86 results on '"Christen P. Dahl"'
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2. The extracellular matrix glycoprotein ADAMTSL2 is increased in heart failure and inhibits TGFβ signalling in cardiac fibroblasts
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Karoline B. Rypdal, Pugazendhi M. Erusappan, A. Olav Melleby, Deborah E. Seifert, Sheryl Palmero, Mari E. Strand, Theis Tønnessen, Christen P. Dahl, Vibeke Almaas, Dirk Hubmacher, Suneel S. Apte, Geir Christensen, and Ida G. Lunde
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Medicine ,Science - Abstract
Abstract Fibrosis accompanies most heart diseases and is associated with adverse patient outcomes. Transforming growth factor (TGF)β drives extracellular matrix remodelling and fibrosis in the failing heart. Some members of the ADAMTSL (a disintegrin-like and metalloproteinase domain with thrombospondin type 1 motifs-like) family of secreted glycoproteins bind to matrix microfibrils, and although their function in the heart remains largely unknown, they are suggested to regulate TGFβ activity. The aims of this study were to determine ADAMTSL2 levels in failing hearts, and to elucidate the role of ADAMTSL2 in fibrosis using cultured human cardiac fibroblasts (CFBs). Cardiac ADAMTSL2 mRNA was robustly increased in human and experimental heart failure, and mainly expressed by fibroblasts. Over-expression and treatment with extracellular ADAMTSL2 in human CFBs led to reduced TGFβ production and signalling. Increased ADAMTSL2 attenuated myofibroblast differentiation, with reduced expression of the signature molecules α-smooth muscle actin and osteopontin. Finally, ADAMTSL2 mitigated the pro-fibrotic CFB phenotypes, proliferation, migration and contractility. In conclusion, the extracellular matrix-localized glycoprotein ADAMTSL2 was upregulated in fibrotic and failing hearts of patients and mice. We identified ADAMTSL2 as a negative regulator of TGFβ in human cardiac fibroblasts, inhibiting myofibroblast differentiation and pro-fibrotic properties.
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- 2021
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3. Wnt5a is associated with right ventricular dysfunction and adverse outcome in dilated cardiomyopathy
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Aurelija Abraityte, Ida G. Lunde, Erik T. Askevold, Annika E. Michelsen, Geir Christensen, Pål Aukrust, Arne Yndestad, Arnt Fiane, Arne Andreassen, Svend Aakhus, Christen P. Dahl, Lars Gullestad, Kaspar Broch, and Thor Ueland
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Medicine ,Science - Abstract
Abstract The Wingless (Wnt) pathway has been implicated in the pathogenesis of dilated cardiomyopathy (DCM). To explore the role of Wnt modulators Wnt5a and sFRP3 in DCM patients we analyzed the expression of Wnt5a and sFRP3 in plasma and myocardium of DCM patients and evaluated their effects on NFAT luciferase activity in neonatal mouse cardiomyocytes. Elevated circulating Wnt5a (n = 102) was associated with increased pulmonary artery pressures, decreased right ventricular function and adverse outcome, with a stronger association in more severely affected patients. A higher Wnt5a/sFRP3 ratio (n = 25) was found in the right ventricle vs. the left ventricle and was correlated with NFAT activation as well as pulmonary artery pressures. Wnt5a induced NFAT activation and sFRP3 release in cardiomyocytes in vitro, while sFRP3 antagonized Wnt5a. Wnt5a is associated with right ventricular dysfunction and adverse outcome in DCM patients and may promote the progression of DCM through NFAT signaling.
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- 2017
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4. Increased Levels of Lectin‐Like Oxidized Low‐Density Lipoprotein Receptor‐1 in Ischemic Stroke and Transient Ischemic Attack
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Tonje Skarpengland, Mona Skjelland, Xiang Yi Kong, Karolina Skagen, Sverre Holm, Kari Otterdal, Christen P. Dahl, Kirsten Krohg‐Sørensen, Ellen L. Sagen, Vigdis Bjerkeli, Anne Hege Aamodt, Azhar Abbas, Ida Gregersen, Pål Aukrust, Bente Halvorsen, and Tuva B. Dahl
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cerebrovascular disease/stroke ,inflammation ,ischemic stroke ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
BackgroundSoluble lectin‐like oxidized low‐density lipoprotein receptor‐1 (sLOX‐1) has been shown to be increased in patients with acute ischemic stroke. Here, we evaluated plasma sLOX‐1 levels and vascular carotid plaque LOX‐1 (ie, OLR1) gene expression in patients with ischemic stroke and transient ischemic attack (TIA) with particular focus on their relation to time since symptom onset. Methods and ResultsPlasma sLOX‐1 (n=232) and carotid plaque OLR1 gene expression (n=146) were evaluated in patients who were referred to evaluation for carotid endarterectomy, as well as in healthy control plasma (n=81). Patients were categorized according to presence of acute ischemic stroke or transient ischemic attack (n=35) ≤7 days, >7 days ≤3 months (n=90), >3 months (n=40), or no reported symptoms before study inclusion (n=67). Our major findings were the following: (1) Patients with carotid atherosclerosis had increased plasma sLOX‐1 levels as compared with controls. (2) Plaque OLR1 mRNA levels were increased in carotid plaques (n=146) compared with nonatherosclerotic vessels (ie, common iliac arteries of organ donors, n=10). (3) There were no differences in sLOX plasma levels or OLR1 gene expression when analyzed according to the time since relevant cerebral ischemic symptoms. (4) Also patients with severe carotid atherosclerosis without any previous ischemic events had raised sLOX‐1 levels. (5) Immunostaining showed colocalization between LOX‐1 and macrophages within the carotid plaques. (6) Also patients with acute stroke (within 7 days) caused by atrial fibrillation (n=22) had comparable raised sLOX‐1 levels. ConclusionssLOX‐1 levels are elevated in patients with ischemic stroke and transient ischemic attack independent of cause and time since the ischemic event.
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- 2018
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5. Low Molecular Mass Myocardial Hyaluronan in Human Hypertrophic Cardiomyopathy
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Christina E. Lorén, Christen P. Dahl, Lan Do, Vibeke M. Almaas, Odd R. Geiran, Stellan Mörner, and Urban Hellman
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hypertrophic cardiomyopathy ,hyaluronan ,metabolomics ,GEMMA ,glucose ,Cytology ,QH573-671 - Abstract
During the development of hypertrophic cardiomyopathy, the heart returns to fetal energy metabolism where cells utilize more glucose instead of fatty acids as a source of energy. Metabolism of glucose can increase synthesis of the extracellular glycosaminoglycan hyaluronan, which has been shown to be involved in the development of cardiac hypertrophy and fibrosis. The aim of this study was to investigate hyaluronan metabolism in cardiac tissue from patients with hypertrophic cardiomyopathy in relation to cardiac growth. NMR and qRT-PCR analysis of human cardiac tissue from hypertrophic cardiomyopathy patients and healthy control hearts showed dysregulated glucose and hyaluronan metabolism in the patients. Gas phase electrophoresis revealed a higher amount of low molecular mass hyaluronan and larger cardiomyocytes in cardiac tissue from patients with hypertrophic cardiomyopathy. Histochemistry showed high concentrations of hyaluronan around individual cardiomyocytes in hearts from hypertrophic cardiomyopathy patients. Experimentally, we could also observe accumulation of low molecular mass hyaluronan in cardiac hypertrophy in a rat model. In conclusion, the development of hypertrophic cardiomyopathy with increased glucose metabolism affected both hyaluronan molecular mass and amount. The process of regulating cardiomyocyte size seems to involve fragmentation of hyaluronan.
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- 2019
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6. High Sensitivity Method to Estimate Distribution of Hyaluronan Molecular Sizes in Small Biological Samples Using Gas-Phase Electrophoretic Mobility Molecular Analysis
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Lan Do, Christen P. Dahl, Susanne Kerje, Peter Hansell, Stellan Mörner, Ulla Lindqvist, Anna Engström-Laurent, Göran Larsson, and Urban Hellman
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Cytology ,QH573-671 - Abstract
Hyaluronan is a negatively charged polydisperse polysaccharide where both its size and tissue concentration play an important role in many physiological and pathological processes. The various functions of hyaluronan depend on its molecular size. Up to now, it has been difficult to study the role of hyaluronan in diseases with pathological changes in the extracellular matrix where availability is low or tissue samples are small. Difficulty to obtain large enough biopsies from human diseased tissue or tissue from animal models has also restricted the study of hyaluronan. In this paper, we demonstrate that gas-phase electrophoretic molecular mobility analyzer (GEMMA) can be used to estimate the distribution of hyaluronan molecular sizes in biological samples with a limited amount of hyaluronan. The low detection level of the GEMMA method allows for estimation of hyaluronan molecular sizes from different parts of small organs. Hence, the GEMMA method opens opportunity to attain a profile over the distribution of hyaluronan molecular sizes and estimate changes caused by disease or experimental conditions that has not been possible to obtain before.
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- 2015
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7. Inhibition of the extracellular enzyme ADAMTS4 prevents cardiac fibrosis and dysfunction
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Maria Vistnes, Pugazendhi Murugan Erusappan, Athiramol Sasi, Einar Sjaastad Nordén, Kaja Bergo, Andreas Romaine, Ida Gjervold Lunde, Lili Zhang, Maria Belland Olsen, Jonas Øgaard, Cathrine Rein Carlson, Christian Hjorth Wang, Jon Riise, Christen P Dahl, Arnt Eltvedt Fiane, IdaMarie Hauge-Iversen, Emil Espe, Arne Olav Melleby, Theis Tønnessen, Jan Magnus Aronsen, Ivar Sjaastad, and Geir Christensen
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Physiology ,Physiology (medical) ,Cardiology and Cardiovascular Medicine - Abstract
Aims Heart failure is a condition with high mortality rates, and there is a lack of therapies that directly target maladaptive changes in the extracellular matrix (ECM), such as fibrosis. We investigated whether the ECM enzyme known as A disintegrin and metalloprotease with thrombospondin motif (ADAMTS) 4 might serve as a therapeutic target in treatment of heart failure and cardiac fibrosis. Methods and results The effects of pharmacological ADAMTS4 inhibition on cardiac function and fibrosis were examined in rats exposed to cardiac pressure overload. Disease mechanisms affected by the treatment were identified based on changes in the myocardial transcriptome. Following aortic banding (AB), rats receiving an ADAMTS inhibitor, with high inhibitory capacity for ADAMTS4, showed substantially better cardiac function than vehicle-treated rats, including ∼30 % reduction in E/e’ and left atrial diameter, indicating an improvement in diastolic function. ADAMTS inhibition also resulted in a marked reduction in myocardial collagen content and a downregulation of transforming growth factor (TGF) β target genes. The mechanism for the beneficial effects of ADAMTS inhibition was further studied in cultured human cardiac fibroblasts producing mature ECM. ADAMTS4 caused a 50% increase in the TGF-β levels in the medium. Simultaneously, ADAMTS4 elicited a not previously known cleavage of TGF-β-binding proteins, i.e. latent binding protein of TGF-β (LTBP1) and extra domain A (EDA)-fibronectin. These effects were abolished by the ADAMTS inhibitor. In failing human hearts, we observed a marked increase in ADAMTS4 expression and cleavage activity. Conclusion Inhibition of ADAMTS4 improves cardiac function and reduces collagen accumulation in rats with cardiac pressure overload, possibly through a not previously known cleavage of molecules that control TGF-β availability. Targeting ADAMTS4 may serve as a novel strategy in heart failure treatment, in particular in heart failure with fibrosis and diastolic dysfunction.
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- 2023
8. The extracellular matrix glycoprotein ADAMTSL2 is increased in heart failure and inhibits TGFβ signalling in cardiac fibroblasts
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Sheryl Palmero, A. Olav Melleby, Dirk Hubmacher, Christen P. Dahl, Suneel S. Apte, Geir Christensen, Deborah E. Seifert, Vibeke M. Almaas, Theis Tønnessen, Mari E. Strand, Ida G. Lunde, Pugazendhi M. Erusappan, and Karoline B. Rypdal
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Cell biology ,Molecular biology ,Science ,Cardiology ,Platelet membrane glycoprotein ,Article ,Extracellular matrix ,Mice ,Medical research ,ADAMTS Proteins ,Fibrosis ,Transforming Growth Factor beta ,medicine ,Extracellular ,Animals ,Humans ,Osteopontin ,Heart Failure ,Thrombospondin ,Extracellular Matrix Proteins ,Multidisciplinary ,biology ,Molecular medicine ,Chemistry ,Cell Differentiation ,Fibroblasts ,medicine.disease ,Extracellular Matrix ,Rats ,Disease Models, Animal ,Gene Expression Regulation ,biology.protein ,Medicine ,Disease Susceptibility ,Myofibroblast ,Biomarkers ,Transforming growth factor ,Signal Transduction - Abstract
Fibrosis accompanies most heart diseases and is associated with adverse patient outcomes. Transforming growth factor (TGF)β drives extracellular matrix remodelling and fibrosis in the failing heart. Some members of the ADAMTSL (a disintegrin-like and metalloproteinase domain with thrombospondin type 1 motifs-like) family of secreted glycoproteins bind to matrix microfibrils, and although their function in the heart remains largely unknown, they are suggested to regulate TGFβ activity. The aims of this study were to determine ADAMTSL2 levels in failing hearts, and to elucidate the role of ADAMTSL2 in fibrosis using cultured human cardiac fibroblasts (CFBs). Cardiac ADAMTSL2 mRNA was robustly increased in human and experimental heart failure, and mainly expressed by fibroblasts. Over-expression and treatment with extracellular ADAMTSL2 in human CFBs led to reduced TGFβ production and signalling. Increased ADAMTSL2 attenuated myofibroblast differentiation, with reduced expression of the signature molecules α-smooth muscle actin and osteopontin. Finally, ADAMTSL2 mitigated the pro-fibrotic CFB phenotypes, proliferation, migration and contractility. In conclusion, the extracellular matrix-localized glycoprotein ADAMTSL2 was upregulated in fibrotic and failing hearts of patients and mice. We identified ADAMTSL2 as a negative regulator of TGFβ in human cardiac fibroblasts, inhibiting myofibroblast differentiation and pro-fibrotic properties.
