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1.	Magnusson, Mia, 1979, et al. (författare) Dynamic Enhancer Methylation - A Previously Unrecognized Switch for Tissue-Type Plasminogen Activator Expression. 2015 Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 10:10 Tidskriftsartikel (refereegranskat)abstract Tissue-type plasminogen activator (t-PA), which is synthesized in the endothelial cells lining the blood vessel walls, is a key player in the fibrinolytic system protecting the circulation against occluding thrombus formation. Although classical gene regulation has been quite extensively studied in order to understand the mechanisms behind t-PA regulation, epigenetics, including DNA methylation, still is a largely unexplored field. The aim of this study was to establish the methylation pattern in the t-PA promoter and enhancer in non-cultured compared to cultured human umbilical vein endothelial cells (HUVECs), and to simultaneously examine the level of t-PA gene expression. Bisulphite sequencing was used to evaluate the methylation status, and real-time RT-PCR to determine the gene expression level. While the t-PA promoter was stably unmethylated, we surprisingly observed a rapid reduction in the amount of methylation in the enhancer during cell culturing. This demethylation was in strong negative correlation with a pronounced (by a factor of approximately 25) increase in t-PA gene expression levels. In this study, we show that the methylation level in the t-PA enhancer appears to act as a previously unrecognized switch controlling t-PA expression. Our findings, which suggest that DNA methylation is quite dynamic, have implications also for the interpretation of cell culture experiments in general, as well as in a wider biological context.
2.	Magnusson, Mia, 1979, et al. (författare) Rapid and specific hypomethylation of enhancers in endothelial cells during adaptation to cell culturing. 2016 Ingår i: Epigenetics. - : Informa UK Limited. - 1559-2308 .- 1559-2294. ; 11:8, s. 614-624 Tidskriftsartikel (refereegranskat)abstract Epigenetics, including DNA methylation, is one way for a cell to respond to the surrounding environment. Traditionally, DNA methylation has been perceived as a quite stable modification; however, lately, there have been reports of a more dynamic CpG methylation that can be affected by, for example, long-term culturing. We recently reported that methylation in the enhancer of the gene encoding the key fibrinolytic enzyme tissue-type plasminogen activator (t-PA) was rapidly erased during cell culturing. In the present study we used sub-culturing of human umbilical vein endothelial cells (HUVECs) as a model of environmental challenge to examine how fast genome-wide methylation changes can arise. To assess genome-wide DNA methylation, the Infinium HumanMethylation450 BeadChip was used on primary, passage 0, and passage 4 HUVECs. Almost 2% of the analyzed sites changed methylation status to passage 4, predominantly displaying hypomethylation. Sites annotated as enhancers were overrepresented among the differentially methylated sites (DMSs). We further showed that half of the corresponding genes concomitantly altered their expression, most of them increasing in expression. Interestingly, the stroke-related gene HDAC9 increased its expression several hundredfold. This study reveals a rapid hypomethylation of CpG sites in enhancer elements during the early stages of cell culturing. As many methods for methylation analysis are biased toward CpG rich promoter regions, we suggest that such methods may not always be appropriate for the study of methylation dynamics. In addition, we found that significant changes in expression arose in genes with enhancer DMSs. HDAC9 displayed the most prominent increase in expression, indicating, for the first time, that dynamic enhancer methylation may be central in regulating this important stroke-associated gene.
3.	Bergh, Niklas, 1979, et al. (författare) Risk of Heart Failure in Congenital Heart Disease: A Nationwide Register-based Cohort Study. 2023 Ingår i: Circulation. - 1524-4539. ; 147:12, s. 982-984 Tidskriftsartikel (refereegranskat)
4.	Forsgard, Niklas, et al. (författare) Cardiac arrest in Wilson's disease after curative liver transplantation: a life-threatening complication of myocardial copper excess? 2019 Ingår i: ESC Heart Failure. - : Wiley. - 2055-5822. ; 6:1, s. 228-231 Tidskriftsartikel (refereegranskat)abstract We report the case of a 38-year-old man who presented with cardiac arrest 1 year after curative liver transplantation for Wilson's disease. Clinical work-up proofed myocardial copper and iron accumulation using mass spectrometry, which led most likely to myocardial fibrosis as visualized by cardiovascular magnetic resonance (unprecedented delayed enhancement pattern) and endomyocardial biopsy. Consequently, cardiac arrest due to ventricular fibrillation and subsequent episodes of sustained ventricular tachycardia were considered as primary cardiac manifestation of Wilson's disease. This can, as illustrated by our case, occur even late after curative liver transplantation, which is an important fact that treating physicians should be aware of during clinical follow-up of these patients.
5.	Larsson, Pia, 1978, et al. (författare) Histone deacetylase inhibitors stimulate tissue-type plasminogen activator production in vascular endothelial cells. 2013 Ingår i: Journal of thrombosis and thrombolysis. - : Springer Science and Business Media LLC. - 1573-742X .- 0929-5305. ; 35:2, s. 185-92 Tidskriftsartikel (refereegranskat)abstract A reduced capacity for acute tissue-type plasminogen activator (t-PA) release is likely to be associated with an impaired endogenous defense against intravascular thrombosis. Efficient approaches to pharmacologically restore a defective t-PA release have been lacking, but recent observations suggest that histone deacetylase inhibitors (HDACis) enhance t-PA production in vitro. HDACis have diverse chemical structures and different HDAC-enzyme sub-class targeting. We here compared the effects of several clinically used HDACis on t-PA production in endothelial cells. Human umbilical vein endothelial cells were exposed to a panel of 11 different HDACis and t-PA mRNA and protein levels were quantified. All HDACis dose-dependently stimulated t-PA mRNA and protein expression with similar maximal efficacy but with different potencies. Already at low concentrations, the majority of inhibitors caused significant and sustained effects on t-PA production. In addition, selected HDACis were capable of normalizing t-PA production when suppressed by the inflammatory cytokine TNF-α. We conclude that HDACis targeting classical HDAC enzymes are powerful inducers of t-PA expression in cultured endothelial cells and could be promising candidates for pharmacological modulation of endogenous fibrinolysis in man.
6.	Larsson, Pia, 1978, et al. (författare) Role of histone acetylation in the stimulatory effect of valproic acid on vascular endothelial tissue-type plasminogen activator expression 2012 Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 7:2 Tidskriftsartikel (refereegranskat)abstract AIMS: Stimulated release of tissue-type plasminogen activator (t-PA) is pivotal for an intravascular fibrinolytic response and protects the circulation from occluding thrombosis. Hence, an impaired t-PA production is associated with increased risk for atherothrombotic events. A pharmacological means to stimulate the production of this enzyme may thus be desirable. We investigated if the anti-epileptic drug valproic acid (VPA) is capable of enhancing t-PA expression in vitro in vascular endothelial cells, and further examined if its histone deacetylase (HDAC)-inhibitory activity is of importance for regulating t-PA expression. METHODS AND RESULTS: Human endothelial cells were exposed to valproic acid and t-PA mRNA and protein levels were quantified. Potential changes in histone acetylation status globally and at the t-PA promoter were examined by western blot and chromatin immunoprecipitation. Valproic acid dose-dependently stimulated t-PA mRNA and protein expression in endothelial cells reaching a 2-4-fold increase at clinically relevant concentrations and 10-fold increase at maximal concentrations. Transcription profiling analysis revealed that t-PA is selectively targeted by this agent. Augmented histone acetylation was detected at the t-PA transcription start site, and an attenuated VPA-response was observed with siRNA knock of HDAC3, HDAC5 and HDAC7. CONCLUSIONS: Valproic acid induces t-PA expression in cultured endothelial cells, and this is associated with increased histone acetylation at the t-PA promoter. Given the apparent potency of valproic acid in stimulating t-PA expression in vitro this substance may be a candidate for pharmacological modulation of endogenous fibrinolysis in man.
7.	Larsson, Pia, 1978, et al. (författare) Valproic acid selectively increases vascular endothelial tissue-type plasminogen activator production and reduces thrombus formation in the mouse. 2016 Ingår i: Journal of thrombosis and haemostasis : JTH. - : Elsevier BV. - 1538-7836. ; 14:12, s. 2496-2508 Tidskriftsartikel (refereegranskat)abstract The endogenous fibrinolytic system has rarely been considered as a target to prevent thrombotic disease. Tissue plasminogen activator (t-PA) is potently increased by histone deacetylase (HDAC) inhibitors in endothelial cells in vitro, but whether this translates into increased vascular t-PA production and an enhanced fibrinolytic capacity in vivo is unknown.
8.	Ulfhammer, Erik, 1974, et al. (författare) Dependence of Proximal GC Boxes and Binding Transcription Factors in the Regulation of Basal and Valproic Acid-Induced Expression of t-PA. 2016 Ingår i: International journal of vascular medicine. - : Hindawi Limited. - 2090-2824 .- 2090-2832. ; 2016 Tidskriftsartikel (refereegranskat)abstract Objective. Endothelial tissue-type plasminogen activator (t-PA) release is a pivotal response to protect the circulation from occluding thrombosis. We have shown that the t-PA gene is epigenetically regulated and greatly induced by the histone deacetylase (HDAC) inhibitor valproic acid (VPA). We now investigated involvement of known t-PA promoter regulatory elements and evaluated dependence of potential interacting transcription factors/cofactors. Methods. A reporter vector with an insert, separately mutated at either the t-PA promoter CRE or GC box II or GC box III elements, was transfected into HT-1080 and HUVECs and challenged with VPA. HUVECs were targeted with siRNA against histone acetyl transferases (HAT) and selected transcription factors from the Sp/KLF family. Results. An intact VPA-response was observed with CRE mutated constructs, whereas mutation of GC boxes II and III reduced the magnitude of the induction by 54 and 79% in HT-1080 and 49 and 50% in HUVECs, respectively. An attenuated induction of t-PA mRNA was observed after Sp2, Sp4, and KLF5 depletion. KLF2 and p300 (HAT) were identified as positive regulators of basal t-PA expression and Sp4 and KLF9 as repressors. Conclusion. VPA-induced t-PA expression is dependent on the proximal GC boxes in the t-PA promoter and may involve interactions with Sp2, Sp4, and KLF5.
