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Biomedical subjects

Jarle Vaage

Publications and source records attributed to Jarle Vaage.

At least 19 recordsLinked to original sources
PubMed2006

Cognitive function after on or off pump coronary artery bypass grafting.

OBJECTIVE: To investigate cognitive outcome after on and off pump coronary artery bypass grafting. METHODS: Seventy patients between 50 and 80 years with stable angina pectoris, ejection fraction >30%, serum creatinine <150 micromol/l, and lack of tight main stem stenosis were randomized to on or off pump coronary artery bypass grafting. Standardized neuropsychological tests evaluated attention, verbal and visuo-spatial short-term and working memory, verbal learning, delayed recall, visuo-motor speed, and aspects of executive functions. Levels of anxiety and depression were also investigated. Testing was performed before and at 1 week, 1 and 6 months after surgery. RESULTS: There was no difference in cognitive impairment (defined as a 20% reduction in at least 20% of the tests) between groups. The incidence at 1 week post-operatively was 57% in the on pump group and 58% in the off pump group, after 1 month 30% and 12% and after 6 months 19% and 15%, respectively (p for interaction=0.19). There was no difference between groups in anxiety (p=0.18) or depression (p=0.48). CONCLUSIONS: This prospective, randomized study showed no differences in post-operative cognitive function after on pump compared to off pump coronary artery bypass grafting in low risk patients.

Aged↗
PubMed2006

Proteasomal proteolysis in anoxia-reoxygenation, preconditioning and postconditioning of isolated cardiomyocytes.

The role of proteasomal proteolysis in the pathogenesis of ischemia-reperfusion is being actively studied. To evaluate the participation of the proteasome in the preconditioning and postconditioning phenomena we used primary culture of neonatal cardiomyocytes. This culture was undergone 30min of anoxia followed by 60min of reoxygenation. Preconditioning was modeled by three cycles of 3min anoxia followed by 3min reoxygenation. Postconditioning was modeled by three cycles of 1min reoxygenation followed by 1min anoxia, respectively. Clasto-lactacystin beta-lactone, a specific proteasome inhibitor, was added to the culture medium right before the cycles of preconditioning or postconditioning in the dose that does not cause cell death (2.5muM). Percentages of living, necrotic, and apoptotic cells were determined by staining with bisbenzimide and propidium iodide. Autophagy was demonstrated by staining vacuolar structures with monodansyl cadaverine. Proteasomal activity was determined by cleavage intensity of specific fluorogenic substrates. Trypsin-like, chymotrypsin-like and peptidyl-glutamyl peptide-hydrolyzing (PGPH) activities were decreased after anoxia. Reoxygenation has led to the increase in trypsin-like and chymotrypsin-like activities comparing to anoxia, but these parameters have never reached the control levels. PGPH activity has been restored up to the initial level. Preconditioning and postconditioning increased numbers of living cells and decreased that of necrotic, apoptotic and autophagic cells. Paradoxically, it was established that proteasome inhibitors prevented the necrotic and apoptotic cell death of cardiomyocytes in anoxia-reoxygenation, but in the same concentration abolished the effects of preconditioning and postconditioning. Low doses of proteasome inhibitors, particularly the ones used in our experiments, resulted in the abolishing of preconditioning and postconditioning phenomena, but at the same time led to the increase of the population of living cells in anoxia-reoxygenation, and can be considered as potential pharmacological agents of preconditioning and postconditioning.

Journal Article↗
PubMed2006

Vein graft harvesting induces inflammation and impairs vessel reactivity.

