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1.
Biol Res Nurs ; 21(5): 466-472, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31272201

RESUMO

Levosimendan is a myocardial Ca2+ sensitizer and opener of ATP-dependent potassium channels with inotropic, vasodilating, and cardioprotective properties. It was originally developed for the treatment of acute decompensated heart failure, but its complex mechanism of action means that it could also play a role in organ protection in response to infection. Using an in vitro approach, we explored whether levosimendan administration influenced cell responses to lipopolysaccharide (LPS). Primary human umbilical vein endothelial cells were stimulated with 1 µg/ml LPS from Escherichia coli (E. coli). Cells were treated with levosimendan at 0, 0.1, 1, or 10 µM 3 hr later. Samples were taken 24 hr after treatment to measure cell necrosis, apoptosis, pro-inflammatory mediators (interleukin 6 [IL-6] and toll-like receptor 4 [TLR4]), and oxidative stress (total reactive oxygen species/reactive nitrogen species [ROS/RNS]). Levosimendan at 1 and 10 µM protected against LPS-induced endothelial cell death and reduced TLR4 expression (p < .05). All doses reduced levels of IL-6 and ROS/RNS (p < .05). Findings suggest that levosimendan may exert protective effects against endothelial cell death in this model via attenuation of inflammation and oxidative stress pathways. Future studies might explore the potential beneficial role of levosimendan in modulating molecular mechanisms triggered by infections.

2.
J Cardiovasc Pharmacol ; 74(3): 218-224, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31356552

RESUMO

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.

3.
Eur J Heart Fail ; 21(3): 272-285, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30714667

RESUMO

Fibrosis is a pivotal player in heart failure development and progression. Measurements of (markers of) fibrosis in tissue and blood may help to diagnose and risk stratify patients with heart failure, and its treatment may be effective in preventing heart failure and its progression. A lack of pathophysiological insights and uniform definitions has hampered the research in fibrosis and heart failure. The Translational Research Committee of the Heart Failure Association discussed several aspects of fibrosis in their workshop. Early insidious perturbations such as subclinical hypertension or inflammation may trigger first fibrotic events, while more dramatic triggers such as myocardial infarction and myocarditis give rise to full blown scar formation and ongoing fibrosis in diseased hearts. Aging itself is also associated with a cardiac phenotype that includes fibrosis. Fibrosis is an extremely heterogeneous phenomenon, as several stages of the fibrotic process exist, each with different fibrosis subtypes and a different composition of various cells and proteins - resulting in a very complex pathophysiology. As a result, detection of fibrosis, e.g. using current cardiac imaging modalities or plasma biomarkers, will detect only specific subforms of fibrosis, but cannot capture all aspects of the complex fibrotic process. Furthermore, several anti-fibrotic therapies are under investigation, but such therapies generally target aspecific aspects of the fibrotic process and suffer from a lack of precision. This review discusses the mechanisms and the caveats and proposes a roadmap for future research.

4.
Cardiovasc Drugs Ther ; 32(6): 617-624, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30402660

RESUMO

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.

6.
Proc Natl Acad Sci U S A ; 115(13): E3036-E3044, 2018 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-29531045

RESUMO

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.


Assuntos
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 , Suínos
7.
J Cardiovasc Pharmacol ; 71(3): 129-136, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28817484

RESUMO

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.

8.
J Cardiovasc Pharmacol ; 71(1): 1-9, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29076887

RESUMO

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.

9.
Eur J Pharmacol ; 818: 278-286, 2018 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-29066415

RESUMO

Na+/Ca2+ exchanger (NCX) is the main Ca2+ transporter in cardiac myocytes. Its inhibition could be expected to exert positive inotropic action by accumulation of cytosolic Ca2+ ([Ca2+]i). However, we have observed only a marginal positive inotropic effect upon selective inhibition of NCX, which was enhanced when forward activity was facilitated. Here we attempted to clarify the underlying mechanism of the limited inotropic action of selective NCX inhibition by a novel inhibitor ORM-10962 on canine ventricular myocytes. 1µM ORM-10962 reduced the Ca2+ content of sarcoplasmic reticulum (SR) when the reverse NCX was favoured, while SR Ca2+ content was increased by ORM-10962 under conditions favouring the forward activity, like elevation of [Ca2+]i. L-type Ca2+ current (ICa) was not affected by 1µM ORM-10962 in the absence of SR Ca2+ release, while ICa was suppressed by ORM-10962 during normal Ca2+ cycling. The apparent degree of forward NCX inhibition was dependent on the elevation of [Ca2+]i, suggesting that an increased driving force of forward NCX can also limit the accumulation of [Ca2+i]. We concluded that in healthy myocardium the possible positive inotropic potential of NCX inhibition is considerably weaker than it was expected earlier by theoretical assumptions. The underlying mechanism may involve the autoregulation of Ca2+ handling and/or the preserved inducibility of forward NCX by high [Ca2+]i. This limitation of selective NCX inhibition seen in undiseased myocardium requires further studies in failing heart, which may allow correct evaluation of the potential therapeutic value of selective NCX inhibitors in the treatment of heart failure.


