transthoracic echocardiography and Doppler examinations, were performed 1 hour before and 48 hours after completion of ambulatory infusion. At 48 hours after ambulatory infusion of levosimendan, a significant increase in the stroke volume (37.47 ± 12.38 mL/beat vs. 45.47 ± 14.48 mL/beat; P < 0.05) and cardiac output (2.64 ± 0.66 L/min vs. 3.26 ± 0.57 L/min; P < 0.05) occurred. Significant postreductions versus prereductions were also recorded in left atrial pressure (27.37 ± 6.62 mm Hg vs. 22.82 ± 4.17 mm Hg; P < 0.01), mean pulmonary artery pressure (27.69 ± 4.64 mm Hg vs. 23.24 ± 5.32; P < 0.01), and inferior vena cava diameter (23.81 ± 7.63 mm vs. 18.53 ± 4.82 mm; P < 0.01). Significant improvements were noted in the resting cardiac power output (0.46 ± 0.15 watt vs. 0.53 ± 0.22 watt; P < 0.01) and the resting cardiac power index (0.24 ± 0.08 watt/m2 vs. 0.28 ± 0.11 watt/m2; P < 0.01). In outpatients with advanced HF, infusion of levosimendan was associated with hemodynamic responses that may contribute to the clinical benefit previously reported in such patients.
Assuntos
Fármacos Cardiovasculares/administração & dosagem , Ecocardiografia Doppler , Insuficiência Cardíaca/tratamento farmacológico , Hemodinâmica/efeitos dos fármacos , Simendana/administração & dosagem , Idoso , Assistência Ambulatorial , Fármacos Cardiovasculares/efeitos adversos , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Projetos Piloto , Valor Preditivo dos Testes , Recuperação de Função Fisiológica , Simendana/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
Heart failure (HF) following myocardial infarction (MI) is associated with high incidence of cardiac arrhythmias. Development of therapeutic strategy requires detailed understanding of electrophysiological remodeling. However, changes of ionic currents in ischemic HF remain incompletely understood, especially in translational large-animal models. Here, we systematically measure the major ionic currents in ventricular myocytes from the infarct border and remote zones in a porcine model of post-MI HF. We recorded eight ionic currents during the cell's action potential (AP) under physiologically relevant conditions using selfAP-clamp sequential dissection. Compared with healthy controls, HF-remote zone myocytes exhibited increased late Na+ current, Ca2+-activated K+ current, Ca2+-activated Cl- current, decreased rapid delayed rectifier K+ current, and altered Na+/Ca2+ exchange current profile. In HF-border zone myocytes, the above changes also occurred but with additional decrease of L-type Ca2+ current, decrease of inward rectifier K+ current, and Ca2+ release-dependent delayed after-depolarizations. Our data reveal that the changes in any individual current are relatively small, but the integrated impacts shift the balance between the inward and outward currents to shorten AP in the border zone but prolong AP in the remote zone. This differential remodeling in post-MI HF increases the inhomogeneity of AP repolarization, which may enhance the arrhythmogenic substrate. Our comprehensive findings provide a mechanistic framework for understanding why single-channel blockers may fail to suppress arrhythmias, and highlight the need to consider the rich tableau and integration of many ionic currents in designing therapeutic strategies for treating arrhythmias in HF.
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Potenciais de Ação/fisiologia , Arritmias Cardíacas/fisiopatologia , Cálcio/metabolismo , Fenômenos Eletrofisiológicos , Insuficiência Cardíaca/fisiopatologia , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/fisiologia , Animais , Células Cultivadas , Miócitos Cardíacos/citologia , SuínosRESUMO
Acute heart failure (AHF) continues to be a substantial cause of illness and death, with in-hospital and 3-month mortality rates of 5% and 10%, respectively, and 6-month re-admission rates in excess of 50% in a range of clinical trials and registry studies; the European Society of Cardiology (ESC) Heart Failure Long-Term Registry recorded a 1-year death or rehospitalization rate of 36%. As regards the short-term treatment of AHF patients, evidence was collected in the ESC Heart Failure Long-Term Registry that intravenous (i.v.) treatments are administered heterogeneously in the critical phase, with limited reference to guideline recommendations. Moreover, recent decades have been characterized by a prolonged lack of successful innovation in this field, with a plethora of clinical trials generating neutral or inconclusive findings on long-term mortality effects from a multiplicity of short-term interventions in AHF. One of the few exceptions has been the calcium sensitizer and inodilator levosimendan, introduced 20 years ago for the treatment of acutely decompensated chronic heart failure. In the present review, we will focus on the utility of this agent in the wider context of i.v. inotropic and inodilating therapies for AHF and related pathologies.
