Institute for Experimental Medical Research

Institute for Experimental Medical Research2011

Annual report 2011

Cover picture: MR 3D scan of a mouse heart

Director’s comment

I am pleased to present the annual report for Institute for Experimental Medical Research (IEMR) for 2011. The report has a new layout, and for 2012 the project catalogue which used to be part of the report, is now a separate document.

At the end of the year the Research Council of Norway (RCN) published the reports on Evaluation of Biology, Medicine and Health Research in Norway. As described on page 14 the research at the institute got excellent ratings. The report also stated that Center for Heart Failure Research is an important strategic development. Several research groups of the institute are members of the center which is headed by Professor Geir Christensen. Also two of the groups are partners of the newly formed KG Jebsen Cardiac Research Center. The institute received support from several sources including RCN, South-Eastern Norway Regional Health Authority, The Lærdal Foundation and The Anders Jahre Fund for Promotion of Science and The Council for Cardiovascular Research. 2011 was a prolific year with important scientific achievements of which some are highlighted on pp. 6-8.

The institute is a department of the Division of Cardiovascular and Pulmonary Diseases of Oslo University Hospital and is also part of Institute of Clinical Medicine of Faculty of Medicine at University of Oslo. The institute collaborates extensively with several clinical departments and in 2011 collaboration with scientists abroad has been expanded and strengthened.

The very favorable reviews, the good infrastructure, available technology and an eminent technical and scientific staff is the best basis for excellent science in the years to come.

Oslo, February 8, 2012

Ole M. Sejersted Head of Department

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Vision and strategy 4

Highlights from 2011 6

Selected publications 6

Prizes and awards 9

PhD theses in 2011 10

Graduates from the Medical Student Research Program 13

International evaluation by the Norwegian Research Council 14

Research groups 15

Collaboration 32

Featured collaborators 32

Collaboration list 34

Core competency at IEMR 36

Meetings and educational activities 40

Publication list 42

Funding 46

table of contents

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oUr Vision

Create tomorrow’s science and therapy by enthusiastically unveiling the secrets of the failing heart

institUte for eXPerimental meDical researcH

www.iemr.no

INSTITUTE FOR EXPERIMENTAL MEDICAL RESEARCH

Head of DepartmentOle M. Sejersted

Head of Section for Preclinical Physiology

Morten Eriksen

Head of Laboratory Section

Lisbeth H. Winer

Administration

Senior Administrative Officer Lisbeth H. Winer

SecretaryJoselan Fabe Larsen

Disease Mechanisms of Heart Failure

Ole M. Sejersted and Ivar Sjaastad

Cardiac fibrinolysis

Arnfinn Ilebekk and Torstein Lyberg

CardiopulmonaryResuscitation

Petter Andreas Steenand Kjetil Sunde

MyocardialRemodeling and

Reverse Remodeling in Pressure Overload

Theis Tønnessen

Atherothrombosisand Vascular Biology

Harald Arnesen and Ingebjørg Seljeflot

Hypoxia and Cardiopulmonary

Circulation

Ole Henning Skjønsberg

Cardiac Biomarkers

Torbjørn Omland

Cellular and Molecular Biology of

Myocardial Hypertrophy and

Heart FailureGeir Christensen

Structural Studies of Ca2+-ATPases in the Plasma Membrane

Jens Preben Morth

Res

earc

h g

roup

s

oUr aimsTo be driven by curiosity and the joy of fitting our scientific pieces in the mosaic of knowledge.

To understand mechanisms of cardiac disease with the aim of developing treatment strategies

To recruit and educate PhD and medical students

Vision and strategy

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Recruit scientists and researchersRecruit and retain talented, competent people and foster their development.

Equipment and technologyMaintain instruments, laboratories and competence to serve scientists in the hospital and the health region with comparative medicine resources.

Scientific and educational training resourceOffer modern surgery and intervention facilities for clinical training.

Produce new scientistsProvide excellent academic and research training for PhD, medical, and masters level students. We aim to promote honest and ethical behavior within science and professional relations.

Secure fundingSeek competitive grants to sustain world-class research.

National and international collaboration Strengthen national and international collaboration with leading researchers to access required technology and competence.

Scientific publicationsPublish research findings in high-impact journals, and present results at national and international meetings.

Novel therapiesImprove prevention, diagnosis and treat ment of cardio-vascular disease by unraveling disease mechanisms.

CommercializationIdentify important findings and protect intellectual property by patenting innovations.

CommunicationCommunicate important research findings to the general public through lectures and popular science publications.

oUr strateGies

RESEARCH EDUCATIONScientific

publications

SOCIETY

Produce newscientists

Popular sciencepublications

Noveltherapies

CommercializationPubliccommunication

National andinternationalcollaboration

Recruitscientists andresearchers

Equipment and technology

Secure funding

Scientific and educationaltraining rescource

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SElECtED PublICatIoNS

Sustained effects of post-cardiac arrest care protocols five years after implementation.

In a previous study of treatment of patients that have survived the initial resuscitation after cardiac arrest, we demonstrated a doubled survival rate with the implementation of systematic intensive care. This year, we published a follow-up study with virtually identical outcomes throughout a five year post-implementation period with the new post-arrest care protocols as part of ordinary care. (Tømte et al . Resuscitation 2011)

The emotional stress of performing cardiopulmonary resuscitation in real life may be an important reason why previous registrations have demonstrated sub-optimal quality. In two studies of simulated cardiac arrest, we have shown that both first responders and professional paramedics can perform adequately even under stressful conditions. Both studies provide important

Serca2 gene disruption was targeted specifically to skeletal muscle, resulting in strongly reduced SERCA2 protein expression only in skeletal muscles of skKO mice (A,B). Functionally, muscle force development was maintained (C), however muscle relaxation rate was slowed (D) in skKO soleus muscles compared to FF.

encouragement to continue to educate and train CPR, and have elucidated possible improvements in such training. (Bjørshol et al. Crit Care Med. and Neset et al A. Acta Anaesthesiol Scand. 2011)

Slowed Relaxation and Preserved Maximal Force in Skeletal Muscle Specific SERCA2KO mice.

The article by Sjåland et al. J Physiol (2011) presents for the first time a mouse model in which the Serca2 gene is specifically disrupted in skeletal muscle (skKO). This model gives the first opportunity to study the role of SERCA2 in skeletal muscle function in adult mice in vivo. Impaired muscle function and muscle disease has been linked to disturbances in the regulation of Ca2+ movement between the intracellular sarcoplasmic reticulum Ca2+ store (SR) and cytoplasm in muscle cells. Loss of SERCA2 resulted in slowed muscle relaxation supporting that reduced SERCA2 reduce Ca2+ transport into the SR

and prolong muscle relaxation time. Reduced SR Ca2+ would be expected to lower the amount of Ca2+ released during contraction, and thereby lower the maximal force. However, maximal force was maintained, suggesting that SERCA-independent mechanisms can contribute to muscle contractile function.

HigHligHts from 2011

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The proteoglycan syndecan-4 is essential for development of pathological growth of the heart

The article by Finsen/Lunde et al. published in PLoS One December 2nd 2011 shows that syndecan-4, a transmembrane proteoglycan localized to the cardiomyocyte Z-disc, is essential for development of concentric myocardial hypertrophy. Mice lacking syndecan-4 did not develop concentric hypertrophy in response to pressure overload, as did wild type mice (Fig. 1A), and protein and gene expression analyses revealed diminished activation of the central, pro-hypertrophic

calcineurin-nuclear factor of activated T-cell (NFAT) signaling pathway. Importantly, cardiomyocytes lacking syndecan-4 responded to mechanical stretch with reduced NFAT activation, suggesting syndecan-4 to be a mechanosensor. A series of experiments finally supported a hypothesis of syndecan-4 being an activator of pro-hypertrophic calcineurin-NFAT signaling in cardiomyocytes in response to pressure overload (Fig. 1B).

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Lack of Chemokine Signaling through CXCR5 Causes Increased Mortality

The article by Waehre et al. published in PLoS One April 18th 2011 shows that mice harboring a systemic knockout of the CXCR5 (CXCR5-/-) displayed increased mortality during a follow-up of 80 days after aortic banding (AB) (Fig). Following three weeks of AB, CXCR5-/- developed significant left ventricular (LV) dilatation compared to wild type (WT) mice. Microarray analysis revealed altered expression of several small leucine-rich proteoglycans (SLRPs) that bind to collagen and modulate fibril assembly. Protein levels of fibromodulin, decorin and lumican (all SLRPs) were significantly reduced in AB CXCR5-/- compared to AB WT mice. Electron microscopy revealed loosely packed extracellular matrix with individual collagen fibers and small networks of proteoglycans in AB CXCR5-/- mice. Addition of CXCL13 to cultured cardiac fibroblasts enhanced the expression of SLRPs. This study demonstrates a critical role of the chemokine CXCL13 and CXCR5 in survival and maintaining of cardiac structure upon pressure overload, by regulating proteoglycans essential for correct collagen assembly.

Cardiac dysfunction in Juvenile Dermatomyositis – a case control study

Through a collaborative study between IEMR and Dept of Rheumatology, OUS, published in Annals of Rheumatic Diseases (2011), PhD student Thomas Schwartz et al have given new insight to a field in the crossroads between cardiology and rheumatology. Diastolic dysfunction (disturbed left ventricular filling, due to stiffness of the heart) has been observed in rheumatic diseases. Data from Helga Sanners matched cohort of 59 unselected patients (95% of the living identified patients in Norway) demonstrated that this also is the case in the rare disease of juvenile dermatomyositis.

With tissue Doppler and standard echocardiography, the investigators showed that possible diastolic dysfunction was present, although yet asymptomatic, in as many as 22% of these young patients (vs. 0% of the controls, p<0.001),

Furthermore, high disease activity early in the disease course proved to predict cardiac affection. These new findings suggest that subclinical heart disease is related to the systemic nature of juvenile dermatomyositis.

HigHligHts from 2011

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The Heart Prize 2011

The Norwegian Council for Cardiovascular Diseases has honored Professor Geir Christensen for his research on the importance of hormone production in the heart, and his efforts to establish the Center for Heart Failure Research. His Majesty King Harald presented the Heart Prize 2011 to Geir Christensen at an award ceremony in Oslo.

