Positive Inotropy Research Articles

Evaluation of esophageal Doppler monitor using various sympathomimetic drugs in Beagle dogs

Introduction: The study evaluated the use of esophageal Doppler monitor during infusion of positive inotropes and vasopressors.

Index of deterioration of patients with mechanical prosthetic heart valve thrombosis

BackgroundMechanical prosthetic heart valves are known for their durability; however, a malfunctioning prosthesis can deteriorate rapidly to become a life-threatening complication. Our aim was to calculate a numerical index to express the rate of clinical deterioration of patients presenting with a mechanical prosthetic heart valve thrombosis (PVT), called the index of deterioration (ID), and to evaluate its usefulness in predicting hospital outcomes.ResultsThe median ID and range were (0.43, 0.03-3) NYHA class/day. A higher ID was significantly related to early development of PVT after native valve replacement, younger age, female gender, pregnancy, non-compliance to oral anticoagulation (OAC), low LVEF%, high mean pressure gradient across a mitral prosthesis, raised serum creatinine, and SGOT on admission (P < 0.05). Independent predictors were early presentation after native valve replacement, female gender, and non-compliance to OAC (P < 0.05).ID correlated positively with the need for urgent/emergency surgery, and the durations of cardiopulmonary bypass, postoperative mechanical ventilation, and positive inotropes. ID correlated negatively with the postoperative LVEF% (P < 0.05). Median ID of the 21 mortalities (0.75, 0.1-3) was > 2.1 times that of survivors (0.35: 0.03−2; P = 0.002), and the median ID of the 29 cases with postoperative complications (0.5, 0.1-1.5) was 2.5 times that of the 39 uneventful cases (0.2, 0.03-2; P = 0.011). The ID significantly predicted both mortality (odds ratio 3.87; 1.33-1.29; P = 0.013) and mortality and hospital complications (odds ratio 4.77; 1.49-15.2; P = 0.008). The respective discriminating abilities were AUC 0.734 (0.616-0.852; P = 0.002) and 0.724 (0.61-0.835; P < 0.001). EuroScore II correlated positively with ID (r = 0.571; P < 0.001) but showed better discriminative abilities.ConclusionThe simple index of deterioration was useful in monitoring deterioration and predicting hospital progression and outcomes in patients presenting with PVT.

Quarantine and Isolation during COVID-19 outbreak: A case of online diagnosis of supraventricular arrhythmia through telemedicine.

The present case report highlights the usefulness of telemedicine during quarantine and isolation. The patient developed a supraventricular arrhythmia, and the diagnosis and management of the arrhythmia was done online.

Positive inotropic effect of atractylodin in normal rats and its underlying mechanism

Objective: To explore the positive inotropic effect of atractylodin which is major active component of Rhzoma Atractylodis Lanceae and its underlying mechanism. Methods: For in vivo study, six male SD rats were randomly selected for the heart pressure-volume loop (P-V loop) experiment. The effects of atractylodin (3 mg/kg, intraperitoneal injection) on hemodynamic parameters such as LVDP (left ventricular developed pressure), SW (stroke work), HR (heart rate), CO (cardiac output), SBP (systolic blood pressure) and DBP (diastolic blood pressure) were analyzed. For in vitro study, left ventricular developed pressure (LVDP) from the Langendroff-perfused isolated rat heart was analyzed before as the control and after atractylodin perfusion. For in vitro study, the effects of atractylodin and atractylodin with H89 (PKA inhibitor) or KN-93 (CaMKII inhibitor or Calyculin A (PP1, PP2A inhibitor) on LVDP were analyzed. The experiments were separated into four parts with six isolated hearts for each as follows: (1) Control→0.1→1→10 μmol/L atractylodin; (2) Control→200 nmol/L H89 (PKA inhibitor)→200 nmol/L H89+10 μmol/L atractylodin; (3) Control→500 nmol/L KN-93 (CaMKII inhibitor)→500 nmol/L KN-93+10 μmol/L atractylodin; (4) Control→10 nmol/L Calyculin A (PP1, PP2A inhibitor)→10 nmol/L Calyculin A+10 μmol/L atractylodin. For the study of rat left ventricular myocyte Ca2+ transient induced by field stimulation, the experiment design was the same as in vitro study. The six cells from the different rats were used for each part experiment. Results: ① Atractylodin (3 mg/kg) significantly increased the heart rate, cardiac output and stroke work (P＜0.05) and decreased the diastolic blood pressure (P＜0.05). ② Atractylodin (0.1, 1, 10 μmol/L) significantly increased the LVDP in a concentration dependent manner (P＜0.05). The positive inotropic effect of atractylodin could be blocked by PKA inhibitor H89. ③ Atractylodin (10 μmol/L) significantly increased the amplitude of SR Ca2+ transient amplitude mediated by facilitating sarcoplasmic reticulum SERCA2a. The enhanced amplitude of SR Ca2+ transient could be blocked by PKA inhibitor H89. Conclusion: Atractylodin had positive inotropic effect in rat heart both in vivo and in vitro with decreased diastolic blood pressure and its underlying mechanism was mediated by PKA. Based on the fact that the atractylodin exerted its positive inotropic effect was mediated by PKA, the PKA-SERCA2a signaling pathway might be the mechanism of the atractylodin's positive inotropy.

