Browsing by Author "Opie, Lionel H"

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    Adenosine and its role in cardioplegia : experimental evaluation in the isolated rat heart and in an-vivo primate model
    (1997) Boehm, Dieter Hermann; Opie, Lionel H; Reichart, B
    This study was designed to investigate the role of adenosine, an endogenous cardioprotectant agent, without high potassium and as cardioplegic additive to high potassium solutions. Adenosine cardioplegia and potassium cardioplegia supplemented by adenosine (K + ADO) were investigated in terms of hemodynamic, metabolic and ultrastructural recovery in the isolated rat heart and in the in-vivo baboon model during periods of global myocardial ischemia, simulating the clinical situation during open heart surgery. The results obtained in both models show that adenosine improved postischemic hemodynamic function when used without high potassium cardioplegia. The combination of adenosine and high potassium was less effective in both models in terms of hemodynamic recovery; however, improved rhythm stability and coronary vasodilatation were still present. In addition adenosine alone was able to induce fast electromechanical arrest in the isolated rat heart. However, failure of even high concentrations of adenosine to limit ventricular fibrillation in the baboon exclude its use as cardioplegic agent on its own without additional interventions. It appears likely that adenosine without high potassium is cardioprotective via activation of A₁ receptors and opening of ATP-sensitive potassium channels, a mechanism which is probably non-functional in a high potassium environment. In view of the limited cardioprotection achieved with the combination of adenosine and high potassium further studies should aim for additional interventions to induce cardioplegia with adenosine and normokalemic solutions.
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    Cardioprotective role of signal transducer activator of transcription 3 (STAT-3) against ischaemai reperfusion injuries
    (2011) King, Jonathan Chan; Lecour, Sandrine; Opie, Lionel H
    Introduction: Sphingosine 1 phosphate (S1P) is a major constituent of high density lipoprotein (HDL) cholesterol. Both S1P preconditioning and ischaemic postconditioning reduce myocardial damage following an ischaemia-reperfusion insult but the mechanisms involved remain unclear. Janus kinase/Signal transducer and activator of transcription 3 (JAK/STAT-3) form part of a recently discovered powerful prosurvival path termed as the Survivor Activating Factor Enhancement (SAFE) pathway. The SAFE pathway plays a critical role in ischaemic preconditioning to promote cell survival but whether activation of STAT-3 is required for S1P preconditioning and ischaemic postconditioning induced cardioprotection is unknown. Hypothesis: Activation of the STAT-3 is required for S1P preconditioning and ischaemic postconditioning.
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    Delineation of the Cardioprotective Agents found in red wine
    (2009) Lamont, Kim; Lecour, Sandrine; Opie, Lionel H
    Secondary leach concentrate (SLC) is an important bleed stream for minor elements from Anglo Platinum's Base Metal Refinery (BMR) which produces copper nickel and cobalt sulphate. It contains mainly sulphur, iron jarosites, unleached base metals and platinum group metals (PGMs), which makes the treatment of SLC necessary. The SLC is currently toll-refined at Umicore's Hoboken smelter and refinery to recover revenue from entrapped valuable metals. This method of treatment results in excessively high costs due to high transport and toll refining expenses as well as penalties. Thus, an in-house method of treatment by Anglo Platinum itself would prove beneficial in that it would eliminate these excessive costs and also provide a method of treatment in the event of residues exporting becoming banned or strongly penalised in future. Therefore, a method for treating SLC in-house is investigated. The first stage of the proposed treatment method involves a pyrometallurgical process where the removal of amphoterics by oxidative fuming, followed by reduction to recover base metals from the slag takes place. The PGMs are reported mainly to the metal alloy phase along with the base metals during this process. The project discussed in this report deals with the treatment of this furnace alloy which is referred to as Cu alloy. The Cu alloy is used to produce anodes to be applied to an electrorefining application for the recovery of Cu as a Cu cathode and PGMs in the form of anode slimes. Spent electrolyte from the