Dickinson W. Richard Memorial Lecture

At AHA Scientific Session 2011 in Orlando, Fl, Professor Petter Andreas Steen was honored for his lifelong devotion to the study of cardiopulmonary resuscitation. He presented this year’s Dickinson W. Richards Lecture titled: “Improving Cardiac Arrest Outcomes: Fine-tuning or Paradigm Shift?”

Scientist of the Month - August 2011

Every month the South-Eastern Norway Regional Health Authority (Helse Sør-Øst) selects a ‘Scientist of the month’. The aim is to focus on ongoing excellent research in the region. Head of Institute Ole Sejersted was appointed ‘Scientist of the Month’ for the month of August for his valuable contribution to heart failure research.

Ole Storsteins prize

Professor Ivar Sjaastad was awarded Ole Storsteins Prize 2010. His prize lecture: Mekanismer formyokardiell dysfunksjon was presented at the NCS (Norsk Cardiologisk Selskaps) winter meeting 2011 at Lillehammer.

Other prizes

Ida G. Lunde was awarded 2nd prize for the popular scientific contribution ‘Fisk blir hjertesyke av stress’ in a communication competition (Formidlingspris) initiated by MLSUiO (Molecular Life Science, University of Oslo).

Selected Poster prizes

In June 2011 Maria Vistnes won a poster prize at ‘The Annual XXX meeting of the European Section of the International Society of Heart Research’ in Haifa, Israel. Mathis Stokke recieved a poster prize at ‘35th Meeting of the ESC Working Group on Cardiac Cellular Electrophysiology’ in Oslo.

PRIzES aND awaRDS

Petter Andreas Steen receiving his plaque from Dr. Karl Kern (the Chair of the Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation)

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The TGF-β/SMAD signaling system and extracellular matrix changes in myocardial remodeling and reverse remodeling following correction of pressure overload

Abstract: Aortic stenosis is the most common valvular lesion in the Western world and the incidence is increasing. Aortic stenosis causes pressure overload of the left ventricle, leading to detrimental myocardial remodeling. Following aortic valve replacement reverse myocardial remodeling usually takes place. If preoperative changes are severe, reduced function may persist. Current knowledge about the reverse remodeling process is limited. However, incomplete reverse remodeling after aortic valve replacement for aortic stenosis is associated with persisting symptoms and increased mortality. Hypertension also leads to pathologic remodeling and subsequent heart failure development. Hypertensive heart failure, once established, may not respond to antihypertensive treatment. Thus, a better insight into the reverse remodeling process might lead to improved treatment.

The aims of this thesis were to study the TGF-β superfamily and ECM changes in human and experimental aortic stenosis and during reverse remodeling following surgical correction of pressure overload. Initially, we demonstrated altered levels of members of the TGF-β superfamily in patients with aortic stenosis and following surgery for aortic stenosis. Downstream SMAD2/3 signaling has been suggested to mediate both deleterious and cardioprotective effects. In a mouse model of pressure overload we found SMAD2 signaling to have deleterious effects on cardiomyocytes. To study reverse remodeling, we established a mouse model of banding-debanding of the ascending aorta, mimicking aortic valve replacement for aortic stenosis. In this model we have demonstrated novel extracellular matrix changes taking place during the early phase of reverse remodeling. We believe our findings may contribute to increased understanding of the reverse remodeling process.

PHD tHESES IN 2011

Johannes Lagethon Bjørnstad

Supervisor: T. Tønnessen

HigHligHts from 2011

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SERCA2-RyR2 interplay at the heart of Ca2+ wave development. Experimental studies on mechanisms underlying triggered arrhythmias

Abstract: Sudden cardiac death caused by ventricular arrhythmias remains a major health problem throughout the world. Triggered arrhythmias are caused by spontaneous action potentials in individual cardiomyocytes. Such action potentials can result from an intracellular self-propagating process of spontaneous Ca2+ release from the sarcoplasmic reticulum, known as Ca2+ waves. This thesis explores the mechanisms for development of Ca2+ waves. The cardiac sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA2) moves Ca2+ from the cytosol to the sarcoplasmic reticulum (SR) and is therefore central in Ca2+ homeostasis. However, its role in Ca2+ wave development remains unresolved. We found that the probability for Ca2+ wave development was halved in genetically modified mice with a 50% reduction in SERCA2 abundance (SERCA2 KO) compared to myocytes with normal levels of SERCA2. This coincided with fewer ventricular extrasystoles in ECGs from SERCA2 KO mice. However, further studies showed that the SERCA2 reduction altered the activity of other Ca2+ handling proteins. As a consequence, sympathetic stimulation doubled the probability for Ca2+ waves in SERCA2 KO myocytes while leaving it unaltered in control myocytes. This difference could be explained by increased activity of Ca2+-calmodulin-dependent kinase II (CaMKII) and CaMKII-dependent phosphorylation of the SR Ca2+ release channel (RyR2) in SERCA2 KO myocytes. These alterations lowered the threshold SR Ca2+ content needed for Ca2+ wave development in the SERCA2 KO. These results show that the effects of reduced SERCA2 activity depend on its interplay with other proteins, mainly RyR2. Clinical trials indicate that L-type Ca2+ channel antagonists could have a preventive effect on triggered arrhythmias. However, the physiological mechanism for such a preventive effect is not clear. We showed that the L-type Ca2+ channel antagonist verapamil lowered SR Ca2+ content, and thereby prevented local SR Ca2+ release events and Ca2+ waves.

Mathis Korseberg Stokke

Supervisors: O.M. Sejersted and I. Sjaastad

Modes of Ca2+ release

Different modes of Ca2+ release illustrated by recordings from a field stimulated mouse cardiomyocyte loaded with fluo-4 AM and exposed to a modified Hepes-Tyrode’s solution containing 100 nM isoproterenol. The left linescan image and 3D visualization of Ca2+ dependent fluorescence show homogenous and synchronous release in Ca2+ transients resulting from 1 Hz stimulation followed by a pause. The right linescan image and 3D visualization show a spontaneous Ca2+ release propagation as a Ca2+ wave throughout the length of the cell. A non propagating, local Ca2+ spark is visualized at the right.

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PHD tHESES IN 2011

Progenitor cells, growth factors and inflammation in acute myocardial infarction

Abstract: Acute myocardial infarction is a major cause of morbidity and mortality in the western part of the world. It is caused by blockage of one of the coronary arteries supplying the heart and leads to death of heart muscle cells. Today acute myocardial infarction is best treated with early restoration of blood flow to the infarcted area by coronary angioplasty. In animal studies it has been shown that bone marrow stem cells and circulating stem cells may partly replace lost heart muscle cells and improve myocardial function after an acute myocardial infarction. Therapy with ones own bone marrow cells have been performed in humans after myocardial infarction, but the effect of such therapy has been meager, perhaps due to the cause that we lack knowledge about factors that may facilitate attraction and lodging and survival of the circulating stem cells to the area of injury.

In the present thesis MD Haakon Kiil Grøgaard and coworkers in studies from both animals and humans with acute myocardial infarction, have studied stem cells in bone marrow and in the circulation, and in addition performed detailed studies of circulating growth factors and inflammation markers.

In one of the studies it has been shown that ones own stem cells from bone marrow accumulate in the infarcted myocardium, and that the accumulation of cells is more prominent when the cells are injected directly into the coronary artery than intravenously. We have also shown that treatment with bone marrow stem cells after acute myocardial infarction leads to an increase in the circulating levels of certain growth factors. The number of stem cells residing in the bone marrow on day five after an acute myocardial infarction is reduced, and simultaneously the circulating number of stem cells is increased possibly due to release from the bone marrow. During the first few days after an acute myocardial infarction we find increased levels of circulating markers of inflammation, which may hamper the survival of stem cells. Growth factors that may facilitate accumulation of stem cells in injured tissue seems to be increased in the circulation 14 days after an acute myocardial infarction.

Haakon Kiil Grøgaard

Supervisors: A. Ilebekk and H. Arnesen

HigHligHts from 2011

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GRaDuatES FRoM tHE MEDICal StuDENt RESEaRCH PRoGRaM IN 2011

Cardiopulmonary Resuscitation by Elderly Bystanders

Abstract: Cardiopulmonary resuscitation (CPR) performed by lay persons before arrival of professional rescuers more than doubles the survival from out-of-hospital cardiac arrest. In two papers we present the results from simulation based testing of 128 lay persons 50 to 75 years of age. Contrary to some previously published results of CPR performance in this age group, we found that quality of chest compressions were high, both in terms of rate and depth. There was no temporal decay of quality, despite the long duration (10 min) of the tests. Chests compression only CPR is a hot topic in resuscitation research. In our study, laypersons were equally capable of performing chests compression only CPR and conventional 30 compressions 2 ventilations CPR. In the second paper, we compared CPR performance in a standard test and in a more realistic simulation. We addressed five factors to enhance realism: the rescuers, the manikin, the duration of the simulation, the environment, and the scenario. The CPR performance was not different in the two tests, and chest compression quality was high.

Mechanisms and new therapeutic approaches to diastolic dysfunction

Abstract: A large part of patients with heart failure have diastolic heart failure and pharmacological therapy of diastolic heart failure is still unsatisfactory. In fact, no medication has shown to reduce mortality in patients with diastolic heart failure. In the search for new treatments of diastolic heart failure it is important to understand the underlying mechanisms of diastolic dysfunction. We have investigated both mechanisms and new therapeutic strategies in two different experimental models. Diastolic dysfunction can be the result of impaired calcium homeostasis. In the first project, we studied diastolic dysfunction due to lack of the sarcoplasmatic reticulum calcium ATPase2 (SERCA2) in the heart. Reduced levels of SERCA2 have been shown in patients with heart failure. We showed that levosimendan, a calcium sensitizer, can improve relaxation in hearts lacking SERCA2, but that it might lead to increased fibrosis. Left ventricular diastolic dysfunction may also develop secondary to pulmonary disease. In our second work we showed that inhibition of the cytokine interleukin-18 can improve diastolic function in alveolar hypoxia. Hence we demonstrate a role for inflammation in the development of diastolic dysfunction and that circulating cytokines are potential therapeutic targets.