9.	Albert, Malin, et al. (författare) Hospitalized patients’ attitudes towards participating in a randomized control trial in case of a cardiac arrest 2024 Ingår i: Resuscitation Plus. - 2666-5204. ; 18 Tidskriftsartikel (refereegranskat)abstract BackgroundNo previous study has evaluated patients attitudes towards inclusion in an ongoing cardiac arrest clinical trial. The aim of this study was to assess patientś willingness and motives to participate in the ongoing randomized controlled drug trial “Vasopressin and Steroids in addition to Adrenaline in cardiac arrest” (VAST-A trial) in case of an in-hospital cardiac arrest (IHCA).ObjectivesHospitalized patients, men ≥ 18 and women ≥ 50 years, were asked for informed consent for inclusion in the VAST-A trial in case of an IHCA, the reason for approving or declining inclusion in the trial and baseline characteristics.MethodsPatients admitted to hospital were asked to give informed consent of inclusion in VAST-A in case of an IHCA during their hospital stay. Patients were also asked why they approved or declined inclusion as well as baseline characteristics questions.Results1,064 patients were asked about willingness to participate in the VAST-A trial, of these 902 (84.8%) patients approved inclusion. A subgroup of 411 patients were, except willingness, also asked about motives to participate or not and basic characteristics. The main reason for approving inclusion was to contribute to research (n = 328, 83.9%). The main reason for declining inclusion was concerns regarding testing the drug treatment (n = 6, 30%).ConclusionAmong hospitalized patients the vast majority gave informed consent to inclusion in an ongoing randomized cardiac arrest drug trial. The main reason for approving inclusion was to contribute to research.
10.	Bartfay, Sven-Erik, et al. (författare) Heart transplantation in patients bridged with mechanical circulatory support: outcome comparison with matched controls 2023 Ingår i: Esc Heart Failure. - 2055-5822. ; 10:4, s. 2621-2629 Tidskriftsartikel (refereegranskat)abstract AimsDue to the shortage of heart donors, increasing numbers of heart transplantation (HTx) candidates are receiving long-term mechanical circulatory support (MCS) as bridge-to-transplantation. Treatment with MCS is associated with increased formation of anti-human leukocyte antigen antibodies (allosensitization), but whether this affects post-HTx outcomes is unclear. Methods and resultsWe included all adult patients who received long-term MCS as bridge-to-transplantation and underwent subsequent HTx at our centre between 2008 and 2018. We also enrolled medically treated HTx recipients without prior MCS as controls. These controls were matched by age, sex, diagnosis, and transplantation era. Outcome parameters were compared between the two study groups. A total of 126 patients (48 +/- 15 years, 84% male) were included of whom 64 were bridged with MCS and 62 were matched controls. Pre-HTx allosensitization occurred more frequently in the MCS group than in the control group (27% vs. 11%, P = 0.03). At post-HTx year 10, the overall survival probability was 84% among patients treated with MCS and 90% among those medically managed (P = 0.32). At post-HTx year 1, freedom from treated rejections (>= ISHLT 2R) was 69% in the MCS group and 70% in the control group (P = 0.94); and freedom from any rejection was 8% and 5%, respectively (P = 0.98). There were no differences in renal function or cardiac allograft vasculopathy (grade >= 1) between groups at 1, 3, and 5 years post-HTx. ConclusionsAlthough patients treated with MCS had a higher frequency of pre-HTx allosensitization, there were no significant differences in post-HTx graft survival, biopsy-proven rejections, or renal function as compared with patients not bridged with MCS.
11.	Bech-Hanssen, Odd, 1956, et al. (författare) Grading right ventricular dysfunction in left ventricular disease using echocardiography: a proof of concept using a novel multiparameter strategy. 2021 Ingår i: ESC heart failure. - : Wiley. - 2055-5822. ; 8:4, s. 3223-3236 Tidskriftsartikel (refereegranskat)abstract Grading right ventricular dysfunction (RVD) in patients with left ventricular (LV) disease has earned little attention. In the present study, we established an echocardiographic RVD score and investigated how increments of the score correspond to RVD at right heart catheterization.We included 95 patients with LV disease consecutively referred for heart transplant or heart failure work-up with catheterization and echocardiography within 48h. The RVD score (5 points) included well-known characteristics of the development from compensated to decompensated right ventricular (RV) function: pulmonary hypertension, reduced RV strain, RV area dilatation, moderate/severe tricuspid regurgitation, and increased right atrial pressure (RAP) by echocardiography. Comparing three groups with increments of RVD score [1 (mild), 2-3 (moderate), and 4-5 (severe)] showed more advanced RVD with increasing RV end-diastolic pressure (P<0.001) and signs of uncoupling to load (reduced ratio between RV and pulmonary artery elastance, P<0.001) and more spherical RV shape (RV area/length, P<0.001). Receiver operating characteristic curve analysis for detection of severe RV (RAP≥10mmHg) showed for the RVD score an area under the curve of 0.88 compared with 0.69, 0.68, and 0.64 for RV strain, tricuspid annular plane systolic excursion, and fractional area change, respectively. A patient with RVD score≥4 had a 6.7-fold increase in likelihood of severe RVD, and no patient with RVD score≤1 had severe RVD.In this proof of concept study, a novel RVD score outperformed the widely used longitudinal parameters regarding grading of RVD severity, with a potential role for refined diagnosis, follow-up, and prognosis assessment in heart failure patients.
12.	Bech-Hanssen, Odd, 1956, et al. (författare) Pulmonary Hypertension Phenotype Can Be Identified in Heart Failure With Reduced Ejection Fraction Using Echocardiographic Assessment of Pulmonary Artery Pressure With Supportive Use of Pressure Reflection Variables 2023 Ingår i: Journal of the American Society of Echocardiography. - : Elsevier BV. - 0894-7317. ; 36:6, s. 604-614 Tidskriftsartikel (refereegranskat)abstract Background: Pulmonary hypertension (PH) is frequent in patients with heart failure and reduced ejection fraction (HFrEF) with 2 different phenotypes: isolated postcapillary PH (IpcPH) and, with the worst prognosis, combined pre- and postcapillary PH (CpcPH). The aims of the present echocardiography study were to investigate (1) the ability to identify PH phenotype in patients with HFrEF using the newly adopted definition of PH (mean pulmonary artery pressure >20 mm Hg) and (2) the relationship between PH phenotype and right ventricular (RV) function. Methods: One hundred twenty-four patients with HFrEF consecutively referred for heart transplant or heart failure workup were included with echocardiography and right heart catheterization within 48 hours. We estimated systolic pulmonary artery pressure (sPAPDoppler) and used a method to detect increased pulmonary vascular resistance (>3 Wood units) based on predefined thresholds of 3 pressure reflection (PRefl) variables (the acceleration time in the RV outflow tract [RVOT], the interval between peak RVOT and peak tricuspid regurgitant velocity, and the RV pressure augmentation following peak RVOT velocity). Results: Using receiver operator characteristic analysis in a derivation group (n = 62), we identified sPAPDoppler ≥35 mm Hg as a cutoff that in a test group (n = 62) increased the likelihood of PH 6.6-fold. The presence of sPAPDoppler >40 mm Hg and 2 or 3 positive PRefl variables increased the probability of CpcPH 6- to 8-fold. A 2-step approach with primarily assessment of sPAPDoppler and the supportive use of PRefl variables in patients with mild/moderate PH (sPAPDoppler 41-59 mm Hg) showed 76% observer agreement and a weighted kappa of 0.63. The steady-state (pulmonary vascular resistance) and pulsatile (compliance, elastance) vascular loading are increased in both IpcPH and CpcPH with a comparable degree of RV dysfunction. Conclusions: The PH phenotype can be identified in HFrEF using standard echocardiographic assessment of pulmonary artery pressure with supportive use of PRefl variables in patients with mild to moderate PH.
13.	Benza, Raymond L., et al. (författare) CS1, a controlled-release formulation of valproic acid, for the treatment of patients with pulmonary arterial hypertension: Rationale and design of a Phase 2 clinical trial 2024 Ingår i: PULMONARY CIRCULATION. - 2045-8932 .- 2045-8940. ; 14:1 Tidskriftsartikel (refereegranskat)abstract Although rare, pulmonary arterial hypertension (PAH) is associated with substantial morbidity and a median survival of approximately 7 years, even with treatment. Current medical therapies have a primarily vasodilatory effect and do not modify the underlying pathology of the disease. CS1 is a novel oral, controlled-release formulation of valproic acid, which exhibits a multi-targeted mode of action (pulmonary pressure reduction, reversal of vascular remodeling, anti-inflammatory, anti-fibrotic, and anti-thrombotic) and therefore potential for disease modification and right ventricular modeling in patients with PAH. A Phase 1 study conducted in healthy volunteers indicated favorable safety and tolerability, with no increased risk of bleeding and significant reduction of plasminogen activator inhibitor 1. In an ongoing randomized Phase 2 clinical trial, three doses of open-label CS1 administered for 12 weeks is evaluating the use of multiple outcome measures. The primary endpoint is safety and tolerability, as measured by the occurrence of adverse events. Secondary outcome measures include the use of the CardioMEMS (TM) HF System, which provides a noninvasive method of monitoring pulmonary artery pressure, as well as cardiac magnetic resonance imaging and echocardiography. Other outcomes include changes in risk stratification (using the REVEAL 2.0 and REVEAL Lite 2 tools), patient reported outcomes, functional capacity, 6-min walk distance, actigraphy, and biomarkers. The pharmacokinetic profile of CS1 will also be evaluated. Overall, the novel design and unique, extensive clinical phenotyping of participants in this trial will provide ample evidence to inform the design of any future Phase 3 studies with CS1.
