Theis Tønnessen

• Kluge, Karsten Engseth; Halvorsen, Sigrun; Andersen, Geir Øystein; Hansen, Charlotte Holst; Seljeflot, Ingebjørg & Tønnessen, Theis [Show all 8 contributors for this article] (2025). Combined complement and coagulation activation in ST-elevation myocardial infarction: associations with myocardial injury and dysfunction. Frontiers in Immunology. 16. doi: 10.3389/fimmu.2025.1613603. Full text in Research Archive Show summary

  Introduction: Preclinical data indicates reciprocal activation of the complement system and the coagulation cascade. The magnitude of this interaction in patients with acute myocardial infarction is unknown. We aimed to determine associations between circulating markers of complement and coagulation activation in patients with acute ST-elevation myocardial infarction (STEMI), and explore a possible link to myocardial injury and left ventricular dysfunction. Materials and methods: We included 864 patients with STEMI. Blood was drawn at a median of 18 hours after percutaneous coronary intervention. Complement activation was assessed by the terminal complement complex (TCC), and coagulation activation by prothrombin fragment 1 + 2 (F1 + 2), D-dimer and endogenous thrombin potential (ETP). Myocardial injury was estimated by peak troponin T (TnT), and left ventricular function was quantified on echocardiography by left ventricular ejection fraction (LVEF). Results: TCC was weakly correlated to F1 + 2 (r=0.086, p=0.012), D-dimer (r=0.176, p<0.001) and ETP (r=0.144, p<0.001). In multivariate binary logistic regression, there was no significant interaction between TCC and the coagulation markers on the risk of having high peak TnT or low LVEF. Conclusion: In this STEMI cohort, complement activation as measured by TCC was weakly associated with markers of coagulation activation, but the measured markers had no combined relation with the risk of high peak TnT or low LVEF. These findings suggest that while simultaneous activation of complement and coagulation cannot be ruled out, combined high levels of TCC and coagulation markers do not mirror the extent of myocardial injury or dysfunction in STEMI.

• Jeppsson, Anders; James, Stefan; Moller, Christian H.; Malm, Carl Johan; Dalén, M. & Vanky, F. [Show all 45 contributors for this article] (2025). Ticagrelor and Aspirin or Aspirin Alone after Coronary Surgery for Acute Coronary Syndrome. New England Journal of Medicine. ISSN 0028-4793. 393(23), p. 2313–2323. doi: 10.1056/NEJMoa2508026. Full text in Research Archive
• Ruud, Marianne; Frisk, Michael; Melleby, Arne Olav; Norseng, Per Andreas; Mohamed, Belal A. & Li, Jia [Show all 22 contributors for this article] (2024). Regulation of cardiomyocyte t-tubule structure by preload and afterload: Roles in cardiac compensation and decompensation. Journal of Physiology. ISSN 0022-3751. 602(18), p. 4487–4510. doi: 10.1113/JP284566. Full text in Research Archive Show summary

  Mechanical load is a potent regulator of cardiac structure and function. Although high workload during heart failure is associated with disruption of cardiomyocyte t-tubules and Ca2+ homeostasis, it remains unclear whether changes in preload and afterload may promote adaptive t-tubule remodelling. We examined this issue by first investigating isolated effects of stepwise increases in load in cultured rat papillary muscles. Both preload and afterload increases produced a biphasic response, with the highest t-tubule densities observed at moderate loads, whereas excessively low and high loads resulted in low t-tubule levels. To determine the baseline position of the heart on this bell-shaped curve, mice were subjected to mildly elevated preload or afterload (1 week of aortic shunt or banding). Both interventions resulted in compensated cardiac function linked to increased t-tubule density, consistent with ascension up the rising limb of the curve. Similar t-tubule proliferation was observed in human patients with moderately increased preload or afterload (mitral valve regurgitation, aortic stenosis). T-tubule growth was associated with larger Ca2+ transients, linked to upregulation of L-type Ca2+ channels, Na+–Ca2+ exchanger, mechanosensors and regulators of t-tubule structure. By contrast, marked elevation of cardiac load in rodents and patients advanced the heart down the declining limb of the t-tubule–load relationship. This bell-shaped relationship was lost in the absence of electrical stimulation, indicating a key role of systolic stress in controlling t-tubule plasticity. In conclusion, modest augmentation of workload promotes compensatory increases in t-tubule density and Ca2+ cycling, whereas this adaptation is reversed in overloaded hearts during heart failure progression.

• Vistnes, Maria; Erusappan, Pugazendhi Murugan; Sasi, Athiramol; Nordén, Einar Sjaastad; Bergo, Kaja Knudsen & Romaine, Andreas [Show all 22 contributors for this article] (2023). Inhibition of the extracellular enzyme A disintegrin and metalloprotease with thrombospondin motif 4 prevents cardiac fibrosis and dysfunction. Cardiovascular Research (CVR). ISSN 0008-6363. 119(10), p. 1915–1927. doi: 10.1093/cvr/cvad078. Full text in Research Archive Show summary

  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, 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 down-regulation 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 and extra domain A-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.

• Malm, Carl Johan; Alfredsson, Joakim; Erlinge, David; Gudbjartsson, Tomas; Gunn, Jarmo & James, Stefan [Show all 11 contributors for this article] (2023). Dual or single antiplatelet therapy after coronary surgery for acute coronary syndrome (TACSI trial): Rationale and design of an investigator-initiated, prospective, multinational, registry-based randomized clinical trial. American Heart Journal. ISSN 0002-8703. 259, p. 1–8. doi: 10.1016/j.ahj.2023.01.011. Full text in Research Archive Show summary

  The TACSI trial (ClinicalTrials.gov Identifier: NCT03560310) tests the hypothesis that 1-year treatment with dual antiplatelet therapy with acetylsalicylic acid (ASA) and ticagrelor is superior to only ASA after isolated coronary artery bypass grafting (CABG) in patients with acute coronary syndrome. The TACSI trial is an investigator-initiated pragmatic, prospective, multinational, multicenter, open-label, registry-based randomized trial with 1:1 randomization to dual antiplatelet therapy with ASA and ticagrelor or ASA only, in patients undergoing first isolated CABG, with a planned enrollment of 2200 patients at Nordic cardiac surgery centers. The primary efficacy end point is a composite of time to all-cause death, myocardial infarction, stroke, or new coronary revascularization within 12 months after randomization. The primary safety end point is time to hospitalization due to major bleeding. Secondary efficacy end points include time to the individual components of the primary end point, cardiovascular death, and rehospitalization due to cardiovascular causes. High-quality health care registries are used to assess primary and secondary end points. The patients will be followed for 10 years. The TACSI trial will give important information useful for guiding the antiplatelet strategy in acute coronary syndrome patients treated with CABG.

• Strand, Mari Elen; Vanhaverbeke, Maarten; Henkens, Michiel T. H. M.; Sikking, Maurits A.; Rypdal, Karoline Bjarnesdatter & Braathen, Bjørn [Show all 11 contributors for this article] (2023). Inflammation and Syndecan-4 Shedding from Cardiac Cells in Ischemic and Non-Ischemic Heart Disease. Biomedicines. 11(4). doi: 10.3390/biomedicines11041066. Full text in Research Archive Show summary

  Circulating biomarkers reflecting cardiac inflammation are needed to improve the diagnostics and guide the treatment of heart failure patients. The cardiac production and shedding of the transmembrane proteoglycan syndecan-4 is upregulated by innate immunity signaling pathways. Here, we investigated the potential of syndecan-4 as a blood biomarker of cardiac inflammation. Serum syndecan-4 was measured in patients with (i) non-ischemic, non-valvular dilated cardiomyopathy (DCM), with (n = 71) or without (n = 318) chronic inflammation; (ii) acute myocarditis (n = 15), acute pericarditis (n = 3) or acute perimyocarditis (23) and (iii) acute myocardial infarction (MI) at day 0, 3 and 30 (n = 119). Syndecan-4 was investigated in cultured cardiac myocytes and fibroblasts (n = 6–12) treated with the pro-inflammatory cytokines interleukin (IL)-1β and its inhibitor IL-1 receptor antagonist (IL-1Ra), or tumor necrosis factor (TNF)α and its specific inhibitor infliximab, an antibody used in treatment of autoimmune diseases. The levels of serum syndecan-4 were comparable in all subgroups of patients with chronic or acute cardiomyopathy, independent of inflammation. Post-MI, syndecan-4 levels were increased at day 3 and 30 vs. day 0. IL-1Ra attenuated IL-1β-induced syndecan-4 production and shedding in vitro, while infliximab had no effect. In conclusion, syndecan-4 shedding from cardiac myocytes and fibroblasts was attenuated by immunomodulatory therapy. Although its circulating levels were increased post-MI, syndecan-4 did not reflect cardiac inflammatory status in patients with heart disease.

• Papotti, Bianca; Opstad, Trine Baur; Åkra, Sissel; Tønnessen, Theis; Braathen, Bjørn & Hansen, Charlotte Holst [Show all 10 contributors for this article] (2023). Macrophage polarization markers in subcutaneous, pericardial, and epicardial adipose tissue are altered in patients with coronary heart disease. Frontiers in Cardiovascular Medicine. 10. doi: 10.3389/fcvm.2023.1055069. Full text in Research Archive Show summary

  Background: Epicardial and pericardial adipose tissue (EAT and PAT) surround and protect the heart, with EAT directly sharing the microcirculation with the myocardium, possibly presenting a distinct macrophage phenotype that might affect the inflammatory environment in coronary heart disease (CHD). This study aims to investigate the expression of genes in different AT compartments driving the polarization of AT macrophages toward an anti-inflammatory (L-Galectin 9; CD206) or pro-inflammatory (NOS2) phenotype. Methods: EAT, PAT, and subcutaneous (SAT) biopsies were collected from 52 CHD patients undergoing coronary artery bypass grafting, and from 22 CTRLs undergoing aortic valve replacement. L-Galectin9 (L-Gal9), CD206, and NOS2 AT gene expression and circulating levels were analyzed through RT-PCR and ELISA, respectively. Results: L-Gal9, CD206, and NOS2 gene expression was similar in all AT compartments in CHD and CTRLs, as were also L-Gal9 and CD206 circulating levels, while NOS2 serum levels were higher in CHD (p = 0.012 vs. CTRLs). In CTRLs, NOS2 expression was lower in EAT vs. SAT (p = 0.007), while in CHD patients CD206 expression was lower in both SAT and EAT as compared to PAT (p = 0.003, p = 0.006, respectively), suggestive of a possible macrophage reprogramming toward a pro-inflammatory phenotype in EAT. In CHD patients, NOS2 expression in SAT correlated to that in PAT and EAT (p = 0.007, both), CD206 expression correlated positively to L-Gal9 (p < 0.001) only in EAT, and CD206 expression associated with that of macrophage identifying markers in all AT compartments (p < 0.001, all). In CHD patients, subjects with LDL-C above 1.8 mmol/L showed significantly higher NOS2 expression in PAT and EAT as compared to subjects with LDL-C levels below (p < 0.05), possibly reflecting increased cardiac AT pro-inflammatory activation. In SAT and PAT, CD206 expression associated with BMI in both CHD and CTRLs (p < 0.05, all), and with L-Gal9 in EAT, however only in CTRLs (p = 0.002). Conclusion: CHD seems to be accompanied by an altered cardiac, and especially epicardial AT macrophage polarization. This may represent an important pathophysiological mechanism and a promising field of therapy targeting the excessive AT inflammation, in need of further investigation.

