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  • 151.
    Cadrin-Tourigny, Julia
    et al.
    Johns Hopkins Univ Hosp, MD 21287 USA; Univ Montreal, Canada.
    Bosman, Laurens P.
    Netherlands Heart Inst, Netherlands; Univ Utrecht, Netherlands.
    Nozza, Anna
    Univ Montreal, Canada.
    Wang, Weijia
    Johns Hopkins Univ Hosp, MD 21287 USA.
    Tadros, Rafik
    Univ Montreal, Canada.
    Bhonsale, Aditya
    Johns Hopkins Univ Hosp, MD 21287 USA.
    Bourfiss, Mimount
    Univ Utrecht, Netherlands.
    Fortier, Annik
    Univ Montreal, Canada.
    Lie, Oyvind H.
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Saguner, Ardan M.
    Univ Heart Ctr Zurich, Switzerland.
    Svensson, Anneli
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Andorin, Antoine
    Univ Montreal, Canada.
    Tichnell, Crystal
    Johns Hopkins Univ Hosp, MD 21287 USA.
    Murray, Brittney
    Johns Hopkins Univ Hosp, MD 21287 USA.
    Zeppenfeld, Katja
    Leiden Univ, Netherlands.
    van den Berg, Maarten P.
    Univ Med Ctr Groningen, Netherlands.
    Asselbergs, Folkert W.
    Netherlands Heart Inst, Netherlands; Univ Utrecht, Netherlands; UCL, England.
    Wilde, Arthur A. M.
    Univ Amsterdam Heart Ctr, AZ 1105 USA.
    Krahn, Andrew D.
    Univ British Columbia, Canada.
    Talajic, Mario
    Univ Montreal, Canada.
    Rivard, Lena
    Univ Montreal, Canada.
    Chelko, Stephen
    Johns Hopkins Univ Hosp, MD 21287 USA.
    Zimmerman, Stefan L.
    Johns Hopkins Univ Hosp, MD 21287 USA.
    Kamel, Ihab R.
    Johns Hopkins Univ Hosp, MD 21287 USA.
    Crosson, Jane E.
    Johns Hopkins Univ Hosp, MD 21287 USA.
    Judge, Daniel P.
    Johns Hopkins Univ Hosp, MD 21287 USA.
    Yap, Sing-Chien
    Erasmus MC, Netherlands.
    van der Heijden, Jeroen F.
    Univ Utrecht, Netherlands.
    Tandri, Harikrishna
    Johns Hopkins Univ Hosp, MD 21287 USA.
    Jongbloed, Jan D. H.
    Univ Groningen, Netherlands.
    Guertin, Marie-Claude
    Univ Montreal, Canada.
    van Tintelen, J. Peter
    Netherlands Heart Inst, Netherlands; Univ Amsterdam, Netherlands.
    Platonov, Pyotr G.
    Lund Univ Hosptial, Sweden.
    Duru, Firat
    Univ Heart Ctr Zurich, Switzerland.
    Haugaa, Kristina H.
    Oslo Univ Hosp, Norway; Univ Oslo, Norway.
    Khairy, Paul
    Univ Montreal, Canada.
    Hauer, Richard N. W.
    Netherlands Heart Inst, Netherlands; Univ Utrecht, Netherlands.
    Calkins, Hugh
    Johns Hopkins Univ Hosp, MD 21287 USA.
    te Riele, Anneline S. J. M.
    Netherlands Heart Inst, Netherlands; Univ Utrecht, Netherlands.
    James, Cynthia A.
    Johns Hopkins Univ Hosp, MD 21287 USA.
    A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy2019In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 40, no 23, p. 1850-1858Article in journal (Refereed)
    Abstract [en]

