Calcium Sensitizer Levosimendan Research Articles

The Effects of the Levosimendan Metabolites OR-1855 and OR-1896 on Endothelial Pro-Inflammatory Responses

The calcium sensitizer levosimendan is used for the treatment of acute decompensated heart failure. A small portion (4-7%) of levosimendan is metabolized to the pharmacologically active metabolite OR-1896 via the inactive intermediate OR-1855. In addition, levosimendan has been shown to exert positive effects on the endothelium in vitro antagonizing vascular dysfunction and inflammation. However, the function of the levosimendan metabolites within this context is still unknown. In this study, we thus investigated the impact of the metabolites OR-1896 and OR-1855 on endothelial inflammatory processes in vitro. We observed a reduction of IL-1β-dependent endothelial adhesion molecule ICAM-1 and VCAM-1 as well as interleukin (IL) -6 expression upon levosimendan treatment but not after treatment with OR-1855 or OR-1896, as assessed by western blotting, flow cytometry, and qRT-PCR. Instead, the metabolites impaired IL-1β-induced ROS formation via inactivation of the MAPK p38, ERK1/2, and JNK. Our results suggest that the levosimendan metabolites OR-1896 and OR-1855 have certain anti-inflammatory properties, partly other than levosimendan. Importantly, they additionally show that the intermediate metabolite OR-1855 does, in fact, have pharmacological effects in the endothelium. This is interesting, as the metabolites are responsible for the long-term therapeutic effects of levosimendan, and heart failure is associated with vascular dysfunction and inflammation.

Levosimendan Ameliorates Cardiopulmonary Function but Not Inflammatory Response in a Dual Model of Experimental ARDS

The calcium sensitiser levosimendan, which is used as an inodilator to treat decompensated heart failure, may also exhibit anti-inflammatory properties. We examined whether treatment with levosimendan improves cardiopulmonary function and is substantially beneficial to the inflammatory response in acute respiratory response syndrome (ARDS). Levosimendan was administered intravenously in a new experimental porcine model of ARDS. For comparison, we used milrinone, another well-known inotropic agent. Our results demonstrated that levosimendan intravenously improved hemodynamics and lung function in a porcine ARDS model. Significant beneficial alterations in the inflammatory response and lung injury were not detected.

Oral application of levosimendan before ischaemia/reperfusion with or without cardioplegic arrest in rats.

Clinical studies have indicated minor beneficial effects of the calcium sensitizer levosimendan on clinical outcomes in patients undergoing cardiac surgery. Here, the influence of levosimendan administered 24 h before cardiac arrest on myocardial function was examined in rat hearts perfused in a Langendorff model. Levosimendan (Levo group) or NaCl (control group) was administered to 53 rats via drinking water 24 h prior to mounting excised hearts on a Langendorff apparatus. Cardiac arrest with or without cardioplegia was induced in both groups; another set of hearts was perfused continuously. During 90-min reperfusion at 36°C, functional parameters were measured and normalized to baseline values. Troponin I was quantified in coronary sinus effluent, and the functionality of isolated cardiomyocytes was studied. Oral application of levosimendan showed therapeutic efficacy. Baseline values were similar in the Levo and NaCl groups except for coronary flow. After ischaemia and reperfusion, Levo hearts did not recover better than NaCl hearts {left ventricular derived pressure: 63 [standard deviation (SD): 36.2] vs 46 (SD: 41.8)% baseline; P = 0.386}, In hearts exposed to cardioplegia, functional recovery only slightly differed in the Levo and NaCl groups [left ventricular derived pressure: 69.96 (SD: 12.7) vs 51.89 (SD: 28.1)% baseline; P = 0.09]. Cell shortening of cardiomyocytes isolated from hearts exposed to ischaemia or perfusion was better in Levo groups [cell shortening: 7.65 (SD: 1.95) %; 7.8 (SD: 1.79)% vs 6.28 (SD: 1.67)%; 6.5 (SD: 1.87)%, P < 0.001]; this benefit was absent in cardioplegia-treated hearts. Levosimendan applied orally before ischaemia/reperfusion improves functional recovery, but this effect is only moderate when cardioplegia is included. Differences between hearts exposed to cardioplegia or to global ischaemia may indicate why levosimendan-related beneficial effects do not directly translate into better clinical outcome.