BACKGROUND: Saphenous veins are often used for coronary artery bypass grafting (CABG), but loss of patency is a problem. The surgical procedure may contribute to graft injury. Our aim was to study the impact of surgical handling of saphenous veins on graft inflammation and vascular function. METHODS: Biopsy samples of saphenous veins were taken from 9 patients undergoing elective CABG at the start of vein harvesting (open technique) and after the last proximal anastomosis was sutured. Messenger RNA was extracted and amplified with semiquantitative reverse transcription polymerase chain reaction. Gene expression of proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta), leukocyte adhesion molecules (E-selectin, intercellular adhesion molecule-1), and vasoactive substances (endothelin-1, inducible and endothelial nitric oxide synthase) was investigated. Translocation of nuclear factor-kappaB (NFkappaB) was evaluated with electrophoretic mobility shift assay. Immunostaining for von Willebrand factor was performed to evaluate loss of endothelium, and in vitro vein reactivity to phenylephrine and endothelin-1 was studied. RESULTS: Gene expression of cytokines and leukocyte adhesion molecules increased after graft harvesting and storage, whereas vasoactive substances did not change. Nuclear translocation of NFkappaB occurred after surgical handling, concurrent with partial loss of endothelium and impaired contractile function. CONCLUSIONS: Standard surgical handling of vein grafts induces NFkappaB-driven inflammation in the vessel wall and impairs vascular function. This may potentially contribute to both early and late graft occlusion.

Biopsy↗
PubMed2006

Postconditioning in rats and mice.

OBJECTIVE: For subsequent studies on the molecular mechanisms of postconditioning, we aimed to identify a robust postconditioning protocol in rat and mouse heart. DESIGN: Isolated rat hearts were subjected to different postconditioning protocols (study 1 and 2). The protection was compared to preconditioning. Rats (study 3) in vivo in two different laboratories were postconditioned. Isolated mouse hearts (study 4) and mice in vivo (study 5) were postconditioned. RESULTS: Postconditioning did not protect isolated, perfused rat hearts, however, preconditioning improved function and reduced infarct size. Postconditioning tended to protect rat hearts in vivo in one laboratory (p = 0.10), whereas protection was seen in the other laboratory (infarct size 51+/-11% vs controls 62+/-3%, p = 0.01). Postconditioned mouse hearts were protected, both ex vivo (16+/-9% vs controls 33+/-18%, p = 0.02) and in vivo (21+/-5% vs 42+/-7%, p < 0.001). CONCLUSIONS: Rat hearts are less suitable for studies of mechanisms of postconditioning. The results suggest that the signaling pathways differ between pre- and postconditioning. Mouse hearts were strongly protected by postconditioning, and genetically engineered mice may be useful for postconditioning research.

Animals↗
PubMed2006

Isoflurane and other commonly used anaesthetics do not protect the isolated buffer perfused mouse heart from ischemia-reperfusion injury.

1. Some anaesthetic agents such as barbiturates and opioids possess cardioprotective properties in rats, rabbits, dogs and pigs. The purpose of this study was to evaluate the effects of some commonly used anaesthetic agents (pentobarbital, isoflurane and a mixture of midazolam, fentanyl and fluanisone) on the tolerance of the isolated mouse heart to ischaemia-reperfusion injury. 2. The isolated, Langendorff-perfused hearts were subjected to 45 min of global ischaemia followed by 60 min of reperfusion. Left ventricular pressures, heart rate and coronary flow were measured and infarct size was determined using triphenyltetrazolium staining. 3. There were no differences in haemodynamic variables during reperfusion between groups. Infarct size was not influenced by the choice of anaesthesia. 4. None of the anaesthesia protocols exerted significant protective effects on the ischaemic-reperfused isolated mouse heart performance. In mice, isoflurane as well as pentobarbital, opioids and benzodiazepines may be safely used for anaesthesia without a risk of protective side-effects in isolated mouse heart studies.

Anesthetics, Inhalation↗
PubMed2005

Lazaroid U-83836E improves tolerance to hemorrhagic shock and limb ischemia and reperfusion in rats and increases cardiac heat shock protein 72.

