Ivar Sjaastad

• Totland, Lasse; Bendiksen, Bård Andre; Nordén, Einar Sjaastad; Hauge-Iversen, Ida Marie; Bergo, Kaja Knudsen & Zhang, Lili [Vis alle 8 forfattere av denne artikkelen] (2026). Strain Rate Angle Distribution as an Indicator of Post-Infarct Myocardial Remodeling: Proof-of-Concept of a Novel Application of the MRI Derived Strain Rate Tensor Field. Magnetic Resonance in Medicine. ISSN 0740-3194. s. 1–14. doi: 10.1002/mrm.70607. Fulltekst i vitenarkiv
• Dukefoss, Henrik B.; Andresen, Kristoffer; Harbo, Markus Borge; Hasselberg, Nina Eide; Grødem, Herman & Korsæth, Truls [Vis alle 18 forfattere av denne artikkelen] (2026). Validation of shear wave elastography for assessing myocardial fibrosis in patients with end-stage heart failure. European Heart Journal-Cardiovascular Imaging. ISSN 2047-2404. 27(4), s. 778–787. doi: 10.1093/ehjci/jeaf375. Fulltekst i vitenarkiv
• Zhang, Lili; Hauge-Iversen, Ida Marie; Kim, Haelin; Nordén, Einar Sjaastad; Sjaastad, Ivar & Espe, Emil Knut Stenersen (2025). Segmented Look–Locker With Inversion Efficiency Correction (SELLIE) for Accurate and Precise Cardiac T1 Mapping in Rat Hearts at 9.4‐T MRI. NMR in Biomedicine. ISSN 0952-3480. 38(8). doi: 10.1002/nbm.70095. Fulltekst i vitenarkiv Vis sammendrag

  ABSTRACT The purpose of this study was to develop a multislice, segmented electrocardiogram (ECG)‐triggered, respiration‐gated Look–Locker T 1 mapping sequence with inversion efficiency (IE) correction, optimized for high‐field MRI. The segmented Look–Locker with inversion efficiency correction (SELLIE) was validated in phantom and in vivo studies using an agarose/NiCl 2 phantom, 5 healthy rats, 23 aortic‐banding rats, and 7 sham‐operated rats. The accuracy, precision, and repeatability of SELLIE were compared with the conventional Look–Locker technique without IE correction using Pearson correlation analysis and the Kruskal–Wallis H test. In the phantom experiments, SELLIE demonstrated significantly improved accuracy ( T 1 estimation error: 0.80 ± 1.17%) compared with the uncorrected Look–Locker method (3.70 ± 1.12%). Additionally, SELLIE showed superior precision (coefficient of variation: 0.71 ± 0.35%) relative to the uncorrected method (1.15 ± 0.39%). In vivo experiments with healthy rats showed good precision for both SELLIE (1.70 ± 0.61%) and the uncorrected technique (1.04 ± 0.49%). In the sham and aortic‐banding rats, T 1 values from SELLIE correlated strongly with the end‐diastolic pressure–volume relationship (EDPVR) ( r  = 0.57, p  = 0.001), outperforming the uncorrected method ( r  = 0.37, p  = 0.04). The mean myocardium native T 1 times of the sham rats (~17 weeks old) from the uncorrected Look–Locker was 1567 ± 32 ms, whereas the mean myocardium T 1 times from SELLIE was 1723 ± 47 ms. In conclusion, SELLIE provides accurate and precise T 1 mapping for high‐field MRI, correcting inversion pulse imperfections. This technique enables reliable longitudinal scanning and comparison across animal models.

• Hauge-Iversen, Ida Marie; Nordén, Einar Sjaastad; Melleby, Arne Olav; Zhang, Lili; Sjaastad, Ivar & Espe, Emil Knut Stenersen (2025). Longitudinal cardiovascular magnetic resonance evaluation of progressive pressure overload due to O-ring induced ascending aortic constriction in rats. Journal of Cardiovascular Magnetic Resonance. ISSN 1097-6647. 27(2). doi: 10.1016/j.jocmr.2025.101969. Fulltekst i vitenarkiv Vis sammendrag

  Background Aortic stenosis is a debilitating disease characterized by pressure overload and development of myocardial fibrosis. Animal models that mimic this disease are crucial for translational research. Aortic constriction in rats is commonly used to induce pressure overload, but the precise disease progression in the O-ring induced model of ascending aortic constriction has not been thoroughly evaluated. Additionally, identifying early imaging biomarkers that can predict fibrosis could enhance the model’s translational relevance. This study aims to evaluate a rat model of progressive pressure overload using cardiovascular magnetic resonance imaging (CMR) by investigating the degree of constriction at different time points and identifying early imaging biomarkers predicting myocardial fibrosis at later stages. Methods Sprague Dawley rats (n=14) underwent aortic banding with O-rings (inner diameter of 1.5 mm or 1.3 mm). Sham-operated rats (n=8) served as controls. CMR was performed every fourth week until 20 weeks post-surgery, followed by tissue harvesting and measurements of fibrosis with histology. Results All banding groups gradually developed left ventricular (LV) hypertrophy, impaired LV diastolic function (increased E/SRe), increased left atrial (LA) size, and impaired LA function (reduced LA ejection fraction and peak LA strain), but preserved LV ejection fraction during the course of study. The tightest constriction exhibited increased LV fibrosis at 20 weeks. LA diameter at 4 weeks independently predicted LV myocardial fibrosis. Conclusion This animal model mimics the gradual progression of stenosis seen in humans, highlighting its translational potential. Early LA diameter predicted myocardial fibrosis. These findings underscore the model’s relevance for studying disease progression in LV pressure overload.

• Mathiesen, Sabrina Bech; Støle, Thea Parsberg; Romaine, Andreas; Lunde, Marianne; Martinsen, Marita & Aronsen, Jan Magnus [Vis alle 10 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Bergo, Kaja Knudsen; Nordén, Einar Sjaastad; Bendiksen, Bård Andre; Espe, Emil Knut Stenersen; Mcginley, Gary George & Hauge-Iversen, Ida Marie [Vis alle 12 forfattere av denne artikkelen] (2025). Sacubitril/valsartan preserves kidney function in rats with cardiorenal syndrome after myocardial infarction. PLOS ONE. 20(10). doi: 10.1371/journal.pone.0335214. Fulltekst i vitenarkiv Vis sammendrag

  Renal dysfunction in heart failure increases mortality, limits treatment options and blunts responses to therapy. Angiotensin receptor-blocker and neprilysin inhibitors (ARNI) may preserve renal function by modulating both the renin-angiotensin-aldosterone system and the natriuretic peptide system. We investigated the renal effects of the ARNI Sacubitril/valsartan (Sac/Val) in rats with systolic dysfunction secondary to myocardial infarction. Male Sprague-Dawley rats underwent surgical MI induction and were randomized to six weeks of treatment with vehicle, valsartan or Sac/Val, and compared to sham operated animals. Renal function was evaluated by creatinine clearance, mean arterial pressure (MAP) by tail-cuff measurements, and cardiac function by magnetic resonance imaging and echocardiography. Vehicle treated animals developed cardiorenal syndrome, with impaired cardiac systolic function and mild renal dysfunction. Both valsartan and Sac/Val preserved renal function compared to vehicle (creatinine clearance mL/min [median with interquartile range]; sham 5.4 [4.8–6.0], vehicle 4.5 [4.1–5.1], valsartan 5.1 [5.1–5.5], Sac/Val 5.1 [5.0–5.6]; vehicle vs valsartan p = 0.034 and vehicle vs Sac/Val p = 0.044). MAP was reduced by both treatments compared to sham and vehicle groups (MAP mmHg ; sham 131 [116–138], vehicle 123 [115–132], valsartan 108 [99–112], Sac/Val 111 [99–119]; sham vs valsartan p < 0.001 and sham vs Sac/Val p = 0.003, vehicle vs valsartan p = 0.006 and vehicle vs Sac/Val p = 0.041). Only Sac/Val reduced left atrial dilatation (diameter mm ; sham 4.1 [3.7–4.4], vehicle 4.6 [3.8–5.6], valsartan 4.6 [4.1–5.5], Sac/Val 3.9 [3.6–4.5]; vehicle vs Sac/Val p = 0.047, valsartan vs Sac/Val p = 0.017) despite no improvement in systolic function in either treatment group. Sac/Val initiated in the acute post-MI phase preserved renal function to the same extent as valsartan alone and uniquely reduced left atrial dilatation, suggesting additional benefits beyond renoprotection in the setting of persistent systolic dysfunction.

• Hauge-Iversen, Ida Marie; Nordén, Einar Sjaastad; Melleby, Arne Olav; Espeland, Linn Stordahl; Zhang, Lili & Sjaastad, Ivar [Vis alle 7 forfattere av denne artikkelen] (2025). Non-invasive estimation of left ventricular chamber stiffness using cardiovascular magnetic resonance and echocardiography. Journal of Cardiovascular Magnetic Resonance. ISSN 1097-6647. 27(1). doi: 10.1016/j.jocmr.2025.101849. Fulltekst i vitenarkiv Vis sammendrag

  Background Preclinical studies exploring the underlying mechanisms of elevated left ventricular (LV) chamber stiffness play a crucial role in developing new therapeutic strategies. However, there is a lack of systematic evaluation of imaging biomarkers of diastolic function against gold standard assessment of LV chamber stiffness in rodents. Therefore, we aimed to evaluate imaging biomarkers of diastolic function from cardiovascular magnetic resonance (CMR) and echocardiography in predicting the slope of the end-diastolic pressure-volume relationship (EDPVR) in rats. Methods Sprague Dawley rats with varying degrees of myocardial stiffness induced by aortic constriction (n=38) and healthy controls (n=9) underwent echocardiography and CMR at approximately 13 weeks post-operation. Imaging biomarkers of diastolic function were evaluated for their ability to predict the EDPVR slope from pressure-volume recordings using regression analysis and receiver operating characteristics analysis. Results Both CMR and echocardiographic imaging biomarkers, in particular those related to the left atrium and mitral flow, were able to predict the EDPVR slope in a rat model with varying stiffness. From CMR, native T1 values, peak early diastolic longitudinal strain rate (SRe(long)) and E/SRe(long), left atrial (LA) ejection fraction, isovolumetric relaxation time (IVRT), E/A and peak LA strain, correlated best with the EDPVR slope (|r|=0.54–0.72). From echocardiography, E/A, E, LA diameter, e’/a’, E/SRe(long) and IVRT correlated with the EDPVR slope (|r|=0.49–0.67), while E/e’, e’ and E-wave deceleration time demonstrated poor correlation (|r|=0.17–0.27). Receiver operating characteristics analysis indicated better performance of CMR imaging biomarkers than echocardiography in predicting increased EDPVR slope. Conclusions Several diastolic imaging biomarkers commonly employed in preclinical studies have poor ability to predict cardiac chamber stiffness. Our study identifies several imaging biomarkers obtained from both echocardiography and CMR that are able to estimate LV chamber stiffness non-invasively, providing an important tool for future mechanistic research on myocardial stiffness.

• Berger, Simon Girmai; Berntsen, Kristin Schjander; Risum, Kristine; Marstein, Henriette Schermacher; Sjaastad, Ivar & Stokke, Mathis Korseberg [Vis alle 7 forfattere av denne artikkelen] (2025). Predictors of persistent active disease and the longitudinal development of organ damage, patient-reported outcomes and autoantibodies in long-term juvenile dermatomyositis. RMD Open. 11(2). doi: 10.1136/rmdopen-2025-005598. Fulltekst i vitenarkiv Vis sammendrag

  Objective To quantify longitudinal development of disease activity, organ damage, patient-reported outcomes, and myositis autoantibody profiles in patients with juvenile dermatomyositis (JDM) after long-term follow-up, and to identify predictors for persistent active disease. Methods Forty patients (65% female) diagnosed with JDM were clinically examined at two different time points (visits 1 and 2). We assessed clinically inactive/active disease by the updated PRINTO criteria and the Juvenile DermatoMyositis Activity Index (JDMAI). Organ damage was evaluated by Myositis Damage Index (MDI) and physical function by Childhood Health Assessment Questionnaire (CHAQ/HAQ). Myositis autoantibodies were measured by myositis line immunoassay. Results Median disease duration from symptom onset was 15.1 (2.0–34.6) at visit 1 and 21.7 (7.6–42.7) years at visit 2. At visit 2, active disease (PRINTO) was found in 53%, impaired physical function (CHAQ/HAQ>0) in 40%, organ damage (MDItotal≥1) in 95% and myositis specific or associated antibodies in 33% of patients. Disease activity (JDMAI) was low in 24%, moderate in 8% and high in 3% of patients. There were no significant differences in organ damage and disease activity between visits. Higher disease activity and organ damage at visit 1 predicted persistent active disease at visit 2. Conclusions After a median of 21.7 years from symptom onset, the majority of JDM patients still had active disease. Higher organ damage and disease activity at the initial visit predicted persistent active disease at follow-up. These results underscore the chronic nature of JDM, emphasising the need for enhanced early and long-term management strategies to improve patient outcomes.

• Smith, Lisa; Skulberg, Vidar Magne; Zhang, Lili; Sjaastad, Ivar & Espe, Emil Knut Stenersen (2025). Feasibility of magnetic resonance elastography in the healthy rat heart. Magnetic Resonance in Medicine. ISSN 0740-3194. 94(2), s. 754–760. doi: 10.1002/mrm.30504. Fulltekst i vitenarkiv
• Nordén, Einar Sjaastad; Bendiksen, Bård Andre; Bergo, Kaja Knudsen; Espe, Emil Knut Stenersen; Mcginley, Gary George & Hasic, Almira [Vis alle 17 forfattere av denne artikkelen] (2024). Sacubitril/valsartan preserves regional cardiac function following myocardial infarction in rats. ESC Heart Failure. doi: 10.1002/ehf2.15145. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Becker, Victoria; Kavaliauskiene, Simona; Sandblom, Erik; Zena, Lucas A.; Gräns, Albin & Louch, William Edward [Vis alle 9 forfattere av denne artikkelen] (2024). Echocardiography - a non-invasive alternative for assessing cardiac morphology and function in Atlantic salmon (Salmo salar L.). Aquaculture. ISSN 0044-8486. 592. doi: 10.1016/j.aquaculture.2024.741223. Fulltekst i vitenarkiv Vis sammendrag

  Cardiac-related mortality is increasing in farmed salmon. Non-invasive tools for examining and screening for cardiac morphology and function are limited, and most common methodologies are lethal, time-consuming, and immobile. Echocardiography has previously been tested as a non-invasive, quick, and portable alternative, though its implementation is minimal. Improvements in echocardiographic techniques during the last decade have enabled more refined assessments of structure and function and hold potential for use in fish farms. Utilising a compact, transportable ultrasound system, we examined the applicability of echocardiography in Atlantic salmon (Salmo salar L.). Several protocols and projections were tested, and intra- and inter-variation for both operators (image acquisition) and observers (image analysis) were assessed. In addition, the accuracy of cardiac structure/function measurements was compared with standard methods. In general, high accuracy and reproducibility of cardiac dimensions and functional parameters were found within the same and between different observers analysing the same dataset (intra- and inter-observer). Measurements between recordings of the same operator (intra-operator) and between different operators (inter-operator) were less accurate and repeatable but comparable to observations in previous human and mammalian studies. Cardiac output was slightly higher when measured with echocardiography compared to transit time flow probe. Yet, a strong correlation exists between the two methods. Furthermore, morphology measured in excised hearts ex vivo was comparable to echocardiography measurements and strongly correlated. Thus, ultrasound presents a highly feasible, non-invasive, and swift alternative to current methods for detailed cardiac assessment of salmon hearts.

