Geir Christensen

• Mathiesen, Sabrina Bech; Støle, Thea Parsberg; Romaine, Andreas; Lunde, Marianne; Martinsen, Marita & Aronsen, Jan Magnus [Show all 10 contributors for this article] (2025). Syndecan-4 interacts directly with β-parvin and regulates the ILK-PINCH-β-parvin complex, the β-parvin-β-PIX-Rac1 axis, and cardiomyocyte geometry in a sex-dependent manner. Frontiers in Cell and Developmental Biology. 13. doi: 10.3389/fcell.2025.1569185. Full text in Research Archive Show summary

  Syndecan-4 is a ubiquitously expressed transmembrane proteoglycan that links the extracellular matrix to intracellular protein networks. It is located at stress-sensing structures in cardiomyocytes, including costameres and Z-discs, and in male mice, it is involved in the hypertrophic response to cardiac pressure overload. We have recently found female syndecan-4 KO cardiomyocytes, without challenge, to be smaller in area. Smaller cardiomyocytes with elongation defects have been observed in animal models with β-parvin deficiency, where the loss of this mechano-sensor disrupts the guanine nucleotide exchange factor (GEF) β-PIX-GTPase Rac1 axis, which is essential for proper cell elongation. β-parvin, together with integrin-linked kinase (ILK) and particularly interesting new cysteine-histidine-rich protein (PINCH), constitutes the IPP complex (ILK-PINCH-parvin), which is part of the integrin consensus adhesome. Interestingly, in a previous large cardiac interactome study, we have identified β-parvin, as well as ILK, β-PIX, and Rac1 as potential syndecan-4 partners. To better understand the syndecan-4-β-parvin association, we mapped their interaction and investigated the effect of syndecan-4 ablation on the IPP complex, the β-parvin-β-PIX-Rac1 axis, and cardiomyocyte geometry in both females and males. Interestingly, genetic ablation of syndecan-4 resulted in shorter cardiomyocytes in females only. The syndecan-4-β-parvin interaction was mapped to accessible sequences within the N-terminal, linker, and CH2 domains of β-parvin and the unique variable C2 cytoplasmic region of syndecan-4. Syndecan-4 ablation resulted in lower levels of membrane-localized β-parvin in both sexes and sex-specific differences in its associated partners ILK and PINCH, suggesting that syndecan-4 is linked to integrin signaling through the IPP complex. Finally, Rac1, known for its involvement in cell size regulation, and some of its regulators, β-PIX, RhoGDIα, and the serine/threonine kinase PAK, showed sex-specific alterations following syndecan-4 ablation. Altogether, our data suggest that syndecan-4 binds directly to β-parvin and regulates cardiomyocyte length, the IPP complex, and the β-parvin-β-PIX-Rac1 in a sex-dependent manner. These findings highlight a sex-specific role for syndecan-4 in cardiomyocyte structure, offering new insight into the molecular basis for sex differences in cardiac biology.

• Rugolo, Ilde; Shen, Xin; Støle, Thea Parsberg; Dahl, Anna Bergan; Manfra, Ornella & Lunde, Marianne [Show all 12 contributors for this article] (2025). Identification of a Small Secretoneurin Derivative That Inhibits CaMKIIδ Activity. Journal of Cellular and Molecular Medicine. ISSN 1582-1838. 29(20). doi: 10.1111/jcmm.70900. Full text in Research Archive Show summary

  ABSTRACT Ventricular arrhythmias, a major cause of sudden cardiac death, are driven by Ca 2+ imbalance in cardiac myocytes, often linked to the overactivation of CaMKIIδ (Ca 2+ /calmodulin‐dependent protein kinase II delta). As such, inhibiting CaMKIIδ represents a promising therapeutic strategy. Based on our previous finding that native secretoneurin (SN) is a weak CaMKIIδ inhibitor, we aimed to develop a more potent derivative of SN to effectively counter aberrant Ca 2+ handling and arrhythmia risk. Various regions of SN were tested for CaMKII binding, identifying the core region as the sequence with the strongest binding capacity. This region was subsequently optimised with two phenylalanine substitutions, resulting in the SN derivative SN‐db‐short. Structural homology modeling and ELISA‐based assays revealed that SN‐db‐short bound both the substrate‐binding (S‐site) region of CaMKIIδ, in addition to the ATP‐binding region, with 8‐fold stronger binding compared to SN. Surface plasmon resonance experiments confirmed that SN‐db‐short exhibited a higher association rate and affinity for CaMKIIδ compared to SN. Consistent with only a partial calmodulin binding motif, SN‐db‐short showed no calmodulin binding, indicating selective CaMKIIδ inhibition. In functional studies, SN‐db‐short inhibited CaMKIIδ‐mediated phosphorylation of ryanodine receptor 2 and appeared more effective than SN in reducing the incidence of Ca 2+ sparks and Ca 2+ waves. SN‐db‐short also more markedly inhibited CaMKIIδ phosphorylation of phospholamban, slowed Ca 2+ reuptake, and reduced the magnitude of Ca 2+ transients during isoproterenol stimulation. SN‐db‐short effectively inhibits CaMKIIδ and significantly counters aberrant Ca 2+ handling in cardiomyocytes. Thus, this optimised peptide holds therapeutic potential for reducing the risk of ventricular arrhythmias.

• Røsjø, Helge Rørvik; Rugolo, Ilde; Berg, Angelica Marianne; Faaren, Arne L; Frantzen, Frank & Christensen, Geir [Show all 11 contributors for this article] (2025). Secretoneurin Concentrations Measured with a High-Throughput Assay and Clinical Outcomes in Patients Hospitalized with Acute Dyspnea: Data from the Akershus Cardiac Examination 2 Study. The Journal of Applied Laboratory Medicine (JALM). ISSN 2576-9456. 10(3), p. 691–703. doi: 10.1093/jalm/jfaf011. Full text in Research Archive Show summary

  Background High-throughput assays are required for novel biomarkers to have clinical potential. Secretoneurin (SN) is a candidate biomarker, and the performance of a new high-throughput SN assay is not known. Methods We measured SN concentrations with a prototype chemiluminescent immunoassay (CLIA) in 299 patients hospitalized with acute dyspnea. We compared the results with a CE-marked SN enzyme linked immunosorbent assay (ELISA). We adjudicated the cause of dyspnea as heart failure (HF) or non-HF, and we obtained information on all-cause mortality during follow-up. Results SN concentrations measured with CLIA and ELISA were closely correlated: rho = 0.81, P < 0.001. SN CLIA concentrations were higher in HF patients (n = 129) compared to patients with non-HF-related dyspnea (n = 170): median 51 (quartile 1–3 40–69) vs 41 (32–54) pmol/L, P < 0.001. The area under the curve (AUC) of SN CLIA to diagnose HF was 0.64 (95% CI, 0.58–0.71) and the AUC of N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 0.85 (0.81–0.89). During median 818 days follow-up, 110 patients died (37%). There was a nonlinear association between SN CLIA concentrations and mortality with optimal cutpoint 53 pmol/L. SN CLIA concentrations >53 pmol/L were associated with mortality after adjusting for clinical variables and NT-proBNP and cardiac troponin T concentrations: hazard ratio 1.7 (95% CI, 1.1–2.7), AUC 0.67 (0.61–0.74). We found similar results for SN ELISA for diagnosis and prognosis with AUC 0.63 (0.57–0.70) for the prediction of mortality. Conclusion The high-throughput SN CLIA correlates with the SN ELISA and provides independent prognostic information over established biomarkers in patients with acute dyspnea.

• Nordén, Einar Sjaastad; Bendiksen, Bård Andre; Bergo, Kaja Knudsen; Espe, Emil Knut Stenersen; Mcginley, Gary George & Hasic, Almira [Show all 17 contributors for this article] (2024). Sacubitril/valsartan preserves regional cardiac function following myocardial infarction in rats. ESC Heart Failure. doi: 10.1002/ehf2.15145. Full text in Research Archive Show summary

  Aims Sacubitril/valsartan (Sac/Val) is used for treatment of heart failure. The effect of Sac/Val on regional dysfunction following myocardial infarction (MI) remains uncertain. This study aimed at understanding the effects of Sac/Val on regional function after MI. Methods and results MI or sham surgery was performed in Sprague–Dawley rats. Animals were randomized to treatment with Sac/Val, valsartan (Val) or vehicle (Veh). Magnetic resonance imaging was used to acquire left ventricular volumes and strain. Left ventricular tissue was obtained for wesern blotting, PCR and Masson's trichrome staining. Isolated cardiac fibroblasts were cultured with Veh, atrial natriuretic peptide (ANP), adrenomedullin (ADM) and sacubitrilat, and collagen expression assessed with droplet digital PCR. Results Sac/Val reduced ventricular end-diastolic volume by 18% compared with Veh, and preserved circumferential systolic strain in the zone proximal to infarction compared with sham after 42 days of treatment (peak strain ± SEM: sham: −0.19 ± 0.01%; Sac/Val: −0.14 ± 0.02%; Val: −0.10 ± 0.02%; Veh: −0.10 ± 0.02%). Masson's trichrome staining demonstrated lower fibrotic deposition in the intermediate zone with Sac/Val treatment than Veh (sham: 2.29 ± 0.17%; Sac/Val: 2.31 ± 0.27%; Val: 3.22 ± 0.60%; Veh: 4.14 ± 0.48%). The amounts of the pro-apoptotic caspase 3 cleavage fragments p19/17 were 89% higher in Val than sham, with Sac/Val showing no significant increase compared with sham. Collagen expression in human fibroblast culture was lower in cells co-treated with sacubitrilat and ANP, an effect not observed with sacubitrilat/ADM co-treatment. Conclusions Sac/Val preserves in vivo myocardial function in the region most proximal to MI in rats and reduces left ventricular dilatation. These effects may be related to a reduction in both fibrosis and pro-apoptotic signalling.

• Udjus, Camilla; Halvorsen, Bente; Kong, Xiang Yi; Sagen, Ellen Lund; Martinsen, Marita & Yang, Kuan [Show all 10 contributors for this article] (2024). Alveolar hypoxia induces organ-specific inflammasome-related inflammation in male mouse lungs. Physiological Reports. 12:e16143(14), p. 1–13. doi: 10.14814/phy2.16143. Full text in Research Archive Show summary

  Inflammation through activation of caspase-1, seems to play a role in pulmonary hypertension induced by alveolar hypoxia. Whether alveolar hypoxia induces caspase-1-mediated inflammation and influx of leukocytes in other organs than the lungs, is not known. Our aim was to explore sites of caspase-1-related inflammation in alveolar hypoxia. Wild type (WT) mice were exposed to environmental hypoxia or room-air, and organs were analyzed. Right heart catheterization was performed after 14 days of alveolar hypoxia in WT mice and mice transplanted with WT or caspase-1−/− bone marrow. Hypoxia induced leukocyte accumulation and increased caspase-1 protein in the lungs, not in other organs. WT mice transplanted with WT or caspase-1−/− bone marrow showed no difference in pulmonary leukocyte accumulation or development of pulmonary hypertension after alveolar hypoxia. Caspase-1 and IL-18 were detected in bronchial epithelium in WT mice, and hypoxia induced IL-18 secretion from bronchial epithelial cells. IL-18 stimulation generated IL-6 mRNA in monocytes. Phosphorylated STAT3 was increased in hypoxic lungs, not in other organs. Alveolar hypoxia induces caspase-1 activation and leukocyte accumulation specific to the lungs, not in other organs. Caspase-1 activation and IL-18 secretion from bronchial epithelial cells might initiate hypoxia-induced inflammation, leading to pulmonary hypertension.

• 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.

• Støle, Thea Parsberg; Lunde, Marianne; Gehmlich, Katja; Christensen, Geir; Louch, William Edward & Carlson, Cathrine Rein (2024). Exploring Syndecan-4 and MLP and Their Interaction in Primary Cardiomyocytes and H9c2 Cells. Cells. 13(11). doi: 10.3390/cells13110947. Full text in Research Archive Show summary

  The transmembrane proteoglycan syndecan-4 is known to be involved in the hypertrophic response to pressure overload. Although multiple downstream signaling pathways have been found to be involved in this response in a syndecan-4-dependent manner, there are likely more signaling components involved. As part of a larger syndecan-4 interactome screening, we have previously identified MLP as a binding partner to the cytoplasmic tail of syndecan-4. Interestingly, many human MLP mutations have been found in patients with hypertrophic (HCM) and dilated cardiomyopathy (DCM). To gain deeper insight into the role of the syndecan-4–MLP interaction and its potential involvement in MLP-associated cardiomyopathy, we have here investigated the syndecan-4–MLP interaction in primary adult rat cardiomyocytes and the H9c2 cell line. The binding of syndecan-4 and MLP was analyzed in total lysates and subcellular fractions of primary adult rat cardiomyocytes, and baseline and differentiated H9c2 cells by immunoprecipitation. MLP and syndecan-4 localization were determined by confocal microscopy, and MLP oligomerization was determined by immunoblotting under native conditions. Syndecan-4–MLP binding, as well as MLP self-association, were also analyzed by ELISA and peptide arrays. Our results showed that MLP-WT and syndecan-4 co-localized in many subcellular compartments; however, their binding was only detected in nuclear-enriched fractions of isolated adult cardiomyocytes. In vitro, syndecan-4 bound to MLP at three sites, and this binding was reduced in some HCM-associated MLP mutations. While MLP and syndecan-4 also co-localized in many subcellular fractions of H9c2 cells, these proteins did not bind at baseline or after differentiation into cardiomyocyte-resembling cells. Independently of syndecan-4, mutated MLP proteins had an altered subcellular localization in H9c2 cells, compared to MLP-WT. The DCM- and HCM-associated MLP mutations, W4R, L44P, C58G, R64C, Y66C, K69R, G72R, and Q91L, affected the oligomerization of MLP with an increase in monomeric at the expense of trimeric and tetrameric recombinant MLP protein. Lastly, two crucial sites for MLP self-association were identified, which were reduced in most MLP mutations. Our data indicate that the syndecan-4–MLP interaction was present in nuclear-enriched fractions of isolated adult cardiomyocytes and that this interaction was disrupted by some HCM-associated MLP mutations. MLP mutations were also linked to changes in MLP oligomerization and self-association, which may be essential for its interaction with syndecan-4 and a critical molecular mechanism of MLP-associated cardiomyopathy.