Ventromedial medullary pathway mediating cardiac responses evoked from periaqueductal gray.

Periaqueductal gray (PAG) is a midbrain region that projects to areas controlling behavioral and autonomic outputs and is involved in the behavioral and physiological components of defense reactions. Since Raphe Pallidus (RPa) is a medial medullary region comprising sympathetic premotor neurons governing heart function, it is worth considering the PAG-RPa path. We assessed: i) whether PAG projects to RPa; ii) the amplitude of cardiac responses evoked from PAG; iii) whether cardiovascular responses evoked from PAG rely on RPa. Experiments conducted in Wistar rats (±300g) were approved by Ethics Committee CEUA-UFG (092/18). Firstly, (n=3), monosynaptic retrograde tracer Retrobeads was injected into RPa; PAG slices were analyzed. Other two groups (n=6 each) were anesthetized with urethane (1.4g/kg) and chloralose (120mg/kg) and underwent craniotomy, tracheostomy, catheterization of femoral artery and vein and of cardiac left ventricle. In one group, we injected the GABAA receptor antagonist, bicuculline methiodide (BMI - 40pmol/100nL) into lateral/dorsolateral PAG. Another group was injected (100nL) with the GABAA receptor agonist muscimol (20mM) into RPa, 20min before BMI into PAG. The results were: i) retrogradely labelled neurons were found in PAG; ii) PAG activation by BMI caused positive chronotropism and inotropism, which were accompanied by afterload increases; iii) RPa inhibition with Muscimol reduced heart rate, arterial and ventricular pressures; iv) the subsequent PAG activation still increased arterial pressure, cardiac chronotropy and inotropy, but these responses were significantly attenuated. In conclusion, PAG activation increases cardiac chronotropy and inotropy, and these responses seem to rely on a direct pathway reaching ventromedial medullary RPa neurons.

Macrophage-mediated regulation of catecholamines in sympathetic neural remodeling after myocardial infarction.

Sympathetic neural remodeling, which involves the inflammatory response, plays an important role in ventricular arrhythmias (VAs) after myocardial infarction (MI). Adrenergic receptors on macrophages potentially modulate the inflammatory response. We hypothesized that the increased level of catecholamines activates macrophages and regulates sympathetic neural remodeling after MI. We treated MI mice with either clodronate or metoprolol for 5days following coronary artery ligation. Mice without treatment after MI and sham-operation mice served as the positive control and negative control, respectively. The norepinephrine levels in plasma and the peri-infarct myocardium increased by almost two-fold in the MI mice compared with the sham-operation mice. Both in vivo and ex vivo electrophysiology examinations showed that the vulnerability to VAs induced by MI was alleviated by macrophage depletion with clodronate and β1-adrenergic blockade with metoprolol, which was in line with circulating and peri-infarct norepinephrine levels, sympathetic reinnervation, and the expression of nerve growth factor (NGF) 7days after surgery. To further verify the interaction between catecholamines and macrophages, we preconditioned lipopolysaccharide-stimulated RAW 264.7 cells using epinephrine or epinephrine with selective adrenergic antagonists. The expression and release of inflammatory factors including NGF were enhanced by epinephrine. This effect was inhibited by metoprolol but not by other subtype antagonists. Our data suggested that the increased level of catecholamines, traditionally known as positive inotropes secreted from sympathetic nerve endings, might regulate cardiac sympathetic neural remodeling through β1-adrenergic receptors on macrophages, subsequently inducing VAs after MI.