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- 2021
9. Hypothermia elongates the contraction-relaxation cycle in explanted human failing heart decreasing the time for ventricular filling during diastole
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Christen P. Dahl, Kurt A. Krobert, Marie-Victoire Cosson, Finn Olav Levy, Arnt E. Fiane, Geir Øystein Andersen, and Halvard Gautefall Hiis
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Adult ,Cardiomyopathy, Dilated ,Male ,Inotrope ,medicine.medical_specialty ,Time Factors ,Contraction (grammar) ,Adolescent ,Systole ,Physiology ,medicine.medical_treatment ,Diastole ,In Vitro Techniques ,030204 cardiovascular system & hematology ,Targeted temperature management ,Ventricular Function, Left ,Contractility ,03 medical and health sciences ,0302 clinical medicine ,Heart Rate ,Hypothermia, Induced ,Physiology (medical) ,Internal medicine ,Humans ,Medicine ,Heart Failure ,business.industry ,Cardiac Pacing, Artificial ,Isoproterenol ,030208 emergency & critical care medicine ,Adrenergic beta-Agonists ,Middle Aged ,Hypothermia ,Myocardial Contraction ,Cardiology ,Female ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Ventricular filling ,Relaxation cycle - Abstract
Targeted temperature management is part of the standardized treatment for patients in cardiac arrest. Hypothermia decreases cerebral oxygen consumption and induces bradycardia; thus, increasing the heart rate may be considered to maintain cardiac output. We hypothesized that increasing heart rate during hypothermia would impair diastolic function. Human left ventricular trabeculae obtained from explanted hearts of patients with terminal heart failure were stimulated at 0.5 Hz, and contraction-relaxation cycles were recorded. Maximal developed force (Fmax), maximal rate of development of force [(dF/d t)max], time to peak force (TPF), time to 80% relaxation (TR80), and relaxation time (RT = TR80 − TPF) were measured at 37, 33, 31, and 29°C. At these temperatures, stimulation frequency was increased from 0.5 to 1.0 and to 1.5 Hz. At 1.5 Hz, concentration-response curves for the β-adrenergic receptor (β-AR) agonist isoproterenol were performed. Fmax, TPF, and RT increased when temperature was lowered, whereas (dF/d t)max decreased. At all temperatures, increasing stimulation frequency increased Fmax and (dF/d t)max, whereas TPF and RT decreased. At 31 and 29°C, resting tension increased at 1.5 Hz, which was ameliorated by β-AR stimulation. At all temperatures, maximal β-AR stimulation increased Fmax, (dF/d t)max, and maximal systolic force, whereas resting tension decreased progressively with lowering temperature. β-AR stimulation reduced TPF and RT to the same extent at all temperatures, despite the more elongated contraction-relaxation cycle at lower temperatures. Diastolic dysfunction during hypothermia results from an elongation of the contraction-relaxation cycle, which decreases the time for ventricular filling. Hypothermic bradycardia protects the heart from diastolic dysfunction and increasing the heart rate during hypothermia should be avoided. NEW & NOTEWORTHY Decreasing temperature increases the duration of the contraction-relaxation cycle in the human ventricular myocardium, significantly reducing the time for ventricular filling during diastole. During hypothermia, increasing heart rate further reduces the time for ventricular filling and in some situations increases resting tension further impairing diastolic function. Modest β-adrenergic receptor stimulation can ameliorate these potentially detrimental changes during diastole while improving contractile force generation during targeted temperature management.
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- 2018
10. Etiology-Dependent Impairment of Diastolic Cardiomyocyte Calcium Homeostasis in Heart Failure With Preserved Ejection Fraction
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Peter P. Jones, Gustavo Jose Justo da Silva, Einar Sjaastad Norden, Lars Gullestad, Emil K. S. Espe, Ornella Manfra, Fouad A. Zouein, Åsmund T. Røe, Ida G. Lunde, Isabelle van Hout, Michael Frisk, Xin Shen, Yufeng Hou, Christopher Le, Martin Laasmaa, Sean Coffey, Christen P. Dahl, Raffaele Altara, Theis Tønnessen, Alessandro Cataliotti, Ivar Sjaastad, Regis R. Lambert, William E. Louch, and J. Magnus Aronsen
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Male ,medicine.medical_specialty ,Diastole ,Concentric hypertrophy ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Medicine ,Homeostasis ,Humans ,Myocytes, Cardiac ,030212 general & internal medicine ,Aged ,Calcium metabolism ,Aged, 80 and over ,Heart Failure, Diastolic ,Ejection fraction ,business.industry ,Middle Aged ,medicine.disease ,Pathophysiology ,Echocardiography ,Heart failure ,Cardiology ,Calcium ,Female ,Cardiology and Cardiovascular Medicine ,Heart failure with preserved ejection fraction ,business - Abstract
Background Whereas heart failure with reduced ejection fraction (HFrEF) is associated with ventricular dilation and markedly reduced systolic function, heart failure with preserved ejection fraction (HFpEF) patients exhibit concentric hypertrophy and diastolic dysfunction. Impaired cardiomyocyte Ca2+ homeostasis in HFrEF has been linked to disruption of membrane invaginations called t-tubules, but it is unknown if such changes occur in HFpEF. Objectives This study examined whether distinct cardiomyocyte phenotypes underlie the heart failure entities of HFrEF and HFpEF. Methods T-tubule structure was investigated in left ventricular biopsies obtained from HFrEF and HFpEF patients, whereas cardiomyocyte Ca2+ homeostasis was studied in rat models of these conditions. Results HFpEF patients exhibited increased t-tubule density in comparison with control subjects. Super-resolution imaging revealed that higher t-tubule density resulted from both tubule dilation and proliferation. In contrast, t-tubule density was reduced in patients with HFrEF. Augmented collagen deposition within t-tubules was observed in HFrEF but not HFpEF hearts. A causative link between mechanical stress and t-tubule disruption was supported by markedly elevated ventricular wall stress in HFrEF patients. In HFrEF rats, t-tubule loss was linked to impaired systolic Ca2+ homeostasis, although diastolic Ca2+ removal was also reduced. In contrast, Ca2+ transient magnitude and release kinetics were largely maintained in HFpEF rats. However, diastolic Ca2+ impairments, including reduced sarco/endoplasmic reticulum Ca2+-ATPase activity, were specifically observed in diabetic HFpEF but not in ischemic or hypertensive models. Conclusions Although t-tubule disruption and impaired cardiomyocyte Ca2+ release are hallmarks of HFrEF, such changes are not prominent in HFpEF. Impaired diastolic Ca2+ homeostasis occurs in both conditions, but in HFpEF, this mechanism for diastolic dysfunction is etiology-dependent.
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- 2020
11. Absence of NLRP3 Inflammasome in Hematopoietic Cells Reduces Adverse Remodeling After Experimental Myocardial Infarction
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Davi de Miranda Fonseca, Tuula A. Nyman, Maria Belland Olsen, E. Schrumpf, Håvard Attramadal, Kuan Yang, Animesh Sharma, Bente Halvorsen, Azita Rashidi, Arne Yndestad, Espen Melum, Magnar Bjørås, Pål Aukrust, Jan Magnus Aronsen, Christen P. Dahl, Katrine Alfsnes, Maria Cornelia Louwe, Ole Jørgen Kaasbøll, Mingyi Yang, Ivar Sjaastad, Linn E. Fosshaug, Jonas Øgaard, Muhammad Shakil Ahmed, Thor Ueland, and Vidar Magne Skulberg
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0301 basic medicine ,Cardiac function curve ,030204 cardiovascular system & hematology ,Proinflammatory cytokine ,03 medical and health sciences ,0302 clinical medicine ,NLRP3 ,inflammasome ,medicine ,Myocardial infarction ,Ventricular remodeling ,Innate immune system ,integumentary system ,business.industry ,Inflammasome ,medicine.disease ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,myocardial infarction ,Cancer research ,Bone marrow ,Preclinical Research ,cardiac remodeling ,Cardiology and Cardiovascular Medicine ,business ,Editorial Comment ,medicine.drug - Abstract
An inflammatory response is required for tissue healing after a myocardial infarction (MI), but the process must be balanced to prevent maladaptive remodeling. This study shows that improved survival and cardiac function following MI, in mice deficient for the NLRP3 inflammasome, can be recapitulated in wild-type mice receiving bone marrow from Nlrp3−/− mice. This suggests that NLRP3 activation in hematopoietic cells infiltrating in the myocardium increases mortality and late ventricular remodeling. Our data should encourage performing clinical trials directly targeting NLRP3 inflammasome and their inflammatory cytokines (interleukin-1β and -18) in MI patients. SEVIER ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER THE CC BY-NC-ND LICENSE ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ) .
- Published
- 2019
12. Thyroid and Glucocorticoid Hormones Promote Functional T-Tubule Development in Human-Induced Pluripotent Stem Cell–Derived Cardiomyocytes
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Daniel J. Blackwell, Nieves Gomez-Hurtado, Michael Frisk, Arnt E. Fiane, William E. Louch, Shan Parikh, Christen P. Dahl, Dmytro O. Kryshtal, Lili Wang, Kyungsoo Kim, Theis Tønnessen, and Bjorn C. Knollmann
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0301 basic medicine ,medicine.medical_specialty ,Matrigel ,Physiology ,Ryanodine receptor ,Cellular differentiation ,030204 cardiovascular system & hematology ,Biology ,Ryanodine receptor 2 ,Extracellular matrix ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Endocrinology ,Internal medicine ,medicine ,Stem cell ,Cardiology and Cardiovascular Medicine ,Induced pluripotent stem cell ,Hormone - Abstract
Rationale: Human-induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CM) are increasingly being used for modeling heart disease and are under development for regeneration of the injured heart. However, incomplete structural and functional maturation of hiPSC-CM, including lack of T-tubules, immature excitation–contraction coupling, and inefficient Ca-induced Ca release remain major limitations. Objective: Thyroid and glucocorticoid hormones are critical for heart maturation. We hypothesized that their addition to standard protocols would promote T-tubule development and mature excitation–contraction coupling of hiPSC-CM when cultured on extracellular matrix with physiological stiffness (Matrigel mattress). Methods and Results: hiPSC-CM were generated using a standard chemical differentiation method supplemented with T3 (triiodothyronine) and/or Dex (dexamethasone) during days 16 to 30 followed by single-cell culture for 5 days on Matrigel mattress. hiPSC-CM treated with T3+Dex, but not with either T3 or Dex alone, developed an extensive T-tubule network. Notably, Matrigel mattress was necessary for T-tubule formation. Compared with adult human ventricular cardiomyocytes, T-tubules in T3+Dex-treated hiPSC-CM were less organized and had more longitudinal elements. Confocal line scans demonstrated spatially and temporally uniform Ca release that is characteristic of excitation–contraction coupling in the heart ventricle. T3+Dex enhanced elementary Ca release measured by Ca sparks and promoted RyR2 (ryanodine receptor) structural organization. Simultaneous measurements of L-type Ca current and intracellular Ca release confirmed enhanced functional coupling between L-type Ca channels and RyR2 in T3+Dex-treated cells. Conclusions: Our results suggest a permissive role of combined thyroid and glucocorticoid hormones during the cardiac differentiation process, which when coupled with further maturation on Matrigel mattress, is sufficient for T-tubule development, enhanced Ca-induced Ca release, and more ventricular-like excitation–contraction coupling. This new hormone maturation method could advance the use of hiPSC-CM for disease modeling and cell-based therapy.
- Published
- 2017
13. Wnt5a is elevated in heart failure and affects cardiac fibroblast function
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Svend Aakhus, Arne Yndestad, Thor Ueland, Annika E. Michelsen, Arnt E. Fiane, Pål Aukrust, Geir Christensen, Ida G. Lunde, Christen P. Dahl, Aurelija Abraityte, Lars Gullestad, Erik T. Askevold, Leif Erik Vinge, Tove Lekva, Katrine Alfsnes, and Trine Ranheim
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Adult ,Male ,0301 basic medicine ,MAPK/ERK pathway ,medicine.medical_specialty ,MAP Kinase Signaling System ,Inflammation ,030204 cardiovascular system & hematology ,Wnt-5a Protein ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Fibrosis ,Internal medicine ,Drug Discovery ,medicine ,Animals ,Humans ,Interleukin 6 ,Wnt Signaling Pathway ,Genetics (clinical) ,Aged ,Heart Failure ,Tissue Inhibitor of Metalloproteinase-1 ,biology ,Interleukin-6 ,business.industry ,Myocardium ,Wnt signaling pathway ,Interleukin ,Fibroblasts ,Middle Aged ,Tissue inhibitor of metalloproteinase ,medicine.disease ,body regions ,030104 developmental biology ,Endocrinology ,Heart failure ,embryonic structures ,biology.protein ,Molecular Medicine ,Female ,sense organs ,medicine.symptom ,business - Abstract
Wnt signaling is dysregulated in heart failure (HF) and may promote cardiac hypertrophy, fibrosis, and inflammation. Blocking the Wnt ligand Wnt5a prevents HF in animal models. However, the role of Wnt5a in human HF and its functions in cardiac cells remain unclear. Here, we investigated Wnt5a regulation in HF patients and its effects on primary mouse and human cardiac fibroblasts. Serum Wnt5a was elevated in HF patients and associated with hemodynamic, neurohormonal, and clinical measures of disease severity. In failing human hearts, Wnt5a protein correlated with interleukin (IL)-6 and tissue inhibitor of metalloproteinase (TIMP)-1. Wnt5a messenger RNA (mRNA) levels were markedly upregulated in failing myocardium and both mRNA and protein levels declined following left ventricular assist device therapy. In primary mouse and human cardiac fibroblasts, recombinant Wnt5a dose-dependently upregulated mRNA and protein release of IL-6 and TIMP-1. Wnt5a did not affect β-catenin levels, but activated extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. Importantly, inhibition of ERK1/2 activation attenuated Wnt5a-induced release of IL-6 and TIMP-1. In conclusion, our results show that Wnt5a is elevated in the serum and myocardium of HF patients and is associated with measures of progressive HF. Wnt5a induces IL-6 and TIMP-1 in cardiac fibroblasts, which might promote myocardial inflammation and fibrosis, and thereby contribute to HF progression. • Wnt5a is elevated in serum and myocardium of HF patients and is associated with measures of progressive HF. • In cardiac fibroblasts, Wnt5a upregulates interleukin (IL)-6 and tissue inhibitor of metalloproteinase (TIMP)-1 through the ERK pathway. • Wnt5a-mediated effects might promote myocardial inflammation and fibrosis, and thereby contribute to HF progression.
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- 2017
14. Enhanced base excision repair capacity in carotid atherosclerosis may protect nuclear DNA but not mitochondrial DNA
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Animesh Sharma, David Russell, Lars Eide, Katja Scheffler, Geir Slupphaug, Anna Kuśnierczyk, Bente Halvorsen, Pål Aukrust, Christen P. Dahl, Tonje Skarpengland, Sverre Holm, Lasse Folkersen, Ida Gregersen, Mirta Mittelsted Leal de Sousa, Filip M. Segers, Karolina Skagen, Tuva B. Dahl, Magnar Bjørås, Kirsten Krohg-Sørensen, and Mona Skjelland
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Carotid Artery Diseases ,Male ,0301 basic medicine ,Mitochondrial DNA ,DNA Repair ,DNA damage ,DNA repair ,Gene Expression ,Biology ,medicine.disease_cause ,DNA, Mitochondrial ,Biochemistry ,03 medical and health sciences ,Physiology (medical) ,Gene expression ,medicine ,Humans ,Cells, Cultured ,Aged ,Macrophages ,Base excision repair ,Middle Aged ,Molecular biology ,Plaque, Atherosclerotic ,Nuclear DNA ,Oxidative Stress ,Carotid Arteries ,030104 developmental biology ,DNA glycosylase ,Case-Control Studies ,Female ,Oxidative stress ,DNA Damage - Abstract
Background Lesional and systemic oxidative stress has been implicated in the pathogenesis of atherosclerosis, potentially leading to accumulation of DNA base lesions within atherosclerotic plaques. Although base excision repair (BER) is a major pathway counteracting oxidative DNA damage, our knowledge on BER and accumulation of DNA base lesions in clinical atherosclerosis is scarce. Here, we evaluated the transcriptional profile of a wide spectrum of BER components as well as DNA damage accumulation in atherosclerotic and non-atherosclerotic arteries. Methods BER gene expression levels were analyzed in 162 carotid plaques, 8 disease-free carotid specimens from patients with carotid plaques and 10 non-atherosclerotic control arteries. Genomic integrity, mitochondrial (mt) DNA copy number, oxidative DNA damage and BER proteins were evaluated in a subgroup of plaques and controls. Results Our major findings were: (i) The BER pathway showed a global increased transcriptional response in plaques as compared to control arteries, accompanied by increased expression of several BER proteins. (ii) Whereas nuclear DNA stability was maintained within carotid plaques, mtDNA integrity and copy number were decreased. (iii) Within carotid plaques, mRNA levels of several BER genes correlated with macrophage markers. (iv) In vitro , some of the BER genes were highly expressed in the anti-inflammatory and pro-resolving M2 macrophages, showing increased expression upon exposure to modified lipids. Conclusions The increased transcriptional response of BER genes in atherosclerosis may contribute to lesional nuclear DNA stability but appears insufficient to maintain mtDNA integrity, potentially influencing mitochondrial function in cells within the atherosclerotic lesion.