    Aims Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for individualized prediction of incident VA/SCD in ARVC patients. Methods and results Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.2 +/- 15.5 years, 44.7% male, were enrolled from five registries in North America and Europe. Over 4.83 (interquartile range 2.44-9.33) years of follow-up, 146 (27.7%) experienced sustained VA, defined as SCD, aborted SCD, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator (ICD) therapy. A prediction model estimating annual VA risk was developed using Cox regression with internal validation. Eight potential predictors were pre-specified: age, sex, cardiac syncope in the prior 6 months, non-sustained ventricular tachycardia, number of premature ventricular complexes in 24 h, number of leads with T-wave inversion, and right and left ventricular ejection fractions (LVEFs). All except LVEF were retained in the final model. The model accurately distinguished patients with and without events, with an optimism-corrected C-index of 0.77 [95% confidence interval (CI) 0.73-0.81] and minimal over-optimism [calibration slope of 0.93 (95% CI 0.92-0.95)]. By decision curve analysis, the clinical benefit of the model was superior to a current consensus-based ICD placement algorithm with a 20.6% reduction of ICD placements with the same proportion of protected patients (P amp;lt; 0.001). Conclusion Using the largest cohort of patients with ARVC and no prior VA, a prediction model using readily available clinical parameters was devised to estimate VA risk and guide decisions regarding primary prevention ICDs (www.arvcrisk.com).

  • 152.
    Cao, Renhai
    et al.
    Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Ji, Hong
    Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Feng, Ninghan
    Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Zhang, Yin
    Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Yang, Xiaojuan
    Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Andersson, Patrik
    Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Stockholm, Sweden.
    Sun, Yuping
    Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong , People's Republic of China.
    Tritsaris, Katerina
    Department of Cellular and Molecular Medicine, Center for Healthy Aging Panum Institute, University of Copenhagen, Copenhagen, Denmark.
    Jon Hansen, Anker
    Department of Neuroscience and Pharmacology, Panum Institute, University of Copenhagen, Copenhagen, Denmark and Novo Nordisk A/S Måløv, Denmark.
    Dissing, Steen
    Department of Cellular and Molecular Medicine, Center for Healthy Aging Panum Institute, University of Copenhagen, Copenhagen, Denmark.
    Cao, Yihai
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, Sweden.
    Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 39, p. 15894-15899Article in journal (Refereed)
    Abstract [en]

    Interplay between various lymphangiogenic factors in promoting lymphangiogenesis and lymphatic metastasis remains poorly understood. Here we show that FGF-2 and VEGF-C, two lymphangiogenic factors, collaboratively promote angiogenesis and lymphangiogenesis in the tumor microenvironment, leading to widespread pulmonary and lymph-node metastases. Coimplantation of dual factors in the mouse cornea resulted in additive angiogenesis and lymphangiogenesis. At the molecular level, we showed that FGFR-1 expressed in lymphatic endothelial cells is a crucial receptor that mediates the FGF-2-induced lymphangiogenesis. Intriguingly, the VEGFR-3-mediated signaling was required for the lymphatic tip cell formation in both FGF-2- and VEGF-C-induced lymphangiogenesis. Consequently, a VEGFR-3-specific neutralizing antibody markedly inhibited FGF-2-induced lymphangiogenesis. Thus, the VEGFR-3-induced lymphatic endothelial cell tip cell formation is a prerequisite for FGF-2-stimulated lymphangiogenesis. In the tumor microenvironment, the reciprocal interplay between FGF-2 and VEGF-C collaboratively stimulated tumor growth, angiogenesis, intratumoral lymphangiogenesis, and metastasis. Thus, intervention and targeting of the FGF-2- and VEGF-C-induced angiogenic and lymphangiogenic synergism could be potentially important approaches for cancer therapy and prevention of metastasis.

  • 153.
    Cao, Renhai
    et al.
    Karolinska Institute, Sweden.
    Ji, Hong
    Karolinska Institute, Sweden.
    Yang, Yunlong
    Karolinska Institute, Sweden.
    Cao, Yihai
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden; University of Leicester, England; Glenfield Hospital, England.
    Editorial Material: Collaborative effects between the TNF alpha-TNFR1-macrophage axis and the VEGF-C-VEGFR3 signaling in lymphangiogenesis and metastasis in ONCOIMMUNOLOGY, vol 4, issue 3, pp2015In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 4, no 3, p. e989777-Article in journal (Other academic)
    Abstract [en]

    Although inflammation and metastasis are two well-known hallmarks of malignant disease, the relationship between inflammation and lymphatic metastasis is an unexplored research area. We recently elucidated a sophisticated mechanism by which TNF alpha-induced tumor inflammation conscripts macrophage-mediated VEGF-C-VEGFR3 signaling in lymphangiogenesis and metastasis.