OBJECTIVES: Aminosteroids of the lazaroid type protect organs from ischemia-reperfusion damage. The authors hypothesized that lazaroid U-83836E may be beneficial in a shock model with hemorrhage combined with limb ischemia. Furthermore, the authors hypothesized that lazaroids induce expression of heat shock proteins (HSPs) of the 72-kDa family. METHODS: Rats were divided into two groups (lazaroid and control groups, n = 8 each) and pretreated with the lazaroid U-83836E (5 mg/kg) or with vehicle intraperitoneally at 12 and 24 hours before experiments. At the time of the experiment, rats were anesthetized, and the femoral artery of each rat was cannulated. After 20 minutes of stabilization, blood was shed from each rat to bring its mean arterial pressure to 24-28 mmHg for 2 hours. Bilateral tourniquets were tightened proximally on the rat thighs during those 2 hours and then released. Shed blood plus equal amounts of Ringer acetate then were infused to restore normal blood pressure, followed by a continuous infusion of Ringer acetate, the rate of which was regulated to maintain blood pressure, until 30 minutes after start of resuscitation. Fluid resuscitation was stopped, and rats were observed for another 3.5 hours. At the end of the observation period, the rats' hearts were collected for immunoblot analysis of HSP72. Additional hearts were collected from similarly pretreated rats not undergoing the episode of hemorrhagic shock and fluid resuscitation. RESULTS: Pretreatment with U-83836E improved mean arterial blood pressure after hemorrhagic shock and fluid resuscitation (p = 0.02), combined with improvements in acid-base balance (improved base excess and standard bicarbonate; p = 0.02 and p = 0.01, respectively). Western blot of cardiac protein extracts demonstrated that lazaroid pretreatment increased expression of HSP72. CONCLUSIONS: Pretreatment with the lazaroid U-83836E improved outcome markers in this hemorrhagic shock model. The observed protection may be caused by increased expression of HSP72.

Acid-Base Equilibrium↗
PubMed2005

Pre- and postconditioning during cardiac surgery.

In spite of improved myocardial protection, postoperative arrhythmias and cardiac failure are still important problems causing morbidity and mortality in cardiac surgery. Ischemic preconditioning has been widely investigated experimentally with the purpose of identifying new therapeutic agents, but we have not unraveled the underlying mechanisms and we are not able yet to exploit them pharmacologically in clinical practice. Studies of preconditioning in cardiac surgery provide conflicting results, but the majority of studies show that ischemic preconditioning is an effective adjunct to myocardial protection in cardiac surgery. Interventions aimed at modifying reperfusion, or postconditioning, have the advantage that they also can be used after the ischemic insult has occurred, i.e. also in situations with "non-scheduled" ischemia. Postconditioning, as preconditioning, needs pharmacological mimics to be used routinely in settings of cardiac surgery or other human interventions. Possible common signaling pathways of the two phenomena are discussed, and suggested directions for clinical studies are outlined.

Animals↗
PubMed2005

Hemostasis in off-pump compared to on-pump coronary artery bypass grafting: a prospective, randomized study.

BACKGROUND: We hypothesized that off-pump coronary artery bypass grafting has less impact on the hemostatic systems than on-pump surgery. METHODS: Thirty-one patients were randomized to on-pump or off-pump coronary artery bypass grafting. Factors of hemostasis as well as markers of endothelial activation were measured up to 24 hours after the operation: Fibrin D dimer, prothrombin fragment 1+2, alpha2-macroglobulin, protein C1 esterase inhibitor, fibronectin, and von Willebrand factor. Overall hemostasis potential, overall coagulation potential, and overall fibrinolysis potential were determined with a previously developed assay. We also measured platelet count before and after surgery. RESULTS: Fibrin D dimer and prothrombin fragment 1+2 concentrations were lower during surgery in the off-pump group (p < 0.001). Four hours after admission to the intensive care unit, these differences were eliminated. alpha2-macroglobulin, protein C1 esterase inhibitor, fibronectin, and von Willebrand factor concentrations did not differ between groups (p = 0.59, p = 0.28, p = 0.22, and p = 0.69). Protein C1 esterase inhibitor and von Willebrand factor concentrations increased over time (p < 0.001) in both groups. Overall hemostasis potential and overall coagulation potential increased over time (p < 0.001), while overall fibrinolysis potential decreased (p < 0.001) with no difference between groups (p = 0.69, p = 0.91). Platelet count decreased on the first postoperative day (p < 0.001), but increased from the first to the third postoperative day (p = 0.004) in both groups without any inter group difference (p = 0.82). CONCLUSIONS: There was a tendency toward less activation of coagulation and fibrinolysis in low-risk patients during elective off-pump coronary artery bypass surgery when compared with on-pump surgery.