- Published
- 2016
15. T-tubule disruption is a prominent feature of HFrEF but not HFpEF
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Ida G. Lunde, Ivar Sjaastad, William E. Louch, Yufeng Hou, Christopher Le, Theis Tønnessen, Michael Frisk, Lars Gullestad, Ole M. Sejersted, Åsmund T. Røe, Xin Shen, Christen P. Dahl, and Peter P. Jones
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medicine.anatomical_structure ,Feature (computer vision) ,medicine ,Biology ,Cardiology and Cardiovascular Medicine ,Molecular Biology ,T-tubule ,Cell biology - Published
- 2020
16. P1744Hypothermia-induced diastolic dysfunction in ventricular trabeculae from human failing explanted hearts is caused by elongated contraction-relaxation cycle time and is worsened by increased heart rate
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Halvard Gautefall Hiis, Marie-Victoire Cosson, Finn Olav Levy, Christen P. Dahl, Arnt E. Fiane, Geir Øystein Andersen, and Kurt A. Krobert
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medicine.medical_specialty ,Contraction (grammar) ,business.industry ,Internal medicine ,Increased heart rate ,medicine ,Diastole ,Cardiology ,Cardiology and Cardiovascular Medicine ,business ,Relaxation cycle - Published
- 2018
17. The extracellular matrix proteoglycan fibromodulin is upregulated in clinical and experimental heart failure and affects cardiac remodeling
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Sheryl Palmero, Ivar Sjaastad, Theis Tønnessen, Ida G. Lunde, Jan Magnus Aronsen, Geir Christensen, Christen P. Dahl, Kristin V. T. Engebretsen, Naiyereh Mohammadzadeh, Mari E. Strand, and Kine Andenæs
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0301 basic medicine ,Male ,Glycobiology ,lcsh:Medicine ,Biochemistry ,Physical Chemistry ,Extracellular matrix ,Mice ,Fibrosis ,Animal Cells ,Medicine and Health Sciences ,Cross-Linking ,Medicine ,Myocyte ,Myocytes, Cardiac ,lcsh:Science ,Connective Tissue Cells ,Mice, Knockout ,Extracellular Matrix Proteins ,Multidisciplinary ,biology ,Heart ,Extracellular Matrix ,Chemistry ,Connective Tissue ,Physical Sciences ,Female ,Proteoglycans ,Anatomy ,Cellular Types ,Fibromodulin ,Research Article ,medicine.medical_specialty ,Cardiology ,Lysyl oxidase ,Cardiomegaly ,Periostin ,03 medical and health sciences ,Internal medicine ,Animals ,Humans ,Pressure overload ,Heart Failure ,Chemical Bonding ,business.industry ,Myocardium ,lcsh:R ,Biology and Life Sciences ,Proteins ,Cell Biology ,Fibroblasts ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Biological Tissue ,Proteoglycan ,Heart failure ,biology.protein ,Cardiovascular Anatomy ,lcsh:Q ,business ,Collagens ,Biomarkers ,Developmental Biology - Abstract
Pressure overload of the heart leads to cardiac remodeling that may progress into heart failure, a common, morbid and mortal condition. Increased mechanistic insight into remodeling is instrumental for development of novel heart failure treatment. Cardiac remodeling comprises cardiomyocyte hypertrophic growth, extracellular matrix alterations including fibrosis, and inflammation. Fibromodulin is a small leucine-rich proteoglycan that regulates collagen fibrillogenesis. Fibromodulin is expressed in the cardiac extracellular matrix, however its role in the heart remains largely unknown. We investigated fibromodulin levels in myocardial biopsies from heart failure patients and mice, subjected fibromodulin knock-out (FMOD-KO) mice to pressure overload by aortic banding, and overexpressed fibromodulin in cultured cardiomyocytes and cardiac fibroblasts using adenovirus. Fibromodulin was 3-10-fold upregulated in hearts of heart failure patients and mice. Both cardiomyocytes and cardiac fibroblasts expressed fibromodulin, and its expression was increased by pro-inflammatory stimuli. Without stress, FMOD-KO mice showed no cardiac phenotype. Upon aortic banding, left ventricles of FMOD-KO mice developed mildly exacerbated hypertrophic remodeling compared to wild-type mice, with increased cardiomyocyte size and altered infiltration of leukocytes. There were no differences in mortality, left ventricle dilatation, dysfunction or expression of heart failure markers. Although collagen amount and cross-linking were comparable in FMOD-KO and wild-type, overexpression of fibromodulin in cardiac fibroblasts in vitro decreased their migratory capacity and expression of fibrosis-associated molecules, i.e. the collagen-cross linking enzyme lysyl oxidase, transglutaminase 2 and periostin. In conclusion, despite a robust fibromodulin upregulation in clinical and experimental heart failure, FMOD-KO mice showed a relatively mild hypertrophic phenotype. In cultured cardiac fibroblasts, fibromodulin has anti-fibrotic effects.
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- 2018
18. Increased Levels of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 in Ischemic Stroke and Transient Ischemic Attack
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Kari Otterdal, Azhar Abbas, Pål Aukrust, Tuva B. Dahl, Sverre Holm, Kirsten Krohg-Sørensen, Tonje Skarpengland, Vigdis Bjerkeli, Christen P. Dahl, Bente Halvorsen, Anne Hege Aamodt, Mona Skjelland, Ellen Lund Sagen, Karolina Skagen, Xiang Yi Kong, and Ida Gregersen
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Carotid Artery Diseases ,Male ,medicine.medical_specialty ,OXIDIZED LOW DENSITY LIPOPROTEIN RECEPTOR 1 ,Inflammation ,030204 cardiovascular system & hematology ,Risk Assessment ,Brain Ischemia ,cerebrovascular disease/stroke ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,medicine ,ischemic stroke ,Humans ,In patient ,cardiovascular diseases ,Acute ischemic stroke ,Aged ,Original Research ,biology ,business.industry ,Lectin ,Middle Aged ,Scavenger Receptors, Class E ,Atherosclerosis ,Plaque, Atherosclerotic ,Up-Regulation ,Stroke ,Endocrinology ,Ischemic Attack, Transient ,inflammation ,Case-Control Studies ,Ischemic stroke ,biology.protein ,Female ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,030217 neurology & neurosurgery ,Biomarkers ,Lipoprotein - Abstract
Background Soluble lectin‐like oxidized low‐density lipoprotein receptor‐1 ( sLOX ‐1) has been shown to be increased in patients with acute ischemic stroke. Here, we evaluated plasma sLOX ‐1 levels and vascular carotid plaque LOX ‐1 (ie, OLR 1 ) gene expression in patients with ischemic stroke and transient ischemic attack ( TIA ) with particular focus on their relation to time since symptom onset. Methods and Results Plasma sLOX ‐1 (n=232) and carotid plaque OLR 1 gene expression (n=146) were evaluated in patients who were referred to evaluation for carotid endarterectomy, as well as in healthy control plasma (n=81). Patients were categorized according to presence of acute ischemic stroke or transient ischemic attack (n=35) ≤7 days, >7 days ≤3 months (n=90), >3 months (n=40), or no reported symptoms before study inclusion (n=67). Our major findings were the following: (1) Patients with carotid atherosclerosis had increased plasma sLOX ‐1 levels as compared with controls. (2) Plaque OLR 1 mRNA levels were increased in carotid plaques (n=146) compared with nonatherosclerotic vessels (ie, common iliac arteries of organ donors, n=10). (3) There were no differences in sLOX plasma levels or OLR 1 gene expression when analyzed according to the time since relevant cerebral ischemic symptoms. (4) Also patients with severe carotid atherosclerosis without any previous ischemic events had raised sLOX ‐1 levels. (5) Immunostaining showed colocalization between LOX ‐1 and macrophages within the carotid plaques. (6) Also patients with acute stroke (within 7 days) caused by atrial fibrillation (n=22) had comparable raised sLOX ‐1 levels. Conclusions sLOX ‐1 levels are elevated in patients with ischemic stroke and transient ischemic attack independent of cause and time since the ischemic event.
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- 2018
19. Microbiota-dependent metabolite trimethylamine-N-oxide is associated with disease severity and survival of patients with chronic heart failure
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Tom H. Karlsen, Rolf K. Berge, Einar Gude, Lars Gullestad, P. Aukrust, Thor Ueland, Christen P. Dahl, Ida Gregersen, Svend Aakhus, Bente Halvorsen, Asbjørn Svardal, Arne Yndestad, Marius Trøseid, Bodil Bjørndal, and Johannes R. Hov
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Male ,medicine.medical_specialty ,Pathology ,Metabolite ,Trimethylamine N-oxide ,Gut flora ,Risk Assessment ,Sensitivity and Specificity ,Severity of Illness Index ,Gastroenterology ,Choline ,Coronary artery disease ,Methylamines ,chemistry.chemical_compound ,Predictive Value of Tests ,Risk Factors ,Internal medicine ,Internal Medicine ,medicine ,Humans ,Prospective Studies ,Carnitine ,Intestinal Mucosa ,Aged ,Heart Failure ,Lipotropic Agents ,biology ,business.industry ,Microbiota ,Middle Aged ,Oxidants ,Prognosis ,biology.organism_classification ,medicine.disease ,Survival Analysis ,Betaine ,Intestines ,chemistry ,Heart failure ,Chronic Disease ,Etiology ,Female ,business ,Biomarkers ,medicine.drug - Abstract
Recent metabolomic, experimental and clinical studies have demonstrated that trimethylamine-N-oxide (TMAO), a microbiota-dependent metabolite from dietary phosphatidylcholine and carnitine, is a strong predictor of coronary artery disease (CAD). This finding suggests a link between the gut microbiota and atherosclerosis. The potential impact of TMAO in chronic heart failure (HF) is unknown. We hypothesized that TMAO levels would provide prognostic information about adverse outcomes in chronic HF.Prospective, observational study including 155 consecutive patients with chronic HF. In addition, 100 patients with stable CAD without HF and 33 matched healthy individuals were included as controls. Plasma levels of TMAO and its precursors choline and betaine were measured, and associations with symptoms, aetiology and transplant-free survival in the patients with HF were explored.Plasma levels of TMAO (P = 0.01), choline (P0.001) and betaine (P0.001) were elevated in patients with chronic HF compared to control subjects, with the highest levels in patients with New York Heart Association (NYHA) classes III and IV. Furthermore, TMAO levels were highest in individuals with ischaemic HF, followed by those with stable CAD and nonischaemic HF. TMAO, but not choline or betaine, was associated with reduced transplant-free survival: approximately 50% of patients in the upper tertile of TMAO levels died or received a heart transplant during 5.2 years of follow-up (unadjusted Cox-regression: hazard ratio 2.24, 95% confidence interval 1.28-3.92, P = 0.005).TMAO levels were elevated in patients with HF and associated with NYHA class, ischaemic aetiology and adverse outcomes. Future studies should focus on gut microbiota, dietary composition and intestinal dysfunction in relation to TMAO levels and clinical outcome in HF.
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- 2014
20. Inhibition of phosphodiesterase-3 by levosimendan is sufficient to account for its inotropic effect in failing human heart
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Tor Skomedal, Ata Sh, Christen P. Dahl, Jon Riise, Geir Øystein Andersen, Øivind Ørstavik, Eirik Qvigstad, Jan-Bjørn Osnes, and Finn Olav Levy
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Pharmacology ,Inotrope ,medicine.medical_specialty ,Lusitropy ,Cilostamide ,business.industry ,Phosphodiesterase 3 ,Levosimendan ,Contractility ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,Ventricle ,Internal medicine ,Isoprenaline ,medicine ,Cardiology ,business ,medicine.drug - Abstract
Background and Purpose Levosimendan is known as a calcium sensitizer, although it is also known to inhibit PDE3. We aimed to isolate each component and estimate their contribution to the increased cardiac contractility induced by levosimendan. Experimental Approach Contractile force was measured in electrically stimulated ventricular strips from explanted failing human hearts and left ventricular strips from normal male Wistar rats. PDE activity was measured in a two-step PDE activity assay on failing human ventricle. Key Results Levosimendan exerted a positive inotropic effect (PIE) reaching maximum at 10−5 M in ventricular strips from failing human hearts. In the presence of the selective PDE3 inhibitor cilostamide, the PIE of levosimendan was abolished. During treatment with a PDE4 inhibitor and a supra-threshold concentration of isoprenaline, levosimendan generated an amplified inotropic response. This effect was reversed by β-adrenoceptor blockade and undetectable in strips pretreated with cilostamide. Levosimendan (10−6 M) increased the potency of β-adrenoceptor agonists by 0.5 log units in failing human myocardium, but not in the presence of cilostamide. Every inotropic response to levosimendan was associated with a lusitropic response. Levosimendan did not affect the concentration–response curve to calcium in rat ventricular strips, in contrast to the effects of a known calcium sensitizer, EMD57033 [5-(1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one]. PDE activity assays confirmed that levosimendan inhibited PDE3 as effectively as cilostamide. Conclusions and Implications Our results indicate that the PDE3-inhibitory property of levosimendan was enough to account for its inotropic effect, leaving a minor, if any, effect to a calcium-sensitizing component.
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- 2014
21. Connective tissue growth factor and bone morphogenetic protein 2 are induced following myocardial ischemia in mice and humans
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Arnt E. Fiane, Jarle Vaage, Arkady Rutkovskiy, Lars Gullestad, Håvard Attramadal, Julia Sagave, Christen P. Dahl, Vigdis Hillestad, Guro Valen, Shakil M Ahmed, Katarina Zihlavnikova Enayati, Gabor Czibik, Anton Baysa, and Jørgen Gravning
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0301 basic medicine ,Adult ,Cardiomyopathy, Dilated ,Male ,Pathology ,medicine.medical_specialty ,Clinical Biochemistry ,Connective tissue ,Bone Morphogenetic Protein 2 ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,Bone morphogenetic protein 2 ,Coronary artery disease ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Left coronary artery ,medicine.artery ,Internal medicine ,medicine ,Animals ,Humans ,Bone morphogenetic protein receptor ,Myocardial infarction ,Coronary Artery Bypass ,Bone Morphogenetic Protein Receptors, Type I ,Aged ,Heart Failure ,business.industry ,Myocardium ,Connective Tissue Growth Factor ,Dilated cardiomyopathy ,General Medicine ,Middle Aged ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Heart failure ,Heart Function Tests ,Cardiology ,Female ,business ,Signal Transduction - Abstract
We aimed to study the cardiac expression of bone morphogenetic protein 2, its receptor 1 b, and connective tissue growth factor, factors implicated in cardiac embryogenesis, following ischemia/hypoxia, heart failure, and in remodeling hearts from humans and mice. Biopsies from the left ventricle of patients with end-stage heart failure due to dilated cardiomyopathy or coronary artery disease were compared with donor hearts and biopsies from patients with normal heart function undergoing coronary artery bypass grafting. Mouse model of post-infarction remodeling was made by permanent ligation of the left coronary artery. Hearts were analyzed by real-time polymerase chain reaction and Western blotting after 24 hours and after 2 and 4 weeks. Patients with dilated cardiomyopathy and mice post-infarction had increased cardiac expression of connective tissue growth factor. Bone morphogenetic protein 2 was increased in human hearts failing due to coronary artery disease and in mice post-infarction. Gene expression of bone morphogenetic protein receptor 1 beta was reduced in hearts of patients with failure, but increased two weeks following permanent ligation of the left coronary artery in mice. In conclusion, connective tissue growth factor is upregulated in hearts of humans with dilated cardiomyopathy, bone morphogenetic protein 2 is upregulated in remodeling due to myocardial infarction while its receptor 1 b in human failing hearts is downregulated. A potential explanation might be an attempt to engage regenerative processes, which should be addressed by further, mechanistic studies.