  • 154.
    Cao, Yihai
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Karolinska Institute, Sweden .
    Angiogenesis and Vascular Functions in Modulation of Obesity, Adipose Metabolism, and Insulin Sensitivity2013In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 18, no 4, p. 478-489Article, review/survey (Refereed)
    Abstract [en]

    White and brown adipose tissues are hypervascularized and the adipose vasculature displays phenotypic and functional plasticity to coordinate with metabolic demands of adipocytes. Blood vessels not only supply nutrients and oxygen to nourish adipocytes, they also serve as a cellular reservoir to provide adipose precursor and stem cells that control adipose tissue mass and function. Multiple signaling molecules modulate the complex interplay between the vascular system and the adipocytes. Understanding fundamental mechanisms by which angiogenesis and vasculatures modulate adipocyte functions may provide new therapeutic options for treatment of obesity and metabolic disorders by targeting the adipose vasculature.

  • 155.
    Cao, Yihai
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Karolinska Institute, Sweden .
    Erythropoietin in cancer: a dilemma in risk therapy2013In: Trends in endocrinology and metabolism, ISSN 1043-2760, E-ISSN 1879-3061, Vol. 24, no 4, p. 190-199Article, review/survey (Refereed)
    Abstract [en]

    Erythropoietin (EPO) is a frequently prescribed drug for treatment of cancer-related and chemotherapy-induced anemia in cancer patients. Paradoxically, recent preclinical and clinical studies indicate that EPO could potentially accelerate tumor growth and jeopardize survival in cancer patients. In this review I critically discuss the current knowledge and broad biological functions of EPO in association with tumor growth, invasion, and angiogenesis. The emphasis is focused on discussing the complex interplay between EPO and other tumor-derived factors in angiogenesis, tumor growth, invasion, and metastasis. Understanding the multifarious functions of EPO and its reciprocal relation with other signaling pathways is crucial for developing more effective agents for cancer therapy and for minimizing risks for cancer patients.

  • 156.
    Cao, Yihai
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Karolinska Institute, Sweden; University of Leicester, England; Glenfield Hospital, England.
    Future options of anti-angiogenic cancer therapy2016In: CHINESE JOURNAL OF CANCER, ISSN 1000-467X, Vol. 35, no 21Article, review/survey (Refereed)
    Abstract [en]

    In human patients, drugs that block tumor vessel growth are widely used to treat a variety of cancer types. Many rigorous phase 3 clinical trials have demonstrated significant survival benefits; however, the addition of an anti-angiogenic component to conventional therapeutic modalities has generally produced modest survival benefits for cancer patients. Currently, it is unclear why these clinically available drugs targeting the same angiogenic pathways produce dissimilar effects in preclinical models and human patients. In this article, we discuss possible mechanisms of various anti-angiogenic drugs and the future development of optimized treatment regimens.

  • 157.
    Cao, Yihai
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Karolinska Institute, Sweden .
    Multifarious functions of PDGFs and PDGFRs in tumor growth and metastasis2013In: Trends in Molecular Medicine, ISSN 1471-4914, E-ISSN 1471-499X, Vol. 19, no 8, p. 460-473Article, review/survey (Refereed)
    Abstract [en]

    Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) are frequently expressed in various tumors and their expression levels correlate with tumor growth, invasiveness, drug resistance, and poor clinical outcomes. Emerging experimental evidence demonstrates that PDGFs exhibit multiple functions in modulation of tumor growth, metastasis, and the tumor microenvironment by targeting malignant cells, vascular cells, and stromal cells. Understanding PDGF PDGFR-mediated molecular signaling may provide new mechanistic rationales for optimizing current cancer therapies and the development of future novel therapeutic modalities.