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Pathological interplay between the heart and kidneys is widely encountered in heart failure (HF) and is linked to worse prognosis and quality of life. Inotropes, along with diuretics and vasodilators, are a core medical response to HF but decompensated patients who need inotropic support often present with an acute worsening of renal function. The impact of inotropes on renal function is thus potentially an important influence on the choice of therapy. There is currently relatively little objective data available to guide the selection of inotrope therapy but recent direct observations on the effects of levosimendan and milrinone on glomerular filtration favour levosimendan. Other lines of evidence indicate that in acute decompensated HF levosimendan has an immediate renoprotective effect by increasing renal blood flow through preferential vasodilation of the renal afferent arterioles and increases in glomerular filtration rate: potential for renal medullary ischaemia is avoided by an offsetting increase in renal oxygen delivery. These indications of a putative reno-protective action of levosimendan support the view that this calcium-sensitizing inodilator may be preferable to dobutamine or other adrenergic inotropes in some settings by virtue of its renal effects. Additional large studies will be required, however, to clarify the renal effects of levosimendan in this and other relevant clinical situations, such as cardiac surgery.
Assuntos
Cardiotônicos , Insuficiência Cardíaca , Humanos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Cardiotônicos/uso terapêutico , Cardiotônicos/efeitos adversos , Resultado do Tratamento , Esquema de Medicação , Contração Miocárdica/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
Relaxation and changes in the transmembrane potential of vascular smooth muscle induced by ORM-3819, a novel inodilating compound, were investigated in isolated porcine coronary arteries. Isometric tone was studied on arterial rings precontracted by KCl (30 mM), and resting membrane potential was investigated by a conventional microelectrode technique. ORM-3819 in the concentration range 0.38-230.6 µM evoked concentration-dependent relaxation with a maximum value of 58.1% and an effective concentration of the relaxing substance that caused 50% of maximum relaxation of 72.2 µM. The maximum hyperpolarization produced by ORM-3819 at a concentration of 120 µM (-2.6 ± 0.81 mV, N = 10) did not differ significantly from that induced by C-type natriuretic peptide (CNP), an endogenous hyperpolarizing mediator, at a concentration of 1.4 µM (-3.6 ± 0.38 mV, N = 17). The same effect elicited by the known inodilator levosimendan was less pronounced at a concentration of 3.7 µM: -1.82 ± 0.44 mV, N = 22 (P < 0.05 vs. CNP). The voltage-gated potassium channel inhibitor 4-aminopyridine, at a concentration of 5 mM, attenuated the relaxation induced by ORM-3819 at concentrations of 41.6 or 117.2 µM. These results suggest that ORM-3819 is a potent vasodilating agent able to relieve coronary artery vasospasm by causing hyperpolarization of vascular smooth muscle cells through processes involving activation of voltage-gated potassium channels.
Assuntos
Vasos Coronários/efeitos dos fármacos , Hidrazonas/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/agonistas , Piridazinas/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Vasos Coronários/metabolismo , Técnicas In Vitro , Potenciais da Membrana , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Peptídeo Natriurético Tipo C/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Transdução de Sinais , Simendana/farmacologia , Sus scrofaRESUMO
Levosimendan is a calcium sensitizer that promotes myocyte contractility through its calcium-dependent interaction with cardiac troponin C. Administered intravenously, it has been used for nearly 2 decades to treat acute and advanced heart failure and to support the heart function in various therapy settings characterized by low cardiac output. Effects of levosimendan on noncardiac muscle suggest a possible new application in the treatment of people with amyotrophic lateral sclerosis (ALS), a neuromuscular disorder characterized by progressive weakness, and eventual paralysis. Previous attempts to improve the muscle response in ALS patients and thereby maintain respiratory function and delay progression of disability have produced some mixed results. Continuing this line of investigation, levosimendan has been shown to enhance in vitro the contractility of the diaphragm muscle fibers of non-ALS patients and to improve in vivo diaphragm neuromuscular efficiency in healthy subjects. Possible positive effects on respiratory function in people with ALS were seen in an exploratory phase 2 study, and a phase 3 clinical trial is now underway to evaluate the potential benefit of an oral form of levosimendan on both respiratory and overall functions in patients with ALS. Here, we will review the various known pharmacologic effects of levosimendan, considering their relevance to people living with ALS.
Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Diafragma/inervação , Neurônios Motores/efeitos dos fármacos , Força Muscular/efeitos dos fármacos , Fármacos Neuromusculares/uso terapêutico , Respiração/efeitos dos fármacos , Insuficiência Respiratória/tratamento farmacológico , Simendana/uso terapêutico , Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/fisiopatologia , Animais , Progressão da Doença , Humanos , Neurônios Motores/patologia , Recuperação de Função Fisiológica , Insuficiência Respiratória/patologia , Insuficiência Respiratória/fisiopatologia , Resultado do TratamentoRESUMO
Levosimendan is an inodilator that promotes cardiac contractility primarily through calcium sensitization of cardiac troponin C and vasodilatation via opening of adenosine triphosphate-sensitive potassium (KATP) channels in vascular smooth muscle cells; the drug also exerts organ-protective effects through a similar effect on mitochondrial KATP channels. This pharmacological profile identifies levosimendan as a drug that may have applications in a wide range of critical illness situations encountered in intensive care unit medicine: hemodynamic support in cardiogenic or septic shock; weaning from mechanical ventilation or from extracorporeal membrane oxygenation; and in the context of cardiorenal syndrome. This review, authored by experts from 9 European countries (Austria, Belgium, Czech republic, Finland, France, Germany, Italy, Sweden, and Switzerland), examines the clinical and experimental data for levosimendan in these situations and concludes that, in most instances, the evidence is encouraging, which is not the case with other cardioactive and vasoactive drugs routinely used in the intensive care unit. The size of the available studies is, however, limited and the data are in need of verification in larger controlled trials. Some proposals are offered for the aims and designs of these additional studies.
Assuntos
Síndrome Cardiorrenal/tratamento farmacológico , Cardiotônicos/uso terapêutico , Unidades de Terapia Intensiva , Choque Cardiogênico/tratamento farmacológico , Choque Séptico/tratamento farmacológico , Simendana/uso terapêutico , Vasodilatadores/uso terapêutico , Animais , Síndrome Cardiorrenal/diagnóstico , Síndrome Cardiorrenal/mortalidade , Síndrome Cardiorrenal/fisiopatologia , Cardiotônicos/efeitos adversos , Cuidados Críticos , Humanos , Recuperação de Função Fisiológica , Fatores de Risco , Choque Cardiogênico/diagnóstico , Choque Cardiogênico/mortalidade , Choque Cardiogênico/fisiopatologia , Choque Séptico/diagnóstico , Choque Séptico/mortalidade , Choque Séptico/fisiopatologia , Simendana/efeitos adversos , Resultado do Tratamento , Vasodilatadores/efeitos adversosRESUMO
Levosimendan is a calcium sensitizer and adenosine triphosphate-dependent potassium channel opener, which exerts sustained hemodynamic, symptomatic, and organ-protective effects. It is registered for the treatment of acute heart failure, and when inotropic support is considered appropriate. In the past 15 years, levosimendan has been widely used in clinical practice and has also been tested in clinical trials to stabilize at-risk patients undergoing cardiac surgery. Recently, 3 randomized, placebo-controlled, multicenter studies (LICORN, CHEETAH, and LEVO-CTS) have been published reporting on the perioperative use of levosimendan in patients with compromised cardiac ventricular function. Taken together, many smaller trials conducted in the past suggested beneficial outcomes with levosimendan in perioperative settings. By contrast, the latest 3 studies were neutral or inconclusive. To understand the reasons for such dissimilarity, a group of experts from Austria, Belgium, Finland, France, Germany, Italy, Switzerland, and Russia, including investigators from the 3 most recent studies, met to discuss the study results in the light of both the previous literature and current clinical practice. Despite the fact that the null hypothesis could not be ruled out in the recent multicenter trials, we conclude that levosimendan can still be viewed as a safe and effective inodilator in cardiac surgery.