BMR copper electrowinning section adjusted to specific pH and Cu concentration is used as electrolyte to which dissolvable metals (such as Ni and Fe) are recovered. The purpose of the process is to recover PGMs to anode slimes with a composition suitable to be blended with the final concentrate that is sent to the Precious Metals Refinery (PMR). The performance of this process on the Cu alloy provided is investigated and the anode slimes produced are characterised in order to propose further methods of purification before blending with PMR feed. The typical energy consumption, cathodic current efficiency, anodic copper dissolution rate and deportment of elements (especially PGMs) are determined. The effects of various operating parameters on the performance are also investigated in order to propose operating conditions. The operating parameters that are investigated are current density, Cu and H2SO4 concentrations in electrolyte and the use of an additive. A preliminary process design based on knowledge and experience gained during the literature review and test work is given. -PAGE 3 OF 181 The major technical factors in electrorefining are the cathode purity, the production rate and the specific energy consumption. These factors are influenced primarily by anode quality, electrolyte conditions and cathode current density. Design considerations and typical design parameters for other industrial Cu electrorefining applications are studied as well as possible further treatment of anode slimes for the concentration of PGMs. A total of eleven experiments were performed with a variety combinations of Cu concentration (30, 40 and 50 g/l), H2SO4 concentration (110, 130, 160 and 190 g/l) and current density (100, 125, 150, 250, 300 A/m2). In each experiment only one parameter was changed while all others were kept constant at the base-case setting of 40 g/l Cu, 160 g/l H2SO4, and 125 A/m2. The testwork showed that electrolytic refining of the Cu alloy, produced by a two stage pyrometallurgical treatment of current SLC, produces a highly concentrated PGM residue at an overall SLC mass reduction of 99.3%, with excellent PGM recovery to the anode slimes material. The different operating parameters that were tested successfully, all showed very good repeatability and greater than 99% PGM recovery from the Cu alloy, which would result in an overall recovery of 98% from SLC. Very little or none of the base metals that were supplied by the anode or the electrolyte feed reported to the anode slimes. The typical operating conditions (cell potential, current efficiency, anodic Cu dissolution and element deportment) that were observed correlated well with literature and the theoretically calculated values. The characteristics of the anode slimes produced stayed relatively similar throughout the different operating parameters and strong confidence can be placed in the production thereof and the recovery of the PGMs. The characteristics of the spent electrolyte and the Cu cathodes were also found to be suitable for integration in the BMR circuit. The anode slimes composition was 20 to 30% PGMs, 20 to 30% base metals, 15 to 20% Ag, As, Te, Se, Pb and 2 to 5% Al, Si, Sb, Bi, Zn and Sn. The blending of these slimes with typical PMR feed will result in a new PMR feed where the Pt grade of the feed to PMR is reduced by 4 to 5.5%, the Cu grade increased by 2 to 4% and the Ni content reduced by +-4%. Other concerns are the increase of As, Te, and Pb by between 0.5 and 1%. -PAGE 4 OF 181 The PGM-rich (<60%) phase in the anode slimes is a mostly amorphous matrix phase containing mostly palladium and other PGMs, arsenic and tellurium [Pd73As6Te21] with small amounts of Cu. Anode slimes produced from electrorefining can either be subjected to an additional process step to remove Ag, Pb and base metals before it is blended with the final concentrate (FICO) as feed for PMR, or it can be sent to the metallics section in PMR which includes a roast and a leach stage. The treatment of the anode slimes depends on the nature of the slimes. A preliminary process design was performed with proposed design parameters of electrolyte concentrations of 40 g/l Cu and 160 g/l H2SO4 at 65 deg C and a current density of 200 A/m2. The process consists out of seven cells in series with 55 anode cathode pairs in parallel per cell. The process has a maximum capacity of 127 t/m of anode material which allows 56 days of downtime per year if the current SLC produced (6600 t/a) is treated. The maximum capacity for Cu production is 1349 t/a and anode slimes 50.3 t/m. The power consumption per kg of anode dissolved will be 0.175 kWh/kg.