Andres Neset

Supervisor: J. Kramer-Johansen

Vigdis Hillestad

Supervisor: Geir Christensen

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In 2010 The Research Council of Norway initiated a comprehensive evaluation of biological, medical, and health research to follow up on the evaluation of Clinical Research from 2003. The evaluation was carried out with seven external panels, and was based on schematic self-assessments and on-site interviews in 2011. The report was published 17th November 2011. Two of the panels were dedicated to clinical medicine: Institute for Experimental Medical Research was evaluated by panel 4b and the research group of Acute Prehospital Medicine was evaluated by panel 4a.

The evaluation took place shortly after the re-organization of Oslo University Hospital and one of the main recommendations regarding cardiac research at Oslo University Hospital was to further improve integration between geographical sites and with clinical activity. The scientific quality of the Institute for Experimental Medical Research was graded excellent and the collaboration with the Centre for Heart Failure Research and its PhD school was identified as an important strategic development. As in the 2003 evaluation The Acute Prehospital Research group was graded excellent and named a top actor in international cardiac arrest research. The good organizational balance between PhD students and post-doctoral fellows was mentioned by the panel, and they recommended to further support the work of this group.

RESultS FRoM tHE 2011 EValuatIoN oF bIoloGy, MEDICINE aND HEaltH RESEaRCH IN NoRway.

HigHligHts from 2011

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researcH groups

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DISEaSE MECHaNISMS oF HEaRt FaIluRE

Heart failure – a condition in which the pumping function of the heart is weak or insufficient - is both crippling and associated with high mortality. There is no available cure and it hits a growing number of patients. Today about 100.000 people in Norway suffer from heart failure and within 5 years at least 50% will have died. The reasons for inefficient pumping by the failing heart are still unknown. We believe that the electrical impulse (reflected in the ECG) that triggers every heart beat is less effectively converted to contraction. A key player is calcium inside the heart cells. A transient rise of intracellular calcium is an essential signal linking electrical activation to contraction and therefore determines how efficient the heart works. A slower or smaller calcium signal may explain why the heart cannot contract properly (systolic heart failure). Also, rapid cessation of the calcium signal is important for the heart to relax and fill with blood before the next beat. Improper relaxation will therefore also cause reduced pumping capacity (diastolic heart failure). In the cells there may be structural or electrical reasons for the altered calcium signal. We also believe that smaller, slower and prolonged contractions may appear in small regions of the heart which of course will make these regions work out of phase with the rest of heart (dyssynchrony). The stress that will develop between regions that are out of phase may promote disease progression.

researcH groups

Professor Ole M. Sejersted

Professor Ivar Sjaastad

The strategy of the group is to use advanced imaging techniques in combination with electrophysiological and molecular biology techniques to unravel the underlying disease mechanisms. The research focus in 2012 will be on 1) altered microstructure and relocation of membrane proteins in failing cardiac cells, 2) altered electrical properties of the failing myocardium, 3) calcium signaling in failing heart cells, 4) altered contraction patterns in failing hearts, 5) skeletal muscle fatigue mechanisms.We are using both patient cohorts and experimental models.

Altered microstructure and relocation of membrane proteins in failing cardiac cells.

Fredrik Swift (Postdoc) Nils Tovsrud (PhD student) Pim Wanichawan (PhD student)

We have shown that the fine architecture of cardiac cells is grossly deranged in heart failure. This impairs contractility by reducing the efficiency of the conversion of the electrical signal into contraction. Specifically, the sites or junctions where the cell membrane connects with the stores of calcium seem to be partly missing. Several important ion transporting membrane proteins are located to these junctions. In addition these proteins may be relocated so that they do not collaborate efficiently (destroyed protein-protein interaction). Also cessation of the calcium signal is dependent on transport proteins. In 2012, we will focus on understanding why the cellular architecture is changed and why membrane proteins are relocated. The data will be incorporated into mathematical models of the heart to understand how these changes affect whole heart function.

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Simultaneous recordings of membrane potential (upper panel) and intracellular Ca2+ (lower panels). Spontaneous Ca2+ waves result in depolarization of the resting membrane potential, events called delayed after depolarizations (DADs), which can lead to arrhythmia.

Altered electrical properties of the failing myocardium.

Mathis Stokke (Postdoc) Magnus Aronsen (PhD student) Ravinea Manotheepan (PhD student) Tore Danielsen (PhD student) Jonas Skogestad (Research Curriculum student) Mani Sadredini (Research Curriculum student)

Another cardinal feature of heart failure is electrical remodeling. This is observed both at the intact heart level and in isolated heart cells and may cause irregular beats and arrhythmias. Irregular electrical activation can also occur by spontaneous intracellular calcium release that develops into self-propagating waves of calcium inside the cell. This can cause sudden death due to ventricular fibrillation in heart failure patients. Other patients have an inherited propensity for such waves to occur (CPVT), or the waves may be triggered by altered electrolyte balance (hypo- or hyperkalemia). It is unclear what causes the spontaneous release of calcium and why the waves travel through the cell. Interestingly, it may be that training has a beneficial effect. Several important membrane proteins that carry calcium across membranes (channels, transporters and ion-pumps) may be involved.

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DISEaSE MECHaNISMS oF HEaRt FaIluRE

researcH groups

Calcium signaling in failing heart cells.

Bill Louch (Researcher) Leiv Øyehaug (Postdoc) Guro Jølle (PhD student) Karina Hougen (PhD student) Michael Frisk (PhD student) Kristian Loose (Research Curriculum student) Ulla Enger (Research engineer, MSc) Jørn B. Sande (Senior engineer)

It is generally believed that most of the calcium that constitutes the calcium signal comes from an intracellular store – the sarcoplasmic reticulum (SR). By

Proximity ligation assay performed in rat cardiomyocyte, showing colocalization of PDE3A and SERCA2 in intact cardiomyocytes.

Myocarial velocities in systole (left) and diastole (right) measured by phase contrast MRI

using a conditional knock out mouse, we have shown that even in the complete absence of SR-function other calcium handling systems can compensate – at least for some time. This model has given a unique insight into the mechanisms that control the size and timing of the calcium signal in normal and diseased hearts. Interestingly, these data have been combined with advanced mathematical models that allow us to integrate data in whole cell models and understand how various molecular and structural perturbations affect whole cell function. We will continue to examine factors that control the calcium transient and expand the modeling to allow us to predict behavior of the intact heart from cellular data.

Altered contraction patterns in failing hearts.

Emil Espe (PhD student) Thomas Schwartz (PhD student)Lili Zhang (Senior engineer)Vidar Magne Skulberg (engineer)Roy Trondsen (Fine Mechanics engineer)

In recent years it has become clear that in many heart failure patients parts of the heart are contracting while others are still relaxing (dyssynchrony). This will cause unfavorable stress that cells can sense. We believe that there are intracellular mechanisms for adapting to altered mechanical stress. Hence cellular dyssynchrony may trigger altered contractions and relaxation patterns in larger parts of the heart. We will investigate the development of regional dysfunction in the failing heart utilizing beyond state of the art high resolution MRI and echocardiography. The mechanisms for regional differences in function will be further examined at the cellular and molecular level in human cardiac biopsies from regions with reduced function.

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Thermography of running mouse

Skeletal muscle fatigue mechanisms.

Per Kristian Lunde (Researcher) Cecilie Sjåland (PhD student) Kristin H. Hortemo (Research Curriculum student)Per Andreas Norseng (Research engineer, Cand Scient)Marianne Lunde (Research engineer, Cand Scient)

Fatigue is an important symptom in heart failure patients. We and many others have proposed that this is partly caused by alterations in skeletal muscle. However, it could be that this is an epiphenomenon that is not present in all cases, and that fatigue is only manifested during certain types of exercise. For example, it is clear that in heart failure muscle performance is better preserved when the muscle is allowed to shorten than during more static work. We are currently investigating the mechanisms underlying fatigue during normal shortening of muscles in both control and heart failure conditions. It seems that contrary to causes of fatigue during static work, shortening capacity may be linked to the phosphorylation of key proteins of the contractile machinery.

Methodologies

We are using experimental approaches for all of these projects, which includes examination of both genetically modified mice and human samples. Importantly, a wide array of techniques is employed, spanning from molecular biology and electrophysiology (patch clamp) to laserscan and electron microscopy. As well, in vivo phenotyping is made possible by MRI and MR spectroscopy. Systems biology has become an important tool and mathematical models are being developed. Last, but not least, important collaboration is established both within Center for Heart Failure Research, within the KG Jebsen Cardiac Research Center and with international colleagues

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CEllulaR aND MolECulaR bIoloGy oF MyoCaRDIal HyPERtRoPHy aND HEaRt FaIluRE

researcH groups

Professor Geir Christensen

that promote myocardial hypertrophy and cardiac dysfunction. We have used microarray technology to identify regulated cytokines in hypertrophied and failing myocardium following myocardial infarction, and we have reported close to twenty cytokines that have never previously been assigned a role in heart failure. Using similar technologies, we have identified cytokines which are upregulated following aortic stenosis and pulmonary stenosis, and in models of cor pulmonale (hypoxia) and cardiomyopathy (conditional knock-out of the SR Ca2+ pump). The latter model, which was made in our institute, develops a severe diastolic dysfunction and has been thoroughly characterized at the organ and cellular level. Moreover, a patent on this mouse model has been published and currently the model is presented to the pharmaceutical industry as a tool for drug testing. The regulated cytokines identified in the various models described above may actively contribute to the development and progression of heart failure

Chronic heart failure is a frequent outcome of several disease states among which hypertension, valvular disease and ischemic heart disease, including myocardial infarction, are leading etiological causes. Despite recent advances in treatment of heart failure, the syndrome is still a major cause of death. The main aim of the work in our group is to develop novel therapeutic approaches and better diagnostic tools for heart failure through new knowledge about molecular mechanisms involved.

Cytokines and heart failure

Cathrine Husberg (Postdoc)Ståle Nygård (Postdoc)Anne Wæhre (PhD student)Maria Vistnes ( PhD student )Vigdis Hillestad (Research Curriculum student)Dina Behmen (Research engineer, MSc)Hilde Dishington (Research engineer)Almira Hasic (Research engineer, MSc)Marita Mathisen (Research engineer)

Increased mechanical stress of the myocardium following hypertension and myocardial infarction induces release of hormonal factors, such as cytokines, which may induce myocardial hypertrophy and progression of heart failure. The strategy of our group is to identify cytokines which are regulated in heart failure, and to study those

A fibroblast isolated from a mouse heart. The cytoskeleton protein actin is colored red while the protein paxillin is colored green. Paxillin is afocal-adhesion protein important in regulating cell-cell interaction and response to mechanical stress.