14.	Bergh, Niklas, 1979, et al. (författare) A new biomechanical perfusion system for ex vivo study of small biological intact vessels 2005 Ingår i: Ann Biomed Eng. - : Springer Science and Business Media LLC. - 0090-6964. ; 33:12, s. 1808-18 Tidskriftsartikel (refereegranskat)abstract The vascular endothelium transduces physical stimuli within the circulation into physiological responses, which influence vascular remodelling and tissue homeostasis. Therefore, a new computerized biomechanical ex vivo perfusion system was developed, in which small intact vessels can be perfused under well-defined biomechanical forces. The system enables monitoring and regulation of vessel lumen diameter, shear stress, mean pressure, variable pulsatile pressure and flow profile, and diastolic reversal flow. Vessel lumen measuring technique is based on detection of the amount of flourescein over a vessel segment. A combination of flow resistances, on/off switches, and capacitances creates a wide range of pulsatile pressures and flow profiles. Accuracy of the diameter measurement was evaluated. The diameters of umbilical arteries were measured and compared with direct ultrasonographic measurement of the vessel diameter. As part of the validation the pulsatile pressure waveform was altered, e.g., in terms of pulse pressure, frequency, diastolic shape, and diastolic reversal flow. In a series of simulation experiments, the hemodynamic homeostasis functions of the system were successfully challenged by generating a wide range of vascular diameters in artificial and intact human vessels. We conclude that the system presented may serve as a methodological and technical platform when performing advanced hemodynamic stimulation protocols.
15.	Bergh, Niklas, 1979 (författare) Development of a New Biomechanical ex vivo Perfusion System - Studies on effects of biomechanical and inflammatory stress on hemostatic genes in human vascular endothelium 2009 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract The vascular endothelium is a multifunctional interface constantly exposed to biomechanical forces such as shear and tensile stress. Biomechanical stress is involved in the pathophysiological process of the vessel wall and thus affects vascular remodeling, atherosclerosis and thrombogenesis. Many different systems have been designed to subject endothelial cells to mechanical stress. However, previous systems have had large limitations in creating physiologically relevant biomechanical stress protocols. Therefore, there is a need for more refined biological perfusion systems that as accurately as possible mimics the in vivo conditions. In the present work, a new biomechanical ex vivo perfusion system for integrative physiological and molecular biology studies of intact vessels of different sizes as well as artificial vessels was developed. This model was constructed for advanced perfusion protocols under strictly controlled biomechanical (shear stress, tensile stress) as well as metabolic (temperature, pH, oxygen tension) conditions. The system enables monitoring and regulation of vessel lumen diameter, shear stress, mean pressure, variable pulsatile pressure and flow profiles, and diastolic reversed flow. The vessel lumen measuring technique is based on detection of the amount of flourescein over a vessel segment. A combination of flow resistances, on/off switches and capacitances creates a wide range of possible combinations of pulsatile pressures and flow profiles. The perfusion platform was extensively evaluated technically as well as biologically by perfusion of high precision made glass capillaries, human umbilical arteries as well as endothelialized artificial vessels. Artificial vessels with a confluent human umbilical vein endothelial cell layer were exposed to different levels of shear stress or different levels of static or pulsatile pressure. Shear stress was a more powerful stimulus than static or pulsatile tensile stress. While shear stress affected mRNA expression of all six studied genes (t-PA, PAI-1, u-PA, thrombomodulin, eNOS and VCAM-1), neither gene was found to be regulated by tensile stress. Shear stress suppressed t-PA and VCAM-1 in a dose response dependent way. The expression of thrombomodulin was also reduced by shear stress. u-PA, eNOS and PAI-1 were induced by shear stress, but showed no obvious dose response effect for these genes. Further, the unexpected suppression of t-PA by shear stress was studied by using mechanistic experiments with pharmacologic inhibitors. Our data indicate that the suppressive effect of shear stress on t-PA was mediated by suppression of JNK and not by p38 MAPK and ERK1/2. The interplay between inflammatory stress and different combination of tensile as well as shear stress was studied on six key anti- and pro-thrombotic genes in HUVEC. The endothelial cell response to TNF-α was not modulated by tensile stress. Again, shear stress was a more potent stimulus. Shear stress counteracted the cytokine-induced expression of VCAM-1, and the cytokine-suppressed expression of thrombomodulin and eNOS. Shear stress and TNF-α additively induced PAI-1, whereas shear stress blocked the cytokine effect on t-PA and u-PA. In conclusion, these findings illustrate that biomechanical forces, particularly shear stress, have important regulatory effects on endothelial gene function. A possible pathophysiological scenario is that an unfavourable hemodynamic milieu leads to a lower threshold for the induction of genes related to endothelial dysfunction in lesion-prone areas upon negative stress, such as inflammation.
16.	Bergh, Niklas, 1979, et al. (författare) Effect of shear stress, statins and TNF-alpha on hemostatic genes in human endothelial cells 2012 Ingår i: Biochemical and biophysical research communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 420:1, s. 166-71 Tidskriftsartikel (refereegranskat)abstract Atherosclerotic plaque formation and progression are dependent on local shear stress patterns and inflammatory cytokines. Statins effectively reduce the progression of atherosclerosis and the incidence of cardiovascular events. However, the benefit of statins cannot be explained by cholesterol reduction alone. This study, investigated the non-lipid lowering effects of simvastatin and rosuvastatin on endothelial anti- and prothrombotic genes under different biomechanical and inflammatory stress conditions. Endothelial cells responded in a similar way to simvastatin and rosuvastatin. However, they were more sensitive to simvastatin. The statins had anti-inflammatory properties counteracting the TNF-alpha effect on the hemostatic genes studied. There was no observed synergistic effect between shear stress and simvastatin. Simvastatin had a counteracting effect on t-PA and PAI-1 compared to TNF-alpha and shear stress. Simvastatin blocked the TNF-alpha suppressive effect on thrombomodulin and eNOS, irrespective of shear stress. The strong inductive effect of TNF-alpha on VCAM-1 was counteracted by simvastatin and shear stress in an additive dose-response dependent way.
17.	Bergh, Niklas, 1979, et al. (författare) Effects of two complex hemodynamic stimulation profiles on hemostatic genes in a vessel-like environment 2008 Ingår i: Endothelium. - : Informa UK Limited. - 1029-2373 .- 1062-3329. ; 15:5-6, s. 231-8 Tidskriftsartikel (refereegranskat)abstract Endothelial cells are the main sensors of changes in the biomechanical flow environment and play a pivotal role in vascular homeostasis. An in vitro perfusion model was developed to study the regulatory effect on gene expression by different flow and pressure profiles. Human umbilical vein endothelial cells were grown to confluence inside capillary microslides or silicone tubes. Thereafter, they were exposed to different levels of shear stress or different levels of static or pulsatile pressure. Genes representing various hemostasis functions of the endothelial cells were analyzed. Shear stress was a more effortful stimulus than static or pulsatile tensile stress. Although shear stress affected mRNA expression of all six studied genes (tissue-type plasminogen activator [t-PA], plasminogen activator inhibitor [PAI]-1, Thrombomodulin [TM], urokinase-type plasminogen activator [u-PA], vascular cell adhesion molecule [VCAM-1], and endothelial nitric oxide synthase [eNOS]), none of the genes was found regulated by pressure. Shear stress down-regulated t-PA and VCAM-1 in a dose response-dependent way, and up-regulated TM. u-PA, eNOS, and PAI-1 were up-regulated by shear stress, but there was no obvious dose-response effect for these genes. These findings suggest that shear stress has a more powerful gene regulatory effect on endothelial gene expression than tensile stress. Low shear stress induced a more proatherogenic endothelial surface but preserved t-PA gene expression levels compared to high shear stress.
18.	Bergh, Niklas, 1979, et al. (författare) Efficacy and safety of clopidogrel versus ticagrelor as part of dual antiplatelet therapy in acute coronary syndrome - a systematic review and meta-analysis. 2022 Ingår i: Journal of cardiovascular pharmacology. - 1533-4023. ; 79:5, s. 620-631 Tidskriftsartikel (refereegranskat)abstract The efficacy and safety of clopidogrel compared with ticagrelor as part of dual antiplatelet therapy (DAPT) in patients with acute coronary syndrome is reviewed. PubMed, Embase, the Cochrane Library, Medline, and HTA databases were searched (Sep 2nd 2020) for randomised controlled trials (RCTs). ACS patients subjected to clopidogrel or ticagrelor as part of DAPT were included. Pooled risk-differences were estimated using random-effects meta-analyses, and certainty of evidence was assessed according to GRADE. In ACS patients subjected to DAPT, the pooled risk difference for all-cause mortality was 0·6% (-0·03% to 1·3%; I2: 18%); cardiovascular mortality: 0·6% (0·01% to 1·1%; I2: 22%); MI: 0·9% (0·4% to 1·3%; I2: 5%); stent thrombosis: 0·7% (0·4 to 1·1%; I2: 0%); clinically significant bleeding: -1·9% (-3·7% to -0·2%; I2: 69%); major bleeding: -0·9% (-1·6% to -0·1%; I2: 32%); and dyspnea: -5·8% (-7·7% to -3·8%; I2: 63%). In the subgroup of older patients there were no differences between the comparison groups regarding all-cause mortality, CV mortality and MI, whereas the risk of clinically significant bleeding and major bleeding was lower in the clopidogrel group, -5·9% (-11 to -0·9%, 1 RCT) and -2·4% (-4·4% to -0·3%, I2: 0%), respectively. Compared with ticagrelor, clopidogrel may result in little or no difference regarding all-cause mortality. In older patients, clopidogrel may be slightly less efficient in reducing the risk of cardiovascular mortality and MI. Clopidogrel results in a reduced risk of bleedings and dyspnea.