Abstract MP105: Python Post-prandial Cardiac Adaptation is Supported by Enhanced Metabolism, Reduced Sarcomere Passive Tension, and Epigenetic Remodeling

Pythons are infrequent feeders that can ingest meals equal to their own body mass. The extreme metabolic response required to digest such large meals is associated with a dramatic increase in the mass of most organs, including the heart. Recently, we have been able to assess functional effects of feeding using isolated python cardiomyocytes and myofibrils, advancing our understanding of extreme cardiac adaptation in python ( Python regius ). Twenty-four hours after feeding, python cardiomyocytes showed prolonged Ca 2+ transients, increased maximal tension and Ca 2+ sensitivity of myofibrils as compared to fasted pythons. Post-prandial positive inotropy was accompanied by enhanced metabolic output via increased mitochondrial ATP production rate and by AMP-dependent kinase (AMPK) activation and phosphofructokinase-2 reduction, suggesting a key role for fatty acid, but not glucose, metabolism after feeding. In addition, 24h post-fed hearts had significantly reduced tissue stiffness and myofibril passive tension. Finally, chromatin condensation was reduced about 30% after feeding in python cardiomyocytes and confirmed by increased histone acetylation, indicating a predominant role for epigenetics in post-prandial adaptation. These results suggest that feeding promotes positive cardiac inotropy in python via a number of coordinated mechanisms to enhance energy production, increase myofibril and tissue compliance, and increase chromatin accessibility. As heart failure is commonly characterized by depressed contractility, compromised energetics, and increased tissue stiffness, assessing post-prandial adaptation in python hearts provides us with powerful insights that could inform the development of therapeutics for human heart diseases.

Echocardiographic and hemodynamic indices of myocardial contractility simultaneously evaluated in telemetered beagle dogs: A HESI-sponsored cross-company evaluation

IntroductionAlterations in cardiac contractility can have significant clinical implications, highlighting the need for early detection of potential liabilities. Pre-clinical methods to assess contractility are typically invasive and their translation to human measures of cardiac function are not well defined. Clinically, cardiac function is most often measured non-invasively using echocardiography. The objective of these studies was to introduce echocardiography into standard large animal cardiovascular safety pharmacology studies and determine the feasibility of this combination. MethodsA consortia of laboratories combined their data sets for evaluation. At each site, telemetered beagle dogs, in a 4 × 4 Latin square crossover study design (n = 4), were administered either pimobendan (positive inotrope) or atenolol (negative inotrope) orally at clinically relevant dose levels. Standard telemetry parameters were collected (heart rate, mean arterial blood pressure, etc.) continuously over 24 h, as well as derived contractility endpoints: QA interval and LV +dP/dtmax. At Tmax, echocardiography was performed in conscious dogs with minimal restraint to collect contractility parameters: ejection fraction (EF) and fractional shortening (FS). ResultsCorrelations between telemetry and echo contractility endpoints showed that, in general, a change in LV +dP/dtmax of 1000 mmHg/s translates to a 5.2% change in EF and a 4.2% change in FS. Poor correlations were shown between QA interval derived simultaneously, to both EF and FS. DiscussionComparing data from telemetry-only groups to those that included echocardiography collections showed no effect in the ability to interpret test article-related effects, providing the foundation for the inclusion of echocardiography without compromising standard telemetry data quality.