The Adenylate Cyclase Activator Forskolin Potentiates the Positive Inotropic Effect of the Phosphodiesterase Inhibitor Milrinone But Not of the Calcium Sensitizer Levosimendan nor of Its Hemodynamically Active Metabolites: An Apparent Conundrum.

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.

Levosimendan in Europe and China: An Appraisal of Evidence and Context.

The calcium sensitiser levosimendan (SIMDAX; Orion Pharma) has been in clinical use for the management of acute heart failure and a range of related syndromes in many countries around the world for two decades. More recently, levosimendan has become available in China. The authors have examined the profile of levosimendan in clinical trials conducted inside and outside China and grouped the findings under six headings: effects on haemodynamics, effects on natriuretic peptides, effect on symptoms of heart failure, renal effects, effect on survival, and safety profile. Their conclusions are that under each of these headings there are reasonable grounds to expect that the effects and clinical benefits established in trials and with wider clinical use in Europe and elsewhere will accrue also to Chinese patients. Therefore, the authors are confident that global experience with levosimendan provides a reliable guide to its optimal use and likely therapeutic effects in patients in China.

Intermittent therapy with levosimendan in patients with advanced heart failure

Abstract Introduction Therapeutic options for patients with advanced heart failure on the high-urgent (HU) heart transplant (HTx) waiting list are limited. In view of the limited data on the usefulness of classic inotropes, the calcium sensitizer levosimendan (Lev) may be a possible alternative for patients in need of a repetitive therapy with an inotropic agent as a bridge to HTx. Method In a single-center open-label study we retrospectively analyzed data from 34 HU-listed patients (from a total collective of 95 HU patients) who repetitively received Lev (12.5 mg; 0,05–0.1 μg/kg/min over 24–48h) in 2–8 weeks intervals due to cardiac instability and/or progressive second organ dysfunction. Potential side effects as well as changes of kidney, liver and heart functional parameters were evaluated (0–6 days before, 4–8 days and 14–20 days after Lev infusion). Patient collective: age 51±10 years, 6 women, 28 men; NYHA stage III-IV. 11 Patients with ischemic cardiomyopathy (32%), 19 patients with dilated cardiomyopathy (56%), 4 patients with arrhythmogenic right ventricular cardiomyopathy (12%). Results The waiting time for HTx was up to 12 months (6±5 months). There were no adverse, serious events (resuscitation, defibrillation for ventricular tachycardia (VT), intubation and ventilation, renal replacement therapy) up to 7 days after Lev infusion. Transient cardiac arrhythmias (ventricular bursts or non-sustained VTs) occurred in 11 patients (32%) with spontaneous termination and no need of urgent anti-arrhythmic therapy. The values for sodium, potassium, Hb and CRP did not change significantly after Lev. In contrast, there was a significant reduction in creatinine after 4–8 days (initially 1.43±0.4 mg/dl; after 4–8 days 1.28±0.3; p&amp;lt;0.0005) with an increase again after 14–20 days (1.43±0.3 mg/dl). The bilirubin value was significantly reduced after 4–8 days (initially 1.63±0.7 mg/dl; after 4–8 days 1.30±0.5; p&amp;lt;0.0005) with only partial (non-significant) increases again over the course (1.34±0.5 mg/dl). The BNP value was significantly reduced 4–8 days after administration of Lev (initially 1565±1136 ng/l; after 4–8 days 1103±895; p&amp;lt;0.0001) and increased again in the longer time course (1462±1001 ng/l; p&amp;lt;0.001 versus 4–8 days). 28 patients were successfully transplanted (82%). 6 patients remained without HTx (18%), of which 1 patient (3%) with clinical improvement could be discharged. 2 patients (6%) received an LVAD and 3 patients (9%) died during the waiting period. Conclusion Intermittent therapy with Lev as “a bridge to transplant” is safe and effective concerning deterioration of heart failure and prevention of progressive kidney/hepatic dysfunction. However, a prospective randomized multi-center trial is necessary to underscore the encouraging data of this observational, single center study. Funding Acknowledgement Type of funding sources: None.

Levosimendan for Treatment of Primary Graft Dysfunction After Heart Transplantation: Optimal Timing of Application.