19.	Bergh, Niklas, 1979, et al. (författare) Estimating the clinical and budgetary impact of using angiotensin receptor neprilysin inhibitor as first line therapy in patients with HFrEF. 2024 Ingår i: ESC heart failure. - 2055-5822. Tidskriftsartikel (refereegranskat)abstract Recent updates of international treatment guidelines for heart failure with reduced ejection fraction (HFrEF) differ regarding the use of angiotensin receptor neprilysin inhibitor (ARNI) as first-line treatment. The American Heart Association/American College of Cardiology/Heart Failure Society of America (AHA/ACC/HFSA) 2022 guidelines gives ARNI a Class IA recommendation for HFrEF patients while the European Society of Cardiology's guidelines are less clear when ARNI could be considered as first line treatment option in de novo patients. This study aimed to model the clinical and budgetary outcomes of implementing these guidelines, comparing conservative ARNI prescription patterns with less conservative in Sweden and in the United Kingdom.A health economic model was developed to compare different treatment patterns for HFrEF. Incident cohorts were included on an annual basis and followed over 10years. The model included treatment specific all-cause mortality and hospitalization rates, as well as drug acquisition, monitoring, and hospitalization costs. Increasing the use of ARNI could lead to about 7000-12300 life years gained and 2600-4600 hospitalizations prevented in Sweden. These health benefits come with an additional cost of 112-195 million euros. Similar results were estimated for the United Kingdom, albeit on a larger population.Increasing the proportion of patients receiving ARNI instead of angiotensin converting enzyme inhibitors as first-line treatment of HFrEF will lead to a considerable number of additional life years gained and prevented hospitalizations but with additional cost in terms of health care expenditure in Sweden and in the United Kingdom.
20.	Bergh, Niklas, 1979, et al. (författare) Invasive haemodynamics in de novo everolimus vs. calcineurin inhibitor heart transplant recipients 2020 Ingår i: ESC Heart Failure. - : Wiley. - 2055-5822. ; 7:2, s. 567-576 Tidskriftsartikel (refereegranskat)abstract Aims: Invasive haemodynamic profiles at rest and during exercise after heart transplantation (HTx) have never been described in a randomized trial where de novo everolimus (EVR)-based therapy with early calcineurin inhibitor (CNI) withdrawal has been compared with conventional CNI treatment. We report central invasive haemodynamic parameters at rest and exercise during a 3 year follow-up after HTx in a sub-study of the SCandiavian Heart transplant Everolimus De novo stUdy with earLy calcineurin inhibitor avoidancE trial. We hypothesized that the nephroprotective properties, the less development of cardiac allograft vasculopathy (CAV), and the antifibrotic properties of EVR, in comparison with CNI-based immunosuppression, would demonstrate favourable invasive haemodynamic profiles in patients at rest and during exercise. Methods and results: Ninety of 115 HTx recipients randomized to EVR or CNI treatment performed right heart catheterization at rest and 68 performed right heart catheterization at exercise up to 3 years after HTx. Haemodynamic profiles were compared between EVR and CNI treatment groups. Resting haemodynamics improved in both groups from pre-HTx to the first follow-up at 7–11 weeks post-HTx and thereafter remained unchanged up to 3 years of follow-up. During follow-up, cardiac reserve during exercise increased with higher levels of maximum heart rate (118 to 148 b.p.m., P < 0.001), mean arterial pressure (103 to 128 mmHg, P < 0.001), and cardiac output (10.3 to 12.2 l/min, P < 0.001). No significant differences in haemodynamic parameters were observed between the EVR and CNI groups at rest or exercise. Isolated post-capillary pulmonary hypertension (mean pulmonary arterial pressure > 20 mmHg, pulmonary arterial wedge pressure ≥ 15 mmHg, and pulmonary vascular resistance <3) were measured in 11% of the patients at 7–11 weeks, 5% at 12 months, and 6% at 36 months after HTx. The EVR group had significantly better kidney function (76 mL/min/1 vs. 60 mL/min/1, P < 0.001) and reduced CAV (P < 0.01) but an increased rate of early biopsy-proven treated rejections (21.2% vs 5.7%, P < 0.01) compared with the CNI group at any time point. The differences in renal function, CAV, or early biopsy-proven treated acute rejections were not associated with altered haemodynamics. Conclusions: De novo EVR treatment with early CNI withdrawal compared with conventional CNI therapy did not result in differences in haemodynamics at rest or during exercise up to 3 years after HTx despite significant differences in renal function, reduced CAV, and number of early biopsy-proven treated rejections.
21.	Björkenstam, Marie, et al. (författare) Case report of eosinophilic granulomatosis with polyangitis presenting as acute myocarditis. 2022 Ingår i: Clinical case reports. - : Wiley. - 2050-0904. ; 10:10 Tidskriftsartikel (refereegranskat)abstract This case presents a challenging diagnosis of EGPA presenting as eosinophilic myocarditis. It is a condition that can mimic many other diseases and where prompt diagnosis and early treatment is essential for recovery. The diagnosis was made after an endomyocardial biopsy (EMB) and showed the importance of EMB in the diagnostic work-up.
22.	Bobbio, Emanuele, et al. (författare) Association between central haemodynamics and renal function in advanced heart failure: a nationwide study from Sweden. 2022 Ingår i: ESC heart failure. - : Wiley. - 2055-5822. ; 9:4, s. 2654-2663 Tidskriftsartikel (refereegranskat)abstract Renal dysfunction in patients with heart failure (HF) has traditionally been attributed to declining cardiac output and renal hypoperfusion. However, other central haemodynamic aberrations may contribute to impaired kidney function. This study assessed the relationship between invasive central haemodynamic measurements from right-heart catheterizations and measured glomerular filtration rate (mGFR) in advanced HF.All patients referred for heart transplantation work-up in Sweden between 1988 and 2019 were identified through the Scandiatransplant organ-exchange organization database. Invasive haemodynamic variables and mGFR were retrieved retrospectively. A total of 1001 subjects (49±13years; 24% female) were eligible for the study. Analysis of covariance adjusted for age, sex, and centre revealed that higher right atrial pressure (RAP) displayed the strongest relationship with impaired GFR [β coefficient -0.59; 95% confidence interval (CI) -0.69 to -0.48; P<0.001], followed by lower mean arterial pressure (MAP) (β coefficient 0.29; 95% CI 0.14-0.37; P<0.001), and finally reduced cardiac index (β coefficient 3.51; 95% CI 2.14-4.84; P<0.003). A combination of high RAP and low MAP was associated with markedly worse mGFR than any other RAP/MAP profile, and high renal perfusion pressure (RPP, MAP minus RAP) was associated with superior renal function irrespective of the degree of cardiac output.In patients with advanced HF, high RAP contributed more to impaired GFR than low MAP. A higher RPP was more closely related to GFR than was high cardiac index.
23.	Bobbio, Emanuele, et al. (författare) Clinical Outcomes and Predictors of Long-Term Survival in Patients With and Without Previously Known Extracardiac Sarcoidosis Using Machine Learning: A Swedish Multicenter Study. 2023 Ingår i: Journal of the American Heart Association. - 2047-9980. ; 12:15 Tidskriftsartikel (refereegranskat)abstract Background Cardiac involvement can be an initial manifestation in sarcoidosis. However, little is known about the association between various clinical phenotypes of cardiac sarcoidosis (CS) and outcomes. We aimed to analyze the relation of different clinical manifestations with outcomes of CS and to investigate the relative importance of clinical features influencing overall survival. Methods and Results A retrospective cohort of 141 patients with CS enrolled at 2 Swedish university hospitals was studied. Presentation, imaging studies, and outcomes of de novo CS and previously known extracardiac sarcoidosis were compared. Survival free of primary composite outcome (ventricular arrhythmias, heart transplantation, or death) was assessed. Machine learning algorithm was used to study the relative importance of clinical features in predicting outcome. Sixty-two patients with de novo CS and 79 with previously known extracardiac sarcoidosis were included. De novo CS showed more advanced New York Heart Association class (P=0.02), higher circulating levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide) (P<0.001), and troponins (P<0.001), as well as a higher prevalence of right ventricular dysfunction (P<0.001). During a median (interquartile range) follow-up of 61 (44-77) months, event-free survival was shorter in patients with de novo CS (P<0.001). The top 5 features predicting worse event-free survival in order of importance were as follows: impaired tricuspid annular plane systolic excursion, de novo CS, reduced right ventricular ejection fraction, absence of β-blockers, and lower left ventricular ejection fraction. Conclusions Patients with de novo CS displayed more severe disease and worse outcomes compared with patients with previously known extracardiac sarcoidosis. Using machine learning, right ventricular dysfunction and de novo CS stand out as strong overall predictors of impaired survival.
24.	Bobbio, Emanuele, et al. (författare) Diagnosis, management, and outcome of cardiac sarcoidosis and giant cell myocarditis: a Swedish single center experience. 2022 Ingår i: BMC cardiovascular disorders. - : Springer Science and Business Media LLC. - 1471-2261. ; 22 Tidskriftsartikel (refereegranskat)abstract Cardiac sarcoidosis (CS) and giant cell myocarditis (GCM) are rare diseases that share some similarities, but also display different clinical and histopathological features. We aimed to compare the demographics, clinical presentation, and outcome of patients diagnosed with CS or GCM.We compared the clinical data and outcome of all adult patients with CS (n=71) or GCM (n=21) diagnosed at our center between 1991 and 2020.The median (interquartile range) follow-up time for patients with CS and GCM was 33.5 [6.5-60.9] and 2.98 [0.6-40.9] months, respectively. In the entire cohort, heart failure (HF) was the most common presenting manifestation (31%), followed by ventricular arrhythmias (25%). At presentation, a left ventricular ejection fraction of<50% was found in 54% of the CS compared to 86% of the GCM patients (P=0.014), while corresponding proportions for right ventricular dysfunction were 24% and 52% (P=0.026), respectively. Advanced HF (NYHA≥IIIB) was less common in CS (31%) than in GCM (76%). CS patients displayed significantly lower circulating levels of natriuretic peptides (P<0.001) and troponins (P=0.014). Eighteen percent of patients with CS included in the survival analysis reached the composite endpoint of death or heart transplantation (HTx) compared to 68% of patients with GCM (P<0.001).GCM has a more fulminant clinical course than CS with severe biventricular failure, higher levels of circulating biomarkers and an increased need for HTx. The histopathologic diagnosis remained key determinant even after adjustment for markers of cardiac dysfunction.