• Ruud, Marianne; Frisk, Michael; Melleby, Arne Olav; Norseng, Per Andreas; Mohamed, Belal A. & Li, Jia [Vis alle 22 forfattere av denne artikkelen] (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), s. 4487–4510. doi: 10.1113/JP284566. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Blom, Kjersti Benedicte; Kro, Grete Anette Birkeland; Midtvedt, Karsten; Jenssen, Trond; Reisæter, Anna Varberg & Rollag, Halvor [Vis alle 14 forfattere av denne artikkelen] (2024). Cellular immunity against cytomegalovirus and risk of infection after kidney transplantation. Frontiers in Immunology. 15, s. 1–11. doi: 10.3389/fimmu.2024.1414830. Fulltekst i vitenarkiv Vis sammendrag

  Introduction Cytomegalovirus (CMV) infection remains a challenge following kidney transplantation (KTx). Currently, CMV-IgG serostatus at transplantation is used to individualize CMV preventive strategies. We assessed the clinical utility of CMV-IGRA for predicting CMV infection following KTx. Methods We performed a nationwide prospective cohort study from August 2016 until December 2022. Data from all adult KTx recipients in Norway, n=1,546 (R+; n=1,157, D+/R-; n=260, D-/R-; 129), were included with a total of 3,556 CMV-IGRA analyses (1,375 at KTx, 1,188 at eight weeks, 993 one-year after KTx) and 35,782 CMV DNAemia analyses. Results In R+ recipients CMV-IGRA status, measured at any of the time-points, could not identify any differential risk of later CMV infection. D+/R- recipients remaining CMV-IGRA negative 1-year after transplantation (regardless of positive CMV DNAemia and/or CMV IgG status at that time) had increased risk of developing later CMV infection compared to D+/R- recipients who had become CMV-IGRA positive (14% vs. 2%, p=0.01). Conclusion Knowledge of pre-transplant CMV-IGRA status did not provide additional information to CMV-IgG serostatus that could improve current post-transplant CMV treatment algorithms. However, D+/R- recipients with a persisting negative CMV-IGRA one-year after transplantation remained at increased risk of experiencing later CMV infection. Therefore we advocate post-transplant CMV-IGRA monitoring in these patients.

• Marstein, Henriette; NOMELAND, BIRGIT; Godang, Kristin; Olarescu, Nicoleta Cristina; Schwartz, Thomas & Flatø, Berit [Vis alle 10 forfattere av denne artikkelen] (2023). Adipokine profile in long-term juvenile dermatomyositis, and associations with adipose tissue distribution and cardiac function: a cross-sectional study. RMD Open. 9:e002815(1), s. 1–9. doi: 10.1136/rmdopen-2022-002815. Fulltekst i vitenarkiv Vis sammendrag

  Objectives In long-term juvenile dermatomyositis (JDM), altered adipose tissue distribution and subclinical cardiac dysfunction have been described. Our aims were to compare adipokine levels in patients with JDM after long-term disease with controls, and explore associations between adipokines and (1) adipose tissue distribution and (2) cardiac function. Methods The study cohort included 59 patients with JDM (60% female, mean age 25.2 years, mean disease duration 16.9 years), and 59 age/sex-matched controls. Updated Pediatric Rheumatology International Trials Organization criteria for clinically inactive JDM were used to stratify patients into active (JDM-active) or inactive (JDM-inactive) disease groups. Lipodystrophy was clinically assessed in all patients. In all study participants, we measured adipose tissue distribution by dual-energy X-ray absorptiometry and cardiac function by echocardiography. Serum adipokines (adiponectin, apelin-12, lipocalin-2, leptin, visfatin and resistin) were analysed using ELISA. Results Patients with JDM had higher leptin levels compared with controls (p≤0.01). In JDM-active, apelin-12 and visfatin were higher compared with JDM-inactive (p≤0.05). In JDM-total and JDM-active, lower adiponectin correlated with lipodystrophy and total fat mass. Also, systolic dysfunction correlated with: lower adiponectin in JDM-total, JDM-inactive and JDM-active, and with lower apelin-12 in JDM-total and JDM-active and resistin in JDM-active (all p≤0.05). Lower adiponectin correlated with diastolic dysfunction in JDM-total and JDM-active. Conclusion After long-term disease, leptin levels were unfavourably regulated in patients with JDM compared with controls, and apelin-12 and visfatin in JDM-active versus JDM-inactive. We found associations between adipokines and both adipose tissue distribution and cardiac systolic function in all patients with JDM, which was most prominent in patients with active disease.

• Nordén, Einar Sjaastad; Veras, Ioanni; Yadav, Prakash; Løken, Kari Gulbrandsen; Dishington, Hilde & Thorstensen, Christian [Vis alle 8 forfattere av denne artikkelen] (2023). Clinical efficacy of buprenorphine after oral dosing in rats undergoing major surgery. Laboratory Animals. ISSN 0023-6772. doi: 10.1177/00236772231178417. Fulltekst i vitenarkiv Vis sammendrag

  Serum corticosterone, serum buprenorphine, body weight change, consumption of food and water and behaviour-based pain assessment were measured in catheterised and non-catheterised male Wistar rats undergoing myocardial infarct (MI) surgery under general anaesthesia following buprenorphine dosing by subcutaneous (Bup-SC, 0.05 mg/kg) and oral (Bup-O, 0.4 mg/kg) routes. Buprenorphine was dosed subcutaneously at half an hour before and 8, 16 and 24 hours after surgery (Bup-SC), orally at one hour before surgery (Bup-O1) or at one hour before and 12 hours after surgery (Bup-O2) in catheterised rats and at one hour before and 24 hours after surgery (Bup-O24) in non-catheterised rats. Serum corticosterone, body weight changes and food and water consumption were not significantly different between treatments in catheterised rats. Bup-SC resulted in rapidly decreasing serum concentrations below the clinically effective concentrations (1 ng/mL) already at two hours after the first dose. Bup-O provided significantly higher and slowly decreasing serum concentrations, at or above clinically effective concentrations, for 24 hours (Bup-O1) and 42 hours (Bup-O2) after surgery. In non-catheterised rats, body weight development and food consumption were significantly higher in Bup-O24 rats compared to Bup-SC rats. The results indicate that a SC buprenorphine dose of 0.05 mg/kg every eight hours provides long periods of serum concentrations below clinically effective levels, and that a higher dose and/or more frequent dosage are required to provide stable serum concentrations at or above clinically effective levels. A single oral buprenorphine dose of 0.4 mg/kg provides clinically effective and stable serum concentrations for 24 hours in rats after MI surgery.

• Vistnes, Maria; Erusappan, Pugazendhi Murugan; Sasi, Athiramol; Nordén, Einar Sjaastad; Bergo, Kaja Knudsen & Romaine, Andreas [Vis alle 22 forfattere av denne artikkelen] (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), s. 1915–1927. doi: 10.1093/cvr/cvad078. Fulltekst i vitenarkiv Vis sammendrag

  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 [Vis alle 13 forfattere av denne artikkelen] (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), s. H881–H892. doi: 10.1152/ajpheart.00701.2022. Fulltekst i vitenarkiv
• Skogestad, Jonas; Albert, Ingrid; Hougen, Karina; Lothe, Gustav B; Lunde, Marianne & Eken, Olav Søvik [Vis alle 25 forfattere av denne artikkelen] (2023). Disruption of Phosphodiesterase 3A Binding to SERCA2 Increases SERCA2 Activity and Reduces Mortality in Mice with Chronic Heart Failure. Circulation. ISSN 0009-7322. 147(16), s. 1221–1236. doi: 10.1161/CIRCULATIONAHA.121.054168. Fulltekst i vitenarkiv
• Berger, Simon Girmai; NOMELAND, BIRGIT; Reiseter, Silje; Schwartz, Thomas; Andersson, Anna Helena & Hetlevik, Siri Opsahl [Vis alle 13 forfattere av denne artikkelen] (2023). Cardiac dysfunction in mixed connective tissue disease: a nationwide observational study. Rheumatology International. ISSN 0172-8172. s. 1055–1065. doi: 10.1007/s00296-023-05308-3. Fulltekst i vitenarkiv Vis sammendrag

  Abstract We aimed to identify cardiac function in patients with established mixed connective tissue disease (MCTD). This was a cross-sectional case–control study of well-characterised MCTD patients who had previously been included in a nationwide cohort. Assessments comprised protocol transthoracic echocardiography, electrocardiogram and blood samples. In patients only, we evaluated the findings of high-resolution pulmonary computed tomography and disease activity. We assessed 77 MCTD patients (mean age 50.5 ± 12.3 years) with a mean disease duration of 16.4 years, and 59 age- and sex-matched healthy controls (49.9 ± 11.7 years). By echocardiography, measures of left ventricular function, i.e. fractional shortening (38.1 ± 6.4% vs. 42.3 ± 6.6%, p &lt; 0.001), mitral annulus plane systolic excursion (MAPSE) (13.7 ± 2.1 mm vs. 15.3 ± 2.3 mm, p &lt; 0.001) and early diastolic velocity of the mitral annulus (e’) (0.09 ± 0.02 m/s vs. 0.11 ± 0.03 m/s, p = 0.002) were subclinical and lower in patients than controls. Right ventricular dysfunction was found in patients assessed by tricuspid annular plane systolic excursion (TAPSE) (22.7 ± 4.0 mm vs. 25.5 ± 4.0 mm, p &lt; 0.001). While cardiac dysfunction was not associated with pulmonary disease, e’ and TAPSE were found to correlate with disease activity at baseline. In this cohort of MCTD patients, echocardiographic examinations demonstrated a higher frequency of cardiac dysfunction than in matched controls. Cardiac dysfunction was associated with disease activity at baseline, but was independent of cardiovascular risk factors and pulmonary disease. Our study indicates that cardiac dysfunction is part of the multi-organ affliction seen in MCTD.

• Tønnessen, Theis Christian; Ueland, Thor; Ahmed, Muhammad Shakil; Attramadal, Håvard; Sjaastad, Ivar & Vinge, Leif Erik (2023). Inflammatory augmentation of the delayed type hypersensitivity arthritis mouse model. Basic & Clinical Pharmacology & Toxicology. ISSN 1742-7835. 132(6), s. 545–549. doi: 10.1111/bcpt.13864. Fulltekst i vitenarkiv
• Hou, Yufeng; Laasmaa, Martin; Li, Jia; Shen, Xin; Manfra, Ornella & Nordén, Einar Sjaastad [Vis alle 12 forfattere av denne artikkelen] (2023). Live-cell photoactivated localization microscopy correlates nanoscale ryanodine receptor configuration to calcium sparks in cardiomyocytes. Nature Cardiovascular Research. 2(3), s. 251–267. doi: 10.1038/s44161-022-00199-2. Fulltekst i vitenarkiv
• Blom, Kjersti Benedicte; Kro, Grete Anette Birkeland; Midtvedt, Karsten; Jenssen, Trond; Reisæter, Anna Varberg & Rollag, Halvor [Vis alle 15 forfattere av denne artikkelen] (2023). Cytomegalovirus High-risk Kidney Transplant Recipients Show No Difference in Long-term Outcomes Following Preemptive Versus Prophylactic Management. Transplantation. ISSN 0041-1337. 107(8), s. 1846–1853. doi: 10.1097/TP.0000000000004615. Fulltekst i vitenarkiv Vis sammendrag

  Background. Following kidney transplantation (KT), cytomegalovirus (CMV) infection remains an important challenge. Both prophylactic and preemptive antiviral protocols are used for CMV high-risk kidney recipients (donor seropositive/recipient seronegative; D+/R–). We performed a nationwide comparison of the 2 strategies in de novo D+/R– KT recipients accessing long-term outcomes. Methods. A nationwide retrospective study was conducted from 2007 to 2018, with follow-up until February 1, 2022. All adult D+/R– and R+ KT recipients were included. During the first 4 y, D+/R– recipients were managed preemptively, changing to 6 mo of valganciclovir prophylaxis from 2011. To adjust for the 2 time eras, de novo intermediate-risk (R+) recipients, who received preemptive CMV therapy throughout the study period, served as longitudinal controls for possible confounders. Results. A total of 2198 KT recipients (D+/R–, n = 428; R+, n = 1770) were included with a median follow-up of 9.4 (range, 3.1–15.1) y. As expected, a greater proportion experienced a CMV infection in the preemptive era compared with the prophylactic era and with a shorter time from KT to CMV infection (P < 0.001). However, there were no differences in long-term outcomes such as patient death (47/146 [32%] versus 57/282 [20%]; P = 0.3), graft loss (64/146 [44%] versus 71/282 [25%]; P = 0.5), or death censored graft loss (26/146 [18%] versus 26/282 [9%]; P = 0.9) in the preemptive versus prophylactic era. Long-term outcomes in R+ recipients showed no signs of sequential era–related bias. Conclusions. There were no significant differences in relevant long-term outcomes between preemptive and prophylactic CMV-preventive strategies in D+/R– kidney transplant recipients.

