Emil Knut Stenersen Espe

• 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
• 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), s. 297–300. doi: 10.1093/cvr/cvag023. 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.

• 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.

• 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.

• 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.

• 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.

• 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.

• Frisk, Michael; Norseng, Per Andreas; Espe, Emil Knut Stenersen & Louch, William Edward (2022). Tubulator: an automated approach to analysis of t-tubule and dyadic organization in cardiomyocytes. Philosophical Transactions of the Royal Society of London. Biological Sciences. ISSN 0962-8436. 377(1864). doi: 10.1098/rstb.2021.0468. Fulltekst i vitenarkiv Vis sammendrag

  During cardiac disease, t-tubules and dyads are remodelled and disrupted within cardiomyocytes, thereby reducing cardiac performance. Given the pathological implications of such dyadic remodelling, robust and versatile tools for characterizing these sub-cellular structures are needed. While analysis programs for continuous and regular structures such as rodent ventricular t-tubules are available, at least in two dimensions, these approaches are less appropriate for assessment of more irregular structures, such as dyadic proteins and non-rodent t-tubules. Here, we demonstrate versatile, easy-to-use software that performs such analyses. This software, called Tubulator, enables automated analysis of t-tubules and dyadic proteins alike, in both tissue sections and isolated myocytes. The program measures densities of subcellular structures and proteins in individual cells, quantifies their distribution into transversely and longitudinally oriented elements, and supports detailed co-localization analyses. Importantly, Tubulator provides tools for three-dimensional assessment and rendering of image stacks, extending examinations from the single plane to the whole-myocyte level. To provide insight into the consequences of dyadic organization for synchrony of Ca2+ handling, Tubulator also creates ‘distance maps', by calculating the distance from all cytosolic positions to the nearest t-tubule and/or dyad. In conclusion, this freely accessible program provides detailed automated analysis of the three-dimensional nature of dyadic and t-tubular structures. This article is part of the theme issue ‘The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease’.

• 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.

• 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.

• 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
• 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
• 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
• 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
• 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’.

• 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.

• 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.

• 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.

• 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
• 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
• Young-Halvorsen, Kristine Skårdal; Espe, Emil Knut Stenersen; Zhang, Lili; Aronsen, Jan Magnus & Sjaastad, Ivar (2016). Three-directional evaluation of mitral flow in the rat heart by phase-contrast cardiovascular magnetic resonance. PLOS ONE. 11(3). doi: 10.1371/journal.pone.0150536. Fulltekst i vitenarkiv Vis sammendrag

  Purpose Determination of mitral flow is an important aspect in assessment of cardiac function. Traditionally, mitral flow is measured by Doppler echocardiography which suffers from several challenges, particularly related to the direction and the spatial inhomogeneity of flow. These challenges are especially prominent in rodents. The purpose of this study was to establish a cardiovascular magnetic resonance (CMR) protocol for evaluation of three-directional mitral flow in a rodent model of cardiac disease. Materials and Methods Three-directional mitral flow were evaluated by phase contrast CMR (PC-CMR) in rats with aortic banding (AB) (N = 7) and sham-operated controls (N = 7). Peak mitral flow and deceleration rate from PC-CMR was compared to conventional Doppler echocardiography. The accuracy of PC-CMR was investigated by comparison of spatiotemporally integrated mitral flow with left ventricular stroke volume assessed by cine CMR. Results PC-CMR portrayed the spatial distribution of mitral flow and flow direction in the atrioventricular plane throughout diastole. Both PC-CMR and echocardiography demonstrated increased peak mitral flow velocity and higher deceleration rate in AB compared to sham. Comparison with cine CMR revealed that PC-CMR measured mitral flow with excellent accuracy. Echocardiography presented significantly lower values of flow compared to PC-CMR. Conclusions For the first time, we show that PC-CMR offers accurate evaluation of three-directional mitral blood flow in rodents. The method successfully detects alterations in the mitral flow pattern in response to cardiac disease and provides novel insight into the characteristics of mitral flow.