• Perdreau-Dahl, Harmonie; Lipsett, David Bruce; Frisk, Michael; Kermani, Fatemeh; Carlson, Cathrine Rein & Brech, Andreas [Show all 19 contributors for this article] (2023). BIN1, Myotubularin, and Dynamin-2 Coordinate T-Tubule Growth in Cardiomyocytes. Circulation Research. ISSN 0009-7330. 132(11), p. E188–E205. doi: 10.1161/CIRCRESAHA.122.321732. Full text in Research Archive
• Bhatnagar, Rahul; Berge, Kristian; Røysland, Ragnhild; Høiseth, Arne Didrik; Brynildsen, Jon & Christensen, Geir [Show all 9 contributors for this article] (2023). Cardiac Troponin T and NT-proBNP for Prediction of 30-Day Readmission or Death in Patients with Acute Dyspnea: Data from the Akershus Cardiac Examination 2 Study. Cardiology. ISSN 0008-6312. 148(6), p. 506–516. doi: 10.1159/000533266. Full text in Research Archive Show summary

  Introduction: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT) measurements are recommended in patients with acute dyspnea. We aimed to assess the prognostic merit of cTnT compared to NT-proBNP for 30-day readmission or death in patients hospitalized with acute dyspnea. Methods: We measured cTnT and NT-proBNP within 24 h in 314 patients hospitalized with acute dyspnea and adjudicated the cause of the index admission. Time to first event of readmission or death ≤30 days after hospital discharge was recorded, and cTnT and NT-proBNP measurements were compared head-to-head. Results: Patients who died (12/314) or were readmitted (71/314) within 30 days had higher cTnT concentrations (median: 32.6, Q1–Q3: 18.4–74.2 ng/L vs. median: 19.4, Q1–Q3: 8.4–36.1 ng/L; p for comparison &amp;lt;0.001) and NT-proBNP concentrations (median: 1,753.6, Q1–Q3: 464.2–6,862.0 ng/L vs. median 984, Q1–Q3 201–3,600 ng/L; for comparison p = 0.027) compared to patients who survived and were not readmitted. cTnT concentrations were associated with readmission or death within 30 days after discharge both in the total cohort (adjusted hazard ratio [aHR]: 1.64, 95% confidence interval [CI]: 1.30–2.05) and in patients with heart failure (HF) (aHR: 1.58, 95% CI: 1.14–2.18). In contrast, NT-proBNP concentrations were not associated with short-term events, neither in the total cohort (aHR: 1.10, 95% CI: 0.94–1.30) nor in patients with adjudicated HF (aHR: 1.06, 95% CI: 0.80–1.40). Conclusion: cTnT concentrations are associated with 30-day readmission or death in patients hospitalized with acute dyspnea, as well as in patients adjudicated HF.

• 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.

• Andreassen, Kristine; Rixon, Chloe Louise; Haugsten, Marie Hansen; Hauge-Iversen, Ida Marie; Zhang, Lili & Sadredini, Mani [Show all 13 contributors for this article] (2023). Beneficial effects of exercise initiated before development of hypertrophic cardiomyopathy in genotype-positive mice. American Journal of Physiology. Heart and Circulatory Physiology. ISSN 0363-6135. 324(6), p. H881–H892. doi: 10.1152/ajpheart.00701.2022. Full text in Research Archive
• 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.

• Sasi, Athiramol; Romaine, Andreas; Erusappan, Pugazendhi Murugan; Melleby, Arne Olav; Hasic, Almira & Dahl, Christen Peder [Show all 14 contributors for this article] (2023). Temporal expression and spatial distribution of the proteoglycan versican during cardiac fibrosis development. Matrix Biology Plus. 19-20. doi: 10.1016/j.mbplus.2023.100135. Full text in Research Archive Show summary

  Cardiac fibrosis is a central pathological feature in several cardiac diseases, but the underlying molecular players are insufficiently understood. The extracellular matrix proteoglycan versican is elevated in heart failure and suggested to be a target for treatment. However, the temporal expression and spatial distribution of versican and the versican cleavage fragment containing the neoepitope DPEAAE in cardiac fibrosis remains to be elucidated. In this study, we have examined versican during cardiac fibrosis development in a murine pressure overload model and in patients with cardiomyopathies. We found that versican, mainly the V1 isoform, was expressed immediately after induction of pressure overload, preceding collagen accumulation, and versican protein levels extended from the perivascular region into the cardiac interstitium. In addition, we found increased production of versican by collagen expressing fibroblasts, and that it was deposited extensively in the fibrotic extracellular matrix during pressure overload. In cardiac cell cultures, the expression of versican was induced by the pro-fibrotic transforming growth factor beta and mechanical stretch. Furthermore, we observed that the proteolytic cleavage of versican (DPEAAE fragment) increased in the late phase of fibrosis development during pressure overload. In patients with hypertrophic and dilated cardiomyopathies, we found elevated levels of versican and a positive correlation between versican and collagen mRNA in the heart, as well as increased cleavage of full-length protein. Taken together, the temporal expression profile and the spatial distribution of both the full-length versican and the DPEAAE fragment observed in this study indicates a role for versican in development of cardiac fibrosis.

• Lunde, Ida Gjervold; Aronsen, Jan Magnus; Melleby, Arne Olav; Strand, Mari Elen; Skogestad, Jonas & Bendiksen, Bård Andre [Show all 11 contributors for this article] (2022). Cardiomyocyte-specific overexpression of syndecan-4 in mice results in activation of calcineurin-NFAT signalling and exacerbated cardiac hypertrophy. Molecular Biology Reports. ISSN 0301-4851. 49(12), p. 11795–11809. doi: 10.1007/s11033-022-07985-y. Full text in Research Archive Show summary

  Abstract Background Cardiomyocyte hypertrophy is a hallmark of cardiac dysfunction in patients with aortic stenosis (AS), and can be triggered by left ventricular (LV) pressure overload in mice by aortic banding (AB). Syndecan-4 is a transmembrane heparan sulphate proteoglycan which is found increased in the myocardium of AS patients and AB mice. The role of syndecan-4 in cardiomyocyte hypertrophy is not well understood. Purpose of the study We developed mice with cardiomyocyte-specific overexpression of syndecan-4 ( Sdc4-Tg ) and subjected these to AB to examine the role of syndecan-4 in hypertrophy and activation of the pro-hypertrophic calcineurin-NFAT signalling pathway. Methods and results Sdc4-Tg mice showed exacerbated cardiac remodelling upon AB compared to wild type (WT). At 2–6 weeks post-AB, Sdc4-Tg and WT mice showed similar hypertrophic growth, while at 20 weeks post-AB, exacerbated hypertrophy and dysfunction were evident in Sdc4-Tg mice. After cross-breeding of Sdc4-Tg mice with NFAT-luciferase reporter mice, we found increased NFAT activation in Sdc4-Tg hearts after AB. Immunoprecipitation showed that calcineurin bound to syndecan-4 in Sdc4-Tg hearts. Isolated cardiomyocytes from Sdc4-Tg mice showed alterations in Ca 2+ fluxes, suggesting that syndecan-4 regulated Ca 2+ levels, and thereby, activating the syndecan-4-calcineurin complex resulting in NFAT activation and hypertrophic growth. Similarly, primary cardiomyocyte cultures from neonatal rats showed increased calcineurin-NFAT-dependent hypertrophic growth upon viral Sdc4 overexpression. Conclusion Our study of mice with cardiomyocyte-specific overexpression of Sdc4 have revealed that syndecan-4 is important for activation of the Ca 2+ -dependent calcineurin-NFAT signalling pathway, hypertrophic remodelling and dysfunction in cardiomyocytes in response to pressure overload.

• Romaine, Andreas; Melleby, Arne Olav; Alam, Jahedul; Lobert, Viola; Lu, Ning & Lockwood, Francesca Eve [Show all 13 contributors for this article] (2022). Integrin α11β1 and syndecan-4 dual receptor ablation attenuates cardiac hypertrophy in the pressure overloaded heart. American Journal of Physiology. Heart and Circulatory Physiology. ISSN 0363-6135. 322(6), p. H1057–H1071. doi: 10.1152/ajpheart.00635.2021. Full text in Research Archive
• 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.

• Berge, Kristian; Brynildsen, Jon; Røysland, Ragnhild; Strand, Heidi; Christensen, Geir & Høiseth, Arne Didrik [Show all 9 contributors for this article] (2022). Prognostic value of cardiac biomarkers and National Early Warning Score 2 in acute dyspnoea. Open heart. 9(1). doi: 10.1136/openhrt-2021-001938. Full text in Research Archive Show summary

  Objective Patients hospitalised with acute dyspnoea due to acute heart failure (AHF) have a grave prognosis, but the European Society of Cardiology guidelines recommend no system to risk stratify these patients. The prognostic value of combining National Early Warning Score (NEWS) 2 and established cardiac biomarkers is not known. Methods We measured high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and calculated NEWS2 in 314 patients with acute dyspnoea within 24 hours of hospitalisation. Their prognostic merits were assessed in the total cohort and for the subgroup with AHF separately. Results The median age was 73 (quartile (Q) 1–3, 63–81) years, 48% were women and 143 patients (46%) were hospitalised with AHF. The 114 patients (36%) who died during follow-up (median 823 days, Q1–3, 471–998) had higher concentrations of hs-cTnT (62 vs 33 ng/L, p&lt;0.001) and NT-proBNP (6995 vs 2605 ng/L, p&lt;0.001), and higher NEWS2 (6.1 vs 4.5 points, p&lt;0.001), compared with survivors. Patients with increased vs low NEWS2 clinical risk had higher mortality rates in adjusted analyses in the total cohort (HR 2.11, 95% CI 1.28 to 3.48) and in patients with AHF (HR 2.00, 95% CI 1.54 to 2.60). NEWS2 provided incremental prognostic information compared with biomarkers alone for the total cohort: area under the curve 0.72 vs 0.70, p=0.042, and for the subpopulation with AHF: 0.70 vs 0.67, p=0.014. Conclusion NEWS2 predicts long-term mortality in patients hospitalised due to acute dyspnoea and the subgroup with AHF and provide incremental prognostic information to hs-cTnT and NT-proBNP.

• Udjus, Camilla; Sjaastad, Ivar; Hjørnholm, Ulla; Tunestveit, Torbjørn Kinne; Hoffmann, Pavel & Hinojosa, Alexis [Show all 11 contributors for this article] (2022). Extreme altitude induces divergent mass reduction of right and left ventricle in mountain climbers. Physiological Reports. 10(3). doi: 10.14814/phy2.15184. Full text in Research Archive Show summary

  Mountain climbing at high altitude implies exposure to low levels of oxygen, low temperature, wind, physical and psychological stress, and nutritional insufficiencies. We examined whether right ventricular (RV) and left ventricular (LV) myocardial masses were reversibly altered by exposure to extreme altitude. Magnetic resonance imaging and echocardiography of the heart, dual x-ray absorptiometry scan of body composition, and blood samples were obtained from ten mountain climbers before departure to Mount Everest or Dhaulagiri (baseline), 13.5 ± 1.5 days after peaking the mountain (post-hypoxia), and six weeks and six months after expeditions exceeding 8000 meters above sea level. RV mass was unaltered after extreme altitude, in contrast to a reduction in LV mass by 11.8 ± 3.4 g post-hypoxia (p = 0.001). The reduction in LV mass correlated with a reduction in skeletal muscle mass. After six weeks, LV myocardial mass was restored to baseline values. Extreme altitude induced a reduction in LV end-diastolic volume (20.8 ± 7.7 ml, p = 0.011) and reduced E’, indicating diastolic dysfunction, which were restored after six weeks follow-up. Elevated circulating interleukin-18 after extreme altitude compared to follow-up levels, might have contributed to reduced muscle mass and diastolic dysfunction. In conclusion, the mass of the RV, possibly exposed to elevated afterload, was not changed after extreme altitude, whereas LV mass was reduced. The reduction in LV mass correlated with reduced skeletal muscle mass, indicating a common denominator, and elevated circulating interleukin-18 might be a mechanism for reduced muscle mass after extreme altitude.