Primary graft dysfunction remains a serious problem after heart transplant. Pharmacological treatment with the calcium sensitizer levosimendan may be an additive treatment for primary graft dysfunction. Patients undergoing heart transplant between 2010 and 2020 were retrospectively reviewed and divided depending on postoperative treatment with (n = 41) or without (n = 109) levosimendan. Recipients who received levosi mendan were further divided with regard to timing of levosimendan application (early group: started ≤48 hours posttransplant [n = 23]; late group: started >48 hours posttransplant [n = 18]). Patients who received levosimendan treatment displayed a remarkable incidence (87.8%) of postoperative primary graft dysfunction with need for venoarterial extracorporeal membrane oxygenation and therefore often presented with perioperative morbidity. Patient with early application of levosimendan showed significantly decreased duration of venoarterial extracorporeal membrane oxygenation support (5.1 ± 3.5 days vs 12.6 ± 9.3 days in those with late application; P < .01) and decreased mortality during venoarterial extracorporeal membrane oxygenation support (0.0% vs 33.3% in early vs late group; P < .01). In addition, compared with patients with late levosimendan application, patients with early application needed fewer blood transfusions (P < .05), had shorter ventilation times (279 ± 235 vs 428 ± 293 h; P = .03), and showed a trend of reduced incidence of postoperative renal failure (69.6% vs 94.4%; P = .06). Moreover, survival analyses indicated an increased survival for patients with early start of levosimendan therapy within the first 48 hours after heart transplant (P = .09). Pharmacotherapy with levosimendan may be a promising additive in the treatment of primary graft dysfunction after heart transplant. With administration of levosimendan within the first 48 hours posttransplant, rates of successful weaning from venoarterial extracorporeal membrane oxygenation and outcomes after heart transplant were shown to increase.

Pharmacological Pre- and Postconditioning With Levosimendan Protect H9c2 Cardiomyoblasts From Anoxia/Reoxygenation-induced Cell Death via PI3K/Akt Signaling.

The calcium sensitizer levosimendan is indicated for the hemodynamic stabilization of patients with acutely decompensated heart failure and has been shown to be protective against reperfusion injury after myocardial infarction. However, affected forms of cell death and underlying signaling pathways remain controversial. Therefore, the aim of this study was to examine the influence of levosimendan preconditioning and postconditioning on anoxia/reoxygenation-induced apoptosis, necrosis, and autophagy in H9c2 myoblasts. To mimic conditions of myocardial ischemia/reperfusion, rat cardiac H9c2 myoblasts were exposed to anoxia/starvation, followed by reoxygenation/refeeding. Apoptosis, necrosis, autophagy, cell viability, survival signaling, and mitochondrial permeability transition pore (mPTP) opening were measured. Both, pharmacological preconditioning and postconditioning with levosimendan were capable to reduce apoptosis as well as necrosis in stressed H9c2 cells. However, preconditioning showed to have the stronger impact compared with postconditioning. Moreover, levosimendan preconditioning increased autophagy, suggesting enhanced repair processes initiated by the early presence of the drug. Underlying mechanisms differ between both interventions: Although both are associated with PI3/Akt activation and reduced mPTP opening, only postconditioning but not preconditioning depended on mKATP activation. This variation might indicate that a pharmacological treatment after the onset of reoxygenation at least in part directly addresses mitochondrial structures for protection. In conclusion, we demonstrate that both pharmacological preconditioning and postconditioning with levosimendan protect anoxia/reoxygenation-stressed cells but differ in the underlying mechanisms. These results are decisive to obtain more insights into the beneficial effects of levosimendan in the treatment of reperfusion-mediated damage.

Reverse use dependence of calcium sensitizer levosimendan on action potential duration shortening prevents ventricular arrhythmia during therapeutic hypothermia