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through induction of hypertrophy and depression of cardiomyocyte contractility. One such example is the cytokine interleukin-18, which was found to be strongly upregulated both after myocardial infarction and in our cor pulmonale model. We have published data showing that interleukin-18 through its effects on phosphorylation of certain intracellular proteins may be importantly involved in development of diastolic dysfunction with possible therapeutic and diagnostic implications. Through our collaboration with the Research Institute for Internal Medicine and the Department of Cardiology at Oslo University Hospital Rikshospitalet (P. Aukrust, L. Gullestad), we have a unique opportunity to verify our findings obtained in experimental models by analyzing cytokine regulation in material from patients with different types of chronic heart failure. By this strategy we have identified activin A, leukemia inhibitory factor, interleukin-18 and fractalkine as novel possible mediators of heart failure development. We have also performed several studies showing that chemokines such as CXCL16, fractalkine and CXCL13 are increased in experimental and clinical heart failure, and identified an important role in extracellular matrix remodeling, especially by regulating a specific group of proteoglycans. Further studies will show how these cytokines directly affect disease progression in humans and whether they can act as targets for therapy or biomarkers of cardiac disease.

Mechanical stress-sensors and myocardial hypertrophy and failure

Cathrine Carlson (Researcher)Geir Florholmen (Postdoc)Zaheer Rana (Postdoc)Ida Gjervold Lunde (PhD student)Kate Herum (PhD student)Mari Elen Strand (PhD student)Bjørg Austbø (Research engineer)Hilde Jarstadmarken (Research engineer, MSc)Heidi Kvaløy (Research engineer, MSc)

We have also identified a putative stress-sensor, syndecan-4, which may act in concert with cytokines, since it is a co-receptor for cytokines. The work was done in collaboration with researchers at Harvard University. An array of experiments has been performed showing that syndecan-4 interacts with calcineurin, which is considered to be one of the most important signaling molecules for myocardial hypertrophy. To ensure the relevance of the identified stress-sensor for human disease, we also analyze their regulation in patients.

Collaborations

Our group has collaborations with several world-leading institutions, but we also collaborate extensively within Center for Heart Failure Research which comprises thirteen groups in the Oslo region and in South-Eastern Norway Health Region. In collaboration with Department of Thoracic Surgery at Oslo University Hospital Ullevål (T. Tønnessen) we have studied the TGF-family of cytokines in patients with aortic stenosis and in mouse models of heart failure, and in collaboration with Department of Pulmonary diseases (O.H. Skjønsberg) we study the role of the innate immune system in lung diseases. Finally, in collaboration with Department of Cardiology at Akershus University Hospital (T. Omland/H. Røsjø) we have filed a patent on granins as biomarkers of cardiac disease based on studies in mice and humans.

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CaRDIoPulMoNaRy RESuSCItatIoN

Out-of-hospital cardiac arrest is a leading cause of death in US and Europe, most frequently due to ischemic heart disease. In industrialized countries there are great variations in hospital discharge rate (1-25 %) and in rate significant neurologic deficits in survivors (3-30 %) between ambulance/hospital systems. Mortality after return of spontaneous circulation (ROSC) is partly attributed to reperfusion injury, and variability in neurologic deficits in survivors partly related to post-ROSC treatment.

We perform clinical, experimental animal and pedagogic cardiac arrest studies with trauma and newborn asphyxia side branches. Translational aspects are integral as experimental findings are tested clinically and vice versa. Consensus and guidelines supported implementation of scientific evidence into clinical practice is slow and non-systematic, and implementation studies are needed.

researcH groups

Professors Petter Andreas Steen

Professor Kjetil Sunde

The chain of survival – conceptual framework for our research

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In our animals studies we use a servo-controlled mechanical chest compression device on anaesthetized pigs.

1 Recognition of cardiac arrest and alerting medical services

Existing protocols, available resources and attitudes determines effectiveness in medical dispatch and the challenges during suspected cardiac arrest are to support bystander CPR attempts and dispatch appropriate resources with extreme time sensitivity as survival decreases by 4-6 % pr min before adequate treatment. The most likely bystander is 60-75 y/o, seldom reached in CPR training and their performance is generally poor when measured. The course «Redd liv sammen» was developed in collaboration with SAFER (Stavanger Acute medicine Foundation for Education and Research) in 2009/2010 focusing on knowledge, confidence and teamwork with medical dispatch (1-1-3). The training concept will be evaluated against traditional courses regarding effectiveness and dissemination. So far, it has been very well received by media, organizations, and lay people. A total of 848 have completed the first course since fall 2010.

2 Performing cardiopulmonary resuscitation – experimentally, bystanders and professionals

Experimentally, quality of CPR determines perfusion, survival, and drug effects. Poor and variable CPR quality can explain failed clinical studies after promising experimental results. We measure CPR quality in animals and clinically and use end-tidal CO2 (ETCO2) as a clinical indicator of cardiac output during CPR. The feasibility of ETCO2 to guide CPR-efforts remains to be tested clinically. There are no clinical data on which compression point that provides best blood flow or possible individual variations. We have shown such individual variations in pigs (Tømte et al, Resuscitation 2009) and will study anthropomorphic variability in a relevant population with MRI.

In our recent randomized, clinical study, intravenous drugs during CPR increased the rate of ROSC but not long-term outcome. In a previous, non-randomized study, adrenaline was detrimental. Factors explaining this discrepancy should be explored, as most CPR guidelines are based on epidemiologic or animal data due to ethical difficulties of randomized studies where informed consent is impossible.

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researcH groups

3 Defibrillation as soon as possible – if appropriate

Ventricular fibrillation (VF) waveform characteristics are altered in ischemic heart disease and may provide clues to underlying conditions, predict shock success, and long-term prognosis. Invasive, costly treatments are available including mechanical CPR during angiography or cardiopulmonary bypass (CPB), but reliable diagnostic tools to select patients for such treatments are lacking. Together with our collaborators we have by far the largest number of publications on such VF analysis.

4 Post-resuscitation treatment to preserve function

Discontinuing intensive treatment has important ethical and socioeconomic implications. Prognostication rules based on signs and lab-data must be reevaluated after the introduction of therapeutic hypothermia (TH) as standard of care. Post-ROSC pathophysiology includes free radical damage, circulating endotoxins, leukocyte dysregulation, increased plasma cytokines and adrenal dysfunction. Parts of this post-cardiac arrest syndrome are potentially treatable. Beneficial effects of post-arrest TH also prove that post-ROSC interventions can affect outcome.

CaRDIoPulMoNaRy RESuSCItatIoN

Main themes of our scientific projects:

CPR  quality:  -­‐ET  CO2  -­‐ Clinical  

-­‐ Experimental  -­‐ Imaging  

Bystanders:  -­‐ Training  

-­‐ Performance  VF-­‐analysis  

Dispatch:  -­‐ Communica9on  

-­‐ Training  

Evidence  into  prac=ce  

Drug  effects:  -­‐ Clinical  

-­‐ Experimental  

Post-­‐ROSC:  -­‐ Prognos9ca9on  -­‐ Pathophysiology  

-­‐ Xe-­‐effects  

Time  from  cardiac  arrest  

TH is reported to reduce mortality and neurologic deficits after newborn asphyxia. To avoid shivering and possible awareness, these patients are sedated with drugs with adverse circulatory side effects. We lack a full understanding of the interactions between TH and optimal haemodynamic management and monitoring during intensive care after cardiac arrest. The noble gas xenon (Xe) has anesthetic properties that are probably sufficient for sedation during TH and is reported to offer neuroprotection. Its potency in newborn during normo- and hypothermia is unknown.

Human resources

Prof. Kjetil Sunde runs most clinical studies with PhD students Øystein Tømte (thesis will be defended February 2012), Eric Qvigstad, Henrik Stær-Hansen, and research nurse Tomas Drægni. Post-doc. Jo Kramer-Johansen runs pedagogic studies and clinical studies with PhD student Tonje Birkenes, Eric Qvigstad, and medical student Andres Neset. Post-doc. Theresa Olasveengen is in charge of analysis of drug effects during clinical CPR and medical dispatch evaluation with PhD student Camilla Hardeland. Animal studies are run by Jo Kramer-Johansen and Lars Wik with Eric Qvigstad in collaboration with other group members and the animal experimental staff.

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SIGNIFICaNCE oF tHE tISSuE PlaSMINoGEN aCtIVatoR (tPa) PoolS IN ENDotHElIal CEllS aND SyMPatHEtIC NERVE tERMINalS FoR INDuCIblE CaRDIaC tPa RElEaSE.

Trude Aspelin (PhD student)

Myocardial infarction is most commonly caused by a coronary thrombus due to rupture of an atheromatous plaque. The formation of a coronary thrombus may be counteracted by the endogenous, constitutive fibrinolysis which in some cases can be so effective as to cause spontaneous recanalization of an occluded vessel. Tissue plasminogen activator (tPA) is the most important fibrinolytic enzyme causing removal of fibrin deposits in the vasculature, and may be rapidly internally released when appropriately stimulated, or recombinant tPA can be injected i.v. and represents an established treatment modality in the acute phase of coronary thrombosis. Endothelial cells and sympathetic neurons are two potential sources for acute tPA release.

In a pig model, which allows sampling of venous blood close to an affected area of myocardium, we have shown a several fold increase in cardiac tPA release after brief ischemic periods (mimicking unstable angina), intracoronary bradykinin infusions and during periods with electric stimulation of the cardiac sympathetic nerves. Supported also by studies on endothelial cells

Professor Arnfinn Ilebekk

Senior scientist Torstein Lyberg

The in vivo porcine heart model

cultured in vitro, we have aimed at deciphering the actual cellular source of tPA, its different release patterns and the possible mechanisms operating during tPA release. These studies will constitute part of a thesis planned to be presented during 2013.