• Støle, Thea Parsberg; Lunde, Marianne; Shen, Xin; Martinsen, Marita; Lunde, Per Kristian & Li, Jia [Show all 12 contributors for this article] (2022). The female syndecan-4^−/− heart has smaller cardiomyocytes, augmented insulin/pSer473-Akt/pSer9-GSK-3β signaling, and lowered SCOP, pThr308-Akt/Akt and GLUT4 levels. Frontiers in Cell and Developmental Biology. 10. doi: 10.3389/fcell.2022.908126. Full text in Research Archive Show summary

  Background: In cardiac muscle, the ubiquitously expressed proteoglycan syndecan-4 is involved in the hypertrophic response to pressure overload. Protein kinase Akt signaling, which is known to regulate hypertrophy, has been found to be reduced in the cardiac muscle of exercised male syndecan-4 −/− mice. In contrast, we have recently found that pSer473-Akt signaling is elevated in the skeletal muscle ( tibialis anterior, TA) of female syndecan-4 −/− mice. To determine if the differences seen in Akt signaling are sex specific, we have presently investigated Akt signaling in the cardiac muscle of sedentary and exercised female syndecan-4 −/− mice. To get deeper insight into the female syndecan-4 −/− heart, alterations in cardiomyocyte size, a wide variety of different extracellular matrix components, well-known syndecan-4 binding partners and associated signaling pathways have also been investigated. Methods: Left ventricles (LVs) from sedentary and exercise trained female syndecan-4 −/− and WT mice were analyzed by immunoblotting and real-time PCR. Cardiomyocyte size and phosphorylated Ser473-Akt were analyzed in isolated adult cardiomyocytes from female syndecan-4 −/− and WT mice by confocal imaging. LV and skeletal muscle (TA) from sedentary male syndecan-4 −/− and WT mice were immunoblotted with Akt antibodies for comparison. Glucose levels were measured by a glucometer, and fasting blood serum insulin and C-peptide levels were measured by ELISA. Results: Compared to female WT hearts, sedentary female syndecan-4 −/− LV cardiomyocytes were smaller and hearts had higher levels of pSer473-Akt and its downstream target pSer9-GSK-3β. The pSer473-Akt inhibitory phosphatase PHLPP1/SCOP was lowered, which may be in response to the elevated serum insulin levels found in the female syndecan-4 −/− mice. We also observed lowered levels of pThr308-Akt/Akt and GLUT4 in the female syndecan-4 −/− heart and an increased LRP6 level after exercise. Otherwise, few alterations were found. The pThr308-Akt and pSer473-Akt levels were unaltered in the cardiac and skeletal muscles of sedentary male syndecan-4 −/− mice. Conclusion: Our data indicate smaller cardiomyocytes, an elevated insulin/pSer473-Akt/pSer9-GSK-3β signaling pathway, and lowered SCOP, pThr308-Akt/Akt and GLUT4 levels in the female syndecan-4 −/− heart. In contrast, cardiomyocyte size, and Akt signaling were unaltered in both cardiac and skeletal muscles from male syndecan-4 −/− mice, suggesting important sex differences.

• 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.

• Aakre, Kristin Moberg; Ottesen, Anett Hellebø; Strand, Heidi; Faaren, Arne L.; Alaour, Bashir & Torsvik, Janniche [Show all 11 contributors for this article] (2021). Biological variation of secretoneurin; a novel cardiovascular biomarker implicated in arrhythmogenesis. Clinical Biochemistry. ISSN 0009-9120. 98, p. 74–77. doi: 10.1016/j.clinbiochem.2021.09.014. Full text in Research Archive Show summary

  Background Secretoneurin is a novel prognostic biomarker that may predict mortality in heart failure and the occurrence of ventricular arrhythmias. This study reports the within subject variation (CVI), between subject variation (CVG), reference change values (RCV) and index of individuality (II) of secretoneurin. Methods Thirty healthy volunteers were included. Non-fasting samples were obtained between 8 and 10 am once a week for ten weeks. Secretoneurin was analyzed in duplicate using ELISA. No outliers were present according to Burnett and Reeds‘ criteria. Simple linear regression did not identify significant trends. Variance homogeneity in the analytical variance and CVI were tested using Cochrane’s and Bartlett’s tests and four participants were excluded. Calculation of CVI, CVG and RCV were done on ln transformed data as described by Fokkema, the II was calculated using retransformed data. Results The median age of the participants was 36 years and 53% were female. Non-fasting glucose, eGFR(CKD-EPI), cTnT and NT-proBNP concentrations were within the normal range. Median secretoneurin concentrations were 38 pmol/L (women) and 33 pmol/L (men), p-value < 0.001. CVI and CVG were 9.8% (CI 8.7% to 11.0%) and 20.0 (CI 15.4% to 28.0%), respectively. RCV were 38.7% (CI 35.5% to 42.7%) and −27.9 (CI −29.9 to −26.2) and the II were 0.60 (CI 0.42–0.78). No gender differences were present. Conclusion Secretoneurin has a fairly low CVI, CVG, RCV and II, indicating that it could be suitable as a diagnostic or prognostic biomarker and that delta values in serial samplings may be preferable for identifying clinical changes.

• Norden, Einar Sjaastad; Bendiksen, Bård Andre; Andresen, Henriette; Bergo, Kaja Knudsen; Espe, Emil Knut Stenersen & Hasic, Almira [Show all 12 contributors for this article] (2021). Sacubitril/valsartan ameliorates cardiac hypertrophy and preserves diastolic function in cardiac pressure overload. ESC Heart Failure. 8(2), p. 918–927. doi: 10.1002/ehf2.13177. Full text in Research Archive
• Rutkovskiy, Arkady; Lyngbakken, Magnus; Dahl, Mai Britt; Bye, Anja; Pedersen, Marit Holmefjord & Wisløff, Ulrik [Show all 10 contributors for this article] (2021). Circulating MicroRNA-210 Concentrations in Patients with Acute Heart Failure: Data from the Akershus Cardiac Examination 2 Study. Clinical Chemistry. ISSN 0009-9147. 67(6), p. 889–898. doi: 10.1093/clinchem/hvab030. Full text in Research Archive Show summary

  Background MicroRNA (miR)-210 expression is induced by acute and chronic hypoxia and provides prognostic information in patients with aortic stenosis and acute coronary syndrome. We hypothesized that circulating miR-210 concentrations could provide diagnostic and prognostic information in patients with acute heart failure (HF). Methods We measured miR-210 concentrations in serum samples on admission from 314 patients hospitalized for acute dyspnea and 9 healthy control subjects. The diagnostic and prognostic properties of miR-210 were tested in patients after adjudication of all diagnoses and with median follow-up of 464 days. Results All patients and control subjects had miR-210 concentrations within the range of detection, and the analytical variation was low as the coefficient of variation of synthetic spike-in RNA was 4%. Circulating miR-210 concentrations were increased in patients with HF compared to healthy control subjects, but miR-210 concentrations did not separate patients with acute HF (n = 143) from patients with non-HF-related dyspnea (n = 171): the area under the curve was 0.50 (95% CI 0.43–0.57). Circulating miR-210 concentrations were associated with mortality (n = 114) after adjustment for clinical risk factors (hazard ratio 1.65 [95% CI 1.03–2.62] per unit miR-210 increase), but this association was attenuated and not significant after adjustment for established cardiac protein biomarkers. Conclusions Circulating miR-210 concentrations are associated with mortality, but do not add to established protein biomarkers for diagnosis or prognosis in patients with acute dyspnea.

• Carlson, Cathrine Rein; Aronsen, Jan Magnus; Dahl, Anna Bergan; Moutty, Marie Christine; Lunde, Marianne & Lunde, Per Kristian [Show all 22 contributors for this article] (2021). AKAP18δ Anchors and Regulates CaMKII Activity at Phospholamban-SERCA2 and RYR. Circulation Research. ISSN 0009-7330. 130(1), p. 27–44. doi: 10.1161/CIRCRESAHA.120.317976. Full text in Research Archive Show summary

  Background: The sarcoplasmic reticulum (SR) Ca2+-ATPase 2 (SERCA2) mediates Ca2+ reuptake into SR and thereby promotes cardiomyocyte relaxation, whereas the ryanodine receptor (RYR) mediates Ca2+ release from SR and triggers contraction. Ca2+/CaMKII (CaM [calmodulin]-dependent protein kinase II) regulates activities of SERCA2 through phosphorylation of PLN (phospholamban) and RYR through direct phosphorylation. However, the mechanisms for CaMKIIδ anchoring to SERCA2-PLN and RYR and its regulation by local Ca2+ signals remain elusive. The objective of this study was to investigate CaMKIIδ anchoring and regulation at SERCA2-PLN and RYR. Methods: A role for AKAP18δ (A-kinase anchoring protein 18δ) in CaMKIIδ anchoring and regulation was analyzed by bioinformatics, peptide arrays, cell-permeant peptide technology, immunoprecipitations, pull downs, transfections, immunoblotting, proximity ligation, FRET-based CaMKII activity and ELISA-based assays, whole cell and SR vesicle fluorescence imaging, high-resolution microscopy, adenovirus transduction, adenoassociated virus injection, structural modeling, surface plasmon resonance, and alpha screen technology. Results: Our results show that AKAP18δ anchors and directly regulates CaMKIIδ activity at SERCA2-PLN and RYR, via 2 distinct AKAP18δ regions. An N-terminal region (AKAP18δ-N) inhibited CaMKIIδ through binding of a region homologous to the natural CaMKII inhibitor peptide and the Thr17-PLN region. AKAP18δ-N also bound CaM, introducing a second level of control. Conversely, AKAP18δ-C, which shares homology to neuronal CaMKIIα activator peptide (N2B-s), activated CaMKIIδ by lowering the apparent Ca2+ threshold for kinase activation and inducing CaM trapping. While AKAP18δ-C facilitated faster Ca2+ reuptake by SERCA2 and Ca2+ release through RYR, AKAP18δ-N had opposite effects. We propose a model where the 2 unique AKAP18δ regions fine-tune Ca2+-frequency-dependent activation of CaMKIIδ at SERCA2-PLN and RYR. Conclusions: AKAP18δ anchors and functionally regulates CaMKII activity at PLN-SERCA2 and RYR, indicating a crucial role of AKAP18δ in regulation of the heartbeat. To our knowledge, this is the first protein shown to enhance CaMKII activity in heart and also the first AKAP (A-kinase anchoring protein) reported to anchor a CaMKII isoform, defining AKAP18δ also as a CaM-KAP.

• Myhre, Peder Langeland; Ottesen, Anett Hellebø; Faaren, Arne L.; Tveit, Sjur Hansen; Springett, Jon & Pyylampi, Johanna [Show all 11 contributors for this article] (2021). Performance of a Novel Research-Use-Only Secretoneurin ELISA in Patients with Suspected Acute Coronary Syndrome: Comparison with an Established Secretoneurin Radioimmunoassay. Cardiology. ISSN 0008-6312. 146(5), p. 566–574. doi: 10.1159/000517444. Full text in Research Archive Show summary

  Background: Circulating secretoneurin (SN) concentrations, as measured by established radioimmunoassay (RIA), risk stratify patients with cardiovascular disease. We now report data for a recently developed research-use-only SN enzyme-linked immunosorbent assay (ELISA) in patients with suspected acute coronary syndrome (ACS). Methods: SN ELISA was developed according to industry standards and tested in 401 unselected chest pain patients. Blood samples were drawn <24 h from admission, and we adjudicated all hospitalizations as ACS or non-ACS. The mean follow-up was 6.2 years. Results: SN ELISA with 2 monoclonal sheep anti-SN antibodies has a measuring range of 10–250 pmol/L and demonstrates excellent analytical precision and accuracy across the range of SN concentrations. SN measured by ELISA and RIA correlated in the chest pain patients: rho = 0.39, p < 0.001. SN concentrations were higher in ACS patients (n = 161 [40%]) than in non-ACS patients (n = 240) for both assays, with an area under the curve (AUC) of 0.66 (95% CI: 0.61–0.71) for ELISA and 0.59 (0.54–0.65) for RIA. SN concentrations were also higher in nonsurvivors (n = 65 [16%]) than survivors, with an AUC of 0.72 (0.65–0.79) for ELISA versus 0.64 (0.56–0.72) for RIA, p = 0.007, for difference between assays. Adjusting for age, sex, blood pressure, previous myocardial infarction, atrial fibrillation, and heart failure in multivariable analysis, SN concentrations as measured by ELISA, but not RIA, remained associated with mortality, with a hazard ratio of 1.71 (1.03–2.84), p = 0.038. Conclusions: The novel SN ELISA has excellent performance, higher AUC for diagnosis, and superior prognostic accuracy compared to the established RIA in chest pain patients.