• Opstad, Trine Baur; Papotti, Bianca; Åkra, Sissel; Hansen, Charlotte Holst; Braathen, Bjørn & Tønnessen, Theis [Show all 8 contributors for this article] (2023). Sirtuin1, not NAMPT, possesses anti-inflammatory effects in epicardial, pericardial and subcutaneous adipose tissue in patients with CHD. Journal of Translational Medicine. 21(1). doi: 10.1186/s12967-023-04518-4. Full text in Research Archive Show summary

  Background Inflammation in cardiac adipose tissue (AT) is associated with atherosclerosis. We investigated whether the epicardial-, pericardial and pre-sternal subcutaneous AT (EAT, PAT and SAT) expression of Sirtuin1 (SIRT1) and nicotinamide phosphoribosyl transferase (NAMPT) are involved in the inflammatory process in coronary heart disease (CHD), and potentially associated to nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-related markers, macrophage polarization markers, cell markers and the cardiometabolic profile. Methods In this cohort study performed between 2016 and 2018, EAT, PAT and SAT biopsies were retrieved from 52 CHD patients (77% men, median age 67) undergoing open-chest coronary artery bypass grafting (CABG), and 22 patients (50% men, median age 69) undergoing aortic valve replacement serving as controls. AT samples were snap-frozen at – 80 °C until RNA extraction and AT expression of actual markers, relatively quantified by PCR. Circulating SIRT1 and NAMPT were measured with Enzyme-linked immunosorbent assays (ELISAs). Non-parametric statistical tests were mainly used, including Friedman’s test coupled to Wilcoxon signed-rank test and Spearman Correlation. Results SIRT1 and NAMPT levels were similar in CHD and controls. In CHD, SIRT1 and NAMPT were inter-correlated in all AT compartments (r = 0.37–0.56, p < 0.01, all), and differently expressed between compartments, with the highest expression in SAT, significantly different from EAT (p < 0.01, both). Circulating SIRT1 and NAMPT levels were inversely associated (r = − 0.32, p = 0.024). In EAT and SAT, SIRT1 expression was inversely associated with IL-18 (r = − 0.43 and r = − 0.38, p < 0.01, both), whereas NAMPT expression was positively associated with the NLRP3 inflammasome-related markers in all compartments (r = 0.37–0.55, p < 0.01, all). While SIRT1 and NAMPT correlated to nitric oxide synthase 2 (NOS2), especially in SAT (r = 0.50–0.52, p ≤ 0.01, both), SIRT1 expression was related to endothelial cells, and NAMPT to macrophages. SIRT1 levels were correlated to weight and waist (r = 0.32 and r = 0.38, p < 0.03, both) and inversely to triglycerides and glycated haemoglobin (HbA1c) (r = − 0.33–− 0.37, p < 0.03, all), the latter positively correlated to NAMPT concentration (r = 0.39, p = 0.010). Conclusion The study indicates that targeting SIRT1, with its anti-inflammatory properties, may be a novel anti-inflammatory strategy in preventing atherosclerosis and CHD progression. NAMPT may be an early player in AT inflammation, mediating/reflecting a pro-inflammatory state. Trial Registration: Registration: Clinicaltrials.gov ID: NCT02760914, registered the 5th of February 2016, http://clinicaltrials.gov/NCT02760914 Graphical Abstract

• Rypdal, Karoline Bjarnesdatter; Melleby, Arne Olav; Robinson, Emma Louise; Li, Jia; Palmero, Sheryl & E., Seifert Deborah [Show all 20 contributors for this article] (2022). ADAMTSL3 knock-out mice develop cardiac dysfunction and dilatation with increased TGFβ signalling after pressure overload. Communications Biology. 5(1). doi: 10.1038/s42003-022-04361-1. Full text in Research Archive Show summary

  Abstract Heart failure is a major cause of morbidity and mortality worldwide, and can result from pressure overload, where cardiac remodelling is characterized by cardiomyocyte hypertrophy and death, fibrosis, and inflammation. In failing hearts, transforming growth factor (TGF)β drives cardiac fibroblast (CFB) to myofibroblast differentiation causing excessive extracellular matrix production and cardiac remodelling. New strategies to target pathological TGFβ signalling in heart failure are needed. Here we show that the secreted glycoprotein ADAMTSL3 regulates TGFβ in the heart. We found that Adamtsl3 knock-out mice develop exacerbated cardiac dysfunction and dilatation with increased mortality, and hearts show increased TGFβ activity and CFB activation after pressure overload by aortic banding. Further, ADAMTSL3 overexpression in cultured CFBs inhibits TGFβ signalling, myofibroblast differentiation and collagen synthesis, suggesting a cardioprotective role for ADAMTSL3 by regulating TGFβ activity and CFB phenotype. These results warrant future investigation of the potential beneficial effects of ADAMTSL3 in heart failure.

• Rixon, Chloe Louise; Andreassen, Kristine; Shen, Xin; Erusappan, Pugazendhi Murugan; Almaas, Vibeke Marie & Palmero, Sheryl [Show all 14 contributors for this article] (2022). Lumican accumulates with fibrillar collagen in fibrosis in hypertrophic cardiomyopathy. ESC Heart Failure. doi: 10.1002/ehf2.14234. Full text in Research Archive Show summary

  Aims Familial hypertrophic cardiomyopathy (HCM) is the most common form of inherited cardiac disease. It is characterized by myocardial hypertrophy and diastolic dysfunction, and can lead to severe heart failure, arrhythmias, and sudden cardiac death. Cardiac fibrosis, defined by excessive accumulation of extracellular matrix (ECM) components, is central to the pathophysiology of HCM. The ECM proteoglycan lumican is increased during heart failure and cardiac fibrosis, including HCM, yet its role in HCM remains unknown. We provide an in-depth assessment of lumican in clinical and experimental HCM.<p> <p>Methods Left ventricular (LV) myectomy specimens were collected from patients with hypertrophic obstructive cardiomyopathy (n = 15), and controls from hearts deemed unsuitable for transplantation (n = 8). Hearts were harvested from a mouse model of HCM; Myh6 R403Q mice administered cyclosporine A and wild-type littermates (n = 8–10). LV tissues were analysed for mRNA and protein expression. Patient myectomy or mouse mid-ventricular sections were imaged using confocal microscopy, direct stochastic optical reconstruction microscopy (dSTORM), or electron microscopy. Human foetal cardiac fibroblasts (hfCFBs) were treated with recombinant human lumican (n = 3) and examined using confocal microscopy.<p> <p>Results Lumican mRNA was increased threefold in HCM patients (P < 0.05) and correlated strongly with expression of collagen I (R² = 0.60, P < 0.01) and III (R² = 0.58, P < 0.01). Lumican protein was increased by 40% in patients with HCM (P < 0.01) and correlated with total (R² = 0.28, P = 0.05) and interstitial (R² = 0.30, P < 0.05) fibrosis. In mice with HCM, lumican mRNA increased fourfold (P < 0.001), and lumican protein increased 20-fold (P < 0.001) in insoluble ECM lysates. Lumican and fibrillar collagen were located together throughout fibrotic areas in HCM patient tissue, with increased co-localization measured in patients and mice with HCM (patients: +19%, P < 0.01; mice: +13%, P < 0.01). dSTORM super-resolution microscopy was utilized to image interstitial ECM which had yet to undergo overt fibrotic remodelling. In these interstitial areas, collagen I deposits located closer to ( 15 nm, P < 0.05), overlapped more frequently with (+7.3%, P < 0.05) and to a larger degree with (+5.6%, P < 0.05) lumican in HCM. Collagen fibrils in such deposits were visualized using electron microscopy. The effect of lumican on collagen fibre formation was demonstrated by adding lumican to hfCFB cultures, resulting in thicker (+53.8 nm, P < 0.001), longer (+345.9 nm, P < 0.001), and fewer ( 8.9%, P < 0.001) collagen fibres. <p>Conclusions The ECM proteoglycan lumican is increased in HCM and co-localizes with fibrillar collagen throughout areas of fibrosis in HCM. Our data suggest that lumican may promote formation of thicker collagen fibres in HCM.

• Andenæs, Kine; Rypdal, Karoline Bjarnesdatter; Palmero, Sheryl; Tønnessen, Theis & Lunde, Ida Gjervold (2022). The small leucine-rich proteoglycan fibromodulin exerts anti-fibrotic effects in cultured human cardiac fibroblasts. Genetics and Molecular Research. 21(1). doi: 10.4238/gmr19007. Full text in Research Archive Show summary

  Cardiac fibrosis is common and detrimental in numerous heart diseases, affecting millions of patients worldwide. Cardiac fibrosis is characterized by excessive production of extracellular matrix (ECM) constituents such as fibrillar collagens, produced by activated cardiac fibroblasts, i.e.: myofibroblasts. Therapeutic targeting of cardiac fibrosis is highly attractive; however, it remains a major medical challenge. Fibromodulin is a small leucine-rich proteoglycan localized in the ECM. Fibromodulin binds to collagen fibrils, and plays a critical role in collagen fibrillogenesis, ECM organization, wound healing and regulation of the pro-fibrotic cytokine transforming growth factor beta (TGFβ) in several organs. Fibromodulin is highly upregulated in mice and patients with heart failure, but little is known about its role in cardiac fibrosis. Our recent findings from primary cultures of cardiac fibroblasts from neonatal rat hearts suggest that fibromodulin has anti-fibrotic effects. Here we investigated the translational value of these findings by overexpressing fibromodulin in cultured human fetal and adult cardiac fibroblasts. The effects of fibromodulin overexpression on gene expression were measured by qPCR and gene arrays, whereas protein levels were measured by Western blotting, and collagen synthesis by radioactive proline incorporation. The results support our previous findings and indicate relevance for human disease. We found that fibromodulin reduced the expression levels of the collagen cross-linking enzymes lysyl oxidase (LOX) and transglutaminase 2 (TGM2). Fibromodulin also reduced the levels of connective tissue growth factor (CTGF) and periostin (POSTN), indicating reduced TGFβ activity. Reduced levels of intercellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1) suggested reduced potential for immune cell adhesion, and gene arrays indicated altered integrin expression, suggesting altered ECM-cell adhesion. Expression of fibrillar collagens was unaffected. In conclusion, fibromodulin reduced TGFβ activity and down-regulated central collagen-crosslinking enzymes, in line with an anti-fibrotic effect of fibromodulin in human cardiac fibroblasts.

