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  • 1.
    Backman, Christer
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Henein, Michael Y
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Burned out myocardium in biventricular hypertrophic cardiomyopathy presenting with congestive heart failure: importance of ECG changes2014In: International Cardiovascular Forum Journal, ISSN 2410-2636, Vol. 1, no 3, p. 159-160Article in journal (Refereed)
  • 2.
    Do, Lan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Dahl, Christen P
    Kerje, Susanne
    Hansell, Peter
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lindqvist, Ulla
    Engström-Laurent, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Larsson, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    High Sensitivity Method to Estimate Distribution of Hyaluronan Molecular Sizes in Small Biological Samples Using Gas-Phase Electrophoretic Mobility Molecular Analysis.2015In: International Journal of Cell Biology, ISSN 1687-8876, E-ISSN 1687-8884, article id 938013Article in journal (Refereed)
    Abstract [en]

    Hyaluronan is a negatively charged polydisperse polysaccharide where both its size and tissue concentration play an important role in many physiological and pathological processes. The various functions of hyaluronan depend on its molecular size. Up to now, it has been difficult to study the role of hyaluronan in diseases with pathological changes in the extracellular matrix where availability is low or tissue samples are small. Difficulty to obtain large enough biopsies from human diseased tissue or tissue from animal models has also restricted the study of hyaluronan. In this paper, we demonstrate that gas-phase electrophoretic molecular mobility analyzer (GEMMA) can be used to estimate the distribution of hyaluronan molecular sizes in biological samples with a limited amount of hyaluronan. The low detection level of the GEMMA method allows for estimation of hyaluronan molecular sizes from different parts of small organs. Hence, the GEMMA method opens opportunity to attain a profile over the distribution of hyaluronan molecular sizes and estimate changes caused by disease or experimental conditions that has not been possible to obtain before.

  • 3.
    Engvall, Christer
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Henein, Michael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Holmgren, Anders
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Can myocardial strain differentiate hypertrophic from infiltrative etiology of a thickened septum?2011In: Echocardiography, ISSN 0742-2822, E-ISSN 1540-8175, Vol. 28, no 4, p. 408-415Article in journal (Refereed)
    Abstract [en]

    Septal systolic strain measurements showed reduced longitudinal function but its localized nature failed to demonstrate radial disturbances in patients with pathologically thickened septum. No difference was found in systolic strain between patients according to the etiology of septal thickness. This limitation might be either technical or is explained by the maintained radial function in all patient groups.

  • 4. Friedrich, Felix W.
    et al.
    Wilding, Brendan R.
    Reischmann, Silke
    Crocini, Claudia
    Lang, Patrick
    Charron, Philippe
    Mueller, Oliver J.
    McGrath, Meagan J.
    Vollert, Ingra
    Hansen, Arne
    Linke, Wolfgang A.
    Hengstenberg, Christian
    Bonne, Gisele
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Wichter, Thomas
    Madeira, Hugo
    Arbustini, Eloisa
    Eschenhagen, Thomas
    Mitchell, Christina A.
    Isnard, Richard
    Carrier, Lucie
    Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy2012In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 21, no 14, p. 3237-3254Article in journal (Refereed)
    Abstract [en]

    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.

  • 5.
    Gennebäck, Nina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Malm, Linus
    Institutionen för skoglig genetik och växtfysiologi, Sveriges lantbruks universitet.
    Larsson, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Rongquist, Gunnar
    Institutionen för medicinska vetenskaper, Klinisk kemi.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Characterisation of exosomes derived from cultured cardiomyocytes treated with different growth factorsArticle in journal (Refereed)
  • 6.
    Gennebäck, Nina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Malm, Linus
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Larsson, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ronquist, Gunnar
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Growth factor stimulation of cardiomyocytes induces changes in the transcriptional contents of secreted exosomes2013In: Journal of Extracellular Vesicles, ISSN 2001-3078, E-ISSN 2001-3078, Vol. 2Article in journal (Refereed)
    Abstract [en]

    Exosomes are nano-sized extracellular vesicles, released from various cells, which can stimulate or repress responses in targets cells. We recently reported that cultured cardiomyocytes are able to release exosomes and that they, in turn, are involved in facilitating events in target cells by alteration of gene expression. We investigated whether external stimuli of the cardiomyocyte might influence the transcriptional content of the released exosomes. Exosomes were isolated from media collected from cultured cardiomyocytes (HL-1) with or without growth factor treatment (TGF-β2 and PDGF-BB), with a series of differential centrifugations, including preparative ultracentrifugation and separation with a sucrose gradient. The exosomes were characterized with dynamic light scattering (DLS), electron microscopy (EM) and Western blot and analyzed with Illumina whole genome microarray gene expression. The exosomes were rounded in shape and had an average size of 50-90 nm in diameter with no difference between treatment groups. Analysis of the mRNA content in repeated experiments conclusively revealed 505 transcripts in the control group, 562 in the TGF-β2-treated group and 300 in the PDGF-BB-treated group. Common transcripts (217) were found in all 3 groups. We show that the mode of stimulation of parental cells affects the characteristics of exosomes released. Hence, there is a difference in mRNA content between exosomes derived from cultured cardiomyocytes stimulated, or not stimulated, with growth factors. We also conclude that all exosomes contain a basic package consisting of ribosomal transcripts and mRNAs coding for proteins with functions within the energy supply system.

  • 7.
    Gennebäck, Nina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Malm, Linus
    Institutionen för skoglig genetik och växtfysiologi, Sveriges lantbruks universitet.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    OPLS-DA of myocardial gene expression in the progression of cardiac hypertrophy in aorta ligated ratArticle in journal (Refereed)
  • 8.
    Gennebäck, Nina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Malm, Linus
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Using OPLS-DA to find new hypotheses in vast amounts of gene expression data - Studying the progression of cardiac hypertrophy in the heart of aorta ligated rat2013In: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 522, no 1, p. 27-36Article in journal (Refereed)
    Abstract [en]

    One of the great problems facing science today lies in data mining of the vast amount of data. In this study we explore a new way of using orthogonal partial least squares-discrimination analysis (OPLS-DA) to analyze multidimensional data. Myocardial tissues from aorta ligated and control rats (sacrificed at the acute, the adaptive and the stable phases of hypertrophy) were analyzed with whole genome microarray and OPLS-DA. Five functional gene transcript groups were found to show interesting clusters associated with the aorta ligated or the control animals. Clustering of "ECM and adhesion molecules" confirmed previous results found with traditional statistics. The clustering of "Fatty acid metabolism", "Glucose metabolism", "Mitochondria" and "Atherosclerosis" which are new results is hard to interpret, thereby being possible subject to new hypothesis formation. We propose that OPLS-DA is very useful in finding new results not found with traditional statistics, thereby presenting an easy way of creating new hypotheses.

  • 9.
    Gennebäck, Nina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Wikström, Gerhard
    Institutionen för Medicinska Vetenskaper, Kardiologi, Uppsala univerisitet.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Samuel, Jane-Lise
    INSERM U 942, Hôpital Lariboisière, Paris, France.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Mörner, Stellam
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Transcriptional regulation of cardiac genes balance pro and anti hypertrophic mechanisms in hypertrophic cardiomyopathy2012In: Cardiogenetics, ISSN 2035-8148, Vol. 2, no 1Article in journal (Refereed)
    Abstract [en]

    Background: Hypertrophic cardiomyopathy (HCM) is characterised by unexplained left ventricular hypertrophy. HCM is often hereditary, but the knowledge about the mechanisms leading from mutation to phenotype is incomplete. The transcriptional expression patterns in the myocardium of HCM patients may contribute to the understanding of the mechanisms that drive and stabilize the hypertrophy.

    Design and Methods: Cardiac myectomies/biopsies from 8 patients with hypertrophic obstructive cardiomyopathy (HOCM) and 5 controls were studied with whole genome Illumina microarray gene expression (detecting 18 189 mRNA).

    Results: When comparing HOCM myocardium to controls, there was significant transcriptional down-regulation of the MYH6, EGR1, APOB and FOS genes, and significant transcriptional up-regulation of the ACE2, JAK2, NPPA (ANP), APOA1 and HDAC5genes. 

    Conclusion: The transcriptional regulation revealed both pro and anti hypertrophic mechanisms. The pro hypertrophic response was explained by the transcriptional down-regulation of MYH6, indicating that the switch to the fetal gene program is maintained, and the transcriptional up-regulation of JAK2 in JAK-STAT pathway. The anti hypertrophic response was seen as a transcriptional down-regulation of the immediate early genes (IEGs), FOS and EGR1, and a transcriptional up-regulation of ACE2 and HDAC5. This can be interpreted as a transcriptional endogenous protection system in the heart of the HOCM patients, neither growing nor suppressing the already hypertrophic myocardium.