  • 158.
    Cao, Yihai
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Arbiser, Jack
    Emory University.
    DAmato, Robert J
    Childrens Hospital, Boston.
    DAmore, Patricia A
    Harvard University.
    Ingber, Donald E
    Childrens Hospital, Boston.
    Kerbel, Robert
    Sunnybrook Health Science Centre.
    Klagsbrun, Michael
    Childrens Hospital, Boston.
    Lim, Sharon
    Karolinska Institute.
    Moses, Marsha A
    Childrens Hospital, Boston.
    Zetter, Bruce
    Childrens Hospital, Boston.
    Dvorak, Harold
    Harvard University.
    Langer, Robert
    MIT.
    Forty-Year Journey of Angiogenesis Translational Research2011In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 3, no 114Article, review/survey (Refereed)
    Abstract [en]

    Forty years ago, Judah Folkman predicted that tumor growth is dependent on angiogenesis and that inhibiting this process might be a new strategy for cancer therapy. This hypothesis formed the foundation of a new field of research that represents an excellent example of how a groundbreaking scientific discovery can be translated to yield benefits for patients. Today, antiangiogenic drugs are used to treat human cancers and retinal vascular diseases. Here, we guide readers through 40 years of angiogenesis research and discuss challenges of antiangiogenic therapy.

  • 159.
    Cao, Ziquan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    VEGF-mediated vascular functions in health and disease2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Angiogenesis is essential for physiological processes including embryonic development, tissue regeneration, and reproduction. Under various pathological conditions the same angiogenic process contribute to the onset, development, and progression of many human diseases including cancer, diabetic complications, ocular disease, chronic inflammation and cardiovascular disease. Vascular endothelial growth factor (VEGF) is a key angiogenic factor for physiological and pathological angiogenesis. In addition to its strong angiogenic activity, VEGF also potently induces vascular permeability, often causing tissue edema in various pathological tissues. VEGF transduces its vascular signal through two tyrosine kinase receptors-VEGFR1 and VEGFR2, the latter being a functional receptor that mediates both angiogenic and vascular permeability effects. To study physiological and pathological functions of VEGF, we developed novel zebrafish disease models that permit us to study hypoxia-induced retinopathy and cancer metastasis processes. We have also administered anti-VEGF and anti-VEGFR specific antibodies to healthy mice to study the homeostatic role of VEGF in the maintenance of vascular integrity and its functions in various tissues and organs.

    Finally, using a zebrafish model, we evaluated if VEGF expression is regulated by circadian clock genes. In paper I, we developed protocols that create hypoxia-induced retinopathy in adult zebrafish. Adult fli1:EGFP zebrafish were placed in hypoxic water for 3-10 days with retinal neovascularization being analyzed using confocal microscopy. This model provides a unique opportunity to kinetically study the development of retinopathy in adult animals using non-invasive protocols and to assess the therapeutic efficacy of orally administered anti-angiogenic drugs. In paper II, we developed a zebrafish metastasis model to dissect the complex events of hypoxia-induced tumor cell invasion and metastasis in association with angiogenesis at the single-cell level. In this model, fluorescent DiI-labeled human or mouse tumor cells were implanted into the perivitelline cavity of 48-hour-old zebrafish embryos, which were subsequently placed in hypoxic water for 3 days. Tumor cell invasion, metastasis and pathological angiogenesis were analyzed using fluorescent microscopy in the living fish. The average experimental time for this model is 7 days. Our protocol offers an opportunity to study molecular mechanisms of hypoxia-induced cancer metastasis. In paper III, we show that systemic delivery of an anti-VEGF or an anti-VEGF receptor (VEGFR)-2 neutralizing antibody cause global vascular regression in mice. Among all examined tissues, the vasculature in endocrine glands, intestinal villi, and the uterus are most affected in response to VEGF or VEGFR-2 blockades. Pro-longed anti-VEGF treatment resulted in a significant decrease in the circulating levels of the predominant thyroid hormone, free thyroxine, but not the minimal isoform of triiodothyronine, suggesting that chronic anti-VEGF treatment impairs thyroid function. These findings provide structural and functional bases of anti-VEGF-specific druginduced side effects in relation to vascular changes in healthy tissues. In paper IV, we show that disruption of the circadian clock by constant exposure to light coupled with genetic manipulation of key genes in the zebrafish led to impaired developmental angiogenesis. A bmal1-specific morpholino inhibited developmental angiogenesis in zebrafish embryos without causing obvious nonvascular phenotypes. Conversely, a period2 morpholino accelerated angiogenic vessel growth, suggesting that Bmal1 and Period2 display opposing angiogenic effects. These results offer mechanistic insights into the role of the circadian clock in regulation of developmental angiogenesis, and our findings may be reasonably extended to other types of physiological or pathological angiogenesis. Overall, the results in this thesis provide further insight to angiogenic mechanistic properties in tissues and suggest possible novel therapeutic targets for the treatment of various angiogenesis-dependent diseases.

