| 1. |
- Walsh, Roddy, et al.
(författare)
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Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls
- 2021
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Ingår i: Genetics in Medicine. - : Nature Publishing Group. - 1098-3600 .- 1530-0366. ; 23:1, s. 47-58
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 x 10(-18)) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 x 10(-13)). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
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| 2. |
- Friedrich, Felix W., et al.
(författare)
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Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy
- 2012
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 21:14, s. 3237-3254
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Tidskriftsartikel (refereegranskat)abstract
- Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular hypertrophy, diastolic dysfunction and myocardial disarray. HCM is caused by mutations in sarcomeric genes, but in 40 of patients, the mutation is not yet identified. We hypothesized that FHL1, encoding four-and-a-half-LIM domains 1, could be another disease gene since it has been shown to cause distinct myopathies, sometimes associated with cardiomyopathy. We evaluated 121 HCM patients, devoid of a mutation in known disease genes. We identified three novel variants in FHL1 (c.134delA/K45Sfs, c.459CA/C153X and c.827GC/C276S). Whereas the c.459CA variant was associated with muscle weakness in some patients, the c.134delA and c.827GC variants were associated with isolated HCM. Gene transfer of the latter variants in C2C12 myoblasts and cardiac myocytes revealed reduced levels of FHL1 mutant proteins, which could be rescued by proteasome inhibition. Contractility measurements after adeno-associated virus transduction in rat-engineered heart tissue (EHT) showed: (i) higher and lower forces of contraction with K45Sfs and C276S, respectively, and (ii) prolonged contraction and relaxation with both mutants. All mutants except one activated the fetal hypertrophic gene program in EHT. In conclusion, this study provides evidence for FHL1 to be a novel gene for isolated HCM. These data, together with previous findings of proteasome impairment in HCM, suggest that FHL1 mutant proteins may act as poison peptides, leading to hypertrophy, diastolic dysfunction and/or altered contractility, all features of HCM.
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| 3. |
- Gennebäck, Nina, 1982-
(författare)
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Cardiac hypertrophy : transcription patterns, hypertrophic progression and extracellular signalling
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The aim of this thesis was to study transcription patterns and extracellular signalling of the hypertrophic heart to better understand the mechanisms initiating, controlling and maintaining cardiac hypertrophy.Cardiac hypertrophy is a risk factor for cardiovascular morbidity and mortality. Hypertrophy of the myocardium is a state, independent of underlying disease, where the myocardium strives to compensate for an increased workload. This remodelling of the heart includes physiological changes induced by a changed gene expression, alteration of the extracellular matrix and diverse cell-to-cell signalling.Shedding microvesicles and exosomes are membrane released vesicles derived from the plasma membrane, which can mediate messages between cells and induce various cell-related processes in target cells.Methods and materials: Two different microarray studies on different materials were performed. In the first study, cardiac myectomies from 8 patients with hypertrophic obstructive cardiomyopathy (HOCM) and 5 controls without cardiac disease were used. In the second study, myocardial tissue from 6 aorta ligated and 6 sham operated (controls) rats at three different time points (1, 6 and 42 days post-surgically) were analysed. To reveal differences in gene expression the materials were analyzed with Illumina whole genome microarray and multivariate data analysis (PCA and OPLS-DA).Cultured cardiomyocytes (HL-1) were incubated with and without growth factors (TGF-β2 or PDGF BB). Microvesicles and exosomes were collected and isolated after differential centrifugations and ultracentrifugations of the cell culture medium. The microvesicles and exosomes were characterized with dynamic light scattering (DLS), flow cytometry, western blot, electron microscopy and Illumina whole genome microarray.Results: The two different microarray studies revealed differentially expressed gene transcripts and groups of transcripts. When comparing HOCM patients to controls significant down-regulation of the MYH6 gene transcript and two immediate early genes (IEGs, EGR1 and FOS), as well as significant up-regulation of the ACE2, JAK2 and HDAC5 gene transcripts were found. In the rat model, 5 gene groups showed interesting clustering after multivariate data analysis (OPLS-DA) associated with the hypertrophic development: “Atherosclerosis”, “ECM and adhesion molecules”, “Fatty acid metabolism”, “Glucose metabolism” and “Mitochondria”.The shedding microvesicles were rounded vesicles, 40-300 nm in size and surrounded by a bilayered membrane. Chromosomal DNA sequences were identified in the microvesicles. The microvesicles could be taken up by fibroblasts resulting in an altered gene expression in the fibroblasts. The exosomes from cultured cardiomyocytes (incubated with TGF-β2 or PDGF BB) had an average diameter of 50-80 nm, similar to the unstimulated control exosomes. A large, for all cardiomyocyte derived exosomes, common pool of mRNA seems stable and a smaller pool varied in mRNA content according to treatment of the cardiomyocyte. Of the common mRNA about 14% were ribosomal, 14% were of unknown locus and 5% connected to the function of the mitochondria.Conclusions: The microarray studies showed that transcriptional regulation at a stable stage of the hypertrophic development is a balance of pro and anti hypertrophic mechanisms and that diverse gene groups are differently regulated at different time points in the hypertrophic progression.OPLS-DA is a very useful and powerful tool when analyzing gene expression data, especially in finding clusters of gene groups not seen with traditional statistics.The extracellular vesicle studies suggests that microvesicles and exosomes released from cardiomyocytes contain DNA and can be involved in events in target cells by facilitating an array of processes including gene expression changes. Different treatment of the cardiomyocyte influence the content of the exosome produced, indicating that the signal function of the exosome might vary according to the state of the cardiomyocyte.