• Rønning, Sissel Beate; Carlson, Cathrine Rein; Aronsen, Jan Magnus; Pisconti, Addolorata; Høst, Vibeke & Lunde, Marianne [Show all 11 contributors for this article] (2020). Syndecan-4–/– Mice Have Smaller Muscle Fibers, Increased Akt/mTOR/S6K1 and Notch/HES-1 Pathways, and Alterations in Extracellular Matrix Components. Frontiers in Cell and Developmental Biology. doi: 10.3389/fcell.2020.00730. Full text in Research Archive Show summary

  Background: Extracellular matrix (ECM) remodeling is essential for skeletal muscle development and adaption in response to environmental cues such as exercise and injury. The cell surface proteoglycan syndecan-4 has been reported to be essential for muscle differentiation, but few molecular mechanisms are known. Syndecan-4–/– mice are unable to regenerate damaged muscle, and display deficient satellite cell activation, proliferation, and differentiation. A reduced myofiber basal lamina has also been reported in syndecan-4–/– muscle, indicating possible defects in ECM production. To get a better understanding of the underlying molecular mechanisms, we have here investigated the effects of syndecan-4 genetic ablation on molecules involved in ECM remodeling and muscle growth, both under steady state conditions and in response to exercise. Methods: Tibialis anterior (TA) muscles from sedentary and exercised syndecan-4–/– and WT mice were analyzed by immunohistochemistry, real-time PCR and western blotting. Results: Compared to WT, we found that syndecan-4–/– mice had reduced body weight, reduced muscle weight, muscle fibers with a smaller cross-sectional area, and reduced expression of myogenic regulatory transcription factors. Sedentary syndecan-4–/– had also increased mRNA levels of syndecan-2, decorin, collagens, fibromodulin, biglycan, and LOX. Some of these latter ECM components were reduced at protein level, suggesting them to be more susceptible to degradation or less efficiently translated when syndecan-4 is absent. At the protein level, TRPC7 was reduced, whereas activation of the Akt/mTOR/S6K1 and Notch/HES-1 pathways were increased. Finally, although exercise induced upregulation of several of these components in WT, a further upregulation of these molecules was not observed in exercised syndecan-4–/– mice. Conclusion: Altogether our data suggest an important role of syndecan-4 in muscle development.

• 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
• Berge, Kristian; Lyngbakken, Magnus; Myhre, Peder Langeland; Brynildsen, Jon; Røysland, Ragnhild & Strand, Heidi [Show all 10 contributors for this article] (2020). High-sensitivity cardiac troponin T and N-terminal pro-B-type natriuretic peptide in acute heart failure: Data from the ACE 2 study. Clinical Biochemistry. ISSN 0009-9120. p. 1–7. doi: 10.1016/j.clinbiochem.2020.11.009. Full text in Research Archive Show summary

  Background To assess if cardiac troponins can improve diagnostics of acute heart failure (AHF) and provide prognostic information in patients with acute dyspnea. Methods We measured cardiac troponin T with a high-sensitivity assay (hs-cTnT) in 314 patients hospitalized with acute dyspnea. The index diagnosis was adjudicated and AHF patients were stratified into AHF with reduced or preserved ejection fraction (HFrEF/HFpEF). The prognostic and diagnostic merit of hs-cTnT was compared to the merit of N-terminal pro-B-type natriuretic peptide (NT-proBNP). Results In the total population, median age was 73 (quartile [Q] 1–3 63–81) years and 48% were women. One-hundred-forty-three patients were categorized as AHF (46%) and these patients had higher hs-cTnT concentrations than patients with non-AHF-related dyspnea: median 38 (Q1-3 22–75) vs. 13 (4–25) ng/L; p < 0.001. hs-cTnT concentrations were similar between patients with HFrEF and HFpEF (p = 0.80), in contrast to NT-proBNP, which was higher in HFrEF (p < 0.001). C-statistics for discriminating HFpEF from non-AHF-related dyspnea was 0.80 (95% CI 0.73–0.86) for hs-cTnT, 0.79 (0.73–0.86) for NT–proBNP, and 0.83 (0.76–0.89) for hs-cTnT and NT-proBNP in combination. Elevated hs-cTnT remained associated with HFpEF in logistic regression analysis after adjusting for demographics, comorbidities and renal function. During median 27 months of follow-up, 114 (36%) patients died in the total population. Higher hs-cTnT concentrations were associated with increased risk of all-cause mortality after adjustment for clinical variables and NT-proBNP: hazard ratio 1.30 (95% CI 1.07–1.58), p = 0.009. Conclusion hs-cTnT measurements improve diagnostic accuracy for HFpEF and provide independent prognostic information in unselected patients with acute dyspnea.

• Mathiesen, Sabrina Bech; Lunde, Marianne; Stensland, Maria; Martinsen, Marita; Nyman, Tuula Anneli & Christensen, Geir Arve [Show all 7 contributors for this article] (2020). The cardiac syndecan-2 interactome. Frontiers in Cell and Developmental Biology. 8:792, p. 1–18. doi: 10.3389/fcell.2020.00792. Full text in Research Archive Show summary

  The extracellular matrix (ECM) is important in cardiac remodeling and syndecans have gained increased interest in this process due to their ability to convert changes in the ECM to cell signaling. In particular, syndecan-4 has been shown to be important for cardiac remodeling, whereas the role of its close relative syndecan-2 is largely unknown in the heart. To get more insight into the role of syndecan-2, we here sought to identify interaction partners of syndecan-2 in rat left ventricle. By using three different affinity purification methods combined with mass spectrometry (MS) analysis, we identified 30 novel partners and 9 partners previously described in the literature, which together make up the first cardiac syndecan-2 interactome. Eleven of the novel partners were also verified in HEK293 cells (i.e., AP2A2, CAVIN2, DDX19A, EIF4E, JPH2, MYL12A, NSF, PFDN2, PSMC5, PSMD11, and RRAD). The cardiac syndecan-2 interactome partners formed connections to each other and grouped into clusters mainly involved in cytoskeletal remodeling and protein metabolism, but also into a cluster consisting of a family of novel syndecan-2 interaction partners, the CAVINs. MS analyses revealed that although syndecan-2 was significantly enriched in fibroblast fractions, most of its partners were present in both cardiomyocytes and fibroblasts. Finally, a comparison of the cardiac syndecan-2 and -4 interactomes revealed surprisingly few protein partners in common.

• Alam, Jahedul; Musiime, Moses; Romaine, Andreas; Sawant, Mugdha; Melleby, Arne Olav & Lu, Ning [Show all 9 contributors for this article] (2020). Generation of a novel mouse strain with fibroblast-specific expression of Cre recombinase. Matrix Biology Plus. 8. doi: 10.1016/j.mbplus.2020.100045. Full text in Research Archive Show summary

  Cell-specific expression of genes offers the possibility to use their promoters to drive expression of Cre-recombinase, thereby allowing for detailed expression analysis using reporter gene systems, cell lineage tracing, conditional gene deletion, and cell ablation. In this context, current data suggest that the integrin α11 subunit has the potential to serve as a fibroblast biomarker in tissue regeneration and pathology, in particular in wound healing and in tissue- and tumor fibrosis. The mesenchyme-restricted expression pattern of integrin α11 thus prompted us to generate a novel ITGA11-driver Cre mouse strain using a ϕC31 integrase-mediated knock-in approach. In this transgenic mouse, the Cre recombinase is driven by regulatory promoter elements within the 3 kb segment of the human ITGA11 gene. β-Galactosidase staining of embryonic tissues obtained from a transgenic ITGA11-Cre mouse line crossed with Rosa 26R reporter mice (ITGA11-Cre;R26R) revealed ITGA11-driven Cre expression and activity in mesenchymal cells in a variety of mesenchymal tissues in a pattern reminiscent of endogenous α11 protein expression in mouse embryos. Interestingly, X-gal staining of mouse embryonic fibroblasts (MEFs) isolated from the ITGA11-Cre;R26R mice indicated heterogeneity in the MEF population. ITGA11-driven Cre activity was shown in approximately 60% of the MEFs, suggesting that the expression of integrin α11 could be exploited for isolation of different fibroblast populations. ITGA11-driven Cre expression was found to be low in adult mouse tissues but was induced in granulation tissue of excisional wounds and in fibrotic hearts following aortic banding. We predict that the ITGA11-Cre transgenic mouse strain described in this report will be a useful tool in matrix research for the deletion of genes in subsets of fibroblasts in the developing mouse and for determining the function of subsets of pro-fibrotic fibroblasts in tissue fibrosis and in different subsets of cancer-associated fibroblasts in the tumor microenvironment.

• Røe, Åsmund Treu; Ruud, Marianne; Espe, Emil Knut Stenersen; Manfra, Ornella; Longobardi, S & Aronsen, Jan Magnus [Show all 16 contributors for this article] (2019). Regional diastolic dysfunction in post-infarction heart failure: role of local mechanical load and SERCA expression. Cardiovascular Research (CVR). ISSN 0008-6363. 115(4), p. 752–764. doi: 10.1093/cvr/cvy257. Full text in Research Archive Show summary

  Aims: Regional heterogeneities in contraction contribute to heart failure with reduced ejection fraction (HFrEF). We aimed to determine whether regional changes in myocardial relaxation similarly contribute to diastolic dysfunction in post-infarction HFrEF, and to elucidate the underlying mechanisms. Methods and results: Using the magnetic resonance imaging phase-contrast technique, we examined local diastolic function in a rat model of post-infarction HFrEF. In comparison with sham-operated animals, post-infarction HFrEF rats exhibited reduced diastolic strain rate adjacent to the scar, but not in remote regions of the myocardium. Removal of Ca2+ within cardiomyocytes governs relaxation, and we indeed found that Ca2+ transients declined more slowly in cells isolated from the adjacent region. Resting Ca2+ levels in adjacent zone myocytes were also markedly elevated at high pacing rates. Impaired Ca2+ removal was attributed to a reduced rate of Ca2+ sequestration into the sarcoplasmic reticulum (SR), due to decreased local expression of the SR Ca2+ ATPase (SERCA). Wall stress was elevated in the adjacent region. Using ex vivo experiments with loaded papillary muscles, we demonstrated that high mechanical stress is directly linked to SERCA down-regulation and slowing of relaxation. Finally, we confirmed that regional diastolic dysfunction is also present in human HFrEF patients. Using echocardiographic speckle-tracking of patients enrolled in the LEAF trial, we found that in comparison with controls, post-infarction HFrEF subjects exhibited reduced diastolic train rate adjacent to the scar, but not in remote regions of the myocardium. Conclusion: Our data indicate that relaxation varies across the heart in post-infarction HFrEF. Regional diastolic dysfunction in this condition is linked to elevated wall stress adjacent to the infarction, resulting in down-regulation of SERCA, disrupted diastolic Ca2+ handling, and local slowing of relaxation.

• Lipsett, David Bruce; Frisk, Michael; Aronsen, Jan Magnus; Norden, Einar Sjaastad; Buonarati, Olivia R. & Cataliotti, Alessandro [Show all 10 contributors for this article] (2019). Cardiomyocyte substructure reverts to an immature phenotype during heart failure. Journal of Physiology. ISSN 0022-3751. 597(7), p. 1833–1853. doi: 10.1113/JP277273. Full text in Research Archive Show summary

  Reactivation of the fetal gene programme has been implicated as a driver of pathological cardiac remodelling. Here we examined whether pathological remodelling of cardiomyocyte substructure and function during heart failure (HF) reflects a reversion to an immature phenotype. Using scanning electron microscopy, we observed that Z‐grooves and t‐tubule openings at the cell surface appeared gradually during cardiac development, and disappeared during HF. Confocal and super‐resolution imaging within the cell interior revealed similar structural parallels; disorganization of t‐tubules in failing cells was strikingly reminiscent of the late stages of postnatal development, with fewer transverse elements and a high proportion of longitudinal tubules. Ryanodine receptors (RyRs) were observed to be laid down in advance of developing t‐tubules and similarly ‘orphaned’ in HF, although RyR distribution along Z‐lines was relatively sparse. Indeed, nanoscale imaging revealed coordinated packing of L‐type Ca2+ channels and RyRs into dyadic junctions during development, and orderly unpacking during HF. These findings support a ‘last in, first out’ paradigm, as the latest stages of dyadic structural development are reversed during disease. Paired imaging of t‐tubules and Ca2+ showed that the disorganized arrangement of dyads in immature and failing cells promoted desynchronized and slowed Ca2+ release in these two states. However, while developing cells exhibited efficient triggering of Ca2+ release at newly formed dyads, dyadic function was impaired in failing cells despite similar organization of Ca2+ handling proteins. Thus, pathologically deficient Ca2+ homeostasis during HF is only partly linked to the re‐emergence of immature subcellular structure, and additionally reflects lost dyadic functionality.

• Brynildsen, Jon; Petaja, Liisa; Myhre, Peder Langeland; Lyngbakken, Magnus; Nygård, Ståle & Stridsberg, Mats [Show all 11 contributors for this article] (2019). Circulating Secretoneurin Concentrations After Cardiac Surgery: Data From the FINNish Acute Kidney Injury Heart Study. Critical Care Medicine. ISSN 0090-3493. 47(5), p. e412–e419. doi: 10.1097/CCM.0000000000003670. Full text in Research Archive
• 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.

