Mathis Korseberg Stokke

• Degezelle, Mahault Mathilde; Chaami, Chahida; Lewis, Christopher T.A.; Zhang, Chengxin; Hessel, Anthony L. & Rainer, Peter P. [Show all 10 contributors for this article] (2026). Destabilization of cardiac myosin acetylation and sequestration with type 2 diabetes mellitus. Cardiovascular Diabetology. 25(1). doi: 10.1186/s12933-025-03052-5. Full text in Research Archive Show summary

  Background Type 2 diabetes mellitus (T2DM) predisposes patients to adverse cardiac remodeling even before the development of cardiomyopathic symptoms. The mechanisms for such early perturbations remain elusive. Given that myosin is the most abundant and energy‑demanding cardiac protein, we tested whether its regulation is impaired even in non‑failing human diabetic hearts. Methods Left ventricular strips were individually isolated from organ donors with and without T2DM. These strips were then subjected to a combination of acetyl‑proteomics, X-ray diffraction, in-silico simulations and Mant-ATP chase experiments. Results Strikingly, we identified nine cardiac myosin (MYH7) lysine residues with significantly altered acetylation levels in T2DM ventricles, many of which were predicted to destabilize the protein coiled‑coil regions. Consistently, X‑ray diffraction revealed increased lattice spacing and a shift towards myosin ON‑state in T2DM tissue. However, and surprisingly, Mant‑ATP chase analyses indicated no bioenergetic consequences at the myosin level. Conclusions Human T2DM myocardium exhibits early, site‑specific myosin acetylations that destabilize myosin structural OFF‑state. This myosin ‘preload’ remodeling occurs at no energetic cost and may constitute a potential early marker of latent myocardial vulnerability in T2DM.

• Nossen, Magnus Berger & Stokke, Mathis Korseberg (2026). Bidirectional ventricular tachycardia caused by occlusion myocardial infarction—a case report. European Heart Journal - Case Reports. 10(2). doi: 10.1093/ehjcr/ytag055. Full text in Research Archive
• Bugge, Cecilie; Five, Christian K.; Ahmed, Tariq Nazir; Skar, Petter M.J.; Castrini, Anna Isotta & Ribe, Margareth [Show all 11 contributors for this article] (2026). Premature ventricular complexes increase with heart rate in patients with mitral valve prolapse. International journal of cardiology: Heart and Vasculature (IJCHA). 64. doi: 10.1016/j.ijcha.2026.101925. Full text in Research Archive
• Espe, Emil Knut Stenersen; Louch, William Edward; Smith, Godfrey L & Stokke, Mathis Korseberg (2026). The border zone after myocardial infarction: clarification of terminology and proposal for a new definition. Cardiovascular Research (CVR). ISSN 0008-6363. 122(3), p. 297–300. doi: 10.1093/cvr/cvag023. Full text in Research Archive
• Borch, Pernille; Aagaard-Nilsen, Stine; Stokke, Mathis Korseberg & Lyseggen, Erik (2026). Effects of atrial fibrillation on cerebral perfusion and cognitive function: A systematic review. International journal of cardiology: Heart and Vasculature (IJCHA). 63. doi: 10.1016/j.ijcha.2026.101891. Full text in Research Archive
• Aagaard-Nilsen, Stine; Dejgaard, Lars; Anfinsen, Ole-Gunnar; Lyseggen, Erik; Holm, Torbjørn & Håland, Trine Synnøve Fink [Show all 11 contributors for this article] (2025). The utility of 24-h electrocardiogram recordings for the prediction of a sufficient number of premature ventricular complexes and mapping strategy during catheter ablation. Frontiers in Cardiovascular Medicine. 12. doi: 10.3389/fcvm.2025.1558130. Full text in Research Archive Show summary

  Background and aims: An insufficient number of premature ventricular complexes (PVCs) during catheter ablation (CA) may prohibit adequate mapping of the site of origin. Parameters to predict this situation have not been established. Our objective was to quantify the association between preprocedural information and the probability of a sufficient number of PVCs for adequate mapping and successful CA. Methods: Clinical characteristics and results from examinations and procedural data were collected retrospectively from health journals for patients admitted for CA of PVCs from 2011 to 2020. Results: In total, 46 of 332 patients (14%) had an insufficient number of PVCs to enable adequate electroanatomical mapping. Patients with a sufficient number of PVCs had nominally more PVCs in the 24-h electrocardiogram (ECG), with a strong statistical trend [16,007 (6,509–26,205) vs. 8,332 (3,066–20,974), p = 0.055]. The receiver operator curve for a sufficient number of PVCs in 24-h ECGs had an area under the curve of 0.610 (95% CI 0.498–0.722, p = 0.055). The best predictive values were found at >10,000 PVCs per 24-h, with a positive predictive value of 67% and a negative predictive value of 57%. Patients for whom activation mapping was used as the sole mapping method had more PVCs in the 24-h ECG than did patients for whom pace mapping was added or used as an alternative [19,769 (10,564–30,526) vs. 15,237 (6,000–25,033), p = 0.022]. Neither acute outcome nor procedure time depended on the mapping strategy. Conclusion: The number of PVCs in a 24-h ECG was moderately associated with the presence of a sufficient number of PVCs to perform electroanatomical mapping during CA. The presence of more PVCs in the preprocedural 24-h ECG was associated with the use of activation mapping as the sole mapping strategy.

• Kindberg, Kristine Lovise Mørk; Nordeng, Jostein; Langseth, Miriam Sjåstad; Schandiz, Hossein Khalkhali; Roald, Borghild & Solheim, Svein [Show all 9 contributors for this article] (2025). IL-6R Signaling Is Associated with PAD4 and Neutrophil Extracellular Trap Formation in Patients with STEMI. International Journal of Molecular Sciences. ISSN 1661-6596. 26(11), p. 1–11. doi: 10.3390/ijms26115348. Full text in Research Archive Show summary

  Inflammation contributes to myocardial injury in ST-elevation myocardial infarction (STEMI). Interleukin-6 receptor (IL-6R) inhibition has been shown to mitigate myocardial injury and reduce levels of the prothrombotic and inflammatory mediator, neutrophil extracellular traps (NETs). The enzyme peptidylarginine deiminase 4 (PAD4) is central in NET formation. We hypothesized that PAD4 links IL-6R activation and NET formation. Methods: We conducted thrombus aspiration and peripheral blood sampling in 33 STEMI patients. In thrombi and leukocytes, we quantified the mRNA of IL-6, IL-6R, and PAD4. In peripheral blood, the protein levels of IL-6, IL-6R, PAD4, dsDNA, H3Cit, MPO-DNA, and troponin T were quantified. Results: In thrombi and circulating leukocytes, PAD4 mRNA was associated with IL-6R mRNA (thrombi: β = 0.34, 95% CI [0.16–0.53], p = 0.001, circulating leukocytes: β = 0.92, 95% CI [0.07–1.77], p = 0.036). There were no correlations between PAD4 and IL-6 in thrombi and leukocytes. The protein levels of IL-6R were associated with the NET marker H3Cit (rs = 0.40, p = 0.02). In thrombi, PAD4 mRNA was associated with high levels of troponin T (β = 1.15 95% CI [0.27–2.04], p = 0.013). Conclusion: We demonstrate an association between PAD4, IL-6R, and troponin release in STEMI patients. Our findings indicate a PAD4-mediated connection between IL-6R and NET formation and highlight PAD4 as a potential treatment target for mitigating inflammation and myocardial injury in STEMI.