  • 10.
    Gustafsson, Sandra
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology. Umeå Heart Centre.
    Grönlund, Christer
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology. Umeå Heart Centre.
    Suhr, Ole
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology. Umeå Heart Centre.
    Can echocardiography differentiate hereditary transthyretin amyloidosis from hypertrophic cardiomyopathy?2013In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 34, no Supplement: 1, p. 213-213Article in journal (Other academic)
    Abstract [en]

    Purpose: Hereditary transthyretin amyloidosis (ATTR) andhypertrophic cardiomyopathy (HCM) have many phenotypic similarities when examined by echocardiography. As the two conditions have different treatment strategies it is of importance to accurately diagnose these patients early in the disease. This study aimed to identify the most accurate echocardiographic method in differentiating these two conditions by using traditional and speckle tracking echocardiographyas well as myocardial texture analysis.

    Methods: We investigated 40 healthy controls, 33 patients with biopsy proven ATTR and 20 with HCM. All patients had septal thickness >12 mm. We measured left ventricular (LV) global strain as intrinsic systolic function and LV E/e' to estimate filling pressures. We also tested septal cyclic integrated backscatter (cIBS) and septal entropy as both being measures for myocardial highly reflection pattern whereas cIBS showing motion of highly reflective echoes and entropy the distribution of highly reflective echoes.

    Results: LV global strain, cIBS and E/e' were not useful in differentiating ATTR from HCM. However, septal entropy was found to be significantly different and showed an area under the curve from ROC analysis of 0.66 separating ATTR from HCM.

    Conclusion: After using detailed analysis of different aspects of LV morphology and function we found that myocardial texture behavior from entropy analysis was the only method useful in differentiating patients with ATTR fromHCM.

  • 11.
    Gustafsson, Ulf
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Assessment of regional rotation patterns improves the understanding of the systolic and diastolic left ventricular function: an echocardiographic speckle-tracking study in healthy individuals2009In: European Journal of Echocardiography, ISSN 1525-2167, E-ISSN 1532-2114, no 10, p. 56-61Article in journal (Refereed)
    Abstract [en]

    AIM To elucidate the complexity of left ventricular motion throughout the cardiac cycle, we studied regional rotation in detail. METHODS AND RESULTS: Regional rotation in six subdivisions of the circumference at three levels was studied by using speckle-tracking echocardiography in 40 healthy subjects. At the basal level the inferoseptal segments rotated significantly more clockwise during systole than the opposing anterolateral segments. At the papillary level the inferoseptal segments differed significantly from the anterolateral segments, where the inferoseptal segments rotated clockwise and the anterolateral segments rotated counter-clockwise. The apical level showed significant difference in regional rotation only at aortic valve opening. In early systole, untwist before the main systolic twist was seen at the basal and apical levels; however, the duration of the basal untwist was much longer than that of the apical. The diastolic phases of rotation at the basal and apical levels matched the different filling phases. CONCLUSION: Large regional differences in rotation are present at the basal and papillary levels in healthy subjects. The diastolic untwist matches the phases of both the E-wave and A-wave and seems to be related with intraventricular pressure differences, indicating that untwist plays an important role in the filling of the ventricle.

  • 12.
    Gustavsson, Sandra
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Granåsen, Gabriel
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Grönlund, Christer
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Umeå University, Faculty of Science and Technology, Centre for Biomedical Engineering and Physics (CMTF).
    Wiklund, Urban
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Henein, Michael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Can echocardiography and ECG discriminate hereditary transthyretin V30M amyloidosis from hypertrophic cardiomyopathy?2015In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 22, no 3, p. 163-170Article in journal (Refereed)
    Abstract [en]

    Objective: Hereditary transthyretin (ATTR) amyloidosis with increased left ventricular wall thickness could easily be misdiagnosed by echocardiography as hypertrophic cardiomyopathy (HCM). Our aim was to create a diagnostic tool based on echocardiography and ECG that could optimise identification of ATTR amyloidosis. Methods: Data were analysed from 33 patients with biopsy proven ATTR amyloidosis and 30 patients with diagnosed HCM. Conventional features from ECG were acquired as well as two dimensional and Doppler echocardiography, speckle tracking derived strain and tissue characterisation analysis. Classification trees were used to select the most important variables for differentiation between ATTR amyloidosis and HCM. Results: The best classification was obtained using both ECG and echocardiographic features, where a QRS voltage >30 mm was diagnostic for HCM, whereas in patients with QRS voltage <30 mm, an interventricular septal/posterior wall thickness ratio (IVSt/PWt) >1.6 was consistent with HCM and a ratio <1.6 supported the diagnosis of ATTR amyloidosis. This classification presented both high sensitivity (0.939) and specificity (0.833). Conclusion: Our study proposes an easily interpretable classification method for the differentiation between HCM and increased left ventricular myocardial thickness due to ATTR amyloidosis. Our combined echocardiographic and ECG model could increase the ability to identify ATTR cardiac amyloidosis in clinical practice.

  • 13. Haas, Jan
    et al.
    Frese, Karen S
    Peil, Barbara
    Kloos, Wanda
    Keller, Andreas
    Nietsch, Rouven
    Feng, Zhu
    Müller, Sabine
    Kayvanpour, Elham
    Vogel, Britta
    Sedaghat-Hamedani, Farbod
    Lim, Wei-Keat
    Zhao, Xiaohong
    Fradkin, Dmitriy
    Köhler, Doreen
    Fischer, Simon
    Franke, Jennifer
    Marquart, Sabine
    Barb, Ioana
    Li, Daniel Tian
    Amr, Ali
    Ehlermann, Philipp
    Mereles, Derliz
    Weis, Tanja
    Hassel, Sarah
    Kremer, Andreas
    King, Vanessa
    Wirsz, Emil
    Isnard, Richard
    Komajda, Michel
    Serio, Alessandra
    Grasso, Maurizia
    Syrris, Petros
    Wicks, Eleanor
    Plagnol, Vincent
    Lopes, Luis
    Gadgaard, Tenna
    Eiskjær, Hans
    Jørgensen, Mads
    Garcia-Giustiniani, Diego
    Ortiz-Genga, Martin
    Crespo-Leiro, Maria G
    Deprez, Rondal H Lekanne Dit
    Christiaans, Imke
    van Rijsingen, Ingrid A
    Wilde, Arthur A.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Bolognesi, Martino
    Bellazzi, Riccardo
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Bermejo, Justo Lorenzo
    Monserrat, Lorenzo
    Villard, Eric
    Mogensen, Jens
    Pinto, Yigal M
    Charron, Philippe
    Elliott, Perry
    Arbustini, Eloisa
    Katus, Hugo A
    Meder, Benjamin
    Atlas of the clinical genetics of human dilated cardiomyopathy2015In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 36, no 18, p. 1123-U43Article in journal (Refereed)
    Abstract [en]

    Aim: We were able to show that targeted Next-Generation Sequencing is well suited to be applied in clinical routine diagnostics, substantiating the ongoing paradigm shift from low- to high-throughput genomics in medicine. By means of our atlas of the genetics of human DCM, we aspire to soon be able to apply our findings to the individual patient with cardiomyopathy in daily clinical practice. Numerous genes are known to cause dilated cardiomyopathy (DCM). However, until now technological limitations have hindered elucidation of the contribution of all clinically relevant disease genes to DCM phenotypes in larger cohorts. We now utilized next-generation sequencing to overcome these limitations and screened all DCM disease genes in a large cohort. Methods and results: In this multi-centre, multi-national study, we have enrolled 639 patients with sporadic or familial DCM. To all samples, we applied a standardized protocol for ultra-high coverage next-generation sequencing of 84 genes, leading to 99.1% coverage of the target region with at least 50-fold and a mean read depth of 2415. In this well characterized cohort, we find the highest number of known cardiomyopathy mutations in plakophilin-2, myosin-binding protein C-3, and desmoplakin. When we include yet unknown but predicted disease variants, we find titin, plakophilin-2, myosin-binding protein-C 3, desmoplakin, ryanodine receptor 2, desmocollin-2, desmoglein-2, and SCN5A variants among the most commonly mutated genes. The overlap between DCM, hypertrophic cardiomyopathy (HCM), and channelopathy causing mutations is considerably high. Of note, we find that >38% of patients have compound or combined mutations and 12.8% have three or even more mutations. When comparing patients recruited in the eight participating European countries we find remarkably little differences in mutation frequencies and affected genes. Conclusion: This is to our knowledge, the first study that comprehensively investigated the genetics of DCM in a large-scale cohort and across a broad gene panel of the known DCM genes. Our results underline the high analytical quality and feasibility of Next-Generation Sequencing in clinical genetic diagnostics and provide a sound database of the genetic causes of DCM.