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- 2017
22. The alternative complement pathway is dysregulated in patients with chronic heart failure
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Thor Ueland, Arne Yndestad, Per H. Nilsson, Mieke C. Louwe, Pål Aukrust, Kaspar Broch, Christen P. Dahl, Lars Gullestad, Negar Shahini, Tom Eirik Mollnes, Annika E. Michelsen, and Karin Ekholt
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0301 basic medicine ,Cardiac function curve ,Male ,Immunology ,Complement Pathway, Alternative ,Comorbidity ,030204 cardiovascular system & hematology ,Systemic inflammation ,Article ,03 medical and health sciences ,0302 clinical medicine ,Complement Factor D ,Medicine ,Humans ,Molecular Biology ,VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Kardiologi: 771 ,VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Cardiology: 771 ,Aged ,Heart Failure ,Multidisciplinary ,biology ,Properdin ,business.industry ,Chronic inflammation ,Complement System Proteins ,Middle Aged ,medicine.disease ,Prognosis ,Complement system ,030104 developmental biology ,Heart failure ,Case-Control Studies ,Complement Factor H ,Chronic Disease ,Heart Function Tests ,Alternative complement pathway ,biology.protein ,Factor D ,Female ,medicine.symptom ,business ,Biomarkers - Abstract
The complement system, an important arm of the innate immune system, is activated in heart failure (HF). We hypothesized that HF patients are characterized by an imbalance of alternative amplification loop components; including properdin and complement factor D and the alternative pathway inhibitor factor H. These components and the activation product, terminal complement complex (TCC), were measured in plasma from 188 HF patients and 67 age- and sex- matched healthy controls by enzyme immunoassay. Our main findings were: (i) Compared to controls, patients with HF had significantly increased levels of factor D and TCC, and decreased levels of properdin, particularly patients with advanced clinical disorder (i.e., NYHA functional class IV), (ii) Levels of factor D and properdin in HF patients were correlated with measures of systemic inflammation (i.e., C-reactive protein), neurohormonal deterioration (i.e., Nt-proBNP), cardiac function, and deteriorated diastolic function, (iii) Low levels of factor H and properdin were associated with adverse outcome in univariate analysis and for factor H, this was also seen in an adjusted model. Our results indicate that dysregulation of circulating components of the alternative pathway explain the increased degree of complement activation and is related to disease severity in HF patients. © 2017 The Authors. Published by Nature Publishing Group. This is an open access article licensed under a Creative Commons Attribution 4.0 International License
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- 2017
23. The Notch Ligands DLL1 and Periostin Are Associated with Symptom Severity and Diastolic Function in Dilated Cardiomyopathy
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Pål Aukrust, Svend Aakhus, Hilde M. Norum, Ida G. Lunde, Geir Christensen, Annika E. Michelsen, Thor Ueland, Arnt E. Fiane, Kaspar Broch, Aurelija Abraityte, Christen P. Dahl, Lars Gullestad, Tove Lekva, and Arne K. Andreassen
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0301 basic medicine ,Cardiac function curve ,Adult ,Cardiomyopathy, Dilated ,Male ,medicine.medical_specialty ,Diastole ,Notch signaling pathway ,Pharmaceutical Science ,030204 cardiovascular system & hematology ,Periostin ,Biology ,Severity of Illness Index ,Ventricular Function, Left ,03 medical and health sciences ,Ventricular Dysfunction, Left ,0302 clinical medicine ,Downregulation and upregulation ,Internal medicine ,Genetics ,medicine ,Humans ,cardiovascular diseases ,Genetics (clinical) ,Aged ,Cell adhesion molecule ,Calcium-Binding Proteins ,Membrane Proteins ,Dilated cardiomyopathy ,Middle Aged ,medicine.disease ,Up-Regulation ,030104 developmental biology ,DLK1 ,Case-Control Studies ,cardiovascular system ,Cardiology ,Molecular Medicine ,Intercellular Signaling Peptides and Proteins ,Female ,Cardiology and Cardiovascular Medicine ,Cell Adhesion Molecules ,Biomarkers - Abstract
In dilated cardiomyopathy (DCM), adverse myocardial remodeling is essential, potentially involving Notch signaling. We hypothesized that secreted Notch ligands would be dysregulated in DCM. We measured plasma levels of the canonical Delta-like Notch ligand 1 (DLL1) and non-canonical Notch ligands Delta-like 1 homologue (DLK1) and periostin (POSN) in 102 DCM patients and 32 matched controls. Myocardial mRNA and protein levels of DLL1, DLK1, and POSN were measured in 25 explanted hearts. Our main findings were: (i) Circulating levels of DLL1 and POSN were higher in patients with severe DCM and correlated with the degree of diastolic dysfunction and (ii) right ventricular tissue expressions of DLL1, DLK1, and POSN were oppositely associated with cardiac function indices, as high DLL1 and DLK1 expression corresponded to more preserved and high POSN expression to more deteriorated cardiac function. DLL1, DLK1, and POSN are dysregulated in end-stage DCM, possibly mediating different effects on cardiac function.
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- 2017
24. Wnt5a is associated with right ventricular dysfunction and adverse outcome in dilated cardiomyopathy
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Kaspar Broch, Svend Aakhus, Arnt E. Fiane, Arne Yndestad, Christen P. Dahl, Lars Gullestad, Annika E. Michelsen, Arne K. Andreassen, Erik T. Askevold, Pål Aukrust, Ida G. Lunde, Geir Christensen, Thor Ueland, and Aurelija Abraityte
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Male ,0301 basic medicine ,Ventricular Dysfunction, Right ,Cardiomyopathy ,Muscle Proteins ,Kaplan-Meier Estimate ,Mice ,Adverse Outcome Pathway ,VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Kardiologi: 771 ,Multidisciplinary ,Wnt signaling pathway ,Dilated cardiomyopathy ,NFAT ,Middle Aged ,Cardiac hypertrophy ,medicine.anatomical_structure ,embryonic structures ,Cardiology ,cardiovascular system ,Medicine ,Female ,Cardiomyopathies ,Signal Transduction ,Cardiomyopathy, Dilated ,medicine.medical_specialty ,Science ,Article ,Wnt-5a Protein ,03 medical and health sciences ,Internal medicine ,medicine.artery ,medicine ,Animals ,Humans ,cardiovascular diseases ,Adaptor Proteins, Signal Transducing ,VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Cardiology: 771 ,Adverse Outcome Pathways ,NFATC Transcription Factors ,business.industry ,medicine.disease ,body regions ,030104 developmental biology ,Endocrinology ,Ventricle ,Pulmonary artery ,sense organs ,business - Abstract
The Wingless (Wnt) pathway has been implicated in the pathogenesis of dilated cardiomyopathy (DCM). To explore the role of Wnt modulators Wnt5a and sFRP3 in DCM patients we analyzed the expression of Wnt5a and sFRP3 in plasma and myocardium of DCM patients and evaluated their effects on NFAT luciferase activity in neonatal mouse cardiomyocytes. Elevated circulating Wnt5a (n = 102) was associated with increased pulmonary artery pressures, decreased right ventricular function and adverse outcome, with a stronger association in more severely affected patients. A higher Wnt5a/sFRP3 ratio (n = 25) was found in the right ventricle vs. the left ventricle and was correlated with NFAT activation as well as pulmonary artery pressures. Wnt5a induced NFAT activation and sFRP3 release in cardiomyocytes in vitro, while sFRP3 antagonized Wnt5a. Wnt5a is associated with right ventricular dysfunction and adverse outcome in DCM patients and may promote the progression of DCM through NFAT signaling. © The Author(s) 2017. Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
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- 2017
25. Thyroid and Glucocorticoid Hormones Promote Functional T-Tubule Development in Human-Induced Pluripotent Stem Cell–Derived CardiomyocytesNovelty and Significance
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Shan S. Parikh, Daniel J. Blackwell, Nieves Gomez-Hurtado, Michael Frisk, Lili Wang, Kyungsoo Kim, Christen P. Dahl, Arnt Fiane, Theis Tønnessen, Dmytro O. Kryshtal, William E. Louch, and Bjorn C. Knollmann
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- 2017
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26. Increased secondary/primary bile acid ratio in chronic heart failure
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Gemma F. Cross, Johannes R. Hov, Pål Aukrust, Lars Gullestad, Thor Ueland, Royce P Vincent, Marius Trøseid, Christiane Caroline Mayerhofer, Kaspar Broch, and Christen P. Dahl
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Adult ,0301 basic medicine ,medicine.medical_specialty ,medicine.drug_class ,education ,clinical outcome ,030204 cardiovascular system & hematology ,Gut flora ,Clinical Outcome ,Bile Acids and Salts ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,In patient ,Prospective Studies ,Gut Microbiota ,Bile Acids Profile ,Aged ,Heart Failure ,Univariate analysis ,biology ,Bile acid ,gut microbiota ,business.industry ,VDP::Medical disciplines: 700::Clinical medical disciplines: 750 ,VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750 ,Metabolism ,Plasma levels ,Middle Aged ,medicine.disease ,biology.organism_classification ,Chronic heart failure ,Gastrointestinal Microbiome ,Cross-Sectional Studies ,030104 developmental biology ,Endocrinology ,Heart failure ,Chronic Disease ,Bile acids profile ,Chronic Heart Failure ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers ,Homeostasis - Abstract
Accepted manuscript version. Published version available at https://doi.org/10.1016/j.cardfail.2017.06.007. Objective Bile acids (BAs) are now recognized as signaling molecules and emerging evidence suggests that BAs affect cardiovascular function. The gut microbiota has recently been linked to the severity of heart failure (HF), and microbial metabolism has a major impact on BA homeostasis. We aimed to investigate the pattern of BAs, and particularly microbiota-transformed (secondary) BAs, in patients with chronic HF. Methods and Results This was a prospective, observational, single-center study including 142 patients with chronic HF and 20 age- and sex-matched healthy control subjects. We measured plasma levels of primary, secondary, and total BAs, and explored their associations with clinical characteristics and survival. Plasma levels of primary BAs were lower (P Conclusions Levels of primary BAs were reduced and specific secondary BAs increased in patients with chronic HF. This pattern was associated with reduced overall survival in univariate analysis, but not in multivariate analyses. Future studies should assess the regulation and potential role of BA metabolism in HF.
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- 2017
27. Limited added value of circulating inflammatory biomarkers in chronic heart failure
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Ursula Wienhues-Thelen, Lars Gullestad, Kaspar Broch, Roberto Latini, Christen P. Dahl, John J.V. McMurray, Arne Yndestad, Thor Ueland, Pieter Muntendam, John G.F. Cleland, John Kjekshus, Erik T. Askevold, Pål Aukrust, John Wikstrand, Jørgen Gravning, Ståle H. Nymo, Royal Brompton & Harefield NHS Foundation Trust, and National Institute for Health Research
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Oncology ,Pathology ,Cardiac & Cardiovascular Systems ,STATIN THERAPY ,Galectin 3 ,heart failure ,030204 cardiovascular system & hematology ,0302 clinical medicine ,ROSUVASTATIN MULTINATIONAL TRIAL ,Cause of Death ,Natriuretic Peptide, Brain ,Natriuretic peptide ,Medicine ,030212 general & internal medicine ,Rosuvastatin Calcium ,Ejection fraction ,Troponin T ,PTX3 ,Blood Proteins ,Prognosis ,Endostatins ,Serum Amyloid P-Component ,C-Reactive Protein ,Galectin-3 ,Cardiovascular Diseases ,inflammation ,mortality ,Biomarker (medicine) ,Cardiology and Cardiovascular Medicine ,Life Sciences & Biomedicine ,medicine.drug ,CORONA TRIAL ,medicine.medical_specialty ,GISSI-HF TRIALS ,medicine.drug_class ,Galectins ,URIC-ACID ,survival ,03 medical and health sciences ,Internal medicine ,Humans ,Rosuvastatin ,Mortality ,CARDIOVASCULAR EVENTS ,SOLUBLE ST2 ,Proportional Hazards Models ,Inflammation ,Science & Technology ,Chemokine CCL21 ,NATRIURETIC PEPTIDE ,business.industry ,chronic ischemic heart disease ,Interleukin-8 ,biomarkers ,CORONA Study Group ,FATAL OUTCOMES ,PREDICTIVE-VALUE ,medicine.disease ,Interleukin-1 Receptor-Like 1 Protein ,Peptide Fragments ,Heart failure ,Chronic Disease ,Cardiovascular System & Cardiology ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,business - Abstract
Objectives: \ud \ud This study sought to evaluate whether a panel of biomarkers improved prognostication in patients with heart failure (HF) and reduced ejection fraction of ischemic origin using a systematized approach according to suggested requirements for validation of new biomarkers.\ud \ud Background: \ud \ud Modeling combinations of multiple circulating markers could potentially identify patients with HF at particularly high risk and aid in the selection of individualized therapy.\ud \ud Methods: \ud \ud From a panel of 20 inflammatory and extracellular matrix biomarkers, 2 different biomarker panels were created and added to the Seattle HF score and the prognostic model from the CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) study (n = 1,497), which included conventional clinical characteristics and C-reactive protein and N-terminal pro–B-type natriuretic peptide. Interactions with statin treatment were also assessed.\ud \ud Results: \ud \ud The two models—model 1 (endostatin, interleukin 8, soluble ST2, troponin T, galectin 3, and chemokine [C-C motif] ligand 21) and model 2 (troponin T, soluble ST2, galectin 3, pentraxin 3, and soluble tumor necrosis factor receptor 2)—significantly improved the CORONA and Seattle HF models but added only modestly to their Harrell’s C statistic and net reclassification index. In addition, rosuvastatin had no effect on the levels of a wide range of inflammatory and extracellular matrix markers, but there was a tendency for patients with a lower level of biomarkers in the 2 panels to have a positive effect from statin treatment.\ud \ud Conclusions: \ud \ud In the specific HF patient population studied, a multimarker approach using the particular panel of biomarkers measured was of limited clinical value for identifying future risk of adverse outcomes.