• Brynildsen, Jon; Myhre, Peder Langeland; Lyngbakken, Magnus; Klæboe, Lars Gunnar; Stridsberg, Mats & Christensen, Geir Arve [Show all 9 contributors for this article] (2019). Circulating secretoneurin concentrations in patients with moderate to severe aortic stenosis. Clinical Biochemistry. ISSN 0009-9120. 71, p. 17–23. doi: 10.1016/j.clinbiochem.2019.06.008. Full text in Research Archive Show summary

  Background Secretoneurin (SN) concentrations provide important prognostic information in patients with myocardial dysfunction. Whether preoperative SN concentrations improve risk assessment in patients with moderate to severe aortic stenosis (AS) is unknown. Methods We included 57 patients with moderate to severe AS referred for presurgical evaluation. All patients were examined with comprehensive echocardiography, electrocardiogram (ECG), and biochemical measurements and compared to 10 age- and sex-matched healthy subjects. Results Median (quartile 1–3) SN concentrations were 141 (121–163) pmol/L in AS patients and 132 (106–148) pmol/L in control subjects (p = .17). Lower estimated creatinine clearance and use of diuretics, but not standard ECG or echocardiographic indices and cardiac biomarkers, were associated with increasing SN concentrations. Fifteen patients (26%) died during 3.5 years median follow-up. SN concentrations were higher in non-survivors than survivors: 156 (133–209) vs. 140 (116–155) pmol/L, p = .007. Higher SN concentrations were associated with increased risk of mortality also after adjustment for established risk indices, biomarkers, and status regarding valvular surgery: hazard ratio per lnSN 15.13 (95% CI 1.05–219.00); p = .046. Receiver operating characteristics area under the curve for SN to predict mortality was 0.74 (95% CI 0.60–0.88) compared to 0.73 (0.59–0.87) for high-sensitivity cardiac troponin T and 0.67 (0.51–0.82) for N-terminal pro-B-type natriuretic peptide. The previously identified cut-off of SN >204 pmol/L in cardiac surgical patients predicted mortality also in this cohort. Conclusions SN concentrations improve risk assessment in patients with moderate to severe AS by providing additional prognostic information to established risk indices such as echocardiography, ECG, and established cardiac biomarkers.

• Mathiesen, Sabrina Bech; Lunde, Marianne; Aronsen, Jan Magnus; Romaine, Andreas; Kaupang, Anita & Martinsen, Marita [Show all 11 contributors for this article] (2019). The cardiac syndecan-4 interactome reveals a role for syndecan-4 in nuclear translocation of muscle LIM protein (MLP). Journal of Biological Chemistry. ISSN 0021-9258. 294(22), p. 8717–8731. doi: 10.1074/jbc.RA118.006423. Full text in Research Archive Show summary

  Costameres are signaling hubs at the sarcolemma and important contact points between the extracellular matrix and cell interior, sensing and transducing biomechanical signals into a cellular response. The transmembrane proteoglycan syndecan-4 localizes to these attachment points and has been shown to be important in the initial stages of cardiac remodeling, but its mechanistic function in the heart remains insufficiently understood. Here, we sought to map the cardiac interactome of syndecan-4 to better understand its function and downstream signaling mechanisms. By combining two different affinity purification methods with MS analysis, we found that the cardiac syndecan-4 interactome consists of 21 novel and 29 previously described interaction partners. Nine of the novel partners were further validated to bind syndecan-4 in HEK293 cells (i.e. CAVIN1/PTRF, CCT5, CDK9, EIF2S1, EIF4B, MPP7, PARVB, PFKM, and RASIP). We also found that 19 of the 50 interactome partners bind differently to syndecan-4 in the left ventricle lysate from aortic-banded heart failure (ABHF) rats compared with SHAM-operated animals. One of these partners was the well-known mechanotransducer muscle LIM protein (MLP), which showed direct and increased binding to syndecan-4 in ABHF. Nuclear translocation is important in MLP-mediated signaling, and we found less MLP in the nuclear-enriched fractions from syndecan-4-/- mouse left ventricles but increased nuclear MLP when syndecan-4 was overexpressed in a cardiomyocyte cell line. In the presence of a cell-permeable syndecan-4-MLP disruptor peptide, the nuclear MLP level was reduced. These findings suggest that syndecan-4 mediates nuclear translocation of MLP in the heart

• Udjus, Camilla; Fadila, Cero; Halvorsen, Bente; Behmen, Dina; Carlson, Cathrine Rein & Bendiksen, Bård Andre [Show all 14 contributors for this article] (2019). Caspase-1 induces smooth muscle cell growth in hypoxia-induced pulmonary hypertension. American Journal of Physiology - Lung cellular and Molecular Physiology. 316(6), p. L999–L1012. doi: 10.1152/ajplung.00322.2018. Full text in Research Archive Show summary

  Lung diseases with hypoxia are complicated by pulmonary hypertension, leading to heart failure and death. No pharmacological treatment exists. Increased proinflammatory cytokines are found in hypoxic patients, suggesting an inflammatory pathogenesis. Caspase-1, the effector of the inflammasome, mediates inflammation through activation of the proinflammatory cytokines interleukin (IL)-18 and IL-1β. Here, we investigate inflammasome-related mechanisms that can trigger hypoxia-induced pulmonary hypertension. Our aim was to examine whether caspase-1 induces development of hypoxia-related pulmonary hypertension and is a suitable target for therapy. Wild-type (WT) and caspase-1−/− mice were exposed to 10% oxygen for 14 days. Hypoxic caspase-1−/− mice showed lower pressure and reduced muscularization in pulmonary arteries, as well as reduced right ventricular remodeling compared with WT. Smooth muscle cell (SMC) proliferation was reduced in caspase-1-deficient pulmonary arteries and in WT arteries treated with a caspase-1 inhibitor. Impaired inflammation was shown in hypoxic caspase-1−/− mice by abolished pulmonary influx of immune cells and lower levels of IL-18, IL-1β, and IL-6, which were also reduced in the medium surrounding caspase-1 abrogated pulmonary arteries. By adding IL-18 or IL-1β to caspase-1-deficient pulmonary arteries, SMC proliferation was retained. Furthermore, inhibition of both IL-6 and phosphorylated STAT3 reduced proliferation of SMC in vitro, indicating IL-18, IL-6, and STAT3 as downstream mediators of caspase-1-induced SMC proliferation in pulmonary arteries. Caspase-1 induces SMC proliferation in pulmonary arteries through the caspase-1/IL-18/IL-6/STAT3 pathway, leading to pulmonary hypertension in mice exposed to hypoxia. We propose that caspase-1 inhibition is a potential target for treatment of pulmonary hypertension.

• Ottesen, Anett Hellebø; Carlson, Cathrine Rein; Eken, Olav Søvik; Sadredini, Mani; Myhre, Peder Langeland & Shen, Xin [Show all 24 contributors for this article] (2019). Secretoneurin Is an Endogenous Calcium/Calmodulin-Dependent Protein Kinase II Inhibitor That Attenuates Ca2+-Dependent Arrhythmia. Circulation: Arrhythmia and Electrophysiology. ISSN 1941-3149. 12(4). doi: 10.1161/CIRCEP.118.007045. Full text in Research Archive Show summary

  Background: Circulating SN (secretoneurin) concentrations are increased in patients with myocardial dysfunction and predict poor outcome. Because SN inhibits CaMKIIδ (Ca2+/calmodulin-dependent protein kinase IIδ) activity, we hypothesized that upregulation of SN in patients protects against cardiomyocyte mechanisms of arrhythmia. Methods: Circulating levels of SN and other biomarkers were assessed in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT; n=8) and in resuscitated patients after ventricular arrhythmia–induced cardiac arrest (n=155). In vivo effects of SN were investigated in CPVT mice (RyR2 [ryanodine receptor 2]-R2474S) using adeno-associated virus-9–induced overexpression. Interactions between SN and CaMKIIδ were mapped using pull-down experiments, mutagenesis, ELISA, and structural homology modeling. Ex vivo actions were tested in Langendorff hearts and effects on Ca2+ homeostasis examined by fluorescence (fluo-4) and patch-clamp recordings in isolated cardiomyocytes. Results: SN levels were elevated in patients with CPVT and following ventricular arrhythmia–induced cardiac arrest. In contrast to NT-proBNP (N-terminal pro-B-type natriuretic peptide) and hs-TnT (high-sensitivity troponin T), circulating SN levels declined after resuscitation, as the risk of a new arrhythmia waned. Myocardial pro-SN expression was also increased in CPVT mice, and further adeno-associated virus-9–induced overexpression of SN attenuated arrhythmic induction during stress testing with isoproterenol. Mechanistic studies mapped SN binding to the substrate binding site in the catalytic region of CaMKIIδ. Accordingly, SN attenuated isoproterenol induced autophosphorylation of Thr287-CaMKIIδ in Langendorff hearts and inhibited CaMKIIδ-dependent RyR phosphorylation. In line with CaMKIIδ and RyR inhibition, SN treatment decreased Ca2+ spark frequency and dimensions in cardiomyocytes during isoproterenol challenge, and reduced the incidence of Ca2+ waves, delayed afterdepolarizations, and spontaneous action potentials. SN treatment also lowered the incidence of early afterdepolarizations during isoproterenol; an effect paralleled by reduced magnitude of L-type Ca2+ current. Conclusions: SN production is upregulated in conditions with cardiomyocyte Ca2+ dysregulation and offers compensatory protection against cardiomyocyte mechanisms of arrhythmia, which may underlie its putative use as a biomarker in at-risk patients.

• Gamage, Thilini Hansamali Gamage Yaddehi; Gunnes, Gjermund; Lee, Robert Hugh; Louch, William Edward; Holmgren, Asbjørn & Bruton, Joseph D. [Show all 19 contributors for this article] (2018). STIM1 R304W causes muscle degeneration and impaired platelet activation in mice. Cell Calcium. ISSN 0143-4160. 76, p. 87–100. doi: 10.1016/j.ceca.2018.10.001. Full text in Research Archive Show summary

  STIM1 and ORAI1 regulate store-operated Ca2+ entry (SOCE) in most cell types, and mutations in these proteins have deleterious and diverse effects. We established a mouse line expressing the STIM1 R304 W gain-of-function mutation causing Stormorken syndrome to explore effects on organ and cell physiology. While STIM1 R304 W was lethal in the homozygous state, surviving mice presented with reduced growth, skeletal muscle degeneration, and reduced exercise endurance. Variable STIM1 expression levels between tissues directly impacted cellular SOCE capacity. In contrast to patients with Stormorken syndrome, STIM1 was downregulated in fibroblasts from Stim1R304W/R304W mice, which maintained SOCE despite constitutive protein activity. In studies using foetal liver chimeras, STIM1 protein was undetectable in homozygous megakaryocytes and platelets, resulting in impaired platelet activation and absent SOCE. These data indicate that downregulation of STIM1 R304 W effectively opposes the gain-of-function phenotype associated with this mutation, and highlight the importance of STIM1 in skeletal muscle development and integrity.

• Melleby, Arne Olav; Romaine, Andreas; Aronsen, Jan Magnus; Veras, Ioanni; Zhang, Lili & Sjaastad, Ivar [Show all 8 contributors for this article] (2018). A novel method for high precision aortic constriction that allows for generation of specific cardiac phenotypes in mice. Cardiovascular Research (CVR). ISSN 0008-6363. doi: 10.1093/cvr/cvy141. Full text in Research Archive Show summary

  Aims Generation of reproducible cardiac disease phenotypes in mice is instrumental for investigating mechanisms leading to heart failure (HF). For decades, suture-based thoracic aortic constriction has been the preferred method for increasing left ventricular (LV) afterload in rodents, but the degree of stenosis resulting from this method is variable. In an effort to improve this methodology, we subjected mice to constriction of the ascending aorta using o-rings with fixed inner diameters (IDs). Methods and results Mice of C57BL/6J and FVB/N background were subjected to constriction of the ascending aorta using o-rings with fixed IDs of 0.71, 0.66, and 0.61 mm. O-ring aortic banding resulted in 98.7% survival 2 weeks post-surgery, with very low intra- and inter-surgeon variation. When using the narrowest o-ring (0.61 mm), mice developed hypertrophy within 1 week. Over 20 weeks, the mice gradually developed reduced LV ejection fraction (LVEF) and dilatation with increased left atrial dimensions and lung weight, indicating congestion. When using o-rings with IDs of 0.66 mm and 0.71 mm, the mice developed hypertrophy, but maintained a compensated state with stabilized LVEF 8–20 weeks post-surgery. The up-regulation of signature genes associated with HF, hypertrophy, fibrosis, and the level of activation of MAPK and NFAT signalling pathways corresponded to the degree of stenosis. Conclusion Here, we introduce a novel method for high precision aortic constriction in mice with high intra- and inter-surgeon reproducibility and low post-operative mortality that allows generation of specific cardiac disease phenotypes.