  • 14.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Hellström, Martin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Engström Laurent, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Aberg, Anna-Maja
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Oliviero, Patricia
    Samuel, Jane-Lise
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Parallel up-regulation of FGF-2 and hyaluronan during development of cardiac hypertrophy in rat2008In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 332, no 1, p. 49-56Article in journal (Refereed)
  • 15.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Malm, Linus
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ma, Li-Ping
    Larsson, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Fu, Michael
    Engström-Laurent, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Growth factor PDGF-BB stimulates cultured cardiomyocytes to synthesize the extracellular matrix component hyaluronan2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 12, p. e14393-Article in journal (Refereed)
    Abstract [en]

    Co-cultivation of cardiomyocytes and fibroblasts (80%/20%) increased HA concentration far more that can be explained by HA synthesis by the two cell types separately, revealing a crosstalk between cardiomyocytes and fibroblasts that induces HA synthesis. We conclude that dynamic changes of the myocardium, such as in cardiac hypertrophy, do not depend on the cardiomyocyte alone, but are achieved when both cardiomyocytes and fibroblasts are present.

  • 16.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Malm, Linus
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ma, Li-Ping
    Larsson, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Fu, Michael
    Engström-Laurent, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Hyaluronan is both a product and stimulator of cardiomyocytes: a study in cell cultures of cardiomyocytes and fibroblastsArticle in journal (Refereed)
  • 17.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Engström-Laurent, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Samuel, Jane-Lise
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Temporal correlation between transcriptional changes and increased synthesis of hyaluronan in experimental cardiac hypertrophy2010In: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 96, no 2, p. 73-81Article in journal (Refereed)
    Abstract [en]

    The role of hyaluronan in cardiac growth has become evident, previously shown by increased myocardial levels of hyaluronan in a rat model of cardiac hypertrophy. To further investigate the role of hyaluronan and regulation of its synthesis in cardiac hypertrophy, quantitative measurements of myocardial hyaluronan concentration was correlated to gene transcription in hypertrophic cardiac tissue. Factor analysis was used to study this correlation over time. A subset of differentially expressed genes was identified with a transcriptional regulation correlating to the increased synthesis of hyaluronan, suggesting a common regulatory pathway. Four transcription factors, Myc, Fos, Junb and Egr1, were also up-regulated. Furthermore, the Ace gene was up-regulated, representing increase of angiotensin II, an inducer of these transcription factors and fetal genes in cardiac hypertrophy. This demonstrates a coordinated synthesis of hyaluronan and pro-hypertrophic gene expression, regulated by immediate early genes, with angiotensin II as a possible mediator.

  • 18.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Henein, Michael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Molecular & Clinical Sciences Research Institute, St. George University, London; Brunel University, Middlesex, UK.
    Genetic variants in cardiac calcification in Northern Sweden2019In: Medicine (Baltimore, Md.), ISSN 0025-7974, E-ISSN 1536-5964, Vol. 98, no 15, article id e15065Article in journal (Refereed)
    Abstract [en]

    Extensive coronary calcification without significant stenosis, described as calcific coronary artery disease (CCAD) may cause abnormal myocardial perfusion and hence generalized ischemia. There is a discrepancy in the expression pattern of CCAD compared to the well-known atherosclerotic disease which raises questions about the exact pathophysiology of coronary calcification and whether there is a genetic etiology for it.

    In this pilot study we studied 3 candidate genes, ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1), ATP Binding Cassette Subfamily C Member 6 (ABCC6), and 5'-Nucleotidase Ecto (NT5E) involved in pyrophosphate (PPi) and inorganic phosphate (Pi) metabolism, which may predispose to coronary arterial or valvular calcification. We studied 70 patients with calcific cardiac disease; 65 with CCAD (age 43-83 years) and 5 with calcific aortic valve disease (CAVD) (age 76-82 years).

    Five DNA variants potentially affecting protein function were found in 6 patients. One variant is a known disease-causing mutation in the ABCC6 gene. Our findings support that disturbances in the PPi and Pi metabolism might influence the development of CCAD and CAVD. However, segregation in the families must first be performed to ascertain any damaging effect of these variants we have found.

    We report 4 new genetic variants potentially related to coronary calcification, through the disturbed Pi and PPi metabolism. The search for direct causative genetic variants in coronary artery and aortic valve calcification must be broadened with other genes particularly those involved with Pi and PPi metabolism.

  • 19.
    Hellström, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Engström-Laurent, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Hyaluronan and collagen in human hypertrophic cardiomyopathy: a morphological analysis2012In: Cardiology Research and Practice, ISSN 2090-8016, E-ISSN 2090-0597, Vol. 2012, p. 545219-Article in journal (Refereed)
    Abstract [en]

    The hypertrophic cardiomyopathy (HCM) disease process is not only limited to cardiomyocyte abnormalities but also engages the extracellular matrix. Hyaluronan (HA) and its receptor CD44 are involved in cellular growth and tissue proliferation but have so far been less studied in myocardial hypertrophy. In HCM, collagens are abundant but their histological distribution and relation to hyaluronan have not been described. Material and Methods. Myocardial specimens from 5 patients with symptomatic left ventricular tract obstruction undergoing myectomy due to HCM were processed for histochemistry and immunohistochemistry. Results. HA staining was more intense in HCM patients. The histological distribution of HA was the same in patients and controls, that is, interstitial staining including the space between cardiomyocytes, in fibrous septa, and in the adventitia of intramyocardial blood vessels. CD44 was not detected in the myocardium of patients or controls. Collagen I showed the same general localisation as HA but detailed distribution differed. Conclusions. This is the first study that describes the distribution of hyaluronan in human HCM. HA staining is more intense in HCM patients but without coexpression of its receptor CD44, at least not in the chronic phase of HCM. HA and collagen I have the same localisation.

  • 20.
    Henein, Michael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Arvidsson, Sandra
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Pilebro, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Backman, Christer
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Long mitral valve leaflets determine left ventricular outflow tract obstruction during exercise in hypertrophic cardiomyopathy2016In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 212, p. 47-53Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Development of left ventricular outflow tract obstruction (LVOTO) in patients with hypertrophic cardiomyopathy (HCM) is important for explaining symptoms and designing management. LVOTO is mostly caused by a combination of septal hypertrophy and systolic anterior movement of the mitral valve (SAM). The aim of the present study was to determine predictors of exercise induced LVOTO in a group of HCM patients.

    METHODS: We performed supine exercise Doppler echocardiography, including measurements of LV morphology and function and anterior mitral leaflet length, in 51 mildly symptomatic HCM (septal thickness≥15mm) and compared them with 50 healthy controls. Measurements were made at 1) rest, 2) Valsalva maneuver, 3) peak exercise and 4) post exercise. LVOTO was diagnosed as a LVOT gradient of >30mmHg at rest, after Valsalva and after exercise or ≥50mmHg at peak exercise.

    RESULTS: All patients stopped exercise because of exhaustion. 35% of the patients had resting LVOTO and 48% during Valsalva. At peak exercise, only 37% had LVOTO, who increased to 64% post exercise. Patients who developed LVOTO at peak exercise were more prone to continue having it post exercise (p<0.001), to have attenuated systolic blood pressure rise (p=0.011) and to have long anterior mitral valve leaflets (p<0.001). Backward multiple regression analysis showed the anterior mitral leaflet length as the strongest single independent predictor (β=0.36, p=0.010) for increased LVOT velocities, followed by basal septal thickness.

    CONCLUSION: In patients with HCM, LV outflow tract obstruction seems to be relatively uncommon during exercise but rather occurring minutes after stopping exercise. Exercise LVOTO seems to be determined by long anterior mitral leaflets in addition to the well established septal hypertrophy.

  • 21.
    Henein, Michael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Holmgren, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Holmner, Fredrik
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Long anterior mitral leaflet causing outflow tract obstruction in a symptomatic patient with hypertrophic cardiomyopathy: the role of mitral valve surgical correction2016In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 204, p. 86-87Article in journal (Refereed)
  • 22.
    Henein, Michael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lindmark, Krister
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Impaired left ventricular systolic function reserve limits cardiac output and exercise capacity in HFpEF patients due to systemic hypertension2013In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 168, no 2, p. 1088-1093Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Heart failure (HF) patients with preserved left ventricular (LV) ejection fraction (EF) (HFpEF) due to systemic hypertension (SHT) are known to have limited exercise tolerance. Despite having normal EF at rest, we hypothesize that these patients have abnormal systolic function reserve limiting their exercise capacity. METHODS: Seventeen patients with SHT (mean age 68±9years) but no valve disease and 14 healthy individuals (mean age of 65±10years) underwent resting and peak exercise echocardiography using conventional, tissue Doppler and speckle tracking techniques. The differences between resting and peak exercise values were also analyzed (Δ). Exercise capacity was determined as the workload divided by body surface area. RESULTS: Resting values for left atrial (LA) volume/BSA (r=-0.66, p<0.001) and global longitudinal strain rate (GLSR) in early (e) and late (a) diastole (r=0.47 and 0.46, p<0.05 for both) correlated with exercise capacity. LVEF increased during exercise in normals (mean Δ EF=10±8%) but failed to do so in patients (mean Δ EF=0.6±9%, p<0.001 between groups). LV GLSR during systole (s) also failed to increase with exercise in patients, to the same extent as it did in normals (0.2±0.2 vs. 0.6±0.3 1/s, p<0.001). The difference between rest and exercise (Δ) in LV lateral wall systolic velocity from tissue Doppler (s') (0.71, p<0.001), Δ in cardiac output (r=0.60, p<0.001) and Δ GLSRs (r=0.48, p<0.05) all correlated with exercise capacity independent of changes in heart rate. CONCLUSION: HFpEF patients with hypertensive LV disease have significantly limited exercise capacity which is related to left atrial enlargement as well as compromised LV systolic function at the time of the symptoms. The limited myocardial systolic function reserve seems to be underlying important explanation for their limited exercise capacity.