25.	Bobbio, Emanuele, et al. (författare) Echocardiography in inflammatory heart disease: A comparison of giant cell myocarditis, cardiac sarcoidosis, and acute non-fulminant myocarditis 2023 Ingår i: IJC Heart and Vasculature. - 2352-9067. ; 46 Tidskriftsartikel (refereegranskat)abstract Background: Giant cell myocarditis (GCM) and cardiac sarcoidosis (CS) are, in contrast to acute non-fulminant myocarditis (ANFM), rare inflammatory diseases of the myocardium with poor prognosis. Although echocardiography is the first-line diagnostic tool in these patients, their echocardiographic appearance has so far not been systematically studied. Methods: We assessed a total of 71 patients with endomyocardial biopsy-proven GCM (n = 21), and CS (n = 25), as well as magnetic resonance-verified ANFM (n = 25). All echocardiographic examinations, performed upon clinical presentation, were reanalysed according to current guidelines including a detailed assessment of right ventricular (RV) dysfunction. Results: In comparison with ANFM, patients with either GCM or CS were older (mean age (±SD) 55 ± 12 or 53 ± 8 vs 25 ± 8 years), more often of female gender (52% or 24% vs 8%), had more severe clinical symptoms and higher natriuretic peptide levels. For both GCM and CS, echocardiography revealed more frequently signs of left ventricular (LV) dysfunction in form of a reduced ejection fraction (p < 0.001), decreased cardiac index (p < 0.001) and lower global longitudinal strain (p < 0.001) in contrast to ANFM. The most prominent increase in LV end-diastolic volume index was observed in CS. In addition, RV dysfunction was more frequently found in both GCM and CS than in ANFM (p = 0.042). Conclusions: Both GCM and CS have an echocardiographic and clinical appearance that is distinct from ANFM. However, the method cannot further differentiate between the two rare entities. Consequently, echocardiography can strengthen the initial clinical suspicion of a more severe form of myocarditis, thus warranting a more rigorous clinical work-up.
26.	Bobbio, Emanuele, et al. (författare) Incidental cardiac findings on somatostatin receptor PET/CT: What do they indicate and are they of clinical relevance? 2022 Ingår i: Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology. - : Springer Science and Business Media LLC. - 1532-6551. ; 29:3, s. 1159-1165 Tidskriftsartikel (refereegranskat)abstract We present the case of a 47-year-old man with a history of recurrent episodes of frontal headache, fever, and chest discomfort as well as longstanding, difficult to treat arterial hypertension. Clinical work-up revealed the unexpected finding of an underlying pheochromocytoma as well as recent "silent" myocardial infarction. Our case highlights the importance of paying attention to incidental cardiac findings on somatostatin receptor positron emission tomography/computed tomography, as routinely performed in patients with clinically suspected neuroendocrine tumors. These incidental cardiac findings cannot only indicate a primary or secondary (metastatic) neuroendocrine tumor, but also areas of myocardial inflammation, as somatostatin receptors cannot only be found on the majority of neuroendocrine tumors, but also among other tissues on the surface of activated macrophages and lymphocytes. The detection of myocardial inflammation is of clinical importance and its underlying etiology should be evaluated to prompt eventual necessary treatment, as it is a potential driving force for cardiac remodeling and poor prognosis.
27.	Bobbio, Emanuele, et al. (författare) Phenotyping of giant cell myocarditis versus cardiac sarcoidosis using cardiovascular magnetic resonance. 2023 Ingår i: International journal of cardiology. - 0167-5273 .- 1874-1754. ; 387 Tidskriftsartikel (refereegranskat)abstract Giant cell myocarditis (GCM) and cardiac sarcoidosis (CS) are rare inflammatory diseases of the myocardium with poor prognosis. Little is known about the cardiovascular magnetic resonance (CMR) appearance of GCM and the methods ability to distinguish the two rare entities from one another.We assessed a total of 40 patients with endomyocardial biopsy-proven GCM (n=14) and CS (n=26) concerning their clinical and CMR appearance in a blinded manner.Patients with GCM and CS were of similar median age (55 vs 56years), and a male predominance was observed in both groups. In GCM, median levels of troponin T (313 vs 31ng/L, p<0.001), and natriuretic peptides (6560 vs 676pg/mL, p<0.001) were higher than in CS, and the clinical outcome worse (p=0.04). On CMR imaging, the observed alterations of left and right ventricular (LV/RV) dimensions and function were similar. GCM showed multifocal LV late gadolinium enhancement (LGE) with a similar longitudinal, circumferential, and radial distribution as in CS, including suggested signature imaging biomarkers of CS like the "hook sign" (71% vs 77%, p=0.702). The median LV LGE enhanced volume was 17% and 22% in GCM and CS (p=0.150), respectively. The number of RV segments with pathologically increased T2 signal and/or LGE were most extensive in GCM.The CMR appearance of both GCM and CS is highly similar, making the differentiation between the two rare entities solely based on CMR challenging. This stands in contrast to the clinical appearance, which seems to be more severe in GCM.
28.	Bobbio, Emanuele, et al. (författare) Short- and long-term outcomes after heart transplantation in cardiac sarcoidosis and giant-cell myocarditis: a systematic review and meta-analysis. 2022 Ingår i: Clinical research in cardiology : official journal of the German Cardiac Society. - : Springer Science and Business Media LLC. - 1861-0692. ; 111:2, s. 125-140 Tidskriftsartikel (refereegranskat)abstract Heart transplantation (HTx) is a valid therapeutic option for end-stage heart failure secondary to cardiac sarcoidosis (CS) or giant-cell myocarditis (GCM). However, post-HTx outcomes in patients with inflammatory cardiomyopathy (ICM) have been poorly investigated. We searched PubMed, Scopus, Science Citation Index, EMBASE, and Google Scholar, screened the gray literature, and contacted experts in the field. We included studies comparing post-HTx survival, acute cellular rejection, and disease recurrence in patients with and without ICM. Data were synthesized by a random-effects meta-analysis. We screened 11,933 articles, of which 14 were considered eligible. In a pooled analysis, post-HTx survival was higher in CS than non-CS patients after 1year (risk ratio [RR] 0.88, 95% confidence interval [CI] 0.60-1.17; I2=0%) and 5years (RR 0.72, 95% CI 0.52-0.91; I2=0%), but statistically significant only after 5years. During the first-year post-HTx, the risk of acute cellular rejection was similar for patients with and without CS, but after 5years, it was lower in those with CS (RR 0.38, 95% CI 0.03-0.72; I2=0%). No difference in post-HTx survival was observed between patients with and without GCM after 1year (RR 1.16, 95% CI 0.05-2.28; I2=0%) or 5years (RR 0.98, 95% CI 0.42-1.54; I2=0%). During post-HTx follow-up, recurrence of CS and GCM occurred in 5% and 8% of patients, respectively. Post-HTx outcomes in patients with CS and GCM are comparable with cardiac recipients with other heart failure etiologies. Patients with ICM should not be disqualified from HTx.
29.	Bollano, Entela, 1970, et al. (författare) Cardiac sarcoidosis and giant cell myocarditis after COVID-19 infection. 2022 Ingår i: ESC heart failure. - : Wiley. - 2055-5822. ; 9:6, s. 4298-4303 Tidskriftsartikel (refereegranskat)abstract Patients infected with SARS-CoV-2 have varying manifestations of cardiac involvement. We report four patients presenting with symptomatic cardiac sarcoidosis (CS) or giant cell myocarditis (GCM) 1-8months after mild COVID-19. All patients received immunosuppressive therapy and improved gradually within the following months. The possible temporal association between the CS/GCM and COVID-19 infection might suggest that COVID-19 could be a trigger for granulomatous myocarditis.
30.	Bollano, Entela, 1970, et al. (författare) Somatostatin receptor positron emission tomography/computed tomography in myocarditis following mRNA COVID-19 vaccination. 2022 Ingår i: European heart journal. Case reports. - : Oxford University Press (OUP). - 2514-2119. ; 6:4 Tidskriftsartikel (refereegranskat)
31.	Eldhagen, Per, et al. (författare) Phenotypic and HLA-DRB1 allele characterization of Swedish cardiac sarcoidosis patients. 2022 Ingår i: International journal of cardiology. - : Elsevier BV. - 1874-1754 .- 0167-5273. ; 359, s. 108-112 Tidskriftsartikel (refereegranskat)abstract Early detection and initiation of treatment in cardiac sarcoidosis (CS) is believed to be crucial to reduce morbidity and mortality. The diagnosis of CS is challenging, especially in isolated CS (ICS). Certain human leukocyte antigen (HLA-DRB1) alleles associate with different phenotypes of sarcoidosis. Phenotypic and genotypic characterization of patients with CS may improve our ability to identify patients being at risk for developing CS.87 patients with CS, identified at two Swedish university hospitals were included. Phenotypic characteristics were extracted from the medical records and the patients were HLA-DRB1 typed.Median age at diagnosis was 55years, 37% were women. HLA-DRB1 distribution was similar to a general sarcoidosis population. A majority of patients (51/87) had CS as the first sarcoidosis presentation. They were younger (p=0.04), more often presenting with ventricular tachycardia (VT) or atrioventricular block (AVB) grade II or III (p<0.001), had lower left ventricular ejection fraction (LVEF) (p=0.002), lower serum angiotensin converting enzyme (s-ACE) (p=0.025), and fewer extra cardiac manifestations (ECM) (p=0.02) than those presenting with CS later.Of Swedish CS patients, 59% presented with cardiac involvement as first manifestation. They had more severe cardiac symptoms than patients presenting with CS later. This phenotype disclosed less ECM and lower s-ACE thus diagnosis can be missed or delayed. We did not observe significant differences in HLA-DRB1 allele frequency between patients with CS compared to sarcoidosis in general. Awareness of CS as a primary manifestation can enable early detection and adequate intervention.