• Sasi, Athiramol; Romaine, Andreas; Erusappan, Pugazendhi Murugan; Melleby, Arne Olav; Hasic, Almira & Dahl, Christen Peder [Vis alle 14 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Shen, Xin; Brink, Jonas van den; Bergan-Dahl, Anna; Kolstad, Terje; Norden, Einar & Hou, Yufeng [Vis alle 11 forfattere av denne artikkelen] (2022). Prolonged β-adrenergic stimulation disperses ryanodine receptor clusters in cardiomyocytes. eLIFE. 11. doi: 10.7554/eLife.77725. Fulltekst i vitenarkiv Vis sammendrag

  Ryanodine Receptors (RyRs) exhibit dynamic arrangements in cardiomyocytes, and we previously showed that 'dispersion' of RyR clusters disrupts Ca2+ homeostasis during heart failure (HF) (Kolstad et al., eLife, 2018). Here, we investigated whether prolonged β-adrenergic stimulation, a hallmark of HF, promotes RyR cluster dispersion, and examined the underlying mechanisms. We observed that treatment of healthy rat cardiomyocytes with isoproterenol for 1 hour triggered progressive fragmentation of RyR clusters. Pharmacological inhibition of CaMKII reversed these effects, while cluster dispersion was reproduced by specific activation of CaMKII, and in mice with constitutively active Ser2814-RyR. A similar role of protein kinase A (PKA) in promoting RyR cluster fragmentation was established by employing PKA activation or inhibition. Progressive cluster dispersion was linked to declining Ca2+ spark fidelity and magnitude, and slowed release kinetics from Ca2+ propagation between more numerous RyR clusters. In healthy cells, this served to dampen the stimulatory actions of β-adrenergic stimulation over the longer term, and protect against pro-arrhythmic Ca2+ waves. However, during HF, RyR dispersion was linked to impaired Ca2+ release. Thus, RyR localization and function are intimately linked via channel phosphorylation by both CaMKII and PKA which, while finely tuned in healthy cardiomyocytes, underlies impaired cardiac function during pathology.ADD A COMMENT +Open annotations. The current annotation count on this page is 0.Data availability

• Tønnessen, Theis Christian; Melleby, Arne Olav; Hauge-Iversen, Ida Marie; Espe, Emil Knut Stenersen; Ahmed, Muhammad Shakil & Ueland, Thor [Vis alle 12 forfattere av denne artikkelen] (2022). Impact of delayed type hypersensitivity arthritis on development of heart failure by aortic constriction in mice. PLOS ONE. 17(1). doi: 10.1371/journal.pone.0262821. Fulltekst i vitenarkiv Vis sammendrag

  Aims Patients with rheumatoid arthritis (RA) have increased risk of heart failure (HF). The mechanisms and cardiac prerequisites explaining this association remain unresolved. In this study, we sought to determine the potential cardiac impact of an experimental model of RA in mice subjected to HF by constriction of the ascending aorta. Methods Aorta was constricted via thoracotomy and placement of o-rings with inner diameter 0.55 mm or 0.66 mm, or sham operated. RA-like phenotype was instigated by delayed-type hypersensitivity arthritis (DTHA) two weeks after surgery and re-iterated after additional 18 days. Cardiac magnetic resonance imaging (MRI) was performed before surgery and at successive time points throughout the study. Six weeks after surgery the mice were euthanized, blood and tissue were collected, organ weights were documented, and expression levels of cardiac foetal genes were analysed. In a supplemental study, DTHA-mice were euthanized throughout 14 days after induction of arthritis, and blood was analysed for important markers and mediators of RA (SAP, TNF-α and IL-6). In order to put the latter findings into clinical context, the same molecules were analysed in serum from untreated RA patients and compared to healthy controls. Results Significant elevations of inflammatory markers were found in both patient- and murine blood. Furthermore, the DTHA model appeared clinically relevant when compared to the inflammatory responses observed in three prespecified RA severity disease states. Two distinct trajectories of cardiac dysfunction and HF development were found using the two o-ring sizes. These differences were consistent by both MRI, organ weights and cardiac foetal gene expression levels. Still, no difference within the HF groups, nor within the sham groups, could be found when DTHA was induced. Conclusion DTHA mediated systemic inflammation did not cause, nor modify HF caused by aortic constriction. This indicates other prerequisites for RA-induced cardiac dysfunction.

• Lunde, Ida Gjervold; Aronsen, Jan Magnus; Melleby, Arne Olav; Strand, Mari Elen; Skogestad, Jonas & Bendiksen, Bård Andre [Vis alle 11 forfattere av denne artikkelen] (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), s. 11795–11809. doi: 10.1007/s11033-022-07985-y. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Smith, Lisa; Skulberg, Vidar Magne; Zhang, Lili; Sjaastad, Ivar & Espe, Emil Knut Stenersen (2022). The effects of geometry on stiffness measurements in high-field magnetic resonance elastography: A study on rodent cardiac phantoms. Journal of The Mechanical Behavior of Biomedical Materials. ISSN 1751-6161. 133. doi: 10.1016/j.jmbbm.2022.105302. Fulltekst i vitenarkiv Vis sammendrag

  Purpose Cardiac magnetic resonance elastography (MRE) can be used to assess myocardial stiffness in vivo. Rodents play an important role in modern cardiovascular research, and small animal cardiac MRE may reveal important aspects of myocardial stiffness. The aim of this study was to explore the feasibility of small animal cardiac MRE through investigation of stiffness measurements of small cardiac phantoms that have known underlying stiffness. Methods Agarose gel phantoms of three different geometrical designs were used: homogeneous gels, solid hearts, and biventricular phantoms. The size of the heart phantoms was comparable with that of an end-diastolic rat heart. All phantoms were made with different underlying stiffnesses agarose concentration, (7.5, 10.0,15.0)g/l, and MRE acquisition was performed with three different frequencies (360, 380, 400)Hz. Two different post-processing methods were applied to the MRE wave images: local frequency estimate (LFE) and direct inversion (DI). Results The stiffness associated with the different agarose concentrations (7.5, 10.0, 15.0)g/l in the homogenous gels at 400 Hz were (1.80 ± 0.18, 3.13 ± 0.20, 4.13 ± 0.37)kPa for LFE and (2.25 ± 0.24, 4.35 ± 0.45, 6.54 ± 0.44)kPa for DI, respectively. Significant differences in MRE-derived stiffness were observed among phantoms with different agarose concentrations for all geometries. However, biases in the stiffness measurements among the different geometries were observed and could not be explained by the measurement variability. The relative stiffness uncertainty was smallest for the LFE inversion algorithm. Conclusions The stiffness measurements validate the use of the MRE technique to differentiate between various underlying stiffnesses in small cardiac phantoms. The stiffness measurements seemed to be dominated by geometrical effects when the cardiac MRE wavelength was longer than half the size of the heart. LFE was the inversion algorithm that was most sensitive to the changes in underlying stiffness.

• Romaine, Andreas; Melleby, Arne Olav; Alam, Jahedul; Lobert, Viola; Lu, Ning & Lockwood, Francesca Eve [Vis alle 13 forfattere av denne artikkelen] (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), s. H1057–H1071. doi: 10.1152/ajpheart.00635.2021. Fulltekst i vitenarkiv
• Rypdal, Karoline Bjarnesdatter; Melleby, Arne Olav; Robinson, Emma Louise; Li, Jia; Palmero, Sheryl & E., Seifert Deborah [Vis alle 20 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Shen, Xin; Brink, Jonas van den; Dahl, Anna; Kolstad, Terje R Selnes; Nordén, Einar Sjaastad & Hou, Yufeng [Vis alle 15 forfattere av denne artikkelen] (2022). Prolonged β-adrenergic stimulation disperses ryanodine receptor clusters in cardiomyocytes and has implications for heart failure. eLIFE. 11. doi: 10.7554/eLife.77725. Fulltekst i vitenarkiv Vis sammendrag

  Ryanodine receptors (RyRs) exhibit dynamic arrangements in cardiomyocytes, and we previously showed that ‘dispersion’ of RyR clusters disrupts Ca 2+ homeostasis during heart failure (HF) (Kolstad et al., eLife, 2018). Here, we investigated whether prolonged β-adrenergic stimulation, a hallmark of HF, promotes RyR cluster dispersion and examined the underlying mechanisms. We observed that treatment of healthy rat cardiomyocytes with isoproterenol for 1 hr triggered progressive fragmentation of RyR clusters. Pharmacological inhibition of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) reversed these effects, while cluster dispersion was reproduced by specific activation of CaMKII, and in mice with constitutively active Ser2814-RyR. A similar role of protein kinase A (PKA) in promoting RyR cluster fragmentation was established by employing PKA activation or inhibition. Progressive cluster dispersion was linked to declining Ca 2+ spark fidelity and magnitude, and slowed release kinetics from Ca 2+ propagation between more numerous RyR clusters. In healthy cells, this served to dampen the stimulatory actions of β-adrenergic stimulation over the longer term and protect against pro-arrhythmic Ca 2+ waves. However, during HF, RyR dispersion was linked to impaired Ca 2+ release. Thus, RyR localization and function are intimately linked via channel phosphorylation by both CaMKII and PKA, which, while finely tuned in healthy cardiomyocytes, underlies impaired cardiac function during pathology.

• Rixon, Chloe Louise; Andreassen, Kristine; Shen, Xin; Erusappan, Pugazendhi Murugan; Almaas, Vibeke Marie & Palmero, Sheryl [Vis alle 14 forfattere av denne artikkelen] (2022). Lumican accumulates with fibrillar collagen in fibrosis in hypertrophic cardiomyopathy. ESC Heart Failure. doi: 10.1002/ehf2.14234. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Haugsten, Marie Hansen; Sadredini, Mani; Hasic, Almira; Anderson, Mark E.; Sjaastad, Ivar & Stokke, Mathis Korseberg (2022). CaMKII and reactive oxygen species contribute to early reperfusion arrhythmias, but oxidation of CaMKIIδ at methionines 281/282 is not a determining factor. Journal of Molecular and Cellular Cardiology. ISSN 0022-2828. 175, s. 49–61. doi: 10.1016/j.yjmcc.2022.12.002. Fulltekst i vitenarkiv Vis sammendrag

  Background Available evidence suggest that Ca2+/calmodulin-dependent protein kinase type IIδ (CaMKIIδ) and reactive oxygen species (ROS) are important in early ischemia-reperfusion arrhythmias (IRA). Since ROS can activate CaMKIIδ by oxidation of two methionines at positions 281/282, oxidized-CaMKIIδ (Ox-CaMKIIδ) has been proposed to be important for IRA. However, direct evidence for this is missing. Methods We exposed Langendorff-perfused hearts and ventricular cardiomyocytes from C57BL/6 mice to global and simulated ischemia, respectively, and recorded arrhythmic events during early reperfusion. Hearts were collected for immunoblotting of key phosphoproteins. We evaluated the effects of beta-adrenoceptor stimulation, inhibition of CaMKII, and reduced ROS levels with isoprenaline, KN93/AIP and N-acetylcysteine (NAC), respectively. We further tested the importance of Ox-CaMKIIδ by using hearts and cardiomyocytes from mice with CaMKIIδ resistant to oxidation of methionines 281 and 282 (MMVV). Results Hearts treated with KN93, AIP or NAC had lower incidence of early IRA, and NAC-treated cardiomyocytes had lower incidence of arrhythmogenic events. However, hearts from MMVV mice had a similar incidence of early IRA to wild type mice (WT), and MMVV and WT cardiomyocytes had a similar frequency of Ca2+ waves and Ca2+ sparks. Immunoblotting confirmed high levels of oxidation in early reperfusion, but revealed no significant differences in the phosphorylation levels of Ca2+-handling proteins in MMVV and WT hearts. Conclusions Although CaMKII and ROS both contribute to early IRA, hearts from mice with CaMKII resistant to oxidation at methionines 281/282 were not protected from such arrhythmias, suggesting that oxidation at these sites is not a determining factor.

• NOMELAND, BIRGIT; Schwartz, Thomas; Barth, Zoltan; Taraldsrud, Eli; Samersaw-Lund, May Brit & Aaløkken, Trond Mogens [Vis alle 9 forfattere av denne artikkelen] (2022). Associations between cardiac and pulmonary involvement in patients with juvenile dermatomyositis—a cross-sectional study. Rheumatology International. ISSN 0172-8172. 42, s. 1213–1220. doi: 10.1007/s00296-021-05071-3. Fulltekst i vitenarkiv Vis sammendrag

  Abstract This study aimed at exploring the association between detectable cardiac and pulmonary involvement in long-term juvenile dermatomyositis (JDM) and to assess if patients with cardiac and pulmonary involvement differ with regard to clinical characteristics. 57 JDM patients were examined mean 17.3 (10.5) years after disease onset; this included clinical examination, myositis specific/associated autoantibodies (immunoblot), echocardiography, pulmonary function tests and high-resolution computed tomography. Cardiac involvement was defined as diastolic and/or systolic left ventricular dysfunction and pulmonary involvement as low diffusing capacity for carbon monoxide, low total lung capacity and/or high-resolution computed tomography abnormalities. Patients were stratified into the following four groups: (i) no organ involvement, (ii) pulmonary only, (iii) cardiac only, and (iv) co-existing pulmonary and cardiac involvement. Mean age was 25.7 (12.4) years and 37% were males. One patient had coronary artery disease, seven had a history of pericarditis, seven had hypertension and three had known interstitial lung disease prior to follow-up. There was no association between cardiac (10/57;18%) and pulmonary (41/57;72%) involvement ( p  = 0.83). After stratifying by organ involvement, 21% of patients had no organ involvement; 61% had pulmonary involvement only; 7% had cardiac involvement only and 11% had co-existing pulmonary or cardiac involvement. Patients with co-existing pulmonary or cardiac involvement had higher disease burden than the remaining patients. Patients with either cardiac or pulmonary involvement only, differed in clinical and autoantibody characteristics. We found no increased risk of developing concomitant cardiac/pulmonary involvement in JDM. Our results shed light upon possible different underlying mechanisms behind pulmonary and cardiac involvement in JDM.