  • 23.
    Henein, Michael
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology. Umeå Heart Center.
    The normal impact of age and gender on right heart structure and function2014In: Echocardiography, ISSN 0742-2822, E-ISSN 1540-8175, Vol. 31, no 1, p. 5-11Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: As the proportion of elderly population increases rapidly, it might be difficult to differentiate physiological changes in cardiac function due to age from the pathophysiological ones. In addition, cardiac function variations with gender are well established. The right ventricular (RV) plays an important role in the overall cardiac function, but reference values varying with age and gender are lacking.

    MATERIAL AND METHODS: We studied 255 healthy individuals from a general population register, mean age of 58 ± 19 (range 22-89) years, 125 were females. We used 2D and M-mode echocardiography to measure RV inflow tract (RVIT) and RV outflow tract (RVOT) dimensions and fractional shortening (fs). Spectral Doppler echocardiography was also used.

    RESULTS: We found a modest decrease in RVIT dimensions (P < 0.05), but increase in RVOT dimensions with advancing age (P < 0.05). A small decrease in RVOT fs with age was also found (P < 0.05). Estimated pulmonary pressures and pulmonary vascular resistance increased (P < 0.001) as did RVOT wall thickness (P < 0.001), but RV diastolic function was not altered (P < 0.001) with age. Despite correction for the BSA, males showed larger RVIT dimensions (P < 0.001 for both), but RVOT end-diastolic dimension was larger in females (P < 0.05). RVIT and RVOT fractional shortening were increased in females (P < 0.01 for both).

    CONCLUSION: In a cohort of normal individuals, age has significant impact on RV structure and function, inlet area falls and outflow tract dimensions increase and fractional shortening also increase in females. In addition, RVOT wall thickness significantly increases and Doppler markers of pulmonary vascular resistance show a consistent rise. The age-related changes should carefully be considered when commenting on normality and when using absolute values.

  • 24.
    Johansson, Bengt
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Stål, Per
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Myocardial capillary supply is limited in hypertrophic cardiomyopathy: a morphological analysis2008In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 126, no 2, p. 252-257Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To clarify the morphological basis of the limited coronary reserve in hypertrophic cardiomyopathy (HCM). BACKGROUND: Some of the symptoms in Hypertrophic cardiomyopathy (HCM), such as chest pain, dyspnea and arrhythmia, may be explained by myocardial ischemia. Many patients with HCM are known to exhibit these symptoms in the absence of atherosclerosis in the major coronary vessels. Decreased myocardial perfusion has been demonstrated in HCM, however, little is known about the myocardial capillary morphology in this disease. METHODS: Using immunohistochemistry and morphometry, we analysed capillaries and cardiomyocytes in myectomy specimens from 5 patients with HCM with moderate hypertrophy and left ventricular outflow tract obstruction and in 5 control hearts. RESULTS: The number of capillaries per cardiomyocyte (p<0.009) and number of capillaries per cardiomyocyte area unit, reflecting cardiomyocyte mass (p=0.009), were lower in individuals with HCM, i.e. indicating loss of capillaries. In HCM, the capillary density was 33% lower (p<0.05). CONCLUSIONS: Our morphologic findings show that the capillary supply, and thus the coronary reserve, is impaired in HCM with moderate hypertrophy and left ventricular outflow tract obstruction. These data may partly explain the limitation of myocardial perfusion in HCM, which is associated with worse prognosis. Furthermore, we present evidence of actual loss of myocardial capillaries in HCM and a defective capillary growth.

  • 25. Kostareva, Anna
    et al.
    Gudkova, Alexandra
    Sjöberg, Gunnar
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Semernin, Eugene
    Krutikov, Alexander
    Shlyakhto, Eugene
    Sejersen, Thomas
    Deletion in TNNI3 gene is associated with restrictive cardiomyopathy2009In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 131, no 3, p. 410-412Article in journal (Refereed)
  • 26.
    Lindqvist, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Borgström, E
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Gustafsson, Ulf
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Henein, Michael Y
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Asynchronous normal regional left ventricular function assessed by speckle tracking echocardiography: appearances can be deceptive2009In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 134, no 2, p. 195-200Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Speckle tracking echocardiography (STE) is an angle independent method with high temporal resolution, which offers quantification of regional left ventricular (LV) wall motion. We studied radial and longitudinal LV wall motion by STE in healthy subjects with normal wall motion analysis (WMA) by eye-balling. MATERIALS AND METHODS: Eighteen healthy subjects were studied. We acquired parasternal short and apical long axis projections to determine the basal, mid and apical radial and longitudinal functions. At each level we measured; (I) radial and longitudinal peak displacement and displacement at aortic valve closure (AVC) and (II) the time interval from the Q-wave to the AVC and peak displacement. RESULTS: WMA indicated normal wall motion in all subjects. The mean peak radial displacement varied in different segments (range 3.9-9.8 mm) with highest values in the mid-level (6.9+/-1.5 mm), compared to basal level (5.9+/-1.0 mm, p<0.01) and apical level (5.4+/-1.0 mm, p<0.001). The time from Q-wave to AVC was 393 ms and in 89% of the analysed segments peak radial displacement occurred after AVC, thus mean peak radial displacement occurred 60 ms after AVC. The peak longitudinal amplitude was more synchronous with respect to AVC and with the highest amplitudes found in the two basal segments. CONCLUSIONS: In normal LV function, significant differences in peak displacement exist between segments at various LV levels using STE. In addition, in early diastole, significant discrepancy occurs between radial and longitudinal time of peak displacement, suggesting a shape change. Finally, while radial displacement was highest at mid-cavity level longitudinal displacement was highest at basal level.

  • 27.
    Lindqvist, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Henein, Michael Y
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Cardiac mechanisms underlying normal exercise tolerance: gender impact2012In: European Journal of Applied Physiology, ISSN 1439-6319, E-ISSN 1439-6327, Vol. 112, no 2, p. 451-459Article in journal (Refereed)
    Abstract [en]

    The aim of this study is to test our hypothesis that normal exercise tolerance differs according to gender and to identify potential functional cardiac relationships, which could explain those differences. A total of 44 healthy individuals with mean age of 49 ± 12 years (28-74 years, 22 males) constituted the study cohort. All individuals underwent resting and exercise Doppler echocardiogram simultaneously with peak oxygen uptake analysis (pVO(2)). At equal pVO(2), males achieved higher peak exercise workload (p < 0.001) and females higher heart rate (p < 0.001) but the two groups maintained similar indexed left ventricular (LV) stroke volume (SV) and cardiac output. Indexed LV end-diastolic (LVDVI) and end-systolic volumes (LVSVI) were smaller in females (p < 0.001 and p < 0.01, respectively), but filling time (FT) was shorter (p < 0.001) and they had higher early diastolic (E) velocity (p = 0.004), E/E (m) (myocardial E velocity) (p < 0.001) and global longitudinal strain rate atrial velocity (GLSRa') (p = 0.02), compared to males. In males, workload (p < 0.01), LVDVI (p < 0.01), LVSVI (p < 0.05), SVI (p < 0.001) directly but LV myocardial isovolumic relaxation time (IVRTm) (p < 0.01) inversely correlated with pVO(2). In females, mitral E velocity (p < 0.01), GLSRs' (p < 0.05) positively and LVFT negatively (p < 0.05) correlated with pVO(2). In a multivariable analysis SVI in males (p < 0.01) and GLSRs' in females (p < 0.01) were the strongest predictors for pVO(2). Thus, normal exercise capacity as determined by pVO(2) is related to the indexed stroke volume in males and left atrial pressure in females. These native normal differences between genders may explain the known vulnerability of women to endurance exercise compared to men.