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    Electrophysiological mechanism of ventricular automaticity : a model foe ventricular arrythmias
    (1984) Saman, Selva; Saman, Selva; Opie, Lionel H
    Ventricular arrhythmias are difficult to study in man. The current experimental models are arrhythmias induced by electrical stimulation, coronary artery ligation or by subsequent reperfusion. An electrophysiological model will be useful for exploring the cellular mechanism of arrhythmias and for studying the mechanism of action of new anti-arrhythmic drugs. This project seeks to establish automaticity as a model for studying ventricular arrhythmias. Objectives 1. To review the literature on the mechanism of ventricular arrhythmias. 2. To explore ventricular automaticity induced by "reperfusion" after O₂ and substrate deprivation. 3 . To explore beta-adrenoceptor mediated ventricular automaticity. 4 . To evaluate possible new anti-arrhythmic drugs, carminomycin and ketanserin.
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    Exercise and the heart : effects of exercise training on coronary artery disease and on myocardial function, metabolism and vulnerability to ventricular fibrillation
    (1981) Noakes, Timothy D; Opie, Lionel H
    There is epidemiological and experimental evidence suggesting that exercise training may reduce the mortality rate from coronary heart disease, in particular the sudden death rate, and that it may improve the peak functional capacity of the heart. This thesis includes experimental work that is relevant to both these questions.
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    Infarct size and free fatty acids in the early phase of acute myocardial infarction
    (1980) Tansey, M J B; Opie, Lionel H
    The management of acute myocardial infarction (AMI) has been improved by the realisation that the size of infarction can influence mortality (Sobel et al, 1972) and that the infarct size can be altered by subsequent therapy (Maroko et al, 1972). The identification of any factor which may have adverse effects on the ischaemic myocardium and which is amenable to treatment would therefore have important prognostic implications. Elevation of circulating free fatty acid (FFA) concentrations is a consistent feature (Kurien and Oliver, 1966; Oliver et al, 1968) of the profound, non-specific metabolic reaction associated with the onset of AMI (Opie, 1975). The FFA rise has been correlated with the development of arrhythmias (Oliver et al, 1968) after AMI, and with the severity of ischaemic damage (Oliver et al, 1968; Gupta et al, 1969; Russell & Oliver, 1978) on clinical grounds. The method of quantifying infarct size developed by Shell et al (1972) has provided a means of correlating the degree of metabolic disturbance with extent of myocardial damage, and of assessing the benefits of metabolic interventions. The purpose of the studies reported in this thesis was to examine in detail the FFA rise in the early phase of AMI and to correlate this rise with the development of arrhythmias and other complications of AMI and with enzymatically estimated infarct size, thus leading to a more rational approach to therapeutic interventions.
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    Metabolism in myocardial ischaemia and reperfusion with specific reference to the role of glucose
    (1996) King, Linda Mary; Opie, Lionel H
    Hypothesis: Glucose is known to be protective in moderate low flow ischaemia due to the production of glycolytic ATP. However, it is questioned whether glucose would still be protective in ultra-low flow ischaemia. Firstly, glycolysis is thought to be inhibited, and secondly, deleterious glycolytic metabolites accumulate. Our hypothesis was that in ultra-low flow ischaemia, glucose utilisation is not inhibited at the level of glycolysis, but by delivery. Increased delivery of glucose should result in increased production of protective glycolytic ATP, but the rate of metabolite accumulation would also increase. Using ultra low flow rates, I wished to investigate how to achieve optimal rates of glycolysis, and how such rates would be balanced by any detrimental component of metabolite accumulation. Methods: The isolated Langendorff-perfused rat heart, with a left ventricular balloon to record ischaemic contracture and reperfusion stunning, was used, with severe flow restriction. Glucose concentrations were changed and pre-ischaemic glycogen contents were altered by