Search

Inotropic agents are generally recommended to use in patients with acute decompensated heart failure (HF) with reduced ejection fraction (HFrEF) concurrent to end-organ dysfunction. However, due to certain pharmacological limitations like developing life threatening arrhythmia and tolerance, cannot be employed as much as needed. Meanwhile, Calcium ion (Ca2+) sensitisers exhibits their inotropic action by increasing the sensitivity of the cardiomyocyte to intracellular Ca2+ ion and have been reported as emerging therapeutic alternative in HF cases. Levosimendan (LEVO) is an inodilator and with its unique pharmacology justifying its use in a wide range of cardiac alterations in HF particularly in undergoing cardiac surgery. It is also reported to be better than classical inotropes in maintaining cardiac mechanical efficacy and reducing congestion in acute HF with hypotension. This review paper was designed to compile various evidence about basic pharmacology and potential clinical aspects of LEVO in cardiac surgery and other HF associated alterations. This will benefit directly to the researcher in initiating research and to fill the gaps in the area of thrust. [ABSTRACT FROM AUTHOR]

Objective: Low cardiac output syndrome can develop in patients who have undergone open heart surgery. Inotropic drug therapy is being initiated to improve cardiac performance, but these drugs also have significant side effects. The primary aim of this study is to determine the relationship between the use of inotropic drugs and 30-day mortality, however its secondary aim is to determine the independent factors predicting mortality. Material and Method: Our retrospective observational study included 1002 patients undergoing cardiac surgery with cardiopulmonary bypass. Demographic and intraoperative characteristics of patients, use of inotropic agents, postoperative 30-day mortality data were obtained from anesthesia records, postoperative intensive care records and epicrises. Results: Dopamine (n=274: 27.3%), dobutamine (n= 110: 11%) and adrenaline (n=63: 6.3%) were used in indicated number of patients. In the univariate analysis, inotropic drug use was associated with mortality, but multiple regression analysis showed that inotropic drug use was not an independent risk factor for mortality alone. Independent risk factors for mortality were found to be advanced age, hypertension, heart failure, low ejection fraction and preoperative anemia. Conclusion: Our findings showed that inotropic use in perioperative period was not an independent predictor of 30- day- mortality. Although this result is not compatible with studies performed with small number of samples, it is correlated with large-scale patient studies. Independent risk factors for 30-day- mortality were advanced age, hypertension, heart failure, low ejection fraction, and peroperative hemoglobin drop. Our findings are compatible with frequently seen risk factors in research. More progress is needed in this regard. [ABSTRACT FROM AUTHOR]

Levosimendan and milrinone may be used in place of dobutamine to increase cardiac output in septic patients with a low cardiac output due to impaired cardiac function. The effects of the two inotropic agents on cardiac inflammation and left ventricular (LV) performance were examined in mice with cecal ligation and puncture (CLP)-induced sepsis. CLP mice displayed significant cardiac inflammation, as indicated by highly increased pro-inflammatory cytokines and neutrophil infiltration in myocardial tissues. When continuously given, levosimendan prevented but milrinone exaggerated cardiac inflammation, but they significantly reduced the elevations in plasma cardiac troponin-I and heart-type fatty acid-binding protein, clinical markers of cardiac injury. Echocardiographic assessment of cardiac function showed that the effect of levosimendan, given by an intravenous bolus injection, on LV performance was impaired in CLP mice, whereas milrinone produced inotropic responses equally in sham-operated and CLP mice. A lesser effect of levosimendan on LV performance after CLP was also found in spontaneously beating Langendorff-perfused hearts. In ventricular myocytes isolated from control and CLP mice, levosimendan, but not milrinone, caused a large increase in the L-type calcium current. This study represents that levosimendan and milrinone have cardioprotective properties but provide different advantages and drawbacks to cardiac inflammation/dysfunction in sepsis. [ABSTRACT FROM AUTHOR]