  • 28.
    Lindqvist, Per
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Olofsson, Bert-Ove
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Backman, Christer
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Lundblad, Dan
    Sunderbyn Research Unit Luleå, Sweden.
    Forsberg, H
    Department of Medicine, Sunderbyn Research Unit,Luleå, Sweden.
    Henein, Michael Y
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Ventricular dysfunction in type 1 myotonic dystrophy: Electrical, mechanical, or both?2010In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 143, no 3, p. 378-384Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Myotonic dystrophy type 1 (DM1) is a systemic disease which affects the heart and may be a cause of sudden death. Conduction disturbances are the major cardiac abnormalities seen in this condition. We sought to assess electrical and mechanical cardiac functions to identify abnormalities that might explain sudden cardiac death in DM1. METHODS: Thirty six patients with DM1 and 16 controls were studied using echocardiography including myocardial Doppler. ECG recordings were also obtained. RESULTS: Left ventricular (LV) dimensions were maintained but systolic function was reduced (p<0.001), including stroke volume (p<0.05). LV segmental myocardial isovolumic contraction time was prolonged (p<0.001) and correlated with PR interval (p<0.001). Isovolumic relaxation time was prolonged (p<0.05) and filling time was reduced (p<0.001). LV cavity was significantly asynchronous demonstrated by prolonged total isovolumic time (t-IVT) (p<0.001), high Tei index (p<0.001) and low ejection index (p<0.001). Right ventricular (RV) strain was reduced (p<0.001) as were its systolic and diastolic velocities (p<0.05 for both). 22/36 patients had prolonged LV t-IVT>12.3 s/min (upper 95% normal CI), 13 of whom had PR>/=200 ms, 11 had QRS duration >120 ms (5 had combined abnormality) and the remaining 5 had neither. Over the 3 years follow up 10 patients had events, 6 of them cardiac. t-IVT was prolonged in 5/6 patients, PR interval in 4 and QRS duration in one. CONCLUSIONS: In DM1 patients, LV conventional measurements are modestly impaired but cardiac time relations suggest marked asynchronous cavity function. Although our findings were primarily explained on the basis of long PR interval or broad QRS duration a minority presented an evidence for myocardial cause of asynchrony rather than electrical. Early identification of such abnormalities may guide towards a need for additional electrical resynchronization therapy which may improve survival in a way similar to what has been shown in heart failure trials.

  • 29.
    Lorén, Christina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Dahl, Christen P.
    Do, Lan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Almaas, Vibeke M.
    Geiran, Odd R.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Low Molecular Mass Myocardial Hyaluronan in Human Hypertrophic Cardiomyopathy2019In: Cells, ISSN 2073-4409, Vol. 8, no 2, article id 97Article in journal (Refereed)
    Abstract [en]

    During the development of hypertrophic cardiomyopathy, the heart returns to fetal energy metabolism where cells utilize more glucose instead of fatty acids as a source of energy. Metabolism of glucose can increase synthesis of the extracellular glycosaminoglycan hyaluronan, which has been shown to be involved in the development of cardiac hypertrophy and fibrosis. The aim of this study was to investigate hyaluronan metabolism in cardiac tissue from patients with hypertrophic cardiomyopathy in relation to cardiac growth. NMR and qRT-PCR analysis of human cardiac tissue from hypertrophic cardiomyopathy patients and healthy control hearts showed dysregulated glucose and hyaluronan metabolism in the patients. Gas phase electrophoresis revealed a higher amount of low molecular mass hyaluronan and larger cardiomyocytes in cardiac tissue from patients with hypertrophic cardiomyopathy. Histochemistry showed high concentrations of hyaluronan around individual cardiomyocytes in hearts from hypertrophic cardiomyopathy patients. Experimentally, we could also observe accumulation of low molecular mass hyaluronan in cardiac hypertrophy in a rat model. In conclusion, the development of hypertrophic cardiomyopathy with increased glucose metabolism affected both hyaluronan molecular mass and amount. The process of regulating cardiomyocyte size seems to involve fragmentation of hyaluronan.

  • 30.
    Lysell-Bergström, Catharina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Widman, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Johnson, Owe
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Progressive conduction disease late after adriamycin treatment of lymphoma, despite normalised ejection fraction2014In: International Cardiovascular Forum Journal, ISSN 2410-2636, Vol. 1, no 3, p. 160-161Article in journal (Refereed)
  • 31. Magnusson, Peter
    et al.
    Gadler, Fredrik
    Liv, Per
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Causes of death and mortality in hypertrophic cardiomyopathy patients with implantable defibrillators in Sweden2016In: Journal of Cardiovascular Medicine, ISSN 1558-2027, E-ISSN 1558-2035, Vol. 17, no 7, p. 478-484Article in journal (Refereed)
    Abstract [en]

    AimsImplantable defibrillators (ICDs) successfully terminate ventricular arrhythmias in hypertrophic cardiomyopathy (HCM), protect against bradycardia, and monitor atrial arrhythmias. This may alter the natural history and causes of death.MethodsThis nationwide observational longitudinal retrospective study of all HCM patients implanted during 1995-2012 obtained data from the Swedish ICD Registry, the National Patient Register, the Cause of Death Register, and were validated by review of medical records.ResultsOf 342 patients (mean age 51.8 years, 70.8% males), 45 died during a total follow-up of 1847 years (mean 5.4 years). Mean age at death was 68.2 years (range 21-83 years; 12 were 75 years). Mean follow-up time among the deceased was 4.9 years (quartiles 1.4-7.4 years). All-cause mortality was higher in HCM patients compared with the age and sex-matched Swedish general population (standardized mortality ratio 3.4; 95% confidence interval 2.4-4.5; P<0.001). Main cause of death was heart failure (n=27), stroke (n=5), cancer (n=3), myocardial infarction (n=2), sepsis (n=2), and others (n=4). Two patients died suddenly, one after the ICD was turned off because of inappropriate shocks, and one patient whose device system was removed after infection. HCM was the main cause of death in 76% of the cases, mainly because of progressive heart failure.ConclusionFor HCM patients, ICDs almost eliminate premature arrhythmic death and result in a shift to heart failure as the cause of death in the majority of cases. Still, mortality in HCM patients remains elevated and management of heart failure and comorbidities must be improved to increase survival.

  • 32.
    Magnusson, Peter
    et al.
    Cardiology Research Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Gadler, Fredrik
    Cardiology Research Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Liv, Per
    Centre for Research and Development, Uppsala University/Region Gävleborg, Gävle, Sweden.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Hypertrophic Cardiomyopathy and Implantable Defibrillators in Sweden: Inappropriate Shocks and Complications Requiring Surgery2015In: Cardiovascular Electrophysiology, ISSN 1045-3873, E-ISSN 1540-8167, Vol. 26, no 10, p. 1088-1094Article in journal (Refereed)
    Abstract [en]

    Inappropriate ICD Shocks and Complications in HCM IntroductionThe expanded use of implantable cardioverter-defibrillators (ICDs) to prevent sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) based on risk stratification in individuals without known previous ventricular arrhythmia is justified by an acceptable risk of device-related adverse events. Such complications, leading to surgical procedures or inappropriate electrical shocks, may impact mortality, morbidity, quality of life, and cost-effectiveness. Methods and ResultsFrom the Swedish ICD Registry, implants due to HCM since 1995 until November 2012 in patients aged 18 years were identified and medical records reviewed. Inappropriate ICD shock occurred in 14.3% (46 of 321 patients; mean follow-up 5.4 years) with a recurrent episode in 28.2% of them. In multivariable analysis, hazard ratio (HR) for atrial fibrillation was 3.5 (95% confidence interval 1.8-6.8; P < 0.001) but showed no significant association to male sex (HR = 0.77), age (HR = 0.99), secondary indication (HR = 1.02) or device, ICD-DR/CRTD vs. ICD-VR (HR 1.07). Inappropriate shocks were triggered by atrial fibrillation/flutter or ectopic tachycardia (56.5%), sinus tachycardia (14.5%), lead dysfunction (14.5%), and T-wave oversensing (13.0%). A reintervention, besides elective device replacement, occurred in 92 patients (totally 150 procedures). The majority were lead-related (70.0%) procedures, especially of the ICD lead. Reintervention was associated with female sex (HR = 1.6 P = 0.04). ConclusionInappropriate ICD shock triggered by atrial arrhythmias, lead dysfunction, or complications requiring surgical interventions, is a concern in HCM patients who will be eligible for long-term prevention of sudden death. Efforts to avoid adverse events and provide balanced risk-benefit information are important, especially in primary prevention.

  • 33. Magnusson, Peter
    et al.
    Gadler, Fredrik
    Liv, Per
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Risk Markers and Appropriate Implantable Defibrillator Therapy in Hypertrophic Cardiomyopathy2016In: Pacing and Clinical Electrophysiology, ISSN 0147-8389, E-ISSN 1540-8159, Vol. 39, no 3, p. 291-301Article in journal (Refereed)
    Abstract [en]

    Background Risk stratification of sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) is mainly based on evaluations from patients at highly specialized centers.

    Aim To evaluate risk markers for appropriate implantable cardioverter defibrillator (ICD) therapy in an unselected, nationwide cohort of HCM. MethodsPatients with an ICD due to HCM were identified from the Swedish ICD Registry since its start in 1995, merged with Patient Register data, and medical records were retrieved. Risk markers for ventricular arrhythmias leading to appropriate ICD therapy were analyzed using Cox proportional hazard ratio (HR).