• Huse, Camilla; Murphy, Sarah Louise Mikalsen; Yang, Kuan; Balzer, Nora Reka; Stokke, Mathis Korseberg & Anstensrud, Anne Kristine [Show all 27 contributors for this article] (2025). The effects of interleukin-6-receptor inhibition on monocytes in STEMI: a substudy of the ASSAIL-MI trial. EBioMedicine. 121, p. 105960–105960. doi: 10.1016/j.ebiom.2025.105960. Full text in Research Archive
• Feng, Miao; Wang, Qian; Kindberg, Kristine Lovise Mørk; Romaine, Andreas; Stokke, Mathis Korseberg & Ochala, Julien (2025). Cardiac Chamber‐Specific Regulation of Myosin Biochemical Super‐Relaxation and Auto‐Inhibition. The FASEB Journal. ISSN 0892-6638. 39(22). doi: 10.1096/fj.202503395r. Full text in Research Archive Show summary

  ABSTRACT Mammal atrial and ventricular cardiomyocytes have distinct contractile and energetic properties. Among the molecular processes thought to be involved in such differences is myosin isoform diversity. Our understanding of the related biophysical consequences remains incomplete. Hence, here, utilizing swine isolated cardiac strips and a combination of Mant‐ATP (2′‐(or‐3′)‐ O ‐( N ‐Methylanthraniloyl) Adenosine 5′‐Triphosphate) chase experiments and all‐atomistic molecular dynamics simulations, we aimed to define whether and how chamber‐specific myosin isoform specificity influences super‐relaxation, critical for heart energetics and contractility. Interestingly, we observed that the proportion of ATP‐conserving super‐relaxed myosin molecules is greater in porcine ventricles than in atria. We also predicted, through simulations, that such findings were directly related to residues belonging to chamber‐specific regulatory light chains differently controlling myosin auto‐inhibition. Altogether, we believe that our data should be taken into account when screening for potential myosin‐centered compounds for atrial or ventricular myopathies.

• Berger, Simon Girmai; Berntsen, Kristin Schjander; Risum, Kristine; Marstein, Henriette Schermacher; Sjaastad, Ivar & Stokke, Mathis Korseberg [Show all 7 contributors for this article] (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. Full text in Research Archive Show summary

  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.

• Kindberg, Kristine Lovise Mørk; Broch, Kaspar; Andersen, Geir Øystein; Anstensrud, Anne Kristine; Åkra, Sissel & Woxholt, Sindre [Show all 23 contributors for this article] (2024). Neutrophil Extracellular Traps in ST-Segment Elevation Myocardial Infarction: Reduced by Tocilizumab and Associated With Infarct Size. JACC: Advances. 3(9). doi: 10.1016/j.jacadv.2024.101193. Full text in Research Archive Show summary

  Background - Interleukin-6-receptor inhibition with tocilizumab improves myocardial salvage in patients with ST-segment elevation myocardial infarction (STEMI). Reduced levels of neutrophil extracellular traps (NETs), which consist of nuclear material studded with proteins released upon neutrophil activation, might contribute to this effect.<p> <p>Objectives - The purpose of this study was to evaluate the effect of tocilizumab on NETs and investigate the association between NETs and myocardial injury in patients with STEMI.<p> <p>Methods - In the ASSAIL-MI study, 199 patients with STEMI were randomized to tocilizumab or placebo during percutaneous coronary intervention. In this substudy, we analyzed blood levels of the NET markers double-stranded deoxyribonucleic acid (dsDNA), myeloperoxidase-DNA, and citrullinated histone 3 (H3Cit) at admission and after 24 hours and 3 to 7 days. In a subgroup of patients, we assessed regulation of transcripts related to the formation of NETs. We also investigated associations between NET markers and the myocardial salvage index (MSI).<p> <p>Results - All NET markers were lower in the tocilizumab group than in the placebo group at 3 to 7 days (all P < 0.04). Several NET-related pathways were downregulated in the tocilizumab group. The beneficial effect of tocilizumab on the MSI seemed to be partly dependent on reduction of NETs (structural equation modeling: 0.05, P = 0.001 [dsDNA] and 0.02, P = 0.055 [H3Cit]). Patients with NETs in the 3 lowest quartiles had higher MSI than patients in quartile 4 (β = 10.9 [95% CI: 4.0-15.0] [dsDNA] and β = 8.9 [95% CI: 2.0-15.9] [H3Cit], both P = 0.01).<p> <p>Conclusions - NETs were reduced by tocilizumab and associated with myocardial injury. The effect of tocilizumab on MSI might be mediated through reduced NETs. (ASSessing the Effect of Anti-IL-6 Treatment in Myocardial Infarction: The ASSAIL-MI Trial [ASSAIL-MI]

• Stokke, Mathis Korseberg; Louch, William Edward & Smith, Godfrey L (2024). Electrophysiological tolerance: a new concept for understanding the electrical stability of the heart. Europace. ISSN 1099-5129. 26(11), p. 1–6. doi: 10.1093/europace/euae282. Full text in Research Archive Show summary

  The co-ordinated electrical activity of ∼2 billion cardiac cells ensures stability of the heartbeat. Indeed, the remarkably low incidence (<1%) of ventricular arrhythmias in the healthy heart is only possible when the electrical event across this syncytium is closely controlled. In contrast, the diseased myocardium is associated with increased electrophysiological heterogeneity, unstable rhythm, and increased incidence of lethal arrhythmias. But what is the link between cellular and tissue level heterogeneity? Recent research has shown the existence of considerable cellular heterogeneity even in the healthy heart, suggesting that cell-to-cell variability in electrical (e.g. action potential duration) and mechanical performance (e.g. twitch amplitude) is a normal property. This observation has been previously unappreciated because the aggregated function in the form of QT-interval and cardiac output varies <1% on a beat-to-beat basis. This article describes the underlying cellular variability that is tolerated—and perhaps needed—by different regions of the heart for normal function and indicates why this variability is not apparent in function at the chamber and organ level. Thus, in contrast to the current dominant view, this article postulates that heterogeneity is normal and potentially endows various functional benefits. This new view of how the component parts of the heart come together to function also suggests novel mechanisms for cardiac pathologies, namely that dysfunction may emerge from changes in the extent and/or nature of heterogeneity. Once understood, restoring normal forms of heterogeneity could be a novel approach to treatment.

• Aagaard-Nilsen, Stine; Dejgaard, Lars; Anfinsen, Ole-Gunnar; Lyseggen, Erik; Holm, Torbjørn & Håland, Trine Synnøve Fink [Show all 11 contributors for this article] (2023). Utility of the Inferior Axis and Left Bundle Branch Block Pattern for Categorization of Patients With Premature Ventricular Complexes Before Catheter Ablation. American Journal of Cardiology. ISSN 0002-9149. 201, p. 148–149. doi: 10.1016/j.amjcard.2023.06.013. Full text in Research Archive
• Andreassen, Kristine; Rixon, Chloe Louise; Haugsten, Marie Hansen; Hauge-Iversen, Ida Marie; Zhang, Lili & Sadredini, Mani [Show all 13 contributors for this article] (2023). Beneficial effects of exercise initiated before development of hypertrophic cardiomyopathy in genotype-positive mice. American Journal of Physiology. Heart and Circulatory Physiology. ISSN 0363-6135. 324(6), p. H881–H892. doi: 10.1152/ajpheart.00701.2022. Full text in Research Archive
• Berger, Simon Girmai; NOMELAND, BIRGIT; Reiseter, Silje; Schwartz, Thomas; Andersson, Anna Helena & Hetlevik, Siri Opsahl [Show all 13 contributors for this article] (2023). Cardiac dysfunction in mixed connective tissue disease: a nationwide observational study. Rheumatology International. ISSN 0172-8172. p. 1055–1065. doi: 10.1007/s00296-023-05308-3. Full text in Research Archive Show summary

  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.