• Berge, Kristian; Lyngbakken, Magnus; Einvik, Gunnar; Winther, Jacob Andreas; Brynildsen, Jon & Røysland, Ragnhild [Show all 11 contributors for this article] (2018). Diagnostic and prognostic properties of procalcitonin in patients with acute dyspnea: Data from the ACE 2 Study. Clinical Biochemistry. ISSN 0009-9120. 59, p. 62–68. doi: 10.1016/j.clinbiochem.2018.07.006. Full text in Research Archive
• Christensen, Geir Arve; Herum, Kate Louise Møller & Lunde, Ida Gjervold (2018). Sweet, yet underappreciated: Proteoglycans and extracellular Matrix remodeling in heart disease. Matrix Biology. ISSN 0945-053X. 75-76, p. 286–299. doi: 10.1016/j.matbio.2018.01.001. Full text in Research Archive
• Lyngbakken, Magnus Nakrem; Pervez, Mohammad Osman; Brynildsen, Jon; Pedersen, Marit Holmefjord; Sølvernes, Janne & Christensen, Geir Arve [Show all 9 contributors for this article] (2018). Fibroblast growth factor 23 in patients with acute dyspnea: Data from the Akershus Cardiac Examination (ACE) 2 Study. Clinical Biochemistry. ISSN 0009-9120. 52, p. 41–47. doi: 10.1016/j.clinbiochem.2017.10.015. Full text in Research Archive Show summary

  Background Circulating fibroblast growth factor 23 (FGF23) concentrations have been linked to left ventricular remodeling and unfavorable cardiovascular outcomes, but whether FGF23 is associated with heart failure (HF) diagnosis and outcome in unselected patients with dyspnea is unknown. Accordingly, we assessed the diagnostic and prognostic properties of FGF23 in patients presenting to the emergency department with acute dyspnea. Methods and results FGF23 was measured in 314 patients admitted with acute dyspnea and the diagnostic and prognostic merit was compared to that of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The diagnosis of acute HF was adjudicated by two independent physicians. Circulating FGF23 concentrations on hospital admission were higher in patients with acute HF vs. patients with non-HF related dyspnea: median 3.60 (IQR 1.24–8.77) vs. 1.00 (0.43–2.20) pmol/L; P < 0.001. The receiver-operating statistics area under the curve for acute HF diagnosis was 0.750 (0.699–0.797) for FGF23 and 0.853 (0.809–0.890) for NT-proBNP. Adjusting for clinical risk indices and cardiac biomarkers in multivariate Cox regression analysis, admission FGF23 concentrations were associated with mortality in the total study population (hazard ratio [HR] per 1 SD in lnFGF23 1.74 [1.40–2.16]). FGF23 also reclassified patients into their correct risk strata on top of clinical variables significantly associated with outcomes in the total cohort (net reclassification index 0.386 [0.161–0.612]). In patients with acute HF, both admission FGF23 and NT-proBNP concentrations were associated with mortality. Conclusion Circulating FGF23 concentrations provide incremental prognostic information to established risk indices in patients with acute dyspnea, but do not improve diagnostic accuracy over NT-proBNP measurements. Lyngbakken, Magnus Nakrem, et al. "Fibroblast growth factor 23 in patients with acute dyspnea: Data from the Akershus Cardiac Examination (ACE) 2 Study." Clinical biochemistry (2017). © 2017. This manuscript version is made available under the CC-BY-NC-ND 4.0 license.

• Røsjø, Helge; Masson, Serge; Caironi, Pietro; Stridsberg, Mats; Magnoli, Michela & Christensen, Geir Arve [Show all 12 contributors for this article] (2018). Prognostic value of secretoneurin in patients with severe sepsis and septic shock: Data from the albumin Italian outcome sepsis study. Critical Care Medicine. ISSN 0090-3493. 46(5), p. e404–e410. doi: 10.1097/CCM.0000000000003050. Full text in Research Archive Show summary

  Objectives: Secretoneurin directly influences cardiomyocyte calcium handling, and circulating secretoneurin levels seem to improve risk prediction in patients with myocardial dysfunction by integrating information on systemic stress, myocardial function, and renal function. Accordingly, in this study, we hypothesized that secretoneurin would improve risk prediction in patients with sepsis and especially in patients with septic shock as these patients are more hemodynamically unstable. Design: Multicenter, interventional randomized clinical trial. Setting: Multicenter, pragmatic, open-label, randomized, prospective clinical trial testing fluid administration with either 20% human albumin and crystalloids or crystalloid solutions alone in patients with severe sepsis or septic shock (The Albumin Italian Outcome Sepsis). Patients or Subjects: In total, 540 patients with septic shock and 418 patients with severe sepsis. Interventions: Either 20% human albumin and crystalloids or crystalloid solutions alone. Measurements and Main Results: We measured secretoneurin on days 1, 2, and 7 after randomization and compared the prognostic value of secretoneurin for ICU and 90-day mortality with established risk indices and cardiac biomarkers in septic shock and severe sepsis. High secretoneurin levels on day 1 were associated with age and serum concentrations of lactate, bilirubin, creatinine, and N-terminal pro-B-type natriuretic peptide. Adjusting for established risk factors and cardiovascular biomarkers, secretoneurin levels on day 1 were associated with ICU (odds ratio, 2.27 [95% CI, 1.05-4.93]; p = 0.04) and 90-day mortality (2.04 [1.02-4.10]; p = 0.04) in patients with septic shock, but not severe sepsis without shock. Secretoneurin levels on day 2 were also associated with ICU (3.11 [1.34-7.20]; p = 0.008) and 90-day mortality (2.69 [1.26-5.78]; p = 0.01) in multivariate regression analyses and improved reclassification in patients with septic shock, as assessed by the net reclassification index. Randomized albumin administration did not influence the associations between secretoneurin and outcomes. Conclusions: Secretoneurin provides early and potent prognostic information in septic patients with cardiovascular instability.

• Pervez, Mohammad Osman; Winther, Jacob Andreas; Brynildsen, Jon; Strand, Heidi; Christensen, Geir Arve & Høiseth, Arne Didrik [Show all 11 contributors for this article] (2018). Prognostic and diagnostic significance of mid-regional pro-atrial natriuretic peptide in acute exacerbation of chronic obstructive pulmonary disease and acute heart failure: data from the ACE 2 Study. Biomarkers. ISSN 1354-750X. p. 1–11. doi: 10.1080/1354750X.2018.1474258. Full text in Research Archive
• 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.

• Romaine, Andreas; Sørensen, Ida Wiig; Zeltz, Cedric; Lu, Ning; Erusappan, Pugazendhi Murugan & Melleby, Arne Olav [Show all 15 contributors for this article] (2017). Overexpression of integrin α11 induces cardiac fibrosis in mice. Acta Physiologica Scandinavica. ISSN 0001-6772. 222:e13025(2), p. 1–17. doi: 10.1111/apha.12932. Full text in Research Archive
• Ottesen, Anett Hellebø; Carlson, Cathrine Rein; Louch, William Edward; Dahl, Mai Britt; Sandbu, Ragnhild Askeland & Johansen, Rune Forstrøm [Show all 15 contributors for this article] (2017). Glycosylated Chromogranin A in Heart Failure: Implications for Processing and Cardiomyocyte Calcium Homeostasis. Circulation: Heart Failure. ISSN 1941-3289. 10(2). doi: 10.1161/CIRCHEARTFAILURE.116.003675. Full text in Research Archive Show summary

  Background—Chromogranin A (CgA) levels have previously been found to predict mortality in heart failure (HF), but currently no information is available regarding CgA processing in HF and whether the CgA fragment catestatin (CST) may directly influence cardiomyocyte function. Methods and Results—CgA processing was characterized in postinfarction HF mice and in patients with acute HF, and the functional role of CST was explored in experimental models. Myocardial biopsies from HF, but not sham-operated mice, demonstrated high molecular weight CgA bands. Deglycosylation treatment attenuated high molecular weight bands, induced a mobility shift, and increased shorter CgA fragments. Adjusting for established risk indices and biomarkers, circulating CgA levels were found to be associated with mortality in patients with acute HF, but not in patients with acute exacerbation of chronic obstructive pulmonary disease. Low CgA-to-CST conversion was also associated with increased mortality in acute HF, thus, supporting functional relevance of impaired CgA processing in cardiovascular disease. CST was identified as a direct inhibitor of CaMKIIδ (Ca2+/calmodulin-dependent protein kinase IIδ) activity, and CST reduced CaMKIIδ-dependent phosphorylation of phospholamban and the ryanodine receptor 2. In line with CaMKIIδ inhibition, CST reduced Ca2+ spark and wave frequency, reduced Ca2+ spark dimensions, increased sarcoplasmic reticulum Ca2+ content, and augmented the magnitude and kinetics of cardiomyocyte Ca2+ transients and contractions. Conclusions—CgA-to-CST conversion in HF is impaired because of hyperglycosylation, which is associated with clinical outcomes in acute HF. The mechanism for increased mortality may be dysregulated cardiomyocyte Ca2+ handling because of reduced CaMKIIδ inhibition.

• Winther, Jacob Andreas; Brynildsen, Jon; Høiseth, Arne Didrik; Strand, Heidi; Følling, Ivar & Christensen, Geir Arve [Show all 9 contributors for this article] (2017). Prognostic and diagnostic significance of copeptin in acute exacerbation of chronic obstructive pulmonary disease and acute heart failure: Data from the ACE 2 study. Respiratory Research. ISSN 1465-9921. 18(184). doi: 10.1186/s12931-017-0665-z. Full text in Research Archive Show summary

  Background Copeptin is a novel biomarker that predicts mortality in lower respiratory tract infections and heart failure (HF), but the diagnostic value of copeptin in acute dyspnea and the prognostic significance of copeptin in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is not clear. Method We determined copeptin and NT-proBNP concentrations at hospital admission in 314 patients with acute dyspnea who were categorized by diagnosis. Survival was registered after a median follow-up of 816 days, and the prognostic and diagnostic properties of copeptin and NT-proBNP were analyzed in acute HF (n = 143) and AECOPD (n = 84) separately. Results The median concentration of copeptin at admission was lower in AECOPD compared to acute HF (8.8 [5.2–19.7] vs. 22.2 [10.2–47.9]) pmol/L, p < 0.001), but NT-proBNP discriminated acute HF from non-HF related dyspnea more accurately than copeptin (ROC-AUC 0.85 [0.81–0.89] vs. 0.71 [0.66–0.77], p < 0.0001). Adjusted for basic risk factors, increased copeptin concentrations predicted mortality in AECOPD (HR per log (ln) unit 1.72 [95% CI 1.21–2.45], p = 0.003) and acute HF (1.61 [1.25–2.09], p < 0.001), whereas NT-proBNP concentrations predicted mortality only in acute HF (1.62 [1.27–2.06], p < 0.001). On top of a basic model copeptin reclassified a significant proportion of patients into a more accurate risk strata in AECOPD (NRI 0.60 [0.19–1.02], p = 0.004) and acute HF (0.39 [0.06–0.71], p = 0.020). Conclusion Copeptin is a strong prognostic marker in both AECOPD and acute HF, while NT-proBNP concentrations predict mortality only in patients with acute HF. NT-proBNP levels are superior to copeptin levels to diagnose acute HF in patients with acute dyspnea.

• Abraityte, Judita Aurelija; Vinge, Leif Erik; Askevold, Erik Tandberg; Lekva, Tove; Michelsen, Annika & Ranheim, Trine [Show all 16 contributors for this article] (2017). Wnt5a is elevated in heart failure and affects cardiac fibroblast function. Journal of Molecular Medicine. ISSN 0946-2716. 95(7), p. 767–777. doi: 10.1007/s00109-017-1529-1. Full text in Research Archive
• Myhre, Peder Langeland; Stridsberg, Mats; Linko, Rita; Okkonen, Marjatta; Nygård, Ståle & Christensen, Geir Arve [Show all 9 contributors for this article] (2017). Circulating chromogranin B levels in patients with acute respiratory failure: data from the FINNALI Study. Biomarkers. ISSN 1354-750X. 22(8), p. 775–781. doi: 10.1080/1354750X.2016.1269200. Full text in Research Archive Show summary

  Purpose: Circulating chromogranin B (CgB) levels are increased in situations characterized by systemic and myocardial stress, but whether CgB provides prognostic information in patients with acute respiratory failure (ARF) is unknown. Methods: We included 584 patients with ARF, defined as ventilatory support >6 h, and with blood samples available on Intensive Care Unit (ICU) admission and day 3 (n=479). CgB levels were measured by radioimmunoassay and follow-up was 90 days. Results: One-hundred-sixty-nine patients (29%) died during follow-up. Admission CgB levels separated non-survivors from survivors: median 1234 (Q1-3 989-1742) vs. 917 (753-1224) pmol/L, respectively, p<0.001. CgB levels on ICU admission (logarithmically transformed) were associated with time to death after adjustment for established risk indices available on ICU admission, including N-terminal pro-B-type natriuretic levels: HR 2.62 (95% C.I. 1.82-3.77), p<0.001. Admission CgB levels also improved prognostication on top of SOFA and SAPS II scores assessed by Cox regression analyses and the category-free net reclassification index. The area under the curve (AUC) for admission CgB levels to separate survivors and non-survivors was 0.72 (95% CI 0.67-0.76), while the AUC on day 3 was 0.60 (0.54-0.66). Conclusions: CgB levels measured on ICU admission provided additional prognostic information to established risk indices in ARF patients. The final version of this research has been published in Biomarkers. © 2017 Taylor & Francis

• Herum, Kate Louise Møller; Lunde, Ida Gjervold; McCulloch, Andrew D. & Christensen, Geir Arve (2017). The Soft- and Hard-Heartedness of Cardiac Fibroblasts: Mechanotransduction Signaling Pathways in Fibrosis of the Heart. Journal of Clinical Medicine. 6(53). doi: 10.3390/jcm6050053. Full text in Research Archive Show summary

  Cardiac fibrosis, the excessive accumulation of extracellular matrix (ECM), remains an unresolved problem in most forms of heart disease. In order to be successful in preventing, attenuating or reversing cardiac fibrosis, it is essential to understand the processes leading to ECM production and accumulation. Cardiac fibroblasts are the main producers of cardiac ECM, and harbor great phenotypic plasticity. They are activated by the disease-associated changes in mechanical properties of the heart, including stretch and increased tissue stiffness. Despite much remaining unknown, an interesting body of evidence exists on how mechanical forces are translated into transcriptional responses important for determination of fibroblast phenotype and production of ECM constituents. Such mechanotransduction can occur at multiple cellular locations including the plasma membrane, cytoskeleton and nucleus. Moreover, the ECM functions as a reservoir of pro-fibrotic signaling molecules that can be released upon mechanical stress. We here review the current status of knowledge of mechanotransduction signaling pathways in cardiac fibroblasts that culminate in pro-fibrotic gene expression.