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- 2017
28. Familial globotriaosylceramide-associated cardiomyopathy mimicking Fabry disease
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Turid Apelland, Vibeke M. Almaas, Kristin Eiklid, Erik H. Strøm, Gunnar Houge, Christen P. Dahl, Einar Gude, Jan-Eric Månsson, Arvid Heiberg, Finn P. Reinholt, and Lars Gullestad
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Adult ,Male ,Heterozygote ,Pathology ,medicine.medical_specialty ,Globotriaosylceramide ,Cardiomyopathy ,Left ventricular hypertrophy ,Polymorphism, Single Nucleotide ,Risk Assessment ,Sampling Studies ,Diagnosis, Differential ,chemistry.chemical_compound ,medicine ,Humans ,Exome sequencing ,Heart Failure ,Kidney ,business.industry ,Trihexosylceramides ,Biopsy, Needle ,Middle Aged ,Prognosis ,medicine.disease ,Immunohistochemistry ,Fabry disease ,Pedigree ,Survival Rate ,Transplantation ,medicine.anatomical_structure ,chemistry ,Heart failure ,Disease Progression ,Fabry Disease ,Female ,Hypertrophy, Left Ventricular ,Cardiomyopathies ,Cardiology and Cardiovascular Medicine ,business - Abstract
Objective To characterise a globotriaosylceramide (Gb3) storage cardiomyopathy mimicking Fabry. Methods We investigated five patients from two unrelated families with early adult onset unexplained left ventricular hypertrophy. Endomyocardial biopsy was performed in all patients and diagnostic kidney biopsies in two of them. We measured α-galactosidase A activity in all patients. Three patients were checked for LAMP1 or LAMP2 deficiency and screened for congenital disorders of glycosylation. Gb3 concentration was quantified in plasma, urinary sediment and cardiac muscle. We sequenced the Fabry and Danon genes and looked for other genetic causes by single-nucleotide polymorphism array haplotyping and whole exome sequencing. Results Three patients had a striking fat distribution around the buttocks and upper thighs. All patients developed bradyarrhythmias and needed pacemakers. Cardiac transplantation was performed in three patients due to end-stage heart failure, one patient died before transplantation. The cardiomyocytes contained lysosomal vacuoles with lamellar myelin-like deposits. Interstitial cells had vacuoles containing granular material. Deposits were found in the kidneys without renal dysfunction. The histological pattern was atypical for Fabry disease. Biochemical studies revealed normal activity of α-galactosidase A and other relevant enzymes. There was a selective accumulation of Gb3 in cardiomyocytes, at levels found in patients with Fabry disease, but no mutations in the Fabry gene, and Fabry disease was excluded. Other known lysosomal storage diseases were also excluded. Single-nucleotide polymorphism array haplotyping and whole exome sequencing could not identify the genetic cause. Conclusions We describe a novel familial Gb3-assoociated cardiomyopathy. Autosomal recessive inheritance is likely, but the genetic and metabolic cause remains to be identified.
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- 2014
29. Expression of bone morphogenetic protein 4 and its receptors in the remodeling heart
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Xueping Wu, Arkady Rutkovskiy, Lars Gullestad, Christen P. Dahl, Julia Sagave, Ståle Nygård, Jarle Vaage, Guro Valen, Fred Haugen, Anton Baysa, and Gabor Czibik
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Adult ,Cardiomyopathy, Dilated ,Male ,Cardiac function curve ,medicine.medical_specialty ,Time Factors ,Myocardial Infarction ,Myocardial Ischemia ,Down-Regulation ,Bone Morphogenetic Protein 4 ,Coronary Artery Disease ,Bone Morphogenetic Protein Receptors, Type II ,Bone morphogenetic protein ,General Biochemistry, Genetics and Molecular Biology ,Coronary artery disease ,Mice ,Young Adult ,Internal medicine ,Animals ,Humans ,Medicine ,Myocytes, Cardiac ,RNA, Messenger ,Myocardial infarction ,General Pharmacology, Toxicology and Pharmaceutics ,Ventricular remodeling ,Bone Morphogenetic Protein Receptors, Type I ,Aged ,Heart Failure ,Ventricular Remodeling ,business.industry ,Dilated cardiomyopathy ,General Medicine ,Middle Aged ,medicine.disease ,BMPR2 ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,Heart failure ,Cardiology ,Female ,business - Abstract
Aims Heart failure is associated with activation of fetal gene programs. Bone morphogenetic proteins (BMPs) regulate embryonic development through interaction with BMP receptors (BMPRs) on the cell surface. We investigated if the expression of BMP4 and its receptors BMPR1a and BMPR2 were activated in post-infarction remodeling and heart failure. Main methods Left ventricular biopsies were taken from explanted hearts of patients with end-stage heart failure due to dilated cardiomyopathy (CMP; n = 15) or ischemic heart disease (CAD; n = 9), and compared with homograft control preparations from organ donors deceased due to non-cardiac causes (n = 7). Other samples were taken from patients undergoing coronary artery bypass grafting (CABG; n = 11). Mice were subjected to induced infarction by permanent coronary artery ligation or sham operation, and hearts were sampled serially thereafter (n = 7 at each time point). Key findings Human and mouse hearts expressed BMP4 and both receptor subtypes. CABG and CMP patients had increased expression of mRNA encoding for BMP4, but unchanged protein. Mouse hearts had increased BMP4 precursor protein 24 h after infarction. BMPR1a protein decreased in CAD patients and initially in postinfarcted mouse hearts, but increased again in the latter after two weeks. Human recombinant BMP4 promoted survival after H 2 O 2 injury in HL-1 cells, and also protected adult mouse cardiomyocytes against hypoxia–reoxygenation injury. Significance Adult hearts express BMP4, the mRNA increasingly so in patients with coronary artery disease with good cardiac function. BMPRs are downregulated in cardiac remodeling and failure. Recombinant BMP4 has protective effects on cultured cardiomyocytes.
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- 2014
30. Noninvasive assessment of myocardial fibrosis in patients with obstructive hypertrophic cardiomyopathy
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Svend Aakhus, Jan P. Amlie, Vibeke M. Almaas, Helge Scott, Erik H. Strøm, Christen P. Dahl, Knut Endresen, Hans-Jørgen Smith, Odd Geiran, Kristina H. Haugaa, and Thor Edvardsen
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Gadolinium DTPA ,Male ,medicine.medical_specialty ,Longitudinal strain ,Contrast Media ,Magnetic Resonance Imaging, Cine ,Interstitial fibrosis ,Predictive Value of Tests ,Risk Factors ,Fibrosis ,Internal medicine ,medicine ,Humans ,In patient ,cardiovascular diseases ,Aged ,business.industry ,Myocardium ,Hypertrophic cardiomyopathy ,Arrhythmias, Cardiac ,Cardiomyopathy, Hypertrophic ,Middle Aged ,medicine.disease ,Myocardial Contraction ,Echocardiography, Doppler ,Septal myectomy ,Cross-Sectional Studies ,Cardiology ,Female ,Myocardial fibrosis ,Obstructive hypertrophic cardiomyopathy ,Cardiology and Cardiovascular Medicine ,business - Abstract
ObjectiveLate gadolinium enhancement cardiac magnetic resonance (LGE-CMR) imaging is the reference standard for non-invasive assessment of fibrosis. In hypertrophic cardiomyopathy (HCM) patients the histological substrate for LGE is still unknown. The aim of this study was to assess the ability of LGE and strain echocardiography to detect type and extent of myocardial fibrosis in obstructive HCM patients undergoing septal myectomy.MethodsThirty-two HCM patients (age 60±10) were included in this cross-sectional study and preoperatively examined by speckle-tracking strain echocardiography and LGE-CMR (n=21). Histological fibrosis was classified as interstitial, replacement and total.ResultsHistological fibrosis was present in 31 patients. The percentage of total, interstitial and replacement fibrosis was 15(7, 31)%, 11(5, 24)% and 3(1, 6)%, respectively. Reduced longitudinal septal strain correlated with total (r=0.50, p=0.01) and interstitial (r=0.40, p=0.03), but not with replacement fibrosis (r=0.28, p=0.14). Septal LGE was detected in 13/21 (62%), but percentage LGE did not correlate with total fibrosis (r=0.25, p=0.28). Extent of fibrosis did not differ between patients with and without septal LGE (20(9, 58)% versus 14(5, 19)% p=0.41). Patients with ventricular arrhythmias (n=8) had lower septal longitudinal strain and increased extent total and interstitial fibrosis in myectomy specimens, but no differences were demonstrated in LGE. Reduced longitudinal septal strain and increased extent of interstitial fibrosis predicted ventricular arrhythmias independently of age and gender.ConclusionsIn myectomised HCM patients, reduced longitudinal septal strain correlated better with interstitial and total fibrosis in myectomy specimens, and was a more powerful tool to predict arrhythmias than LGE.
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- 2013
31. Disturbed carnitine regulation in chronic heart failure — Increased plasma levels of palmitoyl-carnitine are associated with poor prognosis
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Rolf K. Berge, Thor Ueland, Erik T. Askevold, Lars Gullestad, Bodil Bjørndal, Asbjørn Svardal, Ståle H. Nymoen, Christen P. Dahl, Pål Aukrust, and Erik Øie
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Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Inflammation ,Mitochondrion ,Pathogenesis ,chemistry.chemical_compound ,Carnitine ,Internal medicine ,medicine ,Humans ,Adverse effect ,Palmitoylcarnitine ,Aged ,Heart Failure ,Heart transplantation ,business.industry ,Middle Aged ,Prognosis ,medicine.disease ,Endocrinology ,chemistry ,Heart failure ,Chronic Disease ,Disease Progression ,Female ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers ,medicine.drug - Abstract
Background/objectives Heart failure is characterized by disturbed energy metabolism and impaired mitochondrial function. L-carnitine plays a critical role in fatty acid transport into the mitochondria and may thus influence inflammation and myocardial function. The aim of this study was to investigate carnitine metabolism in relation to progression of heart failure (HF). Methods and results We examined plasma levels of free L-carnitine as well as several of its precursors and derivates in HF patients (n=183) and matched healthy controls (n=111) as well as their relationship with cardiac dysfunction as assessed by echocardiographic measurements, inflammation (CRP) and neurohormonal activation (NT-proBNP) in addition to the prognostic value of carnitine derivates in relation to mortality in these patients. High levels of the carnitine derivates acetyl-carnitine and in particular palmitoyl-carnitine were associated with the degree of HF as evaluated by clinical (NYHA functional class) and neurohormonal assessments. Moreover, plasma levels of palmitoyl-carnitine were associated with serious adverse events (i.e., all-cause mortality and heart transplantation) during follow-up, independently of more established risk markers such as CRP and NT-proBNP, when analyzed by cox-regression and continous net reclassification improvement, but not c-statistics. Conclusions Our findings support a role for disturbed carnitine metabolism in the pathogenesis of HF, and suggest that some of its derivates could give prognostic information in these patients.
- Published
- 2013
32. Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan-4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure-overloaded heart
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Geir Christensen, Almira Hasic, Ivar Sjaastad, Maria Vistnes, Ida G. Lunde, Lars Gullestad, Biljana Skrbic, Kate M. Herum, Theis Tønnessen, Zaheer A. Rana, Heidi Kvaløy, Erik T. Askevold, Cathrine R. Carlson, Mari E. Strand, and Christen P. Dahl
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Lipopolysaccharides ,Male ,T-Lymphocytes ,Interleukin-1beta ,Focal adhesion assembly ,Biochemistry ,Syndecan 1 ,Mice ,chemistry.chemical_compound ,Myocytes, Cardiac ,Mice, Knockout ,Ventricular Remodeling ,NF-kappa B ,Heparan sulfate ,Middle Aged ,Extracellular Matrix ,Cell biology ,Benzamides ,Female ,Tumor necrosis factor alpha ,Adult ,animal structures ,Primary Cell Culture ,Biology ,Proinflammatory cytokine ,Cell Adhesion ,medicine ,Animals ,Humans ,RNA, Messenger ,Rats, Wistar ,Ventricular remodeling ,Molecular Biology ,Heart Failure ,Inflammation ,Pressure overload ,Focal Adhesions ,Tumor Necrosis Factor-alpha ,Myocardium ,Cell Biology ,Fibroblasts ,medicine.disease ,Immunity, Innate ,Rats ,Mice, Inbred C57BL ,Toll-Like Receptor 4 ,carbohydrates (lipids) ,Thiazoles ,HEK293 Cells ,Animals, Newborn ,chemistry ,Heart failure ,Immunology ,Syndecan-4 - Abstract
Sustained pressure overload induces heart failure, the main cause of mortality in the Western world. Increased understanding of the underlying molecular mechanisms is essential to improve heart failure treatment. Despite important functions in other tissues, cardiac proteoglycans have received little attention. Syndecan-4, a transmembrane heparan sulfate proteoglycan, is essential for pathological remodeling, and we here investigated its expression and shedding during heart failure. Pressure overload induced by aortic banding for 24 h and 1 week in mice increased syndecan-4 mRNA, which correlated with mRNA of inflammatory cytokines. In cardiac myocytes and fibroblasts, tumor necrosis factor-α, interleukin-1β and lipopolysaccharide through the toll-like receptor-4, induced syndecan-4 mRNA. Bioinformatical and mutational analyses in HEK293 cells identified a functional site for the proinflammatory nuclear factor-κB transcription factor in the syndecan-4 promoter, and nuclear factor-κB regulated syndecan-4 mRNA in cardiac cells. Interestingly, tumor necrosis factor-α, interleukin-1β and lipopolysaccharide induced nuclear factor-κB-dependent shedding of the syndecan-4 ectodomain from cardiac cells. Overexpression of syndecan-4 with mutated enzyme-interacting domains suggested enzyme-dependent heparan sulfate chains to regulate shedding. In cardiac fibroblasts, lipopolysaccharide reduced focal adhesion assembly, shown by immunohistochemistry, suggesting that inflammation-induced shedding affects function. After aortic banding, a time-dependent cardiac recruitment of T lymphocytes was observed by measuring CD3, CD4 and CD8 mRNA, which was reduced in syndecan-4 knockout hearts. Finally, syndecan-4 mRNA and shedding were upregulated in failing human hearts. Conclusively, our data suggest that syndecan-4 plays an important role in the immune response of the heart to increased pressure, influencing cardiac remodeling and failure progression.