    Results Of 321 patients (70.1% males), at least one appropriate therapy occurred in 77 (24.0%) during a mean follow-up of 5.4 years (5.3% per year; primary prevention 4.5%, secondary prevention 7.0%). Cumulative incidences at 1 year, 3 years, and 5 years were 8.1%, 15.3%, and 21.3%, respectively. Cardioversion effectively restored rhythm in 52% of the first episode and antitachycardia pacing was sufficient in the remaining. For the whole cohort, ejection fraction (EF) <50% (HR 2.63; P < 0.001) was associated with appropriate ICD therapy. In primary prevention, patients with established risk markers experienced appropriate therapy; atrial fibrillation (AF; HR 2.54; P = 0.010), EF < 50% (HR 2.78; P = 0.004), and nonsustained ventricular tachycardia (HR 1.80; P = 0.109) had the highest HR, and wall thickness 30 mm, syncope, exercise blood pressure response, or family history of SCD had weaker associations.

    Conclusion ICD therapy successfully terminates ventricular arrhythmias in HCM. In addition to conventional risk markers, a history of AF or EF < 50% may be considered in risk stratification.

  • 34. Magnusson, Peter
    et al.
    Jonsson, Jessica
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Fredriksson, Lennart
    Living with hypertrophic cardiomyopathy and an implantable defibrillator2017In: BMC Cardiovascular Disorders, ISSN 1471-2261, E-ISSN 1471-2261, Vol. 17, article id 121Article in journal (Refereed)
    Abstract [en]

    Background: ICDs efficiently terminate life-threatening arrhythmias, but complications occur during long-term follow-up. Patients' own perspective is largely unknown. The aim of the study was to describe experiences of hypertrophic cardiomyopathy (HCM) patients with implantable defibrillators (ICDs).

    Methods: We analyzed 26 Swedish patient interviews using hermeneutics and latent content analysis.

    Results: Patients (aged 27-76 years) were limited by HCM especially if it deteriorates into heart failure. The ICD implies safety, gratitude, and is accepted as a part of the body even when inappropriate ICD shocks are encountered. Nobody regretted the implant. Both the disease and the ICD affected professional life and leisure time activities, especially at younger ages. Family support was usually strong, but sometimes resulted in overprotection, whereas health care focused on medical issues. Despite limitations, patients adapted, accepted, and managed challenges.

    Conclusion: HCM patients with ICDs reported good spirit and hope even though they had to adapt and accept limitations over time.

  • 35. Magnusson, Peter
    et al.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    EvaLuation Using Cardiac Insertable Devices And TelephonE in Hypertrophic Cardiomyopathy (ELUCIDATE HCM) – rationale and design: a prospective observational study on incidence of arrhythmias in Sweden2017In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 7, no 12, article id e019541Article in journal (Refereed)
    Abstract [en]

    Introduction: Hypertrophic cardiomyopathy (HCM) is a heterogeneous disease associated with sudden cardiac death (SCD) mainly due to ventricular tachycardia (VT) or fibrillation even though life-threatening bradycardia occurs. Risk stratification takes several variables into consideration including non-sustained VT (NSVT). An implantable cardioverter defibrillator effectively prevents SCD. Atrial fibrillation (AF) is common among patients with HCM and warrants anticoagulation even without conventional risk factors according to European guidelines. Routinely, the evaluation of arrhythmias using a 48-hour ambulatory external monitor takes place every 6-24 months if patients do not report palpitations. The remaining time the potential burden arrhythmia is unknown. Therefore, the aim of the present study is to assess NSVT and AF incidence during 18 months by an insertable cardiac monitor (ICM).

    Methods: Adult patients, aged 18-65 years, with a validated diagnosis of HCM are eligible for the study. The study sample is planned to include 30 patients. A Confirm Rx is implanted at the level of the fourth rib on the left side subcutaneously after local anaesthesia. The application for monitoring is installed in the patients' smartphone and symptoms registered by the patient activation and VT detection programmed as 160 bpm during >= 8 intervals. An AF episode is recorded based on >= 2 min duration. Bradycardia is recorded at <= 40 bpm or pause >= 3.0 s. The patients are followed during 18 months before explant.

    Ethics and dissemination: The study was approved by The Regional Ethical Committee in Umea (protocol number 2017/13-31). The study protocol, including variables and prespecified research questions, the study was registered at Clinical Trial Registration NCT03259113. Each patient is informed about the study in both oral and written form by a physician and included after written consent.

  • 36. Magnusson, Peter
    et al.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Gadler, Fredrik
    Karlsson, Jan
    Health-related quality of life in hypertrophic cardiomyopathy patients with implantable defibrillators2016In: Health and Quality of Life Outcomes, ISSN 1477-7525, E-ISSN 1477-7525, Vol. 14, article id 62Article in journal (Refereed)
    Abstract [en]

    Background: Health-related quality of life (HRQL) in hypertrophic cardiomyopathy (HCM) patients with implantable cardioverter-defibrillators (ICDs) is largely unknown. The aim was to assess HRQL, including comparisons between groups, using the questionnaire SF-36, and compare it to a Swedish age-and sex-matched population. Methods and Results: Validated data on adult HCM patients with ICDs were used. The SF-36 response rate was 82.5 % and 245 patients (mean age 55.9 years, 70.2 % men) were analyzed using the Mann-Whitney U-test, t-test, Spearman correlation and effect size calculations. In all SF-36 domains the patients' score was lower (p-value of <0.0001) than norms except for bodily pain. The general health domain showed the highest effect size (0.77) and the impact was more pronounced in the SF-36 physical component summary score (0.62) than the mental component summary score (0.46). Older age was correlated with lower scores on the physical component and higher scores on the mental component. Atrial fibrillation and/or systolic heart failure were associated with worse physical health. HRQL was similar in primary vs secondary prevention cases. Inappropriate ICD shock was associated with worse mental health while appropriate therapy trended toward better mental health. Conclusion: HCM patients with ICDs suffer from poor HRQL regardless of age, sex, or primary vs secondary prevention indication. Atrial fibrillation and systolic heart failure are determinants of poor physical health. Inappropriate shocks, but not appropriate therapies, are associated with poorer mental health.

  • 37. Magnusson, Peter
    et al.
    Palm, Andreas
    Branden, Eva
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology. Heart Center.
    Misclassification of hypertrophic cardiomyopathy: validation of diagnostic codes2017In: Clinical Epidemiology, ISSN 1179-1349, E-ISSN 1179-1349, Vol. 9, p. 403-410Article in journal (Refereed)
    Abstract [en]

    Purpose: To validate diagnostic codes for hypertrophic cardiomyopathy (HCM), analyze misclassfications, and estimate the prevalence of HCM in an unselected Swedish regional cohort.

    Patients and methods: Using the hospitals’ electronic medical records (used for the Swedish National Patient Register), we identified 136 patients from 2006 to 2016 with the HCM-related codes 142.1 and 142.2 (International Classification of Diseases).

    Results: Of a total of 129 residents in the catchment area, 88 patients were correctly classified as HCM (positive predictive value 68.2%) and 41 patients (31.8%) were misclassified as HCM. Among the 88 HCM patients (52.2% males), 74 were alive and 14 were dead (15.9%). This yields an HCM prevalence of 74/183,337, that is, 4.0 diagnosed cases per 10,000 in the adult population aged ≥18 years. The underlying diagnoses of misclassified cases were mainly hypertension (31.7%) and aortic stenosis (22.0%). Other types of cardiomyopathies accounted for several cases of misclassification: dilated (nonischemic or ischemic), left ventricular noncompaction, and Takotsubo. Miscellaneous diagnoses were amyloidosis, pulmonary stenosis combined with ventricular septal defect, aortic insufficiency, athelete’s heart, and atrioventricular conduction abnormality. The mean age was not significantly different between HCM and misclassified patients (65.8±15.8 vs 70.1±13.4 years; P=0.177). There were 47.8% females among HCM and 60.8% females among misclassified (P=0.118).

    Conclusion: One-third of patients diagnosed as HCM are misclassified, so registry data should be interpreted with caution. A correct diagnosis is important for decision-making and implementation of optimal HCM care; efforts should be made to increase awareness of HCM and diagnostic competence throughout the health care system.

  • 38. Maras, Dejan
    et al.
    Chung, Robin
    Duncan, Alison
    Li, Wei
    Thorp, Christine
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Henein, Michael Y
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Patterns of cardiac dysfunction coinciding with exertional breathlessness in hypertrophic cardiomyopathy2013In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 170, no 2, p. 233-238Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The commonest cause of breathlessness in hypertrophic cardiomyopathy (HCM) is left ventricular outflow tract (LVOT) obstruction which improves with its removal. However, in the absence of outflow tract obstruction, as in dilated cardiomyopathy, patients may be limited by similar symptoms, thus suggesting a potential common mechanism for the two conditions. We aimed to assess cardiac function at the time of symptoms in a group of unselected patients with HCM to identify other patterns of cardiac dysfunction which coincide with their breathlessness.