Abstract Background Therapeutic hypothermia (TH) increases the risk of ventricular arrhythmia (VA) by prolonging action potential duration (APD) and steepening the APD restitution (APDR). The calcium sensitizer levosimendan, a medication for heart failure treatment, has been reported to shorten APD by enhancing ATP-sensitive K current and affect the APDR. Purpose We hypothesized that levosimendan might shorten the already prolonged APD particularly at long pacing cycle length (PCL), thus decreases the maximal slope of APDR, and prevent VA during TH. Methods Langendorff-perfused isolated rabbit hearts were subjected to 15-min TH (30°C) followed by 30-min treatment with levosimendan (0.5 μM, n=9) or vehicle (n=8). Using an optical mapping system, APD was evaluated by S1 pacing and APDR curve was plotted using APD70 versus diastolic interval. Ventricular fibrillation (VF) inducibility was evaluated by burst pacing for 30 s at the shortest PCL that achieved 1:1 ventricular capture. Results The APD was shortened from 259±8 ms at TH to 241±18 ms after levosimendan infusion at long PCL of 400 ms (p=0.024). However, at short PCL of 280 ms, the APD was not changed before (194±19) and after (188±23) levosimendan during TH (p=0.61). Levosimendan decreases the maximal slope of APDR curve from 1.99±0.65 at TH to 1.41±0.32 after adding levosimendan (p=0.034). The VF inducibility was decreased by levosimendan from 39±30% at 30°C to 14±12% with levosimendan (p=0.023). In control hearts, the maximal slope of APDR (p=0.75) and VF inducibility (p=0.12) were not changed by vehicle during TH. Conclusion Levosimendan might protect the hearts against VA during TH by shortening APD at long PCL and flattening the APDR. Enhancing ATP-sensitive K current with levosimendan during TH might be a novel approach to prevent VA during TH. Funding Acknowledgement Type of funding source: None

P2564Levosimendan shortens action potential duration, decreases alternans threshold and prevents ventricular arrhythmia during therapeutic hypothermia in isolated rabbit hearts

Abstract Background Therapeutic hypothermia (TH) increases the susceptibility to ventricular arrhythmias (VA) by prolonging action potential duration (APD) and facilitating arrhythmogenic spatially discordant alternans (SDA). The calcium sensitizer levosimendan has been reported to shorten APD by enhancing ATP-sensitive K current. We hypothesize that levosimendan might shorten the already prolonged APD during TH, decreasing SDA threshold, and prevent the occurrence of VA. Methods Langendorff-perfused isolated rabbit hearts were subjected to 15-min TH (30°C) followed by 30-min treatment with levosimendan (0.5 μM, n=9) or vehicle (n=8). Using an optical mapping system, epicardial APD was evaluated by S1 pacing. SDA threshold was defined as the longest pacing cycle length (PCL) that induced SDA phenomenon. Ventricular fibrillation (VF) inducibility was evaluated by burst pacing for 30 s using the shortest PCL that achieved 1:1 ventricular capture. Results Levosimendan shortened the ventricular APD (at PCL 300 ms, from 229±9 ms to 211±18 ms, p=0.02) and decrease the SDA threshold (from 327±88 ms to 311±68 ms, p=0.001) during TH. The VF inducibility was decreased by levosimendan from 39±30% at 30°C to 14±12% after levosimendan infusion. In control hearts, the APD (p=0.75), SDA threshold (p=ns) and VF inducibility (p=0.12) were not changed by vehicle during TH. Conclusions Levosimendan protects the hearts against VA during TH by shortening APD and decreasing SDA threshold. Enhancing ATP-sensitive K current with levosimendan might be a novel approach to prevent VA during TH.

Effects of levosimendan on respiratory muscle function in patients weaning from mechanical ventilation

PurposeRespiratory muscle weakness frequently develops in critically ill patients and is associated with adverse outcome, including difficult weaning from mechanical ventilation. Today, no drug is approved to improve respiratory muscle function in these patients. Previously, we have shown that the calcium sensitizer levosimendan improves calcium sensitivity of human diaphragm muscle fibers in vitro and contractile efficiency of the diaphragm in healthy subjects. The main purpose of this study is to investigate the effects of levosimendan on diaphragm contractile efficiency in mechanically ventilated patients.MethodsIn a double-blind randomized placebo-controlled trial, mechanically ventilated patients performed two 30-min continuous positive airway pressure (CPAP) trials with 5-h interval. After the first CPAP trial, study medication (levosimendan 0.2 µg/kg/min continuous infusion or placebo) was administered. During the CPAP trials, electrical activity of the diaphragm (EAdi), transdiaphragmatic pressure (Pdi), and flow were measured. Neuromechanical efficiency (primary outcome parameter) was calculated.ResultsThirty-nine patients were included in the study. Neuromechanical efficiency was not different during the CPAP trial after levosimendan administration compared to the CPAP trial before study medication. Tidal volume and minute ventilation were higher after levosimendan administration (11 and 21%, respectively), whereas EAdi and Pdi were higher in both groups in the CPAP trial after study medication compared to the CPAP trial before study medication.ConclusionsLevosimendan does not improve diaphragm contractile efficiency.