• Åkra, Sissel; Seljeflot, Ingebjørg; Braathen, Bjørn; Bratset, Vibeke; Hansen, Charlotte Holst & Arnesen, Harald [Show all 8 contributors for this article] (2022). The NLRP3 inflammasome activation in subcutaneous, epicardial and pericardial adipose tissue in patients with coronary heart disease undergoing coronary by-pass surgery. Atherosclerosis Plus. ISSN 2667-0909. doi: 10.1016/j.athplu.2022.03.005. Full text in Research Archive Show summary

  Background and aims Epicardial and pericardial adipose tissue (EAT and PAT) associate with atherosclerosis, however, discussed to have different inflammatory properties. We examined the NLRP3 inflammasome related pathway, playing a pivotal role in atherosclerosis, in EAT, PAT and subcutaneous AT (SAT), their relationship to cell types and anthropometric measures in patients undergoing coronary artery bypass grafting. Methods Biopsies from EAT, PAT and SAT were collected from 52 patients with coronary heart disease (CHD) (median body weight 85.0 kg) and 22 controls. RNA was extracted and expression of interleukin (IL)-1β, IL-18, NLRP3, Caspase-1, toll-like receptor 4 (TLR4), IL-6, IL-6 receptor and gp130 were analyzed by RT-PCR. Results Limited differences in any genes between CHD patients and controls. IL-18 and IL-6 were 4-fold higher expressed in EAT versus PAT (p < 0.01, both) and SAT (p < 0.001, both), whereas caspase-1, IL-6R and gp130 were higher expressed in SAT compared to the other compartments (all p = 0.06-<0.001). Significant correlations between SAT and PAT gene expressions (r = 0.358–0.579, all p ≤ 0.01). Especially NLRP3 and TLR4 associated with the expression of macrophages in all compartments (all p < 0.001). In EAT IL-18 correlated inversely with the expression of macrophages and T-cells. In SAT and PAT most of the mediators associated with body weight. Conclusions Higher expression of IL-18 and IL-6 was observed in EAT in our non-obese CHD patients, not related to inflammatory cells. The NLRP3 inflammasome activation in SAT that mirrored PAT, both related to anthropometrics, suggest that SAT samples, being easily available, to a certain degree, represent adipose tissue inflammation in general.

• Kluge, Karsten Engseth; Langseth, Miriam Sjåstad; Andersen, Geir Øystein; Halvorsen, Sigrun; Opstad, Trine Baur & Arnesen, Harald [Show all 9 contributors for this article] (2022). Complement activation in association with clinical outcomes in ST-elevation myocardial infarction. American Heart Journal Plus: Cardiology Research and Practice (AHJ Plus). 24. doi: 10.1016/j.ahjo.2022.100228. Full text in Research Archive Show summary

  Introduction The complement system and neutrophil extracellular traps (NETs) might contribute to ischemia-reperfusion injury in ST-elevation myocardial infarction (STEMI). We aimed to estimate associations between complement activation and NETs in STEMI, and their prognostic value on clinical endpoints. Methods In this cohort study, 864 patients admitted for PCI during STEMI were included. Complement activation was analyzed by the terminal complement complex (TCC), while NETs were analyzed by myeloperoxidase-DNA, citrullinated histone 3 (CitH3) and dsDNA. The composite endpoint was reinfarction, unscheduled revascularization, stroke, hospitalization due to heart failure, or death, and the secondary endpoint was total mortality. The association between TCC and clinical endpoints was assessed by Cox regression and ROC curve analysis. Results TCC was weakly correlated to dsDNA (r = 0.127, p < 0.001) and CitH3 (r = 0.102, p = 0.003). After a median follow-up time of 4.6 years, 184 (21.3 %) patients had reached a clinical endpoint. TCC was not associated with the composite endpoint, but with total mortality (HR: 1.673, 95 % CI: [1.014, 2.761], p = 0.044). The significant association was lost when adjusting for CRP, NT-proBNP, LVEF and time from symptoms to PCI. In ROC curve analysis of total mortality, the AUC for TCC alone was 0.549 (95 % CI: [0.472, 0.625]), AUC for dsDNA alone was 0.653 (95 % CI: [0.579, 0.720]), while AUC for TCC and dsDNA combined was 0.660 (95 % CI: [0.590, 0.730]). Conclusions In this STEMI cohort, TCC was not associated with the composite endpoint, but somewhat with total mortality. Combining TCC and dsDNA did not increase the prognostic value compared to dsDNA alone.

• Rypdal, Karoline Bjarnesdatter; Erusappan, Pugazendhi Murugan; Melleby, Arne Olav; Seifert, Deborah E.; Palmero, Sheryl & Strand, Mari Elen [Show all 13 contributors for this article] (2021). The extracellular matrix glycoprotein ADAMTSL2 is increased in heart failure and inhibits TGFβ signalling in cardiac fibroblasts. Scientific Reports. 11(1), p. 1–15. doi: 10.1038/s41598-021-99032-2. Full text in Research Archive Show summary

  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.

• Frisk, Michael; Le, Christopher; Shen, Xin; Røe, Åsmund Treu; Hou, Yufeng & Manfra, Ornella [Show all 24 contributors for this article] (2021). Etiology-dependent impairment of diastolic cardiomyocyte calcium homeostasis in heart failure with preserved ejection fraction. Journal of the American College of Cardiology. ISSN 0735-1097. 77(4), p. 405–419. doi: 10.1016/j.jacc.2020.11.044. Full text in Research Archive Show summary

  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.

• Martinsson, Andreas; Nielsen, Susanne J.; Milojevic, Milan; Redfors, Björn; Omerovic, Elmir & Tønnessen, Theis [Show all 9 contributors for this article] (2021). Life expectancy after surgical aortic valve replacement. Journal of the American College of Cardiology. ISSN 0735-1097. 78(22), p. 2147–2157. doi: 10.1016/j.jacc.2021.09.861. Full text in Research Archive Show summary

  Background Surgical risk, age, perceived life expectancy, and valve durability influence the choice between surgical aortic valve replacement (SAVR) and transcatheter aortic valve implantation. The contemporaneous life expectancy after SAVR, in relation to surgical risk and age, is unknown. Objectives The purpose of this study was to determine median survival time in relation to surgical risk and chronological age in SAVR patients. Methods Patients ≥60 years with aortic stenosis who underwent isolated SAVR with a bioprosthesis (n = 8,353) were risk-stratified before surgery into low, intermediate, or high surgical risk using the logistic EuroSCORE (2001-2011) or EuroSCORE II (2012-2017) and divided into age groups. Median survival time and cumulative 5-year mortality were estimated with Kaplan-Meier curves. Cox regression analysis was used to further determine the importance of age. Results There were 7,123 (85.1%) low-risk patients, 942 (11.3%) intermediate-risk patients, and 288 (3.5%) high-risk patients. Median survival time was 10.9 years (95% confidence interval: 10.6-11.2 years) in low-risk, 7.3 years (7.0-7.9 years) in intermediate-risk, and 5.8 years (5.4-6.5 years) in high-risk patients. The 5-year cumulative mortality was 16.5% (15.5%-17.4%), 30.7% (27.5%-33.7%), and 43.0% (36.8%-48.7%), respectively. In low-risk patients, median survival time ranged from 16.2 years in patients aged 60 to 64 years to 6.1 years in patients aged ≥85 years. Age was associated with 5-year mortality only in low-risk patients (interaction P < 0.001). Conclusions Eighty-five percent of SAVR patients receiving bioprostheses have low surgical risk. Estimated survival is substantial following SAVR, especially in younger, low-risk patients, which should be considered in Heart Team discussions.

• Herum, Kate Louise Møller; Romaine, Andreas; Wang, Ariel; Melleby, Arne Olav; Strand, Mari Elen & Pacheco, Julian [Show all 16 contributors for this article] (2020). Syndecan-4 Protects the Heart From the Profibrotic Effects of Thrombin-Cleaved Osteopontin. Journal of the American Heart Association (JAHA). 9(3). doi: 10.1161/JAHA.119.013518. Full text in Research Archive Show summary

  Background Pressure overload of the heart occurs in patients with hypertension or valvular stenosis and induces cardiac fibrosis because of excessive production of extracellular matrix by activated cardiac fibroblasts. This initially provides essential mechanical support to the heart, but eventually compromises function. Osteopontin is associated with fibrosis; however, the underlying signaling mechanisms are not well understood. Herein, we examine the effect of thrombin‐cleaved osteopontin on fibrosis in the heart and explore the role of syndecan‐4 in regulating cleavage of osteopontin. Methods and Results Osteopontin was upregulated and cleaved by thrombin in the pressure‐overloaded heart of mice subjected to aortic banding. Cleaved osteopontin was higher in plasma from patients with aortic stenosis receiving crystalloid compared with blood cardioplegia, likely because of less heparin‐induced inhibition of thrombin. Cleaved osteopontin and the specific osteopontin peptide sequence RGDSLAYGLR that is exposed after thrombin cleavage both induced collagen production in cardiac fibroblasts. Like osteopontin, the heparan sulfate proteoglycan syndecan‐4 was upregulated after aortic banding. Consistent with a heparan sulfate binding domain in the osteopontin cleavage site, syndecan‐4 was found to bind to osteopontin in left ventricles and cardiac fibroblasts and protected osteopontin from cleavage by thrombin. Shedding of the extracellular part of syndecan‐4 was more prominent at later remodeling phases, at which time levels of cleaved osteopontin were increased. Conclusions Thrombin‐cleaved osteopontin induces collagen production by cardiac fibroblasts. Syndecan‐4 protects osteopontin from cleavage by thrombin, but this protection is lost when syndecan‐4 is shed in later phases of remodeling, contributing to progression of cardiac fibrosis.