32.	Giglio, Daniel, 1977, et al. (författare) Brist på tid och pengar hindrar läkarstuderande från att forska : [Lack of time and money prevent medical students from conducting research] 2008 Ingår i: Läkartidningen. - 0023-7205. ; 105:14, s. 1011-4 Tidskriftsartikel (refereegranskat)
33.	Glise, Lars, 1988, et al. (författare) Disturbed Laminar Blood Flow Causes Impaired Fibrinolysis and Endothelial Fibrin Deposition In Vivo 2019 Ingår i: Thrombosis and Haemostasis. - : Georg Thieme Verlag KG. - 0340-6245 .- 2567-689X. ; 119:2, s. 223-233 Tidskriftsartikel (refereegranskat)abstract Endothelial expression of tissue-type plasminogen activator (t-PA) is crucial for maintaining an adequate endogenous fibrinolysis. It is unknown how endothelial t-PA expression and fibrinolysis are affected by blood flow in vivo. In this study, we investigated the impact of different blood flow profiles on endothelial t-PA expression and fibrinolysis in the arterial vasculature. Induction of disturbed laminar blood flow (D-flow) in the mouse carotid artery potently reduced endothelial t-PA messenger ribonucleic acid and protein expression, and caused fibrin deposition. En face immunohistochemistry demonstrated that arterial areas naturally exposed to D-flow had markedly lower endothelial t-PA levels than areas with sustained laminar blood flow (S-flow), and displayed pronounced fibrin deposition despite an intact endothelium. In t-PA and plasminogen-deficient mice, fibrin deposition did not extend into S-flow areas, indicating that areas of D-flow and S-flow differ, not only in fibrinolytic capacity, but also in coagulation. Furthermore, plasminogen accumulation was found at D-flow areas, and infusion of recombinant t-PA activated fibrinolysis and significantly reduced the fibrin deposits. In conclusion, D-flow potently impairs the fibrinolytic capacity and causes endothelial fibrin deposition in vivo. Our data also indicate that t-PA is the limiting factor for efficient fibrinolysis at the thrombosis-prone D-flow areas in the arterial vasculature.
34.	Hellsén, Gustaf, et al. (författare) Predicting recurrent cardiac arrest in individuals surviving Out-of-Hospital cardiac arrest 2023 Ingår i: Resuscitation. - : Elsevier BV. - 0300-9572 .- 1873-1570. ; 184 Tidskriftsartikel (refereegranskat)abstract Background: Despite improvements in short-term survival for Out-of-Hospital Cardiac Arrest (OHCA) in the past two decades, long-term survival is still not well studied. Furthermore, the contribution of different variables on long-term survival have not been fully investigated. Aim: Examine the 1-year prognosis of patients discharged from hospital after an OHCA. Furthermore, identify factors predicting re-arrest and/or death during 1-year follow-up. Methods: All patients 18 years or older surviving an OHCA and discharged from the hospital were identified from the Swedish Register for Car-diopulmonary Resuscitation (SRCR). Data on diagnoses, medications and socioeconomic factors was gathered from other Swedish registers. A machine learning model was constructed with 886 variables and evaluated for its predictive capabilities. Variable importance was gathered from the model and new models with the most important variables were created. Results: Out of the 5098 patients included, 902 (-18%) suffered a recurrent cardiac arrest or death within a year. For the outcome death or re-arrest within 1 year from discharge the model achieved an ROC (receiver operating characteristics) AUC (area under the curve) of 0.73. A model with the 15 most important variables achieved an AUC of 0.69. Conclusions: Survivors of an OHCA have a high risk of suffering a re-arrest or death within 1 year from hospital discharge. A machine learning model with 15 different variables, among which age, socioeconomic factors and neurofunctional status at hospital discharge, achieved almost the same predictive capabilities with reasonable precision as the full model with 886 variables.
35.	Henningsson, Anna, et al. (författare) Prehospital monitoring of cerebral circulation during out of hospital cardiac arrest ? : A feasibility study 2022 Ingår i: Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine. - : Springer Science and Business Media LLC. - 1757-7241. ; 30:1 Tidskriftsartikel (refereegranskat)abstract BackgroundAbout two-thirds of the in-hospital deaths after out-of-hospital cardiac arrests (OHCA) are a consequence of anoxic brain injuries, which are due to hypoperfusion of the brain during the cardiac arrests. Being able to monitor cerebral perfusion during cardiopulmonary resuscitation (CPR) is desirable to evaluate the effectiveness of the CPR and to guide further decision making and prognostication.MethodsTwo different devices were used to measure regional cerebral oxygen saturation (rSO2): INVOS™ 5100 (Medtronic, Minneapolis, MN, USA) and Root® O3 (Masimo Corporation, Irvine, CA, USA). At the scene of the OHCA, advanced life support (ALS) was immediately initiated by the Emergency Medical Services (EMS) personnel. Sensors for measuring rSO2 were applied at the scene or during transportation to the hospital. rSO2 values were documented manually together with ETCO2 (end tidal carbon dioxide) on a worksheet specially designed for this study. The study worksheet also included a questionnaire for the EMS personnel with one statement on usability regarding potential interference with ALS.ResultsTwenty-seven patients were included in the statistical analyses. In the INVOS™5100 group (n = 13), the mean rSO2 was 54% (95% CI 40.3–67.7) for patients achieving a return of spontaneous circulation (ROSC) and 28% (95% CI 12.3–43.7) for patients not achieving ROSC (p = 0.04). In the Root® O3 group (n = 14), the mean rSO2 was 50% (95% CI 46.5–53.5) and 41% (95% CI 36.3–45.7) (p = 0.02) for ROSC and no ROSC, respectively. ETCO2 values were not statistically different between the groups. The EMS personnel graded the statement of interference with ALS to a median of 2 (IQR 1–6) on a 10-point Numerical Rating Scale.ConclusionOur results suggest that both INVOS™5100 and ROOT® O3 can distinguish between ROSC and no ROSC in OHCA, and both could be used in the pre-hospital setting and during transport with minimal interference with ALS.
36.	Hjalmarsson, Clara, 1969, et al. (författare) Severe heart failure in a unique case of cobalamin-C-deficiency resolved with LVAD implantation and subsequent heart transplantation. 2024 Ingår i: Molecular genetics and metabolism reports. - 2214-4269. ; 39 Tidskriftsartikel (refereegranskat)abstract Introduction Cobalamin c deficiency (cblC), an inborn error of vitamin B12 metabolism, is caused by mutations of the MMACHC gene. It usually leads to a multisystemic disease; 50% of all patients with cblC have various structural heart defects. Severe congestive heart failure (HF) may also occur and its prognosis is poorly documented. Case report We present the case of a young man who had been diagnosed with cblC due to C331T mutation in the MMACHC gene at the age of 3days and had been treated with substitution therapy (OH-Cbl, mecobalamine, carnitine, betaine, and calcium folinate) since then. He had mildly impaired cognitive function; an ectopic hypophysis/pituitary insufficiency, with adequate hormone replacement therapy; obstructive sleep apnea syndrome, treated with CPAP, bronchial asthma, and obesity (BMI of 30). The liver and kidney functions were normal. He developed severe dilated cardiomyopathy and HF at the age of 12y. With medical treatment, his condition improved and he was stable (NYHA class II) for several years. Six years later, his status deteriorated rapidly, as he developed advanced HF, INTERMACS 3. The cardiac ultrasound revealed dilated ventricles with severely depressed ejection fraction (EF), increased filling pressures, and pulmonary hypertension (sPAP 60mmHg). Cardiac MRI showed extremely dilated chambers (LVedv 609mL, RVedv 398mL) with pronounced non-compaction, and a left ventricle EF of 13%. A primary prophylactic ICD and a left ventricular assist device (LVAD/HM3) were implanted, and the patient was subsequently listed for heart transplantation (HTx). After 25months on the waiting list, he underwent an uncomplicated HTx. However postoperatively, he got two episodes of cardiac tamponade, as well as mediastinitis, treated with antibiotics and vaccum assisted closure. He developed severe kidney failure, which fully recovered after two months, and was treated successfully for an early moderate allograft rejection (ISHT 2). At the latest outward visit, twelve months after HTx, the patient was doing excellent. Summary To the best of our knowledge, this is the first ever reported case of a patient with CblC undergoing an LVAD implantation and subsequently a HTx. Although both interventions were complicated with bleeding events, this seems to be a treatment option for advanced HF in patients with CblC.