Inotropic assessment in engineered 3D cardiac tissues using human induced pluripotent stem cell-derived cardiomyocytes in the BiowireTM II platform

To develop therapeutics for cardiovascular disease, especially heart failure, translational models for assessing cardiac contractility are necessary for preclinical target validation and lead optimization. The availability of stem cell-derived cardiomyocytes (SC-CM) has generated a great opportunity in developing new in-vitro models for assessing cardiac contractility. However, the immature phenotype of SC-CM is a well-recognized limitation in inotropic evaluation, especially regarding the lack of or diminished positive inotropic response to β-adrenergic agonists. Recent development of 3D engineered cardiac tissues (ECTs) using human induced pluripotent stem cell derived-cardiomyocytes (hiPSC-CM) in the BiowireTM II platform has shown improved maturation. To evaluate their suitability to detect drug-induced changes in cardiac contractility, positive inotropes with diverse mechanisms, including β-adrenergic agonists, PDE3 inhibitors, Ca2+-sensitizers, myosin and troponin activators, and an apelin receptor agonist, were tested blindly. A total of 8 compounds were evaluated, including dobutamine, milrinone, pimobendan, levosimendan, omecamtiv mecarbil, AMG1, AMG2, and pyr-apelin-13. Contractility was evaluated by analyzing the amplitude, velocity and duration of contraction and relaxation. All tested agents, except pyr-apelin-13, increased contractility by increasing the amplitude of contraction and velocity. In addition, myosin and troponin activators increase contraction duration. These results indicate that ECTs generated in the BiowireTM II platform can identify inotropes with different mechanisms and provides a human-based in-vitro model for evaluating potential therapeutics.

Video-based assessment of drug-induced effects on contractile motion properties using human induced pluripotent stem cell-derived cardiomyocytes

IntroductionDrug-induced inotropic change is a risk factor in drug development; thus, de-risking is desired in the early stages of drug development. Unlike proarrhythmic risk assessment using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), few in vitro models were validated to predict cardiac contractility. Motion field imaging (MFI), a high-resolution block matching-based optical flow technique, was expected to possess high quantitative predictivity in the detection of contraction speed. We aimed to establish an in vitro model to assess drug-induced contractile changes using hiPSC-CMs and MFI. MethodsMFI was designed to noninvasively characterize cardiomyocyte contractile behavior by analyzing light microscope video images, and maximum contraction speed (MCS) was used as the index of contractility. Using MFI, 9 inactive compounds, 10 negative inotropes, and 10 positive inotropes were tested. Two negative chronotropes, ZD7288 and ivabradine, were also tested. To determine the sensitivity and specificity of the assay, the minimum effective concentration of the MCS was compared with the human effective total therapeutic concentration for 28 compounds in clinical use. ResultsFor 8 negative and 8 positive inotropes, the effects observed in in vivo and clinical studies were detected in MFI assay. MFI assay showed negative chronotropic changes without inotropic changes. MFI assay presented sufficient specificity (83%) and sensitivity (88%), and RNA-sequence analysis provided an insight into the relationship between occurrence of the false compounds and target gene expression. DiscussionWe demonstrated the utility of MFI assay using hiPSC-CMs to assess drug-induced contractile function. These results will facilitate the de-risking of compounds during early drug development.

Cardiovascular Effects of Polychlorinated Biphenyls and Their Major Metabolites.

Background:Xenobiotic metabolism is complex, and accounting for bioactivation and detoxification processes of chemicals remains among the most challenging aspects for decision making with in vitro new approach methods data.Objectives:Considering the physiological relevance of human organotypic culture models and their utility for high-throughput screening, we hypothesized that multidimensional chemical-biological profiling of chemicals and their major metabolites is a sensible alternative for the toxicological characterization of parent molecules vs. metabolites in vitro.Methods:In this study, we tested 25 polychlorinated biphenyls (PCBs) [PCB 3, 11, 52, 126, 136, and 153 and their relevant metabolites (hydroxylated, methoxylated, sulfated, and quinone)] in concentration–response () for effects in human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) and endothelial cells (ECs) (iPSC-derived and HUVECs). Functional phenotypic end points included effects on beating parameters and intracellular flux in CMs and inhibition of tubulogenesis in ECs. High-content imaging was used to evaluate cytotoxicity, mitochondrial integrity, and oxidative stress.Results:Data integration of a total of 19 physicochemical descriptors and 36 in vitro phenotypes revealed that chlorination status and metabolite class are strong predictors of the in vitro cardiovascular effects of PCBs. Oxidation of PCBs, especially to di-hydroxylated and quinone metabolites, was associated with the most pronounced effects, whereas sulfation and methoxylation of PCBs resulted in diminished bioactivity.Discussion:Risk characterization analysis showed that although in vitro derived effective concentrations exceeded the levels measured in the general population, risks cannot be ruled out due to the potential for population variability in susceptibility and the need to fill data gaps using read-across approaches. This study demonstrated a strategy for how in vitro data can be used to characterize human health risks from PCBs and their metabolites. https://doi.org/10.1289/EHP7030