• Marstein, Henriette; Witczak, Birgit Nomeland; Godang, Kristin; Schwartz, Thomas; Flatø, Berit & Bollerslev, Jens [Vis alle 8 forfattere av denne artikkelen] (2022). Adipose tissue distribution is associated with cardio-metabolic alterations in adult patients with juvenile-onset dermatomyositis. Rheumatology. ISSN 1462-0324. 62(2), s. 1–9. doi: 10.1093/rheumatology/keac293. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Objectives Primary aims were to compare adipose tissue distribution in adult patients with juvenile-onset DM (JDM), with matched controls. Secondary aims were to explore how adipose tissue distribution is associated with cardio-metabolic status (cardiac dysfunction and metabolic syndrome) in patients. Methods Thirty-nine JDM patients (all aged ≥18 y, mean age 31.7 y and 51% female) were examined mean 22.7 y (s.d. 8.9 y) after disease onset and compared with 39 age/sex-matched controls. In patients, disease activity and lipodystrophy were assessed by validated tools and use of prednisolone noted. In all participants, dual-energy X-ray absorptiometry (DXA) and echocardiography were used to measure visceral adipose tissue (VAT)(g) and cardiac function, respectively. Risk factors for metabolic syndrome were measured and associations with adipose tissue distribution explored. For primary and secondary aims, respectively, P-values ≤0.05 and ≤0.01 were considered significant. Results Patients exhibited a 2.4-fold increase in VAT, and reduced HDL-cholesterol values compared with controls (P-values ≤ 0.05). Metabolic syndrome was found in 25.7% of the patients and none of the controls. Cardiac dysfunction (systolic and/or diastolic) was found in 23.7% of patients and 8.1% of controls (P = 0.07). In patients, VAT levels were correlated with age, disease duration and occurrence of metabolic syndrome and cardiac dysfunction. Occurrence of lipodystrophy (P = 0.02) and male sex (P = 0.04) tended to be independently associated with cardiac dysfunction. Conclusion Adults with JDM showed more central adiposity and cardio-metabolic alterations than controls. Further, VAT was found increased with disease duration, which was associated with development of cardio-metabolic syndrome.

• Udjus, Camilla; Sjaastad, Ivar; Hjørnholm, Ulla; Tunestveit, Torbjørn Kinne; Hoffmann, Pavel & Hinojosa, Alexis [Vis alle 11 forfattere av denne artikkelen] (2022). Extreme altitude induces divergent mass reduction of right and left ventricle in mountain climbers. Physiological Reports. 10(3). doi: 10.14814/phy2.15184. Fulltekst i vitenarkiv Vis sammendrag

  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 [Vis alle 12 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Harbo, Markus Borge; Stokke, Mathis Korseberg; Sjaastad, Ivar & Espe, Emil Knut Stenersen (2022). One step closer to myocardial physiology: From PV loop analysis to state-of-the-art myocardial imaging. Acta Physiologica. ISSN 1748-1708. 234(2). doi: 10.1111/apha.13759. Fulltekst i vitenarkiv
• Robinson, Emma L.; Drawnel, Faye M.; Mehdi, Saher; Archer, Caroline R.; Liu, Wei & Okkenhaug, Hanneke [Vis alle 15 forfattere av denne artikkelen] (2022). MSK-Mediated Phosphorylation of Histone H3 Ser28 Couples MAPK Signalling with Early Gene Induction and Cardiac Hypertrophy. Cells. 11(4). doi: 10.3390/cells11040604. Fulltekst i vitenarkiv Vis sammendrag

  Heart failure is a leading cause of death that develops subsequent to deleterious hypertrophic cardiac remodelling. MAPK pathways play a key role in coordinating the induction of gene expression during hypertrophy. Induction of the immediate early gene (IEG) response including activator protein 1 (AP-1) complex factors is a necessary and early event in this process. How MAPK and IEG expression are coupled during cardiac hypertrophy is not resolved. Here, in vitro, in rodent models and in human samples, we demonstrate that MAPK-stimulated IEG induction depends on the mitogen and stress-activated protein kinase (MSK) and its phosphorylation of histone H3 at serine 28 (pH3S28). pH3S28 in IEG promoters in turn recruits Brg1, a BAF60 ATP-dependent chromatin remodelling complex component, initiating gene expression. Without MSK activity and IEG induction, the hypertrophic response is suppressed. These studies provide new mechanistic insights into the role of MAPK pathways in signalling to the epigenome and regulation of gene expression during cardiac hypertrophy.

• Edwards, Andrew; Mørk, Halvor; Stokke, Mathis; Lipsett, David; Sjaastad, Ivar & Richard, Sylvain [Vis alle 8 forfattere av denne artikkelen] (2021). Sarcoplasmic Reticulum Calcium Release Is Required for Arrhythmogenesis in the MouseData_Sheet_1.pdf. Frontiers in Physiology. 129247113307196118101757330290951073619410426311810310255549995881112965921565931388107972921061031069987209102119109419102782. doi: 10.3389/fphys.2021.74473010.3389/fphys.2021.744730.s001. Fulltekst i vitenarkiv
• Berger, Simon Girmai; Sjaastad, Ivar & Stokke, Mathis Korseberg (2021). Right ventricular involvement in hypertrophic cardiomyopathy: evidence and implications from current literature. Scandinavian Cardiovascular Journal. ISSN 1401-7431. s. 1–10. doi: 10.1080/14017431.2021.1901979. Fulltekst i vitenarkiv Vis sammendrag

  Objectives. In current guidelines, hypertrophic cardiomyopathy (HCM) is defined by hypertrophy of the left ventricle (LV). Less attention has been given to the right ventricle (RV) in patients with HCM. We wanted to provide an overview of current literature on RV involvement in HCM. Design. We performed a systematic search in PubMed and added additional articles by manual screening of references. The quality of the articles was assessed according to the GRADE system. Results. We identified 35 original articles on RV involvement in HCM. Based on these publications, RV hypertrophy occurs in 28–44% of HCM patients, depending on the cut-off value for hypertrophy and the method for assessment. Histological studies show the same structural changes in RV as are typically described in the LV cardiomyocyte hypertrophy and disarray, as well as fibrosis. These changes are similar, but less pronounced in the RV than in the LV. We discuss how HCM can impact the RV, either through a primary involvement similar to the LV or secondary to hemodynamic effects resulting from LV dysfunction. RV dysfunction in HCM is associated with higher mortality, partly due to an increased risk of ventricular tachycardia and sudden cardiac death. Conclusions. The evidence for RV involvement in HCM is limited. Multimodal imaging assessment of the RV should be included in the work-up of patients with HCM, and the added value of including RV function in the risk stratification algorithm should be further explored.

• Wanichawan, Pimthanya; Skogestad, Jonas; Lunde, Marianne; Støle, Thea Parsberg; Stensland, Maria & Nyman, Tuula Anneli [Vis alle 10 forfattere av denne artikkelen] (2021). Design of a proteolytically stable sodium-calcium exchanger 1 activator peptide for in vivo studies. Frontiers in Pharmacology. 12(638646). doi: 10.3389/fphar.2021.638646. Fulltekst i vitenarkiv Vis sammendrag

  The cardiac sodium–calcium exchanger (NCX1) is important for normal Na + - and Ca 2+ -homeostasis and cardiomyocyte relaxation and contraction. It has been suggested that NCX1 activity is reduced by phosphorylated phospholemman (pSer68-PLM); however its direct interaction with PLM is debated. Disruption of the potentially inhibitory pSer68-PLM-NCX1 interaction might be a therapeutic strategy to increase NCX1 activity in cardiac disease. In the present study, we aimed to analyze the binding affinities and kinetics of the PLM-NCX1 and pSer68-PLM-NCX1 interactions by surface plasmon resonance (SPR) and to develop a proteolytically stable NCX1 activator peptide for future in vivo studies. The cytoplasmic parts of PLM (PLM cyt ) and pSer68-PLM (pSer68-PLM cyt ) were found to bind strongly to the intracellular loop of NCX1 (NCX1 cyt ) with similar K D values of 4.1 ± 1.0 nM and 4.3 ± 1.9 nM, but the PLM cyt -NCX1 cyt interaction showed higher on/off rates. To develop a proteolytically stable NCX1 activator, we took advantage of a previously designed, high-affinity PLM binding peptide (OPT) that was derived from the PLM binding region in NCX1 and that reverses the inhibitory PLM (S68D)-NCX1 interaction in HEK293. We performed N- and C-terminal truncations of OPT and identified PYKEIEQLIELANYQV as the minimum sequence required for pSer68-PLM binding. To increase peptide stability in human serum, we replaced the proline with an N-methyl-proline (NOPT) after identification of N-terminus as substitution tolerant by two-dimensional peptide array analysis. Mass spectrometry analysis revealed that the half-life of NOPT was increased 17-fold from that of OPT. NOPT pulled down endogenous PLM from rat left ventricle lysate and exhibited direct pSer68-PLM binding in an ELISA-based assay and bound to pSer68-PLM cyt with a K D of 129 nM. Excess NOPT also reduced the PLM cyt -NCX1 cyt interaction in an ELISA-based competition assay, but in line with that NCX1 and PLM form oligomers, NOPT was not able to outcompete the physical interaction between endogenous full length proteins. Importantly, cell-permeable NOPT-TAT increased NCX1 activity in cardiomyocytes isolated from both SHAM-operated and aorta banded heart failure (HF) mice, indicating that NOPT disrupted the inhibitory pSer68-PLM-NCX1 interaction. In conclusion, we have developed a proteolytically stable NCX1-derived PLM binding peptide that upregulates NCX1 activity in SHAM and HF cardiomyocytes.

• Marstein, Henriette; Godang, Kristin; Flatø, Berit; Sjaastad, Ivar; Bollerslev, Jens & Sanner, Helga (2021). Bone mineral density and explanatory factors in children and adults with juvenile dermatomyositis at long term follow-up; a cross sectional study. Pediatric Rheumatology. 19(1), s. 1–11. doi: 10.1186/s12969-021-00543-z. Fulltekst i vitenarkiv Vis sammendrag

  Background Juvenile dermatomyositis (JDM) is the most common idiopathic inflammatory myopathy in children and adolescents. Both the disease and its treatment with glucocorticoids may negatively impact bone formation. In this study we compare BMD in patients (children/adolescence and adults) with long-standing JDM with matched controls; and in patients, explore how general/disease characteristics and bone turnover markers are associated with BMD. Methods JDM patients (n = 59) were examined median 16.8y (range 6.6–27.0y) after disease onset and compared with 59 age/sex-matched controls. Dual-energy X-ray absorptiometry (DXA) was used to measure BMD of the whole body and lumbar spine (spine) in all participants, and of ultra-distal radius, forearm and total hip in participants ≥20y only. Markers of bone turnover were analysed, and associations with outcomes explored. Results Reduced BMD Z-scores (<−1SD) were found in 19 and 29% of patients and 7 and 9% of controls in whole body and spine, respectively (p-values < 0.05). BMD and BMD Z-scores for whole body and spine were lower in all patients and for < 20y compared with their respective controls. In participants ≥20y, only BMD and BMD Z-score of forearm were lower in the patients versus controls. In patients, BMD Z-scores for whole body and/or spine were found to correlate negatively with prednisolone use at follow-up (yes/no) (age < 20y), inflammatory markers (age ≥ 20y) and levels of interferon gamma-induced protein 10 (IP-10) (both age groups). In all patients, prednisolone use at follow-up (yes/no) and age ≥ 20y were independent correlates of lower BMD Z-scores for whole body and spine, respectively. Conclusion In long-term JDM, children have more impairment of BMD than adults in spine and whole-body. Associations with BMD were found for both prednisolone and inflammatory markers, and a novel association was discovered with the biomarker of JDM activity, IP-10.

• NOMELAND, BIRGIT; Bollerslev, Jens; Godang, Kristin; Schwartz, Thomas; Flatø, Berit & Molberg, Øyvind [Vis alle 8 forfattere av denne artikkelen] (2021). Body composition in long-standing juvenile dermatomyositis: associations with disease activity, muscle strength and cardiometabolic measures. Rheumatology. ISSN 1462-0324. 61(7), s. 2959–2968. doi: 10.1093/rheumatology/keab805. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Objective To (i) compare body composition parameters in patients with longstanding juvenile dermatomyositis (JDM) and controls and (ii) explore associations between body composition and disease activity/inflammation, muscle strength, health-related quality of life (HRQL) and cardiometabolic measures. Methods In a cross-sectional study, we included 59 patients (median disease duration 16.7 y; median age 21.5 y) and 59 age- and sex-matched controls. Active/inactive disease were defined by the PRINTO criteria. Body composition was assessed by total body dual-energy absorptiometry (DXA), inflammation by hs-CRP and cytokines, muscle strength by manual muscle test (MMT-8), HRQL by 36-item short form survey physical component score (SF-36 PCS) and cardiometabolic function by echocardiography (systolic and diastolic function) and serum-lipids. Results DXA analyses revealed lower appendicular lean mass index (ALMI) (reflecting limb skeletal muscle mass), higher body fat percentage (BF%) and higher android: gynoid fat ratio (A: G ratio) (reflecting central fat distribution) in patients than controls, despite similar BMI. Patients with active disease had lower ALMI and higher BF% than those with inactive disease; lower ALMI and higher BF% were associated with inflammation (elevated monocyte attractant protein-1 (MCP-1) and hs-CRP). Lower ALMI was associated with reduced muscle strength; higher BF% was associated with impaired HRQL. Central fat distribution (higher A: G ratio) was associated with impaired cardiac function and unfavorable serum-lipids. Conclusion : Despite normal BMI, patients with JDM, especially those with active disease, had unfavorable body composition, which was associated with impaired HRQL/muscle strength and cardiometabolic function. The association between central fat distribution and cardiometabolic alterations is a novel finding in JDM.

• Frisk, Michael; Le, Christopher; Shen, Xin; Røe, Åsmund Treu; Hou, Yufeng & Manfra, Ornella [Vis alle 24 forfattere av denne artikkelen] (2021). Etiology-dependent impairment of diastolic cardiomyocyte calcium homeostasis in heart failure with preserved ejection fraction. Journal of the American College of Cardiology. ISSN 0735-1097. 77(4), s. 405–419. doi: 10.1016/j.jacc.2020.11.044. Fulltekst i vitenarkiv Vis sammendrag

  Background Whereas heart failure with reduced ejection fraction (HFrEF) is associated with ventricular dilation and markedly reduced systolic function, heart failure with preserved ejection fraction (HFpEF) patients exhibit concentric hypertrophy and diastolic dysfunction. Impaired cardiomyocyte Ca2+ homeostasis in HFrEF has been linked to disruption of membrane invaginations called t-tubules, but it is unknown if such changes occur in HFpEF. Objectives This study examined whether distinct cardiomyocyte phenotypes underlie the heart failure entities of HFrEF and HFpEF. Methods T-tubule structure was investigated in left ventricular biopsies obtained from HFrEF and HFpEF patients, whereas cardiomyocyte Ca2+ homeostasis was studied in rat models of these conditions. Results HFpEF patients exhibited increased t-tubule density in comparison with control subjects. Super-resolution imaging revealed that higher t-tubule density resulted from both tubule dilation and proliferation. In contrast, t-tubule density was reduced in patients with HFrEF. Augmented collagen deposition within t-tubules was observed in HFrEF but not HFpEF hearts. A causative link between mechanical stress and t-tubule disruption was supported by markedly elevated ventricular wall stress in HFrEF patients. In HFrEF rats, t-tubule loss was linked to impaired systolic Ca2+ homeostasis, although diastolic Ca2+ removal was also reduced. In contrast, Ca2+ transient magnitude and release kinetics were largely maintained in HFpEF rats. However, diastolic Ca2+ impairments, including reduced sarco/endoplasmic reticulum Ca2+-ATPase activity, were specifically observed in diabetic HFpEF but not in ischemic or hypertensive models. Conclusions Although t-tubule disruption and impaired cardiomyocyte Ca2+ release are hallmarks of HFrEF, such changes are not prominent in HFpEF. Impaired diastolic Ca2+ homeostasis occurs in both conditions, but in HFpEF, this mechanism for diastolic dysfunction is etiology-dependent.