• Haugsten, Marie Hansen; Sadredini, Mani; Hasic, Almira; Eriksen, Morten & Stokke, Mathis Korseberg (2023). Myocardial oxidative stress is increased in early reperfusion, but systemic antioxidative therapy does not prevent ischemia-reperfusion arrhythmias in pigs. Frontiers in Cardiovascular Medicine. 10. doi: 10.3389/fcvm.2023.1223496. Full text in Research Archive Show summary

  Background Arrhythmias in the early phase of reperfusion after myocardial infarction (MI) are common, and can lead to hemodynamic instability or even cardiac arrest. Reactive oxygen species (ROS) are thought to play a key role in the underlying mechanisms, but evidence from large animal models is scarce, and effects of systemic antioxidative treatment remain contentious. Methods MI was induced in 7 male and 7 female pigs (Norwegian landrace, 35–40 kg) by clamping of the left anterior descending artery (LAD) during open thorax surgery. Ischemia was maintained for 90 min, before observation for 1 h after reperfusion. Pigs were randomized 1:1 in an operator-blinded fashion to receive either i.v. N-acetylcysteine (NAC) from 70 min of ischemia and onwards, or 0.9% NaCl as a control. Blood samples and tissue biopsies were collected at baseline, 60 min of ischemia, and 5 and 60 min of reperfusion. ECG and invasive blood pressure were monitored throughout. Results The protocol was completed in 11 pigs. Oxidative stress, as indicated by immunoblotting for Malondialdehyde in myocardial biopsies, was increased at 5 min of reperfusion compared to baseline, but not at 60 min of reperfusion, and not reduced with NAC. We found no significant differences in circulating biomarkers of myocardial necrosis, nor in the incidence of idioventricular rhythm (IVR), non-sustained ventricular tachycardia (NSVT), ventricular tachycardia (VT) or ventricular fibrillation (VF) between NAC-treated and control pigs during reperfusion. Conclusion Myocardial oxidation was increased early after reperfusion in a porcine model of MI, but systemic antioxidative treatment did not protect against reperfusion arrhythmias.

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

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

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

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

• Andreassen, Kristine; Dejgaard, Lars; Lie, Øyvind Haugen; Håland, Trine Synnøve Fink; Lunde, Ida Gjervold & Edvardsen, Thor [Show all 8 contributors for this article] (2022). Exercise training during childhood and adolescence is associated with favorable diastolic function in hypertrophic cardiomyopathy. International Journal of Cardiology. ISSN 0167-5273. 364, p. 65–71. doi: 10.1016/j.ijcard.2022.06.042. Full text in Research Archive Show summary

  Background Diastolic dysfunction is an important part of the clinical phenotype in hypertrophic cardiomyopathy (HCM). While exercise training is known to improve left ventricular (LV) diastolic function in normal hearts, the effects of exercise training during childhood and adolescence in carriers of HCM-associated genetic variants are unknown. Methods In a cross-sectional and retrospective study, we combined clinical and echocardiographic data with history of exercise training from childhood to time of examination in 187 participants with HCM or an HCM-causative genotype. Multiple linear regression was used to identify correlations between exercise training performed prior to 20 years of age and LV diastolic parameters from echocardiography. Results Exercise training during childhood and adolescence was correlated with a favorable e’, E/e’, E deceleration time, and end-diastolic volume (EDV), when adjusting for the effects of age at examination, and presence of left ventricular hypertrophy (LVH). This correlation was evident both in patients with a HCM phenotype (HCM LVH+), and in individuals with an HCM-causative genotype without LV hypertrophy (G+ LVH-). None of the diastolic parameters correlated unfavorably with increasing exercise exposure. Conclusion More exercise training during childhood and adolescence was associated with favorable LV diastolic function in both HCM LVH+ and G+ LVH- groups, regardless of presence of hypertrophy at the time of examination. These results indicate that exercise training initiated during childhood and adolescence has positive effects on cardiac function later in life for individuals with HCM or an HCM-causative genotype.

• 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, p. 49–61. doi: 10.1016/j.yjmcc.2022.12.002. Full text in Research Archive Show summary

  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.

• 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. Full text in Research Archive
• Edwards, Andrew; Mørk, Halvor; Stokke, Mathis; Lipsett, David; Sjaastad, Ivar & Richard, Sylvain [Show all 8 contributors for this article] (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. Full text in Research Archive
• 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. p. 1–10. doi: 10.1080/14017431.2021.1901979. Full text in Research Archive Show summary

  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.

• Edwards, Andrew G.; Mørk, Halvor Kjeang; Stokke, Mathis Korseberg; Lipsett, David Bruce; Sjaastad, Ivar & Richard, Sylvain [Show all 8 contributors for this article] (2021). Sarcoplasmic Reticulum Calcium Release Is Required for Arrhythmogenesis in the Mouse. Frontiers in Physiology. 12, p. 1–13. doi: 10.3389/fphys.2021.744730. Full text in Research Archive Show summary

  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.

• 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. Full text in Research Archive Show summary

  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 [Show all 7 contributors for this article] (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), p. H446–H460. doi: 10.1152/ajpheart.00011.2021. Full text in Research Archive
• Danielsen, Tore Kristian; Sadredini, Mani; Manotheepan, Ravinea; Aronsen, Jan Magnus; Frisk, Michael & Haugsten, Marie Hansen [Show all 13 contributors for this article] (2021). Exercise training stabilizes RyR2-dependent Ca2+ release in post-infarction heart failure. Frontiers in Cardiovascular Medicine. 7. doi: 10.3389/fcvm.2020.623922. Full text in Research Archive Show summary

  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.

• Tazmini, Kiarash; Fraz, Mai; Nymo, Ståle Haugset; Stokke, Mathis Korseberg; Louch, William Edward & Øie, Erik (2020). Potassium infusion increases the likelihood of conversion of recent-onset atrial fibrillation- A single-blinded, randomized clinical trial. American Heart Journal. ISSN 0002-8703. 221, p. 114–124. doi: 10.1016/j.ahj.2019.12.014. Full text in Research Archive Show summary

  Background The optimal antiarrhythmic management of recent-onset atrial fibrillation (ROAF) or atrial flutter is controversial and there is a considerable variability in clinical treatment strategies. It is not known if potassium infusion has the potential to convert ROAF or atrial flutter to sinus rhythm (SR). Therefore, we aimed to investigate if patients with ROAF or atrial flutter and plasma-potassium levels ≤4.0 mmol/L have increased probability to convert to SR if the plasma-potassium level is increased towards the upper reference range (4.1-5.0 mmol/L). Methods In a placebo-controlled, single-blinded trial, patients with ROAF or atrial flutter and plasma-potassium ≤4.0 mmol/L presenting between April 2013 and November 2017 were randomized to receive potassium chloride (KCl) infusion (n = 60) or placebo (n = 53). Patients in the KCl group received infusions at one of three different rates: 9.4 mmol/h (n = 11), 12 mmol/h (n = 19), or 15 mmol/h (n = 30). Results There was no statistical difference in the number of conversions to SR between the KCl group and placebo [logrank test, P = .29; hazard ratio (HR) 1.20 (CI 0.72-1.98)]. However, KCl-infused patients who achieved an above-median hourly increase in plasma-potassium (>0.047 mmol/h) exhibited a significantly higher conversion rate compared with placebo [logrank P = .002; HR 2.40 (CI 1.36-4.21)] and KCl patients with below-median change in plasma-potassium [logrank P < .001; HR 4.41 (CI 2.07-9.40)]. Due to pain at the infusion site, the infusion was prematurely terminated in 10 patients (17%). Conclusions Although increasing plasma-potassium levels did not significantly augment conversion of ROAF or atrial flutter to SR in patients with potassium levels in the lower-normal range, our results indicate that this treatment may be effective when a rapid increase in potassium concentration is tolerated and achieved.