37.	Karlsson, Lars O, 1975, et al. (författare) Cyclosporine A, 2.5 mg/kg, Does Not Reduce Myocardial Infarct Size in a Porcine Model of Ischemia and Reperfusion 2012 Ingår i: Journal of cardiovascular pharmacology and therapeutics. - : SAGE Publications. - 1940-4034 .- 1074-2484. ; 17:2, s. 159-63 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: In recent years, cyclosporine A (CsA) has emerged as a promising therapy to limit myocardial ischemic-reperfusion injury, presumably by inhibiting the opening of the mitochondrial permeability transition pore. Results from different large animal models are conflicting, however, with failure to prove beneficial effects of 10 mg/kg CsA administered at reperfusion. Recently, a small clinical study using a bolus of 2.5 mg/kg CsA showed promising but not unequivocal results. The aim of the present study was to estimate the magnitude of a possible infarct reduction with the use of the latter regimen in a closed-chest porcine model for ischemia and reperfusion. Materials and METHODS: Pigs underwent catheterization with balloon occlusion of the left descending coronary artery for 40 minutes, followed by reperfusion for 4 hours. They were randomized to receive an intravenous bolus 7 minutes before reperfusion of either 2.5 mg/kg CsA (n = 12) or saline (control, n = 11). Hearts were stained to quantify area at risk and infarct size. RESULTS: Throughout the experiment, there were no differences between the groups in baseline characteristics or hemodynamic variables. CsA treatment did not reduce infarct size as a proportion of area at risk compared with control (51% +/- 6% and 54% +/- 6%, respectively, P = .75). CONCLUSION: In a closed-chest porcine model for myocardial ischemia and reperfusion injury, 2.5 mg/kg CsA administered before reperfusion did not reduce infarct size.
38.	Karlsson, Lars O, 1975, et al. (författare) Dose-dependent cardioprotection of enkephalin analogue Eribis peptide 94 and cardiac expression of opioid receptors in a porcine model of ischaemia and reperfusion 2012 Ingår i: European journal of pharmacology. - : Elsevier BV. - 1879-0712 .- 0014-2999. ; 674:2-3, s. 378-383 Tidskriftsartikel (refereegranskat)abstract Opioids confer cardioprotection after myocardial ischaemia and reperfusion. The primary aim of the present study was to evaluate the cardioprotective effect of different doses of enkephalin analogue Eribis peptide 94 (EP 94) in a porcine model of ischaemia and reperfusion. A secondary aim was to analyse the impact of ischaemia and reperfusion on the expression of opioid receptor subtypes in the porcine heart. Thirty-four anesthetised pigs underwent 40 min of balloon occlusion of the left anterior descending coronary artery followed by four hours of reperfusion. Pigs were given either vehicle (0.9% NaCl) or one of four doses of EP 94 (0.2, 1, 5 or 25 ug/kg at each administration, respectively), intravenously after 26, 33 and 40 min of ischaemia. Hearts were stained to quantify area at risk and infarct size. mRNA and protein expressions of the opioid receptor subtypes were detected with RT-PCR, immunoblotting and immunohistochemistry in the control and ischaemic/reperfused areas. There was a significant dose-response relationship between higher doses of EP 94 and reduced infarct size. Expression of kappa- and delta-opioid receptors was detected at both mRNA and protein levels. In ischaemic/reperfused areas, an increased expression of mRNA for both receptors was observed, whereas only protein expression for the delta subtype was up-regulated. The mu-opioid receptor was not detected.
39.	Ljungman, Charlotta, 1977, et al. (författare) Differences in phenotypes, symptoms, and survival in patients with cardiomyopathy-a prospective observational study from the Sahlgrenska CardioMyoPathy Centre. 2023 Ingår i: Frontiers in cardiovascular medicine. - 2297-055X. ; 10 Tidskriftsartikel (refereegranskat)abstract Cardiomyopathy is the fourth most common cause of heart failure. The spectrum of cardiomyopathies may be impacted by changes in environmental factors and the prognosis may be influenced by modern treatment. The aim of this study is to create a prospective clinical cohort, the Sahlgrenska CardioMyoPathy Centre (SCMPC) study, and compare patients with cardiomyopathies in terms of phenotype, symptoms, and survival.The SCMPC study was founded in 2018 by including patients with all types of suspected cardiomyopathies. This study included data on patient characteristics, background, family history, symptoms, diagnostic examinations, and treatment including heart transplantation and mechanical circulatory support (MCS). Patients were categorized by the type of cardiomyopathy on the basis of the diagnostic criteria laid down by the European Society of Cardiology (ESC) working group on myocardial and pericardial diseases. The primary outcomes were death, heart transplantation, or MCS, analyzed by Kaplan-Meier and Cox proportional regression, adjusted for age, gender, LVEF and QRS width on ECG in milliseconds.In all, 461 patients and 73.1% men with a mean age of 53.6±16 years were included in the study. The most common diagnosis was dilated cardiomyopathy (DCM), followed by cardiac sarcoidosis and myocarditis. Dyspnea was the most common initial symptom in patients with DCM and amyloidosis, while patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) presented with ventricular arrythmias. Patients with ARVC, left-ventricular non-compaction cardiomyopathy (LVNC), hypertrophic cardiomyopathy (HCM), and DCM had the longest time from the debut of symptoms until inclusion in the study. Overall, 86% of the patients survived without heart transplantation or MCS after 2.5 years. The primary outcome differed among the cardiomyopathies, where the worst prognosis was reported for ARVC, LVNC, and cardiac amyloidosis. In a Cox regression analysis, it was found that ARVC and LVNC were independently associated with an increased risk of death, heart transplantation, or MCS compared with DCM. Further, female gender, a lower LVEF, and a wider QRS width were associated with an increased risk of the primary outcome.The SCMPC database offers a unique opportunity to explore the spectrum of cardiomyopathies over time. There is a large difference in characteristics and symptoms at debut and a remarkable difference in outcome, where the worst prognosis was reported for ARVC, LVNC, and cardiac amyloidosis.
40.	Lund, Lars H, et al. (författare) Rationale and design of ENDEAVOR: A sequential phase 2b-3 randomized clinical trial to evaluate the effect of myeloperoxidase inhibition on symptoms and exercise capacity in heart failure with preserved or mildly reduced ejection fraction. 2023 Ingår i: European journal of heart failure. - 1879-0844. Tidskriftsartikel (refereegranskat)abstract Mitiperstat (formerly AZD4831) is a novel selective myeloperoxidase inhibitor. Currently, no effective therapies target comorbidity-induced systemic inflammation, which may be a key mechanism underlying heart failure with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF). Circulating neutrophils secrete myeloperoxidase, causing oxidative stress, microvascular endothelial dysfunction, interstitial fibrosis, cardiomyocyte remodelling and diastolic dysfunction. Mitiperstat may therefore improve function of the heart and other organs, and ameliorate heart failure symptoms and exercise intolerance. ENDEAVOR is a combined, seamless phase 2b-3 study of the efficacy and safety of mitiperstat in patients with HFpEF/HFmrEF.In phase 2b, approximately 660 patients with heart failure and ejection fraction >40% are being randomized 1:1:1 to mitiperstat 2.5 mg, 5 mg or placebo for 48 weeks. Eligible patients have baseline 6-min walk distance (6MWD) of 30-400 m with a <50 m difference between screening and randomization and Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS) ≤90 points at screening and randomization. The dual primary endpoints are change from baseline to week 16 in 6MWD and KCCQ-TSS. The sample size provides 85% power to detect placebo-adjusted improvements of 21 m in 6MWD and 6.0 points in KCCQ-TSS at overall two-sided alpha of 0.05. Safety is monitored throughout treatment, with a focus on maculopapular rash. In phase 3 of ENDEAVOR, approximately 820 patients will be randomized 1:1 to mitiperstat or placebo.ENDEAVOR is the first phase 2b-3 study to evaluate whether myeloperoxidase inhibition can improve symptoms and exercise capacity in patients with HFpEF/HFmrEF.
41.	Polte, Christian Lars, et al. (författare) Cardiac involvement in immune-mediated necrotizing myopathy: insights from CMR and somatostatin receptor PET/CT. 2021 Ingår i: European heart journal. Cardiovascular Imaging. - : Oxford University Press (OUP). - 2047-2412 .- 2047-2404. ; 23:5 Tidskriftsartikel (refereegranskat)
42.	Polte, Christian Lars, et al. (författare) Cardiovascular Magnetic Resonance in Myocarditis. 2022 Ingår i: Diagnostics (Basel, Switzerland). - : MDPI AG. - 2075-4418. ; 12:2 Tidskriftsartikel (refereegranskat)abstract Myocarditis is an inflammatory disease of the myocardium, and its diagnosis remains challenging owing to a varying clinical presentation and broad spectrum of underlying aetiologies. In clinical practice, cardiovascular magnetic resonance has become an invaluable non-invasive imaging tool in the evaluation of patients with clinically suspected myocarditis, mainly thanks to its unique multiparametric tissue characterization ability. Although considered as useful, the method also has its limitations. This review aims to provide an up-to-date overview of the strengths and weaknesses of cardiovascular magnetic resonance in the diagnostic work-up of patients with clinically suspected myocarditis in a broad clinical context.
43.	Polte, Christian Lars, et al. (författare) Somatostatin Receptor Positron Emission Tomography/Computed Tomography in Giant Cell Myocarditis: A Promising Approach to Molecular Myocardial Inflammation Imaging. 2022 Ingår i: Circulation. Cardiovascular imaging. - 1942-0080. ; 15:1 Tidskriftsartikel (refereegranskat)
44.	Saluveer, Ott, 1974, et al. (författare) Acute vascular effects of atorvastatin in hypertensive men: a pilot study. 2013 Ingår i: Scandinavian cardiovascular journal : SCJ. - : Informa UK Limited. - 1651-2006 .- 1401-7431. ; 47:5, s. 275-80 Tidskriftsartikel (refereegranskat)abstract Abstract Objectives. Statins have multiple pleiotropic effects that are independent of their cholesterol-lowering properties including rapid improvement of endothelial function in vitro. Hypertension is characterized by endothelial dysfunction and we hypothesized that a single-dose of atorvastatin may have an acute effect on vascular function. Design. Endothelium-dependent vasodilation (EDV) and endothelium-independent vasodilation were assessed with venous occlusion plethysmography during intra-arterial infusion of acetylcholine (ACH) and sodium nitroprusside (SNP), respectively, in 13 hypertensive men after wash-out from antihypertensive medication. Vasoconstrictive responses were evaluated in response to angiotensin II (Ang II) infusion. The protocol was repeated 1 h after 80 mg oral atorvastatin (ATV; Lipitor(®)). Results. ATV treatment significantly increased baseline forearm blood flow from 3.38 (0.27) to 4.31 (0.35) ml/min/100 ml tissue (p < 0.05). ATV did not affect ACH-induced EDV. Forearm vascular resistance in response to SNP was significantly lowered by ATV (p < 0.05). Vasoconstriction in response to Ang II was significantly inhibited by ATV treatment (p = 0.005). Conclusions. The observed acute statin effects in hypertension appear to be endothelium-independent and related to vascular smooth muscle cell function. These actions may in part contribute to the beneficial pleiotropic effects of statin therapy even in the acute in vivo setting.