• Norden, Einar Sjaastad; Bendiksen, Bård Andre; Andresen, Henriette; Bergo, Kaja Knudsen; Espe, Emil Knut Stenersen & Hasic, Almira [Vis alle 12 forfattere av denne artikkelen] (2021). Sacubitril/valsartan ameliorates cardiac hypertrophy and preserves diastolic function in cardiac pressure overload. ESC Heart Failure. 8(2), s. 918–927. doi: 10.1002/ehf2.13177. Fulltekst i vitenarkiv
• Blom, Kjersti Benedicte; Åsberg, Anders; Sjaastad, Ivar; Kalleberg, Karl Trygve; Søraas, Arne Vasli & Midtvedt, Karsten [Vis alle 7 forfattere av denne artikkelen] (2021). Kidney Transplant Recipient Behavior During the Early COVID-19 Pandemic: A National Survey Study in Norway. Kidney Medicine. 4(2). doi: 10.1016/j.xkme.2021.09.006. Fulltekst i vitenarkiv Vis sammendrag

  Rationale & Objective Studies published from countries with a high prevalence of COVID-19 have found increased incidence and a more severe disease course of coronavirus disease 2019 (COVID-19) in kidney transplant recipients than in the general population. We investigated how the first wave of the COVID-19 pandemic affected the everyday life of kidney transplant recipients in a country with a low infection burden. Study Design Prospective case-control study. Setting & Participants All adult kidney transplant recipients in Norway with a functioning graft and listed in the public phone registry (n = 3,060) and a group of randomly recruited individuals >18 years from the general population (n = 20,000) were invited to participate in the study by an SMS text message. In parallel, all kidney transplant recipients in Norway were invited to measure severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG from mid-June to October 2020. Predictors The participants were asked to fill out a questionnaire focused on everyday life, travel history, exposure to known COVID-19 cases, and demographics. Analytical Approach Groups were compared with independent tests using 2-sided 0.05 significance levels. Results A total of 1,007 kidney transplant recipients and 4,409 controls answered the questionnaire. The kidney transplant recipients reported being more concerned about SARS-CoV-2 infection (27%) than the control group (7%; P value < 0.001); ie, they behaved more carefully in their everyday life (not going to the grocery store, 5.9% vs 0.9%, P < 0.001; keeping at least 1 meter distance, 16.6% vs 5.8%, P < 0.001). Of the kidney transplant responders, 81% had a SARS-CoV-2 IgG taken; all were negative. Limitations Mortality data is not reliable because of the low number of SARS-CoV-2 infected kidney transplant recipients in Norway. The relatively low questionnaire response rate for kidney transplant recipients is not optimal. Conclusions The questionnaire shows that kidney transplant recipients have behaved more carefully compared with the general population with less social interaction and a very high degree of adherence to governmental advice.

• Edwards, Andrew G.; Mørk, Halvor Kjeang; Stokke, Mathis Korseberg; Lipsett, David Bruce; Sjaastad, Ivar & Richard, Sylvain [Vis alle 8 forfattere av denne artikkelen] (2021). Sarcoplasmic Reticulum Calcium Release Is Required for Arrhythmogenesis in the Mouse. Frontiers in Physiology. 12, s. 1–13. doi: 10.3389/fphys.2021.744730. Fulltekst i vitenarkiv Vis sammendrag

  Dysfunctional sarcoplasmic reticulum Ca 2+ handling is commonly observed in heart failure, and thought to contribute to arrhythmogenesis through several mechanisms. Some time ago we developed a cardiomyocyte-specific inducible SERCA2 knockout mouse, which is remarkable in the degree to which major adaptations to sarcolemmal Ca 2+ entry and efflux overcome the deficit in SR reuptake to permit relatively normal contractile function. Conventionally, those adaptations would also be expected to dramatically increase arrhythmia susceptibility. However, that susceptibility has never been tested, and it is possible that the very rapid repolarization of the murine action potential (AP) allows for large changes in sarcolemmal Ca 2+ transport without substantially disrupting electrophysiologic stability. We investigated this hypothesis through telemetric ECG recording in the SERCA2-KO mouse, and patch-clamp electrophysiology, Ca 2+ imaging, and mathematical modeling of isolated SERCA2-KO myocytes. While the SERCA2-KO animals exhibit major (and unique) electrophysiologic adaptations at both the organ and cell levels, they remain resistant to arrhythmia. A marked increase in peak L-type calcium ( I CaL ) current and slowed I CaL decay elicited pronounced prolongation of initial repolarization, but faster late repolarization normalizes overall AP duration. Early afterdepolarizations were seldom observed in KO animals, and those that were observed exhibited a mechanism intermediate between murine and large mammal dynamical properties. As expected, spontaneous SR Ca 2+ sparks and waves were virtually absent. Together these findings suggest that intact SR Ca 2+ handling is an absolute requirement for triggered arrhythmia in the mouse, and that in its absence, dramatic changes to the major inward currents can be resisted by the substantial K + current reserve, even at end-stage disease.

• Bendiksen, Bård Andre; Mcginley, Gary George; Sjaastad, Ivar; Zhang, Lili & Espe, Emil Knut Stenersen (2021). A 4D continuous representation of myocardial velocity fields from tissue phase mapping magnetic resonance imaging. PLOS ONE. 16(3). doi: 10.1371/journal.pone.0247826. Fulltekst i vitenarkiv
• Carlson, Cathrine Rein; Aronsen, Jan Magnus; Dahl, Anna Bergan; Moutty, Marie Christine; Lunde, Marianne & Lunde, Per Kristian [Vis alle 22 forfattere av denne artikkelen] (2021). AKAP18δ Anchors and Regulates CaMKII Activity at Phospholamban-SERCA2 and RYR. Circulation Research. ISSN 0009-7330. 130(1), s. 27–44. doi: 10.1161/CIRCRESAHA.120.317976. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Sadredini, Mani; Manotheepan, Ravinea; Lehnart, Stephan E.; Anderson, Mark E.; Sjaastad, Ivar & Stokke, Mathis K. (2021). The oxidation-resistant CaMKII-MM281/282VV mutation does not prevent arrhythmias in CPVT1. Physiological Reports. 9(18). doi: 10.14814/phy2.15030. Fulltekst i vitenarkiv Vis sammendrag

  Catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) is an inherited arrhythmogenic disorder caused by missense mutations in the cardiac ryanodine receptors (RyR2), that result in increased β-adrenoceptor stimulation-induced diastolic Ca2+ leak. We have previously shown that exercise training prevents arrhythmias in CPVT1, potentially by reducing the oxidation of Ca2+/calmodulin-dependent protein kinase type II (CaMKII). Therefore, we tested whether an oxidation-resistant form of CaMKII protects mice carrying the CPVT1-causative mutation RyR2-R2474S (RyR2-RS) against arrhythmias. Antioxidant treatment (N-acetyl-L-cysteine) reduced the frequency of β-adrenoceptor stimulation-induced arrhythmogenic Ca2+ waves in isolated cardiomyocytes from RyR2-RS mice. To test whether the prevention of CaMKII oxidation exerts an antiarrhythmic effect, mice expressing the oxidation-resistant CaMKII-MM281/282VV variant (MMVV) were crossed with RyR2-RS mice to create a double transgenic model (RyR2-RS/MMVV). Wild-type mice served as controls. Telemetric ECG surveillance revealed an increased incidence of ventricular tachycardia and an increased arrhythmia score in both RyR2-RS and RyR2-RS/MMVV compared to wild-type mice, both following a β-adrenoceptor challenge (isoprenaline i.p.), and following treadmill exercise combined with a β-adrenoceptor challenge. There were no differences in the incidence of arrhythmias between RyR2-RS and RyR2-RS/MMVV mice. Furthermore, no differences were observed in β-adrenoceptor stimulation-induced Ca2+ waves in RyR2-RS/MMVV compared to RyR2-RS. In conclusion, antioxidant treatment reduces β-adrenoceptor stimulation-induced Ca2+ waves in RyR2-RS cardiomyocytes. However, oxidation-resistant CaMKII-MM281/282VV does not protect RyR2-RS mice from β-adrenoceptor stimulation-induced Ca2+ waves or arrhythmias. Hence, alternative oxidation-sensitive targets need to be considered to explain the beneficial effect of antioxidant treatment on Ca2+ waves in cardiomyocytes from RyR2-RS mice.

• Sadredini, Mani; Haugsten, Marie Hansen; Frisk, Michael; Louch, William E.; Lehnart, Stephan E. & Sjaastad, Ivar [Vis alle 7 forfattere av denne artikkelen] (2021). CaMKII inhibition has dual effects on spontaneous Ca²⁺release and Ca²⁺ alternans in ventricular cardiomyocytes from mice with a gain-of-function RyR2 mutation. American Journal of Physiology. Heart and Circulatory Physiology. ISSN 0363-6135. 321(2), s. H446–H460. doi: 10.1152/ajpheart.00011.2021. Fulltekst i vitenarkiv
• Danielsen, Tore Kristian; Sadredini, Mani; Manotheepan, Ravinea; Aronsen, Jan Magnus; Frisk, Michael & Haugsten, Marie Hansen [Vis alle 13 forfattere av denne artikkelen] (2021). Exercise training stabilizes RyR2-dependent Ca2+ release in post-infarction heart failure. Frontiers in Cardiovascular Medicine. 7. doi: 10.3389/fcvm.2020.623922. Fulltekst i vitenarkiv Vis sammendrag

  Aim: Dysfunction of the cardiac ryanodine receptor (RyR2) is an almost ubiquitous finding in animal models of heart failure (HF) and results in abnormal Ca 2+ release in cardiomyocytes that contributes to contractile impairment and arrhythmias. We tested whether exercise training (ET), as recommended by current guidelines, had the potential to stabilize RyR2-dependent Ca 2+ release in rats with post-myocardial infarction HF. Materials and Methods: We subjected male Wistar rats to left coronary artery ligation or sham operations. After 1 week, animals were characterized by echocardiography and randomized to high-intensity interval ET on treadmills or to sedentary behavior (SED). Running speed was adjusted based on a weekly VO 2max test. We repeated echocardiography after 5 weeks of ET and harvested left ventricular cardiomyocytes for analysis of RyR2-dependent systolic and spontaneous Ca 2+ release. Phosphoproteins were analyzed by Western blotting, and beta-adrenoceptor density was quantified by radioligand binding. Results: ET increased VO 2max in HF-ET rats to 127% of HF-SED ( P &amp;lt; 0.05). This coincided with attenuated spontaneous SR Ca 2+ release in left ventricular cardiomyocytes from HF-ET but also reduced Ca 2+ transient amplitude and slowed Ca 2+ reuptake during adrenoceptor activation. However, ventricular diameter and fractional shortening were unaffected by ET. Analysis of Ca 2+ homeostasis and major proteins involved in the regulation of SR Ca 2+ release and reuptake could not explain the attenuated spontaneous SR Ca 2+ release or reduced Ca 2+ transient amplitude. Importantly, measurements of beta-adrenoceptors showed a normalization of beta 1 -adrenoceptor density and beta 1 :beta 2 -adrenoceptor ratio in HF-ET. Conclusion: ET increased aerobic capacity in post-myocardial infarction HF rats and stabilized RyR2-dependent Ca 2+ release. Our data show that these effects of ET can be gained without major alterations in SR Ca 2+ regulatory proteins and indicate that future studies should include upstream parts of the sympathetic signaling pathway.

• Rønning, Sissel Beate; Carlson, Cathrine Rein; Aronsen, Jan Magnus; Pisconti, Addolorata; Høst, Vibeke & Lunde, Marianne [Vis alle 11 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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 [Vis alle 16 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Espe, Emil Knut Stenersen; Bendiksen, Bård Andre; Zhang, Lili & Sjaastad, Ivar (2020). Analysis of right ventricular mass from magnetic resonance imaging data: a simple post-processing algorithm for correction of partial-volume effects. American Journal of Physiology. Heart and Circulatory Physiology. ISSN 0363-6135. 320(2), s. 912–922. doi: 10.1152/ajpheart.00494.2020. Fulltekst i vitenarkiv
• Gonzalez, Alba; Nome, Cecilie; Bendiksen, Bård Andre; Sjaastad, Ivar; Zhang, Lili & Aleksandersen, Mona [Vis alle 9 forfattere av denne artikkelen] (2020). Assessment of cardiac structure and function in a murine model of temporal lobe epilepsy. Epilepsy Research. ISSN 0920-1211. 161, s. 1–7. doi: 10.1016/j.eplepsyres.2020.106300. Fulltekst i vitenarkiv Vis sammendrag

  Sudden unexpected death in epilepsy (SUDEP) is a significant cause of premature seizure-related death. An association between SUDEP and cardiac remodeling has been suggested. However, whether SUDEP is a direct consequence of acute or recurrent seizures is unsettled. The purpose of this study was to evaluate the impact of status epilepticus (SE) and chronic seizures on myocardial structure and function. We used the intracortical kainate injection model of temporal lobe epilepsy to elicit SE and chronic epilepsy in mice. In total, 24 C57/BL6 mice (13 kainate, 11 sham) were studied 2 and 30 days post-injection. Cardiac structure and function were investigated in-vivo with a 9.4 T MRI, electrocardiography (ECG), echocardiography, and histology [Haematoxylin/Eosin (HE) and Martius Scarlet Blue (MSB)] for staining of collagen proliferation and fibrin accumulation. In conclusion, we did not detect any significant changes in cardiac structure and function neither in mice 2 days nor 30 days post-injection.