- Published
- 2013
33. Increased amount of interstitial fibrosis predicts ventricular arrhythmias, and is associated with reduced myocardial septal function in patients with obstructive hypertrophic cardiomyopathy
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Svend Aakhus, Vibeke M. Almaas, Knut Endresen, Helge Scott, Erik H. Strøm, Jan P. Amlie, Kristina H. Haugaa, Thor Edvardsen, Odd Geiran, Christen P. Dahl, and Trond P. Leren
- Subjects
Adult ,Male ,medicine.medical_specialty ,Population ,Speckle tracking echocardiography ,Ventricular tachycardia ,Sensitivity and Specificity ,Septal Ablation ,Fibrosis ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,cardiovascular diseases ,education ,education.field_of_study ,business.industry ,Hypertrophic cardiomyopathy ,Reproducibility of Results ,Cardiomyopathy, Hypertrophic ,Middle Aged ,Endomyocardial Fibrosis ,medicine.disease ,Septal myectomy ,Echocardiography ,Ventricular Fibrillation ,cardiovascular system ,Cardiology ,Elasticity Imaging Techniques ,Female ,Myocardial fibrosis ,Cardiology and Cardiovascular Medicine ,business - Abstract
Aims Reduced echocardiographic strain is associated with ventricular arrhythmias in hypertrophic cardiomyopathy (HCM) patients. The aim of this cross-sectional study was to investigate which type of histological fibrosis contributes to ventricular arrhythmias and reduced septal longitudinal strain, in obstructive HCM-patients with or without additional coronary artery disease (CAD) and/or hypertension (HT). Methods and results Sixty-three HCM-patients (mean age 57 ± 13 years) were included. Strain by speckle tracking echocardiography was performed prior to either percutaneous transluminal septal ablation ( n = 37) or septal myectomy ( n = 26). In 24 patients myectomy specimens were available (histology population) and allowed determination of %area of interstitial and replacement fibrosis. Twenty-nine (46%) patients had concomitant CAD and/or HT, and 15 (24%) experienced ventricular arrhythmias defined as documented ventricular tachycardia or arrhythmogenic suspected syncope. The patients with ventricular arrhythmias had lower septal longitudinal strain compared with those without arrhythmias (−9.0 ± 4.0 vs. −13.6 ± 5.6%, P = 0.006). In the histology population reduced septal longitudinal strain correlated to interstitial ( R 2 = 0.36 P = 0.003), but not to replacement fibrosis ( R 2 = 0.03 P = 0.43). By logistic regression analyses, interstitial fibrosis predicted ventricular arrhythmias (OR 1.16, 95% CI 1.02–1.32, P = 0.03), while replacement fibrosis did not (OR 1.22, 95% CI 0.93–1.59, P = 0.15). Conclusion Total amount of fibrosis was a marker of ventricular arrhythmias in obstructive HCM-patients. Interstitial fibrosis seemed to be more important compared with replacement fibrosis in arrhythmogenesis, and was related to reduced septal myocardial function. These findings suggest that interstitial fibrosis may play an important role as the arrhythmogenic substrate, and that strain echocardiography can help detection of patients at risk.
- Published
- 2013
34. Tetradecylthioacetic Acid Increases Fat Metabolism and Improves Cardiac Function in Experimental Heart Failure
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Christen P. Dahl, Jan Otto Beitnes, Erik Øie, Pavol Bohov, Arne Yndestad, Pål Aukrust, Thor Edvardsen, Thor Ueland, and Rolf K. Berge
- Subjects
Male ,medicine.medical_specialty ,Clinical chemistry ,Myocardial Infarction ,Sulfides ,030204 cardiovascular system & hematology ,Biology ,Biochemistry ,Antioxidants ,Fats ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Fatty Acids, Omega-6 ,Internal medicine ,Fatty Acids, Omega-3 ,medicine ,Animals ,Myocardial infarction ,Rats, Wistar ,030304 developmental biology ,Heart Failure ,2. Zero hunger ,chemistry.chemical_classification ,0303 health sciences ,Cholesterol ,Myocardium ,Organic Chemistry ,Hemodynamics ,Fatty acid ,Tetradecylthioacetic acid ,Heart ,Cell Biology ,Lipid Metabolism ,medicine.disease ,Lipids ,Rats ,3. Good health ,Endocrinology ,chemistry ,Heart failure ,Myocardial infarction complications ,lipids (amino acids, peptides, and proteins) ,sense organs ,Oxidation-Reduction ,Polyunsaturated fatty acid - Abstract
Changes in myocardial metabolism, including a shift from fatty acid to glucose utilization and changes in fatty acid availability and composition are characteristics of heart failure development. Tetradecylthioacetic acid (TTA) is a fatty acid analogue lacking the ability to undergo mitochondrial β-oxidation. TTA promotes hepatic proliferation of mitochondria and peroxisomes and also decreases serum triglycerides and cholesterol in animals. We investigated the effect of TTA, in combination with a high-fat or regular diet, in a rat model of post-myocardial infarction heart failure. TTA had a beneficial effect on cardiac function in post-myocardial infarction heart failure without affecting myocardial remodeling. These effects of TTA on myocardial function were accompanied by decreased free fatty acids in plasma, increased myocardial proportion of n-3 polyunsaturated fatty acids (PUFA) and a decreased proportion of n-6 PUFA. Myocardial enzyme gene expression during TTA treatment suggested that the increase in n-3 PUFA could reflect increased n-3 PUFA synthesis and inadequately increased n-3 PUFA β-oxidation. Based on our data, it is unlikely that the changes are secondary to alterations in other tissues as plasma and liver showed an opposite pattern with decreased n-3 PUFA during TTA treatment. The present study suggests that TTA may improve myocardial function in heart failure, potentially involving its ability to decrease the availability of FFA and increase the myocardial proportion of n-3 PUFA.
- Published
- 2013
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35. A Cross-Sectional Study of the Prevalence of Gastrointestinal Symptoms and Pathology in Patients With Common Variable Immunodeficiency
- Author
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Silje F. Jørgensen, Anne-Marte Bakken Kran, Vemund Paulsen, Liv T. N. Osnes, Kristin Kaasen Jørgensen, Knut E.A. Lundin, Hans-Richard Brattbakk, Annika E. Michelsen, Torunn Fiskerstrand, Ellen Holter, Henrik M. Reims, Jorunn Bratlie, Tor J. Eide, Christen P. Dahl, Pål Aukrust, Kristian Holm, Børre Fevang, Kurt Hanevik, Thor Ueland, Rune Rose Tronstad, Fatemeh Kaveh, Didrik Frydenlund, and Tom H. Karlsen
- Subjects
0301 basic medicine ,Male ,Abdominal pain ,Pathology ,Esophageal Mucosa ,Cross-sectional study ,Gastrointestinal Diseases ,Colonoscopy ,0302 clinical medicine ,Intestinal mucosa ,Prevalence ,Endoscopy, Digestive System ,Lymphocytes ,Young adult ,Intestinal Mucosa ,Aged, 80 and over ,Gastrointestinal tract ,B-Lymphocytes ,medicine.diagnostic_test ,Gastroenterology ,Middle Aged ,Diarrhea ,030211 gastroenterology & hepatology ,Female ,medicine.symptom ,Adult ,medicine.medical_specialty ,Duodenum ,Plasma Cells ,03 medical and health sciences ,Young Adult ,medicine ,Humans ,Aged ,Hepatology ,business.industry ,Common variable immunodeficiency ,medicine.disease ,Abdominal Pain ,Gastrointestinal Tract ,Celiac Disease ,030104 developmental biology ,Common Variable Immunodeficiency ,Cross-Sectional Studies ,Gastric Mucosa ,business ,Transcriptome ,Constipation - Abstract
The objective of this study was to study the prevalence of gastrointestinal (GI) symptoms and histopathology in patients with common variable immunodeficiency (CVID) as well as linking the findings to GI infections and markers of systemic immune activation.In this cross-sectional study, we addressed GI symptoms in 103 patients and GI histopathological findings in 53 patients who underwent upper and lower endoscopic examination. The most frequent histopathological findings were linked to GI symptoms, B-cell phenotype, and markers of systemic immune activation (soluble (s)CD14, sCD25, and sCD163). Microarray analysis compared "celiac-like disease" in CVID to celiac disease. Screening for selected bacterial and viral infections in fecal samples and gut mucosal biopsies was performed.The main findings of this study were as follows: most common GI symptoms were bloating (34%), pain (30%), and diarrhea (26%). The most frequent histopathological findings were increased intraepithelial lymphocytes in the descending part of the duodenum, i.e., "celiac-like disease" (46% of patients), decreased numbers of plasma cells in GI tract mucosa (62%), and lymphoid hyperplasia (38%), none of which were associated with GI symptoms. Reduced plasma cells in GI mucosa were associated with B-cell phenotypic characteristics of CVID, and increased serum levels of sCD14 (P=0.025), sCD25 (P=0.01), and sCD163 (P=0.04). Microarray analyses distinguished between CVID patients with "celiac-like disease" and celiac disease. Positive tests for bacterial and viral infections were scarce both in fecal samples and gut mucosal biopsies, including PCR test for norovirus in biopsy specimens (0 positive tests).In conclusion, GI pathology is common in CVID, but does not necessarily cause symptoms. However, reduced plasma cells in GI mucosa were linked to systemic immune activation, "celiac-like disease" in CVID and true celiac disease appear to be different disease entities, as assessed by gene expression, and infections (including norovirus) are rarely a cause of the CVID enteropathy.
- Published
- 2016
36. The Heparan Sulfate Proteoglycan Glypican-6 Is Upregulated in the Failing Heart, and Regulates Cardiomyocyte Growth through ERK1/2 Signaling
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Geir Christensen, Ida G. Lunde, Biljana Skrbic, Mari E. Strand, Arnt E. Fiane, Jorge Filmus, Andreas Romaine, Kate M. Herum, Ivar Sjaastad, Christen P. Dahl, and Arne Olav Melleby
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Cell signaling ,Glypican ,Glycobiology ,lcsh:Medicine ,Protein Synthesis ,030204 cardiovascular system & hematology ,Signal transduction ,Biochemistry ,Muscle hypertrophy ,Mice ,0302 clinical medicine ,Animal Cells ,Medicine and Health Sciences ,Myocyte ,Myocytes, Cardiac ,lcsh:Science ,Connective Tissue Cells ,Multidisciplinary ,Ejection fraction ,Sulfates ,Signaling cascades ,Chemical Synthesis ,Heart ,Up-Regulation ,Chemistry ,Connective Tissue ,Physical Sciences ,Proteoglycans ,Cellular Types ,Anatomy ,Research Article ,medicine.medical_specialty ,MAPK signaling cascades ,Biosynthetic Techniques ,MAP Kinase Signaling System ,Immunoblotting ,Cardiology ,Molecular Probe Techniques ,Biology ,Research and Analysis Methods ,03 medical and health sciences ,Downregulation and upregulation ,Glypicans ,Internal medicine ,medicine ,Animals ,Humans ,Rats, Wistar ,Molecular Biology Techniques ,Molecular Biology ,Pressure overload ,Heart Failure ,lcsh:R ,Chemical Compounds ,Biology and Life Sciences ,Proteins ,Cell Biology ,Fibroblasts ,medicine.disease ,Rats ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,Biological Tissue ,HEK293 Cells ,Heart failure ,Cardiovascular Anatomy ,NIH 3T3 Cells ,Salts ,lcsh:Q - Abstract
Pressure overload is a frequent cause of heart failure. Heart failure affects millions of patients worldwide and is a major cause of morbidity and mortality. Cell surface proteoglycans are emerging as molecular players in cardiac remodeling, and increased knowledge about their regulation and function is needed for improved understanding of cardiac pathogenesis. Here we investigated glypicans (GPC1-6), a family of evolutionary conserved heparan sulfate proteoglycans anchored to the extracellular leaflet of the cell membrane, in experimental and clinical heart failure, and explored the function of glypican-6 in cardiac cells in vitro. In mice subjected to pressure overload by aortic banding (AB), we observed elevated glypican-6 levels during hypertrophic remodeling and dilated, end-stage heart failure. Consistently, glypican-6 mRNA was elevated in left ventricular myocardium from explanted hearts of patients with end-stage, dilated heart failure with reduced ejection fraction. Glypican-6 levels correlated negatively with left ventricular ejection fraction in patients, and positively with lung weight after AB in mice. Glypican-6 mRNA was expressed in both cardiac fibroblasts and cardiomyocytes, and the corresponding protein displayed different sizes in the two cell types due to tissue-specific glycanation. Importantly, adenoviral overexpression of glypican-6 in cultured cardiomyocytes increased protein synthesis and induced mRNA levels of the pro-hypertrophic signature gene ACTA1 and the hypertrophy and heart failure signature genes encoding natriuretic peptides, NPPA and NPPB. Overexpression of GPC6 induced ERK1/2 phosphorylation, and co-treatment with the ERK inhibitor U0126 attenuated the GPC6-induced increase in NPPA, NPPB and protein synthesis. In conclusion, our data suggests that glypican-6 plays a role in clinical and experimental heart failure progression by regulating cardiomyocyte growth through ERK signaling.
- Published
- 2016
37. Circulating levels of non-phosphorylated undercarboxylated matrix Gla protein are associated with disease severity in patients with chronic heart failure
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Thor Ueland, Rita Skårdal, Svend Aakhus, Pål Aukrust, Leon J. Schurgers, Lars Gullestad, Kaspar Broch, Cees Vermeer, Christen P. Dahl, Biochemie, and RS: CARIM School for Cardiovascular Diseases
- Subjects
Adult ,Male ,medicine.medical_specialty ,medicine.drug_class ,Diastole ,Inflammation ,Ventricular Function, Left ,calcification ,left ventricular function ,Calcinosis ,Internal medicine ,Matrix gla protein ,medicine ,Natriuretic peptide ,Humans ,Phosphorylation ,Aged ,Heart Failure ,Extracellular Matrix Proteins ,biology ,business.industry ,Calcium-Binding Proteins ,nutritional and metabolic diseases ,matrix gamma-carboxylated glutamate protein (MGP) ,General Medicine ,Middle Aged ,medicine.disease ,chronic heart failure ,Endocrinology ,Echocardiography ,Heart failure ,Chronic Disease ,Disease Progression ,biology.protein ,Cardiology ,Etiology ,Regression Analysis ,all-cause mortality ,Female ,medicine.symptom ,business ,Calcification - Abstract
We recently demonstrated that circulating MGP [matrix Gla (γ-carboxylated glutamate) protein] levels were associated with left ventricular dysfunction and increased mortality in patients with symptomatic aortic stenosis. We hypothesized that patients with chronic HF (heart failure) would have dysregulated MGP levels. We examined plasma dp-cMGP (non-phosphorylated carboxylated MGP) and dp-ucMGP (non-phosphorylated undercarboxylated MGP) in 179 patients with chronic HF and matched healthy controls as well as the relationship between MGP and cardiac dysfunction as assessed by echocardiographic measurements, inflammation [CRP (C-reactive protein)] and neurohormonal activation [NT-proBNP (N-terminal proB-type natriuretic peptide)] and the prognostic value of MGP levels in relation to mortality in these patients. We found markedly enhanced plasma dp-cMGP and, in particular, of dp-ucMGP in chronic HF with increasing levels with disease severity. Elevated MGP species were associated with ischaemic aetiology, increased CRP and NT-proBNP levels, as well as systolic and diastolic dysfunction. Finally, dp-ucMGP was associated with long-term heart transplant-free survival (n=48) in univariate, but not in multivariate, analysis. However, plasma dp-ucMGP was markedly higher in patients who died because of progression of HF (n=12) and gave prognostic information also in multivariate analysis. In conclusion, a dysregulated MGP system could be involved in left ventricular dysfunction in patients with chronic HF.