• Lieve, Krystien V.V.; Dusi, Veronica; Werf, Christian Van Der; Bos, J. Martijn; Lane, Conor M. & Stokke, Mathis Korseberg [Show all 34 contributors for this article] (2020). Heart Rate Recovery after Exercise Is Associated with Arrhythmic Events in Patients with Catecholaminergic Polymorphic Ventricular Tachycardia. Circulation: Arrhythmia and Electrophysiology. ISSN 1941-3149. 13(3). doi: 10.1161/CIRCEP.119.007471. Full text in Research Archive Show summary

  Background: Risk stratification in catecholaminergic polymorphic ventricular tachycardia remains ill defined. Heart rate recovery (HRR) immediately after exercise is regulated by autonomic reflexes, particularly vagal tone, and may be associated with symptoms and ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. Our objective was to evaluate whether HRR after maximal exercise on the exercise stress test (EST) is associated with symptoms and ventricular arrhythmias. Methods: In this retrospective observational study, we included patients ≤65 years of age with an EST without antiarrhythmic drugs who attained at least 80% of their age- and sex-predicted maximal HR. HRR in the recovery phase was calculated as the difference in heart rate (HR) at maximal exercise and at 1 minute in the recovery phase (ΔHRR1′). Results: We included 187 patients (median age, 36 years; 68 [36%] symptomatic before diagnosis). Pre-EST HR and maximal HR were equal among symptomatic and asymptomatic patients. Patients who were symptomatic before diagnosis had a greater ΔHRR1′ after maximal exercise (43 [interquartile range, 25–58] versus 25 [interquartile range, 19–34] beats/min; P<0.001). Corrected for age, sex, and relatedness, patients in the upper tertile for ΔHRR1′ had an odds ratio of 3.4 (95% CI, 1.6–7.4) of being symptomatic before diagnosis (P<0.001). In addition, ΔHRR1′ was higher in patients with complex ventricular arrhythmias at EST off antiarrhythmic drugs (33 [interquartile range, 22–48] versus 27 [interquartile range, 20–36] beats/min; P=0.01). After diagnosis, patients with a ΔHRR1′ in the upper tertile of its distribution had significantly more arrhythmic events as compared with patients in the other tertiles (P=0.045). Conclusions: Catecholaminergic polymorphic ventricular tachycardia patients with a larger HRR following exercise are more likely to be symptomatic and have complex ventricular arrhythmias during the first EST off antiarrhythmic drug.

• Stokke, Mathis Korseberg; Castrini, Anna Isotta; Aneq, Meriam Åström; Jensen, Henrik K.; Madsen, Trine & Hansen, Jim [Show all 12 contributors for this article] (2020). Absence of ECG Task Force Criteria does not rule out structural changes in genotype positive ARVC patients. International Journal of Cardiology. ISSN 0167-5273. doi: 10.1016/j.ijcard.2020.05.095. Full text in Research Archive Show summary

  Aims In Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), electrophysiological pathology has been claimed to precede morphological and functional pathology. Accordingly, an ECG without ARVC markers should be rare in ARVC patients with pathology identified by cardiac imaging. We quantified the prevalence of ARVC patients with evidence of structural disease, yet without ECG Task Force Criteria (TFC). Methods and results We included 182 probands and family members with ARVC-associated mutations (40 ± 17 years, 50% women, 73% PKP2 mutations) from the Nordic ARVC Registry in a cross-sectional analysis. For echocardiography and cardiac MR (CMR), we differentiated between “abnormalities” and TFC. “Abnormalities” were defined as RV functional or structural measures outside TFC reference values, without combinations required to fulfill TFC. ECG TFC were used as defined, as these are not composite parameters. We found that only 4% of patients with ARVC fulfilled echocardiographic TFC without any ECG TFC. However, importantly, 38% of patients had imaging abnormalities without any ECG TFC. These results were supported by CMR data from a subset of 51 patients: 16% fulfilled CMR TFC without fulfilling ECG TFC, while 24% had CMR abnormalities without any ECG TFC. In a multivariate analysis, echocardiographic TFC were associated with arrhythmic events. Conclusion More than one third of ARVC genotype positive patients had subtle imaging abnormalities without fulfilling ECG TFC. Although most patients will have both imaging and ECG abnormalities, structural abnormalities in ARVC genotype positive patients cannot be ruled out by the absence of ECG TFC.

• Castrini, Anna Isotta; Lie, Øyvind Haugen; Leren, Ida Skrinde; Estensen, Mette-Elise; Stokke, Mathis Korseberg & Klæboe, Lars Gunnar [Show all 8 contributors for this article] (2019). Number of pregnancies and subsequent phenotype in a cross-sectional cohort of women with arrhythmogenic cardiomyopathy. European Heart Journal-Cardiovascular Imaging. ISSN 2047-2404. 20(2), p. 192–198. doi: 10.1093/ehjci/jey061. Full text in Research Archive Show summary

  Aims We aimed to assess the relation between number of pregnancies and cardiac structure, function, and arrhythmic events in women with arrhythmogenic cardiomyopathy (AC). Methods and results We included female AC patients in a cross-sectional study. Number of pregnancies and pregnancy related symptoms were recorded. Ventricular arrhythmias were defined as aborted cardiac arrest, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator therapy. Right and left ventricular dimensions and function, including strain analyses, were assessed by echocardiography and magnetic resonance imaging. We created a new AC severity score to grade the severity of AC disease. We included 77 women (age 47 ± 16, 43 probands and 34 AC mutation positive female relatives), 19 ± 14 years after last pregnancy. Median number of pregnancies was 2 (0–4); 19 had no previous pregnancies, 16 had 1 pregnancy, 30 had 2, and 12 had ≥3 pregnancies. Presence of a definite AC diagnosis (P = 0.36), severity of AC disease (P = 0.53), and arrhythmic events (P = 0.25) did not differ between groups of pregnancies. Number of pregnancies was related to increased right ventricular outflow tract diameter in single variable analyses [odds ratio (OR) 1.76, 95% confidence interval (CI) 1.08–2.87; P = 0.02], but not when adjusted for body surface area and age (OR 1.56, 95% CI 0.91–2.66; P = 0.11). The number of pregnancies was not associated with any other measures of cardiac structure and function. Conclusion Higher number of pregnancies did not seem to relate to a worse phenotype in women with AC.

• Conte, Giulio; Belhassen, Bernard; Lambiase, Pier; Ciconte, Giuseppe; Asmundis, Carlo de & Arbelo, Elena [Show all 51 contributors for this article] (2019). Out-of-hospital cardiac arrest due to idiopathic ventricular fibrillation in patients with normal electrocardiograms: Results from a multicentre long-term registry. Europace. ISSN 1099-5129. 21(11), p. 1670–1677. doi: 10.1093/europace/euz221. Full text in Research Archive
• Skogestad, Jonas; Aronsen, Jan Magnus; Tovsrud, Nils; Wanichawan, Pimthanya; Hougen, Karina & Stokke, Mathis Korseberg [Show all 10 contributors for this article] (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), p. 78–90. doi: 10.1093/cvr/cvz087. Full text in Research Archive
• Ottesen, Anett Hellebø; Carlson, Cathrine Rein; Eken, Olav Søvik; Sadredini, Mani; Myhre, Peder Langeland & Shen, Xin [Show all 24 contributors for this article] (2019). Secretoneurin Is an Endogenous Calcium/Calmodulin-Dependent Protein Kinase II Inhibitor That Attenuates Ca2+-Dependent Arrhythmia. Circulation: Arrhythmia and Electrophysiology. ISSN 1941-3149. 12(4). doi: 10.1161/CIRCEP.118.007045. Full text in Research Archive Show summary

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

• Danielsen, Tore Kristian; Manotheepan, Ravinea; Sadredini, Mani; Leren, Ida Skrinde; Edwards, Andrew & Vincent, Kevin P. [Show all 11 contributors for this article] (2018). Arrhythmia initiation in catecholaminergic polymorphic ventricular tachycardia type 1 depends on both heart rate and sympathetic stimulation. PLOS ONE. 13:e0207100(11), p. 1–21. doi: 10.1371/journal.pone.0207100. Full text in Research Archive Show summary

  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.

• Lie, Øyvind Haugen; Dejgaard, Lars; Saberniak, Jørg; Rootwelt, Christine; Stokke, Mathis Korseberg & Edvardsen, Thor [Show all 7 contributors for this article] (2018). Harmful effects of exercise intensity and exercise duration in patients with arrhythmogenic cardiomyopathy. JACC: Clinical Electrophysiology. ISSN 2405-500X. 4(6), p. 744–753. doi: 10.1016/j.jacep.2018.01.010. Full text in Research Archive Show summary

  Objectives The goal of this study was to explore the association between exercise duration versus exercise intensity and adverse outcome in patients with arrhythmogenic cardiomyopathy (AC). Background Vigorous exercise aggravates and accelerates AC, but there are no data assessing the harmful effects of exercise intensity and duration in these patients. Methods Exercise habits at time of diagnosis were recorded by standardized interviews in consecutive AC patients. Exercise >6 metabolic equivalents was defined as high intensity, and exercise duration was categorized as long if above median. Life-threatening ventricular arrhythmia (VA) was defined as aborted cardiac arrest, documented sustained ventricular tachycardia, ventricular fibrillation, or appropriate implantable cardioverter-defibrillator therapy. Results We included 173 AC patients (53% probands; 44% female; 41 ± 16 years of age). Median weekly exercise duration was 2.5 h (interquartile range: 2.0 to 5.5 h), and 91 patients (52%) reported high-intensity exercise. VA had occurred in 83 patients (48%) and was more prevalent in patients with high-intensity exercise than low-intensity exercise (74% vs. 20%, p < 0.001), and more prevalent in long-duration than short-duration exercise (65% vs. 31%, p < 0.001). High-intensity exercise was a strong and independent marker of VA, even when adjusted for the interaction with long-duration exercise (odds ratio: 3.8; 95% confidence interval: 1.3 to 11.0, p < 0.001), whereas long-duration exercise was not. Conclusions High-intensity exercise was a strong and independent marker of life-threatening VA in AC patients, independent of exercise duration. AC patients could be advised to restrict their exercise intensity.