A pragmatic approach to the use of inotropes for the management of acute and advanced heart failure: An expert panel consensus

Inotropes aim at increasing cardiac output by enhancing cardiac contractility. They constitute the third pharmacological pillar in the treatment of patients with decompensated heart failure, the other two being diuretics and vasodilators. Three classes of parenterally administered inotropes are currently indicated for decompensated heart failure, (i) the beta adrenergic agonists, including dopamine and dobutamine and also the catecholamines epinephrine and norepinephrine, (ii) the phosphodiesterase III inhibitor milrinone and (iii) the calcium sensitizer levosimendan. These three families of drugs share some pharmacologic traits, but differ profoundly in many of their pleiotropic effects. Identifying the patients in need of inotropic support and selecting the proper inotrope in each case remain challenging. The present consensus, derived by a panel meeting of experts from 21 countries, aims at addressing this very issue in the setting of both acute and advanced heart failure.

Thioimidate Bond Formation between Cardiac Troponin C and Nitrile-containing Compounds.

We have investigated the mechanism and reactivity of covalent bond formation between cysteine-84 of the regulatory domain of cardiac troponin C and compounds containing a nitrile moiety similar to the calcium sensitizer levosimendan. The results of modifications to the levosimendan framework ranged from a large increase in covalent bond formation to complete inactivity. We present the biological activity of one of the most potent compounds. Limitations, including compound solubility and degradation at acidic pH, have prevented thorough investigation of the potential of these compounds. Our studies reveal the efficacious nature of the malononitrile moiety in targeting cNTnC and its potential in future cardiotonic drug design.

In vitro effects of levosimendan on muscle of malignant hyperthermia susceptible and non-susceptible swine

BackgroundThe calcium sensitizer levosimendan is increasingly used to improve hemodynamics in patients with acutely decompensated heart failure. By binding to cardiac troponin C the conformation of the calcium-troponin C complex is stabilized, which leads to acceleration of actin-myosin crossbrigde formation and increased force generating capacity of muscle fibers. Besides indications in cardiac failure, beneficial effects of levosimendan in skeletal muscle disorders are currently evaluated. The aim of this study was to investigate differential effects of levosimendan on skeletal muscle of pigs with and without susceptibility to malignant hyperthermia (MH) in order to identify possible risks of this emerging drug for patients with predisposition to MH.MethodsMuscle bundles of 17 pigs (9 MH susceptible (MHS); 8 MH non-susceptible (MHN)) were excised under general anesthesia and examined in the tissue bath with increasing concentrations of levosimendan (0.065; 0.125; 0.5; 1.0; 10 and 50 μg/ml). Baseline tension and twitch force were monitored continuously. Data are presented as median and interquartile range. Statistical evaluation was performed using D’Agostino & Pearson test for normal distribution and student’s t test and 2-way ANOVA for differences between the groups. P < 0.05 was considered significant.ResultsThere were no differences between the groups concerning length, weight, initial twitch force and pre-drug resting tension of the investigated muscle strips. After an initial decrease in both groups, twitch amplitude was significantly higher in MHN (− 3.0 [− 5.2–0.2] mN) compared to MHS (− 7.5 [− 10.8- -4.5] mN) (p = 0.0034) muscle at an applied levosimendan concentration of 50 μg/ml. A marked increase in resting tension was detected following levosimendan incubation with 50 μg/ml in MHS muscle bundles (3.3 [0.9–6.1] mN) compared to MHN (− 0.7 [− 1.3–0.0] mN) (p < 0.0001).ConclusionsThis in vitro investigation revealed the development of significant contractures in muscle bundles of MHS pigs after incubation with levosimendan. However, the effect appeared only at supra-therapeutic concentrations and further research is needed to determine the impact of levosimendan on MHS individuals in vivo.