Assuntos
Acetamidas/farmacologia , Cromanos/farmacologia , Ventrículos do Coração/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Piperidinas/farmacologia , Trocador de Sódio e Cálcio/antagonistas & inibidores , Animais , Cálcio/metabolismo , Cães , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Feminino , Masculino , Miócitos Cardíacos/citologia , Retículo Sarcoplasmático/efeitos dos fármacos
10.
Eur J Heart Fail ; 19(11): 1361-1378, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28949064

RESUMO

Despite improvements in medical therapy and device-based treatment, heart failure (HF) continues to impose enormous burdens on patients and health care systems worldwide. Alterations in autonomic nervous system (ANS) activity contribute to cardiac disease progression, and the recent development of invasive techniques and electrical stimulation devices has opened new avenues for specific targeting of the sympathetic and parasympathetic branches of the ANS. The Heart Failure Association of the European Society of Cardiology recently organized an expert workshop which brought together clinicians, trialists and basic scientists to discuss the ANS as a therapeutic target in HF. The questions addressed were: (i) What are the abnormalities of ANS in HF patients? (ii) What methods are available to measure autonomic dysfunction? (iii) What therapeutic interventions are available to target the ANS in patients with HF, and what are their specific strengths and weaknesses? (iv) What have we learned from previous ANS trials? (v) How should we proceed in the future?


Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Cardiologia , Consenso , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Sociedades Médicas , Pesquisa Médica Translacional/métodos , Europa (Continente) , Humanos
11.
ESC Heart Fail ; 4(4): 595-604, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28834396

RESUMO

AIMS: Intermittent levosimendan administration has been suggested to improve survival in patients with advanced heart failure (AdHF). Quality of life is a key issue for AdHF patients and is negatively affected by frequent hospitalizations. METHODS AND RESULTS: CENTRAL, Google Scholar, MEDLINE/PubMed, Scopus, and the Cochrane Central Register of clinical trials (updated 15/1/2017) were searched for randomized controlled trials investigating the effect of intermittent levosimendan administration in patients with AdHF. The primary outcome was the number of patients requiring rehospitalization 3 months after the end of treatment. A total of 319 patients from six trials were included. Overall pooled analysis showed that the use of levosimendan was associated with a significant reduction in the number of rehospitalizations at 3 months: 33/207 (16%) vs. 39/113 (35%), risk ratio 0.40, 95% confidence interval 0.27-0.59, P < 0.001, I2  = 0%. This result was confirmed by sensitivity analyses. CONCLUSIONS: Within the limitations of this meta-analysis including also studies in which endpoints were not independently adjudicated and not clearly specified, repetitive or intermittent administration of levosimendan for patients with AdHF was associated with a reduction in the rehospitalization rate at 3 months. Large, high-quality randomized controlled trials are needed to confirm this finding.


Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Hidrazonas/administração & dosagem , Readmissão do Paciente/tendências , Piridazinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Causas de Morte/tendências , Relação Dose-Resposta a Droga , Esquema de Medicação , Saúde Global , Insuficiência Cardíaca/mortalidade , Humanos , Simendana , Taxa de Sobrevida/tendências , Vasodilatadores/administração & dosagem
12.
Int J Cardiol ; 243: 389-395, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28571618