• Lie, Øyvind Haugen; Rootwelt, Christine; Dejgaard, Lars; Leren, Ida Skrinde; Stokke, Mathis Korseberg & Edvardsen, Thor [Show all 7 contributors for this article] (2018). Prediction of Life-Threatening Ventricular Arrhythmia in Patients With Arrhythmogenic Cardiomyopathy: A Primary Prevention Cohort Study. JACC Cardiovascular Imaging. ISSN 1936-878X. 11(10), p. 1377–1386. doi: 10.1016/j.jcmg.2018.05.017. Full text in Research Archive Show summary

  Objectives: This study aimed to identify clinical, electrocardiographic (ECG) and cardiac imaging predictors of first-time life-threatening ventricular arrhythmia in patients with arrhythmogenic cardiomyopathy (AC). Background: The role of clinical, electrocardiographic, and cardiac imaging parameters in risk stratification of patients without ventricular arrhythmia is unclear. Methods: We followed consecutive AC probands and mutation-positive family members with no documented ventricular arrhythmia from time of diagnosis to first event. We assessed clinical, electrocardiographic, and cardiac imaging parameters according to Task Force Criteria of 2010 in addition to left ventricular (LV) and strain parameters. High-intensity exercise was defined as >6 metabolic equivalents. Results: We included 117 patients (29% probands, 50% female, age 40 ± 17 years). During 4.2 (interquartile range [IQR]: 2.4 to 7.4) years of follow-up, 18 (15%) patients experienced life-threatening ventricular arrhythmias. The 1-, 2-, and 5-year incidence was 6%, 9%, and 22%, respectively. History of high-intensity exercise, T-wave inversions ≥V3, and greater LV mechanical dispersion were the strongest risk markers (adjusted hazard ratio [HR]: 4.7 [95% confidence interval (CI): 1.2 to 17.5]; p = 0.02, 4.7 [95% CI: 1.6 to 13.9]; p = 0.005), and 1.4 [95% CI: 1.2 to 1.6] by 10-ms increments; p < 0.001, respectively). Median arrhythmia-free survival in patients with all risk factors was 1.2 (95% CI: 0.4 to 1.9) years, compared with an estimated 12.0 (95% CI: 11.5 to 12.5) years in patients without any risk factors. Conclusions: History of high-intensity exercise, electrocardiographic T-wave inversions ≥V3, and greater LV mechanical dispersion were strong predictors of life-threatening ventricular arrhythmia. Patients without any of these risk factors had minimal risk, whereas ≥2 risk factors increased the risk dramatically. This may help to make decisions on primary preventive implantable cardioverter defibrillator (ICD) therapy.

• Dejgaard, Lars; Skjølsvik, Eystein Theodor Ek; Lie, Øyvind Haugen; Ribe, Margareth; Stokke, Mathis Korseberg & Hegbom, Finn [Show all 13 contributors for this article] (2018). The Mitral Annulus Disjunction Arrhythmic Syndrome. Journal of the American College of Cardiology. ISSN 0735-1097. 72(14), p. 1600–1609. doi: 10.1016/j.jacc.2018.07.070. Full text in Research Archive Show summary

  Background: Mitral annulus disjunction (MAD) is an abnormal atrial displacement of the mitral valve leaflet hinge point. MAD has been associated with mitral valve prolapse (MVP) and sudden cardiac death. Objectives: The purpose of this study was to describe the clinical presentation, MAD morphology, association with MVP, and ventricular arrhythmias in patients with MAD. Methods: The authors clinically examined patients with MAD. By echocardiography, the authors assessed the presence of MVP and measured MAD distance in parasternal long axis. Using cardiac magnetic resonance (CMR), the authors assessed circumferential MAD in the annular plane, longitudinal MAD distance, and myocardial fibrosis. Aborted cardiac arrest and sustained ventricular tachycardia were defined as severe arrhythmic events. Results: The authors included 116 patients with MAD (age 49 ± 15 years; 60% female). Palpitations were the most common symptom (71%). Severe arrhythmic events occurred in 14 (12%) patients. Longitudinal MAD distance measured by CMR was 3.0 mm (interquartile range [IQR]: 0 to 7.0 mm) and circumferential MAD was 150° (IQR: 90° to 210°). Patients with severe arrhythmic events were younger (age 37 ± 13 years vs. 51 ± 14 years; p = 0.001), had lower ejection fraction (51 ± 5% vs. 57 ± 7%; p = 0.002) and had more frequently papillary muscle fibrosis (4 [36%] vs. 6 [9%]; p = 0.03). MVP was evident in 90 (78%) patients and was not associated with ventricular arrhythmia. Conclusions: Ventricular arrhythmias were frequent in patients with MAD. A total of 26 (22%) patients with MAD did not have MVP, and MVP was not associated with arrhythmic events, indicating MAD itself as an arrhythmogenic entity. MAD was detected around a large part of the mitral annulus circumference and was interspersed with normal tissue.

• Lie, Øyvind Haugen; Saberniak, Jørg; Dejgaard, Lars A.; Stokke, Mathis Korseberg; Hegbom, Finn & Anfinsen, Ole-Gunnar [Show all 8 contributors for this article] (2017). Lower than expected burden of premature ventricular contractions impairs myocardial function. ESC Heart Failure. 4(4), p. 585–594. doi: 10.1002/ehf2.12180. Full text in Research Archive
• Logantha, Sunil Jit R.; Stokke, Mathis Korseberg; Atkinson, Andrew J.; Kharche, Sanjay R.; Parveen, Sajida & Saeed, Yawer [Show all 9 contributors for this article] (2016). Ca2+ -clock-dependent pacemaking in the sinus node is impaired in mice with a cardiac specific reduction in SERCA2 abundance. Frontiers in Physiology. 7:197. doi: 10.3389/fphys.2016.00197. Full text in Research Archive
• Sadredini, Mani; Danielsen, Tore Kristian; Aronsen, Jan Magnus; Manotheepan, Ravinea; Hougen, Karina & Sjaastad, Ivar [Show all 7 contributors for this article] (2016). Beta-adrenoceptor stimulation reveals Ca2+ waves and sarcoplasmic reticulum Ca2+ depletion in left ventricular cardiomyocytes from post-infarction rats with and without heart failure. PLOS ONE. 11(4). doi: 10.1371/journal.pone.0153887. Full text in Research Archive Show summary

  Abnormal cellular Ca2+ handling contributes to both contractile dysfunction and arrhythmias in heart failure. Reduced Ca2+ transient amplitude due to decreased sarcoplasmic reticulum Ca2+ content is a common finding in heart failure models. However, heart failure models also show increased propensity for diastolic Ca2+ release events which occur when sarcoplasmic reticulum Ca2+ content exceeds a certain threshold level. Such Ca2+ release events can initiate arrhythmias. In this study we aimed to investigate if both of these aspects of altered Ca2+ homeostasis could be found in left ventricular cardiomyocytes from rats with different states of cardiac function six weeks after myocardial infarction when compared to sham-operated controls. Video edge-detection, whole-cell Ca2+ imaging and confocal linescan imaging were used to investigate cardiomyocyte contractile properties, Ca2+ transients and Ca2+ waves. In baseline conditions, i.e. without beta-adrenoceptor stimulation, cardiomyocytes from rats with large myocardial infarction, but without heart failure, did not differ from sham-operated animals in any of these aspects of cellular function. However, when exposed to beta-adrenoceptor stimulation, cardiomyocytes from both non-failing and failing rat hearts showed decreased sarcoplasmic reticulum Ca2+ content, decreased Ca2+ transient amplitude, and increased frequency of Ca2+ waves. These results are in line with a decreased threshold for diastolic Ca2+ release established by other studies. In the present study, factors that might contribute to a lower threshold for diastolic Ca2+ release were increased THR286 phosphorylation of Ca2+/calmodulin-dependent protein kinase II and increased protein phosphatase 1 abundance. In conclusion, this study demonstrates both decreased sarcoplasmic reticulum Ca2+ content and increased propensity for diastolic Ca2+ release events in ventricular cardiomyocytes from rats with heart failure after myocardial infarction, and that these phenomena are also found in rats with large myocardial infarctions without heart failure development. Importantly, beta-adrenoceptor stimulation is necessary to reveal these perturbations in Ca2+ handling after a myocardial infarction.