• Dhondup, Yangchen; Sjaastad, Ivar; Sandanger, Øystein; Aronsen, Jan Magnus; Ahmed, Muhammad Shakil & Attramadal, Håvard [Show all 14 contributors for this article] (2017). Toll-like receptor 9 promotes survival in SERCA2a KO heart failure mice. Mediators of Inflammation. ISSN 0962-9351. 2017:9450439, p. 1–11. doi: 10.1155/2017/9450439. Full text in Research Archive Show summary

  Aim. Inflammation is important in heart failure (HF). The role of the immune receptor toll-like receptor 9 (TLR9) in HF is not understood and not investigated in diastolic HF. We investigated the role of TLR9 in a murine diastolic HF model caused by cardiomyocyte SERCA2a excision. Methods and Results. We crossed SERCA2a KO and TLR9 KO mice to generate four mouse lines. Tamoxifen-induced cardiomyocyte SERCA2a gene excision was carried out in mice, causing diastolic HF. After 7.6 weeks, cardiac functions and dimensions were analyzed by echocardiography and heart tissues were processed. HF mice depleted of TLR9 demonstrated reduced survival compared to SERC2a KO mice, with a median life expectancy of 58 days compared to 63 days. Both HF groups displayed increased left atrium size, lung weight, fetal gene expressions, monocyte/macrophage infiltration, and fibrosis. However, there were no significant differences between the groups. Conclusion. In mice with SERCA2a KO-induced diastolic HF, the absence of TLR9 reduced median life expectancy. The cause remains elusive, as all investigated HF parameters were unaltered. Still, these findings support a salutary role of TLR9 in some subsets of HF conditions and underline the importance for future studies on the mechanisms of TLR9 in diastolic HF.

• Ottesen, Anett Hellebø; Christensen, Geir Arve; Omland, Torbjørn & Røsjø, Helge (2017). Glycosylated Chromogranin A: Potential Role in the Pathogenesis of Heart Failure. Current Heart Failure Reports. ISSN 1546-9530. 14, p. 478–478. doi: 10.1007/s11897-017-0360-x. Full text in Research Archive Show summary

  Purpose of Review Endocrine and paracrine factors influence the cardiovascular system and the heart by a number of different mechanisms. The chromogranin-secretogranin (granin) proteins seem to represent a new family of proteins that exerts both direct and indirect effects on cardiac and vascular functions. The granin proteins are produced in multiple tissues, including cardiac cells, and circulating granin protein concentrations provide incremental prognostic information to established risk indices in patients with myocardial dysfunction. In this review, we provide recent data for the granin proteins in relation with cardiovascular disease, and with a special focus on chromogranin A and heart failure. Recent Findings Chromogranin A is the most studied member of the granin protein family, and shorter, functionally active peptide fragments of chromogranin A exert protective effects on myocardial cell death, ischemia-reperfusion injury, and cardiomyocyte Ca2+ handling. Granin peptides have also been found to induce angiogenesis and vasculogenesis. Protein glycosylation is an important post-translational regulatory mechanism, and we recently found chromogranin A molecules to be hyperglycosylated in the failing myocardium. Chromogranin A hyperglycosylation impaired processing of full-length chromogranin A molecules into physiologically active chromogranin A peptides, and patients with acute heart failure and low rate of chromogranin A processing had increased mortality compared to other acute heart failure patients. Other studies have also demonstrated that circulating granin protein concentrations increase in parallel with heart failure disease stage. Summary The granin protein family seems to influence heart failure pathophysiology, and chromogranin A hyperglycosylation could directly be implicated in heart failure disease progression. This is a post-peer-review, pre-copyedit version of an article published in Current Heart Failure Reports. The final authenticated version is available online at: http://dx.doi.org/10.1007/s11897-017-0360-x

• Pervez, Mohammad Osman; Lyngbakken, Magnus Nakrem; Myhre, Peder Langeland; Brynildsen, Jon; Langsjøen, Eva Camilla & Høiseth, Arne Didrik [Show all 9 contributors for this article] (2017). Mid-regional pro-adrenomedullin in patients with acute dyspnea: Data from the Akershus Cardiac Examination (ACE) 2 Study. Clinical Biochemistry. ISSN 0009-9120. 50(7-8), p. 394–400. doi: 10.1016/j.clinbiochem.2016.12.010. Full text in Research Archive Show summary

  Abstract Background Mid-regional pro-adrenomedullin (MR-proADM) is a surrogate marker for adrenomedullin; a hormone that attenuates myocardial remodeling. Accordingly, we hypothesized that MR-proADM could provide diagnostic and prognostic information in patients with acute dyspnea. Methods and results We measured MR-proADM by a commercial ELISA on hospital admission in 311 patients with acute dyspnea and compared the utility of MR-proADM with N-terminal pro-B-type natriuretic peptide (NT-proBNP). Blood samples were also available after 24 h (n = 232) and before discharge (n = 94). The principal diagnosis of the index hospitalization was determined by an adjudication committee. MR-proADM concentrations on hospital admission were higher in patients with acute heart failure (HF; n = 143) vs. patients hospitalized with non-HF-related dyspnea (n = 168): 1.31 (Q1-3 0.97–1.89) vs. 0.85 (0.59–1.15) nmol/L; p < 0.001. The receiver-operating characteristics area under the curve (ROC-AUC) for MR-proADM to diagnose HF was 0.77 (95% CI 0.72–0.82) and 0.86 (0.82–0.90) for NT-proBNP. During a median follow-up of 816 days, 66/143 patients (46%) with acute HF and 35/84 patients (42%) with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) died; p = 0.58 between groups. In multivariate Cox regression analyses, admission MR-proADM concentrations were associated with mortality in patients with acute HF (HR 5.90 [3.43–10.13], p < 0.001), but not in patients with AECOPD. Admission MR-proADM concentrations also improved risk stratification in acute HF as assessed by the net reclassification index. MR-proADM concentrations decreased from admission to later time points. Conclusion Admission MR-proADM concentrations provide strong prognostic information in patients with acute HF, but modest diagnostic information in patients with acute dyspnea. Pervez, Mohammad Osman, et al. "Mid-regional pro-adrenomedullin in patients with acute dyspnea: Data from the Akershus Cardiac Examination (ACE) 2 Study." Clinical biochemistry 50.7-8 (2017): 394-400. © 2017. This manuscript version is made available under the CC-BY-NC-ND 4.0 license.

• Abraityte, Judita Aurelija; Lunde, Ida Gjervold; Askevold, Erik Tandberg; Michelsen, Annika; Christensen, Geir Arve & Aukrust, Pål [Show all 14 contributors for this article] (2017). Wnt5a is associated with right ventricular dysfunction and adverse outcome in dilated cardiomyopathy. Scientific Reports. 7(1). doi: 10.1038/s41598-017-03625-9. Full text in Research Archive Show summary

  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.

• Olsen, Maria Belland; Hildrestrand, Gunn Annette; Scheffler, Katja; Vinge, Leif Erik; Alfsnes, Katrine & Palibrk, Vuk [Show all 29 contributors for this article] (2017). NEIL3-Dependent Regulation of Cardiac Fibroblast Proliferation Prevents Myocardial Rupture. Cell reports. 18, p. 82–92. doi: 10.1016/j.celrep.2016.12.009. Full text in Research Archive Show summary

  Myocardial infarction (MI) triggers a reparative response involving fibroblast proliferation and differentiation driving extracellular matrix modulation necessary to form a stabilizing scar. Recently, it was shown that a genetic variant of the base excision repair enzyme NEIL3 was associated with increased risk of MI in humans. Here, we report elevated myocardial NEIL3 expression in heart failure patients and marked myocardial upregulation of Neil3 after MI in mice, especially in a fibroblast-enriched cell fraction. Neil3−/− mice show increased mortality after MI caused by myocardial rupture. Genome-wide analysis of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) reveals changes in the cardiac epigenome, including in genes related to the post-MI transcriptional response. Differentially methylated genes are enriched in pathways related to proliferation and myofibroblast differentiation. Accordingly, Neil3−/− ruptured hearts show increased proliferation of fibroblasts and myofibroblasts. We propose that NEIL3-dependent modulation of DNA methylation regulates cardiac fibroblast proliferation and thereby affects extracellular matrix modulation after MI.

• Norum, Hilde Margrethe; Broch, Kaspar; Michelsen, Annika; Lunde, Ida Gjervold; Lekva, Tove & Abraityte, Judita Aurelija [Show all 14 contributors for this article] (2017). The Notch Ligands DLL1 and Periostin Are Associated with Symptom Severity and Diastolic Function in Dilated Cardiomyopathy. Journal of Cardiovascular Translational Research (JCTR). ISSN 1937-5387. p. 1–10. doi: 10.1007/s12265-017-9748-y. Full text in Research Archive
• Høiseth, Arne Didrik; Brynildsen, Jon; Hagve, Tor-Arne; Christensen, Geir Arve; Søyseth, Vidar & Omland, Torbjørn [Show all 7 contributors for this article] (2016). The influence of heart failure co-morbidity on high-sensitivity troponin T levels in COPD exacerbation in a prospective cohort study: Data from the Akershus cardiac examination (ACE) 2 study. Biomarkers. ISSN 1354-750X. 21(2), p. 173–179. doi: 10.3109/1354750X.2015.1126645. Full text in Research Archive
• Lunde, Ida Gjervold; Herum, Kate Louise Møller; Carlson, Cathrine Rein & Christensen, Geir Arve (2016). Syndecans in heart fibrosis. Cell and Tissue Research. ISSN 0302-766X. 365(3), p. 539–552. doi: 10.1007/s00441-016-2454-2. Full text in Research Archive
• Myhre, Peder Langeland; Ottesen, Anett Hellebø; Okkonen, Marjatta; Linko, Rita; Stridsberg, Mats & Nygård, Ståle [Show all 10 contributors for this article] (2016). Prognostic value of secretoneurin in patients with acute respiratory failure:Data from the FINNALI study. Clinical Chemistry. ISSN 0009-9147. 62(10), p. 1380–1389. doi: 10.1373/clinchem.2016.258764. Full text in Research Archive
• Frisk, Michael; Ruud, Marianne; Espe, Emil Knut Stenersen; Aronsen, Jan Magnus; Røe, Åsmund Treu & Zhang, Lili [Show all 11 contributors for this article] (2016). Elevated ventricular wall stress disrupts cardiomyocyte t-tubule structure and calcium homeostasis. Cardiovascular Research (CVR). ISSN 0008-6363. doi: 10.1093/cvr/cvw111. Full text in Research Archive Show summary

  Aims Invaginations of the cellular membrane called t-tubules are essential for maintaining efficient excitation–contraction coupling in ventricular cardiomyocytes. Disruption of t-tubule structure during heart failure has been linked to dyssynchronous, slowed Ca2+ release and reduced power of the heartbeat. The underlying mechanism is, however, unknown. We presently investigated whether elevated ventricular wall stress triggers remodelling of t-tubule structure and function. Methods and results MRI and blood pressure measurements were employed to examine regional wall stress across the left ventricle of sham-operated and failing, post-infarction rat hearts. In failing hearts, elevated left ventricular diastolic pressure and ventricular dilation resulted in markedly increased wall stress, particularly in the thin-walled region proximal to the infarct. High wall stress in this proximal zone was associated with reduced expression of the dyadic anchor junctophilin-2 and disrupted cardiomyocyte t-tubular structure. Indeed, local wall stress measurements predicted t-tubule density across sham and failing hearts. Elevated wall stress and disrupted cardiomyocyte structure in the proximal zone were also associated with desynchronized Ca2+ release in cardiomyocytes and markedly reduced local contractility in vivo. A causative role of wall stress in promoting t-tubule remodelling was established by applying stretch to papillary muscles ex vivo under culture conditions. Loads comparable to wall stress levels observed in vivo in the proximal zone reduced expression of junctophilin-2 and promoted t-tubule loss. Conclusion Elevated wall stress reduces junctophilin-2 expression and disrupts t-tubule integrity, Ca2+ release, and contractile function. These findings provide new insight into the role of wall stress in promoting heart failure progression.