• Mohammadzadeh, Naiyereh; Melleby, Arne Olav; Palmero, Sheryl; Sjaastad, Ivar; Chakravarti, Shukti & Engebretsen, Kristin V Thunheim [Show all 9 contributors for this article] (2020). Moderate Loss of the Extracellular Matrix Proteoglycan Lumican Attenuates Cardiac Fibrosis in Mice Subjected to Pressure Overload. Cardiology. ISSN 0008-6312. 145(3), p. 187–198. doi: 10.1159/000505318. Full text in Research Archive
• Kluge, Karsten Engseth; Langseth, Miriam Sjåstad; Opstad, Trine Baur; Pettersen, Alf Åge Reistad; Arnesen, Harald & Tønnessen, Theis [Show all 8 contributors for this article] (2020). Complement Activation in Association with Markers of Neutrophil Extracellular Traps and Acute Myocardial Infarction in Stable Coronary Artery Disease. Mediators of Inflammation. ISSN 0962-9351. 2020. doi: 10.1155/2020/5080743. Full text in Research Archive Show summary

  Complement activation and neutrophil extracellular traps (NETs) have both been suggested to drive atherosclerotic plaque progression. Although experimental studies suggest interplay between these two innate immunity components, the relevance in patients with coronary artery disease (CAD) is unclear. The aim of this study was to assess associations between complement activation and NETs in patients with stable CAD and examine the role of complement activation on clinical outcome. Blood samples from a cohort of patients with angiographically verified stable CAD (n = 1001) were analyzed by ELISA for the terminal complement complex (TCC) and by relative quantification for gene expression of the C5a receptor 1 (C5aR1) as markers of complement activation. As markers of NETs, dsDNA was analyzed by fluorescent nucleic acid stain and myeloperoxidase-DNA (MPO-DNA) by ELISA. Clinical outcome was defined as unstable angina, nonhemorrhagic stroke, acute myocardial infarction (MI), or death (n = 106, whereof 36 MI). Levels of TCC and C5aR1 were not significantly correlated to dsDNA (TCC: r = −0:045, p = 0:153; C5aR1: r = −0:060, p = 0:434) or MPO-DNA (TCC: r = 0:026, p = 0:414; C5aR1: r = 0:123, p = 0:107). When dividing TCC and C5aR1 levels into quartiles (Q), levels of MPO-DNA differed significantly across quartiles (TCC: p = 0:008, C5aR1: 0.049), while dsDNA did not (TCC: p = 0:181, C5aR1: p = 0:771). Patients with TCC levels in Q4 had significantly higher levels of MPO-DNA than Q1-3 (p = 0:019), and C5aR1 levels in Q3-4 had significantly higher levels of MPO-DNA than Q1-2 (p = 0:046). TCC levels did not differ between patients experiencing a clinical endpoint or not, but high levels were associated with increased risk of acute MI (OR. 1.97, 95% CI: 0.99-3.90, p = 0:053) during two-year follow up, also when adjusted for relevant covariates. In conclusion, TCC and C5aR1 were moderately associated with the NET marker MPO-DNA, and TCC levels were related to the risk of future MI in this cohort of patients with stable CAD.

• Danielsen, Stein Ove; Moons, Philip; Leegaard, Marit; Solheim, Svein; Tønnessen, Theis & Lie, Irene (2020). Facilitators of and barriers to reducing thirty-day readmissions and improving patient-reported outcomes after surgical aortic valve replacement: a process evaluation of the AVRre trial. BMC Health Services Research. 20(256). doi: 10.1186/s12913-020-05125-5. Full text in Research Archive Show summary

  Background: The Aortic Valve Replacement Readmission (AVRre) randomized control trial tested whether a telephone intervention would reduce hospital readmissions following surgical aortic valve replacement (SAVR). The telephone support provided 30 days of continuous phone-support (hotline) and two scheduled phone-calls from the hospital after discharge. The intervention had no effect on reducing 30-day all-cause readmission rate (30- DACR) but did reduce participants’ anxiety compared to a control group receiving usual care. Depression and participant-reported health state were unaffected by the intervention. To better understand these outcomes, we conducted a process evaluation of the AVRre trial to gain insight into the (1) the dose and fidelity of the intervention, (2) mechanism of impacts, and (3) contextual factors that may have influenced the outcomes. Methods: The process evaluation was informed by the Medical Research Council framework, a widely used set of guidelines for evaluating complex interventions. A mix of quantitative (questionnaire and journal records) and qualitative data (field notes, memos, registration forms, questionnaire) was prospectively collected, and retrospective interviews were conducted. We performed descriptive analyses of the quantitative data. Content analyses, assisted by NVivo, were performed to evaluate qualitative data. Results: The nurses who were serving the 24/7 hotline intervention desired to receive more preparation before intervention implementation. SAVR patient participants were highly satisfied with the telephone intervention (58%), felt safe (86%), and trusted having the option of calling in for support (91%). The support for the telephone hotline staff was perceived as a facilitator of the intervention implementation. Content analyses revealed themes: “gap in the care continuum,” “need for individualized care,” and “need for easy access to health information” after SAVR. Differences in local hospital discharge management practices influenced the 30-DACR incidence. Conclusions: The prospective follow-up of the hotline service during the trial facilitated implementation of the intervention, contributing to high participant satisfaction and likely reduced their anxiety after SAVR. Perceived less- than-optimal preparations for the hotline could be a barrier to AVRre trial implementation. Integrating user experiences into a mixed-methods evaluation of clinical trials is important for broadening understanding of trial outcomes, the mechanism of impact, and contextual factors that influence clinical trials.

• Mennander, Ari; Gudbjartsson, Tomas; Jeppsson, Anders; Hjortdal, Vibeke & Tønnessen, Theis (2019). Specialist training for cardiothoracic surgery in the Nordic countries. Journal of Thoracic and Cardiovascular Surgery. ISSN 0022-5223. doi: 10.1016/j.jtcvs.2019.07.110. Full text in Research Archive Show summary

  Sweden, Denmark, Finland, Norway, and Iceland form the 5 culturally uniform Nordic countries. Each of the countries owns a high-standard tradition of individual steering in cardiothoracic education aiming at securing the needs and features of the local area. Indisputably, mastering a Nordic language and applying a high-standard individual steering in education ensure that a dedicated trainee is selected to the cardiothoracic program in accordance with the needs and features of the local area.

• Mohammadzadeh, Naiyereh; Lunde, Ida Gjervold; Andenæs, Kine; Strand, Mari Elen; Aronsen, Jan Magnus & Skrbic, Biljana [Show all 15 contributors for this article] (2019). The extracellular matrix proteoglycan lumican improves survival and counteracts cardiac dilatation and failure in mice subjected to pressure overload. Scientific Reports. 9:9206, p. 1–13. doi: 10.1038/s41598-019-45651-9. Full text in Research Archive Show summary

  Left ventricular (LV) dilatation is a key step in transition to heart failure (HF) in response to pressure overload. Cardiac extracellular matrix (ECM) contains fibrillar collagens and proteoglycans, important for maintaining tissue integrity. Alterations in collagen production and cross-linking are associated with cardiac LV dilatation and HF. Lumican (LUM) is a collagen binding proteoglycan with increased expression in hearts of patients and mice with HF, however, its role in cardiac function remains poorly understood. To examine the role of LUM in pressure overload induced cardiac remodeling, we subjected LUM knock-out (LUMKO) mice to aortic banding (AB) and treated cultured cardiac fibroblasts (CFB) with LUM. LUMKO mice exhibited increased mortality 1–14 days post-AB. Echocardiography revealed increased LV dilatation, altered hypertrophic remodeling and exacerbated contractile dysfunction in surviving LUMKO 1–10w post-AB. LUMKO hearts showed reduced collagen expression and cross-linking post-AB. Transcriptional profiling of LUMKO hearts by RNA sequencing revealed 714 differentially expressed transcripts, with enrichment of cardiotoxicity, ECM and inflammatory pathways. CFB treated with LUM showed increased mRNAs for markers of myofibroblast differentiation, proliferation and expression of ECM molecules important for fibrosis, including collagens and collagen cross-linking enzyme lysyl oxidase. In conclusion, we report the novel finding that lack of LUM attenuates collagen cross-linking in the pressure-overloaded heart, leading to increased mortality, dilatation and contractile dysfunction in mice.

• Bjørnnes, Ann Kristin; Moons, Philip; Parry, Monica; Halvorsen, Sigrun; Tønnessen, Theis & Lie, Irene (2019). Experiences of informal caregivers after cardiac surgery: a systematic integrated review of qualitative and quantitative studies. BMJ Open. 9:e032751(11), p. 1–10. doi: 10.1136/bmjopen-2019-032751. Full text in Research Archive Show summary

  Objectives: To provide a comprehensive synthesis of informal caregivers’ experiences of caring for a significant other following discharge from cardiac surgery. Design: Systematic integrated review without meta-analysis. Data sources: A bibliographic search for publications indexed in six databases (Cochrane Library, CINAHL, MEDLINE, EMBASE, AMED and PsycINFO), including a scan of grey literature sources (GreyNet International, Google Scholar, Web of Science, WorldCat and the Clinical Trials Registry) was conducted in October 2018. Eligibility criteria for selecting: studies Studies were included if they described views and perspectives of informal caregivers of cardiac surgery patients (non-intervention studies (qualitative and quantitative)), and the effectiveness of interventions to evaluate support programme for informal caregivers of cardiac surgery patients (intervention studies). Results: Of the 4912 articles identified in searches, 42 primary research studies were included in a narrative synthesis with 5292 participants, including 3231 (62%) caregivers of whom 2557 (79%) were women. The median sample size across studies was 96 (range 6–734). Three major themes emerged from the qualitative study data: (1) caregiver information needs; (2) caregiver work challenges and (3) caregivers adaption to recovery. Across the observational studies (n=22), similar themes were found. The trend across seven intervention studies focused on caregiver information needs related to patient disease management and symptom monitoring, and support for caregivers to reduce symptoms of emotional distress. Conclusion: Informal caregivers want to assist in the care of their significant others after hospital discharge postcardiac surgery. However, caregivers feel insecure and overwhelmed and they lack clear/concise discharge information and follow-up support during the early at-home recovery period. The burden of caregiving has been recognised and reported since the early 1990s, but there remains a limited number of studies that assesses the effectiveness of caregiver interventions.