• Manotheepan, Ravinea; Danielsen, Tore Kristian; Sadredini, Mani; Anderson, Mark E.; Carlson, Cathrine Rein & Lehnart, Stefan [Show all 8 contributors for this article] (2016). Exercise training prevents ventricular tachycardia in CPVT1 due to reduced CaMKII-dependent arrhythmogenic Ca2+ release. Cardiovascular Research (CVR). ISSN 0008-6363. 111(3), p. 295–306. doi: 10.1093/cvr/cvw095. Full text in Research Archive
• Stokke, Mathis Korseberg (2015). Ventrikulære ekstrasystoler - årsak, risiko og behandling. Hjerteforum. ISSN 0802-1465. 28, p. 11–19. Full text in Research Archive
• Aronsen, Jan Magnus; Skogestad, Jonas; Lewalle, Alexandre; Louch, William Edward; Hougen, Karina & Stokke, Mathis Korseberg [Show all 11 contributors for this article] (2015). Hypokalaemia induces Ca2+ overload and Ca2+ waves in ventricular myocytes by reducing Na+ ,K+-ATPase α2 activity. Journal of Physiology. ISSN 0022-3751. 593(6), p. 1509–1521. doi: 10.1113/jphysiol.2014.279893. Full text in Research Archive
• Manotheepan, Ravinea; Saberniak, Jørg; Danielsen, Tore Kristian; Edvardsen, Thor; Sjaastad, Ivar & Haugaa, Kristina [Show all 7 contributors for this article] (2014). Effects of individualized exercise training in patients with catecholaminergic polymorphic ventricular tachycardia Type 1. American Journal of Cardiology. ISSN 0002-9149. 113(11), p. 1829–1833. doi: 10.1016/j.amjcard.2014.03.012. Full text in Research Archive
• Stokke, Mathis Korseberg; Tovsrud, Nils; Louch, William Edward; Øyehaug, Leiv; Hougen, Karina & Sejersted, Ole M [Show all 8 contributors for this article] (2013). I-CaL inhibition prevents arrhythmogenic Ca2+ waves caused by abnormal Ca2+ sensitivity of RyR or SR Ca2+ accumulation. Cardiovascular Research (CVR). ISSN 0008-6363. 98(2), p. 315–325. doi: 10.1093/cvr/cvt037. Full text in Research Archive
• Stokke, Mathis Korseberg; Rivelsrud, Frederic; Sjaastad, Ivar; Sejersted, Ole M & Swift, Fredrik (2012). Fra global til lokal - ny forståelse av den elektromekaniske koblingen i hjertet. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 132(12-13), p. 1457–1460. doi: 10.4045/tidsskr.11.1353. Full text in Research Archive
• Louch, William Edward; Stokke, Mathis Korseberg; Sjaastad, Ivar; Christensen, Geir Arve & Sejersted, Ole M (2012). No rest for the weary: Diastolic calcium homeostasis in the normal and failing myocardium. Physiology. ISSN 1548-9213. 27, p. 308–323. doi: 10.1152/physiol.00021.2012. Full text in Research Archive

View all works in NVA

• Halnes, Geir; Javaid, Anam; Solvang, Michael; Nichele, Stefano; Riegler, Michael & Singstad, Bjørn-Jostein [Show all 82 contributors for this article] (2025). Proceedings of NORA’s annual conference 2025. Nordic Machine Intelligence (NMI). 5(3), p. 1–14. doi: 10.5617/nmi.12551. Full text in Research Archive
• Stokke, Mathis Korseberg & Bébarová, Markéta (2024). Lessons on the non-linear path of medical progress and biological complexity from mouse models of the Brugada syndrome. Europace. ISSN 1099-5129. 26(6). doi: 10.1093/europace/euae152. Full text in Research Archive
• Espe, Emil Knut Stenersen & Stokke, Mathis Korseberg (2024). Editorial for “MRI Assessment of Myocardial Deformation for Risk Stratification of Major Arrhythmic Events in Patients with Non-Ischemic Cardiomyopathy Eligible for Primary Prevention Implantable Cardioverter Defibrillators”. Journal of Magnetic Resonance Imaging. ISSN 1053-1807. doi: 10.1002/jmri.29300. Full text in Research Archive
• Mjølstad, Ole Christian; Radtke, Maria Anita; Brodtkorb, Eylert; Edvardsen, Frode; Rødseth, Brede Wenche & Aamo, Trond Oskar [Show all 9 contributors for this article] (2023). Recurrent malignant ventricular arrhythmias and paresthesia—a mystery revealed as aconitine poisoning: a case report. Journal of Medical Case Reports. doi: 10.1186/s13256-023-04304-2. Full text in Research Archive Show summary

  Background: We report a case of a clinical challenge lasting for 12 months, with severe and unresolved clinical features involving several medical disciplines. Case presentation: A 53-year-old Caucasian male, who had been previously healthy apart from a moderate renal impairment, was hospitalized 12 times during a 1-year period for a recurrent complex of neurological, cardiovascular, and gastrointestinal symptoms and signs, without any apparent etiology. On two occasions, he suffered a cardiac arrest and was successfully resuscitated. Following the first cardiac arrest, a cardiac defibrillator was inserted. During the 12th admission to our hospital, aconitine poisoning was suspected after a comprehensive multidisciplinary evaluation and confirmed by serum and urine analyses. Later, aconitine was also detected in a hair segment, indicating exposure within the symptomatic period. After the diagnosis was made, no further episodes occurred. His cardiac defibrillator was later removed, and he returned to work. A former diagnosis of epilepsy was also abandoned. Criminal intent was suspected, and his wife was sentenced to 11 years in prison for attempted murder. To make standardized assessments of the probability for aconitine poisoning as the cause of the eleven prior admissions, an “aconitine score” was established. The score is based on neurological, cardiovascular, gastrointestinal, and other clinical features reported in the literature. We also make a case for the use of hair analysis to confirm suspected poisoning cases evaluated after the resolution of clinical features. Conclusion: This report illustrates the medical challenge raised by cases of covert poisoning. In patients presenting with symptoms and signs from several organ systems without apparent cause, poisoning should always be suspected. To solve such cases, insight into the effects of specific toxic agents is needed. We present an “aconitine score” that may be useful in cases of suspected aconitine poisoning.