• Melleby, Arne Olav; Strand, Mari Elen; Romaine, Andreas; Herum, Kate Louise Møller; Skrbic, Biljana & Dahl, Christen Peder [Show all 11 contributors for this article] (2016). The heparan sulfate proteoglycan glypican-6 is upregulated in the failing heart, and regulates cardiomyocyte growth through ERK1/2 Signaling. PLOS ONE. 11(10). doi: 10.1371/journal.pone.0165079. Full text in Research Archive
• Røsjø, Helge; Stridsberg, Mats; Ottesen, Anett Hellebø; Nygård, Ståle; Christensen, Geir Arve & Pettilä, Ville [Show all 11 contributors for this article] (2016). Prognostic Value of Secretoneurin in Critically Ill Patients with Infections. Critical Care Medicine. ISSN 0090-3493. 44(10), p. 1882–1890. doi: 10.1097/CCM.0000000000001832. Full text in Research Archive
• Winther, Jacob Andreas; Brynildsen, Jon; Høiseth, Arne Didrik; Følling, Ivar; Brekke, Pål Haugar & Christensen, Geir Arve [Show all 10 contributors for this article] (2016). Prevalence and prognostic significance of hyponatremia in patients with acute exacerbation of chronic obstructive pulmonary disease: Data from the akershus cardiac examination (ACE) 2 study. PLOS ONE. 11:e0161232(8). doi: 10.1371/journal.pone.0161232. Full text in Research Archive Show summary

  Background Hyponatremia is prevalent and associated with mortality in patients with heart failure (HF). The prevalence and prognostic implications of hyponatremia in acute exacerbation of chronic obstructive pulmonary (AECOPD) have not been established. Method We included 313 unselected patients with acute dyspnea who were categorized by etiology of dyspnea according to established guidelines (derivation cohort). Serum Na+ was determined on hospital admission and corrected for hyperglycemia, and hyponatremia was defined as [Na+]<137 mmol/L. Survival was ascertained after a median follow-up of 816 days and outcome was analyzed in acute HF (n = 143) and AECOPD (n = 83) separately. Results were confirmed in an independent AECOPD validation cohort (n = 99). Results In the derivation cohort, median serum Na+ was lower in AECOPD vs. acute HF (138.5 [135.9–140.5] vs. 139.2 [136.7–141.3] mmol/L, p = 0.02), while prevalence of hyponatremia (27% [22/83] vs. 20% [29/143], p = 0.28) and mortality rate (42% [35/83] vs. 46% [66/143], p = 0.56) were similar. By univariate Cox regression analysis, hyponatremia was associated with increased mortality in acute HF (HR 1.85 [95% CI 1.08, 3.16], p = 0.02), but not in AECOPD (HR 1.00 [0.47, 2.15], p = 1.00). Analogous to the results of the derivation cohort, hyponatremia was prevalent also in the AECOPD validation cohort (25% [25/99]), but not associated with mortality. The diverging effect of hyponatremia on outcome between AECOPD and acute HF was statistically significant (p = 0.04). Conclusion Hyponatremia is prevalent in patients with acute HF and AECOPD, but is associated with mortality in patients with acute HF only.

• Hillestad, Vigdis; Espe, Emil Knut Stenersen; Fadila, Cero; Larsen, Karl-Otto; Sjaastad, Ivar & Nygård, Ståle [Show all 8 contributors for this article] (2015). IL-18 neutralization during alveolar hypoxia improves left ventricular diastolic function in mice. Acta Physiologica. ISSN 1748-1708. 213(2), p. 492–504. doi: 10.1111/apha.12376. Full text in Research Archive
• Dhondup, Yangchen; Sjaastad, Ivar; Scott, Helge; Sandanger, Øystein; Zhang, Lili & Haugstad, Solveig Bjærum [Show all 17 contributors for this article] (2015). Sustained toll-like receptor 9 activation promotes systemic and cardiac inflammation, and aggravates diastolic heart failure in SERCA2a KO Mice. PLOS ONE. 10:e0139715(10). doi: 10.1371/journal.pone.0139715. Full text in Research Archive Show summary

  Aim Cardiac inflammation is important in the pathogenesis of heart failure. However, the consequence of systemic inflammation on concomitant established heart failure, and in particular diastolic heart failure, is less explored. Here we investigated the impact of systemic inflammation, caused by sustained Toll-like receptor 9 activation, on established diastolic heart failure. Methods and Results Diastolic heart failure was established in 8–10 week old cardiomyocyte specific, inducible SERCA2a knock out (i.e., SERCA2a KO) C57Bl/6J mice. Four weeks after conditional KO, mice were randomized to receive Toll-like receptor 9 agonist (CpG B; 2μg/g body weight) or PBS every third day. After additional four weeks, echocardiography, phase contrast magnetic resonance imaging, histology, flow cytometry, and cardiac RNA analyses were performed. A subgroup was followed, registering morbidity and death. Non-heart failure control groups treated with CpG B or PBS served as controls. Our main findings were: (i) Toll-like receptor 9 activation (CpG B) reduced life expectancy in SERCA2a KO mice compared to PBS treated SERCA2a KO mice. (ii) Diastolic function was lower in SERCA2a KO mice with Toll-like receptor 9 activation. (iii) Toll-like receptor 9 stimulated SERCA2a KO mice also had increased cardiac and systemic inflammation. Conclusion Sustained activation of Toll-like receptor 9 causes cardiac and systemic inflammation, and deterioration of SERCA2a depletion-mediated diastolic heart failure.

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• 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
• Rønning, Sissel Beate; Carlson, Cathrine Rein; Aronsen, Jan Magnus; Høst, Vibeke; Pisconti, Addolorate & Lunde, Marianne [Show all 11 contributors for this article] (2019). Extracellular Matrix remodeling and multiple signaling pathways are regulated by syndecan-4 during myogenesis. Full text in Research Archive
• Udjus, Camilla; Cero, Fadila; Halvorsen, Bente; Aukrust, Pål; Christensen, Geir Arve & Skjønsberg, Ole Henning [Show all 7 contributors for this article] (2018). Inhibition of caspase-1 reduces hypoxia-induced pulmonary hypertension by downregulating smooth muscle cell growth. Full text in Research Archive
• Ottesen, Anett Hellebø; Carlson, Cathrine Rein; Laver, Derek R; Myhre, Peder Langeland; Dalhus, Bjørn & Lunde, Per Kristian [Show all 14 contributors for this article] (2017). Secretoneurin is an Endogenous CaMKII Inhibitor That Attenuates Ca2+-Dependent Arrhythmogenesis. Circulation. ISSN 0009-7322. 136, p. A13900–A13900. Full text in Research Archive
• Rønning, Sissel Beate; Carlson, Cathrine Rein; Aronsen, Jan Magnus; Høst, Vibeke; Liland, Kristian Hovde & Stang, Espen [Show all 10 contributors for this article] (2017). Syndecan-4 is a skeletal muscle regenerator and is important for normal skeletal muscle fibre development. Full text in Research Archive
• Lipsett, David Bruce; Frisk, Michael; Aronsen, Jan Magnus; Sejersted, Ole M; Sjaastad, Ivar & Christensen, Geir Arve [Show all 7 contributors for this article] (2016). Sarcolemmal structure and function revert to an immature phenotype in failing cardiomyocytes. 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
• Mathiesen, Sabrina Bech; Lunde, Marianne; Christensen, Geir Arve & Carlson, Cathrine Rein (2016). Mass spectrometry analysis of cytoplasmic binding partners of cardiac syndecan-2. Full text in Research Archive
• Lipsett, David Bruce; Frisk, Michael; Aronsen, Jan Magnus; Singh, Neha; Sejersted, Ole M & Sjaastad, Ivar [Show all 9 contributors for this article] (2016). BIN1 triggers t-tubule development in cardiomyocytes. Full text in Research Archive
• Lunde, Ida Gjervold; Wakimoto, Hiroko; Jiang, Jianming; Burke, Michael A.; Soukoulis, Victor & Unger, Andreas [Show all 13 contributors for this article] (2016). Titin A-band truncation mutation in mice causes stress-induced dilated cardiomyopathy. 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
• Melleby, Arne Olav; Strand, Mari Elen; Herum, Kate Louise Møller; Skrbic, Biljana; Dahl, Christen Peder & Sjaastad, Ivar [Show all 10 contributors for this article] (2016). Glypican-6 is upregulated in heart failure and mediates cardiomyocyte growth through ERK1/2 signaling. Full text in Research Archive
• Aronsen, Jan Magnus; Singbrant, Sofie; Christensen, Geir Arve & Iversen, Per Ole (2016). Evidence for splenic stress-induced erythropoiesis in mice with post-infarction heart failure. Full text in Research Archive
• Lunde, Ida Gjervold; Wakimoto, Hiroko; Jiang, Jianming; Burke, Michael A.; Soukoulis, Victor & Unger, Andreas [Show all 13 contributors for this article] (2016). Study of a mouse with proximal titin A-band truncation reveals disease mechanisms and modifiers of titin dilated cardiomyopathy. Full text in Research Archive
• Rønning, Sissel Beate; Carlson, Cathrine Rein; Høst, Vibeke; Aronsen, Jan Magnus; Liland, Kristian Hovde & Stang, Espen [Show all 9 contributors for this article] (2016). Syndecan-4 is important for normal skeletal muscle fibre development. Full text in Research Archive
• Strand, Mari Elen; Aronsen, Jan Magnus; Skrbic, Biljana; Gelazauskaite, Monika; Sjaastad, Ivar & Christensen, Geir Arve [Show all 7 contributors for this article] (2016). The heparanase-syndecan-4 axis in the heart: upregulation in response to immune activation indicates a role in cardiac inflammation. Full text in Research Archive
• Romaine, Andreas; Sørensen, Ida Wiig; Melleby, Arne Olav; Zeltz, Cedric; Zhang, Lili & Bendiksen, Bård Andre [Show all 12 contributors for this article] (2016). Overexpression of integrin a11 induces cardiac hypertrophy and fibrosis. Full text in Research Archive
• Strand, Mari Elen; Aronsen, Jan Magnus; Skrbic, Biljana; Gelazaukaite, Monika; Sjaastad, Ivar & Christensen, Geir Arve [Show all 7 contributors for this article] (2016). The heparanase-syndecan-4 axis in the heart: upregulation in response to immune activation indicates a role in cardiac inflammation. Full text in Research Archive
• Ruud, Marianne; Frisk, Michael; Espe, Emil Knut Stenersen; Aronsen, Jan Magnus; Zhang, Lili & Norseng, Per Andreas [Show all 10 contributors for this article] (2016). Elevated ventricular wall stress disrupts cardiomyocyte t-tubular structure and Ca2+ homeostasis. Full text in Research Archive
• Mathiesen, Sabrina Bech; Lunde, Marianne; Christensen, Geir Arve & Carlson, Cathrine Rein (2016). Mass spectrometry analysis of cytoplasmic binding partners of cardiac syndecan - 2. Full text in Research Archive
• Ottesen, Anett; Carlson, Cathrine; Edwards, Andrew; Landsverk, Ole; Johansen, Rune & Moe, Morten [Show all 10 contributors for this article] (2015). Secretoneurin, a Novel Endogenous CaMKII Inhibitor, Augments Cardiomyocyte Calcium Handling and Inhibits Arrhythmogenic Calcium Release. 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
• Lunde, Ida Gjervold; Wakimoto, Hiroko; Burke, Michael A.; Soukoulis, Victor; Linke, Wolfgang A. & Gorham, joshua [Show all 10 contributors for this article] (2015). Proximal titin A-band truncation causes dilated cardiomyopathy in response to increased afterload in mice. Full text in Research Archive
• Sandbu, Ragnhild Askeland; Dahl, Mai Britt; Ottesen, Anett Hellebø; Jørgensen, M; Stridsberg, Mats & Sjaastad, Ivar [Show all 10 contributors for this article] (2015). Chromogranin A is glycosylated in acute heart failure and this is associated with reduced processing to the functional peptide catestatin and increased mortality. 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
• Carlson, Cathrine Rein; Nygård, Ståle; Sirnes, Solveig; Jarstadmarken, Hilde; Martinsen, Marita & Lunde, Marianne [Show all 9 contributors for this article] (2015). A protein-protein interaction (PPI) map of cardiac syndecan-4. Full text in Research Archive
• Melleby, Arne Olav; Strand, Mari Elen; Herum, Kate Louise Møller; Skrbic, Biljana; Dahl, Christen Peder & Sjaastad, Ivar [Show all 10 contributors for this article] (2015). Glypican-6 is increased in experimental and clinical heart failure and might play a role in cardiac fibrosis through BMP4 signalling. Full text in Research Archive
• Røsjø, Helge; Masson, Serge; Caironi, Pietro; Stridsberg, Mats; Fanizza, Caterina & Christensen, Geir Arve [Show all 11 contributors for this article] (2015). The novel cardiac biomarker secretoneurin provides independent prognostic information in severe sepsis and septic shock: data from the ALBIOS study. Circulation. ISSN 0009-7322. 132(A14598). Full text in Research Archive
• Ottesen, Anett Hellebø; Carlson, Cathrine Rein; Louch, William Edward; Johansen, Rune F.; Stridsberg, Mats & Jarstadmarken, Hilde [Show all 12 contributors for this article] (2015). Chromogranin A is a potent prognostic biomarker in acute heart failure, and its fragment catestatin regulates cardiomyocyte calcium homeostasis by CaMKII inhibition. Full text in Research Archive
• Cero, Fadila; Larsen, Karl-Otto; Hillestad, Vigdis; Olsen, Maria Belland; Udjus, Camilla & Sjaastad, Ivar [Show all 11 contributors for this article] (2015). The inflammasome adaptor ASC mediates pulmonary artery remodelling. Full text in Research Archive

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