• Frisk, Michael; Ruud, Marianne; Espe, Emil Knut Stenersen; Aronsen, Jan Magnus; Røe, Åsmund Treu & Zhang, Lili [Vis alle 11 forfattere av denne artikkelen] (2016). Elevated ventricular wall stress disrupts cardiomyocyte t-tubule structure and calcium homeostasis. Cardiovascular Research (CVR). ISSN 0008-6363. doi: 10.1093/cvr/cvw111. Fulltekst i vitenarkiv Vis sammendrag

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

• Hillestad, Vigdis; Espe, Emil Knut Stenersen; Fadila, Cero; Larsen, Karl-Otto; Sjaastad, Ivar & Nygård, Ståle [Vis alle 8 forfattere av denne artikkelen] (2015). IL-18 neutralization during alveolar hypoxia improves left ventricular diastolic function in mice. Acta Physiologica. ISSN 1748-1708. 213(2), s. 492–504. doi: 10.1111/apha.12376. Fulltekst i vitenarkiv
• Espe, Emil Knut Stenersen; Aronsen, Jan Magnus; Eriksen, Guro Søe; Zhang, Lili; Smiseth, Otto A. & Edvardsen, Thor [Vis alle 8 forfattere av denne artikkelen] (2015). Assessment of regional myocardial work in rats. Circulation Cardiovascular Imaging. ISSN 1941-9651. 8. doi: 10.1161/CIRCIMAGING.114.002695. Fulltekst i vitenarkiv
• Espe, Emil Knut Stenersen; Zhang, Lili & Sjaastad, Ivar (2014). Unwrapping eddy current compensation: improved compensation of eddy current induced baseline shifts in high-resolution phase-contrast MRI at 9.4 Tesla. Magnetic Resonance in Medicine. ISSN 0740-3194. 72, s. 1096–1102. doi: 10.1002/mrm.25023. Fulltekst i vitenarkiv
• Espe, Emil Knut Stenersen; Aronsen, Jan Magnus; Skårdal, Kristine; Schneider, Jürgen; Zhang, Lili & Sjaastad, Ivar (2013). Novel insight into the detailed myocardial motion and deformation of the rodent heart using high-resolution phase contrast cardiovascular magnetic resonance. Journal of Cardiovascular Magnetic Resonance. ISSN 1097-6647. 15(82), s. 1–11. doi: 10.1186/1532-429X-15-82. Fulltekst i vitenarkiv Vis sammendrag

  Background Phase contrast velocimetry cardiovascular magnetic resonance (PC-CMR) is a powerful and versatile tool allowing assessment of in vivo motion of the myocardium. However, PC-CMR is sensitive to motion related artifacts causing errors that are geometrically systematic, rendering regional analysis of myocardial function challenging. The objective of this study was to establish an optimized PC-CMR method able to provide novel insight in the complex regional motion and strain of the rodent myocardium, and provide a proof-of-concept in normal and diseased rat hearts with higher temporal and spatial resolution than previously reported. Methods A PC-CMR protocol optimized for assessing the motion and deformation of the myocardium in rats with high spatiotemporal resolution was established, and ten animals with different degree of cardiac dysfunction underwent examination and served as proof-of-concept. Global and regional myocardial velocities and circumferential strain were calculated, and the results were compared to five control animals. Furthermore, the global strain measurements were validated against speckle-tracking echocardiography, and inter- and intrastudy variability of the protocol were evaluated. Results The presented method allows assessment of regional myocardial function in rats with high level of detail; temporal resolution was 3.2 ms, and analysis was done using 32 circumferential segments. In the dysfunctional hearts, global and regional function were distinctly altered, including reduced global peak values, increased regional heterogeneity and increased index of dyssynchrony. Strain derived from the PC-CMR data was in excellent agreement with echocardiography (r = 0.95, p < 0.001; limits-of-agreement −0.02 ± 3.92%strain), and intra- and interstudy variability were low for both velocity and strain (limits-of-agreement, radial motion: 0.01 ± 0.32 cm/s and −0.06 ± 0.75 cm/s; circumferential strain: -0.16 ± 0.89%strain and −0.71 ± 1.67%strain, for intra- and interstudy, respectively). Conclusion We demonstrate, for the first time, that PC-CMR enables high-resolution evaluation of in vivo circumferential strain in addition to myocardial motion of the rat heart. In combination with the superior geometric robustness of CMR, this ultimately provides a tool for longitudinal studies of regional function in rodents with high level of detail.