Acute chloroquine poisoning: A comprehensive experimental toxicology assessment of the role of diazepam

Background and PurposeResurgence in the use of chloroquine as a potential treatment for COVID‐19 has seen recent cases of fatal toxicity due to unintentional overdoses. Protocols for the management of poisoning recommend diazepam, although there are uncertainties in its pharmacology and efficacy in this context. The aim was to assess the effects of diazepam in experimental models of chloroquine cardiotoxicity.Experimental ApproachIn vitro experiments involved cardiac tissues isolated from rats and incubated with chloroquine alone or in combination with diazepam. In vivo models of toxicity involved chloroquine administered intravenously to pentobarbitone‐anaesthetised rats and rabbits. Randomised, controlled treatment studies in rats assessed diazepam, clonazepam and Ro5‐4864 administered: (i) prior, (ii) during and (iii) after chloroquine and the effects of diazepam: (iv) at high dose, (v) in urethane‐anaesthetised rats and (vi) co‐administered with adrenaline.Key ResultsChloroquine decreased the developed tension of left atria, prolonged the effective refractory period of atria, ventricular tissue and right papillary muscles, and caused dose‐dependent impairment of haemodynamic and electrocardiographic parameters. Cardiac arrhythmias indicated impairment of atrioventricular conduction. Studies (i), (ii) and (v) showed no differences between treatments and control. Diazepam increased heart rate in study (iv) and as with clonazepam also prolonged the QTc interval in study (iii). Combined administration of diazepam and adrenaline in study (vi) improved cardiac contractility but caused hypokalaemia.Conclusion and ImplicationsNeither diazepam nor other ligands for benzodiazepine binding sites protect against or attenuate chloroquine cardiotoxicity. However, diazepam may augment the effects of positive inotropes in reducing chloroquine cardiotoxicity.Linked ArticlesThis article is part of a themed issue on The Pharmacology of COVID‐19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc

Blinded, Multicenter Evaluation of Drug-induced Changes in Contractility Using Human-induced Pluripotent Stem Cell-derived Cardiomyocytes.

Animal models are 78% accurate in determining whether drugs will alter contractility of the human heart. To evaluate the suitability of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for predictive safety pharmacology, we quantified changes in contractility, voltage, and/or Ca2+ handling in 2D monolayers or 3D engineered heart tissues (EHTs). Protocols were unified via a drug training set, allowing subsequent blinded multicenter evaluation of drugs with known positive, negative, or neutral inotropic effects. Accuracy ranged from 44% to 85% across the platform-cell configurations, indicating the need to refine test conditions. This was achieved by adopting approaches to reduce signal-to-noise ratio, reduce spontaneous beat rate to ≤ 1 Hz or enable chronic testing, improving accuracy to 85% for monolayers and 93% for EHTs. Contraction amplitude was a good predictor of negative inotropes across all the platform-cell configurations and of positive inotropes in the 3D EHTs. Although contraction- and relaxation-time provided confirmatory readouts forpositive inotropes in 3D EHTs, these parameters typically served as the primary source of predictivity in 2D. The reliance of these “secondary” parameters to inotropy in the 2D systems was not automatically intuitive and may be a quirk of hiPSC-CMs, hence require adaptations in interpreting the data from this model system. Of the platform-cell configurations, responses in EHTs aligned most closely to the free therapeutic plasma concentration. This study adds to the notion that hiPSC-CMs could add value to drug safety evaluation.