- Published
- 2011
38. Osteoprotegerin levels predict mortality in patients with symptomatic aortic stenosis
- Author
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Svend Aakhus, Theis Tønnessen, P. Aukrust, Christen P. Dahl, Ole Geir Solberg, Trygve Husebye, Thor Ueland, and Lars Gullestad
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musculoskeletal diseases ,Cardiac function curve ,medicine.medical_specialty ,Pathology ,business.industry ,medicine.drug_class ,medicine.disease ,Stenosis ,Osteoprotegerin ,Internal medicine ,Heart failure ,Predictive value of tests ,Internal Medicine ,medicine ,Cardiology ,Natriuretic peptide ,In patient ,business ,Calcification - Abstract
Objectives To examine the prognostic value of osteoprotegerin (OPG) levels in relation to all-cause mortality in patients with symptomatic severe aortic stenosis (AS). Design We measured plasma OPG levels in 136 patients with symptomatic severe AS and investigated associations with transvalvular gradients, valve area, valve calcification (using ultrasonic backscatter analysis as an estimate) and measures of heart failure. Then, we assessed the prognostic value of elevated plasma OPG in determining all-cause mortality (n = 29) in these patients. Results Elevated OPG was poorly correlated with the degree of AS but was associated with increased backscatter measurements and impaired cardiac function. Furthermore, OPG was associated with all-cause mortality in patients with symptomatic AS, even after adjustment for conventional risk markers. The strongest association was obtained by using a combination of high levels of both OPG and N-terminal pro-brain natriuretic peptide (NT-proBNP), suggesting that these markers may reflect distinct pathways in the development and progression of AS. Conclusion The level of circulating OPG is significantly associated with all-cause mortality alone and in combination with NT-proBNP in patients with severe symptomatic AS.
- Published
- 2011
39. Fatty acid composition in chronic heart failure: low circulating levels of eicosatetraenoic acid and high levels of vaccenic acid are associated with disease severity and mortality
- Author
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Arne Yndestad, P. Aukrust, Erik Øie, Lars Gullestad, Christen P. Dahl, Rolf K. Berge, Thor Ueland, C. Berge, and Pavol Bohov
- Subjects
Cardiac function curve ,medicine.medical_specialty ,education.field_of_study ,business.industry ,Eicosatetraenoic acid ,Population ,Vaccenic acid ,Inflammation ,Systemic inflammation ,medicine.disease ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Biochemistry ,Internal medicine ,Heart failure ,Internal Medicine ,medicine ,medicine.symptom ,education ,Energy source ,business - Abstract
Objectives Free fatty acids (FFAs) are the major energy sources of the heart, and fatty acids (FAs) are active components of biological membranes. Data indicate that levels of FAs and their composition may influence myocardial function and inflammation. The aim of this study was to investigate whether total levels and composition of FAs and FFAs in plasma are altered in clinical heart failure (HF) and whether any alterations in these parameters are correlated with the severity of HF. Subjects Plasma from 183 patients with stable HF was compared with plasma from 44 healthy control subjects. Results Our main findings are as follows: (i) patients with HF had decreased levels of several lipid parameters and increased levels of FFAs in plasma, compared with controls, which were significantly correlated with clinical disease severity. (ii) Patients with HF also had a decreased proportion in the plasma of several n-3 polyunsaturated FAs, an increased proportion of several monounsaturated FAs, and a decreased proportion of some readily oxidized long-chain saturated FAs. (iii) These changes in FA composition were significantly associated with functional class, impaired cardiac function (i.e., decreased cardiac index and increased plasma N-terminal pro-B-type natriuretic peptide levels) and enhanced systemic inflammation (i.e., increased high-sensitivity C-reactive protein levels). (iv) Low levels of C20:4n-3 (eicosatetraenoic acid) and in particular high levels of C18:1n-7 (vaccenic acid) were significantly associated with total mortality in this HF population. Conclusions Our data demonstrate that patients with HF are characterized by a certain FA phenotype and may support a link between disturbed FA composition and the progression of HF.
- Published
- 2011
40. Undercarboxylated matrix Gla protein is associated with indices of heart failure and mortality in symptomatic aortic stenosis
- Author
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Thor Ueland, Leon J. Schurgers, Svend Aakhus, Cees Vermeer, P. Aukrust, Christen P. Dahl, Ole Geir Solberg, Lars Gullestad, Biochemie, and RS: CARIM School for Cardiovascular Diseases
- Subjects
Cardiac function curve ,Male ,medicine.medical_specialty ,Calcification inhibitor ,heart failure ,Blood Pressure ,calcification ,Internal medicine ,medicine.artery ,Cause of Death ,Matrix gla protein ,Internal Medicine ,medicine ,Humans ,Aorta ,Aged ,Aged, 80 and over ,Extracellular Matrix Proteins ,biology ,business.industry ,matrix Gla protein ,Calcium-Binding Proteins ,nutritional and metabolic diseases ,Anticoagulants ,Calcinosis ,aortic stenosis ,Aortic Valve Stenosis ,Middle Aged ,medicine.disease ,Prognosis ,Stenosis ,Echocardiography ,Heart failure ,Aortic Valve ,Aortic pressure ,Cardiology ,biology.protein ,all-cause mortality ,Female ,Warfarin ,business ,Biomarkers ,Calcification - Abstract
Ueland T, Gullestad L, Dahl CP, Aukrust P, Aakhus S, Solberg OG, Vermeer C, Schurgers LJ (Research Institute for Internal Medicine, University of Oslo, Oslo; University of Oslo, Oslo, Norway; and VitaK & Cardiovascular Research Institute CARIM (CV, LS), Maastricht University, Maastricht, The Netherlands) Undercarboxylated matrix Gla protein is associated with indices of heart failure and mortality in symptomatic aortic stenosis. J Intern Med 2010; 268: 483–492. Objective. Matrix Gla protein (MGP) is a calcification inhibitor and alterations in circulating MGP have been observed in different populations characterized by vascular calcification. We hypothesized that patients with calcific valvular aortic stenosis (AS) would have dysregulated circulating MGP levels. Design and subjects. We examined plasma levels of nonphosphorylated carboxylated and undercarboxylated MGP (dp-cMGP and dp-ucMGP, respectively) in 147 patients with symptomatic severe AS and in matched healthy controls. Main outcome measures. We further investigated the relationship between MGP levels and aortic pressure gradients and valve area by echocardiography and measures of heart failure. Finally, we assessed the prognostic value of elevated plasma dp-ucMGP level in relation to all-cause mortality in patients with AS. Results. We found markedly enhanced plasma levels of dp-cMGP and in particular of dp-ucMGP in patients with symptomatic AS. Although only weak correlations were found with the degree of AS, circulating dp-ucMGP was associated with cardiac function and long-term mortality in multivariate analysis. Conclusions. A dysregulated MGP system may have a role in the development of left ventricular dysfunction in patients with symptomatic AS.
- Published
- 2010
41. T-Tubule Loss is a Prominent Feature of HFrEF but not HFpEF
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Michael Frisk, Christopher Le, Christen P. Dahl, Ida G. Lunde, Vibeke M. Almaas, Lars Gullestad, Svend Aakhus, Ole M. Sejersted, Theis Tønnessen, and William E. Louch
- Subjects
0301 basic medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Chemistry ,Feature (computer vision) ,Biophysics ,medicine ,030217 neurology & neurosurgery ,T-tubule ,Cell biology - Published
- 2018
42. Increased Production of CXCL16 in Experimental and Clinical Heart Failure
- Author
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Svend Aakhus, Arne Yndestad, Leif Erik Vinge, Jan Kristian Damås, Geir Christensen, Bente Halvorsen, Cathrine Husberg, Christen P. Dahl, Pål Aukrust, Anne Waehre, Lars Gullestad, Erik Øie, Alexandra Vanessa Finsen, Geir Florholmen, and Thor Ueland
- Subjects
Male ,Chemokine ,Chemokine CXCL6 ,Infarction ,Pathogenesis ,Extracellular matrix ,Mice ,Myocytes, Cardiac ,Cells, Cultured ,Receptors, Scavenger ,Ventricular Remodeling ,biology ,Middle Aged ,Extracellular Matrix ,Up-Regulation ,Matrix Metalloproteinase 9 ,Cardiology ,Matrix Metalloproteinase 2 ,Female ,Collagen ,Inflammation Mediators ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Chemokines, CXC ,Adult ,medicine.medical_specialty ,Proline ,Heart Ventricles ,Inflammation ,Internal medicine ,medicine ,Animals ,Humans ,RNA, Messenger ,Rats, Wistar ,Ventricular remodeling ,CXCL16 ,Aged ,Cell Proliferation ,Heart Failure ,business.industry ,JNK Mitogen-Activated Protein Kinases ,Chemokine CXCL16 ,Fibroblasts ,medicine.disease ,Rats ,Enzyme Activation ,Disease Models, Animal ,Animals, Newborn ,Heart failure ,Chronic Disease ,biology.protein ,business - Abstract
Background— Inflammation has been implicated in the pathogenesis of heart failure (HF), but knowledge about the production and role of inflammatory actors remains incomplete. On the basis of its role in vascular inflammation, vascular proliferation, and matrix degradation, we hypothesized a role for the chemokine CXCL16 in the pathogenesis of myocardial remodeling and development of HF. Methods and Results— Our main findings were (1) patients with chronic HF (n=188) had increased plasma levels of CXCL16, which correlated with disease severity. (2) Left ventricular tissue from patients with end-stage HF (n=8) showed enhanced CXCL16 levels compared with nonfailing left ventricular (n=6) as assessed by Western blotting. (3) In mice with postmyocardial infarction HF, expression of CXCL16, as assessed by real-time RT-PCR, was increased in the infarcted and the noninfarcted areas of left ventricular 3 and 7 days after coronary ligation, indicating early onset of CXCL16 production. Furthermore, mice exposed to aortic banding had enhanced CXCL16 expression in left ventricular, indicating that CXCL16 expression is not related to ischemia alone. (4) In vitro, CXCL16 promoted proliferation and impaired collagen synthesis in myocardial fibroblasts, and in cardiomyocytes and myocardial fibroblasts, CXCL16 increased matrix metalloproteinase activity, primarily reflecting increased matrix metalloproteinase-2 levels. (5) By using specific inhibitors, we showed that the effect of CXCL16 on fibroblasts involved activation of Jun N-terminal kinase. Conclusion— We show enhanced myocardial CXCL16 expression in experimental and clinical HF. The effect of CXCL16 on cardiomyocytes and fibroblasts suggests a role for CXCL16 in matrix remodeling and ultimately in the development of HF.
- Published
- 2009
43. 5-HT4 -elicited positive inotropic response is mediated by cAMP and regulated by PDE3 in failing rat and human cardiac ventricles
- Author
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Ivar Sjaastad, Kjetil Wessel Andressen, Finn Olav Levy, Christen P. Dahl, Jan-Bjørn Osnes, Tor Skomedal, Eirik Qvigstad, Halvor K. Mørk, F. Afzal, and Jan Magnus Aronsen
- Subjects
Pharmacology ,Inotrope ,medicine.medical_specialty ,Lusitropy ,business.industry ,Phosphodiesterase 3 ,Cardiac Ventricle ,medicine.disease ,Contractility ,medicine.anatomical_structure ,Endocrinology ,Ventricle ,Heart failure ,Internal medicine ,Circulatory system ,Medicine ,business - Abstract
Background and purpose: The left ventricle in failing hearts becomes sensitive to 5-HT parallelled by appearance of functional Gs-coupled 5-HT4 receptors. Here, we have explored the regulatory functions of phosphodiesterases in the 5-HT4 receptor-mediated functional effects in ventricular muscle from failing rat and human heart. Experimental approach: Extensive myocardial infarctions were induced by coronary artery ligation in Wistar rats. Contractility was measured in left ventricular papillary muscles of rat, 6 weeks after surgery and in left ventricular trabeculae from explanted human hearts. cAMP was quantified by RIA. Key results: In papillary muscles from postinfarction rat hearts, 5-HT4 stimulation exerted positive inotropic and lusitropic effects and increased cAMP. The inotropic effect was increased by non-selective PDE inhibition (IBMX, 10 μM) and selective inhibition of PDE3 (cilostamide, 1 μM), but not of PDE2 (EHNA, 10 μM) or PDE4 (rolipram, 10 μM). Combined PDE3 and PDE4 inhibition enhanced inotropic responses beyond the effect of PDE3 inhibition alone, increased the sensitivity to 5-HT, and also revealed an inotropic response in control (sham-operated) rat ventricle. Lusitropic effects were increased only during combined PDE inhibition. In failing human ventricle, the 5-HT4 receptor-mediated positive inotropic response was regulated by PDEs in a manner similar to that in postinfarction rat hearts. Conclusions and implications: 5-HT4 receptor-mediated positive inotropic responses in failing rat ventricle were cAMP-dependent. PDE3 was the main PDE regulating this response and involvement of PDE4 was disclosed by concomitant inhibition of PDE3 in both postinfarction rat and failing human hearts. 5-HT, PDE3 and PDE4 may have pathophysiological functions in heart failure. British Journal of Pharmacology (2008) 155, 1005–1014; doi:10.1038/bjp.2008.339; published online 1 September 2008
- Published
- 2008
44. Increased expression of LIGHT/TNFSF14 and its receptors in experimental and clinical heart failure☆
- Author
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Pål Aukrust, Børre Fevang, Erik Øie, Stig S. Frøland, Wiggo J. Sandberg, Are Martin Holm, Bente Halvorsen, Linn Landrø, Jan Kristian Damås, Kari Otterdal, Arne Yndestad, Leif Erik Vinge, Lars Gullestad, Arnt E. Fiane, and Christen P. Dahl
- Subjects
Adult ,Male ,Tumor Necrosis Factor Ligand Superfamily Member 14 ,medicine.medical_specialty ,CD3 Complex ,Endothelium ,Heart Ventricles ,T-Lymphocytes ,CD3 ,Myocardial Infarction ,Inflammation ,In Vitro Techniques ,Peripheral blood mononuclear cell ,Monocytes ,Immune system ,Lymphotoxin beta Receptor ,Internal medicine ,medicine ,Animals ,Humans ,Myocytes, Cardiac ,Rats, Wistar ,Receptor ,Aged ,Heart Failure ,biology ,Interleukin-6 ,business.industry ,Interleukin ,Middle Aged ,Rats ,Up-Regulation ,Disease Models, Animal ,medicine.anatomical_structure ,Endocrinology ,biology.protein ,Female ,Tumor necrosis factor alpha ,Endothelium, Vascular ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Receptors, Tumor Necrosis Factor, Member 14 ,Signal Transduction - Abstract
Background: Clinical and experimental studies suggest a pathogenic role for inflammation in chronic heart failure (HF). LIGHT is a member of the tumour necrosis factor superfamily involved in innate and adaptive immune responses. Aims: We sought to investigate a potential pathogenic role of LIGHT in chronic HF. Methods: We used various clinical and experimental approaches including studies in post-infarction HF rats and in vitro studies of endothelial cells and peripheral blood mononuclear cells (PBMC). Results: Our main findings were: (i) LIGHT and its receptors (i.e., HVEM and lymphotoxin-β receptor) were regulated during experimental HF, with strong expression in the infarcted area accompanied by up-regulation of HVEM in cardiomyocytes and endothelial cells also in the non-ischaemic part of the left ventricle. (ii) Patients with chronic HF had significantly increased expression of LIGHT on CD3+ T-cells accompanied by increased expression of HVEM on monocytes and within the failing myocardium. (iii) LIGHT induced interleukin (IL)-6 expression in endothelial cells. In HF patients, but not in healthy controls, such an IL-6-inducing effect was also seen in LIGHT activated PBMC. Conclusion: Our findings in both clinical and experimental HF may suggest a role for LIGHT signalling pathways in the progression of chronic HF involving IL-6-related mechanisms.