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StRuCtuRal StuDIES oF Ca2+-atPaSES IN tHE PlaSMa MEMbRaNE

Jens Preben Morth is a group leader at the Centre for Molecular Medicine Norway (NCMM), Nordic EMBL Partnership, Oslo University, Norway. He also holds an adjunct appointment at the Institute for Experimental Medical Research, Oslo University Hospital Ullevaal, Oslo, Norway

researcH groups

Senior scientist Jens Preben Morth

Protein structure of Serca 2

Scientific Mission

Kim Langmach Hein (Postdoc)Harmonie Perdreau (Postdoc)Hanne Guldsten (Research engineer)

Since moving to University of Oslo per 1st October 2010 a fully functional membrane protein crystallographic laboratory has been established. The focus is on two different classes of membrane proteins. 1) The bicarbonate/sulfate and proton transporters and 2) The P-type ATPases in virulence and Calcium homeostasis. Bicarbonate transporters are involved with the exchange of acids and the tightly control and regulation of intracellular pH across the plasma membrane. I wish to continue my previous work on P-type ATPases, and have continued interest in calcium and magnesium homeostasis and the regulation of sodium and potassium levels across the membrane. There is increasing evidence that calcium acts in signaling in bacteria. Several examples demonstrate that bacteria keep tight control

of their [Ca2+]i with values very similar to those found in eukaryotes (100–300 nM) (Gangola P et al., 1987 J. Biol. Chem; Torrecilla I et al., 2000 Plant Physiol). Like eukaryotes, bacterial cells have ion channels, primary and secondary transporters, and Ca2+ binding proteins which may be involved in Ca2+ homeostasis, like the Ca2+/H+ antiporter from cyanobacteria (Waditee R et al., 2004 J. Biol. Chem). Furthermore, there is evidence that calcium is also involved in a number of bacterial processes such as maintenance of cell structure, motility and cell division,(Norris V et al., 1996 J. Bacteriol). Even certain bacteria make use of a Na+/Ca2+ exchanger, involved with efflux of Ca2+. Distant homolog’s have been found in an increasing number of bacterial genomes (Cai X et al., 2004 Mol. Biol. Evol).

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MyoCaRDIal REMoDElING aND REVERSE REMoDElING IN PRESSuRE oVERloaD

Johannes Bjørnstad ( Post doc)Biljana Skrbic ( PhD student)Kristin Engebretsen (PhD student)Henriette Marstein (Research engineer, MSc)

Our group is conducting experimental/translational research studying cardiac pathophysiology related to aortic stenosis and pressure overload. Aortic stenosis is the most common valvular lesion in the Western world. In patients with aortic stenosis, excessive myocardial remodeling (hypertrophy, fibrosis and expression of fetal genes) leads to increased operative risk during aortic valve replacement (AVR). There is currently no effective treatment for postoperative low-output syndrome due to diastolic dysfunction, making this a major challenge in cardiac surgery. Incomplete reverse remodeling after AVR for aortic stenosis is associated with persisting symptoms and increased mortality. Hence, studies addressing myocardial remodeling and reverse myocardial remodeling are warranted. We have established a mouse model of reversible left ventricular pressure overload mimicking AVR for

Figure 1. SM16 attenuated the phosphorylation of SMAD2. (A-B) Pressure overload increased left ventricular phosphorylation of SMAD2, but not SMAD3. SM16 attenuated SMAD2 phosphorylation. (C-D) Total SMAD2 and SMAD3 were not altered. Data are presented as mean+SEM. Sham STD=1. AB:aortic banding, p-SMAD:phosphorylated SMAD, sAB:sham aortic banding, SM16:SM16 chow, STD:standard chow. * p≤0.05 vs sham, † p≤0.05 vs AB STD (n=4-8). (E-F) TGF-β1 stimulation of cardiomyocytes induced SMAD2 phosphorylation which was attenuated by SM16. Ctrl+no SM16=1.* p≤0.05 vs ctrl, † p≤0.05 vs no SM16 (n=4-6). Western blot membranes were stained with Coomassie Blue for protein loading control. (Bjørnstad et al, Cardivascular Res, 2011)

Professor Theis Tønnessen

aortic stenosis and found novel extracellular matrix (ECM) changes during reverse remodeling. To extend these findings we have established a “loss of function” approach in which we use a collagen VIII knock out mouse to examine the importance of this collagen isoform in remodeling and reverse remodeling after relief of pressure overload. Data processing are currently in progression.

Another important aim has been to reveal the importance of the SMAD2 signaling system in pressure overload. We have found that inhibition of SMAD2 by a small peptide inhibitor (SM16) improves cardiac function, possibly due to effects on SERCA2 and intracellular calcium handling. We are currently also investigating the role of SLRPs in myocardial remodelling and the transition to heart failure.

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CaRDIotHoRaCIC RESEaRCH GRouP, akERSHuS uNIVERSIty HoSPItal

Helge Røsjø (PhD student)Anett H. Ottesen ( PhD student)Mai Britt Dahl (Research engineer, MSc)

Cardiothoracic Research Group (CRG), Akershus University Hospital is headed by Professor Torbjørn Omland and focuses on translational research and international collaboration in epidemiological and clinical trials. The goal of the group is to enhance scientific impact through quality publications. The close collaboration with the group of Professor Geir Christensen, IEMR, in translational biomarker discovery has lead to several patent applications relating to the granin protein family. Recently, chromogranin B, patented by CRG and IEMR researchers, has been promoted by other groups as a promising cardiac biomarker (Heidrich et al. Congest Heart Fail 2011;17:314-5). In 2011, we have performed several clinical studies that support chromogranin B as an independent risk marker in critical illness and cardiac disease (Røsjø H, et al. Unpublished data). Moreover, by identifying proteins that increase in proportion to the severity of disease, we may also identify novel pathophysiology in cardiac disease. In close collaboration with IEMR, we have identified a second cardiac biomarker patented by us, secretoneurin, to modulate cardiomyocyte calcium handling (Ottesen et al. Circulation 2011: ISSN 0009-7322. 124).

researcH groups

Professor Torbjørn Omland

By using experimental models we have access to myocardial tissue and can identify proteins that increase in the left ventricle during cardiac disease. Proteins are separated by gel electrophoresis as demonstrated here by Professor T. Omland (left), H. Røsjø, MD (center), and Professor G. Christensen (right) and proteins are later characterized by mass spectrometry or immunoblotting.

For 2012, we will continue the work on these novel cardiac biomarkers by exploring functional aspects in experimental models and the importance for human disease by testing these proteins as independent risk markers in clinical trials.

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tHE EFFECt oF HyPoxIa-INDuCED uP-REGulatIoN oF INtERlEukIN-18 oN INFlaMMatoRy CHaNGES IN luNGS, HEaRt aND PulMoNaRy CIRCulatIoN

Karl-Otto Larsen ( Post doc)Fadila Cero (PhD student))

Alveolar hypoxia is a prominent feature of several lung diseases, including COPD. Our research group has established an experimental model for in vivo investigations on signal pathways linking alveolar hypoxia and inflammatory processes within the lungs, heart and pulmonary vasculature. Mice are exposed to a hypoxic environment in closely monitored chambers for varying periods of time, and compared to control animals living under normoxic conditions. The development of pulmonary hypertension can be documented by ecco- cardiography and heart catheterization, and similar methods are employed to study the function of both ventricles.

We have found that alveolar hypoxia leads to the development of diastolic dysfunction in both ventricles, and that the pro-inflammatory cytokine interleukin (IL)-18 seems to be an important mediator in this process. Alveolar hypoxia induces a marked increase in circulating IL-18, and we are now studying the effect of this cytokine on the lungs, heart and pulmonary circulation, also in combination with IL-12, another mediator which is increased during hypoxia. The release of IL-18 is linked to activation of the innate immune system through

Hypoxia chambers

Professor Ole Henning Skjønsberg

caspase-1 mediated cleavage of pro-IL-18. Capase-1 is a component of the NLRP3 inflammasome, which we hypothesize, is being activated by alveolar hypoxia. We will use NLRP3 and ASC knock out mice to study this hypothesis. Recently, we have shown that alveolar hypoxia also induces influx of NLRP3 and ASC positive leukocytes to the lungs, surrounding pulmonary arteries and bronchioli.

We are now studying the relationship between this leukocyte influx and hypoxia induced generation of inflammatory mediators in the lungs, and the impact of these processes on the airways, lung parenchyma and pulmonary vasculature. By identifying and blocking hypoxia induced mediators, we hope to influence the negative effect of hypoxia on these structures. In addition to experimental studies, we perform physiological studies on healthy subjects and COPD under hypoxic conditions. The combination of experimental and clinical studies gives us an opportunity to translate the results of basal research to a clinical setting. By further developing our theories, we hope to enhance the possibility of establishing new therapeutic strategies for patients with severe lung diseases.

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CENtER FoR ClINICal HEaRt RESEaRCH; atHERotHRoMboSIS aND VaSCulaR bIoloGy

Trine Baur Opstad (PhD student)Vibeke Bratseth (Research engineer, MSc)

The research is based on larger trials with clinically relevant problems, mainly randomized intervention studies with additional ex vivo translational studies in the field of atherothrombosis and vascular biology. We aim at exploring the atherothrombotic process in patients undergoing different intervention regimens, for basic understanding of molecular signaling, genetic regulation, and downstream effects on the protein level. In most projects a main issue is therefore to establish biobanks based on standardized protocols.

Atherothrombosis is the main pathogenetic prosess behind coronary heart disease (CHD). It is a chronic low-graded inflammatory process, mainly induced by traditional risk factors, and an acute complicating thrombotic process induced by rupture of an atherosclerotic plaque or by minor lesions and denudation of the vascular endothelium. In this complex process a series of biochemical reactions, intra- and extracellularly will take place. In the circulation as well is in the arterial wall a multitude of cells with changing phenotypes participate and their complex interplay in mutual signaling pathways will determine the dominating effects at a given time.

researcH groups

In this report we focus on three main issues:

1) The association between CHD, Diabetes, Metabolic Syndrome (METS), Obesity and Inflammation: Facing the increasing incidence of obesity, METS and diabetes type 2 in the population, differences in atherothrombosis and vascular biology in these conditions are investigated. Inflammatory and haemostatic variables expressed in the circulation and also in adipose tissue have visualised new predictive markers like IL-18, a strong predictor for future events specially linked to hyperglycemia.