RESUMO

Patients in the latest stages of heart failure are severely compromised, with poor quality of life and frequent hospitalizations. Heart transplantation and left ventricular assist device implantation are viable options only for a minority, and intermittent or continuous infusions of positive inotropes may be needed as a bridge therapy or as a symptomatic approach. In these settings, levosimendan has potential advantages over conventional inotropes (catecholamines and phosphodiesterase inhibitors), such as sustained effects after initial infusion, synergy with beta-blockers, and no increase in oxygen consumption. Levosimendan has been suggested as a treatment that reduces re-hospitalization and improves quality of life. However, previous clinical studies of intermittent infusions of levosimendan were not powered to show statistical significance on key outcome parameters. A panel of 45 expert clinicians from 12 European countries met in Rome on November 24-25, 2016 to review the literature and envision an appropriately designed clinical trial addressing these needs. In the earlier FIGHT trial (daily subcutaneous injection of liraglutide in heart failure patients with reduced ejection fraction) a composite Global Rank Score was used as primary end-point where death, re-hospitalization, and change in N-terminal-prohormone-brain natriuretic peptide level were considered in a hierarchical order. In the present study, we tested the same end-point post hoc in the PERSIST and LEVOREP trials on oral and repeated i.v. levosimendan, respectively, and demonstrated superiority of levosimendan treatment vs placebo. The use of the same composite end-point in a properly powered study on repetitive levosimendan in advanced heart failure is strongly advocated.


Assuntos
Cardiotônicos/administração & dosagem , Conferências de Consenso como Assunto , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/epidemiologia , Hidrazonas/administração & dosagem , Piridazinas/administração & dosagem , Administração Oral , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/normas , Esquema de Medicação , Europa (Continente)/epidemiologia , Medicina Baseada em Evidências/normas , Medicina Baseada em Evidências/tendências , Insuficiência Cardíaca/diagnóstico , Humanos , Infusões Intravenosas , Roma/epidemiologia , Simendana
13.
PLoS One ; 11(11): e0166041, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27832106

RESUMO

BACKGROUND: In this study the effects of a new, highly selective sodium-calcium exchanger (NCX) inhibitor, ORM-10962 were investigated on cardiac NCX current, Ca2+ transients, cell shortening and in experimental arrhythmias. The level of selectivity of the novel inhibitor on several major transmembrane ion currents (L-type Ca2+ current, major repolarizing K+ currents, late Na+ current, Na+/K+ pump current) was also determined. METHODS: Ion currents in single dog ventricular cells (cardiac myocytes; CM), and action potentials in dog cardiac multicellular preparations were recorded utilizing the whole-cell patch clamp and standard microelectrode techniques, respectively. Ca2+ transients and cell shortening were measured in fluorescent dye loaded isolated dog myocytes. Antiarrhythmic effects of ORM-10962 were studied in anesthetized ouabain (10 µg/kg/min i.v.) pretreated guinea pigs and in ischemia-reperfusion models (I/R) of anesthetized coronary artery occluded rats and Langendorff perfused guinea pigs hearts. RESULTS: ORM-10962 significantly reduced the inward/outward NCX currents with estimated EC50 values of 55/67 nM, respectively. The compound, even at a high concentration of 1 µM, did not modify significantly the magnitude of ICaL in CMs, neither had any apparent influence on the inward rectifier, transient outward, the rapid and slow components of the delayed rectifier potassium currents, the late and peak sodium and Na+/K+ pump currents. NCX inhibition exerted moderate positive inotropic effect under normal condition, negative inotropy when reverse, and further positive inotropic effect when forward mode was facilitated. In dog Purkinje fibres 1 µM ORM-10962 decreased the amplitude of digoxin induced delayed afterdepolarizations (DADs). Pre-treatment with 0.3 mg/kg ORM-10962 (i.v.) 10 min before starting ouabain infusion significantly delayed the development and recurrence of ventricular extrasystoles (by about 50%) or ventricular tachycardia (by about 30%) in anesthetized guinea pigs. On the contrary, ORM-10962 pre-treatment had no apparent influence on the time of onset or the severity of I/R induced arrhythmias in anesthetized rats and in Langendorff perfused guinea-pig hearts. CONCLUSIONS: The present study provides strong evidence for a high efficacy and selectivity of the NCX-inhibitory effect of ORM-10962. Selective NCX inhibition can exert positive as well as negative inotropic effect depending on the actual operation mode of NCX. Selective NCX blockade may contribute to the prevention of DAD based arrhythmogenesis, in vivo, however, its effect on I/R induced arrhythmias is still uncertain.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Antiarrítmicos/química , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Trocador de Sódio e Cálcio/antagonistas & inibidores , Animais , Antiarrítmicos/farmacologia , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/patologia , Cálcio/metabolismo , Células Cultivadas , Cães , Descoberta de Drogas , Cobaias , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos Sprague-Dawley , Trocador de Sódio e Cálcio/metabolismo
14.
Expert Rev Cardiovasc Ther ; 14(12): 1335-1347, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27778514