Aged↗
PubMed2005

Peripheral blood monocyte activation during coronary artery bypass grafting with or without cardiopulmonary bypass.

OBJECTIVE: The aim of this prospective, randomized study was to investigate the impact of coronary artery bypass grafting (CABG) on peripheral monocytes and to evaluate the additional effect of cardiopulmonary bypass (CPB). DESIGN: Twenty patients admitted for elective CABG were randomized to either on-pump (ONCAB, n = 9) or off-pump (OFFCAB, n = 11) surgery and blood samples were drawn before, during and 24 h after the operation. The total number of monocytes and the proportion of the more mature CD16+/CD14+ monocytes were measured. Expression of activation markers (CD11b, CD35 and CD62L) and oxidative burst were determined using flow cytometry on both resting and in vitro stimulated cells. Serum concentrations of soluble CD14 and monocytes/macrophage chemotactic protein 1 (MCP-1) were analysed. RESULTS: During surgery there was a selective decrease in the proportion of CD16+/CD14+ monocytes compared to total monocytes. These had returned to preoperative values 24 h after surgery while the total number of monocytes had increased more than 100%. Intracellular production of oxygen free radical H2O2 was increased in the ONCAB group during surgery compared to OFFCAB. Monocyte expression and in vitro mobilization of complement receptors, CD11b and CD35, were similar in both study groups during and after surgery as was the expression of CD62L. Serum levels of MCP-1 decreased during surgery as did soluble CD14, both with increased levels again the day after surgery. CONCLUSION: It is concluded that the circulating monocyte population is activated during and as a consequence of CABG. There were few apparent additional effects of CPB found in this study. In this setting the inflammation caused by the surgery procedure per se probably surpasses the impact of the CPB on circulating blood monocytes.

Aged↗
PubMed2005

Intraperitoneal injection induces a delayed preconditioning-like effect in mice.

We hypothesized that intraperitoneal injections of anaesthetics or fluid per se might evoke a delayed preconditioning-like response in mice hearts isolated and Langendorff perfused 24 h later. To test this, mice were given opioid anaesthesia by intraperitoneal injections or sham treated and the hearts were harvested and subjected to global ischaemia and reperfusion 24 h later in series 1. In series 2, mice were subjected to intraperitoneal injection of Ringer, sham needle prick procedure, or no intervention 24 h before heart isolation. In series 3, intraperitoneal Ringer injection 24 h earlier was compared with the effects of classic preconditioning or no pretreatment of the isolated heart or no treatment. Heart function was measured in all series. At the end of reperfusion, hearts in series 1 and 2 were frozen and infarct size was estimated by triphenyltetrazolium chloride solution. In series 3, separate hearts were frozen for immunoblotting to detect phosphorylation of mitogen-activated protein (MAP) kinases. Cardiac activation of nuclear factor kappa B (NFkappaB) was measured using a NFkappaB luciferase firefly reporter mouse. The ischaemia-induced impairment of left ventricular function was attenuated by opioid anaesthesia injected 24 h earlier, which also reduced infarct size. Injection of fluid, but not the sham needle prick procedure, reduced infarct size. The functional protection afforded by classic preconditioning and Ringer pretreatment was comparable. Neither cardiac MAP kinases nor NFkappaB were influenced by the interventions. In conclusion, this study demonstrates a delayed preconditioning-like effect of the heart caused by intraperitoneal administration of opioid anaesthetics and of fluid only in the mouse. The mechanism of protection remains to be determined.

Analysis of Variance↗
PubMed2004

Role of tumor necrosis factor alpha and its receptor I in preconditioning by hyperoxia.