• Stokke, Mathis Korseberg & Gjesdal, Knut Tjøl (2022). EKG-SPALTEN. Arytmi under arbeidsbelastning. Hjerteforum. ISSN 0802-1465. 35(4), p. 10–12. Full text in Research Archive
• Stokke, Mathis K.; Castrini, Anna I.; Aneq, Meriam Åström; Jensen, Henrik K.; Madsen, Trine & Hansen, Jim [Show all 12 contributors for this article] (2021). Reply to: TFC ECG in arrhythmogenic cardiomyopathy: Inadequate mixture of criteria? International Journal of Cardiology. ISSN 0167-5273. 323, p. 203–203. doi: 10.1016/j.ijcard.2020.08.050. Full text in Research Archive
• Haugaa, Kristina & Stokke, Mathis Korseberg (2019). Cardiac electrical and mechanical alterations - united in the long QT syndrome. International Journal of Cardiology. ISSN 0167-5273. 274, p. 190–191. doi: 10.1016/j.ijcard.2018.09.048. Full text in Research Archive
• Sadredini, Mani; Manotheepan, Ravinea; Danielsen, Tore Kristian; Lehnart, Stefan; Sjaastad, Ivar & Stokke, Mathis Korseberg (2016). Epac2 inhibition reduces arrhythmogenic Ca2+ wave frequently in cardiomyocytes from mice With catecholaminergic polymorphic ventricular tachcardia type 1. Full text in Research Archive
• Danielsen, Tore Kristian; Manotheepan, Ravinea; Sadredini, Mani; Leren, I.S.; Edwards, Andrew & Vincent, K. [Show all 11 contributors for this article] (2016). Mechanisms underlying the frequency-dependence of triggered arrhythmias in catecholaminergic polymorphic ventricular tachycardia type 1. Full text in Research Archive
• Manotheepan, Ravinea; Danielsen, Tore Kristian; Saberniak, Jorg; Sadredini, Mani; Anderson, Mark e. & Carlson, Cathrine Rein [Show all 11 contributors for this article] (2016). Exercise training as anti-arrhythmic therapy in cathecholaminergic polymorphic ventricular tachycardia type 1. Full text in Research Archive
• Manotheepan, Ravinea; Danielsen, Tore Kristian; Sadredini, Mani Nikoo; Anderson, Mark e.; Carlson, Cathrine Rein & Lehnart, Stefan [Show all 8 contributors for this article] (2015). Exercise training reduced CaMKII-dependent arrhythmogenic Ca2+ release and prevents ventricular tachycardia in CPVT 1. Full text in Research Archive
• Sadredini, Mani Nikoo; Danielsen, Tore Kristian; Aronsen, Jan Magnus; Manotheepan, Ravinea; Hougen, Karina & Sjaastad, Ivar [Show all 7 contributors for this article] (2015). Beta-adrenoreceptor stimulation reveals Ca2+ overload paradox in left ventricular cardiomyocytes from post-infarction rats with and without heart failure. Full text in Research Archive
• Danielsen, Tore Kristian; Manotheepan, Ravinea; Sadredini, Mani Nikoo; Gaur, Namit; Leren, IS & Edwards, Andrew [Show all 11 contributors for this article] (2015). Mechanisms for the frequency-dependence of triggered activity in catecholaminergic polymorphic ventricular tachycardia type 1. Full text in Research Archive
• Kolstad, Terje R Selnes; Stokke, Mathis Korseberg; Stang, Espen; Brorson, Sverre Henning; Louch, William Edward & Sejersted, Ole M (2015). Serca located in the junctional SR shapes calcium release in cardiac myocytes. Biophysical Journal. ISSN 0006-3495. 108, p. 503a–503a. Full text in Research Archive
• Sadredini, Mani Nikoo; Danielsen, Tore Kristian; Aronsen, Jan Magnus; Manotheepan, Ravinea; Hougen, Karina & Sjaastad, Ivar [Show all 7 contributors for this article] (2015). Beta-adrenoceptor stimulation reveals Ca2+ overload paradox in left ventricular cardiomyocytes from post-infarction rats with and without heart failure. Full text in Research Archive
• Danielsen, Tore Kristian; Manotheepan, Ravinea; Sadredini, Mani Nikoo; Aronsen, Jan Magnus; Hougen, Karina & Sejersted, Ole M [Show all 8 contributors for this article] (2014). The effect of exercise training on Ca2+ wave probability after myocardial infarction varies with cardiac function at onset of training. Full text in Research Archive
• Manotheepan, Ravinea; Danielsen, Tore Kristian; Sadredini, Mani Nikoo; Lehnart, Stefan; Sjaastad, Ivar & Stokke, Mathis Korseberg (2014). Exercise training reduces CaMKII-dependent phosphorylation of the cardiac ryanodine receptor and arrhythmogenic SR Ca2+ leak in mice with mutant cardiac ryanodine receptor 2. Full text in Research Archive
• Kolstad, Terje R Selnes; Stokke, Mathis Korseberg; Stang, Espen; Brorson, Sverre Henning; Christensen, Geir Arve & Louch, William Edward [Show all 7 contributors for this article] (2014). SERCA localized near the dyad regulates calcium release in cardiac myocytes. Full text in Research Archive
• Kolstad, Terje R Selnes; Stokke, Mathis Korseberg; Stang, Espen; Brorson, Sverre Henning; Louch, William Edward & Sejersted, Ole M (2014). SERCA localized near the dyad regulates calcium release in cardiac myocytes. Full text in Research Archive
• Manotheepan, Ravinea; Danielsen, Tore Kristian; Sadredini, Mani Nikoo; Anderson, Mark E.; Lehnart, Stephan & Sjaastad, Ivar [Show all 7 contributors for this article] (2014). Exercise training reduces CaMKII-dependent phosphorylation of RyR2 and arrhythmogenic SR Ca2+ release in mince with CPVT. Full text in Research Archive
• Kolstad, Terje R Selnes; Stokke, Mathis Korseberg; Stang, Espen; Brorson, Sverre Henning; Louch, William Edward & Sejersted, Ole M (2014). SERCA localized near the dyad regulates calcium release in cardiac myoctyes. Full text in Research Archive
• Danielsen, Tore Kristian; Manotheepan, Ravinea; Sadredini, Mani Nikoo; Aronsen, Jan Magnus; Hougen, Karina & Sejersted, Ole M [Show all 8 contributors for this article] (2013). The effect of exercise training on ca2+ wave probability after myocardial infarction depends on cardiac function at onset of training. Heart Rhythm. ISSN 1547-5271. 10, p. 1749–1749. Full text in Research Archive
• Sadredini, Mani Nikoo; Danielsen, Tore Kristian; Aronsen, Jan Magnus; Manotheepan, Ravinea; Sjaastad, Ivar & Stokke, Mathis Korseberg (2013). Ca2+ wave probability is differently affected in cardiomyocytes from rats with failing and non-failing cardiac function after myocardial infarction. Full text in Research Archive
• Manotheepan, Ravinea; Danielsen, Tore Kristian; Sadredini, Mani Nikoo; Lehnart, Stephan; Sjaastad, Ivar & Stokke, Mathis Korseberg (2013). Exercise training reduces Ca2+ -calmodulin-dependent protein kinase type II dependent phosphorylation of the cardiac ryanodine receptor and Ca2+ leak from the sarcoplasmic reticulum in mice with mutant cardiac ryanodine receptor. Full text in Research Archive
• Manotheepan, Ravinea; Danielsen, Tore Kristian; Sadredini, Mani Nikoo; Lehnart, Stephen; Sjaastad, Ivar & Stokke, Mathis Korseberg (2013). Exercise training reduces Ca2+-calmodulin-dependent protein kinase type II dependent phosphorylation of the cardiac ryanodine receptor and Ca2+ leak from the sarcoplasmic reticulum in mice with mutant cardiac ryanodine receptor 2. Circulation. ISSN 0009-7322. 128. Full text in Research Archive
• Manotheepan, Ravinea; Danielsen, Tore Kristian; Sadredini, Mani Nikoo; Lehnart, Stephan; Sjaastad, Ivar & Stokke, Mathis Korseberg (2013). Can exercise training prevent arrhythmogenic Ca2+ release in RyR2-R2474S mice? Full text in Research Archive
• Danielsen, Tore Kristian; Manotheepan, Ravinea; Sadredini, Mani Nikoo; Aronsen, Jan Magnus; Hougen, Karina & Sejersted, Ole M [Show all 8 contributors for this article] (2013). The effect of exercise training on Ca2+ wave probability after myocardial infarction depends on cardiac function at onset of training. Full text in Research Archive