Assuntos
Fármacos Cardiovasculares/uso terapêutico , Cardiopatias/cirurgia , Assistência Perioperatória/métodos , Simendana/uso terapêutico , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Fármacos Cardiovasculares/efeitos adversos , Tomada de Decisão Clínica , Congressos como Assunto , Consenso , Medicina Baseada em Evidências/métodos , Cardiopatias/diagnóstico , Cardiopatias/fisiopatologia , Humanos , Seleção de Pacientes , Assistência Perioperatória/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Simendana/efeitos adversos , Resultado do TratamentoRESUMO
The use of inotropes for correcting hemodynamic dysfunction in patients with congestive heart failure has been described over many decades. However, negative or insufficient data have been collected regarding the effects of cardiac glycosides, catecholamines, and phosphodiesterase inhibitors on quality of life and survival. More recently, the calcium sensitizer and potassium channel-opener levosimendan has been proposed as a safer inodilator than traditional agents in some heart failure settings, such as advanced heart failure. At the 2017 annual congress of the Heart Failure Association of the European Society of Cardiology (Paris, April 30-May 2), a series of tutorials delivered by lecturers from 8 European countries examined how to use levosimendan safely and effectively in acute and advanced heart failure. The proceedings of those tutorials have been collated in this review to provide an expert perspective on the optimized use of levosimendan in those settings.
Assuntos
Cardiotônicos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Simendana/uso terapêutico , Vasodilatadores/uso terapêutico , Doença Aguda , Cardiotônicos/efeitos adversos , Doença Crônica , Tomada de Decisão Clínica , Congressos como Assunto , Bases de Dados Factuais , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Contração Miocárdica/efeitos dos fármacos , Seleção de Pacientes , Recuperação de Função Fisiológica , Fatores de Risco , Simendana/efeitos adversos , Resultado do Tratamento , Vasodilatação/efeitos dos fármacos , Vasodilatadores/efeitos adversosRESUMO
Levosimendan, a calcium sensitizer and potassium channel-opener, is widely appreciated by many specialist heart failure practitioners for its effects on systemic and pulmonary hemodynamics and for the relief of symptoms of acute heart failure. The drug's impact on mortality in large randomized controlled trials has been inconsistent or inconclusive but, in contrast to conventional inotropes, there have been no indications of worsened survival and some signals of improved heart failure-related quality of life. For this reason, levosimendan has been proposed as a safer inodilator option than traditional agents in settings, such as advanced heart failure. Positive effects of levosimendan on renal function have also been described. At the HEART FAILURE 2018 congress of the Heart Failure Association of the European Society of Cardiology, safe and effective use levosimendan in acute and advanced heart failure was examined in a series of expert tutorials. The proceedings of those tutorials are summarized in this review, with special reference to advanced heart failure and heart failure with concomitant renal dysfunction. Meta-analysis of clinical trials data is supportive of a renal-protective effect of levosimendan, while physiological observations suggest that this effect is exerted at least in part via organ-specific effects that may include selective vasodilation of glomerular afferent arterioles and increased renal blood flow, with no compromise of renal oxygenation. These lines of evidence require further investigation and their clinical significance needs to be evaluated in specifically designed prospective trials.
Assuntos
Cardiotônicos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Contração Miocárdica/efeitos dos fármacos , Simendana/uso terapêutico , Vasodilatadores/uso terapêutico , Doença Aguda , Cardiotônicos/efeitos adversos , Doença Crônica , Congressos como Assunto , Medicina Baseada em Evidências , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Rim/efeitos dos fármacos , Rim/fisiopatologia , Recuperação de Função Fisiológica , Simendana/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Vasodilatadores/efeitos adversosRESUMO
As a calcium sensitizer and inodilator that augments cardiac contractility without increasing myocardial oxygen demand or exacerbating ischaemia, levosimendan may be well configured to deliver inotropic support in cases of acute heart failure (AHF). Other factors favouring levosimendan in this setting include its extended duration of action due to the formation of an active metabolite and the lack of any attenuation of effect in patients treated with beta-blockers. Effects of levosimendan on systemic haemodynamics include its significant, dose-dependent increases in cardiac output, stroke volume and heart rate, and decreases in right and left ventricular filling and total peripheral resistance. Rapid and sustained reduction in levels of natriuretic peptides is a consistent effect of levosimendan use and potentially favourable effects on other neurohormonal indicators of cardiac distress are also observed. Levosimendan has repeatedly been shown to be effective in relief of symptoms of AHF, notably dyspnoea and fatigue, while mortality data from clinical trials and registries suggest that levosimendan is markedly less likely than catecholaminergic inotropes to worsen prognosis. The vasodilator pharmacology of levosimendan is also pertinent to the drug's use in AHF, in which setting organ under-perfusion is often a key pathology. These considerations suggest that levosimendan may have a more favourable impact on the circumstances of the majority of AHF patients than adrenergic agents that act only or primarily as cardiac stimulants. They also suggest that levosimendan may advantageously be integrated into a comprehensive strategy of early intervention designed and intended to prevent cardiac destabilization worsening to the point where hospitalization is necessary. Levosimendan should be used with caution and with tightened haemodynamic monitoring in patients who have low baseline blood pressure (systolic blood pressure <100 mmHg; diastolic blood pressure <60 mmHg), or who are at risk of a hypotensive episode.