Extracorporeal Membrane Oxygenation for Coronavirus Disease 2019 in Shanghai, China.

Severe cases of coronavirus disease 2019 (COVID-19) cannot be adequately managed with mechanical ventilation alone. The role and outcome of extracorporeal membrane oxygenation (ECMO) in the management of COVID-19 is currently unclear. Eight COVID-19 patients have received ECMO support in Shanghai with seven with venovenous (VV) ECMO support and one veno arterial (VA) ECMO during cardiopulmonary resuscitation. As of March 25, 2020, four patients died (50% mortality), three patients (37.5%) were successfully weaned off ECMO after 22, 40, and 47 days support, respectively, but remain on mechanical ventilation. One patient is still on VV ECMO with mechanical ventilation. The partial pressure of oxygen/fractional of inspired oxygen ratio before ECMO initiation was between 54 and 76, and all were well below 100. The duration of mechanical ventilation before ECMO ranged from 4 to 21 days. Except the one emergent VA ECMO during cardiopulmonary resuscitation, other patients were on ECMO support for between 18 and 47 days. In conclusion, ensuring effective, timely, and safe ECMO support in COVID-19 is key to improving clinical outcomes. Extracorporeal membrane oxygenation support might be an integral part of the critical care provided for COVID-19 patients in centers with advanced ECMO expertise.

Increased sarcoplasmic/endoplasmic reticulum calcium ATPase 2a activity underlies the mechanism of the positive inotropic effect of ivabradine.

What is the central question of this study? The therapeutic effect of ivabradine on patients with chronic heart failure and chronic stable angina pectoris is mediated through a reduction in heart rate: what are the haemodynamic characteristics and the mechanism of the inotropic effect? What is the main finding and its importance? Ivabradine has a positive inotropic effect and lowers the heart rate both in vivo and in vitro. These effects are likely mediated by ivabradine's significant increase of the fast component rate constant mediated by sarcoplasmic/endoplasmic reticulum calcium ATPase 2a and decrease of the slow component rate constant that is mediated by the Na+ /Ca2+ exchanger and sarcolemmal Ca2+ -ATPase during the Ca2+ transient decay phase. Ivabradine's therapeutic effect is mediated by a reduction of the heart rate; however, its haemodynamic characteristics and the mechanism of its inotropic effect are poorly understood. We aimed to investigate the positive inotropic effect of ivabradine and its underlying mechanism. The results demonstrated that ivabradine increased the positive inotropy of the rat heart in vivo by increasing the stroke work, cardiac output, stroke volume, end-diastolic volume, end-systolic pressure, ejection fraction, ±dP/dtmax , left ventricular end-systolic elastance and systolic blood pressure without altering the diastolic blood pressure and arterial elastance. This inotropic effect was observed in both non-paced and paced rat isolated heart. Ivabradine increased the Ca2+ transient amplitude and the reuptake rates of sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a), lowered the diastolic Ca2+ level and suppressed the combined extrusion rate of the Na+ /Ca2+ exchanger and the sarcolemmal Ca2+ -ATPase. In addition, ivabradine widened the action potential duration, hyperpolarized the resting membrane potential, increased sarcoplasmic reticulum Ca2+ content and reduced Ca2+ leak. Overall, ivabradine had a positive inotropic effect brought about by enhanced SERCA2a activity, which might be mediated by increased phospholamban phosphorylation. The positive inotropic effect along with the lowered heart rate underlies ivabradine's therapeutic effect in heart failure.