• Skogestad, Jonas; Aronsen, Jan Magnus; Hougen, Karina; Stokke, Mathis Korseberg; Swift, Fredrik & Sejersted, Ole M [Show all 7 contributors for this article] (2013). Extracellular potassium regulates Ca2+ homeostasis through interaction between NCX and NKA. Full text in Research Archive
• Danielsen, Tore Kristian; Manotheepan, Ravinea; Sadredini, Mani Nikoo; Aronsen, Jan Magnus; Hougen, Karina & Sejersted, Ole M [Show all 8 contributors for this article] (2013). The effect of exercise training on Ca2+ wave probability after myocardial infarction depends on cardiac function at onset of training. Full text in Research Archive
• Sadredini, Mani Nikoo; Danielsen, Tore Kristian; Aronsen, Jan Magnus; Manotheepan, Ravinea; Sjaastad, Ivar & Stokke, Mathis Korseberg (2013). Ca2+ wave probability is differently affected in cardiomyocytes from rats with failing and non-failing cardiac function after myocardial infarction. Full text in Research Archive
• Swift, Fredrik; Tovsrud, Nils; Aronsen, Jan Magnus; Louch, William Edward; Stokke, Mathis Korseberg & Enger, Ulla Helene [Show all 8 contributors for this article] (2012). Crosstalk between NKA and NCX in a shared microdomain. Full text in Research Archive
• Manotheepan, Ravinea; Saberniak, Jorg; Danielsen, Tore Kristian; Edvardsen, Thor; Sjaastad, Ivar & Haugaa, Kristina [Show all 7 contributors for this article] (2012). Beneficial effects on aerobic capacity and threshold heart rate for arrhythmias from exercise training in patients with catecholaminergic polymorphic ventricular tachycardia. Circulation. ISSN 0009-7322. 126, p. A13277–A13277. Full text in Research Archive
• Sadredini, Mani Nikoo; Danielsen, Tore Kristian; Aronsen, Jan Magnus; Sjaastad, Ivar & Stokke, Mathis Korseberg (2012). Ca2+ wave probability in rats with varying levels of cardiac contractile dysfunction after myocardial infarction. Full text in Research Archive
• Sadredini, Mani Nikoo; Danielsen, Tore Kristian; Aronsen, Jan Magnus; Sjaastad, Ivar & Stokke, Mathis Korseberg (2012). Ca2+ wave probability in rats with varying levels of cardiac contractile dysfunction after myocardial infarction. Full text in Research Archive
• Swift, Fredrik; Aronsen, Jan Magnus; Stokke, Mathis Korseberg; Hougen, Karina; Egger, Marcel & Roderick, Llewelyn [Show all 8 contributors for this article] (2012). IP3 receptors in heart failure: arrhythmogenic troublemakers or SR calcium security valves? Biophysical Journal. ISSN 0006-3495. 102(3), p. 101a–101a. Full text in Research Archive
• Skogestad, Jonas; Aronsen, Jan Magnus; Hougen, Karina; Stokke, Mathis Korseberg; Swift, Fredrik & Sejersted, Ole M [Show all 7 contributors for this article] (2012). Extracellular potassium regulates Ca2+ homeostasis through interaction between NCX and NKA. Full text in Research Archive
• Loose, Kristian; Sadredini, Mani Nikoo; Sejersted, Ole M; Stokke, Mathis Korseberg & Louch, William Edward (2012). Ca2+ wave velocity in cardiomyocytes is regulated by ryanodine receptor Ca2+ sensitivity and SR Ca2+ content. Full text in Research Archive
• Loose, Kristian; Sadredini, Mani Nikoo; Sejersted, Ole M; Stokke, Mathis Korseberg & Louch, William Edward (2012). Ca2+ wave velocity in cardiomyocytes is regulated by ryanodine receptor Ca2+ sensitivity and SR 2+ content. Biophysical Journal. ISSN 0006-3495. 102(3), p. 99a–100a. Full text in Research Archive
• Danielsen, Tore Kristian; Manotheepan, Ravinea; Sadredini, Mani Nikoo; Aronsen, Jan Magnus; Sejersted, Ole M & Sjaastad, Ivar [Show all 7 contributors for this article] (2012). Short-term protocols are sufficient to induce exercise effects in rodents. Full text in Research Archive
• Manotheepan, Ravinea; Saberniak, Jorg; Danielsen, Tore Kristian; Edvardsen, Thor; Sjaastad, Ivar & Haugaa, Kristina [Show all 7 contributors for this article] (2012). Beneficial effects on aerobic capacity and threshold heart rate for arrhythmias from exercise training in patients with catecholaminergic polymorphic ventricular tachycardia. Full text in Research Archive
• Skogestad, Jonas; Aronsen, Jan Magnus; Hougen, Karina; Stokke, Mathis Korseberg; Swift, Fredrik & Sejersted, Ole M [Show all 7 contributors for this article] (2012). Extracellular potassium regulates Ca2+ homeostasis through interaction between NCX and NKA. Full text in Research Archive
• Sadredini, Mani Nikoo; Danielsen, Tore Kristian; Aronsen, Jan Magnus; Sjaastad, Ivar & Stokke, Mathis Korseberg (2012). Ca2+ wave probability in rats with varying levels of cardiac contractile dysfunction after myocardial infarction. Full text in Research Archive
• Louch, William Edward; Li, Liren; Swift, Fredrik; Stokke, Mathis Korseberg; Niederer, Steven A. & Sossalla, Samuel [Show all 11 contributors for this article] (2011). Causes and consequences of cardiomyocyte Na+ loading following SERCA2 knockout. Full text in Research Archive
• Øyehaug, Leiv; Jølle, Guro five; Stokke, Mathis Korseberg; Sejersted, Ole M; Sjaastad, Ivar & Louch, William Edward (2011). Structural remodelling and decreased SERCA function desynchronize Ca2+ release in failing cardiomyocytes. Full text in Research Archive
• Øyehaug, Leiv; Jølle, Guro five; Stokke, Mathis Korseberg; Sejersted, Ole M; Sjaastad, Ivar & Louch, William Edward (2011). Structural remodelling and decreased SERCA function desynchronize Ca2+ release in failing cardiomyocytes. Full text in Research Archive
• Tovsrud, Nils; Stokke, Mathis Korseberg; Sjaastad, Ivar; Sejersted, Ole M & Swift, Fredrik (2011). Stress-induced arrhythmias caused by reduction of ankyrin B. Full text in Research Archive
• Stokke, Mathis Korseberg; Tovsrud, Nils; Swift, Fredrik; Louch, William Edward; Sejersted, Ole M & Sjaastad, Ivar (2011). L-type Ca2+ current inhibition prevents arrhythmogenic SR Ca2+ release by reducing SR Ca2+ content. Full text in Research Archive
• Swift, Fredrik; Aronsen, Jan Magnus; Stokke, Mathis Korseberg; Hougen, Karina & Sejersted, Ole M (2011). IP3 receptors in heart failure: Arrhythmogenic troublemakers or SR Ca2+ security valves? Full text in Research Archive
• Loose, Kristian; Sadredini, Mani N; Sejersted, Ole M; Stokke, Mathis Korseberg & Louch, William Edward (2011). Ca2+ wave velocity in cardiomyocytes is regulated by ryanodine receptor Ca2+ sensitivity and SR Ca2+ content. Full text in Research Archive
• Loose, Kristian; Sadredini, Mani N; Sejersted, Ole M; Stokke, Mathis Korseberg & Louch, William Edward (2011). Ryanodine receptor sensitivity determines Ca2+ wave velocity in cardiomyocytes. Full text in Research Archive
• Øyehaug, Leiv; Jølle, Guro Five; Stokke, Mathis Korseberg; Sejersted, Ole M; Sjaastad, Ivar & Louch, William Edward (2011). Structural remodelling of failing cardiomyocytes and impairment of SERCA function - consequences for dyssynchrony of Ca2+ release. Full text in Research Archive
• Stokke, Mathis Korseberg; Sjaastad, Ivar & Sejersted, Ole M (2011). SERCA2-RyR2 interplay at the heart of Ca²⁺ wave development : experimental studies on mechanisms underlying triggered arrhythmias. Faculty of Medicine, University of Oslo. Full text in Research Archive

View all works in NVA