45.	Saluveer, Ott, 1974, et al. (författare) Profibrinolytic effect of the epigenetic modifier valproic Acid in man. 2014 Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 9:10 Tidskriftsartikel (refereegranskat)abstract The aim of the study was to test if pharmacological intervention by valproic acid (VPA) treatment can modulate the fibrinolytic system in man, by means of increased acute release capacity of tissue plasminogen activator (t-PA) as well as an altered t-PA/Plasminogen activator inhibitor -1 (PAI-1) balance. Recent data from in vitro research demonstrate that the fibrinolytic system is epigenetically regulated mainly by histone deacetylase (HDAC) inhibitors. HDAC inhibitors, including VPA markedly upregulate t-PA gene expression in vitro.
46.	Sattar, N., et al. (författare) Twenty Years of Cardiovascular Complications and Risk Factors in Patients With Type 2 Diabetes: A Nationwide Swedish Cohort Study 2023 Ingår i: Circulation. - 0009-7322. ; 147:25, s. 1872-1886 Tidskriftsartikel (refereegranskat)abstract Background:The goal of this work was to investigate trends (2001-2019) for cardiovascular events and cardiometabolic risk factor levels in individuals with type 2 diabetes (T2D) and matched control subjects. Methods:This study included 679 072 individuals with T2D from the Swedish National Diabetes Register and 2 643 800 matched control subjects. Incident outcomes comprised coronary artery disease, acute myocardial infarction, cerebrovascular disease, and heart failure (HF). Trends in time to first event for each outcome were analyzed with Cox regression and standardized incidence rates. In the group with T2D, Cox regression was also used to assess risk factor levels beyond target and outcomes, as well as the relative importance of each risk factor to each model. Results:Among individuals with T2D, incidence rates per 10 000 person-years in 2001 and 2019 were as follows: acute myocardial infarction, 73.9 (95% CI, 65.4-86.8) and 41.0 (95% CI, 39.5-42.6); coronary artery disease, 205.1 (95% CI, 186.8-227.5) and 80.2 (95% CI, 78.2-82.3); cerebrovascular disease, 83.9 (95% CI, 73.6-98.5) and 46.2 (95% CI, 44.9-47.6); and HF, 98.3 (95% CI, 89.4-112.0) and 75.9 (95% CI, 74.4-77.5). The incidence for HF plateaued around 2013, a trend that then persisted. In individuals with T2D, glycated hemoglobin, systolic blood pressure, estimated glomerular filtration rate, and lipids were independently associated with outcomes. Body mass index alone potentially explained >30% of HF risk in T2D. For those with T2D with no risk factor beyond target, there was no excess cardiovascular risk compared with control subjects except for HF, with increased hazard with T2D even when no risk factor was above target (hazard ratio, 1.50 [95% CI, 1.35-1.67]). Risk for coronary artery disease and cerebrovascular disease increased in a stepwise fashion for each risk factor not within target. Glycated hemoglobin was most prognostically important for incident atherosclerotic events, as was body mass index for incident of HF. Conclusions:Risk and rates for atherosclerotic complications and HF are generally decreasing among individuals with T2D, although HF incidence has notably plateaued in recent years. Modifiable risk factors within target levels were associated with lower risks for outcomes. This was particularly notable for systolic blood pressure and glycated hemoglobin for atherosclerotic outcomes and body mass index for heart failure.
47.	Simsa, Robin, et al. (författare) Brain organoid formation on decellularized porcine brain ECM hydrogels 2021 Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 16:1 Tidskriftsartikel (refereegranskat)abstract Human brain tissue models such as cerebral organoids are essential tools for developmental and biomedical research. Current methods to generate cerebral organoids often utilize Matrigel as an external scaffold to provide structure and biologically relevant signals. Matrigel however is a nonspecific hydrogel of mouse tumor origin and does not represent the complexity of the brain protein environment. In this study, we investigated the application of a decellularized adult porcine brain extracellular matrix (B-ECM) which could be processed into a hydrogel (B-ECM hydrogel) to be used as a scaffold for human embryonic stem cell (hESC)-derived brain organoids. We decellularized pig brains with a novel detergent- and enzyme-based method and analyzed the biomaterial properties, including protein composition and content, DNA content, mechanical characteristics, surface structure, and antigen presence. Then, we compared the growth of human brain organoid models with the B-ECM hydrogel or Matrigel controls in vitro. We found that the native brain source material was successfully decellularized with little remaining DNA content, while Mass Spectrometry (MS) showed the loss of several brain-specific proteins, while mainly different collagen types remained in the B-ECM. Rheological results revealed stable hydrogel formation, starting from B-ECM hydrogel concentrations of 5 mg/mL. hESCs cultured in B-ECM hydrogels showed gene expression and differentiation outcomes similar to those grown in Matrigel. These results indicate that B-ECM hydrogels can be used as an alternative scaffold for human cerebral organoid formation, and may be further optimized for improved organoid growth by further improving protein retention other than collagen after decellularization.
48.	Simsa, Robin, et al. (författare) Effect of fluid dynamics on decellularization efficacy and mechanical properties of blood vessels 2019 Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 14:8 Tidskriftsartikel (refereegranskat)abstract Decellularization of blood vessels is a promising approach to generate native biomaterials for replacement of diseased vessels. The decellularization process affects the mechanical properties of the vascular graft and thus can have a negative impact for in vivo functionality. The aim of this study was to determine how detergents under different fluid dynamics affects decellularization efficacy and mechanical properties of the vascular graft. We applied a protocol utilizing 1% TritonX, 1% Tributyl phosphate (TnBP) and DNase on porcine vena cava. The detergents were applied to the vessels under different conditions; static, agitation and perfusion with 3 different perfusion rates (25, 100 and 400 mL/min). The decellularized grafts were analyzed with histological, immunohistochemical and mechanical tests. We found that decellularization efficacy was equal in all groups, however the luminal ultrastructure of the static group showed remnant cell debris and the 400 mL/min perfusion group showed local damage and tearing of the luminal surface. The mechanical stiffness and maximum tensile strength were not influenced by the detergent application method. In conclusion, our results indicate that agitation or low-velocity perfusion with detergents are preferable methods for blood vessel decellularization.
49.	Simsa, Robin, et al. (författare) Systematic in vitro comparison of decellularization protocols for blood vessels. 2018 Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 13:12 Tidskriftsartikel (refereegranskat)abstract Decellularization of native blood vessels is a promising technology to generate 3D biological scaffolds for vascular grafting. Blood vessel decellularization has been performed in previous studies under various experimental conditions, that complicates comparison and optimization of suitable protocols. The goal of this work was to systematically compare the decellularization and recellularization efficacy of 5 different protocols utilizing the detergents sodium dodecyl sulfate (SDS), sodium deoxycholate (SDC), CHAPS and TritonX-100 together with DNA-removing enzymes on porcine vena cava in a perfusion bioreactor setup. Additionally, we tested the effect of DNase on the extracellular matrix (ECM) properties. We found that all protocols could efficiently decellularize blood vessels. Mechanical strength, collagen preservation and ECM integrity were similar among all tested detergents, yet TritonX protocols required long-term DNase application for complete decellularization. However, TritonX-based protocols showed the greatest recellularization efficacy with HUVECs in vitro. Furthermore, we developed a novel protocol for TritonX which improved recellularization and reduced total process time and ECM stiffness compared to previous protocols. SDS, SDC and CHAPS based protocols had a lower recellularization potential. In conclusion, decellularization of blood vessels can be achieved with all tested reagents, but TritonX treated ECM can be most efficiently recellularized with endothelial cells.
50.	Spanos, Elias, et al. (författare) Cardioprotection of the enkephalin analog Eribis peptide 94 in a rat model of ischemia and reperfusion is highly dependent on dosing regimen and timing of administration 2015 Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999. ; 747, s. 1-6 Tidskriftsartikel (refereegranskat)abstract Eribis Peptide 94 (EP94) is an enkephalin analog with cardioprotective properties in ischemia and reperfusion. The aim of the present study was to define the optimal timing and dosing of the administration of EP94 during ischemia and reperfusion in a rat model. 172 anesthetized and mechanically ventilated male Sprague-Dawley rats were randomly assigned to different administration protocols of EP94 and subjected to 30 or 40min of coronary artery occlusion followed by 2h of reperfusion. EP94 was administered intravenously at different doses and time intervals. Area at risk (AAR) and infarct size (IS) were determined by staining with Evans Blue (EB) and Triphenyl tetrazolium chloride (TTC), respectively. EP94 reduced IS/AAR when administered as a double bolus (0.5µg/kg per dose), whereas single (1μg/kg) or triple boluses (0.5μg/kg per dose) did not confer any protection. Reduction of IS/AAR was of highest magnitude if EP94 was administered 5 and 0min before the 30min ischemic period (47% reduction, P<0.05), with declining cardioprotective effect with later administration during ischemia. When EP94 was administered after 15 and 20min of a 40-min ischemic period, reduction of IS/AAR was of the same magnitude as when given after 5 and 10min of a 30-min ischemic period. It is concluded that EP94 confers cardioprotection after double bolus administration. The effects are highly dependent on the timing of administration in relation to ischemia and reperfusion. Time of reperfusion from drug administration seems to be more critical than the total duration of ischemia.

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