The CardioMEMS system in the clinical management of end-stage heart failure patients: three case reports

BackgroundRecent clinical trials have shown that pulmonary artery pressure-guided therapy via the CardioMEMS™ system reduces the risk of recurrent hospitalizations in chronic heart failure (HF) patients. The CardioMEMS™ pressure sensor is percutaneously implanted in a branch of the pulmonary artery and allows telemetric pressure monitoring via a receiver. According to the most recent ESC guidelines, this technology has currently a class IIb indication in patients with class III New York Heart Association symptoms and a previous hospitalization for congestive heart failure within the last year, regardless of ejection fraction. Aim of this guided-therapy is multifold, including an early prediction of upcoming decompensation, optimization of patients’ therapy and thereby avoidance of hospital admissions. In addition, it can be used during acute decompensation events as a novel tool to direct intra-hospital therapeutic interventions such as inotropes infusion or left ventricular (LV) assist device monitoring, with the aim of achieving an optimal volume status.Case presentationWe present a case series of three end-stage HF patients with reduced ejection fraction (HFrEF) who received a CardioMEMS™ device as an aid in their clinical management. The CardioMEMS™ system enabled a closer non-invasive hemodynamic monitoring of these patients and guided the extent of therapeutic interventions. Patients were free from device- or system-related complications. In addition, no pressure-sensor failure was observed. Two patients received a 24-h infusion of the calcium sensitizer levosimendan. One patient showed a refractory acute decompensation and underwent LV assist device (LVAD) implantation as a bridge to cardiac transplantation. Switching a patient with recurrent hospitalizations to the Angiotensin Receptor Neprilysin Inhibitor (ARNI, Sacubitril-Valsartan) on top of the optimal heart failure-therapy improved its subjective condition and hemodynamics, avoiding further hospitalization.ConclusionsOur case series underlines the potential impact of CardioMEMS™ derived data in the daily clinical management of end-stage HF patients. The new concept to combine CardioMEMS™ in the setting of an outpatient levosimendan program as well as a bridge to LVAD-implantation/heart transplantation looks promising but needs further investigations.

Энергетическая оценка влияния левосимендана на кислородный бюджет при экстренном аортокоронарном шунтировании у больных с острым коронарным синдромом

Цель. Оценка эффективности левосимендана как инотропного препарата в периоперационном периоде при выполнении аортокоронарного шунтирования (АКШ) в экстренном порядке у больных с острым коронарным синдромом (ОКС) на основе исследования энергетики кровообращения.&#x0D; Материалы и методы. АКШ в экстренном порядке выполнено 80 пациентам с ОКС. В 1–й группе (40 больных) использовали локальный протокол анестезии и интенсивной терапии, больным 2–й группы (40) дополнительно вводили левосимендан. Фиксировали фракцию выброса (ФВ) левого желудочка, сердечный выброс (СВ), уровень лактата, доставку, потребление и потребность в добутамине. Рассчитывали предложенный энергетический индекс, отражающий степень удовлетворения тканей в кислороде.&#x0D; Результаты. Левосимендан способствует более быстрому восстановлению СВ и транспорта кислорода без повышения энергозатрат, энергетический индекс при этом достоверно выше – 10,73 ± 3,50 по сравнению с 8,74 ± 2,47 (p &lt; 0,05).&#x0D; Выводы. Кальциевый сенситизатор левосимендан при экстренном АКШ у больных с ОКС способствует более быстрому восстановлению насосной функции миокарда и снижает потребность в добутамине. Применение левосимендана у больных с ОКС при выполнении экстренного АКШ позволяет повысить энергетическую эффективность транспорта кислорода и обеспечивает антигипоксический эффект.

Cardiogenic shock : Current evidence

This CME article addresses the pathophysiology, incidence, current survival outcome and treatment options for patients with cardiogenic shock as a complication of acute myocardial infarction. The shock spiral of left heart failure due to cardiac infarction, subsequent vasoconstriction and paradoxical vasodilation due to the systemic inflammation response syndrome (SIRS) is a vicious circle which must be interrupted. Treatment focuses on the evidence from randomized clinical trials and the current guideline recommendations. With respect to interventional and surgical treatment the question of culprit lesion vs. complete revascularization is still unsolved. For medicinal treatment acetylsalicylic acid (ASA) and heparin are more often supplemented with prasugrel and ticagrelor. In the case of inotropes, dobutamine remains the first-line treatment option and for vasopressors norepinephrine. The calcium sensitizer levosimendan has not provided the hoped for superiority over conventional treatment in randomized trials. The use of intra-aortic balloon pumps (IABP) is no longer recommended as circulatory support in acute heart failure (reduced to classIII). The use of percutaneous implantable mechanical circulatory support devices has not shown asurvival benefit in the few randomized trials carried out so far even when compared with IABP, due to increased bleeding complications.