perfusion with different substrates (acetate - depletion~ glucose + insulin - loading) or by preconditioning, with 5 min ischaemia and 5 min reperfusion prior to sustained ischaemia. Results: Analysis of glucose uptake relative to delivery showed that in severe low flow ischaemia, the extraction of glucose was increased, and glycolysis was thus limited more by substrate supply than by enzyme inhibition. Analysis of metabolites confirmed this concept. The optimal glucose concentration during severe low flow ischaemia was 11 mM, giving maximal recovery on reperfusion. Both lower and higher glucose concentrations increased ischaemic contracture. Changes in pre-ischaemic glycogen levels correlated with the time to onset of contracture, such that a reduction in glycogen accelerated contracture. Prior glycogen depletion or loading did not improve functional recovery. The benefits of preconditioning on reperfusion function following sustained total global ischaemia could not be related to glycogen depletion. If preconditioning were followed by sustained low flow ischaemia, glucose uptake was increased, but no benefit was found, possibly because a low residual flow abolished the effects of preconditioning. Many of the above results are consistent with the hypothesis that too low a rate of glycolysis results. in insufficient ATP production for protection, while excess glycolytic rates lead to excess metabolite accumulation with detrimental effects. Conclusions: Provision of glucose at the correct concentration, when the benefit associated with glycolytic ATP outweighs the detriment associated with moderate metabolite accumulation, is protective to the low-flow ischaemic myocardium, which can upregulate its ability to extract glucose. Improved residual flow enhances this benefit. Prior glycogen depletion is not beneficial, despite a reduced metabolite accumulation. This mechanism cannot be related to the protective effect of preconditioning.
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    Myocardial intermediary metabolism: with special reference to the isolated, contracting, perfused rat heart
    (1961) Opie, Lionel H
    Studies of myocardial metabolism In vivo have been considerably advanced by the introduction of coronary sinus catheterization. By determining the coronary arterio-venous differences of various substrates, Sing and other workers (Goodale, Olson) have been able to describe the overall picture of myocardial metabollism in man and intact experimental animals. This technique dos not, however, allow adequate pinpointing of the precise pathways of cardiac metabolism in health and disease, and Bing concludes a recent review (1958) by advocating further studies using newer techniques such as radio-isotopes in a controlled in vitro system.
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    The pharmacological modification of reperfusion injury with particular reference to calcium fluxes in the isolated rat heart
    (1994) Du Toit, Eugene Francois; Opie, Lionel H
    Myocardial reperfusion injury is thought to be caused by reperfusion induced i) cytosolic Ca²⁺ overload and/or, ii) the formation of oxygen derived freeradicals. At the start of this study, data implicating cytosolic Ca²⁺ overload in the genesis of reversible reperfusion injury were inconclusive. Although several workers have approached this problem by measurements of cytosolic calcium ions, it was my aim to examine the potential sources of such calcium overload. The experiments reported in this thesis were therefore designed to examine the role of altered intracellular and transsarcolemmal Ca²⁺ fluxes in the genesis of reperfusion stunning and arrhythmias. The study was also aimed at elucidating the possible sources and entry pathways contributing to this proposed cytosolic Ca²⁺ overload. In order to investigate the possible role of altered reperfusion Ca²⁺ fluxes in reperfusion injury, we exposed the isolated working, and Langendorff perfused rat heart model to ischaemia and reperfusion to induce reperfusion stunning and arrhythmias. Hearts were pre-treated (before ischaemia) or reperfused with pharmacological compounds, or by interventions known to enhance or inhibit intracellular or transsarcolemmal Ca²⁺ fluxes. The severity of reperfusion stunning (mechanical dysfunction) was measured by reperfusion aortic output, coronary flow and left ventricular pressure. The incidence of reperfusion ventricular arrhythmias was measured by the incidence of