• Braathen, Bjørn; Husebye, Trygve Guttorm; Lunde, Ida Gjervold & Tønnessen, Theis (2019). Trifecta has lower gradient and less prosthesis-patient mismatch than Mosaic Ultra in the aortic position: a prospective randomized study. Journal of Thoracic and Cardiovascular Surgery. ISSN 0022-5223. p. 1–9. doi: 10.1016/j.jtcvs.2018.11.020. Full text in Research Archive
• Nuru, Abdul; Weltzien, Joachim Hagesveen; Sandvik, Leiv; Tønnessen, Theis & BJØRNSTAD, JOHANNES (2019). Short- and long-term survival after isolated coronary artery bypass grafting, the impact of gender and age. Scandinavian Cardiovascular Journal. ISSN 1401-7431. p. 1–6. doi: 10.1080/14017431.2019.1646430. Full text in Research Archive Show summary

  Objectives. Assess the short- and long-term survival for patients who underwent isolated coronary artery bypass grafting (CABG) and evaluate the impact of gender and age. Furthermore to assess the long-term survival in the CABG group compared to the general population. Design. This study included 4044 consecutive patients who underwent isolated CABG at Oslo University Hospital, Ullevål, in Oslo, Norway in the time period from 01 January 2003 to 31 December 2015. Patient data was collected retrospectively from the quality register at the department. Information on survival status was obtained from the Norwegian National Registry. Life expectancy data for the general population was gained from Statistics Norway. Results. Female patients were significantly older than male patients at the time of surgery (mean age 67.0 and 63.9 years, respectively, p < .001), and had significantly lower 30-day survival (mortality was 1.4% and 0.6%, respectively, p = .017). Male gender was independently associated with lower long-term survival (p = .0037) in a multivariate analysis. Male patients aged less than 60 years also showed significantly lower long-term survival (SMR = 1.84, 95% CI = 1.49–2.25) compared to the age-matched general population. Among patients older than 60 years, survival was similar to survival in the age-matched general population. Conclusions. Survival was excellent for patients undergoing surgery. Despite increased age and operative mortality, female patients had better adjusted long-time survival than male patients. There was lower long-term survival among male patients aged less than 60 compared to the general population. Our findings may help clinicians in selecting appropriate patients for surgery.

• Tønnessen, Theis (2019). Cardiac Amyloidosis – A Devil in Disguise. Cardiology. ISSN 0008-6312. 142(4), p. 250–252. doi: 10.1159/000500448. Full text in Research Archive
• Danielsen, Stein Ove; Moons, Philip; Sandvik, Leiv; Leegaard, Marit; Solheim, Svein & Tønnessen, Theis [Show all 7 contributors for this article] (2019). Impact of telephone follow-up and 24/7 hotline on 30-day readmission rates following aortic valve replacement - A randomized controlled trial. International Journal of Cardiology. ISSN 0167-5273. doi: 10.1016/j.ijcard.2019.07.087. Full text in Research Archive Show summary

  Background: Thirty-day all-cause readmissions are high after aortic valve replacement (AVR). We aimed to assess the effectiveness of a structured telephone follow-up (TFU) and a 24/7 hotline on reducing 30-day all-cause readmission (30-DACR) after AVR, on reducing symptoms of anxiety and depression and on improving perceived health state. Methods: A prospective randomized controlled trial was conducted. Patients (n = 288) were randomly allocated to either post-discharge usual care or to care that provided TFU and access to a 24/7 hotline after AVR. Ancillary endpoints were time-to-event (readmission), proportion of avoidable versus unavoidable readmissions after AVR, and predictors of 30-DACR after AVR. Results: 30-DACR was 22.3%. The structured TFU and 24/7 hotline intervention failed to reduce 30-DACR rates after AVR (P = 0.274). Symptoms of anxiety were significantly reduced 30 days after surgery (P = 0.031), an effect that did not persist one year after surgery (P = 0.108). Most readmissions occurred before 15 days post-discharge, and 75% of them were deemed to be unavoidable. Pleural drainage before hospital discharge (P = 0.027) and symptoms of anxiety before surgery (P = 0.003) were predictors of 30-DACR after AVR. Conclusion: The TFU and 24/7 hotline had no effect on reducing 30-DACR after AVR. However, we did measure reduced symptoms of anxiety the first month after AVR. Anxiety reduction appeared to be an important target for intervention, because we found it to be a risk factor for readmission. Future research should focus on the effectiveness of interventions to prevent avoidable unplanned readmissions.

• Danielsen, Stein Ove; Moons, Philip; Sandven, Irene; Leegaard, Marit; Solheim, Svein & Tønnessen, Theis [Show all 7 contributors for this article] (2018). Thirty-day readmissions in surgical and transcatheter aortic valve replacement: A systematic review and meta-analysis. International Journal of Cardiology. ISSN 0167-5273. doi: 10.1016/j.ijcard.2018.05.026. Full text in Research Archive Show summary

  Background: The 30-day all-cause readmission rate after surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR) vary substantially. We conducted a systematic review and meta-analysis to examine the overall incidence, causes, and risk factors of 30-day all-cause readmission rate after SAVR and TAVR. Methods: Eight medical research databases were searched; Cochrane, Medline, Embase, UpToDate, PROSPERO, National Guideline Clearinghouse, SweMed and Oria. We followed The Preferred Reporting Items for Systematic reviews and Meta-analysis (PRISMA) for this study. Results: Thirty-three articles were included in the systematic review, 32 of which were appropriate for the meta-analysis. Overall, 17% (95% CI: 16-18%) of patients in the SAVR group, and 16% (95% CI: 15-18%) in the TAVR groups were readmitted within 30 days. Heart failure, arrhythmia, infection, and respiratory problems were the most frequent causes of all-cause readmission after SAVR and TAVR. Most frequent reported prior risk factors for all-cause readmission following TAVR were diabetes, chronic lung disease/chronic obstructive pulmonary disease, atrial fibrillation, kidney problems, and transapical approach/nonfemoral access. For SAVR, no risk factors for 30-day all-cause readmission were reported in the literature to date. Conclusion: In conclusion, the overall proportion of 30-day all-cause readmission after SAVR and TAVR are high. Interventions to prevent avoidable readmissions ought to be developed and implemented.

• Andenæs, Kine; Lunde, Ida Gjervold; Mohammadzadeh, Naiyereh; Dahl, Christen Peder; Aronsen, Jan Magnus & Strand, Mari Elen [Show all 11 contributors for this article] (2018). The extracellular matrix proteoglycan fibromodulin is upregulated in clinical and experimental heart failure and affects cardiac remodeling. PLOS ONE. 13(7), p. 1–20. doi: 10.1371/journal.pone.0201422. Full text in Research Archive Show summary

  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.

• Lie, Irene; Danielsen, Stein Ove; Tønnessen, Theis; Solheim, Svein; Leegaard, Marit & Sandvik, Leiv [Show all 10 contributors for this article] (2017). Determining the impact of 24/7 phone support on hospital readmissions after aortic valve replacement surgery (the AVRre study): Study protocol for a randomised controlled trial. Trials. 18:246, p. 1–9. doi: 10.1186/s13063-017-1971-y. Full text in Research Archive
• Parikh, Shan S.; Blackwell, Daniel J.; Gomez-Hurtado, Nieves; Frisk, Michael; Wang, Lili & Kim, Kyungsoo [Show all 12 contributors for this article] (2017). Thyroid and glucocorticoid hormones promote functional t-tubule Development in human-induced pluripotent stem cell-derived cardiomyocytes. Circulation Research. ISSN 0009-7330. 121(12), p. 1323–1330. doi: 10.1161/CIRCRESAHA.117.311920. Full text in Research Archive
• Lie, Irene; Danielsen, Stein Ove; Tønnessen, Theis; Solheim, Svein; Leegaard, Marit & Sandvik, Leiv [Show all 10 contributors for this article] (2017). Determining the impact of 24/7 phone support on hospital readmissions after aortic valve replacement surgery (the AVRre study): study protocol for a randomised controlled trial. Trials. 18. doi: 10.1186/s13063-017-1971-y. Full text in Research Archive
• Kaljusto, Mari-Liis; Skaga, Nils Oddvar; Pillgram, Johan Larsen & Tønnessen, Theis (2015). Survival predictor for penetrating cardiac injury; a 10-year consecutive cohort from a scandinavian trauma center. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine. 23(1). doi: 10.1186/s13049-015-0125-z. Full text in Research Archive Show summary

  Background Penetrating cardiac injuries in Europe have been poorly studied. We present a 10-year outcome for patients with penetrating heart injuries at Oslo University Hospital. Methods Data from 01.01.2001 until 31.12.2010 was collected from the Oslo University Hospital Trauma Registry and from the patients’ records. Results Thirty-one patients were admitted with a penetrating cardiac injury. Fourteen patients survived (45 %). Four out of 8 patients (50 %) with gunshot wounds survived compared to 10 out of 23 (44 %) with stab wounds. Median (quartiles) for the following values were: Injury Severity Score 25 (21–35), Revised Trauma Score 0 (0–6,9), Probability of Survival 0,015 (0,004–0,956), Glasgow Coma Scale 3 (3–13). Thirteen patients had signs of life on admission and survived. Eighteen patients were admitted without signs of life and received emergency department thoracotomy. Eight of these had no signs of life at the scene of injury and did not survive. Out of the remaining 10 patients, one survived. Conclusions The outcome of patients with penetrating cardiac injury reaching the emergency department with signs of life was excellent. Hemodynamic instability indicates immediate surgery. Stable patients with penetrating thoracic trauma and possible cardiac injury detected by imaging should be considered for conservative treatment. Published Open Access with Springerlink.com

• Herum, Kate Louise Møller; Lunde, Ida Gjervold; Skrbic, Biljana; Louch, William Edward; Hasic, Almira & Boye, Sigurd [Show all 13 contributors for this article] (2015). Syndecan-4 is a key determinant of collagen cross-linking and passive myocardial stiffness in the pressure-overloaded heart. Cardiovascular Research (CVR). ISSN 0008-6363. 106, p. 217–226. doi: 10.1093/cvr/cvv002. Full text in Research Archive
• Majak, Piotr; Lunde, Ida Gjervold; Hasic, Almira; Husebye, Trygve Guttorm; Christensen, Geir Arve & Tønnessen, Theis [Show all 7 contributors for this article] (2015). Reduced visfatin levels in aortic stenosis increase after aortic valve replacement and may contribute to reverse left ventricular remodelling. Journal of Cardiovascular Surgery. ISSN 0021-9509. 56(3), p. 483–492. Full text in Research Archive
• Strand, Mari Elen; Aronsen, Jan Magnus; Braathen, Bjørn; Sjaastad, Ivar; Kvaløy, Heidi & Tønnessen, Theis [Show all 8 contributors for this article] (2015). Shedding of syndecan-4 promotes immune cell recruitment and mitigates cardiac dysfunction after lipopolysaccharide challenge in mice. Journal of Molecular and Cellular Cardiology. ISSN 0022-2828. 88, p. 133–144. doi: 10.1016/j.yjmcc.2015.10.003. Full text in Research Archive Show summary