    METHODS: We studied 37 HCM patients (aged 55±15years, 13 female) with septal thickness >15mm and 17 controls (aged 58±12years, 12 female) using Doppler echocardiography, at rest and at peak dobutamine stress. Stress end points were symptoms, >20mmHg drop in systolic blood pressure, arrhythmia, or maximum dobutamine dosage of 40μg/kg/min.

    RESULTS: At rest: LV systolic function was maintained (EF 68±7 v 76±12%, respectively), LVOT velocity raised (p<0.005), lateral and septal long axis amplitude reduced (p<0.05 and p<0.005, respectively) and dyssynchronous and QRS duration was also broader (p<0.005) in patients compared to controls. At peak stress: Overall LVOT velocities were higher in patients than controls (4.3±1.7 v 1.7±1.0m/s, p<0.005, respectively) due to systolic anterior movement of the mitral valve and mitral regurgitation developing. In the 15 patients who did not develop significant LVOT obstruction (velocity <4m/s), LV ejection time increased and peak systolic amplitude did not increase. In the 10 patients with neither LVOT obstruction nor restrictive filling, QRS duration prolonged by 12ms (p <0.05), post-ejection shortening worsened and peak systolic amplitude fell (p<0.005). Also, LV ejection time prolonged by 5s/min (p<0.05), filling time failed to increase as it did in controls (p<0.005) and Tei index was higher than controls (p<0.01).

    CONCLUSION: Exertional breathlessness in HCM is associated with LV outflow tract obstruction and functional mitral regurgitation in almost two thirds of patients. The remaining one third have either resistant restrictive physiology or dyssynchronous cavity at fast heart rate. Despite similar exercise limiting breathlessness in the three groups, means of management should be quite different.

  • 39.
    Mörner, Stellan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Suhr, Ole B
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Kazzam, Elsadig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Amyloid heart disease mimicking hypertrophic cardiomyopathy.2005In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 258, no 3, p. 225-230Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate the importance of transthyretin (TTR) gene mutations in explaining the phenotypic expression in patients diagnosed with hypertrophic cardiomyopathy (HCM) in northern Sweden. BACKGROUND: Hypertrophic cardiomyopathy is relatively common and often caused by mutations in sarcomeric protein genes. Mutations in the TTR gene are also common, one of which causes familial amyloid polyneuropathy (FAP), with peripheral polyneuropathy and frequently, cardiac hypertrophy. These circumstances were highlighted by the finding of an index case with amyloidosis, presenting itself as HCM. Initial rectal and fat biopsies did not show amyloid deposits. Later on, the patient was shown to carry a TTR gene mutation, and cardiac amyloidosis was confirmed by myocardial biopsy. Only then was a repeated fat biopsy positive for amyloid deposits. DESIGN: Cross-sectional study. SETTING: Cardiology tertiary referral centre. SUBJECTS: Forty-six unrelated individuals with HCM and the index case were included. Common diagnostic criteria for HCM were used. The 46 patients with HCM were previously analysed for mutations in eight sarcomeric protein genes and the TTR gene was now analysed by denaturing high-performance liquid chromatography and direct sequencing. RESULTS: One mutation in the TTR gene (Val30Met) was found in three individuals and the index case. CONCLUSIONS: Three of the 46 cases with HCM carried the Val30Met mutation, and were considered likely to have cardiac amyloidosis, like the index case. As a correct diagnosis of cardiac amyloidosis is mandatory for a potentially life-saving treatment, TTR mutation analysis should be considered in cases of HCM not explained by mutations in sarcomeric protein genes.

  • 40.
    Mörner, Stellan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology. Heart centre, Umeå.
    Henein, Michael Y
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology. Heart centre, Umeå.
    Cardiovascular genetics: the ultimate investigation for optimum management?2013In: International Cardiovascular Forum Journal, ISSN 2410-2636, Vol. 1, no 2, p. 57-58Article in journal (Other academic)
  • 41.
    Mörner, Stellan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Henein, Michael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Arrhythmogenic left ventricular apical aneurysm in hypertrophic cardiomyopathy2010In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 151, no 1, p. e8-e9Article in journal (Refereed)
    Abstract [en]

    A 70-year old lady with prior myectomy for hypertrophic obstructive cardiomyopathy presented with sustained ventricular tachycardia. She was found to have a large left ventricular (LV) apical aneurysm. Surgical intervention was not advised, due to the risk of creating a small LV cavity after surgery and ICD was not advised based on the risk of injuring a very thin walled aneurysm. The patient's arrhythmia settled on medical therapy, but unfortunately she suffered an unwitnessed death three months later.

    This case represents a rare complication to a rare disease with limited management options. In such patients evidence based medicine is of little help, if any.

  • 42.
    Mörner, Stellan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Johansson, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Henein, Michael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Letter to editor: Tako-tsubo cardiomyopathy in the setting of pre-existing myocardial disease2010In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 145, no 3, p. 605-Article, review/survey (Other academic)
  • 43.
    Mörner, Stellan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Mellberg, Caroline
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Olofsson, Bert-Ove
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Backman, Christer
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Henein, Michael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lundblad, Dan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Forsberg, H
    Profound cardiac conduction delay predicts mortality in myotonic dystrophy type 1.2010In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 268, no 1, p. 59-65Article in journal (Refereed)
    Abstract [en]

    Background. Myotonic dystrophy type 1 (DM1) is known to affect mainly the musculoskeletal system. Early mortality is related to respiratory disease and possibly additional cardiovascular complications. Aims. To identify possible cardiovascular disturbances that could predict survival of DM1 patients. Methods. We studied 30 DM1 patients (mean age 41 +/- 13.5 years, range 16-71, 15 women) who were cardiovascularly stable and compared them with 29 controls (mean age 55 +/- 7.8 years, range 42-66, 14 women) using electrocardiography (ECG) and conventional transthoracic echocardiography. The subgroup that survived a follow-up period of 17 years was re-examined using the same protocol. Results. Of the 30 patients, 10 died of a documented respiratory cause and three of acute myocardial incidents. Compared with controls, left ventricular cavity size, corrected to body surface area, was slightly enlarged at end systole (P < 0.05) and hence fractional shortening was reduced (P < 0.01). Nine patients had first-degree heart block and 15 had a QRS duration >90 ms. Of all ECG and echocardiographic measurements, the sum of QRS duration + PR interval was the best predictor of mortality as shown by the area under the receiver operating characteristic curve of 85%, sensitivity of 70% and specificity of 84%. Conclusions. These findings suggest that silent cardiac dysfunction in DM1 patients may cause significant disturbances that over time result in serious complications. Regular follow-up of such patients with detailed electrical and mechanical cardiac assessment may suggest a need for early intervention that may avoid early mortality in some.

  • 44.
    Mörner, Stellan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Kazzam, Elsadig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Right ventricular dysfunction in hypertrophic cardiomyopathy as evidenced by the myocardial performance index2007In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 124, no 1, p. 57-63Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Left ventricular function in hypertrophic cardiomyopathy (HCM) has been extensively studied, whereas right ventricular function is much less explored. The myocardial performance index (MPI) has been shown to be useful in functional assessment of both ventricles. Furthermore, right ventricular MPI was found to be of predictive value in heart failure due to dilated cardiomyopathy and ischemic heart disease. The aim of this study was, therefore, to evaluate the right ventricular MPI in patients with HCM. METHODS: Fifty patients with HCM and 250 healthy controls were studied by conventional Doppler echocardiography and Doppler tissue imaging. RESULTS: Patients showed increased global, 0.48 (0.15) vs. 0.21 (0.14), and regional, 0.71 (0.23) vs. 0.55 (0.17), right ventricular MPI, as compared to controls, p<0.001. Tricuspid annular plane systolic excursion and peak myocardial systolic velocities were also reduced. Patients with dyspnoea had increased global right ventricular MPI (0.53 vs. 0.36, p<0.05) as compared to those without dyspnoea. CONCLUSION: In the present study, patients with HCM showed evidence of both global and regional right ventricular dysfunction. Previous studies of the right ventricle in HCM have only shown evidence of diastolic dysfunction, contrary to our results, showing impairment of both systolic and diastolic function. This study suggests that HCM should not only be regarded as an isolated disease of the left ventricle, but rather as a biventricular disease. The predictive value of our findings in HCM needs to be assessed in a separate study with special reference to those with and without dyspnoea.