• Espe, Emil Knut Stenersen; Aronsen, Jan Magnus; Skrbic, Biljana; Skulberg, Vidar Magne; Schneider, Jürgen & Sejersted, Ole M [Vis alle 8 forfattere av denne artikkelen] (2013). Improved MR phase contrast velocimetry utilizing a novel nine-point balanced motion encoding scheme with increased robustness to eddy current effects. Magnetic Resonance in Medicine. ISSN 0740-3194. 69(1), s. 48–61. doi: 10.1002/mrm.24226. Fulltekst i vitenarkiv
• Espe, Emil Knut Stenersen; Zhang, Lili & Sjaastad, Ivar (2013). Unwrapping eddy current compensation: improved compensation of eddy current induced baseline shifts in high-resolution phase-contrast MRI at 9.4 Tesla. Magnetic Resonance in Medicine. ISSN 0740-3194. doi: 10.1002/mrm.25023. Fulltekst i vitenarkiv
• Land, Sander; Niederer, Steven A.; Aronsen, Jan Magnus; Espe, Emil Knut Stenersen; Zhang, Lili & Louch, William Edward [Vis alle 9 forfattere av denne artikkelen] (2012). An analysis of deformation-dependent electromechanical coupling in the mouse heart. Journal of Physiology. ISSN 0022-3751. 590(18), s. 4553–4569. doi: 10.1113/jphysiol.2012.231928. Fulltekst i vitenarkiv

Se alle arbeider i NVA

• Dahl, Anna Bergan; Dietrichs, Erik Sveberg & Espe, Emil Knut Stenersen (2026). Abels tårn - Institutt for eksperimentell medisinsk forskning fyller 75 år. [Radio]. NRK P2. Fulltekst i vitenarkiv
• Jemterud, Torkild; Delsett, Lene Liebe; Espe, Emil Knut Stenersen & Røislien, Jo (2025). Kan et lyn redde livet ditt? - Abels tårn - NRK Radio. [Radio]. NRKP2. Fulltekst i vitenarkiv Vis sammendrag