• Mohammadzadeh, Naiyereh; Melleby, Arne Olav; Palmero, Sheryl; Sjaastad, Ivar; Chakravarti, Shukti & Engebretsen, Kristin V Thunheim [Vis alle 9 forfattere av denne artikkelen] (2020). Moderate Loss of the Extracellular Matrix Proteoglycan Lumican Attenuates Cardiac Fibrosis in Mice Subjected to Pressure Overload. Cardiology. ISSN 0008-6312. 145(3), s. 187–198. doi: 10.1159/000505318. Fulltekst i vitenarkiv
• Louwe, Maria Cornelia; Olsen, Maria Belland; Kaasbøll, Ole Jørgen; Yang, Kuan; Fosshaug, Linn Elisabeth Lillerud & Alfsnes, Katrine [Vis alle 25 forfattere av denne artikkelen] (2020). Absence of NLRP3 Inflammasome in Hematopoietic Cells Reduces Adverse Remodeling After Experimental Myocardial Infarction. JACC: Basic to Translational Science. ISSN 2452-302X. 5(12), s. 1210–1224. doi: 10.1016/j.jacbts.2020.09.013. Fulltekst i vitenarkiv Vis sammendrag

  An inflammatory response is required for tissue healing after a myocardial infarction (MI), but the process must be balanced to prevent maladaptive remodeling. This study shows that improved survival and cardiac function following MI, in mice deficient for the NLRP3 inflammasome, can be recapitulated in wild-type mice receiving bone marrow from Nlrp3−/− mice. This suggests that NLRP3 activation in hematopoietic cells infiltrating in the myocardium increases mortality and late ventricular remodeling. Our data should encourage performing clinical trials directly targeting NLRP3 inflammasome and their inflammatory cytokines (interleukin-1β and -18) in MI patients.

• Longobardi, S.; Lewalle, A.; Coveney, S.; Sjaastad, Ivar; Espe, Emil Knut Stenersen & Louch, William Edward [Vis alle 9 forfattere av denne artikkelen] (2020). Predicting left ventricular contractile function via Gaussian process emulation in aortic-banded rats: Aortic banded rat heart simulations. Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences. ISSN 1364-503X. 378(2173). doi: 10.1098/rsta.2019.0334. Fulltekst i vitenarkiv
• Harbo, Markus Borge; Norden, Einar Sjaastad; Narula, Jagat; Sjaastad, Ivar & Espe, Emil Knut Stenersen (2020). Quantifying left ventricular function in heart failure: What makes a clinically valuable parameter? Progress in cardiovascular diseases. ISSN 0033-0620. s. 1–9. doi: 10.1016/j.pcad.2020.05.007. Fulltekst i vitenarkiv Vis sammendrag

  In heart failure (HF) management, noninvasive quantification of left ventricular (LV) function is rapidly evolving. Deformation parameters, such as strain, continue to challenge the central role of ejection fraction (EF) in diagnosis and prognostication of LV dysfunction in HF. The increasing recognition and use of deformation parameters motivates a conceptual discussion about what makes a parameter clinically valuable. To do this, we introduce a framework for parameter evaluation. The framework considers three aspects that are important for parameter value; 1) how these parameters couple with underlying myocardial function; 2) the evidence base of the parameters; and 3) the technical feasibility of their measurement. In particular, we emphasize that the coupling of each parameter to the underlying myocardial function (aspect 1) is crucial for parameter value. While EF offers information about cardiac dysfunction trough measuring changes in LV volume, deformation parameters more closely reflect underlying myocardial processes that contribute to cardiac pumping function. This is a fundamental advantage of deformation parameters that could explain why a growing number of studies supports their use. A close coupling to underlying function is, however, not sufficient for high clinical value by itself. A parameter also needs a strong evidence base (aspect 2) and a high degree of technical feasibility (aspect 3). By considering these three aspects, this review discusses the present and potential clinical value of EF and deformation parameters in HF management.

• Longobardi, Stefano; Lewalle, Alexandre; Coveney, Sam; Sjaastad, Ivar; Espe, Emil Knut Stenersen & Louch, William Edward [Vis alle 9 forfattere av denne artikkelen] (2020). Predicting left ventricular contractile function via Gaussian process emulation in aortic-banded rats. Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences. ISSN 1364-503X. 378(2173), s. 20190334–20190334. doi: 10.1098/rsta.2019.0334. Fulltekst i vitenarkiv Vis sammendrag

  Cardiac contraction is the result of integrated cellular, tissue and organ function. Biophysical in silico cardiac models offer a systematic approach for studying these multi-scale interactions. The computational cost of such models is high, due to their multi-parametric and nonlinear nature. This has so far made it difficult to perform model fitting and prevented global sensitivity analysis (GSA) studies. We propose a machine learning approach based on Gaussian process emulation of model simulations using probabilistic surrogate models, which enables model parameter inference via a Bayesian history matching (HM) technique and GSA on whole-organ mechanics. This framework is applied to model healthy and aortic-banded hypertensive rats, a commonly used animal model of heart failure disease. The obtained probabilistic surrogate models accurately predicted the left ventricular pump function (R2 = 0.92 for ejection fraction). The HM technique allowed us to fit both the control and diseased virtual bi-ventricular rat heart models to magnetic resonance imaging and literature data, with model outputs from the constrained parameter space falling within 2 SD of the respective experimental values. The GSA identified Troponin C and cross-bridge kinetics as key parameters in determining both systolic and diastolic ventricular function. This article is part of the theme issue ‘Uncertainty quantification in cardiac and cardiovascular modelling and simulation’.

• Sokolova, Marina; Yang, Kuan; Hansen, Simen Hyll; Louwe, Maria Cornelia; Kummen, Martin & Hov, Johannes Espolin Roksund [Vis alle 12 forfattere av denne artikkelen] (2020). NLRP3 inflammasome deficiency attenuates metabolic disturbances involving alterations in the gut microbial profile in mice exposed to high fat diet. Scientific Reports. 10:21006, s. 1–16. doi: 10.1038/s41598-020-76497-1. Fulltekst i vitenarkiv Vis sammendrag

  Obesity-related diseases (e.g. type 2 diabetes mellitus and cardiovascular disorders) represent an increasing health problem worldwide. NLRP3 inflammasome activation may underlie obesity-induced inflammation and insulin resistance, and NLRP3 deficient mice exposed to high fat diet (HFD) appear to be protected from left ventricle (LV) concentric remodeling. Herein, we investigated if these beneficial effects were associated with alterations in plasma metabolites, using metabolomic and lipidomic analysis, and gut microbiota composition, using 16S rRNA sequencing of cecum content, comparing NLRP3 deficient and wild type (WT) mice on HFD and control diet. Obese NLRP3 deficient mice had lower systemic ceramide levels, potentially resulting attenuating inflammation, altered hepatic expression of fatty acids (FA) with lower mono-saturated FA and higher polyunsaturated FA levels, potentially counteracting development of liver steatosis, downregulated myocardial energy metabolism as assessed by proteomic analyses of LV heart tissue, and different levels of bile acids as compared with WT mice. These changes were accompanied by an altered composition of gut microbiota associated with decreased systemic levels of tri-methylamine-N-oxide and lipopolysaccharide, potentially inducing attenuating systemic inflammation and beneficial effects on lipid metabolism. Our findings support a role of NLRP3 inflammasome in the interface between metabolic and inflammatory stress, involving an altered gut microbiota composition.

• Tazmini, Kiarash; Frisk, Michael; Lewalle, Alexandre; Laasmaa, Martin; Morotti, Stefano & Lipsett, David Bruce [Vis alle 16 forfattere av denne artikkelen] (2020). Hypokalemia promotes arrhythmia by distinct mechanisms in atrial and ventricular myocytes. Circulation Research. ISSN 0009-7330. 126(7), s. 889–906. doi: 10.1161/CIRCRESAHA.119.315641. Fulltekst i vitenarkiv Vis sammendrag

  Rationale: Hypokalemia occurs in up to 20% of hospitalized patients and is associated with increased incidence of ventricular and atrial fibrillation. It is unclear whether these differing types of arrhythmia result from direct and perhaps distinct effects of hypokalemia on cardiomyocytes. Objective: To investigate proarrhythmic mechanisms of hypokalemia in ventricular and atrial myocytes. Methods and Results: Experiments were performed in isolated rat myocytes exposed to simulated hypokalemia conditions (reduction of extracellular [K+] from 5.0 to 2.7 mmol/L) and supported by mathematical modeling studies. Ventricular cells subjected to hypokalemia exhibited Ca2+ overload and increased generation of both spontaneous Ca2+ waves and delayed afterdepolarizations. However, similar Ca2+-dependent spontaneous activity during hypokalemia was only observed in a minority of atrial cells that were observed to contain t-tubules. This effect was attributed to close functional pairing of the Na+-K+ ATPase and Na+-Ca2+ exchanger proteins within these structures, as reduction in Na+ pump activity locally inhibited Ca2+ extrusion. Ventricular myocytes and tubulated atrial myocytes additionally exhibited early afterdepolarizations during hypokalemia, associated with Ca2+ overload. However, early afterdepolarizations also occurred in untubulated atrial cells, despite Ca2+ quiescence. These phase-3 early afterdepolarizations were rather linked to reactivation of nonequilibrium Na+ current, as they were rapidly blocked by tetrodotoxin. Na+ current-driven early afterdepolarizations in untubulated atrial cells were enabled by membrane hyperpolarization during hypokalemia and short action potential configurations. Brief action potentials were in turn maintained by ultra-rapid K+ current (IKur); a current which was found to be absent in tubulated atrial myocytes and ventricular myocytes. Conclusions: Distinct mechanisms underlie hypokalemia-induced arrhythmia in the ventricle and atrium but also vary between atrial myocytes depending on subcellular structure and electrophysiology.

• Røe, Åsmund Treu; Ruud, Marianne; Espe, Emil Knut Stenersen; Manfra, Ornella; Longobardi, S & Aronsen, Jan Magnus [Vis alle 16 forfattere av denne artikkelen] (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), s. 752–764. doi: 10.1093/cvr/cvy257. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Barth, Zoltan; Schwartz, Thomas; Flatø, Berit; Aaløkken, Trond Mogens; Koller, Akos & Lund, May-Brith [Vis alle 8 forfattere av denne artikkelen] (2019). The association between nailfold capillary density and pulmonary and cardiac involvement in medium-to long-standing juvenile dermatomyositis. Arthritis care & research. ISSN 2151-464X. 71(4), s. 492–497. doi: 10.1002/acr.23687. Fulltekst i vitenarkiv Vis sammendrag

  Objective To explore the associations between microvascular abnormalities as assessed by nailfold capillaroscopy (NFC) and pulmonary and cardiac involvement in patients with juvenile dermatomyositis (DM) who are assessed after medium‐ to long‐term follow‐up. Methods Fifty‐eight patients with juvenile DM were examined a mean ± SD of 17.0 ± 10.6 years after symptom onset. Nailfold capillary density (NCD) and a neovascular pattern (defined as an active or late scleroderma pattern) were analyzed, with blinding to clinical data. Pulmonary involvement was assessed by pulmonary function tests including spirometry, diffusing capacity for carbon monoxide (DLco ), and body plethysmography. High‐resolution computed tomography (HRCT) was also performed. Cardiac involvement was assessed by electrocardiography, Holter monitoring (heart rate variability), and echocardiography. Results Patients with low NCD (<6 capillaries/mm) (n = 21), compared to patients with normal NCD (≥6 capillaries/mm) (n = 37) had lower forced vital capacity (89.7% versus 98.5% predicted), total lung capacity (87.8% versus 94.5% predicted), and more often had low DLco values (15 [71%] of 21 patients versus 14 [38%] of 37 controls) (all P < 0.05). Use of HRCT to assess airway disease was more frequent in the group with low NCD (6 [30%] of 20 patients versus 3 [8%] of 36 patients in the normal NCD group; P = 0.034). No associations between NCD and cardiac parameters or between neovascular pattern and pulmonary or cardiac parameters were observed. Conclusion In patients with juvenile DM, low NCD was associated with lung involvement, which was mostly subclinical. No significant associations with cardiac involvement were observed. These results shed light on possible mechanisms underlying organ involvement, but further and preferably larger studies are needed to identify NCD as a potential biomarker for lung and cardiac involvement in juvenile DM.

• Berntsen, Kristin Schjander; Edvardsen, Elisabeth; Hansen, Bjørge Hermann; Flatø, Berit; Sjaastad, Ivar & Sanner, Helga (2019). Cardiorespiratory fitness in long-term juvenile dermatomyositis: A controlled, cross-sectional study of active/inactive disease. Rheumatology. ISSN 1462-0324. 58(3), s. 492–501. doi: 10.1093/rheumatology/key342. Fulltekst i vitenarkiv Vis sammendrag

  Objectives. To compare cardiorespiratory fitness (CRF) expressed as maximal oxygen uptake (VO2max) between patients with long-term JDM and controls and between patients with active and inactive disease, as well as to explore exercise limiting factors and associations between CRF and disease variables. Methods. JDM patients (n=45) and age- and gender-matched controls (n=45) performed a cardiopulmonary exercise test (CPET) on a treadmill until exhaustion. Physical activity was measured by accelerometers. Disease activity, damage and muscle strength/function were assessed by validated tools. Clinically inactive disease was defined according to PRINTO criteria. Results. The mean disease duration was 20.8 (S.D. 11.9) years and 29/45 (64%) patients had inactive disease. A low VO2max was found in 27% of patients vs 4% of controls (P = 0.006). The mean VO2max and maximal ventilation (VEmax) were lower in patients with active and inactive disease compared with controls. Patients with active disease also had lower maximal voluntary ventilation (MVV) compared with controls and lower VEmax and MVV compared with those with inactive disease. Patients with inactive disease had lower physical activity levels compared with controls. VO2max correlated negatively with disease damage in patients with inactive disease and positively with muscle strength/function in patients with active disease. Conclusion. CRF was lower in JDM patients, both with active and inactive disease, compared with controls after a mean 20 years disease duration. Cardiopulmonary exercise test results suggested different limiting factors contributing to the reduced CRF according to disease activity, including deconditioning in inactive disease and reduced ventilatory capacity in active disease. Further research is needed to verify this.

• Lipsett, David Bruce; Frisk, Michael; Aronsen, Jan Magnus; Norden, Einar Sjaastad; Buonarati, Olivia R. & Cataliotti, Alessandro [Vis alle 10 forfattere av denne artikkelen] (2019). Cardiomyocyte substructure reverts to an immature phenotype during heart failure. Journal of Physiology. ISSN 0022-3751. 597(7), s. 1833–1853. doi: 10.1113/JP277273. Fulltekst i vitenarkiv Vis sammendrag

  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.