Due to the limited results achieved in the clinical treatment of heart failure, a new inotropic strategy of myosin motor activation has been developed. The lead molecule of myosin activator agents is omecamtiv mecarbil, which binds directly to the heavy chain of the cardiac β-myosin and enhances cardiac contractility by lengthening the lifetime of the acto-myosin complex and increasing the number of the active force-generating cross-bridges. In the absence of relevant data, the effect of omecamtiv mecarbil on canine cardiac ryanodine receptors (RyR 2) has been investigated in the present study by measuring the electrical activity of single RyR 2 channels incorporated into planar lipid bilayer. When applying 100 nM Ca 2+ concentration on the cis side ([Ca 2+ ] cis ) omecamtiv mecarbil (1–10 µM) significantly increased the open probability and opening frequency of RyR 2, while the mean closed time was reduced. Mean open time was increased moderately by 10 µM omecamtiv mecarbil. When [Ca 2+ ] cis was elevated to 322 and 735 nM, the effect of omecamtiv mecarbil on open probability was evident only at higher (3–10 µM) concentrations. All effects of omecamtiv mecarbil were fully reversible upon washout. Omecamtiv mecarbil (up to 10 µM) had no effect on the open probability of RyR 1, isolated from either canine or rabbit skeletal muscles. It is concluded that the direct stimulatory action of omecamtiv mecarbil on RyR 2 has to be taken into account when discussing the mechanism of action or the potential side effects of the compound. [ABSTRACT FROM AUTHOR]

Background While developed countries seek to lower the gestational age and birthweight parameters in retinopathy of prematurity (ROP) screening, older, larger infants still develop ROP in other parts of the world. The aim of this study was therefore to define criteria to identify potential ROP developers who are outliers of the common screening range. Methods A retrospective medical record review was performed in 147 inborn moderately preterm infants admitted to the neonatal intensive care unit during the study period. Univariate and logistic regression analysis was carried out. Results Forty-two infants developed ROP. Gestational age (31.4 ± 1.1 vs 32.4 ± 1.0 weeks, P = 0.000) and birthweight (1607.7 ± 339.4 vs 1846.4 ± 317.2 g, P = 0.000) were lower in those who developed ROP. Respiratory distress syndrome ( P = 0.026) and documented sepsis ( P = 0.003) were significant comorbidities on univariate analysis. Inotrope need >72 h starting in the first week of life ( P = 0.004; OR, 5.181) and more than three transfusions of packed red blood cells ( P = 0.028; OR, 3.891) were also significant, both on univariate and multivariate analysis. Conclusions In moderately preterm infants, status should be evaluated in order to effectively select candidates for ROP screening without missing potential ROP developers. [ABSTRACT FROM AUTHOR]

The activity of phospholipase Cβ1b (PLCβ1b) is selectively elevated in failing myocardium and cardiac expression of PLCβ1b causes contractile dysfunction. PLCβ1b can be selectively inhibited by expressing a peptide inhibitor that prevents sarcolemmal localization. The inhibitory peptide, PLCβ1b-CT was expressed in heart from a mini-gene using adeno-associated virus (rAAV6-PLCβ1b-CT). rAAV6-PLCβ1b-CT, or blank virus, was delivered IV (4 × 10 9 vg/g body weight) and trans-aortic-constriction (TAC) or sham-operation was performed 8 weeks later. Expression of PLCβ1b-CT prevented the loss of contractile function, eliminated lung congestion and improved survival following TAC with either a ‘moderate’ or ‘severe’ pressure gradient. Hypertrophy was attenuated but not eliminated. Expression of the PLCβ1b-CT peptide 2–3 weeks after TAC reduced contractile dysfunction and lung congestion, without limiting hypertrophy. PLCβ1b inhibition ameliorates pathological responses following acute pressure overload. The targeting of PLCβ1b to the sarcolemma provides the basis for the development of a new class of inotropic agent. [ABSTRACT FROM AUTHOR]