  Inflammation is central to heart failure progression. Innate immune signaling increases expression of the transmembrane proteoglycan syndecan-4 in cardiac myocytes and fibroblasts, followed by shedding of its ectodomain. Circulating shed syndecan-4 is increased in heart failure patients, however the pathophysiological and molecular consequences associated with syndecan-4 shedding remain poorly understood. Here we used lipopolysaccharide (LPS) challenge to investigate the effects of syndecan-4 shedding in the heart. Wild-type mice (10 mg/kg, 9 h) and cultured neonatal rat cardiomyocytes and fibroblasts were subjected to LPS challenge. LPS increased cardiac syndecan-4 mRNA without altering full-length protein. Elevated levels of shedding fragments in the myocardium and blood from the heart confirmed syndecan-4 shedding in vivo. A parallel upregulation of ADAMTS1, ADAMTS4 and MMP9 mRNA suggested these shedding enzymes to be involved. Echocardiography revealed reduced ejection fraction, diastolic tissue velocity and prolonged QRS duration in mice unable to shed syndecan-4 (syndecan-4 KO) after LPS challenge. In line with syndecan-4 shedding promoting immune cell recruitment, expression of immune cell markers (CD8, CD11a, F4/80) and adhesion receptors (Icam1, Vcam1) were attenuated in syndecan-4 KO hearts after LPS. Cardiomyocytes and fibroblasts exposed to shed heparan sulfate-substituted syndecan-4 ectodomains showed increased Icam1, Vcam1, TNFα and IL-1β expression and NF-κB-activation, suggesting direct regulation of immune cell recruitment pathways. In cardiac fibroblasts, shed ectodomains regulated expression of extracellular matrix constituents associated with collagen synthesis, cross-linking and turnover. Higher syndecan-4 levels in the coronary sinus vs. the radial artery of open heart surgery patients suggested that syndecan-4 is shed from the human heart. Our data demonstrate that shedding of syndecan-4 ectodomains is part of the cardiac innate immune response, promoting immune cell recruitment, extracellular matrix remodeling and mitigating cardiac dysfunction in response to LPS.

• Skrbic, Biljana; Engebretsen, Kristin V Thunheim; Strand, Mari Elen; Lunde, Ida Gjervold; Herum, Kate Louise Møller & Marstein, Henriette [Show all 12 contributors for this article] (2015). Lack of collagen VIII reduces fibrosis and promotes early mortality and cardiac dilatation in pressure overload in mice. Cardiovascular Research (CVR). ISSN 0008-6363. 106(1), p. 32–42. doi: 10.1093/cvr/cvv041. Full text in Research Archive
• Engebretsen, Kristin V Thunheim; Skårdal, Kristine; Bjørnstad, Sigrid; Marstein, Henriette; Skrbic, Biljana & Sjaastad, Ivar [Show all 9 contributors for this article] (2014). Attenuated development of cardiac fibrosis in left ventricular pressure overload by SM16, an orally active inhibitor of ALK5. Journal of Molecular and Cellular Cardiology. ISSN 0022-2828. 76, p. 148–157. doi: 10.1016/j.yjmcc.2014.08.008. Full text in Research Archive
• Nygård, Ståle; Reitan, Trond; Clancy, Trevor; Nygaard, Vegard; BJØRNSTAD, JOHANNES & Skrbic, Biljana [Show all 9 contributors for this article] (2014). Identifying pathogenic processes by integrating microarray data with prior knowledge. BMC Bioinformatics. 15(1). doi: 10.1186/1471-2105-15-115. Full text in Research Archive Show summary

  Background It is of great importance to identify molecular processes and pathways that are involved in disease etiology. Although there has been an extensive use of various high-throughput methods for this task, pathogenic pathways are still not completely understood. Often the set of genes or proteins identified as altered in genome-wide screens show a poor overlap with canonical disease pathways. These findings are difficult to interpret, yet crucial in order to improve the understanding of the molecular processes underlying the disease progression. We present a novel method for identifying groups of connected molecules from a set of differentially expressed genes. These groups represent functional modules sharing common cellular function and involve signaling and regulatory events. Specifically, our method makes use of Bayesian statistics to identify groups of co-regulated genes based on the microarray data, where external information about molecular interactions and connections are used as priors in the group assignments. Markov chain Monte Carlo sampling is used to search for the most reliable grouping. Results Simulation results showed that the method improved the ability of identifying correct groups compared to traditional clustering, especially for small sample sizes. Applied to a microarray heart failure dataset the method found one large cluster with several genes important for the structure of the extracellular matrix and a smaller group with many genes involved in carbohydrate metabolism. The method was also applied to a microarray dataset on melanoma cancer patients with or without metastasis, where the main cluster was dominated by genes related to keratinocyte differentiation. Conclusion Our method found clusters overlapping with known pathogenic processes, but also pointed to new connections extending beyond the classical pathways.

• Wanichawan, Pimthanya; Lubelwana, Tandekile; Hodne, Kjetil; Aronsen, Jan Magnus; Lunde, Ida Gjervold & Dalhus, Bjørn [Show all 13 contributors for this article] (2014). Molecular basis of calpain cleavage and inactivation of the sodium-calcium exchanger 1 in heart failure. Journal of Biological Chemistry. ISSN 0021-9258. 289(49), p. 33984–33998. doi: 10.1074/jbc.M114.602581. Full text in Research Archive Show summary

  Cardiac sodium (Na+)-calcium (Ca2+) exchanger 1 (NCX1) is central to the maintenance of normal Ca2+ homeostasis and contraction. Studies indicate that the Ca2+-activated protease calpain cleaves NCX1. We hypothesized that calpain is an important regulator of NCX1 in response to pressure overload and aimed to identify molecular mechanisms and functional consequences of calpain binding and cleavage of NCX1 in the heart. NCX1 full-length protein and a 75-kDa NCX1 fragment along with calpain were up-regulated in aortic stenosis patients and rats with heart failure. Patients with coronary artery disease and sham-operated rats were used as controls. Calpain co-localized, co-fractionated, and co-immunoprecipitated with NCX1 in rat cardiomyocytes and left ventricle lysate. Immunoprecipitations, pull-down experiments, and extensive use of peptide arrays indicated that calpain domain III anchored to the first Ca2+ binding domain in NCX1, whereas the calpain catalytic region bound to the catenin-like domain in NCX1. The use of bioinformatics, mutational analyses, a substrate competitor peptide, and a specific NCX1-Met369 antibody identified a novel calpain cleavage site at Met369. Engineering NCX1-Met369 into a tobacco etch virus protease cleavage site revealed that specific cleavage at Met369 inhibited NCX1 activity (both forward and reverse mode). Finally, a short peptide fragment containing the NCX1-Met369 cleavage site was modeled into the narrow active cleft of human calpain. Inhibition of NCX1 activity, such as we have observed here following calpain-induced NCX1 cleavage, might be beneficial in pathophysiological conditions where increased NCX1 activity contributes to cardiac dysfunction.

• Louch, William Edward; Hake, Johan Elon; Mørk, Halvor Kjeang; Hougen, Karina; Skrbic, Biljana & Ursu, Daniel [Show all 9 contributors for this article] (2013). Slow Ca2+ sparks de-synchronize Ca2+ release in failing cardiomyocytes: Evidence for altered configuration of Ca2+ release units? Journal of Molecular and Cellular Cardiology. ISSN 0022-2828. 58, p. 41–52. doi: 10.1016/j.yjmcc.2013.01.014. Full text in Research Archive
• Strand, Mari Elen; Herum, Kate Louise Møller; Rana, Zaheer Ahmad; Skrbic, Biljana; Askevold, Erik Tandberg & Dahl, Christen Peder [Show all 15 contributors for this article] (2013). 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. The FEBS Journal. ISSN 1742-464X. 280(10), p. 2228–2247. doi: 10.1111/febs.12161. Full text in Research Archive
• Engebretsen, Kristin V Thunheim; Lunde, Ida Gjervold; Strand, Mari Elen; Sjaastad, Ivar; Marstein, Henriette & Skrbic, Biljana [Show all 12 contributors for this article] (2013). Lumican is increased in experimental and clinical heart failure, and its production by cardiac fibroblasts is induced by mechanical and proinflammatory stimuli. The FEBS Journal. ISSN 1742-464X. 280(10), p. 2382–2398. doi: 10.1111/febs.12235. Full text in Research Archive
• Engebretsen, Kristin V Thunheim; Wæhre, Anne; BJØRNSTAD, JOHANNES; Skrbic, Biljana; Sjaastad, Ivar & Behmen, Dina [Show all 11 contributors for this article] (2013). Decorin, lumican, and their GAG chain-synthesizing enzymes are regulated in myocardial remodeling and reverse remodeling in the mouse. Journal of applied physiology. ISSN 8750-7587. 114(8), p. 988–997. doi: 10.1152/japplphysiol.00793.2012. Full text in Research Archive
• Skrbic, Biljana; BJØRNSTAD, JOHANNES; Marstein, Henriette; Carlson, Cathrine Rein; Sjaastad, Ivar & Nygård, Ståle [Show all 9 contributors for this article] (2013). Differential regulation of extracellular matrix constituents in myocardial remodeling with and without heart failure following pressure overload. Matrix Biology. ISSN 0945-053X. 32(2), p. 133–142. doi: 10.1016/j.matbio.2012.11.011. Full text in Research Archive
• Majak, Piotr; Braathen, Bjørn; BJØRNSTAD, JOHANNES & Tønnessen, Theis (2012). GDF-15 is increased during early reperfusion following aortic valve replacement. Scandinavian Cardiovascular Journal. ISSN 1401-7431. 46(2), p. 99–106. doi: 10.3109/14017431.2011.649489. Full text in Research Archive
• Sadi, Lin; Tønnessen, Theis & Pillgram, Johan Larsen (2012). Short and long-term survival in type A aortic dissection justifies the operative risk and effort. Scandinavian Cardiovascular Journal. ISSN 1401-7431. 46(1), p. 45–50. doi: 10.3109/14017431.2011.626439. Full text in Research Archive
• Bjørnstad, Johannes L.; Skrbic, Biljana; Sjaastad, Ivar; Bjørnstad, Sigrid; Christensen, Geir Arve & Tønnessen, Theis (2012). A mouse model of reverse cardiac remodelling following banding-debanding of the ascending aorta. Acta Physiologica. ISSN 1748-1708. 205(1), p. 92–102. doi: 10.1111/j.1748-1716.2011.02369.x. Full text in Research Archive
• BJØRNSTAD, JOHANNES; Skrbic, Biljana; Marstein, Henriette; Hasic, Almira; Sjaastad, Ivar & Louch, William Edward [Show all 9 contributors for this article] (2012). Inhibition of SMAD2 phosphorylation preserves cardiac function during pressure overload. Cardiovascular Research (CVR). ISSN 0008-6363. 93(1), p. 100–110. doi: 10.1093/cvr/cvr294. Full text in Research Archive
• Kaljusto, Mari-Liis & Tønnessen, Theis (2012). How to mend a broken heart: a major stab wound of the left ventricle. World Journal of Emergency Surgery. p. 17–17. doi: 10.1186/1749-7922-7-17. Full text in Research Archive Show summary

  A 28-year-old male admitted with a stab wound under his left nipple, underwent emergency surgery because of confusion, a decreasing blood pressure and increasing tachycardia. A median sternotomy incision was made and after establishing cardiopulmonary bypass, a 7 cm wound in the left ventricle and a smaller wound in the left atrium were repaired. An injured segment of lung was resected and the left anterior descending and circumflex arteries were grafted after weaning from cardiopulmonary bypass was initially unsuccessful. Although the patient suffered a stroke, probably due to prehospital hypoperfusion, he eventually recovered without major sequelae. In addition to the case report we present a literature review of the last 15 years pertaining the management of penetrating cardiac injury.