To further explore the regulatory pathways of such markers, any influence of genetic polymorphism are studied, and intervention studies on patients with combined CHD and diabetes, with physical exercise as well as with new anti-diabetic drugs are ongoing.

The associations between non-diagnosed diabetes and acute myocardial infarction have been extensively studied the last years (in collaboration with the Intensive Coronary Care Unit).

2) Response to antithrombotic treatment is focused in a large prospective randomized trial, and the results elucidate the association between laboratory measures on platelet function and clinical outcome during aspirin or clopidogrel treatment. Mechanisms behind the laboratory response-phenomenon are further explored, also genetically.

3) In patient populations with atrial fibrillation, an increasing health problem, the role of vascular function and inflammation are explored, and new insight into basic mechanisms on the remodeling process, as well as on endothelial function has been obtained. This field of research will continue in close collaboration with Vestre Viken HF, Asker & Bærum Hospital.

Professor Ingebjørg Seljeflot

Professor Harald Arnesen

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FEatuRED CollaboRatoRS

collaboration

Elucidating the role of PTMs in development of heart disease

IEMR started collaborating with Dr. Jennifer Van Eyk, Ph.D. in 2008. In 2009/10 post doc Cathrine Husberg, Ph.D. was visiting Dr.Van Eyk’s lab. Our mutual focus has been the importance of post-translational protein modifications (PTMs) in cellular dysregulation and development of heart disease. Dr Van Eyk is Professor of Medicine, Biological Chemistry and Biomedical Engineering at Johns Hopkins University, Baltimore

and Director of both the Hopkins NHLBI Proteomics Innovation Group and the JHU Bayview Proteomics Center. Her research laboratory studies the underlying molecular mechanism of cardiovascular disease using a large number of proteomic methodologies allowing development of better therapeutic intervention and robust biomarkers for the diagnosis, prognosis and risk stratification of heart disease.

Cellular dysregulation in heart failure. Schematic presentation of features in a failing cardiomyocyte:increased neurohormonal stimulation and mechanical stress affects cellular contractility, energy metabolism, conduction, intracellular signaling, and cell structure mislocalization. Important in all these features are a dynamic regulation of post-translational modifications (Agnetti, Husberg and Van Eyk, Circ. Res. 2011).

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The cover of Circulation Research, June 2001. A figure from the collaborative publication ‘Contraction and intracellular Ca(2+) handling in isolated skeletal muscle of rats with congestive heart failure by Lunde et al fronted the cover page.

Figure from a collaborative work published by Wæhre et al in PloS One 2011. Electron microscopic analysis showing loss of orginized fibrillar structure in myocardium of mice lacking the chemokine CXCR5 following aortic banding (AB)

Cardiac and skeletal muscle physiology

For more than 10 years IEMR has collaborated with Håkan Westerblad, Professor of Cellular Muscle Physiology Department of Physiology and Pharmacology Karolinska Institutet, Stockholm.

The group investigates the mechanisms behind muscle adaptations/maladaptations in disease and the fundamental causes of muscle fatigue. The original research focus was to discover the cellular causes of fatigue in skeletal muscle. The accumulated findings of the group and others have firmly established that muscle fatigue is not caused by increased lactate or acidosis. The studies of the basic mechanisms underlying muscle fatigue continue. Numerous common disorders, such as diabetes, heart failure, mitochondrial myopathies and general inflammatory diseases such as rheumatoid arthritis, are associated with skeletal and cardiac muscle dysfunction. Therefore, a large proportion of the research is dedicated to uncovering the mechanisms that produce functional adaptations/maladaptations in skeletal and more recently also cardiac muscle. The group has shown that increased in calcium transients dureng beta-adrenergic stimulation is partly mediated by increased production of ROS. Per Kristian Lunde is currently spending a sabbatical year in Westerblad’s group to explore if there is a connection between ROS production and altered contractility during HF.

Inflammation and heart failure

IEMR has collaborated with Professors Lars Gullestad and Pål Aukrust at Oslo University Hospital for more than a decade. Our mutual focus has been the role of inflammation during development of heart failure. Professor Gullestad has unique experience in studies on patients with various types of heart failure, and Professor Aukrust is a leading expert within the area of inflammation. The combination of their expertise and the experimental environment at IEMR has lead to a large number of publications in high ranked journals such as Circulation.

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CollaboRatIoN lISt

collaboration

International collaborators

Becker, Lance B, Professor and Director, Dept of Emergency Medicine, Univ of Pennsylvania, Phil, USA

Brown, Joan H, Dept Pharmacol, Univ of California San Diego, San Diego, USA

Castrén, Maaret, Professor Emergency Medicine, Karolinska Institutet, Sweden

Couchman, John, Professor, Biotech Research and Innovation Centre, Univ of Copenhagen, Denmark

Egger, Marcel, Professor, Dept of Physiology, Univ of Bern, Switzerland

Eisner, David, Professor, Univ of Manchester, Manchester, UK

Eyk, Jennifer Van, DirectorThe Hopkins NHLBI Proteomics Center, Dir Bayview Proteomics Group, Professor of Medicine, Biological Chemistry and Biomedical Engineering, Division of Cardiology, John Hopkins Univ, Baltimore, Maryland, USA

Franzini-Armstrong, Clara, Professor, Univ of Pennsylvania School of Medicine, Phil, USA

Gomez, Maria F, Associate Professor, Dept of Clinical Sciences, Lund University, Malmø, Sweden

Hajjar, Roger, Professor, Cardivascular Research Center, Mount Sinai School of Medicine, NY, USA

Hilfiker-Kleiner, Denise, Professor, Dept of Cardiology and Angiology, Hannover Medical School, Germany

Lamb, Graham D, Professor, Dept of Zoology, LaTrobe Univ, Melbourne, Australia

Lederer, W Jonathan, Professor, Univ of Maryland School of Medicine, Baltimore, MD, USA.

Lehnart, Stephan, Professor, Dept of Cardiology, Univ of Goettingen, Goettingen, Germany

Maier, Lars, Professor, Dept of Cardiology, Univ of Goettingen, Goettingen, Germany

Neurater, Andreas, Dipl Ing, Univ-Klinik für Anaesthesie und Allg. Intensivmedizin, Austria

Nielsen, Niklas, Senior consultant, Hypothermia network, Helsingborg, Sweden

Niggli, Ernst, Professor, Dept of Physiology, Univ of Bern, Switzerland

Overton, Jerry, Exec Director Richmond Ambulance Authority; Dept Emerg Medicine, Virginia, USA

Paulus, Walter, Professor, Free Univ of Amsterdam, Amsterdam, Netherlands

Quackenbush, John, Professor, Bioinformatics Dept of Biostatistics, Dana-Farber Cancer Inst and Harvard School of Public Health, Boston, USA

Richard, Sylvain, Dir of research INSERM U390, Montpellier, France

Roderick, Llewellyn, Senior Researcher, Dep. of Pharmacology, Univ of Cambridge, and The Brabraham Inst, Cambridge, UK

Schneider, Jürgen, Professor, Univ of Oxford, Oxford, UK

Scott, John D, Professor, Dept of Pharmacology, Univ of Washington, USA

Smith, Nic, Professor, Imaging Sciences & Biomedical Engineering Division, St Thomas’ Hospital, Kings College, London, UK

Strohmenger, Hans-Ulrich, Dr. Leopold-Franzent Univ, Austria

Touchburn, André, Med DirectorAmbulance Services, New Brunswick Dept of Health, Canada

Trafford, Andrew, Professor, Univ of Manchester, Manchester, UK

Wenzel, Volker, Dr. Leopold-Franzen’s Univ, Austria

Westerblad, Håkan, Dept of Physiol and Pharmacology, Karolinska Inst, Stockholm, Sweden

National collaborators

Afseth, Nils K, PhD, Norfima Mat, UMB, Ås

Andersen, Geir, Senior Consultant and Researcher, Dept of Cardiology, OUH

Atar, Dan, Professor, Dept of Cardiology, OUH

Attramadal, Håvard, Professor, Inst for Surgical Research, OUH

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Aukrust, Pål, Professor, Research Inst of Internal Medicine, OUH

Berg, Jens P, Professor, Dept of Clinical Chemistry, OUH

Bjertnes, Espen, PhD, Inst of general Practice and Community Medicine, UoO

Bjørnerheim, Reidar, PhD, Chief physician, Dept of Cardiology, OUH

Bjørnerud, Atle, Professor, Intervention Center, OUH

Bjørås, Magnar, Professor, Inst for Microbiol, OUH

Brorson, Sverre Henning, Senior scientist, Inst for Pathology, OUH

Eftestøl, Trygve, Professor, Inst for Electrotechnics and Data, UoS

Ellingsen, Øyvind, Professor, Dept of Circulation and Medical Imaging, NTNU

Frigessi, Arnoldo, Professor, Section for Medical Statistics, UoO

Grøttum, Per, Professor, Inst of Informatics, UoO

Gullestad, Lars, Professor, Research Inst of Internal Medicine, OUH

Hallén, Jostein, Professor, Norwegian Univ of Sport and Physical Education

Haraldseth, Olav, Professor, Dept of Circulation and Medical Imaging, NTNU

Hovig, Eivind, Professor, Dept of Tumor Biology and Dept of Medical Informatics, OUH

Iversen, Per Ole, Professor, Section of Nutrition, UoO

Jacobsen, Dag, Professor, Dept of Acute Medicine, OUH

Klungland, Arne, Professor, CMBN, OUH

Leergaard, Trygve, Ass. Professor, CMBN, OUH

Levy, Finn Olav, Professor, Inst for Pharmacology, UoO

Lines, Glenn T, PhD, Simula Research Center

Lyberg, Torstein, Senior Scientist, Center for Clinical Research, OUH

Myklebust, Helge, Laerdal Medical, Stavanger

Mykletun, Reidar, Professor, Norwegian School of Hotel Management, UoS

Roald, Borghild, Professor, Dept of Pathology, OUH

Saatcioglu, Fahri, Professor, IMBV, UoO

Skjønsberg, Ole Henning, Professor, Dept of Pulmonary Medicine, OUH

Skogvoll, Eirik, Professor, Dept of Circ. and Med. Imaging, NTNU

Skomedal, Tor, Professor, Dept of Pharmacology, UoO

Smiseth, Otto, Head of Clinic, Professor, Dept of Cardiology, OUH

Søreide, Eldar, Professor, Dept of Anaesthesia and Intensive Care, Stavanger Univ Hospital/UoB

Taskén, Kjetil, Professor and DirectorThe Biotechnology Center of Oslo, UoO

Wang, Line G, Researcher, Dept of Nutrition, UoO

Wiig, Helge, Professor, Inst for Biomedicine, UoB

Wisløff, Ulrik, Professor, Dept of Circulation and Medical Imaging, NTNU

Yndestad, Arne, PhD, Research Inst of Internal Medicine, OUH

Øie, Erik, PhD, Dept of Cardiology and Inst for Surgical Research, OUH

Abbreviation

UoO = University of OsloOUH = Oslo University HospitalNTNU = Norwegian University of Science and Technology UoB = University of BergenUoS = University of StavangerUMB=Norwegian University of Life ScienceCMBN=Centre for Molecular Biology and Neuroscience

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core competency at iemr

MRI

In 2010/11, a state-of-the art Agilent 9.4 T MR scanner was installed at the institute, and is now part of a Core Facility Regional Health Authority South-East. The instrument offers unique non-invasive imaging capabilities in small animals, including high resolution Magnetic Resonance Imaging (MRI). Standard imaging techniques are used, such as contrast enhanced visualization of myocardial infarctions. The instrument is ideal for non-invasive visualization of most organ systems.