ventricular tachycardia and/ or fibrillation. In selected studies, the metabolic status of hearts was evaluated using biochemical assays performed on myocardial tissue samples. Data obtained in these studies indicate that increased Ca²⁺ fluxes through sarcolemmal L-type Ca²⁺ channels during early reperfusion exacerbate stunning, while inhibition of these fluxes with the Ca²⁺ antagonist drug nisoldipine or by Mg²⁺ or Mn²⁺ improve reperfusion function. These data also suggest that although interventions increasing Ca²⁺ fluxes early in reperfusion exacerbate reperfusion stunning, these same interventions improve reperfusion function when performed later. The data also indicate that Ca²⁺ may enter the myocyte indirectly via activation of the Na⁺/H⁺ and Na⁺/Ca²⁺ exchanger during reperfusion. Inhibition of Na⁺/H⁺ exchange activity by HOE 694 during reperfusion attenuated reperfusion stunning and arrhythmias. Both activation of the Na⁺/H⁺ (and Na⁺/Ca²⁺) exchanger and Ca²⁺ influx via the Ca²⁺ channel could contribute to reperfusion induced Ca²⁺ overload and subsequent injury. The study also showed that altered intracellular Ca²⁺ oscillations play a role in reperfusion stunning and arrhythmias as shown by the use of the SR Ca²⁺ release channel blocker, ryanodine. Inhibition of the sarcoplasmic reticulum Ca²⁺ A TP-ase pump by two novel inhibitors, thapsigargin and cyclopiazonic acid, during ischaemia and early reperfusion improved reperfusion function and reduced the incidence of ventricular arrhythmias. function when unphysiologically high concentrations of the peptide were infused into the heart during reperfusion. Taken together, these data suggest that: 1) Ca²⁺ fluxes during early reperfusion (intracellular and transsarcolemmal) play a role in reperfusion injury, 2) that both the Ca²⁺ channel and Na⁺/H⁺ exchange activity contribute to reperfusion injury by possibly contributing to cytosolic Ca²⁺ overload and that, 3) altered intracellular Ca²⁺ oscillations through the SR play a role in both stunning and arrhythmias. Thus the proposal is that modulation of Ca²⁺ fluxes through either the sarcolemma or the sarcoplasmic reticulum, lessen reperfusion injury (stunning and arrhythmias). Although these data do not provide direct evidence of reperfusion Ca²⁺ overload, they support the concept that calcium ions play a role in the genesis of reversible reperfusion injury.
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    PKCε and cardioprotection : an exploration of putative mechanisms
    (2006) McCarthy, Joy; Essop, Faadiel; Opie, Lionel H
    Recent studies have investigated the underlying regulatory mechanisms that may explain the cardioprotective role of PKCε. Sub-proteome analysis has identified interactions between activated PKCε and various mitochondrial proteins, which orchestrate mitochondrial homeostasis, including proteins governing mitochondrial oxidative phosphorylation, electron transfer, ion transport and control of mitochondrial permeability transition (MPT). MPT disruption is regarded as a key step in the initiation of an apoptotic cascade. However, brief pore opening may be beneficial in triggering the generation of small amounts of protective reactive oxygen species (ROS) and restoring calcium homeostasis. PKCε also interacts with adenine nucleotide translocases (ANTs), inner mitochondrial membrane proteins essential for ATP production and an integral component of the permeability transition pore. An augmented capacity to generate ATP would fundamentally enhance resilience to ischemia.
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    Preconditioning and augmented preconditioning via manipulation of metabolic and signalling pathways in the rat heart
    (2000) Makaula, Siyanda S S; Opie, Lionel H; Sack, Michael N
    Cardiac ischaemic preconditioning (IPC) describes a biological phenomenon whereby a short ischaemic stimulus confers protection to the heart against subsequent prolonged ischaemia and reperfusion injury. Understanding this survival programme will enable us to augment tissue tolerance against cell death. Ischaemic preconditioning is poorly understood, however, certain metabolic events and activation intracellular signalling events are known to trigger this cardioprotection. The purpose of this study was to investigate the metabolic and intracellular signalling events which occur during ischaemic preconditioning and their effects on improvement of contractile recovery following an ischaemia/reperfusion insult.