Hyperoxic pretreatment (>95% O(2)) can evoke myocardial adaptation to ischemia, a method which is potentially clinically usable. We wanted to investigate the role of tumor necrosis factor alpha (TNFalpha) and its p55 receptor (receptor I) in signaling of hyperoxic adaptation to ischemia. Mice deficient for TNFalpha (TNFalpha -/-) or the TNF receptor I (TNFRI -/-) gene and their wild types were subjected to 60 minutes of hyperoxia or sham treatment. Their lungs were then collected for immunoblotting, their hearts isolated and subjected to global ischemia and reperfusion in a Langendorff system, and aortic rings mounted in organ baths for reactivity studies. Hyperoxia increased expression of TNFalpha and TNFalpha converting enzyme in pulmonary proteins from wild type mice, in which hyperoxia increased myocardial tolerance to ischemia. Post-ischemic heart function was improved and infarct size reduced in wild type mice, but not in TNFalpha -/- or TNFRI -/-. The contractile response to TNFalpha on aortic rings was attenuated by hyperoxic pretreatment and by TNFRI -/-. Thus we conclude that TNFalpha, acting through TNFRI, appears important for the protective effects of hyperoxia.

ADAM Proteins↗
PubMed2004

Ischemic postconditioning: brief ischemia during reperfusion converts persistent ventricular fibrillation into regular rhythm.

OBJECTIVES: Brief episodes of myocardial ischemia-reperfusion employed during reperfusion after a prolonged ischemic insult may attenuate the total ischemia-reperfusion injury. This phenomenon has been termed ischemic postconditioning. In the present study, we studied the possible effect of postconditioning on persistent reperfusion-induced ventricular fibrillation (VF) in the isolated rat heart model. METHODS: Isolated Langendorff-perfused rat hearts (n = 46) were subjected to 30 min of regional ischemia and reperfusion. The hearts with persistent VF (n = 11) present after 15 min of reperfusion were then randomly assigned into one of the two groups: (1) control hearts (n = 6) in which perfusion was continued without intervention; (2) postconditioned hearts (n = 5) subjected to 2 min of global ischemia followed by reperfusion. Left ventricular pressures, heart rate, coronary flow, and electrogram were monitored throughout the experiment. RESULTS: Conversion of VF into regular rhythm was observed in all hearts subjected to postconditioning. Regular beating was maintained by all postconditioned hearts during the subsequent reperfusion. None of the hearts in the control group had normal rhythm at the end of the experiment. At the end of reperfusion, the left ventricular developed pressure was lower in beating postconditioned hearts compared to the hearts that did not develop persistent VF. CONCLUSIONS: Ischemic postconditioning possesses strong antiarrhythmic effect against persistent reperfusion-induced tachyarrhythmias. Postconditioning may be an interesting, novel adjunct strategy to protect the heart.

Animals↗
PubMed2004

Myocardial protection by remote preconditioning: the role of nuclear factor kappa-B p105 and inducible nitric oxide synthase.

OBJECTIVE: Adaptation to ischemia by brief episodes of ischemia and reperfusion (preconditioning) of the heart protects the heart against sustained ischemia, where the transcription factor nuclear factor kappa-B (NFkappaB) appears crucial for the protection. Preconditioning of the heart may even be evoked by brief episodes of ischemia and reperfusion in other organs. The present study investigates a possible role for NFkappaB and inducible nitric oxide synthase (iNOS) in adaption to ischemia by remote, delayed protection. METHODS: Mice (wild-types, or with targeted deletions of the NFkappaB p105 or the iNOS gene) were subjected to cycles of occlusion and reperfusion of both hind limbs, and 24 h later their hearts were isolated and Langendorff-perfused with induced global ischemia and reperfusion. Infarct size was measured. Skeletal muscles from ischemized limbs as well as hearts were also collected for polymerase chain reaction (PCR) and electromobility shift assay (EMSA). RESULTS: Hind limb preconditioning protected left ventricular function and reduced infarct size during reperfusion in wild-type mice. Nuclear translocation of NFkappaB was detected in both heart and preconditioned skeletal muscle 1-2 h after the preconditioning episodes (EMSA); while cardiac mRNA for iNOS gradually increased in a 24-h time course after hind limb preconditioning (real-time PCR). When hind limbs of mice with targeted deletions for the p105 subunit of NFkappaB or the iNOS gene were preconditioned, no beneficial effect was observed in the heart. CONCLUSIONS: Delayed cardioprotection induced by hind limb preconditioning involves signaling through NFkappaB and iNOS.