MR scanners can also be used for investigation of metabolic processes, and we have obtained spectra from both skeletal muscles and the heart. This is an interesting area of research which will be pursued during the next years, and the method will be extended to other organs.

Echocardiography

The Vevo 2100 High-Frequency Ultrasound System from Visual Sonics is available in our Institute for imaging of small animals in a preclinical setting. It allows detailed mapping of both cardiac structure and function, but is also available for e.g. cancer research.

The institute also has a clinical scanner, a Vivid 7 from GE, which is used in our translational research in collaboration with Department of Cardiology.

IN VIVo IMaGING

The Agilent 9.4 T MR scanner Echocardiography

From the MR control room

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Small animals

The Institute is equipped for mouse and rat microsurgery and genetic manipulation to create and study models of cardiovascular diseases, which provides unique and valuable research tools for translational research from animal studies to humans.

A wide variety of animal models are established at our institute, both genetically engineered and with clinically relevant diseases. We have access to an animal care facility, in which our MR scanner is situated.

The animal models are investigated and phenotyped with state of the art equipment, such as the MR scanner, echocardiography, telemetry, patch clamp and molecular biological methods.

PHENotyPING FaCIlItIES

Activity in the operating theatre

Large animals

In 2010, three new operating rooms for pigs and accessory facilities were opened. Porcine models are widely used in cardiopulmonary resuscitation research because of the similarities with the human torso and circulation physiology. They are also suitable for development and testing of equipment in sizes relevant for humans, while still manageable in an experimental setting.

The close collaboration between our scientific staff and clinical practitioners in the Dept. of Anaesthesiology and Dept. of Prehospital Emergency Medicine provide excellent opportunities for translational approaches. We have previously used experimental models to explain and expand our knowledge based on clinical experience and vice versa developed protocols for clinical trials based on experimental findings.

The facility is equipped for coronary angiography, opening a new field of research where interventions on ischemic and/or reperfused myocardium during CPR, after angiographic induction of myocardial ischemia can be tested.

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core competency at iemr

Fluorescence microscopy

Three confocal microscopes are available at IEMR (Zeiss LSM710, Live7 and LSM510). Laser scanning confocal microscopy allows detailed studies of Ca2+ signaling since the method allows superior resolution. By combining the technique with molecular biological methods, we can obtain detailed information on eg colocalization of proteins.

Also, two setups for whole cell fluorescence are available to study Ca2+ and Na+ dynamics. Both confocal and whole cell fluorescent techniques are combined with microelectrode techniques (patch clamp) to study transmembrane protein function.

Electron microscopy

We have access to a FEI Tecnai 120kV electron microscope located at Dept. of Pathology, Oslo University Hospital. Electron microscopy is employed to study ultrastructural changes in cardiomyocytes and extracellular matrix during disease. Immunogold technique allows studies on protein distribution, and 3D cellular structure is visualized by tomography.

aDVaNCED MICRoSCoPy

The LSM 710 Confocal microscope set-up

Transients and Ca2+ waves

Electron micrograph of the sarcomere. T-tubules (T) form tight junctions, called dyads, with the junctional sarcoplasmic reticulum (jSR) at regular intervals throughout the cardiac muscle. jSR cisternae are connected in a network of free SR (SR). Shown are also the I-band and A-bands of the sarcomere, the z-lines (z) and mitochondria (M).

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The institute provides the appropriate expertise and techniques to analyze functions of individual bio-molecules and interactions between the various systems of a cell, including different types of DNA, RNA and proteins.

We are in particular focusing on signaling pathways, protein-protein interactions, development and use of high affinity cell-permeable peptide as pro-drugs

MolECulaR bIoloGy PlatFoRM

(fig. ahead). We are using methods like SDS-PAGE, immunoblotting, quantitative gene expression analyses (RT-PCR), immunohistochemistry, different pull down systems, reporter and radioactive labeling systems, DNA and peptide arrays, mutagenese analysis, transfection studies and peptide treatment of various cell cultures, kinase and phosphatase assays, deglycosylation assays and antibody mapping.

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meetings and educational actiVities

On September 17-19th 2011 IEMR members organized the annual meeting of the ESC Working Group on Cardiac Cellular Electrophysiology. The meeting is an important opportunity for exchange of ideas on ongoing projects presented by young investigators as well as state-of-the art updates from leading researchers within the field. This year´s meeting was held at the University library, Blindern, and was attended by 140 scientists from Europe, US and South-America. The meeting was part of the 200th Anniversary program of the University of Oslo and included a public lecture by Prof. Fabio Di Lisa from the University of Padova, Italy.

35tH MEEtING oF tHE ESC woRkING GRouP oN CaRDIaC CEllulaR ElECtRoPHySIoloGy

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meetings and educational actiVities

During 2011 members of IEMR have been involved in the organization of several events arranged by CHFR, including the 9th Annual CHFR Symposium, CHFR workshop: Mechanisms for arrhythmias, CHFR workshop: Mechanisms of diastolic myocardial dysfunction and PhD School of Heart Research: metodekurs i hjerteforskning. For further

The institute serves as host to courses in surgical training for external users. In 2011 courses in Advanced Pediatric Life Support (APLS), gastric surgery, laparoscopic surgery, vascular surgery, general surgery and paramedics were arranged in the operating theatres for large animals.

Training course in gastric surgery

EVENtS aRRaNGED by CENtER FoR HEaRt FaIluRE RESEaRCH (CHFR)

tRaINING CouRSES IN tHE IEMR oPERatING tHEatRES

information about the center please visit the CHFR website www.heartfailure.no

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publication list

Theses

Stokke MK. SERCA2-RyR2 interplay at the heart of Ca2+ wave development. Experimental studies on mechanisms underlying triggered arrythmias. 2011. IEMR.

Bjørnstad JL. The TGF-ß/SMAD signalling system and extracellular matrix changes in myocardial remodelling and reverse remodelling following correction of pressure overload. 2011. Dept. of Cardiothoracic Surgery, OUH Ullevål and IEMR.

Grøgaard HK. Progenitor cells, growth factors and inflammation in acute myocardial infarction. 2011. Dept. of Cardiology, OUH Ullevål and IEMR.

Articles

Afzal F, Qvigstad E, Aronsen JM, Moltzau LR, Sjaastad I, Skomedal T, Osnes JB, & Levy FO. Agents increasing cyclic GMP amplify 5-HT4-elicited positive inotropic response in failing rat cardiac ventricle. Naunyn Schmiedebergs Arch Pharmacol 2011;384:543-553.

Afzal F, Aronsen JM, Moltzau LR, Sjaastad I, Levy FO, Skomedal T, Osnes JB, & Qvigstad E. Differential regulation of β2-adrenoceptor-mediated inotropic and lusitropic response by PDE3 and PDE4 in failing and non-failing rat cardiac ventricle. Br J Pharmacol 2011;162:54-71.

Agnetti G, Husberg C, & Van Eyk JE. Divide and conquer: the application of organelle proteomics to heart failure. Circ Res. 2011;108:512-526.

Bjørnstad JL, Sjaastad I, Nygård S, Hasic A, Ahmed MS, Attramadal H, Finsen AV, Christensen G, & Tønnessen T. Collagen isoform shift during the early phase of reverse left ventricular remodelling after relief of pressure overload. Eur Heart J. 2011;32:236-245.

*Bjørshol CA, Myklebust H, Nilsen KL, Hoff T, Bjorkli C, Illguth E, Soreide E, & Sunde K. Effect of socioemotional stress on the quality of cardiopulmonary resuscitation during advanced life support in a randomized manikin study. Crit Care Med. 2011;39:300-304.

Grøgaard HK, Solheim S, Landsverk KS, Seljeflot I, Hoffmann P, Arnesen H, & Ilebekk A. Circulating CD34+ progenitor cells and growth factors in patients treated with PCI for acute myocardial infarction or stable angina pectoris. Scand J Clin Lab Invest. 2011;71:322-329.

Hussain RI, Afzal F, Mørk HK, Aronsen JM, Sjaastad I, Osnes JB, Skomedal T, Levy FO, & Krobert KA. Cyclic AMP-dependent inotropic effects are differentially regulated by muscarinic Gi-dependent constitutive inhibition of adenylyl cyclase in failing rat ventricle. Br J Pharmacol. 2011;162:908-916.

Johansen I.B., Lunde IG, Røsjø H, Christensen G, Göran E, Bakken M, & Øverli Ø. Cortisol response to stress is associated with myocardial remodeling in salmonid fishes. J Exp Biol. 2011;214:1313-1321.

Kramer-Johansen J. Cardiopulmonary resuscitation or shock first - no answers yet? Prehosp Emerg Care. 2011;15:577-578.