Short-term respiratory outcome of mechanically ventilated preterm infants treated by dexmedetomidine: randomized controlled trial

Background The evidence of routine use of sedatives in mechanically ventilated preterm infants is not established because of adverse effects of commonly used drugs. Dexmedetomidine (DEX) is an emerging alternative. Objective To assess safety and efficacy of DEX use as a sedative in mechanically ventilated preterm neonates. Patients and methods A double-blind, randomized controlled trial was conducted on 40 preterm infants less than or equal to 32 weeks of gestation who required mechanical ventilation (MV) during the first 5 days of life. They were randomly assigned to receive DEX (0.1 μg/kg/h) during the first 5 days or placebo. Time to first extubation was our primary outcome, and secondary outcomes were plasma Krebs von den Lundgen-6 at seventh day, bronchopulmonary dysplasia, total duration of MV, total duration of oxygen supplementation, need for postnatal steroid, pain score, necrotizing enterocolitis, intraventricular hemorrhage, patent ductus arteriosus, need for positive inotropes, retinopathy of prematurity requiring intervention, days to reach 100 ml/kg enteral feeds, adverse effects of DEX, and mortality. Results A total of 40 neonates (20 in each group) were enrolled. DEX use was associated with earlier extubation of mechanically ventilated preterm infants (P=0.001) compared with placebo. Durations of respiratory support and MV were significantly shorter in DEX group compared with placebo. DEX therapy was associated with lower level of serum Krebs von den Lundgen-6 and Echelle de Douleur et d’Inconfort du Nouveau-ne pain score compared with placebo. Patients in DEX group have less need to fentanyl dosing and low incidence of sepsis and intraventricular hemorrhage. There was no significant difference between groups regarding other secondary outcomes. There is no significant difference between groups regarding adverse effects. Conclusion We concluded that DEX has beneficial effect on short-term respiratory outcome in mechanically ventilated preterm infants without significant effect on neonatal mortality.

Evolving Targets for Heart Failure: the Journey so far

The treatment of heart failure has included vasodilators, positive inotropes and most successfully neuro-hormonal blockade. Recent research has looked at metabolic and immune modulatory approaches, and implantable, mainly electrical devices. The near future in pharmacological research for heart failure remains focussed on classic methodologies and small molecules, but despite significant improvements we still know relatively little of the complex interactions in HF particularly for HFpEF.. Pharmacotherapy will in future be combined with advances in biotechnology, nanotechnology and devices and a digital revolution will help us to monitor patients at a distance, using wireless devices. Heart failure research has achieved much over the last 4 decades but the pace of innovation and research has not abated and future advances in this disabling condition are indeed likely.

3071Peptidomimetic targeting of CavBeta2 improves contractility in models of senescence- or genetically (MYBPC3 KI)-induced heart failure

Abstract Background L-type calcium channel (LTCC) trafficking controls LTCC density at T-tubule levels for optimal Excitation-Coupling (EC) and resultant adaptive heart work. In some forms of heart failure (HF), abnormalities in calcium-induced calcium-release have been proposed to arise from alteration of T-tubular dyad architecture (LTCC-RyRs) associated with impaired LTCC density. Recently, the R7W-MP peptide, working as a binder of the LTCC Cavβ2 chaperone, was shown to restore the altered density of LTCC current by both promoting forward and reducing reverse trafficking, which consequently improved cellular calcium homeostasis. Accordingly, R7W-MP improved the impaired cardiomyocyte calcium current density and the reduced Ejection Fraction (EF%) in a pharmacologically-induced diabetes model (STZ mice). We aimed to investigate further the benefit to improve LTCC trafficking pathway with R7W-MP in a more physiological model of HF (senescent mice) and in a Dilated Cardiomyopathy (DCM) model (HO MYBPC3 targeted KI mutant). Methods Senescent male C57Bl/6J mice (26 months) or HO MYBPC3 KI male mice (2 months) were treated with R7W-MP (3 mg/kg/d IP for 3 days). Echocardiographies (echo) were conducted before treatment and 4-hours after the last injection. When applied, Pressure-Volume (PV)-loop investigations were conducted one day post-echo 4 hours following an additional R7W-MP injection. Results In senescent mice population, HF was characterized by a midrange ejection fraction (EF%= 43±2 vs 55±1 for young adult mice) associated with enlarged ventricles and decreased cardiac contractility. In contrast to a scrambled peptide (scrP), R7W-MP markedly increased EF% monitored by echo (+38%, 63±3 vs 45±1 for scrP, p≤0.001, n=6–7) without modification of heart rate. EF% improvement was confirmed by PV-loop analysis (78±3 vs 51±4 for scrP (+54%), p≤0.001, n=5), associated with a marked, although not significant, 2.5-fold increase in myocardial contractility [end systolic pressure volume relationship (ESPVR) = 12.1±3.6 vs 4.9±1.3 for scrP, p=0.10, n=4]. Stroke volume, cardiac output and end diastolic volume tended to decrease suggesting an impaired LV filling at this dose regimen. In the DCM model, HF was more severe with a dramatically low EF% (26±1, n=8), impaired myocardial contractility and a pronounced left ventricle enlargement. R7W-MP significantly increased EF% (+17%, reaching 31±1, p≤0.01, n=8) without altering heart rate. Stroke volume was significantly increased by 36% (32±3 vs 24±3 mL at baseline, p≤0.01), without any impairment of diastolic function. All parameters returned to baseline after a 2 week-washout period. Conclusions R7W-MP displays potent positive inotrope properties in senescent or DCM mice models. Although further asses tsments of diastolic function are needed (different dosing and duration), these data underline the potential benefit brought by LTCC trafficking modulation to treat severe dilated cardiomyopathy.