Aims: Therapeutic approaches to treat familial dilated cardiomyopathy (DCM), which is characterized by depressed sarcomeric tension and susceptibility to Ca2+-related arrhythmias, have been generally unsuccessful. Our objective in the present work was to determine the effect of the angiotensin II type 1 receptor (AT1R) biased ligand, TRV120023, on contractility of hearts of a transgenic mouse model of familial DCM with mutation in tropomyosin at position 54 (TG-E54K). Our rationale is based on previous studies, which have supported the hypothesis that biased G-proteincoupled receptor ligands, signalling via β-arrestin, increase cardiac contractility with no effect on Ca2+ transients. Our previous work demonstrated that the biased ligand TRV120023 is able to block angiotensin-induced hypertrophy, while promoting an increase in sarcomere Ca2+ response. Methods and results: We tested the hypothesis that the depression in cardiac function associated with DCM can be offset by infusion of the AT1R biased ligand, TRV120023. We intravenously infused saline, TRV120023, or the unbiased ligand, losartan, for 15 min in TG-E54K and non-transgenic mice to obtain left ventricular pressure-volume relations. Hearts were analysed for sarcomeric protein phosphorylation. Results showed that the AT1R biased ligand increases cardiac performance in TG-E54K mice in association with increased myosin light chain-2 phosphorylation. Conclusion: Treatment of mice with an AT1R biased ligand, acting via b-arrestin signalling, is able to induce an increase in cardiac contractility associated with an increase in ventricular myosin light chain-2 phosphorylation. AT1R biased ligands may prove to be a novel inotropic approach in familial DCM. [ABSTRACT FROM AUTHOR]

Inotropic agents are often used to improve the contractile performance of the failing myocardium, but this is often at a cost of increased myocardial ischemia and arrhythmia. Myocyte contractility depends on the release of Ca2+ from the sarcoplasmic reticulum, and this Ca2+ is subject to regulation by the phosphorylation status of phospholamban (PLN). Many currently used inotropic agents function by increasing the phosphorylation of PLN, but these also heighten the risk of ischemia. Another approach is to reduce the dephosphorylation of PLN, which can be achieved by inhibiting pathways upstream or downstream of the protein kinase Cα. Phospholipase Cβ1b is responsible for activating protein kinase Cα, and its activity is substantially heightened in failing myocardium. We propose phospholipase Cβ1b, a cardiac-specific enzyme, as a promising target for the development of a new class of inotropic agents. By reversing changes that accompany the transition to heart failure, it may be possible to provide well-tolerated improvement in pump performance. [ABSTRACT FROM AUTHOR]

Copyright of Reanimation is the property of Lavoisier and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aim We evaluated the effect of pimobendan, a positive inotropic agent, in elderly patients with frequent readmission as a result of heart failure despite conventional therapy. Methods Pimobendan was given to five male patients with severe chronic heart failure ( New York Heart Association class III- IV) (age range 69-89 years; mean 78 ± 8 years; ischemic cardiomyopathy in three cases, dilated cardiomyopathy in two cases) who required repeated admission for heart failure despite conventional therapy with angiotensin inhibitors, beta-blockers, diuretics and anti-arrhythmic agents. After the addition of pimobendan at a dose of 1.25-3.75 mg/day, we evaluated serum levels of brain natriuretic peptide ( BNP), left ventricular ejection fraction ( LVEF), septal e′ and left ventricular end-diastolic diameter ( LVDD) by echocardiography, as well as readmission rates for more than 2 years. Results The serum level of BNP significantly decreased after treatment with pimobendan, although its level returned to pretreatment levels after 2 years. LVEF significantly improved after the treatment, with the improvement continuing beyond the 2 years, although LVDD did not change after treatment. Septal e′ significantly improved after the treatment, although its level returned to pretreatment levels at 2 years after the treatment. Readmission rates significantly decreased for 2 years after the treatment, although one patient required cardiac resynchronization therapy for severe heart failure, and another patient required cardiac pacemaker implantation for sick sinus syndrome 2 years after adding pimobendan. Conclusions Pimobendan in conjunction with conventional therapy for heart failure decreases the readmission rate in elderly patients with severe heart failure for at least 2 years. Geriatr Gerontol Int 2014; 14: 109-114. [ABSTRACT FROM AUTHOR]