RESUMO

INTRODUCTION: The later stages of heart failure are characterized by a steady decline in quality of life. Clinical priorities should be to maintain functional capacity and quality of life. In the absence of sufficient organs for transplantation, options include left ventricular assist devices and inotropic support. Areas covered: We examined data published in the last two decades on the use of inotropes and inodilators in advanced heart failure. Expert commentary: In the literature, use of conventional inotropes, including adrenergic agonists and phosphodiesterase inhibitors, appears to be suboptimal for achieving the clinical priorities of late-stage heart failure. Evidence suggests instead that the calcium-sensitizing inodilator levosimendan, administered intermittently, delivers improvements in functional capacity and quality of life and does so with no adverse impact on life expectancy. At a terminal or near-terminal stage of heart failure, the therapeutic philosophy should shift towards meeting patients' existential priorities rather than traditional heart failure-centric targets.


Assuntos
Insuficiência Cardíaca/terapia , Hidrazonas/uso terapêutico , Piridazinas/uso terapêutico , Qualidade de Vida , Cardiotônicos/uso terapêutico , Insuficiência Cardíaca/fisiopatologia , Coração Auxiliar , Humanos , Simendana
15.
Int J Cardiol ; 222: 303-312, 2016 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-27498374

RESUMO

Levosimendan is a positive inotrope with vasodilating properties (inodilator) indicated for decompensated heart failure (HF) patients with low cardiac output. Accumulated evidence supports several pleiotropic effects of levosimendan beyond inotropy, the heart and decompensated HF. Those effects are not readily explained by cardiac function enhancement and seem to be related to additional properties of the drug such as anti-inflammatory, anti-oxidative and anti-apoptotic ones. Mechanistic and proof-of-concept studies are still required to clarify the underlying mechanisms involved, while properly designed clinical trials are warranted to translate preclinical or early-phase clinical data into more robust clinical evidence. The present position paper, derived by a panel of 35 experts in the field of cardiology, cardiac anesthesiology, intensive care medicine, cardiac physiology, and cardiovascular pharmacology from 22 European countries, compiles the existing evidence on the pleiotropic effects of levosimendan, identifies potential novel areas of clinical application and defines the corresponding gaps in evidence and the required research efforts to address those gaps.


Assuntos
Cardiotônicos/uso terapêutico , Prova Pericial/normas , Insuficiência Cardíaca/tratamento farmacológico , Coração/efeitos dos fármacos , Hidrazonas/uso terapêutico , Piridazinas/uso terapêutico , Doença Aguda , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Cardiotônicos/farmacologia , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/normas , Prova Pericial/métodos , Coração/fisiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Hidrazonas/farmacologia , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Piridazinas/farmacologia , Simendana , Resultado do Tratamento
16.
Int J Cardiol ; 218: 150-157, 2016 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-27232927

RESUMO

Acute heart failure and/or cardiogenic shock are frequently triggered by ischemic coronary events. Yet, there is a paucity of randomized data on the management of patients with heart failure complicating acute coronary syndrome, as acute coronary syndrome and cardiogenic shock have frequently been defined as exclusion criteria in trials and registries. As a consequence, guideline recommendations are mostly driven by observational studies, even though these patients have a particularly poor prognosis compared to heart failure patients without signs of coronary artery disease. In acute heart failure, and especially in cardiogenic shock related to ischemic conditions, vasopressors and inotropes are used. However, both pathophysiological considerations and available clinical data suggest that these treatments may have disadvantageous effects. The inodilator levosimendan offers potential benefits due to a range of distinct effects including positive inotropy, restoration of ventriculo-arterial coupling, increases in tissue perfusion, and anti-stunning and anti-inflammatory effects. In clinical trials levosimendan improves symptoms, cardiac function, hemodynamics, and end-organ function. Adverse effects are generally less common than with other inotropic and vasoactive therapies, with the notable exception of hypotension. The decision to use levosimendan, in terms of timing and dosing, is influenced by the presence of pulmonary congestion, and blood pressure measurements. Levosimendan should be preferred over adrenergic inotropes as a first line therapy for all ACS-AHF patients who are under beta-blockade and/or when urinary output is insufficient after diuretics. Levosimendan can be used alone or in combination with other inotropic or vasopressor agents, but requires monitoring due to the risk of hypotension.


Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Antiarrítmicos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Hidrazonas/uso terapêutico , Piridazinas/uso terapêutico , Síndrome Coronariana Aguda/complicações , Sinergismo Farmacológico , Insuficiência Cardíaca/etiologia , Humanos , Guias de Prática Clínica como Assunto , Prognóstico , Simendana
17.
Int J Cardiol ; 215: 26-31, 2016 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-27107540

RESUMO

BACKGROUND: In the SURVIVE trial, including 1327 acute heart failure patients, no statistically significant difference between levosimendan and dobutamine in the 180-day all-cause mortality was seen. Country-specific differences in outcome were, however, present. In the Finnish sub-population in fact, mortality was significantly lower in levosimendan treated patients. We aim to understand the reasons for this disparity. METHODS: The risk factors for all-cause mortality were identified in the whole study population using multivariate Cox proportional hazards regression analysis. Those factors were evaluated in the 95 patients of the Finnish sub-population. RESULTS: The treatment by country interaction for mortality in Finland vs. other countries was significant, p=0.029. Levosimendan treated patients had a lower 180-day mortality compared to dobutamine treated (17% vs. 40%, p=0.023) in the Finnish sub-population. Baseline variables predicting survival in the whole SURVIVE trial population included age, systolic blood pressure, heart rate, myocardial infarction during admission, levels of NT-pro-BNP, glucose, creatinine, and alanine transferase, use of ACE inhibitors and ß-blockers, oliguria, time from hospital admission to randomization, history of cardiac arrest, and left ventricular ejection fraction. Finnish patients were more frequently treated with ß-blockers (88% vs. 52%, p<0.0001), their study treatment was started earlier (mean±SD 41±40h vs. 81±154; p<0.0001), and they had more often acute myocardial infarction at admission (39% vs. 16%, p<0.0001). CONCLUSION: The lower mortality in the Finnish patients treated with levosimendan was associated with higher use of ß-blockers, higher frequency of myocardial infarction at admission, and shorter delay between randomization and start of treatment.


Assuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Dobutamina/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/mortalidade , Hidrazonas/administração & dosagem , Piridazinas/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Dobutamina/efeitos adversos , Quimioterapia Combinada , Feminino , Finlândia/epidemiologia , Humanos , Hidrazonas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Piridazinas/efeitos adversos , Estudos Retrospectivos , Simendana , Análise de Sobrevida , Resultado do Tratamento
18.
Eur J Pharmacol ; 775: 120-9, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26872993

RESUMO

This study is the first pharmacological characterization of the novel chemical entity, ORM-3819 (L-6-{4-[N'-(4-Hydroxi-3-methoxy-2-nitro-benzylidene)-hydrazino]-phenyl}-5-methyl-4,5-dihydro-2H-pyridazin-3-one), focusing primarily on its cardiotonic effects. ORM-3819 binding to cardiac troponin C (cTnC) was confirmed by nuclear magnetic resonance spectroscopy, and a selective inhibition of the phosphodiesterase III (PDE III) isozyme (IC50=3.88±0.3 nM) was revealed during in vitro enzyme assays. The Ca(2+)-sensitizing effect of ORM-3819 was demonstrated in vitro in permeabilized myocyte-sized preparations from left ventricles (LV) of guinea pig hearts (ΔpCa50=0.12±0.01; EC50=2.88±0.14 µM). ORM-3819 increased the maximal rate of LV pressure development (+dP/dtmax) (EC50=8.9±1.7 nM) and LV systolic pressure (EC50=7.63±1.74 nM) in Langendorff-perfused guinea pig hearts. Intravenous administration of ORM-3819 increased LV+dP/dtmax (EC50=0.13±0.05 µM/kg) and improved the rate of LV pressure decrease (-dP/dtmax); (EC50=0.03±0.02 µM/kg) in healthy guinea pigs. In an in vivo dog model of myocardial stunning, ORM-3819 restored the depressed LV+dP/dtmax and improved % segmental shortening (%SS) in the ischemic area (to 18.8±3), which was reduced after the ischaemia-reperfusion insult (from 24.1±2.1 to 11.0±2.4). Our data demonstrate ORM-3819 as a potent positive inotropic agent exerting its cardiotonic effect by a cTnC-dependent Ca(2+)-sensitizing mechanism in combination with the selective inhibition of the PDE III isozyme. This dual mechanism of action results in the concentration-dependent augmentation of the contractile performance under control conditions and in the postischemic failing myocardium.