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    The role of melatonin in red wine-induced cardioprotection
    (2012) Lamont, Kim; Lecour, Sandrine; Opie, Lionel H
    Several epidemiological studies have suggested that the regular moderate consumption of red wine confers cardioprotection. However, the exact components in red wine that confer this effect are unclear. Previous studies performed in our laboratory suggest that neither the well-known polyphenol resveratrol nor alcohol (12%) present in red wine contribute to the cardioprotective effect of red wine when administered chronically, on their own. Therefore, other compounds present in red wine may contribute to its beneficial effects. The aim of the study was to explore whether melatonin, recently discovered in red wine, may play a vital role in red wine-induced cardioprotection. Furthermore, we propose that the protective effect may be mediated via the activation of the survivor-acting factor enhancement (SAFE) pathway that involves two integral components, tumour necrosis factor ± and signal transducer and activator of transcription 3 (STAT3). The drinking water of either male Wistar rats, TNF KO or STAT3 KO mice and their wild-type littermates were supplemented with a French Cabernet Sauvignon (12% alcohol by volume) or melatonin (75ng/â ) to a final concentration corresponding to the concentration found in two glasses of wine per day. After 14 days of treatment hearts were subjected to an ex vivo or an in vivo ischemia reperfusion insult or to a permanent ligation of the left descending coronary artery as a model of ischemic heart failure. Functional parameters and infarct size were assessed. The chronic moderate consumption of red wine for 14 days reduced infarct size from 60±2.3% to 23.3±1.8% after ischemia reperfusion injury, p<0.001. The pretreatment with melatonin protected to a similar extent as red wine given on its own (infarct size of 20.1±1.7%, p<0.001). Interestingly, the cardioprotective effect of red wine was partially abolished with prazosin, a melatonin receptor 3 inhibitor (40±0.9%, p<0.001 vs. wine). Furthermore, the cardioprotective effects of regular moderate consumption of red wine or melatonin were abolished in STAT3 KO and TNF KO mice. In a model of ischemic heart failure melatonin improved ejection fraction and fractional shortening compared to plain drinking water control in wild-type mice (p<0.001). The protective effect of melatonin was not abolished in TNK KO and STAT3 KO mice p<0.001 vs. control), therefore suggesting that the long-term treatment with melatonin in ischemic heart failure protects independently of the SAFE pathway. Our novel findings suggest that the moderate regular consumption of red wine (equivalent to 2-3 glasses per day) confers cardioprotection, in part due to its melatonin content. The protective effect against ischemia I/R injury of both melatonin and red wine is mediated via the activation of melatonin receptor 3 and the activation of the SAFE pathway while the protective effect of melatonin against ischemic heart failure is independent of the SAFE pathway. Melatonin is a safe, cheap and easily accessible drug that may be considered as an innovative therapeutic agent in the treatment against acute myocardial infarction and ischemic heart failure.
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    Role of nuclear factors kappa-B in TNFα-induced cytoprotection
    (2006) Somers, Sarin J; Lecour, Sandrine; Opie, Lionel H
    Includes bibliographical references (leaves 67-81).
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    The role of sublethal stress on mitochondria and the development of cardiac preconditioning
    (2003) Minners, Jan O; Opie, Lionel H; Sack, Michael N
    Cardiac preconditioning describes a cell survival program whereby a trigger renders the heart partially resistant to subsequent ischaemia/reperfusion induced cell death.
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    The role of Toll-like receptor 4 (TLR-4) in wine-induced cardioprotection
    (2012) Albertyn, Zulfah; Lecour, Sandrine; Opie, Lionel H
    Moderate and chronic consumption of red wine confers cardioprotection. Melatonin, present in wine, may contribute to this cardioprotective effect. Melatonin confers cardioprotection via the activation of tumor necrosis factoralpha (TNF-α) and the signal transducer and activator of transcription-3(STAT-3), via mechanisms that still remain to be delineated. We therefore hypothesise that South African red and white wines confer a cardioprotective effect in relation to their melatonin content. Furthermore, we propose that the cardioprotective effect of melatonin (at a concentration found in red wine) is dependent on the activation of Toll-like receptor 4 (TLR-4) to activate TNF-α/STAT-3.