What is known and objective Positive inotropic agents are frequently used in acute decompensated heart failure (ADHF) due to left ventricular systolic dysfunction. These agents are known to improve cardiac performance and peripheral perfusion in the short-term treatment. However, several preclinical and clinical studies emphasized detrimental effects of these drugs on myocardial oxygen demand and on sympathetic tone entailing arrhythmogenesis. Levosimendan is an inotropic agent with an original mechanism of action. This review focuses on major data available for levosimendan. Methods A literature search was conducted in the PubMed database by including studies published in English using combinations of the following key words, levosimendan, inotropic drugs and acute heart failure. Furthermore, bibliographies of selected references were also evaluated for relevant articles. The collection for this review was limited to the most recently available human and animal data. Results and discussion Levosimendan's vasodilatory and cardioprotective effects are mediated by calcium sensitization of contractile proteins and opening of adenosine triphosphate ( ATP)-dependent K+ channels in vascular smooth muscle cells and on mitochondrial ATP-sensitive potassium [mito.K(ATP)] channels. This inotropic agent has mild PDE inhibitory action. Unlike other inotropic agents, levosimendan improves cardiac performance without activating the sympathetic nervous system. Moreover, there are evidences that levosimendan has additional anti-inflammatory and anti-apoptotic properties that prevent cardiac toxicity and contributes to positive hemodynamic response of the drug. Four randomized trials evaluated the effects of levosimendan on mortality in patients with acute decompensated chronic heart failure; nevertheless, a clear benefit has not been demonstrated so far. Although levosimendan is indicated for the treatment of ADHF (class of recommendation IIa, level of evidence B), it is has not been approved in all countries. What is new and conclusion This review summarizes the characteristics and the current knowledge of the literature on levosimendan and its active metabolite OR-1896. [ABSTRACT FROM AUTHOR]

Abstract: Probenecid is a highly lipid soluble benzoic acid derivative originally used to increase serum antibiotic concentrations. It was later discovered to have uricosuric effects and was FDA approved for gout therapy. It has recently been found to be a potent agonist of transient receptor potential vanilloid 2 (TRPV2). We have shown that this receptor is in the cardiomyocyte and report a positive inotropic effect of the drug. Using echocardiography, Langendorff and isolated myocytes, we measured the change in contractility and, using TRPV2−/− mice, proved that the effect was mediated by TRPV2 channels in the cardiomyocytes. Analysis of the expression of Ca2+ handling and β-adrenergic signaling pathway proteins showed that the contractility was not increased through activation of the β-ADR. We propose that the response to probenecid is due to activation of TRPV2 channels secondary to SR release of Ca2+. [Copyright &y& Elsevier]

Abstract: Background: Right ventricular (RV) dysfunction is associated with adverse outcomes in heart failure (HF). Mechanical unloading should be more effective than pharmacologic therapy to reduce RV afterload and improve RV function. We compared RV size and function after aggressive medical unloading therapy to that achieved in the same patients after 3 months of left ventricular assist device (LVAD) support. Methods and Results: We studied 20 patients who underwent isolated LVAD placement (9 pulsatile and 11 axial flow). Echocardiograms were performed after inpatient optimization with diuretic and inotropic therapy and compared with studies done after 3 months of LVAD support. After medical optimization right atrial pressure was 11 ± 5 mm Hg, mean pulmonary artery pressure 36 ± 11 mm Hg, pulmonary capillary wedge pressure 23 ± 9 mm Hg, and cardiac index 2.0 ± 0.6 L·min·m2. Preoperatively, RV dysfunction was moderate (2.6 ± 0.9 on a 0 to 4 scale), RV diameter at the base was 3.1 ± 0.6 cm, and mid-RV was 3.5 ± 0.6 cm. After median LVAD support of 123 days (92 to 170), RV size and global RV dysfunction (2.6 ± 0.9) failed to improve, despite reduced RV afterload. Conclusions: RV dysfunction seen on intensive medical therapy persisted after 3 months of LVAD unloading therapy. Selection of candidates for isolated LV support should anticipate persistence of RV dysfunction observed on inotropic therapy. [Copyright &y& Elsevier]