Assuntos
Cardiotônicos/farmacologia , Hidrazonas/farmacologia , Contração Miocárdica/efeitos dos fármacos , Inibidores da Fosfodiesterase 3/farmacologia , Piridazinas/farmacologia , Animais , Cálcio/fisiologia , Cães , Feminino , Cobaias , Ventrículos do Coração/citologia , Técnicas In Vitro , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Troponina C/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos
19.
J Med Econ ; 19(5): 506-14, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26707159

RESUMO

OBJECTIVE: To evaluate the cost-benefit of using levosimendan compared with dobutamine, in the perioperative treatment of patients undergoing cardiac surgery who require inotropic support. METHODS: A two-part Markov model was designed to simulate health-state transitions of patients undergoing cardiac surgery, and estimate the short- and long-term health benefits of treatment. Hospital length of stay (LOS), mortality, medication, and adverse events were key clinical- and cost-inputs. Cost-benefits were evaluated in terms of costs and bed stays within the German healthcare system. Drug prices were calculated from the German Drug Directory (€/2014) and published literature, with a 3% annual discount rate applied. The base case analysis was for a 1-year time horizon. RESULTS: The use of levosimendan vs dobutamine was associated with cost savings of €4787 per patient from the German hospital perspective due to reduced adverse events and shorter hospital LOS, leading to increased bed capacity and hospital revenue. LIMITATIONS: A pharmacoeconomic calculation for the specific situation of the German healthcare system that is based on international clinical trial carries a substantial risk of disregarding potentially relevant but unknown confounding factors (i.e., ICU-staffing, co-medications, standard-ICU care vs fast-tracking, etc.) that may either attenuate or increase the outcome pharmacoeconomic effects of a drug; however, since these conditions would also apply for patients treated with comparators, their net effects may not necessarily influence the conclusions. CONCLUSIONS: The use of levosimendan in patients undergoing cardiac surgery who require inotropic support appears to be cost-saving. The results of the analysis provide a strong rationale to run local clinical studies with pharmacoeconomic end-points which would allow a much more precise computation of the benefits of levosimendan.


Assuntos
Procedimentos Cirúrgicos Cardíacos/métodos , Cardiotônicos/economia , Cardiotônicos/uso terapêutico , Hidrazonas/economia , Hidrazonas/uso terapêutico , Piridazinas/economia , Piridazinas/uso terapêutico , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Procedimentos Cirúrgicos Cardíacos/mortalidade , Cardiotônicos/administração & dosagem , Cardiotônicos/efeitos adversos , Análise Custo-Benefício , Dobutamina/economia , Dobutamina/uso terapêutico , Alemanha , Humanos , Hidrazonas/administração & dosagem , Hidrazonas/efeitos adversos , Seguro Saúde/economia , Tempo de Internação , Cadeias de Markov , Modelos Econométricos , Piridazinas/administração & dosagem , Piridazinas/efeitos adversos , Simendana
20.
Int J Cardiol ; 191: 22017 Apr, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25981363

RESUMO

End of life is an unfortunate but inevitable phase of the heart failure patients' journey. It is often preceded by a stage in the progression of heart failure defined as advanced heart failure, and characterised by poor quality of life and frequent hospitalisations. In clinical practice, the efficacy of treatments for advanced heart failure is often assessed by parameters such as clinical status, haemodynamics, neurohormonal status, and echo/MRI indices. From the patients' perspective, however, quality-of-life-related parameters, such as functional capacity, exercise performance, psychological status, and frequency of re-hospitalisations, are more significant. The effects of therapies and interventions on these parameters are, however, underrepresented in clinical trials targeted to assess advanced heart failure treatment efficacy, and data are overall scarce. This is possibly due to a non-universal definition of the quality-of-life-related endpoints, and to the difficult standardisation of the data collection. These uncertainties also lead to difficulties in handling trade-off decisions between quality of life and survival by patients, families and healthcare providers. A panel of 34 experts in the field of cardiology and intensive cardiac care from 21 countries around the world convened for reviewing the existing data on quality-of-life in patients with advanced heart failure, discussing and reaching a consensus on the validity and significance of quality-of-life assessment methods. Gaps in routine care and research, which should be addressed, were identified. Finally, published data on the effects of current i.v. vasoactive therapies such as inotropes, inodilators, and vasodilators on quality-of-life in advanced heart failure patients were analysed.


Assuntos
Progressão da Doença , Insuficiência Cardíaca/psicologia , Hospitalização/tendências , Qualidade de Vida/psicologia , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/terapia , Humanos , Taxa de Sobrevida/tendências , Resultado do Tratamento
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