Development of prediction model for identifying heart failure patients with high risk of developing hyponatremia

Background: Despite its significant contribution to morbidity and mortality, studies reported that hyponatremia is still inadequately recognised and treated. Objective: To obtain a prediction model for predicting the risk of hyponatremia in patients hospitalized from heart failure. Methods: Patients included in this research were patients hospitalized from heart failure at Fatmawati Hospital in Jakarta, Indonesia during the 2011 – 2014 period. Logistic regression analysis was performed for the derivation of prediction model by including variables obtained during admission as the predictors. Brier-score and Nagelkerke R2 (NR2) were measured to assess overall predictive ability and area under the curve (AUC) of the Receiver Operating Characteristics (ROC) and calibration plot along with Hosmer-Lemeshow test were measured to assess discrimination and calibration ability, respectively. Internal validation was performed using a bootstrapping approach. Results: Out of 464 patients included in the research 102 (22%) were hyponatremic during hospitalization. Accordingly, 306 non-hyponatremic patients were selected as controls matched by age and gender. Variables significantly associated with hyponatremia were serum sodium level, fatigue, ascites, positive inotropes, heparin and antibiotics. Prediction model containing those six variables exhibits good predictive ability both overall (brier-score=0.107, NR2=0.531) and specifically of discrimination (AUC of ROC curve=0.90) and calibration ability (p-value of HL test=0.899). Optimism observed from internal validation did not reduce its predictive performance. Conclusion: Risk prediction for predicting the risk of hyponatremia in patients hospitalized from heart failure can be derived by including predictors taken from information obtained during admission.

Why has positive inotropy failed in chronic heart failure? Lessons from prior inotrope trials.

Current pharmacological therapies for heart failure with reduced ejection fraction are largely either repurposed anti‐hypertensives that blunt overactivation of the neurohormonal system or diuretics that decrease congestion. However, they do not address the symptoms of heart failure that result from reductions in cardiac output and reserve. Over the last few decades, numerous attempts have been made to develop and test positive cardiac inotropes that improve cardiac haemodynamics. However, definitive clinical trials have failed to show a survival benefit. As a result, no positive inotrope is currently approved for long‐term use in heart failure. The focus of this state‐of‐the‐art review is to revisit prior clinical trials and to understand the causes for their findings. Using the learnings from those experiences, we propose a framework for future trials of such agents that maximizes their potential for success. This includes enriching the trials with patients who are most likely to derive benefit, using biomarkers and imaging in trial design and execution, evaluating efficacy based on a wider range of intermediate phenotypes, and collecting detailed data on functional status and quality of life. With a rapidly growing population of patients with advanced heart failure, the epidemiologic insignificance of heart transplantation as a therapeutic intervention, and both the cost and morbidity associated with ventricular assist devices, there is an enormous potential for positive inotropic therapies to impact the outcomes that matter most to patients.