• Lunde, Ida Gjervold; Aronsen, Jan Magnus; Kvaløy, Heidi; Qvigstad, Eirik; Sjaastad, Ivar & Tønnessen, Theis [Show all 9 contributors for this article] (2012). Cardiac O-GlcNAc signaling is increased in hypertrophy and heart failure. Physiological Genomics. ISSN 1094-8341. 44(2), p. 162–172. doi: 10.1152/physiolgenomics.00016.2011. Full text in Research Archive

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• Højskov, Ida; Bjørnnes, Ann Kristin; Tønnessen, Theis; Halvorsen, Sigrun; Blakø, Mitti & Møller, Christian H. [Show all 10 contributors for this article] (2023). Informal caregivers must open the door to information during heart surgery patients hospitalization. A qualitative study. Full text in Research Archive
• Lie, Irene; Moons, Philip; Tønnessen, Theis; Halvorsen, Sigrun; Blakø, Mitti & Christian, Møller [Show all 10 contributors for this article] (2023). Experiences of informal caregivers taking care of heart surgery patients after discharge from hospital: A qualitative study. Full text in Research Archive
• Neerland, Bjørn Erik; Busund, Rolf; Haaverstad, Rune; Helbostad, Jorunn L.; Landsverk, Svein A. & Martinaityte, Ieva [Show all 19 contributors for this article] (2022). Alpha-2-adrenergic receptor agonists for the prevention of delirium and cognitive decline after open heart surgery (ALPHA2PREVENT): protocol for a multicentre randomised controlled trial. BMJ Open. 12(6). doi: 10.1136/bmjopen-2021-057460. Full text in Research Archive
• Tønnessen, Theis; Christensen, Geir; Carlson, Cathrine Rein; Skrbic, Biljana & Sjaastad, Ivar (2022). Calcineurin-NFAT dynamics corresponds to cardiac remodeling during aortic banding and debanding, mimicking aortic valve replacement. Frontiers in Molecular Medicine for Cardiology. doi: 10.3389/fmmed.2022.980717. Full text in Research Archive
• Kluge, Karsten Engseth; Langseth, Miriam Sjåstad; Bratset, Vibeke; Pettersen, Alf Åge Reistad; Arnesen, Harald & Tønnessen, Theis [Show all 8 contributors for this article] (2020). Circulating levels of the terminal complement complex are associated with hypercoagulability in patients with stable coronary artery disease. Thrombosis Research. ISSN 0049-3848. 196, p. 106–108. doi: 10.1016/j.thromres.2020.08.023. Full text in Research Archive
• Parikh, Shan; Blackwell, DJ; Gomez-Hurtado, N; Frisk, Michael; Wang, L & Kim, K [Show all 11 contributors for this article] (2017). Thyroid and Glucocorticoid Hormones Promote Functional T-tubule Development in Human Induced Pluripotent Stem Cell Derived Cardiomyocytes. Circulation. ISSN 0009-7322. 136, p. A14975–A14975. Full text in Research Archive
• Danielsen, Stein Ove; Moons, Philip; Tønnessen, Theis; Solheim, Svein; Leegaard, Marit & Lie, Irene (2017). 24/7 telephone support after discharge for surgical aortic valve replacement as a potential lifesaving intervention -a clinical case from the AVRre study. Full text in Research Archive
• Ruud, Marianne; Frisk, Michael; Aronsen, Jan Magnus; Dahl, Christen Peder; Jølle, Guro Five & Aakhus, Svend [Show all 15 contributors for this article] (2016). Mechanical load regulates cardiomyocyte t-tubular structure and Ca2+ homeostasis. Full text in Research Archive
• Mohammadzadeh, Naiyereh; Engebretsen, Kristin; Lunde, Ida Gjervold; Sjaastad, Ivar; Strand, Mari Elen & Marstein, Henriette [Show all 14 contributors for this article] (2016). Lack of the extracellular matrix proteoglycan lumican leads to ventricular dilatation, attenuated hypertrophy and contractile dysfunction in response to pressure overload. Full text in Research Archive
• Mohammadzadeh, Naiyereh; Engebretsen, Kristin V Thunheim; Lunde, Ida Gjervold; Sjaastad, Ivar; Strand, Mari Elen & Marstein, Henriette [Show all 14 contributors for this article] (2016). Lack of the extracellular matrix proteoglycan lumican leads to cardiac dysfunction in response to pressure overload. Full text in Research Archive
• Frisk, Michael; Aronsen, Jan Magnus; Dahl, Christen Peder; Lunde, Ida Gjervold; Jølle, Guro Five & Almaas, Victor [Show all 13 contributors for this article] (2015). Maintained cardiomyocyte t-tubule structure and function in patients with non-dilated hypertrophy. Full text in Research Archive
• Mohammadzadeh, Naiyereh; Andenæs, Kine; Engebretsen, Kristin V.; Lunde, Ida Gjervold; Sjaastad, Ivar & Marstein, Henriette [Show all 12 contributors for this article] (2015). The role of lumican in Cardiac pressure overload. Full text in Research Archive
• Andenæs, Kine; Mohammadzadeh, Naiyereh; Lunde, Ida Gjervold; Strand, Mari Elen; Marstein, Henriette & Dahl, Christen Peder [Show all 10 contributors for this article] (2015). The extracellular matrix proteoglycan fibromodulin is up-regulated in experimental and clinical heart failure, and might be involved in regulation of myocardial fibrosis by interacting with TGF-B. Full text in Research Archive
• Strand, Mari Elen; Aronsen, Jan Magnus; Braathen, Bjørn; Sjaastad, Ivar; Kvaløy, Heidi & Tønnessen, Theis [Show all 8 contributors for this article] (2015). Shedding of syndecan-4 promotes immune cell recruitment and mitigates cardiac dysfunction after lipopolysaccharide challenge in mice. Full text in Research Archive
• Mohammadzadeh, Naiyereh; Andenæs, Kine; Engebretsen, Kristin V Thunheim; Lunde, Ida Gjervold; Sjaastad, Ivar & Marstein, Henriette [Show all 12 contributors for this article] (2015). The role of lumican in Cardiac pressure overload. Full text in Research Archive
• Bandlien, Caroline; Engebretsen, Kristin V Thunheim; Skrbic, Biljana; Marstein, Henriette; Lunde, Ida Gjervold & Sjaastad, Ivar [Show all 9 contributors for this article] (2014). Lack of lumican in cardiac pressure overload attenuates development of cardiac fibrosis leading to premature left ventricle dilatation. Full text in Research Archive
• Strand, Mari Elen; Skrbic, Biljana; Kvaløy, Heidi; Sjaastad, Ivar; Tønnessen, Theis & Christensen, Geir Arve [Show all 7 contributors for this article] (2014). Syndecan-4 shedding mediates innate immune responses of the heart to lipopolysaccharide challenge and pressure overload. Full text in Research Archive
• Melleby, Arne Olav; Strand, Mari Elen; Skrbic, Biljana; Dahl, Christen Peder; Tønnessen, Theis & Sjaastad, Ivar [Show all 10 contributors for this article] (2014). Glypican 6 is up-regulated in pressure overload induced pathological left ventricular remodeling, mediates bFGF signaling and may affect cardiac fibrosis development. Full text in Research Archive
• Herum, Kate Louise Møller; Lunde, Ida Gjervold; Skrbic, Biljana; Louch, William Edward; Hasic, Almira & Boye, Sigurd [Show all 13 contributors for this article] (2014). Syndecan-4 is a key determinant of collagen cross-linking and myocardial stiffness in the pressure-overloaded heart. Full text in Research Archive
• Strand, Mari Elen; Skrbic, Biljana; Kvaløy, Heidi; Sjaastad, Ivar; Tønnessen, Theis & Christensen, Geir Arve [Show all 7 contributors for this article] (2014). Syndecan-4 shedding mediates immune cell infiltration to the heart in response to lipopolysaccharide challenge. Full text in Research Archive
• Bandlien, Caroline; Engebretsen, Kristin V Thunheim; Skrbic, Biljana; Lunde, Ida Gjervold; Sjaastad, Ivar & Christensen, Geir Arve [Show all 7 contributors for this article] (2014). Lack of lumican in cardiac pressure overload attenuates development of cardiac fibrosis leading to premature left ventricle dilatation. Full text in Research Archive
• Hodne, Kjetil; Wanichawan, Pimthanya; Hafver, Tandekile Lubelwana; Aronsen, Jan Magnus; Lunde, Ida Gjervold & Lunde, Marianne [Show all 12 contributors for this article] (2014). Identification and functional role of calpain cleavage site in Na+-Ca2+ exchanger 1 (NCX1). Biophysical Journal. ISSN 0006-3495. 106, p. 762a–762a. Full text in Research Archive
• Herum, Kate Louise Møller; Lunde, Ida Gjervold; Skrbic, Biljana; Tønnessen, Theis; Louch, William Edward & Hasic, Almira [Show all 10 contributors for this article] (2014). Syndecan-4 promotes myocardial stiffness by regulating collagen expression and cross-linking in response to pressure overload. The FASEB Journal. ISSN 0892-6638. 28. Full text in Research Archive
• Melleby, Arne Olav; Strand, Mari Elen; Skrbic, Biljana; Dahl, Christen Peder; Tønnessen, Theis & Sjaastad, Ivar [Show all 10 contributors for this article] (2014). The heparan sulfate proteoglycan glypican-6 is increased in experimental and clinical heart failure and might play a role in myocardial fibrosis. European Journal of Heart Failure. ISSN 1388-9842. 16, p. 116–116. Full text in Research Archive
• Strand, Mari Elen; Herum, Kate Louise Møller; Skrbic, Biljana; Kvaløy, Heidi; Sjaastad, Ivar & Tønnessen, Theis [Show all 8 contributors for this article] (2013). Syndecan-4 shedding in the hypertrophic heart is likely mediated by the MMP9 and ADAMTS4 enzymes, a process involved in cardiac inflammation and failure progression. Full text in Research Archive