Animals↗
PubMed2004

Activation of complement and leukocyte receptors during on- and off pump coronary artery bypass surgery.

OBJECTIVE: The aim of this prospective, randomised study was to investigate the influence of extracorporeal circulation on the inflammatory response, our hypothesis being that off pump coronary artery bypass grafting (OFFCAB) procedures would generate less activation than on pump procedures (ONCAB). METHODS: Patients admitted for elective CABG were randomised to either ONCAB or OFFCAB surgery and blood samples were taken during and up to 24 h after the operation. We measured complement factors C5a and the terminal complement complex (TCC, C59-b), and the interleukins IL-6 and IL-8. Leukocytes were studied for cellular counts and adhesion molecules (CD11b, CD35 and CD62L) by flow cytometry. We included a combination of activity markers with different aspects of neutrophil function and combined these with in vitro activation. RESULTS: The complement factors C5a and TCC showed a more rapid (P=0.02, P<0.001) and TCC a more profound (P<0.001) increase in the ONCAB group than in the OFFCAB group during the operation, after that there were no inter-group differences. Cellular markers, cell counts and interleukin levels were activated by surgery but with no difference between groups. CONCLUSION: This prospective, randomised study showed less complement activation in low risk OFFCAB, compared to ONCAB patients.

Aged↗
PubMed2004

Metabolic changes induced by ischemia and cardioplegia: a study employing cardiac microdialysis in pigs.

OBJECTIVE: The present study investigates dynamic changes of myocardial metabolism in response to ischemia, cardioplegia, and extracorporeal circulation (ECC) in order to differentiate between the contributing effects of each of these interventions. Furthermore, warm blood cardioplegia versus empty beating of the heart were compared as methods to resuscitate the ischemic myocardial metabolism. METHODS: Swedish Landrace pigs on ECC (ECC) were compared with pigs on ECC with warm ischemic cardiac arrest (ischemia) or on ECC with warm ischemic arrest followed by warm blood cardioplegia (ischemia-cardioplegia), using sham-operated pigs as controls (n=7 in each group). Microdialysis probes were placed on the surface of the left ventricle and in the femoral artery for serial evaluation of metabolites in the intracardiac extracellular fluid and arterial blood. When hearts started in ventricular fibrillation (VF), it was electroconverted after 10 min of normal blood reperfusion. If VF started after 10 min of reperfusion electroconversion was immediately performed. RESULTS: There were no differences between groups in arterial contents of serine, citrulline, arginine, inosine, hypoxanthine, guanosine, aspartate, glutamate, pyruvate, or asparagine throughout the observation period. Systemic lactate increased in pigs subjected to ischemia (P<0.001) or ischemia and cardioplegia (P=0.002), highest in the ischemia only group (P=0.002). In left ventricular microdialysates, lactate increased in pigs subjected to ischemia alone (P<0.001 vs. ECC) and ischemia and cardioplegia (P=0.004 vs. ECC). Guanosine increased in ischemia versus ECC (P=0.002), while hypoxanthine was increased in microdialysates of both ischemic (P=0.002) and ischemic-cardioplegic (P=0.001) pig hearts. Inosine was increased in pigs subjected to ischemia and cardioplegia (P<0.001 vs. ECC). All ischemic hearts started with VF, but while in the warm ischemia group VF started within 10 min of reperfusion, the ischemia-cardioplegia group had a longer asystolia with VF starting 11-22 min of blood reperfusion. CONCLUSION: The heart should be allowed to start empty beating rather than by the use of warm continuous blood cardioplegia. Microdialysis and sampling of interstitial metabolites may be advantageous when an increased sensitivity is needed or when repeated blood sampling is difficult or contraindicated in monitoring of the myocardium.

Analysis of Variance↗