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• Hauge-Iversen, Ida Marie & Espe, Emil Knut Stenersen (2024). Editorial for “Impact of Type 2 Diabetes Mellitus on Left Atrioventricular Coupling and Left Atrial Deformation in Patients With Essential Hypertension: An MRI Feature Tracking Study”. Journal of Magnetic Resonance Imaging. ISSN 1053-1807. doi: 10.1002/jmri.29472. Fulltekst i vitenarkiv
• 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. Fulltekst i vitenarkiv
• Espe, Emil Knut Stenersen & Schneider, Jurgen E. (2023). Editorial for “Reference Ranges of Ventricular Morphology and Function in Healthy Chinese Adults: A Multicenter 3T MRI Study”. Journal of Magnetic Resonance Imaging. ISSN 1053-1807. doi: 10.1002/jmri.28901. Fulltekst i vitenarkiv
• Marshall, Serena; Børstad, Mira Halvorsen; Skogestad, Jonas; Albert, Ingrid; Lothe, Gustav B & Espe, Emil Knut Stenersen [Vis alle 10 forfattere av denne artikkelen] (2016). SERCA2 activation is beneficial in chronic heart disease. Fulltekst i vitenarkiv
• Skårdal, Kristine; Espe, Emil Knut Stenersen; Bendiksen, Bård Andre; Aronsen, Jan Magnus; Zhang, Lili & Sjaastad, Ivar (2016). Parametrizing active and passive diastolic function non-invasively using phase contrast MRI. Fulltekst i vitenarkiv
• Røe, Åsmund Treu; Ruud, Marianne; Espe, Emil Knut Stenersen; Aronsen, Jan Magnus; Sejersted, Ole M & Sjaastad, Ivar [Vis alle 7 forfattere av denne artikkelen] (2016). Elevated ventricular wall stress disrupts diastolic Calcium homeostasis of the cardiomyocyte. Fulltekst i vitenarkiv
• Bendiksen, Bård Andre; Zhang, Lili; Espe, Emil Knut Stenersen; Schneider, Jurgen E. & Sjaastad, Ivar (2016). Cardiac diffusion tensor imaging of the rodent heart utilizing an optimized gradient configuration with multiple encoding strengths. Fulltekst i vitenarkiv
• McGinley, Gary George; Bendiksen, Bård Andre; Zhang, Lili; Sjaastad, Ivar & Espe, Emil Knut Stenersen (2016). Accelerated myocardial velocity and strain estimation with phase-contrast magnetic resonance imaging using compressed sensing with adaptive thresholding. Fulltekst i vitenarkiv
• Ruud, Marianne; Frisk, Michael; Espe, Emil Knut Stenersen; Aronsen, Jan Magnus; Zhang, Lili & Norseng, Per Andreas [Vis alle 10 forfattere av denne artikkelen] (2016). Elevated ventricular wall stress disrupts cardiomyocyte t-tubular structure and Ca2+ homeostasis. Fulltekst i vitenarkiv
• Espe, Emil Knut Stenersen; Aronsen, Jan Magnus; Skårdal, Kristine; Zhang, Lili & Sjaastad, Ivar (2015). Noninvasive detection of congestive heart failure in postinfarction rats. Fulltekst i vitenarkiv
• Ruud, Marianne; Frisk, Michael; Norseng, Per Andreas; Røe, Åsmund Treu; Espe, Emil Knut Stenersen & Aronsen, Jan Magnus [Vis alle 10 forfattere av denne artikkelen] (2015). Regulation of cardiomyocyte t-tubule organization and density by ventricular wall stress. Biophysical Journal. ISSN 0006-3495. 108, s. 443a–443a. Fulltekst i vitenarkiv
• Ruud, Marianne; Frisk, Michael; Espe, Emil Knut Stenersen; Aronsen, Jan Magnus; Norseng, Per Andreas & Sjaastad, Ivar [Vis alle 9 forfattere av denne artikkelen] (2015). Elevated ventricular wall stress disrupts cardiomyocyte t-tubular structure and Ca2+ homeostasis. Fulltekst i vitenarkiv
• Ruud, Marianne; Frisk, Michael; Espe, Emil Knut Stenersen; Aronsen, Jan Magnus; Norseng, Per Andreas & Sjaastad, Ivar [Vis alle 9 forfattere av denne artikkelen] (2015). Elevated ventricular wall stress disrupts cardiomyocyte t-tubular structure and Ca2+ homeostasis. Fulltekst i vitenarkiv
• Ruud, Marianne; Espe, Emil Knut Stenersen; Aronsen, Jan Magnus; Norseng, Per Andreas; Sjaastad, Ivar & Sejersted, Ole M [Vis alle 8 forfattere av denne artikkelen] (2015). Elevated ventricular wall stress disrupts cardiomyocyte t-tubular structure and Ca 2+ homeostasis. Fulltekst i vitenarkiv
• Frisk, Michael; Ruud, Marianne; Espe, Emil Knut Stenersen; Aronsen, Jan Magnus; Røe, Åsmund Treu & Zhang, Lili [Vis alle 11 forfattere av denne artikkelen] (2015). Ventricular wall stress predicts disruption of cardiomyocyte t-tubule structure and Ca2+ homeostasis across the infarcted heart. Biophysical Journal. ISSN 0006-3495. 108, s. 106a–106a. Fulltekst i vitenarkiv
• Frisk, Michael; Espe, Emil Knut Stenersen; Røe, Åsmund Treu; Aronsen, Jan Magnus; Enger, Ulla Helene & Sejersted, Ole M [Vis alle 8 forfattere av denne artikkelen] (2014). In vivo strain measurements predict regional disruption of cardiomyocyte structure and Ca2+ homeostasis during heart failure. Fulltekst i vitenarkiv
• Skårdal, Kristine; Espe, Emil Knut Stenersen; Aronsen, Jan Magnus; Zhang, Lili & Sjaastad, Ivar (2014). Evaluation of mitral inflow in a rat model of aortic stenosis using phase contrast MRI. Fulltekst i vitenarkiv
• Skårdal, Kristine; Espe, Emil Knut Stenersen; Aronsen, Jan Magnus; Zhang, Lili & Sjaastad, Ivar (2014). EVALUATION OF MITRAL INFLOW IN A RAT MODEL OF AORTIC STENSOSIS USING PHASE CONTRAST CARDIAC MAGNETIC RESONANCE. Fulltekst i vitenarkiv
• Frisk, Michael; Espe, Emil Knut Stenersen; Røe, Åsmund Treu; Aronsen, Jan Magnus; Enger, Ulla Helene & Sejersted, Ole M [Vis alle 8 forfattere av denne artikkelen] (2014). Regional left ventricular strain and wall stress predict cardiomyocyte T-tubular structure and Ca2+ homeostasis following myocardial infarction. Fulltekst i vitenarkiv
• Espe, Emil Knut Stenersen; Aronsen, Jan Magnus; Eriksen, Guro Søe; Zhang, Lili; Smiseth, Otto A. & Edvardsen, Thor [Vis alle 8 forfattere av denne artikkelen] (2014). Assessment of regional myocardial work in rats. Fulltekst i vitenarkiv
• Zhang, Lili; Skårdal, Kristine; Espe, Emil Knut Stenersen & Sjaastad, Ivar (2014). NEWS ON THE 9.4T ANIMAL SCANNER IN OSLO: CARDIAC MRI IN RODENTS. Fulltekst i vitenarkiv
• Espe, Emil Knut Stenersen; Aronsen, Jan Magnus; Skårdal, Kristine; Schneider, Jürgen; Zhang, Lili & Sjaastad, Ivar (2013). Novel insight into the detailed myocardial motion and deformation of the roden heart using high-resolution phase contrast MRI. Fulltekst i vitenarkiv
• Skårdal, Kristine; Espe, Emil Knut Stenersen; Haugstad, Solveig Bjærum; Aronsen, Jan Magnus; Skulberg, Vidar Magne & Zhang, Lili [Vis alle 7 forfattere av denne artikkelen] (2013). Evaluation of diastolic function using phase contrast MRI. Fulltekst i vitenarkiv
• Espe, Emil Knut Stenersen; Aronsen, Jan Magnus; Hougen, Karina; Skogestad, Jonas; Louch, William Edward & Sejersted, Ole M [Vis alle 8 forfattere av denne artikkelen] (2012). Detailed assessment of the contractility in the infarcted heart using high-resolution MRI phase contrast velocimetry. Fulltekst i vitenarkiv
• Land, Sander; Niederer, Steven A.; Aronsen, Jan Magnus; Espe, Emil Knut Stenersen; Zhang, Lili & Louch, William Edward [Vis alle 8 forfattere av denne artikkelen] (2012). Developing a virtual physiological mouse model of the heart: multi-scale coupling is key for controlling ventricular pressure. Fulltekst i vitenarkiv
• Land, Sander; Niederer, Steven; Nordbø, Øyvind; Espe, Emil Knut Stenersen; Sjaastad, Ivar & William, Louch [Vis alle 9 forfattere av denne artikkelen] (2011). An electromechanical model of the mouse heart. Fulltekst i vitenarkiv
• Espe, Emil Knut Stenersen; Zhang, Lili; Aronsen, Jan Magnus; Skrbic, Biljana; Schneider, Jürgen & Sejersted, Ole M [Vis alle 7 forfattere av denne artikkelen] (2011). MRI phase contrast velocimetry utilizing a nine-point balanced motion encoding scheme for increased accuracy and reduction in acquisition time. Fulltekst i vitenarkiv
• Espe, Emil Knut Stenersen (2014). Measuring in vivo Regional Myocardial Function Using High-Field MRI: Development and application of high-resolution MR imaging of the beating hear. Universitetet i Oslo. ISSN 9788282648899. Fulltekst i vitenarkiv Vis sammendrag