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| 4. |
- Long, A J, et al.
(författare)
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Final Report of the INQUA Shorelines Subcommission on Western Europe
- 2005
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Ingår i: Journal of Coastal Research. - 0749-0208 .- 1551-5036. ; , s. 43-51
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Tidskriftsartikel (refereegranskat)abstract
- We provide a short report on the final year of the INQUA Shorelines Subcommission on Western Europe (2002-3). This includes a review of activities under four themes: sea-level changes in the next century; sea-level changes along a north-south transect from the uplifting coasts of Fennoseandanvia to the subsiding coasts of the North Sea and the Baltic, and the meta stable areas such as Portugal and France; comparisons between modeled and empirical observations of relative sea-level (RSL) change, and palaeo-tsunami and storm records. We conclude by providing a report on the final 2002 Annual Meeting including its field meeting at Greifswald and Mecklenburg-West Pomerania and provide a list of some recent publications by members of the INQUA Shorelines Subcommission.
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| 5. |
- Magnusson, Peter, et al.
(författare)
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Positron emission tomography (O-15-water, C-11-acetate, C-11-HED) risk markers and nonsustained ventricular tachycardia in hypertrophic cardiomyopathy
- 2020
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Ingår i: IJC Heart & Vasculature. - : Elsevier BV. - 2352-9067. ; 26:26
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Tidskriftsartikel (refereegranskat)abstract
- Background: The objectives of the study were to describe positron emission tomography (PET) parameters, using the tracers O-15-water at rest/stress, C-11-acetate, and C-11-HED, with regard to nonsustained ventricular tachycardia (NSVT) in hypertrophic cardiomyopathy (HCM). PET offers quantitative assessment of pathophysiology throughout the left ventricular segments, including the endocardium/epicardium. The potential use PET in risk stratification remains to be elucidated. NSVT provides a marker for sudden cardiac death.Methods: Patients with a validated diagnosis of HCM who had an implantable cardioverter-defibrillator were interrogated at 12 months and independently of PET-examinations.Results: In total, 25 patients (mean age 56.8 +/- 12.9 years, 76% males) were included and 10 reported NSVT. Mean myocardial blood flow (MBF) at rest was 0.91 ml/g/min and decreased at stress, 1.59 ml/ g/min. The mean gradient (endocardium/epicardium quotient) at rest was 1.14 +/- 0.09, while inverse at stress (mean 0.92 +/- 0.16). Notably, MBF gradient at stress was significantly lower in patients with NSVT (p = 0.022) and borderline at rest (p = 0.059) while global MBF at rest and stress were not. Mean myocardial oxygen consumption (MVO2) was 0.088 ml/g/min (higher in NSVT, p = 0.023) and myocardial external efficiency 18.5%. Using C-11-HED, the mean retention index was 0.11 min (1) and a higher volume of distribution (p = 0.089) or transmural gradient of clearance rate (p = 0.061) or lower clearance rate (p = 0.052) showed a tendency of association of NSVT.Conclusions: The endocardium/epicardium MBF gradient at stress is significantly lower in HCM patients with NSVT. This provides a novel approach to further refine risk stratification of sudden cardiac death.
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| 6. |
- Månsson, Alf, et al.
(författare)
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Effects of amrinone on twitch, tetanus and shortening kinetics in mammalian skeletal muscle
- 1989
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Ingår i: Acta Physiologica Scandinavica. - : Wiley. - 0001-6772 .- 1365-201X. ; 136:1, s. 37-45
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Tidskriftsartikel (refereegranskat)abstract
- The contractile effects of amrinone were studied on twitch and tetanus responses of mouse lumbrical muscles. Amrinone (1.1 mM) increased the maximum force level during the tetanus, reduced the rate of rise of force during the onset of tetanus and prolonged the time from the last stimulus to half-relaxation. The rate of redevelopment of force after a release during the tetanus plateau was likewise reduced. Amrinone (I.I 0.5 mM) increased the time to peak twitch force and the time to half-relaxation during the twitch. The peak twitch force was not significantly changed. The force-velocity relation was markedly affected by amrinone: there was a decrease in maximum velocity of shortening, an increase in maximum isometric force and a decrease in curvature of the force–velocity relation. The results suggest that amrinone modulates the kinetic properties of the myosin cross-bridges by exerting a specific effect upon the myofilament system. The latter effects are mainly responsible for the contractile changes produced by amrinone in mouse skeletal muscle. Amrinone appears to have little effect on the metabolism of activator calcium in this particular preparation.