• NOMELAND, BIRGIT; Hetlevik, Siri Opsahl; Sanner, Helga; Barth, Zoltan; Schwartz, Thomas & Flatø, Berit [Vis alle 8 forfattere av denne artikkelen] (2019). Cardiac function is impaired in longstanding juvenile-onset mixed connective tissue disease - a controlled study. Journal of Rheumatology. ISSN 0315-162X. 46(7), s. 739–747. doi: 10.3899/jrheum.180526. Fulltekst i vitenarkiv Vis sammendrag

  To assess cardiac function in patients with juvenile mixed connective tissue disease (JMCTD) compared to matched controls, and to investigate possible associations between cardiac impairment and disease variables and cardiovascular risk factors.Fifty JMCTD patients (86% female) examined median 14.9 (6.6–23.0) years after disease onset were compared with 50 age- and sex-matched controls. Electrocardiogram and echocardiography [including e′ as a marker for diastolic dysfunction and long-axis strain (LAS) and left ventricular (LV) ejection fraction (EF) as markers of systolic function] were performed. LV dysfunction (LVD) was defined as low EF, low LAS, or low e′. Right ventricular function was assessed with tricuspid annular plane systolic excursion (TAPSE). Cardiovascular risk factors and disease variables were assessed.LVD was found in 16% of patients and 4% of controls (p = 0.035). EF and LAS were lower in patients compared to controls (6% lower, p &lt; 0.001, and 4% lower, p = 0.044, respectively). TAPSE was 8% lower in patients versus controls (p = 0.008). No patients had signs of pulmonary hypertension. Patients had longer corrected QT time than controls (p = 0.012). LVD was associated with higher levels of apolipoprotein B, higher disease activity measured by physician’s global assessment, longer prednisolone treatment, and more organ damage assessed with the Myositis Damage Index.Patients with JMCTD had impaired left and right ventricular function compared to matched controls after median 15 years disease duration. High disease activity and longer treatment with prednisolone were factors associated with LVD.

• Mohammadzadeh, Naiyereh; Lunde, Ida Gjervold; Andenæs, Kine; Strand, Mari Elen; Aronsen, Jan Magnus & Skrbic, Biljana [Vis alle 15 forfattere av denne artikkelen] (2019). The extracellular matrix proteoglycan lumican improves survival and counteracts cardiac dilatation and failure in mice subjected to pressure overload. Scientific Reports. 9:9206, s. 1–13. doi: 10.1038/s41598-019-45651-9. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Espe, Emil Knut Stenersen; Aronsen, Jan Magnus; Norden, Einar Sjaastad; Zhang, Lili & Sjaastad, Ivar (2019). Regional right ventricular function in rats: a novel magnetic resonance imaging method for measurement of right ventricular strain. American Journal of Physiology. Heart and Circulatory Physiology. ISSN 0363-6135. 318(1), s. 143–153. doi: 10.1152/ajpheart.00357.2019. Fulltekst i vitenarkiv Vis sammendrag

  The function of the right ventricle (RV) is linked to clinical outcome in many cardiovascular diseases, but its role in experimental heart failure remains largely unexplored due to difficulties in measuring RV function in vivo. We aimed to advance RV imaging by establishing phase-contrast MRI (PC-MRI) as a robust method for measuring RV function in rodents. A total of 46 Wistar-Hannover rats with left ventricular (LV) myocardial infarction and 10 control rats (sham) were examined 6 wk after surgery. Using a 9.4-T preclinical MRI system, we utilized PC-MRI to measure strain/strain rate in the RV free wall under isoflurane anesthesia. Cine MRI was used to measure RV volumes. LV end-diastolic pressure (LVEDP) was measured and used to identify pulmonary congestion. The infarct rats were divided into two groups: those with signs of pulmonary congestion (PC), with LVEDP ≥ 15 mmHg ( n = 26) and those without signs of pulmonary congestion (NPC), with LVEDP &lt; 15 mmHg ( n = 20). The NPC rats exhibited preserved RV strains/strain rates, whereas the PC rats exhibited reduced strains/strain rates (26–48% lower than sham). Of the strain parameters, longitudinal strain and strain rate exhibited the highest correlations to LVEDP and lung weight (rho = 0.65–0.72, P &lt; 0.001). Basal longitudinal strain was most closely associated with signs of pulmonary congestion and indexes of RV remodeling. Longitudinal RV strain had higher area under the curve than ejection fraction for detecting subtle RV dysfunction (area under the curve = 0.85 vs. 0.67). In conclusion, we show for the first time that global and regional RV myocardial strain can be measured robustly in rodents. Reduced RV strain was closely associated with indexes of pulmonary congestion and molecular markers of RV remodeling. NEW &amp; NOTEWORTHY Global and regional right ventricular myocardial strain can be measured with high reproducibility and low interobserver variability in rodents using tissue phase mapping MRI. Reduced right ventricular strain was associated with indexes of pulmonary congestion and molecular markers of right ventricular remodeling. Regional strain in the basal myocardium was considerably higher than in the apical myocardium.

• Mathiesen, Sabrina Bech; Lunde, Marianne; Aronsen, Jan Magnus; Romaine, Andreas; Kaupang, Anita & Martinsen, Marita [Vis alle 11 forfattere av denne artikkelen] (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), s. 8717–8731. doi: 10.1074/jbc.RA118.006423. Fulltekst i vitenarkiv Vis sammendrag

  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

• Mcginley, Gary George; Bendiksen, Bård Andre; Zhang, Lili; Aronsen, Jan Magnus; Norden, Einar Sjaastad & Sjaastad, Ivar [Vis alle 7 forfattere av denne artikkelen] (2019). Accelerated magnetic resonance imaging tissue phase mapping of the rat myocardium using compressed sensing with iterative soft-thresholding. PLOS ONE. 14:e0218874(7), s. 1–17. doi: 10.1371/journal.pone.0218874. Fulltekst i vitenarkiv Vis sammendrag

  Introduction Tissue Phase Mapping (TPM) MRI can accurately measure regional myocardial velocities and strain. The lengthy data acquisition, however, renders TPM prone to errors due to variations in physiological parameters, and reduces data yield and experimental throughput. The purpose of the present study is to examine the quality of functional measures (velocity and strain) obtained by highly undersampled TPM data using compressed sensing reconstruction in infarcted and non-infarcted rat hearts. Methods Three fully sampled left-ventricular short-axis TPM slices were acquired from 5 non-infarcted rat hearts and 12 infarcted rat hearts in vivo. The datasets were used to generate retrospectively (simulated) undersampled TPM datasets, with undersampling factors of 2, 4, 8 and 16. Myocardial velocities and circumferential strain were calculated from all datasets. The error introduced from undersampling was then measured and compared to the fully sampled data in order to validate the method. Finally, prospectively undersampled data were acquired and compared to the fully sampled datasets. Results Bland Altman analysis of the retrospectively undersampled and fully sampled data revealed narrow limits of agreement and little bias (global radial velocity: median bias = -0.01 cm/s, 95% limits of agreement = [-0.16, 0.20] cm/s, global circumferential strain: median bias = -0.01%strain, 95% limits of agreement = [-0.43, 0.51] %strain, all for 4x undersampled data at the mid-ventricular level). The prospectively undersampled TPM datasets successfully demonstrated the feasibility of method implementation. Conclusion Through compressed sensing reconstruction, highly undersampled TPM data can be used to accurately measure the velocity and strain of the infarcted and non-infarcted rat myocardium in vivo, thereby increasing experimental throughput and simultaneously reducing error introduced by physiological variations over time.

• Blom, Kjersti Benedicte; Bergo, Kaja Knudsen; Espe, Emil Knut Stenersen; Rosseland, Vigdis; Grøtta, Ole Jørgen & Mjøen, Geir [Vis alle 17 forfattere av denne artikkelen] (2019). Cardiovascular rEmodelling in living kidNey donorS with reduced glomerular filtration rate: rationale and design of the CENS study. Blood Pressure. ISSN 0803-7051. 29(2), s. 1–13. doi: 10.1080/08037051.2019.1684817. Fulltekst i vitenarkiv Vis sammendrag

  Purpose: Until recently, it has been believed that donating a kidney not represents any risk for development of cardiovascular disease. However, a recent Norwegian epidemiological study suggests that kidney donors have an increased long-term risk of cardiovascular mortality. The pathophysiological mechanisms linking reduced kidney function to cardiovascular disease are not known. Living kidney donors are screened for cardiovascular morbidity before unilateral nephrectomy, and are left with mildly reduced glomerular filtration rate (GFR) after donation. Therefore, they represent an unique model for investigating the pathogenesis linking reduced GFR to cardiovascular disease and cardiovascular remodelling. We present the study design of Cardiovascular rEmodelling in living kidNey donorS with reduced glomerular filtration rate (CENS), which is an investigator-initiated prospective observational study on living kidney donors. The hypothesis is that living kidney donors develop cardiovascular remodelling due to a reduction of GFR. Materials and methods: 60 living kidney donors and 60 age and sex matched healthy controls will be recruited. The controls will be evaluated to fulfil the Norwegian transplantation protocol for living kidney donors. Investigations will be performed at baseline and after 1, 3, 6 and 10 years in both groups. The investigations include cardiac magnetic resonance imaging, echocardiography, bone density scan, flow mediated dilatation, laser Doppler flowmetry, nailfold capillaroscopy, office blood pressure, 24-h ambulatory blood pressure, heart rate variability and investigation of microbiota and biomarkers for inflammation, cardiovascular risk and the calcium-phosphate metabolism. Conclusions: The present study seeks to provide new insight in the pathophysiological mechanisms linking reduced kidney function to cardiovascular disease. In addition, we aim to enlighten predictors of adverse cardiovascular outcome in living kidney donors.

• Udjus, Camilla; Fadila, Cero; Halvorsen, Bente; Behmen, Dina; Carlson, Cathrine Rein & Bendiksen, Bård Andre [Vis alle 14 forfattere av denne artikkelen] (2019). Caspase-1 induces smooth muscle cell growth in hypoxia-induced pulmonary hypertension. American Journal of Physiology - Lung cellular and Molecular Physiology. 316(6), s. L999–L1012. doi: 10.1152/ajplung.00322.2018. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Skogestad, Jonas; Aronsen, Jan Magnus; Tovsrud, Nils; Wanichawan, Pimthanya; Hougen, Karina & Stokke, Mathis Korseberg [Vis alle 10 forfattere av denne artikkelen] (2019). Coupling of the Na+/K+-ATPase to Ankyrin B controls Na+/Ca2+ exchanger activity in cardiomyocytes. Cardiovascular Research (CVR). ISSN 0008-6363. 116(1), s. 78–90. doi: 10.1093/cvr/cvz087. Fulltekst i vitenarkiv
• Skogestad, Jonas; Lines, Glenn; Louch, William Edward; Sejersted, Ole M; Sjaastad, Ivar & Aronsen, Jan Magnus (2019). Evidence for heterogeneous subsarcolemmal Na+ Levels in rat ventricular myocytes. American Journal of Physiology. Heart and Circulatory Physiology. ISSN 0363-6135. 316(5). doi: 10.1152/ajpheart.00637.2018. Fulltekst i vitenarkiv
• Marstein, Henriette; Schwartz, Thomas; Aaløkken, Trond M; Samersaw-Lund, May Brit; Flatø, Berit & Sjaastad, Ivar [Vis alle 7 forfattere av denne artikkelen] (2019). Novel associations between cytokines and pulmonary involvement in juvenile dermatomyositis - a cross-sectional study of long-term disease. Rheumatology. ISSN 1462-0324. 59(8), s. 1862–1870. doi: 10.1093/rheumatology/kez531. Fulltekst i vitenarkiv Vis sammendrag

  To examine associations between cytokines and pulmonary involvement in patients with medium- to long-term JDM. In a cross-sectional study, 58 patients examined median (range) 16.8 (6.6–27.0) years after symptom onset were stratified in inactive (JDM-inactive) and active (JDM-active) disease (updated PRINTO criteria); 56 age/sex matched controls were included. Twenty-nine cytokines (in serum) were analysed (Luminex technology/ELISA). Pulmonary function test included forced vital capacity, total lung capacity (TLC) and diffusing capacity for carbon monoxide reported as % of predicted and low forced vital capacity/TLC/diffusing capacity for carbon monoxide. In patients, the presence of clinical pulmonary damage was assessed and high resolution computed tomography scans were scored for interstitial lung disease, chest wall calcinosis and airways disease. Median age of patients was 21 (7–55) years, 59% were female and 36% inactive. In JDM-active and all patients, higher MCP-1, IP-10 and eotaxin correlated with high-resolution computed tomography findings (rs 0.34–0.61; P &lt; 0.05). MCP-1 and eotaxin correlated with pulmonary damage in JDM-active and all patients (rs 0.41–0.49; P &lt; 0.01). Higher TGF-β1 and PDGF (growth factors) were associated with lower lung volumes (forced vital capacity/TLC measures) in all patients; PDGF in JDM-active and TGF-β1 in JDM-inactive patients. IP-10 correlated with TLC% in JDM-active patients. No associations between cytokines and pulmonary function test were found in controls. In JDM, we found a novel association (not previously described in myositis) between eotaxin and pulmonary involvement; we have previously shown an association between eotaxin and cardiac dysfunction. The associations between IP-10/growth factors/MCP-1 and pulmonary involvement are novel in JDM and were mostly seen in JDM-active patients.

• Berntsen, Kristin Schjander; Raastad, Truls; Marstein, Henriette; Kirkhus, Eva Astrid; Merckoll, Else & Cumming, Kristoffer Toldnes [Vis alle 9 forfattere av denne artikkelen] (2019). Functional and Structural Adaptations of Skeletal Muscle in Long-Term Juvenile Dermatomyositis; a Controlled Cross-Sectional Study. Arthritis & Rheumatology. ISSN 2326-5191. doi: 10.1002/art.41174. Fulltekst i vitenarkiv Vis sammendrag

  Objective: To compare muscle strength and endurance of the knee extensors between patients with long‐term juvenile dermatomyositis (DM) and controls and between patients with active disease and those with inactive disease, and to explore associations between strength/endurance and 1) clinical parameters, 2) physical activity, and 3) humoral/structural adaptation in the skeletal muscle of patients. Methods: In a cross‐sectional study (44 patients and 44 age‐ and sex‐matched controls), we tested isometric muscle strength (peak torque, in Nm) and dynamic muscle endurance (total work, in Joules) of the knee extensors, physical activity (measured by accelerometer), and serum myokine levels (by enzyme‐linked immunosorbent assay). Patients were examined with validated tools (clinical muscle tests and measures of disease activity/damage and inactive disease) and using magnetic resonance imaging of the thigh muscles, which included evaluation of the quadriceps cross‐sectional area (CSA). Needle biopsy samples of the vastus lateralis muscle (obtained from 12 patients ages ≥18 years) were assessed by histochemistry. Results: After a mean ± SD disease duration of 21.8 ± 11.8 years, peak torque was lower in patients with juvenile DM compared to controls (mean difference 29 Nm, 95% confidence interval 13–46; P = 0.001). Similarly, total work of the knee extensors was lower in patients compared to controls (median 738J [interquartile range 565–1,155] versus 1,249J [interquartile range 815–1,665]; P < 0.001). Both peak torque and total work were lower in patients with active juvenile DM compared to those with inactive disease (both P < 0.019); in analyses controlled for quadriceps CSA, only total work remained lower in patients with active disease. Moreover, peak torque and total work correlated with findings from clinical muscle tests in patients with active disease (r = 0.57–0.84). Muscle biopsy results indicated that the fiber type composition was different, but capillary density was similar, between patients with active disease and those with inactive disease. Conclusion: In patients with long‐term juvenile DM, both muscle strength and endurance of the knee extensors were lower when compared to matched controls, and also lower in patients with active disease compared to those with inactive disease. Our results indicate a need for more sensitive muscle tests in this clinical setting. We hypothesize that impaired muscle endurance in patients with active juvenile DM may be influenced by structural/functional adaptations of muscle tissue independent of muscle size.