  Heart failure (HF) is one of the major causes of mortality in the Western world, recognized by a compromised ability of the heart to supply the body with blood. The poor understanding of the disease mechanisms and lack of adequate therapy strategies are reflected in the grim prognosis of HF. Great research efforts over the last decades have been aimed at revealing the factors responsible for the reduction in function the left ventricle (LV) of the heart. In this, small-animal models of cardiac disease plays an irreplaceable role, enabling isolation and identification of structural and functional alterations on cellular and/or subcellular level. However, to be able to relate findings on the microscopic scale to alterations in cardiac function, there is a great need for methodology, preferably noninvasive, that allows detailed assessment of in vivo regional myocardial function. The hearts of mice and rats are more than two orders of magnitudes smaller than human hearts by weight, and beats up to ten times faster. Measurement of cardiac function in mice and rats thus understandably requires considerably higher resolution than in humans to offer comparable data yield. Phase contrast magnetic resonance imaging (PC-MRI) is a well-established and versatile noninvasive imaging technique allowing measurement of time-resolved 3D motion. We have developed an improved PC-MRI technique able to measure myocardial motion in small animals with improved accuracy and resolution compared to earlier approaches (Paper I). A major consequence of pushing the limits of achievable spatiotemporal resolution in PC-MRI is increased generation of eddy currents in the systems, which introduces severe baseline shifts in the measured motion that may render the data unusable. This required further development of eddy current correction techniques (Paper II). We developed this imaging technique further and introduced and validated a protocol for calculating regional myocardial strain from PCMRI velocity data. We applied this protocol, as a proof-of-concept, in normal and regionally dysfunctional rat hearts (Paper III). Finally, we incorporated a mathematical model allowing calculation of regional myocardial work from PC-MRI data, in combination with identification of the mitral and aortic valve events and a simple measurement of peak blood pressure. This protocol was also demonstrated in normal and dysfunctional rat hearts (Paper IV). The work in this thesis demonstrates that PC-MRI allows noninvasive measurement of regional myocardial motion, strain and work in small-animal models of cardiac disease with high resolution. The results are readily extendable to human applications, ultimately allowing higher sensitivity and/or resolution and extended data yield in functional cardiac MRI.

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