RESUMO
As in other organs, oxidative stress-induced injury and cell death may result from free oxygen radical-dependent mechanisms and alterations in signal transduction pathways leading to apoptosis. Among the new suggested therapies for injuries caused by oxidative stress, the use of levosimendan has been reported to be quite promising. In the present study, we aimed to examine the protective effects of levosimendan against liver oxidative stress in anesthetized rats and to analyze the involvement of mitochondrial adenosine triphosphate-dependent potassium (mitoK(ATP)) channels and nitric oxide (NO). In 50 anesthetized rats, liver ischemia/reperfusion (I/R) was performed via nontraumatic portal occlusion. In some animals, levosimendan was infused into the portal vein at the onset of reperfusion, whereas other rats received the vehicle only. Moreover, in some rats, levosimendan was given after the intraportal administration of L-Nω-nitro-arginine methyl ester (L-NAME) or 5-hydroxydecanoate (5HD). The portal vein blood flow was measured, and blood samples were taken for the determination of transaminases, thiobarbituric acid reactive substances (TBARS), and reduced glutathione (GSH); liver biopsy samples were used for B cell lymphoma 2-associated X protein, caspase-9, Akt, and endothelial nitric oxide synthase (eNOS) activation through western blotting. Also, caspase-3 activity was measured. In rats, I/R caused an increase in apoptotic markers, transaminases, and TBARS and a decrease in GSH and Akt activation. Levosimendan administration was able to counteract oxidative damage and apoptosis in a dose-dependent way and to increase GSH, Akt, and eNOS activation. All effects of levosimendan were abolished by pretreatment with L-NAME and 5HD. In conclusion, the results of the present study show that levosimendan can exert protection against ischemic liver damage through mechanisms related to NO production and mitoKATP channel function. These data provide interesting perspectives into the use of levosimendan in hepatic surgery and transplantation.
Assuntos
Hidrazonas/uso terapêutico , Fígado/patologia , Piridazinas/uso terapêutico , Traumatismo por Reperfusão/terapia , Anestesia , Animais , Apoptose , Biópsia , Velocidade do Fluxo Sanguíneo , Caspase 3/metabolismo , Sobrevivência Celular , Ácidos Decanoicos/química , Glutationa/química , Hidroxiácidos/química , NG-Nitroarginina Metil Éster/química , Óxido Nítrico/química , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo , Inibidores de Fosfodiesterase/química , Veia Porta/patologia , Canais de Potássio/química , Ratos , Simendana , Substâncias Reativas com Ácido Tiobarbitúrico/química , Proteína X Associada a bcl-2/metabolismoRESUMO
Acute heart failure (AHF) emerges as a major and growing epidemiological concern with high morbidity and mortality rates. Current therapies in patients with acute heart failure rely on different strategies. Patients with hypotension, hypoperfusion, or shock require inotropic support, whereas diuretics and vasodilators are recommended in patients with systemic or pulmonary congestion. Traditionally inotropic agents, referred to as Ca mobilizers load the cardiomyocyte with Ca and thereby increase oxygen consumption and risk for arrhythmias. These limitations of traditional inotropes may be avoided by sarcomere targeted agents. Direct activation of the cardiac sarcomere may be achieved by either sensitizing the cardiac myofilaments to Ca or activating directly the cardiac myosin. In this review, we focus on sarcomere targeted inotropic agents, emphasizing their mechanisms of action and overview the most relevant clinical considerations.