Abstract: Objective: We have recently identified an activation site on (Na+ +K+)-ATPase and found that binding of antibody SSA412 to this specific site of the enzyme markedly augments (Na+ +K+)-ATPase catalytic activity. Demonstration of whether activation of (Na+ +K+)-ATPase affects heart function in animal in vivo was the object of this investigation. Methods: Male wild-type CD-1 mouse and specific antibody SSA412 were used for the study. A pressure–volume micromanometer-conductance catheter in anesthetized mouse assessed in vivo cardiac functions. Results: Specific antibody SSA412 infusion in mouse shifted pressure–volume loop leftward with increased stroke volume and enhanced end-systolic elastance. Global systolic parameters such as ejection fraction and cardiac output, and load independent contractile parameters including dP/dt max/IP, PMX/EDV, Ees, and PRSW, were all increased without any effect on relaxation following administration of SSA412. Cardiac preload indexed by EDV and afterload by ESP did not alter, suggesting that SSA412-enhanced myocardial performance is a direct cardiac effect caused by the activation of (Na+ +K+)-ATPase. Conclusion: Our study provides the first in vivo physiological evidence to demonstrate that activation of (Na+ +K+)-ATPase induces significant positive inotropic effect in intact animal heart. The finding may lead to new therapeutic strategies for the treatment of heart failure. [Copyright &y& Elsevier]

Discusses a study which investigated how nicorandil affects left ventricular function of in situ adult rat hearts through the entire cardiovascular system. Two modes of actions that mediate the effect of nicorandil on different parts of the vascular system; Materials and methods; Comparison of effects of nicorandil infusion with those of vehicle infusion; Effects of KATP channel blockers on the positive inotropic effect of nicorandil infusion.

1 Voltage-gated Na+ channel blockers have been widely used as local anaesthetics and antiarrhythmic agents. It has recently been proposed that Na+ channel agonists can be used as inotropic agents. Here, we report the identification of a natural substance that acts as a Na+ channel agonist. 2 Using the patch-clamp technique in isolated rat ventricular myocytes, we investigated the electrophysiological effects of the substances isolated from the root extract of Salvia miliiorrhizu. which is known as "Danshen" in Asian traditional medicine. By the intensive activity-guided fractionation. we identified dimethyl lithospermate B (dmLSB) as the most active component, while LSB, which is the major component of the extract, showed negligible electrophysiological effect. Action potential duration (APD90) was increased by 20 μM dmLSB from 58.8 ± 12.1 to 202.3 ± 9.5 ms. In spite of the prolonged APD, no early after-depolarization (EAD) was observed. 3 dmLSB had no noticeable effect on K+ or Ca2+ currents, but selectively affected Na+ currents (INa). dmLSB slowed the inactivation kinetics of INa by increasing the proportion of slowly inactivating component without inducing any persistent INa. The relative amplitude of slow component compared to the peak fast INa was increased dose dependently by dmLSB (EC50 = 20 μM). Voltage dependence of inactivation was not affected by dmLSB, while voltage dependenee of activation shifted by 5mV to the depolarised direction. 4 Since the APD prolongation by dmLSB did not provoke EAD, which is thought as a possible mechanism for the proarrhythmia seen in other Na+ channel agonists. dmLSB might be an excellent candidate for a Na+ channel agonist. [ABSTRACT FROM AUTHOR]