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| 7. |
- Mörner, J, et al.
(författare)
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Effects of amrinone on the electromechanical coupling in frog skeletal muscle fibres
- 1990
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Ingår i: Acta Physiologica Scandinavica. - : Wiley. - 0001-6772 .- 1365-201X. ; 139, s. 289-295
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Tidskriftsartikel (refereegranskat)abstract
- The contractile effects of I.I mM amrinone were studied on isolated skeletal muscle fibres of the frog (2–5 °C, slack length). Amrinone potentiated the twitch amplitude and the maximum tetanic tension and also enhanced the maximum contracture response elicited by 117.5 mM K+ (mean increase 6.3 ± 1.8 %, n = 6, P < 0.02). The time to halfrelaxation of the potassium contracture was slightly increased (mean change 13.8 ± 3.5%, n = 7, P < 0.01). Amrinone furthermore shifted the S-shaped curve relating contracture tension to log K+ to the left, and thus reduced the threshold depolarization (the mechanical threshold needed) to elicit a contracture (mean reduction 11 ± 1 mV). The duration of the action potential at the –25 mV level was slightly increased by amrinone, whereas the resting membrane potential was unaffected.
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| 8. |
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| 9. |
- Sörensen, Jens, et al.
(författare)
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Diagnosis of left ventricular hypertrophy using non-ECG-gated 15O-water PET
- 2022
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Ingår i: Journal of Nuclear Cardiology. - : Springer. - 1071-3581 .- 1532-6551. ; , s. 2361-2373
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Tidskriftsartikel (refereegranskat)abstract
- Aim: To develop a method for diagnosing left ventricular (LV) hypertrophy from cardiac perfusion 15O-water positron emission tomography (PET).Methods: We retrospectively pooled data from 139 subjects in four research cohorts. LV remodeling patterns ranged from normal to severe eccentric and concentric hypertrophy. 15O-water PET scans (n = 197) were performed with three different PET devices. A low-end scanner (66 scans) was used for method development, and remaining scans with newer devices for a blinded evaluation. Dynamic data were converted into parametric images of perfusable tissue fraction for semi-automatic delineation of the LV wall and calculation of LV mass (LVM) and septal wall thickness (WT). LVM and WT from PET were compared to cardiac magnetic resonance (CMR, n = 47) and WT to 2D-echocardiography (2DE, n = 36). PET accuracy was tested using linear regression, Bland–Altman plots, and ROC curves. Observer reproducibility were evaluated using intraclass correlation coefficients.Results: High correlations were found in the blinded analyses (r ≥ 0.87, P < 0.0001 for all). AUC for detecting increased LVM and WT (> 12 mm and > 15 mm) was ≥ 0.95 (P < 0.0001 for all). Reproducibility was excellent (ICC ≥ 0.93, P < 0.0001).Conclusion: 15O-water PET might detect LV hypertrophy with high accuracy and precision.
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| 10. |
- Sörensen, Jens, et al.
(författare)
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Diagnostic accuracy of 15O-water PET for left-ventricular hypertrophy
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Aim: To develop and validate a method for diagnosing left ventricular (LV) hypertrophy from cardiac perfusion 15O-water positron emission tomography (PET).Methods:This was a retrospective study with pooled data from 139 subjects in four research cohorts. LV remodeling patterns ranged from normal to severe eccentric and concentric hypertrophy. 15O-water PET scans (n=197) were performed with three different PET devices. Data from a low-end scanner (66 scans) were used for method development, remaining scans were used for a blinded evaluation. Dynamic data were converted into parametric images of perfusable tissue fraction for semi-automatic delineation of the LV wall in the short axis view. The enclosed region was used to calculate LV mass (LVM) and septal wall thickness (WT). LVM and WT from PET were compared to cardiac magnetic resonance (CMR, n=47) and WT to 2D-echocardiography (2DE, n=36). PET accuracy was tested using linear regression, Bland-Altman plots, and ROC curves. Observer reproducibility were evaluated using intraclass correlation coefficients. Results: Correlations (PET-LVM and PET-WT towards CMR; PET-WT towards 2DE) were high (r≥0.87, P<0.0001 for all) with high-end scanners, and slightly lower for LVM (r=0.84) and WT (r=0.76, both P<0.0001) with a low-end scanner. There was no significant bias for WT, but a proportional bias for LVM was found. The area-under-the-curve for blinded detection of increased LVM and WT (>12 mm and >15 mm) diagnosed by conventional imaging was ≥0.95 (P<0.0001 for all). Reproducibility was excellent (ICC ≥ 0.93, P<0.0001). Conclusion: 15O-water PET might detect LV hypertrophy with high accuracy and precision.
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