• Wanichawan, Pimthanya; Hafver, Tandekile Lubelwana; Lunde, Ida Gjervold; Aronsen, Jan Magnus; Lunde, Marianne & Kvaløy, Heidi [Show all 10 contributors for this article] (2013). Calpain induces cleavage of the cardiac Na+ - Ca2+ exchanger 1 (NCX1) in pressure-overloaded hearts: Molecular interactions and identification of a calpain cleavage site. Full text in Research Archive
• Lunde, Ida Gjervold; Skrbic, Biljana; Tønnessen, Theis; Kvaløy, Heidi; Enger, Ulla Helene & Dahl, Christen Peder [Show all 9 contributors for this article] (2013). Clinical and Experimental Aortic Stenosis; Attenuation of Activated Pro-Hypertrophic NFAT Transcription Factor Isoforms by Relief of Pressure Overload. Circulation. ISSN 0009-7322. 128. Full text in Research Archive
• Frisk, Michael; Jølle, Guro Five; Lunde, Ida Gjervold; Skrbic, Biljana; Sejersted, Ole M & Tønnessen, Theis [Show all 8 contributors for this article] (2013). Aortic stenosis triggers t-tubule growth in human and murine cardiomyocytes. Full text in Research Archive
• Engebretsen, Kristin V Thunheim; Skårdal, Kristine; Bjørnstad, S; Marstein, Henriette; Skrbic, Biljana & Sjaastad, Ivar [Show all 9 contributors for this article] (2013). Inhibiting phosphorylation of SMAD2/3 by the small molecule SM16 in left ventricular pressure overload reduces fibrosis and signs of heart failure, possibly due to better diastolic function. Full text in Research Archive
• Strand, Mari Elen; Herum, Kate Louise Møller; Skrbic, Biljana; Kvaløy, Heidi; Sjaastad, Ivar & Tønnessen, Theis [Show all 8 contributors for this article] (2013). Syndecan-4 shedding in the hypertrophic heart is likely mediated by MMP9 and ADAMTS4, a process believed to modulate cardiac inflammation. Full text in Research Archive
• Skrbic, Biljana; Engebretsen, Kristin V Thunheim; Strand, Mari Elen; Marstein, Henriette; Sjaastad, Ivar & Lunde, Ida Gjervold [Show all 10 contributors for this article] (2013). Lack of collagen type 8 in pressure overload causes left ventricular dilatation and overt heart failure in mice, suggesting a role in transition to heart failure in patients with aortic stenosis. Circulation. ISSN 0009-7322. 128, p. A14408–A14408. Full text in Research Archive
• Skrbic, Biljana; Engebretsen, Kristin V Thunheim; Strand, Mari Elen; Marstein, Henriette; Sjaastad, Ivar & Lunde, Ida Gjervold [Show all 10 contributors for this article] (2013). Lack of collagen type 8 in pressure overload causes left ventricular dilatation and overt heart failure in mice, suggesting a role in transition to heart failure in patients with aortic stenosis. Full text in Research Archive
• Wanichawan, Pimthanya; Hafver, Tandekile; Aronsen, Jan Magnus; Lunde, Ida Gjervold; Lunde, Marianne & Kvaløy, Heidi [Show all 10 contributors for this article] (2013). Modulation of the Sodium-calcium Exchanger 1 (NCX1) by Calpain; Molecular Interactions and Identification of a Calpain Cleavage Site. Circulation. ISSN 0009-7322. 128. Full text in Research Archive
• Herum, Kate Louise Møller; Lunde, Ida Gjervold; Skrbic, Biljana; Tønnessen, Theis; Louch, William Edward & Hasic, Almira [Show all 13 contributors for this article] (2013). Syndecan-4 promotes myocardial stiffness by regulating myofibroblast differentiation and extracellular matrix structure in response to pressure overload. Full text in Research Archive
• Herum, Kate Louise Møller; Lunde, Ida Gjervold; Skrbic, Biljana; Tønnessen, Theis; Louch, William Edward & Hasic, Almira [Show all 11 contributors for this article] (2013). Syndecan-4 regulates myocardial stiffness by inducing myofibroblast differentiation, extracellular matrix production and collagen cross-linking in response to pressure overload. Full text in Research Archive
• Lunde, Ida Gjervold; Skrbic, Biljana; Tønnessen, Theis; Dahl, Christen Peder; Kvaløy, Heidi & Enger, Ulla Helene [Show all 9 contributors for this article] (2013). Clinical and experimental aortic stenosis; attenuation of activated pro-hypertrophic NFAT transcription factor isoforms during reverse remodeling. Full text in Research Archive
• Røe, Åsmund Treu; Aronsen, Jan Magnus; Frisk, Michael; Lunde, Ida Gjervold; Riise, Jon & Sejersted, Ole M [Show all 10 contributors for this article] (2013). Compensatory alterations in cardiomyocytes Ca2+ homeostasis during aortic stenosis. Circulation. ISSN 0009-7322. 128. Full text in Research Archive
• Herum, Kate Louise Møller; Lunde, Ida Gjervold; Skrbic, Biljana; Tønnessen, Theis; Louch, William Edward & Hasic, Almira [Show all 13 contributors for this article] (2013). Syndecan-4 regulates myocardial stiffness by inducing myofibroblast differentiation, extracellular matrix production and collagen cross-linking in response to pressure overload. Circulation. ISSN 0009-7322. 128. Full text in Research Archive
• Lunde, Ida Gjervold; Skrbic, Biljana; Tønnessen, Theis; Kvaløy, Heidi; Sjaastad, Ivar & Christensen, Geir Arve [Show all 7 contributors for this article] (2013). Experimental and clinical aortic stenosis; myocardial activation of the four pro-hypertrophic NFAT transcription factors is attenuated by relief of pressure overload. European Journal of Heart Failure. Supplements. ISSN 1567-4215. 12(1), p. S3–S3. Full text in Research Archive
• Søraas, Camilla Lund; Friis, Charlotte Mathilde; Engebretsen, Kristin V Thunheim; Sandvik, Leiv; Kjeldsen, Sverre Erik & Tønnessen, Theis (2013). Authors' reply to the letter from Dr Wang: Troponins after coronary artery bypass grafting: Continuous or cut-point approach? American Heart Journal. ISSN 0002-8703. 166(2). doi: 10.1016/j.ahj.2013.05.001. Full text in Research Archive
• Wanichawan, Pimthanya; Lunde, Ida Gjervold; Aronsen, Jan Magnus; Austbø, Bjørg; Lunde, Marianne & Tønnessen, Theis [Show all 8 contributors for this article] (2013). Modulation of the Na+-Ca2+ exchanger 1(NCX1) by calpain; molecular interactions and identification of a calpain cleavage site. Full text in Research Archive
• Wanichawan, Pimthanya; Lunde, Ida Gjervold; Aronsen, Jan Magnus; Austbø, Bjørg; Lunde, Marianne & Tønnessen, Theis [Show all 9 contributors for this article] (2013). Calpain mediates proteolysis of the cardiac Na+- Ca2+ exchanger 1(NCX1) in failing hearts through its catalytic site (IIb) and domain III. Full text in Research Archive
• Frisk, Michael; Jølle, Guro Five; Lunde, Ida Gjervold; Skrbic, Biljana; Sejersted, Ole M & Tønnessen, Theis [Show all 8 contributors for this article] (2013). Aortic Stenosis Triggers T-Tubule Growth in Human and Murine Cardiomyocytes. Biophysical Journal. ISSN 0006-3495. 104(2), p. 603A–603A. Full text in Research Archive
• Lunde, Ida Gjervold; Skrbic, Biljana; Tønnessen, Theis; Kvaløy, Heidi; Enger, Ulla Helene & Sjaastad, Ivar [Show all 8 contributors for this article] (2012). Aortic stenosis in mice and men; myocardial activation of the four calcineurin-dependent NFAT transcription factor isoforms is attenuated by relief of pressure overload. Full text in Research Archive
• Lunde, Ida Gjervold; Skrbic, Biljana; Tønnessen, Theis; Kvaløy, Heidi; Enger, Ulla Helene & Sjaastad, Ivar [Show all 8 contributors for this article] (2012). Aortic stenosis in mice and men; myocardial activation of pro-hypertrophic NFAT transcription factor isoforms is attenuated by relief of pressure overload. Circulation. ISSN 0009-7322. 126, p. A14212–A14212. Full text in Research Archive
• Louch, William Edward; Hake, Johan; Mørk, Halvor Kjeang; Hougen, Karina; Skrbic, Biljana & Lines, Glenn [Show all 9 contributors for this article] (2012). Slow Ca2+ Sparks De-synchronize Ca2+ Release in Failing Cardiomyocytes: Evidence for Altered Ryanodine Receptor Distribution? Full text in Research Archive
• Strand, Mari Elen; Herum, Kate Louise Møller; Rana, Zaheer Ahmad; Skrbic, Biljana; Vistnes, Maria & Hasic, Almira [Show all 12 contributors for this article] (2012). The adhesion site transmembrane proteoglycan syndecan-4; an integrator of pro-hypertrophic and pro-inflammatory signaling in the heart? Full text in Research Archive
• Wanichawan, Pimthanya; Lunde, Ida Gjervold; Aronsen, Jan Magnus; Lunde, Marianne; Tønnessen, Theis & Sjaastad, Ivar [Show all 8 contributors for this article] (2012). Calpain mediated proteolysis of the cardiac sodium-calcium exchanger 1 (NCX1) in failing hearts: molecular interactions. Circulation. ISSN 0009-7322. 126. Full text in Research Archive
• Wanichawan, Pimthanya; Lunde, Ida Gjervold; Aronsen, Jan Magnus; Austbø, Bjørg; Lunde, Marianne & Tønnessen, Theis [Show all 9 contributors for this article] (2012). Calpain induces cleavage of the cardiac Na+-Ca2+ exchanger1 (NCX1) in failing hearts: Molecular interaction. Full text in Research Archive

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