• Sokolova, Marina; Sjaastad, Ivar; Louwe, Maria Cornelia; Alfsnes, Katrine; Aronsen, Jan Magnus & Zhang, Lili [Vis alle 15 forfattere av denne artikkelen] (2019). NLRP3 inflammasome promotes myocardial remodeling during diet-induced obesity. Frontiers in Immunology. 10:1621(JULY), s. 1–13. doi: 10.3389/fimmu.2019.01621. Fulltekst i vitenarkiv Vis sammendrag

  Background: Obesity is an increasingly prevalent metabolic disorder in the modern world and is associated with structural and functional changes in the heart. The NLRP3 inflammasome is an innate immune sensor that can be activated in response to endogenous danger signals and triggers activation of interleukin (IL)-1β and IL-18. Increasing evidence points to the involvement of the NLRP3 inflammasome in obesity-induced inflammation and insulin resistance, and we hypothesized that it also could play a role in the development of obesity induced cardiac alterations. Methods and Results: WT, Nlrp3−/−, and ASC−/− (Pycard−/−) male mice were exposed to high fat diet (HFD; 60 cal% fat) or control diet for 52 weeks. Cardiac structure and function were evaluated by echocardiography and magnetic resonance imaging, respectively. Whereas, NLRP3 and ASC deficiency did not affect the cardiac hypertrophic response to obesity, it was preventive against left ventricle concentric remodeling and impairment of diastolic function. Furthermore, whereas NLRP3 and ASC deficiency attenuated systemic inflammation in HFD fed mice; long-term HFD did not induce significant cardiac fibrosis or inflammation, suggesting that the beneficial effects of NLRP3 inflammasome deficiency on myocardial remodeling at least partly reflect systemic mechanisms. Nlrp3 and ASC (Pycard) deficient mice were also protected against obesity-induced systemic metabolic dysregulation, as well as lipid accumulation and impaired insulin signaling in hepatic and cardiac tissues. Conclusions: Our data indicate that the NLRP3 inflammasome modulates cardiac concentric remodeling in obesity through effects on systemic inflammation and metabolic disturbances, with effect on insulin signaling as a potential mediator within the myocardium.

• Ottesen, Anett Hellebø; Carlson, Cathrine Rein; Eken, Olav Søvik; Sadredini, Mani; Myhre, Peder Langeland & Shen, Xin [Vis alle 24 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Kolstad, Terje; Brink, Jonas van den; MacQuaide, Niall; Lunde, Per; Frisk, Michael & Aronsen, Jan [Vis alle 12 forfattere av denne artikkelen] (2018). Ryanodine Receptor Dispersion Disrupts Ca2+-Release in Failing Cardiac Myocytes. eLIFE. 7. doi: 10.7554/eLife.39427. Fulltekst i vitenarkiv
• Danielsen, Tore Kristian; Manotheepan, Ravinea; Sadredini, Mani; Leren, Ida Skrinde; Edwards, Andrew & Vincent, Kevin P. [Vis alle 11 forfattere av denne artikkelen] (2018). Arrhythmia initiation in catecholaminergic polymorphic ventricular tachycardia type 1 depends on both heart rate and sympathetic stimulation. PLOS ONE. 13:e0207100(11), s. 1–21. doi: 10.1371/journal.pone.0207100. Fulltekst i vitenarkiv Vis sammendrag

  Aims: Catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) predisposes to ventricular tachyarrhythmias (VTs) during high heart rates due to physical or psychological stress. The essential role of catecholaminergic effects on ventricular cardiomyocytes in this situation is well documented, but the importance of heart rate per se for arrhythmia initiation in CPVT1 is largely unexplored. Methods and results: Sixteen CPVT1 patients performed a bicycle stress-test. Occurrence of VT triggers, i.e. premature ventricular complexes (PVC), depended on high heart rate, with individual thresholds. Atrial pacing above the individual PVC threshold in three patients did not induce PVCs. The underlying mechanism for the clinical observation was explored using cardiomyocytes from mice with the RyR2-R2474S (RyR2-RS) mutation, which exhibit exercise-induced VTs. While rapid pacing increased the number of Ca2+ waves in both RyR2-RS and wild-type (p<0.05), β-adrenoceptor (βAR) stimulation induced more Ca2+ waves in RyR2-RS (p<0.05). Notably, Ca2+ waves occurred despite decreased sarcoplasmic reticulum (SR) Ca2+ content in RyR2-RS (p<0.05), suggesting increased cytosolic RyR2 Ca2+ sensitivity. A computational model of mouse ventricular cardiomyocyte electrophysiology reproduced the cellular CPVT1 phenotype when RyR2 Ca2+ sensitivity was increased. Importantly, diastolic fluctuations in phosphorylation of RyR2 and SR Ca2+ content determined Ca2+ wave initiation. These factors were modulated towards increased propensity for arrhythmia initiation by increased pacing rates, but even more by βAR stimulation. Conclusion: In CPVT1, VT propensity depends on individual heart rate thresholds for PVCs. Through converging data from clinical exercise stress-testing, cellular studies and computational modelling, we confirm the heart rate-independent pro-arrhythmic effects of βAR stimulation in CPVT1, but also identify an independent and synergistic contribution from effects of high heart rate.

• Melleby, Arne Olav; Romaine, Andreas; Aronsen, Jan Magnus; Veras, Ioanni; Zhang, Lili & Sjaastad, Ivar [Vis alle 8 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Barth, Zoltan; NOMELAND, BIRGIT; Flatø, Berit; Koller, Akos; Sjaastad, Ivar & Sanner, Helga (2018). Assessment of Microvascular Abnormalities by Nailfold Capillaroscopy in Juvenile Dermatomyositis After Medium- to Long-Term Followup. Arthritis care & research. ISSN 2151-464X. 70(5), s. 768–776. doi: 10.1002/acr.23338. Fulltekst i vitenarkiv
• Kolstad, Terje R Selnes; Brink, Jonas van Den; Macquaide, Niall; Lunde, Per Kristian; Frisk, Michael & Aronsen, Jan Magnus [Vis alle 13 forfattere av denne artikkelen] (2018). Ryanodine receptor dispersion disrupts Ca2+ release in failing cardiac myocytes. eLIFE. 7. doi: 10.7554/eLife.39427. Fulltekst i vitenarkiv Vis sammendrag

  Reduced cardiac contractility during heart failure (HF) is linked to impaired Ca2+ release from Ryanodine Receptors (RyRs). We investigated whether this deficit can be traced to nanoscale RyR reorganization. Using super-resolution imaging, we observed dispersion of RyR clusters in cardiomyocytes from post-infarction HF rats, resulting in more numerous, smaller clusters. Functional groupings of RyR clusters which produce Ca2+ sparks (Ca2+ release units, CRUs) also became less solid. An increased fraction of small CRUs in HF was linked to augmented ‘silent’ Ca2+ leak, not visible as sparks. Larger multi-cluster CRUs common in HF also exhibited low fidelity spark generation. When successfully triggered, sparks in failing cells displayed slow kinetics as Ca2+ spread across dispersed CRUs. During the action potential, these slow sparks protracted and desynchronized the overall Ca2+ transient. Thus, nanoscale RyR reorganization during HF augments Ca2+ leak and slows Ca2+ release kinetics, leading to weakened contraction in this disease.

• Andenæs, Kine; Lunde, Ida Gjervold; Mohammadzadeh, Naiyereh; Dahl, Christen Peder; Aronsen, Jan Magnus & Strand, Mari Elen [Vis alle 11 forfattere av denne artikkelen] (2018). The extracellular matrix proteoglycan fibromodulin is upregulated in clinical and experimental heart failure and affects cardiac remodeling. PLOS ONE. 13(7), s. 1–20. doi: 10.1371/journal.pone.0201422. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Aronsen, Jan Magnus; Espe, Emil Knut Stenersen; Young-Halvorsen, Kristine Skårdal; Hasic, Almira; Zhang, Lili & Sjaastad, Ivar (2017). Noninvasive stratification of postinfarction rats based on the degree of cardiac dysfunction using magnetic resonance imaging and echocardiography. American Journal of Physiology. Heart and Circulatory Physiology. ISSN 0363-6135. 312(5), s. H932–H942. doi: 10.1152/ajpheart.00668.2016. Fulltekst i vitenarkiv
• Romaine, Andreas; Sørensen, Ida Wiig; Zeltz, Cedric; Lu, Ning; Erusappan, Pugazendhi Murugan & Melleby, Arne Olav [Vis alle 15 forfattere av denne artikkelen] (2017). Overexpression of integrin α11 induces cardiac fibrosis in mice. Acta Physiologica Scandinavica. ISSN 0001-6772. 222:e13025(2), s. 1–17. doi: 10.1111/apha.12932. Fulltekst i vitenarkiv
• Ottesen, Anett Hellebø; Carlson, Cathrine Rein; Louch, William Edward; Dahl, Mai Britt; Sandbu, Ragnhild Askeland & Johansen, Rune Forstrøm [Vis alle 15 forfattere av denne artikkelen] (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. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Espe, Emil Knut Stenersen; Aronsen, Jan Magnus; Eriksen, Morten; Sejersted, Ole M; Zhang, Lili & Sjaastad, Ivar (2017). Regional dysfunction after myocardial infarction in rats. Circulation Cardiovascular Imaging. ISSN 1941-9651. 10(9), s. e005997–e005997. doi: 10.1161/CIRCIMAGING.116.005997. Fulltekst i vitenarkiv
• Espe, Emil Knut Stenersen; Young-Halvorsen, Kristine Skårdal; Aronsen, Jan Magnus; Zhang, Lili & Sjaastad, Ivar (2017). A semiautomatic method for rapid segmentation of velocity-encoded myocardial magnetic resonance imaging data. Magnetic Resonance in Medicine. ISSN 0740-3194. 78(3), s. 1199–1207. doi: 10.1002/mrm.26486. Fulltekst i vitenarkiv
• Thienpont, Bernard; Aronsen, Jan Magnus; Robinson, Emma Louise; Okkenhaug, Hanneke; Loche, Elena & Ferrini, Arianna [Vis alle 14 forfattere av denne artikkelen] (2017). The H3K9 dimethyltransferases EHMT1/2 protect against pathological cardiac hypertrophy. Journal of Clinical Investigation. ISSN 0021-9738. 127(1), s. 335–348. doi: 10.1172/JCI88353. Fulltekst i vitenarkiv
• Meier, Silja; Andressen, Kjetil Wessel; Aronsen, Jan Magnus; Sjaastad, Ivar; Hougen, Karina & Skomedal, Tor [Vis alle 10 forfattere av denne artikkelen] (2017). PDE3 inhibition by C-type natriuretic peptide-induced cGMP enhances cAMP-mediated signaling in both non-failing and failing hearts. European Journal of Pharmacology. ISSN 0014-2999. 812, s. 174–183. doi: 10.1016/j.ejphar.2017.07.014. Fulltekst i vitenarkiv
• Dhondup, Yangchen; Sjaastad, Ivar; Sandanger, Øystein; Aronsen, Jan Magnus; Ahmed, Muhammad Shakil & Attramadal, Håvard [Vis alle 14 forfattere av denne artikkelen] (2017). Toll-like receptor 9 promotes survival in SERCA2a KO heart failure mice. Mediators of Inflammation. ISSN 0962-9351. 2017:9450439, s. 1–11. doi: 10.1155/2017/9450439. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Gattoni, Sara; Røe, Åsmund Treu; Aronsen, Jan Magnus; Sjaastad, Ivar; Louch, William Edward & Smith, Nicolas P. [Vis alle 7 forfattere av denne artikkelen] (2017). Compensatory and decompensatory alterations in cardiomyocyte Ca2+ dynamics in hearts with diastolic dysfunction following aortic banding. Journal of Physiology. ISSN 0022-3751. 595(12), s. 3867–3889. doi: 10.1113/JP273879. Fulltekst i vitenarkiv
• MANNER, INGJERD W; Waldum-Grevbo, Bård Endre; NOMELAND, BIRGIT; Bækken, Morten; Øktedalen, Olav & Os, Ingrid [Vis alle 8 forfattere av denne artikkelen] (2017). Immune markers, diurnal blood pressure profile and cardiac function in virologically suppressed HIV-infected patients. Blood Pressure. ISSN 0803-7051. 26(6), s. 332–340. doi: 10.1080/08037051.2017.1346459. Fulltekst i vitenarkiv
• Røe, Åsmund Treu; Sjaastad, Ivar & Louch, William Edward (2017). Hjertesvikt med bevart ejeksjonsfraksjon [Heart failure with preserved ejection fraction]. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 137(18), s. 1–8. doi: 10.4045/tidsskr.16.1068. Fulltekst i vitenarkiv

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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. Fulltekst i vitenarkiv
• Shen, Xin; Kolstad, Terje; Brink, Jonas van den; Frisk, Michael; Hou, Yufeng & Norden, Einar [Vis alle 9 forfattere av denne artikkelen] (2020). 3D Dstorm Imaging Reveals Camkii-Dependent Dispersal of Ryanodine Receptor Clusters in Failing Rat Cardiomyocytes. Fulltekst i vitenarkiv
• Rønning, Sissel Beate; Carlson, Cathrine Rein; Aronsen, Jan Magnus; Høst, Vibeke; Pisconti, Addolorate & Lunde, Marianne [Vis alle 11 forfattere av denne artikkelen] (2019). Extracellular Matrix remodeling and multiple signaling pathways are regulated by syndecan-4 during myogenesis. Fulltekst i vitenarkiv

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