Several randomized clinical trials of vesnarinone and milrinone in patients with heart failure left disappointing results in the 1990s, Thereafter, use of positive inotropic agents has been avoided, Exceptions are the use of digitalis glycosides to treat mild-moderate heart failure and the intravenous administration of catecholamines and phosphodiesterase inhibitors in patients with acute and/or refractory heart failure. It is not, however, exactly known whether chronic enhancement of cardiac contractility indeed has harmful effects, besides increased risk of arrhythmia and mortality. We investigated the potential chronic benefit of positive inotropic modification to treat progressive cardiomyopathy and associated heart failure using a genetic complementation strategy of muscle lim-protein and phospholamban (PLN) double mutagenesis in the mouse and found clear evidence of positive effects, Subsequent somatic modification of PLN function via gene transfer with recombinant adeno-associated virus vectors in small animal models of dilated cardiomyopathy further supported the chronic benefit of enhanced cardiac function achieved in an adrenergic stimulus-independent manner. This study examines current small animal models of dilated cardiomyopathy and recent multiple attempts to use these models as novel gene-based inotropic therapies. [ABSTRACT FROM AUTHOR]

The mechanisms underlying myocardial dysfunction in sepsis remain poorly understood. The theoretical benefits of nitric oxide synthase (NOS) inhibition in reversing the haemodynamic changes that characterise septic shock have not been supported by clinical trials, some of which have demonstrated detrimental myocardial effects. We have therefore assessed the effects of endotoxaemia on NOS enzyme expression as well as a number of functional responses of myocardial tissue from rats. Atrial tissue expressed high levels of mRNA for inducible (i)NOS and released increased levels of nitrite after animals were treated with endotoxin. In parallel, the inotropic response stimulated by isoprenaline was reduced in atria from endotoxin-treated animals, an effect that was reversed when endogenous release of NO was maximised. Our results suggest that myocardial contractility is maintained by NO production and that inhibitors may compromise cardiac output; this may explain the deleterious effects of NOS inhibition on cardiac function in clinical trials. [Copyright &y& Elsevier]

SUMMARY 1. We have already shown that the left ventricular (LV) end-systolic pressure–volume relationship (ESPVR) of rat hearts in situ is an upward convex curve and that LV end- systolic pressure (ESPmLVV) and the systolic pressure–volume area (PVAmLVV) at a mid-range LV volume (mLVV) sensitively reflect acute changes in LV contractility and work capability. Milrinone is a non-glycosidic, non-sympathomimetic drug that increases myocardial cAMP concentrations by selective inhibition of cardiac phosphodiesterase III. Therefore, milrinone could act on the entire cardiovascular system and cause an increase in inotropy, arterial vasodilatation and venodilatation. The aim of the present study was to investigate whether the approach we have recently instituted is able to detect the effects of milrinone on the entire cardiovascular system. 2. We measured simultaneously, in anaesthetized rats, continuous LV pressure using a catheter-tip micromanometer and LV volume by LV volumetry using a conductance catheter. We obtained steady state LV pressure–volume loops and intermittently obtained the LV ESPVR by gradual occlusion of the ascending aorta. We then evaluated LV function by assessing milrinone-induced changes in the ESPVR (i.e. ESPmLVV and PVAmLVV) and vasodilator actions by assessing milrinone-induced changes in ESPESV and effective arterial elastance (Ea), defined as the ESPESV/stroke volume ratio. 3. Milrinone (total dose 49.5 μg; infusion rate 3.3–6.7 μg/min, 7–10 μg/kg per min; blood concentration 53.9 ng/mL) largely shifted the ESPVR upwards and, thus, significantly increased end-systolic pressure (ESP0.08) and the systolic pressure–volume area (PVA0.08) at a mid-range LV volume (= 0.08 mL/g myocardium). Milrinone also significantly decreased LV ESPESV and decreased Ea, although these decreases were not significant. 4. The results of the present study suggest that our own recently instituted approach to evaluate LV function by measuring LV pressure–volume loops and ESPVR succeeded in detecting a cardiotonic action of milrinone with arterial vasodilatation in normal rat hearts. [ABSTRACT FROM AUTHOR]