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    Signalling pathways involved in TNFα-induced cytoprotection : role of reactive oxygen species
    (2005) Lacerda, Lydia; Lecour, Sandrine; Opie, Lionel H
    Tumour necrosis factor alpha (TNFa) is a pleiotropic cytokine which has both beneficial and deleterious effects. It has previously been shown in our laboratory that TNFa can mimic ischemic preconditioning (IPC). However, the signalling pathways involved in this protection remain incompletely understood. One potential protective pathway involves the generation of reactive oxygen species (ROS), which are known to be activated by TNFa. It was therefore hypothesized that TNFa-induced cytoprotection requires the generation of ROS. In addition, it was postulated that this ROS generation originates in the mitochondria.
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    Testing metabolic and pharmacological agents for recovery following de novo acute heart failure in an isolated rat heart model
    (2014) Deshpande, Gaurang; Opie, Lionel H; Lecour, Sandrine
    Acute heart failure is a potentially lethal clinical emergency without any effective therapy. Using an isolated rat heart model, we established and validated a model of de novo acute heart failure to study novel putative cardio protective therapies against acute heart failure, including glucose, insulin and the molecular agent sphingosine-1-phosphate(component of high density lipoprotein) for recovery. In isolated rat hearts, the protocol consisted of three phases: stabilization at normotensive perfusion pressure, hypotensive acute heart failure and recovery by restoring normotension. Low glucose (2.5mM) and high albumin-bound free fatty acids (1.3mM) (±adrenaline 10-M) were added in theperfusate. Molecular and metabolic agents were administered either alone or in combination in the acute heart failure or recovery phases. Effects of glucose, insulin and sphingosine-1-phosphatewere observed on heart function, cell death and mitochondrial respiration. In the absence of adrenaline, combination of glucose andsphingosine-1-phosphateduring acute heart failure improved functional recovery by increasing the heart rate. In the presence of adrenaline, glucose and sphingosine-1-phosphate administered separately were cardioprotective in the recovery phase by improving heart rate. The combination of glucose+insulin and glucose+sphingosine-1-phosphate in the recovery phase also increased heart rate. Glucos9+sphingosine-1-phosphate+insulin increased heart rate and left ventricular developed pressure.Sphingosine-1-phosphate reduced expression of cytochrome C, but metabolic agents had no effect.AG490 (inhibitor of signal transducer and activator of transcription 3) attenuated the cardio protective effect of sphingosine-1-phosphatewithincreased expression of the phosphorylated inactive form of this transcription factor protein. Conclusion: We have established and validated an ex-vivo model of de novoacute heart failure. The combination of metabolic and molecular treatments improved heart function by increasingsinus node activity_ Sphingosine-1-phosphate not only improved heart rate, but also reduced cell death, an effect mediated via activation of signal transducer and activator of transcription 3. Our data provide novel principles and approaches for the treatment of acute heart failure.
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    Time is muscle : a systematic review investigating the role of remote ischaemic preconditioning and glucose-insulin-potassium infusions as adjunctive therapies to revascularisation in coronary artery disease
    (2015) Mothilal, Shikar; Opie, Lionel H; Engel, Mark E
    In the management of coronary artery disease (CAD) most advances have concerned improvements in catheter-based interventional techniques and complex pharmacotherapy, with an emphasis on time, which unfortunately, cannot always achieved. However, simple measures with reassuring benefit that can be performed even by non-cardiologists have been largely overlooked, or understated. These include limiting reperfusion injury by remote ischaemic conditioning (RIPC), a powerful protective mechanism that can be elicited by the transient occlusion of blood flow to a limb with a blood pressure cuff. More controversially, glucose-insulin-potassium (GIK) therapy in early ST elevation myocardial infarction (STEMI) has the potential to improve outcomes especially when timely restoration of vessel patency is difficult to achieve. This systematic review will evaluate the role of these therapies as adjuncts to revascularisation for treating coronary artery disease either electively or during an acute coronary syndrome. Objectives: To determine if RIPC or GIK therapy for CAD leads to reduced mortality (primary objective), infarct size, cardiac enzyme release or major adverse cardiac and cerebral events (MACCE) and to identify adverse effects associated with RIPC or GIK (secondary objectives).