  • 45.
    Mörner, Stellan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Richard, Pascale
    Kazzam, Elsadig
    Hainque, Bernard
    Schwartz, Ketty
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Deletion in the cardiac troponin I gene in a family from Northern Sweden with hypertrophic cardiomyopathy2000In: Journal of Molecular and Cellular Cardiology, ISSN 0022-2828, E-ISSN 1095-8584, Vol. 32, no 3, p. 521-525Article in journal (Refereed)
    Abstract [en]

    The cardiac troponin I gene has been described to be associated with hypertrophic cardiomyopathy. Until now, mutations in this gene have been found only in the Japanese population. We now present the first non-Japanese family, from northern Sweden, with a mutation in the cardiac troponin I gene. Clinical diagnose was based on echocardiography, with a maximum left ventricular wall thickness of >13 mm, or major electrocardiographic abnormalities, excluding subjects with other known causes of cardiac hypertrophy. Mutation screening was performed with a single-strand conformation polymorphism analysis and identification of mutation by direct DNA sequencing. We have identified a 33-bp deletion in exon 8 encompassing the stop codon. Nine individuals in three generations were tested, and four were carriers of this deletion. The mother was genetically affected and died of heart failure aged 90. Echocardiography at 71 years of age revealed no hypertrophy, but the electrocardiogram showed signs of left ventricular hypertrophy. Her two sons, also genetically affected, had left ventricular hypertrophy, with maximum wall thickness of 15 and 16 mm, respectively. One daughter and four grandchildren were clinically unaffected, but one of them, a 27-year-old woman with maximum wall thickness of 8 mm and normal electrocardiogram, was found to be genetically affected. In conclusion, we describe a non-Japanese family in which hypertrophic cardiomyopathy is due to a genetic defect in the cardiac troponin I gene. This mutation is a deletion of 33 bp in the last exon, whereas the previously described mutations in this gene are single nucleotide changes and a single codon deletion. The deletion of the C-terminal part of the cardiac troponin I protein, seems in this particular family to be associated with a mild phenotypic expression of familial hypertrophic cardiomyopathy.

  • 46.
    Mörner, Stellan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Richard, Pascale
    Kazzam, Elsadig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hainque, Bernard
    Schwartz, Ketty
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Identification of the genotypes causing hypertrophic cardiomyopathy in northern Sweden2003In: Journal of Molecular and Cellular Cardiology, ISSN 0022-2828, E-ISSN 1095-8584, Vol. 35, no 7, p. 841-849Article in journal (Refereed)
    Abstract [en]

    Hypertrophic cardiomyopathy (HCM) is a heterogenous disease, with variable genotypic and phenotypic expressions, often caused by mutations in sarcomeric protein genes. The aim of this study was to identify the genotypes and associated phenotypes related to HCM in northern Sweden. In 46 unrelated individuals with familial or sporadic HCM, mutation analysis of eight sarcomeric protein genes was performed; the cardiac beta-myosin heavy chain, cardiac myosin-binding protein C, cardiac troponin T, alpha-tropomyosin, cardiac essential and regulatory myosin light chains, cardiac troponin I and cardiac alpha-actin. A total of 11 mutations, of which six were novel ones, were found in 13 individuals. Seven mutations were located in the myosin-binding protein C gene, two in the beta-myosin heavy chain gene and one in the regulatory myosin light chain and troponin I genes, respectively. This is the first Swedish study, where a population with HCM has been genotyped. Mutations in the cardiac myosin-binding protein C gene were the most common ones found in northern Sweden, whereas mutations in the beta-myosin heavy chain gene were less frequent than previously described. There are differences in the phenotypes mediated by these genes characterised by a more late-onset disease for the myosin-binding protein C gene mutations. This should be taken into consideration, when evaluating clinical findings in the diagnosis of the disease, especially in young adults in families with HCM, where penetrance can be expected to be incomplete in the presence of a myosin-binding protein C gene mutation.

  • 47.
    Mörner, Stellan
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wiklund, Urban
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Rask, Peter
    Olofsson, Bert-Ove
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Kazzam, Elsadig
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Parasympathetic dysfunction in hypertrophic cardiomyopathy assessed by heart rate variability: comparison between short-term and 24-h measurements2005In: Clinical Physiology and Functional Imaging, ISSN 1475-0961, E-ISSN 1475-097X, Vol. 25, no 2, p. 90-99Article in journal (Other academic)
    Abstract [en]

    In this study, we evaluate cardiac autonomic function in hypertrophic cardiomyopathy (HCM) by assessing heart rate variability (HRV), comparing a short-term laboratory method with an ambulatory (24-h) method, in patients with and without beta-blockade. Reduced HRV is a risk factor for adverse events in some cardiac diseases, but is not a proven risk indicator in HCM. Analysis of HRV has been based on either short- or long-term electrocardiographic recordings and previous studies in HCM have shown conflicting results. There is no consensus on which method to prefer, and we evaluate, for the first time, both short- and long-term analyses in patients with HCM. Long- and short-term HRV analyses were performed in 43 patients with HCM. They were divided in two groups, 22 patients on beta-blockade and 21 non-treated patients. As controls, 121 healthy subjects were used. Young patients without beta-blockade showed a reduction in HRV parameters reflecting parasympathetic function, both in the short- and long-term registrations, which was attenuated by beta-blockade. Parasympathetic autonomic regulation was found to be impaired in young patients with HCM. This may be of clinical relevance as abnormal autonomic function might be a substrate for malignant dysrhythmias. The impairment was attenuated by beta-blockade, which might indicate a clinically useful effect. We also show that short- and long-term methods yield similar results, suggesting that a short-term registration might be sufficient to assess HRV in patients with HCM.

  • 48.
    Stattin, Eva-Lena
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Westin, Ida Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Cederquist, Kristina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jonasson, Jenni
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jonsson, Björn-Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Norberg, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Krantz, Peter
    Wisten, Aase
    Genetic screening in sudden cardiac death in the young can save future lives2016In: International journal of legal medicine (Print), ISSN 0937-9827, E-ISSN 1437-1596, Vol. 130, no 1, p. 59-66Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Autopsy of sudden cardiac death (SCD) in the young shows a structurally and histologically normal heart in about one third of cases. Sudden death in these cases is believed to be attributed in a high percentage to inherited arrhythmogenic diseases. The purpose of this study was to investigate the value of performing post-mortem genetic analysis for autopsy-negative sudden unexplained death (SUD) in 1 to 35 year olds.

    METHODS AND RESULTS: From January 2009 to December 2011, samples from 15 cases suffering SUD were referred to the Department of Clinical Genetics, Umeå University Hospital, Sweden, for molecular genetic evaluation. PCR and bidirectional Sanger sequencing of genes important for long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome type 1 (BrS1), and catecholaminergic polymorphic ventricular tachycardia (CPVT) (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, and RYR2) was performed. Multiplex ligation-dependent probe amplification (MLPA) was used to detect large deletions or duplications in the LQTS genes. Six pathogenic sequence variants (four LQTS and two CPVT) were discovered in 15 SUD cases (40%). Ten first-degree family members were found to be mutation carriers (seven LQTS and three CPVT).

    CONCLUSION: Cardiac ion channel genetic testing in autopsy-negative sudden death victims has a high diagnostic yield, with identification of the disease in 40 of families. First-degree family members should be offered predictive testing, clinical evaluation, and treatment with the ultimate goal to prevent sudden death.

  • 49.
    Suhr, Ole B
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Anan, Intissar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Backman, Clas
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Karlsson, A
    Department of Clinical Chemistry, Karolinska Hospital, Stockholm, Sweden.
    Lindqvist, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Do troponin and B-natriuretic peptide detect cardiomyopathy in transthyretin amyloidosis?2008In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 263, no 3, p. 294-301Article in journal (Refereed)
  • 50.
    Wisten, Aase
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Boström, Ida Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Mutation analysis of cases of sudden unexplained death, 15 years after death: Prompt genetic evaluation after resuscitation can save future lives2012In: Resuscitation, ISSN 0300-9572, E-ISSN 1873-1570, Vol. 83, no 10, p. 1229-1234Article in journal (Refereed)
    Abstract [en]

    Introduction: The aim of this study is to use genetic mutation analysis to determine the cause of sudden unexpected death in young (SUDY) persons with normal autopsy findings, and to provide relatives with an identified cardiac mutation with suitable cardiovascular prevention. Methods: We performed mutation analysis on blood samples from first-degree relatives of 25 cases with normal autopsy findings identified in the national Swedish study of sudden cardiac death in 15- to 35-year-olds from 1992 to 1999. Results: We found three families with long QT syndrome through mutation screening, and the mutations were verified in two of the deceased. Eight family members were found to be mutation carriers and have been provided with suitable cardiovascular prevention. Mutation screening also identified a number of common polymorphisms in the individuals screened. Clinical history revealed one family each with short QT syndrome and hypertrophic cardiomyopathy, respectively, but no mutations were found in the family members or in the deceased. Two SCDs each had occurred in two of the affected families. Conclusion: Cardiac/genetic evaluation of relatives long after SUDY can reveal a diagnosis in 5/25 (20%) of cases. Since DNA extraction of formalin fixed paraffin embedded samples is unreliable, it is important that blood or tissue samples be stored at autopsy of such cases. This can facilitate establishing a diagnosis and thereby save lives in the future. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

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