Kramer-Johansen J, Pytte M, Tomlinson AE, Sunde K, Dorph E, Svendsen JVH, Eriksen M, Strømme TA, & Wik L. Mechanical chest compressions with trapezoidal waveform improve haemodynamics during cardiac arrest. Resuscitation. 2011;82:213-218.

Larsen KO, Yndestad A, Sjaastad I, Løberg EM, Goverud IL, Halvorsen B, Jia J, Andreassen AK, Husberg C, Jonasson S, Lipp M, Christensen G, Aukrust P, & Skjønsberg OH. Lack of CCR7 induces pulmonary hypertension involving perivascular leukocyte infiltration and inflammation. Am J Physiol Lung Cell Mol Physiol. 2011;301:L50-L59.

* highlighted as selected publication

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publication list

Li L, Louch WE, Niederer SA, Andersson KB, Christensen G, Sejersted OM, & Smith NP. Calcium Dynamics in the Ventricular Myocytes of SERCA2 Knockout Mice: A Modeling Study. Biophys J. 2011;100:322-331.

Liu XH, Zhang ZY, Andersson KB, Husberg C, Enger UH, Ræder MG, Christensen G, & Louch WE. Cardiomyocyte-specific disruption of Serca2 in adult mice causes sarco(endo)plasmic reticulum stress and apoptosis. Cell Calc. 2011;49:201-207.

Louch WE, Sheehan KA, & Wolska BM. Methods in cardiomyocyte isolation, culture, and gene transfer. J Mol Cell Cardiol. 2011;51:288-298.

Lunde IG, Kvaløy H, Austbø B, Christensen G, & Carlson CR. Angiotensin II and norepinephrine activate specific calcineurin-dependent NFAT transcription factor isoforms in cardiomyocytes. J Appl Physiol. 2011;111:1278-1289.

Lunde IG, Anton SL, Bruusgaard JC, Rana ZA, Ellefsen S, & Gundersen K. Hypoxia inducible factor 1α links fast-patterned muscle activity and fast muscle phenotype in rats. J Physiol. 2011;589.6: 1443-1454.

Munkvik M, Lunde PK, Aronsen JM, Birkeland JA, Sjaastad I, & Sejersted OM. Attenuated Fatigue in Slow Twitch Skeletal Muscle during Isotonic Exercise in Rats with Chronic Heart Failure. PLoS One 6, 2011;e22695.

*Neset A, Birkenes TS, Furunes T, Myklebust H, Mykletun RJ, Ødegaard S, Olasveengen TM, & Kramer-Johansen J. A randomized trial on elderly laypersons’ CPR performance in a realistic cardiac arrest simulation. Acta Anesthesiol Scand. 2011;56:124-131.

Russell K, Smiseth OA, Gjesdal O, Qvigstad E, Norseng PA, Sjaastad I, Opdahl A, Skulstad H, Edvardsen T, & Remme EW. Mechanism of prolonged electromechanical delay in late activated myocardium during left bundle branch block. Am J Physiol Heart Circ Physiol. 2011:301: H2334-H2343.

Sanner H, Aaløkken TM, Gran JT, Sjaastad I, Johansen B, & Flatø B. Pulmonary outcome in juvenile dermatomyositis: a case-control study. Ann Rheum Dis. 2011;70:86-91.

*Schwartz T, Sanner H, Husebye T, Flatø B, & Sjaastad I. Cardiac dysfunction in juvenile dermatomyositis - a case control study. Ann Rheum Dis. 2011:70:766-771.

Sejersted OM. Calcium controls cardiac function - by all means! J Physiol 2011:589:2919-2920.

*Sjåland C, Lunde PK, Swift F, Munkvik M, Ericsson M, Lunde M, Boye S, Christensen G, Ellingsen O, Sejersted OM, & Andersson B. Slowed Relaxation and Preserved Maximal Force in Soleus Muscles of Mice with Targeted Disruption of the Serca2 gene in Skeletal Muscle. J Physiol 2011;589:6139-6155.

Stokke MK, Briston SJ, Jølle GF, Manzoor I, Louch WE, Øyehaug L, Christensen G, Eisner DA, Trafford AW, Sejersted OM, & Sjaastad I. Ca2+ wave probability is determined by the balance between SERCA2-dependent Ca2+ reuptake and threshold SR Ca2+ content. Cardiovasc Res 2011;90: 503-512.

Tømte Ø, Drægni T, Mangschau A, Jacobsen D, Auestad BH, & Sunde K. A comparison of intravascular and surface cooling techniques in comatose cardiac arrest survivors. Crit Care Med 2011;39:443-449.

*Tømte Ø, Andersen GO, Jacobsen D, Draegni T, Auestad B, & Sunde K. Strong and weak aspects of an established post-resuscitation treatment protocol-A five-year observational study. Resuscitation 2011;82:1186-1193.

Wanichawan P, Louch WE, Hortemo KH, Austbo B, Lunde PK, Scott JD, Sejersted OM, & Carlson CR. Full-length cardiac Na+/Ca2+ exchanger 1 protein is not phosphorylated by protein kinase A. Am J Physiol Cell Physiol 2011;300:C989-C997.

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publication list

*Wæhre A, Halvorsen B, Yndestad A, Husberg C, Sjaastad I, Nygård S, Dahl CP, Ahmed MS, Finsen AV, Reims HM, Louch WE, Hilfiker-Kleiner D, Vinge LE, Roald B, Attramadal H, Lipp M, Gullestad L, Aukrust P, & Christensen G. Lack of chemokine signaling through CXCR5 causes increased mortality, ventricular dilatation and deranged matrix during cardiac pressure overload. PLoS One 2011;6:e18668.

From the Department of Anesthesiology, Oslo University Hospital and Institute for Clinical Medicine, Faculty of Medicine, Oslo University Hospital

Bjørshol CA, Myklebust H, Nilsen KL, Hoff T, Bjorkli C, Illguth E, Soreide E, & Sunde K. Effect of socioemotional stress on the quality of cardiopulmonary resuscitation during advanced life support in a randomized manikin study. Crit Care Med. 2011;39:300-304.

Nielsen N, Sunde K, Hovdenes J, Riker RR, Rubertsson S, Stammet P, Nilsson F, & Friberg H. Adverse events and their relation to mortality in out-of-hospital cardiac arrest patients treated with therapeutic hypothermia. Crit Care Med. 2011;39:57-64.

Sunde K & Soreide E. Therapeutic hypothermia after cardiac arrest: where are we now? Curr Opin Crit Care 2011;17:247-253.

Bjørshol CA, Sunde K, Myklebust H, Assmus J, Søreide E. Decay in chest compression quality due to fatigue is rare during prolonged advanced life support in a manikin model. Scand J Trauma Resusc Emerg Med. 2011 Aug 9;19:46.

Articles in press (accepted 2011)

Aramendi E, Ayala U, Irusta U, Alonso E, Eftestøl T, Kramer-Johansen J, Suppression of the cardiopulmonary resuscitation artefacts using the instantaneous chest compression rate extracted from the thoracic impedance, Resuscitation. 2011. In Press.

Birkenes TS, Myklebust H, Neset A, Olasveengen TM, & Kramer-Johansen J. Video analysis of dispatcher-rescuer teamwork-Effects on CPR technique and performance. Resuscitation. 2011. In Press.

Bjørnstad JL, Skrbic B, Sjaastad I, Bjørnstad S, Christensen G, & Tønnessen T. A mouse model of reverse cardiac remodelling following banding-debanding of the ascending aorta. Acta Physiologica. 2011. In Press.

Bjørnstad JL, Skrbic B, Marstein HS, Hasic A, Sjaastad I, Louch WE, Florholmen G, Christensen G, & Tønnessen T. Inhibition of SMAD2 phosphorylation preserves cardiac function during pressure overload. Cardiovasc Res. 2011. In Press.

*Finsen AV, Lunde IG, Sjaastad I, Østli EK, Lyngra M, Jarstadmarken HO, Hasic A, Nygård S, Wilcox-Adelman S, Goetinck PF, Lyberg T, Skrbic B, Florholmen G, Tønnessen T, Louch WE, Djurovic S, Carlson CR, & Christensen G. Syndecan-4 is essential for development of concentric myocardial hypertrophy via stretch-induced activation of the calcineurin-NFAT pathway. PLoS One. 2011. In Press.

Lunde IG, Aronsen JM, Kvaloy H, Qvigstad E, Sjaastad I, Tonnessen T, Christensen G, Gronning-Wang LM, & Carlson CR. Cardiac O-GlcNAc signaling is increased in hypertrophy and heart failure. Physiol Genomics. 2011. In Press.

* highlighted as selected publication

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publication list

Olasveengen TM, Wik L, Sunde K, & Steen PA. Outcome when adrenaline (epinephrine) was actually given vs. not given - post hoc analysis of a randomized clinical trial. Resuscitation. 2011. In Press.

Rehn TA, Munkvik M, Lunde PK, Sjaastad I, & Sejersted OM. Intrinsic skeletal muscle alterations in chronic heart failure patients: a disease-specific myopathy or a result of deconditioning? Heart Fail Rev. 2011. In Press.

Schwartz T, Magdi G, Steen TW, & Sjaastad I. HIV as a risk factor for cardiac disease in Botswana - a cross-sectional study. International Health. 2011. In Press.

Textbook

Aronsen JM, Birkeland JA, Munkvik M, Sjaastad I. Repeter! Farmakologi. Gyldendal Akademisk 211 sider. 2011. ISBN:978-82-05-40130-3.

Patents (Filed)

Granin proteins as markers of heart disease. PCT/GB0818650.4. In collaboration with Department of Cardiology at Akershus University Hospital. (Omland T./Røsjø H.).Christensen G, Stridsberg M.

SgII as a prognostic marker in conditions which require critical care. PCT/GB0919901.9. In collaboration with Department of Cardiology at Akershus University Hospital. (Omland T./Røsjø H.). Christensen G, Stridsberg M.

Abstracts

59 abstracts were published in 2011

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funding

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funding

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Institute for Experimental Medical Research

Institute for Experimental Medical Research

Institute for Experimental Medical Research (IEMR)

Oslo University Hospital

Ullevål, Kirkeveien 166

NO-0407 Oslo, Norway

Phone: +47 23 01 68 00 | Fax: +47 23 01 67 99 | www.iemf.no

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