- Published
- 2008
45. Prognostic Importance of Renal Function 1 Year After Heart Transplantation for All-Cause and Cardiac Mortality and Development of Allograft Vasculopathy
- Author
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Rita Skaardal, Arne K. Andreassen, S. Arora, Einar Gude, Svein Simonsen, Ina Hoel, Odd Geiran, Lars Gullestad, and Christen P. Dahl
- Subjects
Adult ,medicine.medical_specialty ,Time Factors ,medicine.medical_treatment ,Renal function ,Coronary Disease ,Coronary Angiography ,Kidney ,urologic and male genital diseases ,Risk Factors ,Cause of Death ,Internal medicine ,Epidemiology ,Humans ,Transplantation, Homologous ,Medicine ,Risk factor ,Cause of death ,Heart Failure ,Heart transplantation ,Transplantation ,business.industry ,Prognosis ,medicine.disease ,Surgery ,Heart failure ,cardiovascular system ,Cardiology ,Heart Transplantation ,business ,Follow-Up Studies ,Glomerular Filtration Rate ,Kidney disease - Abstract
Impaired renal function is associated with increased mortality among heart failure patients. Although a significant proportion of heart transplant (HTx) recipients have reduced renal function at 1 year post-HTx, no previous study has evaluated the associated risk for both all-cause and cardiac mortality. Hence, we assessed the relationship between glomerular filtration rate (GFR) at 1 year post-HTx and all-cause and cardiac mortality and development of cardiac allograft vasculopathy (CAV).We evaluated 381 patients with a minimum survival of 1 year post-HTx and the Modification of Diet in Renal Disease Study formula was used to calculate estimated GFR. Mortality and angiographic CAV were defined as separate endpoints, and median follow-up was 7.4 and 4.0 years, respectively.During the follow-up period, 122 patients died and 154 patients developed CAV. Reduced GFR pre-HTx was not a risk factor for either endpoint. Overall, 193 (51%) patients had GFR60 ml/min/1.73 m at one year post-HTx and this was an independent predictor of all-cause mortality with an adjusted hazard ratio of 1.7 (P=0.01) for a GFR between 30-60 and 3.2 (P=0.006) for GFR30 ml/min/1.73 m. GFR60 ml/min/1.73 m at 1 year post-HTx was also associated with a higher risk of cardiac mortality (HR=1.9; P=0.04) but did not predict the development of CAV.Renal impairment is evident in a majority of HTx recipients at 1 year post-HTx. It is an important risk factor for both all-cause and cardiac mortality but does not predict the development of angiographic CAV.
- Published
- 2007
46. Low Circulating Levels of Mitochondrial and High Levels of Nuclear DNA Predict Mortality in Chronic Heart Failure
- Author
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Øystein Sandanger, Alexandra Vanessa Finsen, Lars Gullestad, Ivar Sjaastad, Anne Waehre, Pål Aukrust, Erik T. Askevold, Arnt E. Fiane, Thor Ueland, Leif Erik Vinge, Yangchen Dhondup, Christen P. Dahl, Ingrid Kristine Ohm, and Arne Yndestad
- Subjects
0301 basic medicine ,Male ,Mitochondrial DNA ,medicine.medical_specialty ,Kaplan-Meier Estimate ,030204 cardiovascular system & hematology ,Mitochondrion ,Severity of Illness Index ,Statistics, Nonparametric ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Predictive Value of Tests ,Reference Values ,Internal medicine ,Medicine ,Humans ,Receptor ,Aged ,Heart Failure ,Innate immune system ,business.industry ,Middle Aged ,medicine.disease ,Prognosis ,Survival Analysis ,Nuclear DNA ,Mitochondria ,030104 developmental biology ,Endocrinology ,chemistry ,Heart failure ,Case-Control Studies ,Immunology ,Female ,Signal transduction ,Cardiology and Cardiovascular Medicine ,business ,Co-Repressor Proteins ,DNA ,Biomarkers - Abstract
Background Mitochondrial DNA (mtDNA) and possibly nuclear DNA (nDNA) are released as danger-associated molecular patterns during cardiac stress, and may activate several innate immune receptors. The purpose of this study was to investigate the regulation of these danger-associated molecular patterns during human heart failure (HF). Methods and Results Plasma levels of mtDNA and nDNA from HF patients (n = 84) were analyzed by reverse transcriptase-polymerase chain reaction and compared with controls (n = 72). Increased levels of mtDNA were found in New York Heart Association (NYHA) I-II and NYHA III-IV. There was evidence of increased nDNA in NYHA III-IV compared with controls and NYHA I-II. Kaplan-Meier analysis revealed higher mortality in patients with high nDNA levels, whereas high levels of mtDNA were associated with survival. Conclusions Plasma levels of mtDNA and nDNA are elevated in human HF associated with increased and decreased mortality, respectively. This study may suggest a rationale for exploring interventions within inflammatory signaling pathways activated by nucleic acids as novel targets in treatment of HF.
- Published
- 2015
47. High Sensitivity Method to Estimate Distribution of Hyaluronan Molecular Sizes in Small Biological Samples Using Gas-Phase Electrophoretic Mobility Molecular Analysis
- Author
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Susanne Kerje, Urban Hellman, Lan Do, Peter Hansell, Göran Larsson, Christen P. Dahl, Anna Engström-Laurent, Stellan Mörner, and Ulla Lindqvist
- Subjects
Article Subject ,integumentary system ,lcsh:Cytology ,Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) ,Cell Biology ,Biology ,Bioinformatics ,Gas phase ,Molecular analysis ,Extracellular matrix ,carbohydrates (lipids) ,Electrophoresis ,Cell and molecular biology ,Molecular size ,Biophysics ,Distribution (pharmacology) ,lcsh:QH573-671 ,Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) ,Research Article - Abstract
Hyaluronan is a negatively charged polydisperse polysaccharide where both its size and tissue concentration play an important role in many physiological and pathological processes. The various functions of hyaluronan depend on its molecular size. Up to now, it has been difficult to study the role of hyaluronan in diseases with pathological changes in the extracellular matrix where availability is low or tissue samples are small. Difficulty to obtain large enough biopsies from human diseased tissue or tissue from animal models has also restricted the study of hyaluronan. In this paper, we demonstrate that gas-phase electrophoretic molecular mobility analyzer (GEMMA) can be used to estimate the distribution of hyaluronan molecular sizes in biological samples with a limited amount of hyaluronan. The low detection level of the GEMMA method allows for estimation of hyaluronan molecular sizes from different parts of small organs. Hence, the GEMMA method opens opportunity to attain a profile over the distribution of hyaluronan molecular sizes and estimate changes caused by disease or experimental conditions that has not been possible to obtain before.
- Published
- 2015
48. The p66ShcA adaptor protein regulates healing after myocardial infarction
- Author
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Andrea Carpi, Dusan Bilbija, Tania Zaglia, Julia Sagave, Marika Campesan, Jarle Vaage, Lars Gullestad, Marco Giorgio, Fabio Di Lisa, Marco Mongillo, Anton Baysa, Maria Troitskaya, Guro Valen, and Christen P. Dahl
- Subjects
Male ,Physiology ,Cardiac fibrosis ,Myocardial Infarction ,Fluorescent Antibody Technique ,Matrix metalloproteinase ,Inbred C57BL ,medicine.disease_cause ,Mice ,Collagen ,Healing ,Heart rupture ,MMP-2 ,Myocardial infarction ,ShcA ,Aged ,Animals ,Blotting, Western ,Female ,Humans ,Immunohistochemistry ,Matrix Metalloproteinase 2 ,Mice, Inbred C57BL ,Mice, Knockout ,Middle Aged ,Oxidative Stress ,Real-Time Polymerase Chain Reaction ,Shc Signaling Adaptor Proteins ,Ventricular Remodeling ,Cardiology and Cardiovascular Medicine ,Physiology (medical) ,Medicine (all) ,Blotting ,medicine.anatomical_structure ,Knockout mouse ,cardiovascular system ,Cardiology ,Western ,medicine.medical_specialty ,Src Homology 2 Domain-Containing, Transforming Protein 1 ,Knockout ,Heart Rupture ,Internal medicine ,medicine ,cardiovascular diseases ,Fibroblast ,business.industry ,medicine.disease ,Heart failure ,business ,Oxidative stress - Abstract
Heart rupture and heart failure are deleterious complications of myocardial infarction. The ShcA gene encodes for three protein isoforms, p46-, p52- and p66ShcA. p66ShcA induces oxidative stress. We studied the role of p66ShcA post-infarction. Expression of p66ShcA was analyzed in myocardium of patients with stable angina (n = 11), in explanted hearts with end-stage ischemic heart failure (n = 9) and compared to non-failing hearts not suitable for donation (n = 7). p66ShcA was increased in the patients with stable angina, but not in the patients with end-stage heart failure. Mice (n = 105) were subjected to coronary artery ligation. p66ShcA expression and phosphorylation were evaluated over a 6-week period. p66ShcA expression increased transiently during the first weeks post-infarction. p66ShcA knockout mice (KO) were compared to wild type (n = 82 in total). KO had improved survival and reduced occurrence of heart rupture post-infarction. Expression of cardiac matrix metalloproteinase 2 (MMP-2) was reduced; fibroblast activation and collagen accumulation were facilitated, while oxidative stress was attenuated in KO early post-infarction. 6 weeks post-infarction, reactive fibrosis and left ventricular dilatation were diminished in KO. p66ShcA regulation of MMP-2 was demonstrated in cultured fibroblasts: lack or overexpression of p66ShcA in vitro altered expression of MMP-2. Myocardial infarction induced cardiac p66ShcA. Deletion of p66ShcA improved early survival, myocardial healing and reduced cardiac fibrosis. Upon myocardial infarction p66ShcA regulates MMP-2 activation. The role of p66ShcA in human cardiac disease deserves further study as a potential target for reducing adverse cardiac remodeling post-infarction.
- Published
- 2015
49. Altered Levels of Fatty Acids and Inflammatory and Metabolic Mediators in Epicardial Adipose Tissue in Patients With Systolic Heart Failure
- Author
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Ståle H. Nymo, Ivar Risnes, Linn E. Fosshaug, Pål Aukrust, Leif Erik Vinge, Pavol Bohov, Erik Øie, Christen P. Dahl, Lars Gullestad, Odd Geiran, Arne Yndestad, and Rolf K. Berge
- Subjects
Adult ,Male ,medicine.medical_specialty ,medicine.drug_class ,Subcutaneous Fat ,Adipose tissue ,Enzyme-Linked Immunosorbent Assay ,Real-Time Polymerase Chain Reaction ,Statistics, Nonparametric ,chemistry.chemical_compound ,Internal medicine ,Natriuretic Peptide, Brain ,medicine ,Natriuretic peptide ,Palmitoleic acid ,Humans ,RNA, Messenger ,Cardiac Surgical Procedures ,Aged ,Ultrasonography ,chemistry.chemical_classification ,Chi-Square Distribution ,business.industry ,Fatty Acids ,Fatty acid ,Middle Aged ,medicine.disease ,Peptide Fragments ,Adrenomedullin ,Endocrinology ,C-Reactive Protein ,chemistry ,Adipose Tissue ,Docosahexaenoic acid ,Elective Surgical Procedures ,Heart failure ,Case-Control Studies ,Circulatory system ,Linear Models ,Female ,Cardiology and Cardiovascular Medicine ,business ,Pericardium ,Biomarkers ,Heart Failure, Systolic - Abstract
Background Adipose tissue has endocrine properties, secreting a wide range of mediators into the circulation, including factors involved in cardiovascular disease. However, little is known about the potential role of adipose tissue in heart failure (HF), and the aim of this study was to investigate epicardial (EAT) and subcutaneous (SAT) adipose tissue in HF patients. Methods and Results Thirty patients with systolic HF and 30 patients with normal systolic function undergoing thoracic surgery were included in the study. Plasma was sampled and examined with the use of enzyme-linked immunosorbent assays, whereas SAT and EAT biopsies were collected and examined by means of reverse-transcription polymerase chain reaction and gas chromatography. Significantly higher expressions of mRNA encoding interleukin-6, adrenomedullin, peroxisome proliferator–activated receptor α, and fatty acid (FA)–binding protein 3, as well as higher levels of monounsaturated FA and palmitoleic acid, were seen in the EAT of HF patients, whereas the levels of docosahexaenoic acid were lower. Palmitoleic acid levels in EAT were correlated with 2 parameters of cardiac remodeling: increasing left ventricular end-diastolic diameter and N-terminal pro–B-type natriuretic peptide. Conclusions Our results demonstrate adipose tissue depot–specific alterations of synthesis of FA and inflammatory and metabolic mediators in systolic HF patients. EAT may be a source of increased circulatory and myocardial levels of these mediators through endocrine actions.
- Published
- 2014
50. The homeostatic chemokine CCL21 predicts mortality in aortic stenosis patients and modulates left ventricular remodeling
- Author
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Alexandra Vanessa, Finsen, Thor, Ueland, Ivar, Sjaastad, Trine, Ranheim, Mohammed S, Ahmed, Christen P, Dahl, Erik T, Askevold, Svend, Aakhus, Cathrine, Husberg, Arnt E, Fiane, Martin, Lipp, Lars, Gullestad, Geir, Christensen, Pål, Aukrust, Arne, Yndestad, and MDC Library
- Subjects
Male ,Cancer Research ,lcsh:Medicine ,Vascular Medicine ,Electrocardiography ,Mice ,Medicine and Health Sciences ,Homeostasis ,lcsh:Science ,Ventricular Remodeling ,Messenger RNA ,Calcinosis ,Animal Models ,Immunohistochemistry ,Matrix Metalloproteinase 9 ,Research Design ,Aortic Valve ,Cytokines ,Matrix Metalloproteinase 2 ,Female ,Collagen ,Dilatation, Pathologic ,Research Article ,Receptors, CCR7 ,endocrine system ,Inbred C57BL Mice ,Clinical Research Design ,Immunology ,Aortic Diseases ,Cardiology ,Mouse Models ,570 Life Sciences ,Research and Analysis Methods ,610 Medical Sciences, Medicine ,Model Organisms ,Pressure ,Humans ,Animals ,RNA, Messenger ,Animal Models of Disease ,Pathologic Dilatation ,Aged ,Heart Failure ,CCR7 Receptors ,Chemokine CCL21 ,Myocardium ,lcsh:R ,Biology and Life Sciences ,Aortic Valve Stenosis ,Molecular Development ,Atherosclerosis ,Mice, Inbred C57BL ,Immune System ,Animal Studies ,Clinical Immunology ,lcsh:Q ,Developmental Biology - Abstract
BACKGROUND: CCL21 acting through CCR7, is termed a homeostatic chemokine. Based on its role in concerting immunological responses and its proposed involvement in tissue remodeling, we hypothesized that this chemokine could play a role in myocardial remodeling during left ventricular (LV) pressure overload. METHODS AND RESULTS: Our main findings were: (i) Serum levels of CCL21 were markedly raised in patients with symptomatic aortic stenosis (AS, n = 136) as compared with healthy controls (n = 20). (ii) A CCL21 level in the highest tertile was independently associated with all-cause mortality in these patients. (iii) Immunostaining suggested the presence of CCR7 on macrophages, endothelial cells and fibroblasts within calcified human aortic valves. (iv). Mice exposed to LV pressure overload showed enhanced myocardial expression of CCL21 and CCR7 mRNA, and increased CCL21 protein levels. (v) CCR7-/- mice subjected to three weeks of LV pressure overload had similar heart weights compared to wild type mice, but increased LV dilatation and reduced wall thickness. CONCLUSIONS: Our studies, combining experiments in clinical and experimental LV pressure overload, suggest that CCL21/CCR7 interactions might be involved in the response to pressure overload secondary to AS.
- Published
- 2014
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