Electrophysiological Properties of Calcium-Sensitiser Levosimendan During Rewarming From Severe Hypothermia In Vivo

Electrophysiological Properties of Calcium-Sensitiser Levosimendan During Rewarming From Severe Hypothermia In Vivo

LEVOSIMENDAN IN PREOPERATION THERAPY FOR CARDIOSURGERY IN PATIENTS WITH CHRONIC HEART FAILURE

Aim . To evaluate the efficacy of action of the calcium sensitizer levosimendan (LS) in patients with various grade of heart failure (HF) severity before cardiosurgery. Material and methods. LS was applied as a part of HF treatment while preparing patients for surgery in 2-4 days. Performed dose was 0,025 — 0,1 µg/kg/min. The drug was not administered in bolus. Preoperation group of participants included 108 patients (62% — men, 38% — women, aged 20 — 72 years (53±13)) with CHF III-IV FC by NYHA, with ejection fraction of the left ventricle (LVEF) about in average 27±8%.Mean level of natriuretic B-type peptide was 1129 (Me 854, Q 25 396, Q 75 1419) pg/mL. Main etiology of chronic HF in participants was dilation cardiomyopathy: noncoronary cardiomyopathy in 30 patients (27,7%), ischemic cardiomyopathy (ischemic heart disease, postinfarction cardiosclerosis) in 72 patients (66,7%) and acquired valve defects in 6 patients (5,6%). For assessment of efficacy of the drug in various grade of HF severity, patients were selected to subgroups according to the level of LVEF decrease (less 20%, 21-30%, 31-40%, more 40%), and pulmonary artery pressure (PAWP) (less 40 mmHg, 40-70 mmHg, more 70 mmHg). Results. Infusion of the drug led to statistically significant increase of LVEF comparing to the baseline (57%), decrease of PAWP (64%) and BNP concentration in 77% cases. Conclusion. The LS is an effective medication which can be applied with the aims to prepare HF patients to cardiosurgical operations. Most sensitive parameters of LS efficacy are PAWP, LVEF and BNP concentration. The highest efficacy of the drug was observed in subgroup with EF ≤40%, PAWP ≥40 mmHg and BNP ≥600 pg/mL. LS, applied in HF patients before cardiosurgery, can be used for assessment of reserves of myocardial capacity.

Acute infusion of levosimendan enhances atrial fibrillation in an experimental whole-heart model

BackgroundThe calcium sensitizer levosimendan is clinically employed in decompensated heart failure. The aim of the present study was to assess effects of levosimendan on atrial electrophysiology in an experimental whole-heart model. Methods and results13 rabbit hearts were isolated and Langendorff-perfused. Thereafter, hearts were paced at cycle lengths of 350ms, 250ms and 200ms in the atrium. A standardized protocol employing atrial burst pacing induced atrial fibrillation (AF) in 4 of 13 hearts under baseline conditions (mean: 3.3±2.1 episodes). Subsequently, levosimendan was administered in two concentrations (0.25μM, 0.5μM). Two monophasic action potential recordings on the left- and two on the right atrial epicardium displayed a decrease of atrial action potential duration (aAPD, −27ms, p<0.05) and atrial effective refractory period (aERP; −29ms, p<0.05) under the influence of 0.5μM levosimendan. The described alterations of atrial electrophysiology led to and increased inducibility of AF. Of note, treatment with 0.25μM levosimendan resulted in induction of AF in 11 of 13 hearts (mean: 8.9±3.5 episodes). Under the influence of 0.5μM levosimendan 12 of 13 hearts were inducible (mean: 9.8±3.8 episodes). ConclusionIn the present study acute infusion of levosimendan in isolated rabbit hearts resulted in an abbreviation of atrial action potential duration and a reduction of aERP. This led to a significantly elevated inducibility of atrial fibrillation. These results suggest a proarrhythmic effect of levosimendan regarding atrial fibrillation. This aspect should be further investigated in the clinical setting.