    List of papers
    1. Hypoxia-induced retinopathy model in adult zebrafish
    Open this publication in new window or tab >>Hypoxia-induced retinopathy model in adult zebrafish
    Show others...
    2010 (English)In: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 5, no 12, p. 1903-1910Article in journal (Refereed) Published
    Abstract [en]

    Hypoxia-induced vascular responses, including angiogenesis, vascular remodeling and vascular leakage, significantly contribute to the onset, development and progression of retinopathy. However, until recently there were no appropriate animal disease models recapitulating adult retinopathy available. In this article, we describe protocols that create hypoxia-induced retinopathy in adult zebrafish. Adult fli1: EGFP zebrafish are placed in hypoxic water for 3-10 d and retinal neovascularization is analyzed using confocal microscopy. It usually takes 11 d to obtain conclusive results using the hypoxia-induced retinopathy model in adult zebrafish. This model provides a unique opportunity to study kinetically the development of retinopathy in adult animals using noninvasive protocols and to assess therapeutic efficacy of orally active antiangiogenic drugs.

    Place, publisher, year, edition, pages
    Nature Publishing Group, 2010
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-63381 (URN)10.1038/nprot.2010.149 (DOI)000284884100003 ()
    Available from: 2010-12-17 Created: 2010-12-17 Last updated: 2017-12-11Bibliographically approved
    2. Hypoxia-induced metastasis model in embryonic zebrafish
    Open this publication in new window or tab >>Hypoxia-induced metastasis model in embryonic zebrafish
    Show others...
    2010 (English)In: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 5, no 12, p. 1911-1918Article in journal (Refereed) Published
    Abstract [en]

    Hypoxia facilitates tumor invasion and metastasis by promoting neovascularization and co-option of tumor cells in the peritumoral vasculature, leading to dissemination of tumor cells into the circulation. However, until recently, animal models and imaging technology did not enable monitoring of the early events of tumor cell invasion and dissemination in living animals. We recently developed a zebrafish metastasis model to dissect the detailed events of hypoxia-induced tumor cell invasion and metastasis in association with angiogenesis at the single-cell level. In this model, fluorescent DiI-labeled human or mouse tumor cells are implanted into the perivitelline cavity of 48-h-old zebrafish embryos, which are subsequently placed in hypoxic water for 3 d. Tumor cell invasion, metastasis and pathological angiogenesis are detected under fluorescent microscopy in the living fish. The average experimental time for this model is 7 d. Our protocol offers a remarkable opportunity to study molecular mechanisms of hypoxia-induced cancer metastasis.

    Place, publisher, year, edition, pages
    Nature Publishing Group, 2010
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-63382 (URN)10.1038/nprot.2010.150 (DOI)000284884100004 ()
    Available from: 2010-12-17 Created: 2010-12-17 Last updated: 2017-12-11Bibliographically approved
    3. Anti-VEGF- and anti-VEGF receptor-induced vascular alteration in mouse healthy tissues
    Open this publication in new window or tab >>Anti-VEGF- and anti-VEGF receptor-induced vascular alteration in mouse healthy tissues
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    2013 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, no 29, p. 12018-12023Article in journal (Refereed) Published
    Abstract [en]

    Systemic therapy with anti-VEGF drugs such as bevacizumab is widely used for treatment of human patients with various solid tumors. However, systemic impacts of such drugs in host healthy vasculatures remain poorly understood. Here, we show that, in mice, systemic delivery of an anti-VEGF or an anti-VEGF receptor (VEGFR)-2 neutralizing antibody caused global vascular regression. Among all examined tissues, vasculatures in endocrine glands, intestinal villi, and uterus are the most affected in response to VEGF or VEGFR-2 blockades. Thyroid vascular fenestrations were virtually completely blocked by VEGF blockade, leading to marked accumulation of intraendothelial caveolae vesicles. VEGF blockade markedly increased thyroid endothelial cell apoptosis, and withdrawal of anti-VEGF resulted in full recovery of vascular density and architecture after 14 d. Prolonged anti-VEGF treatment resulted in a significant decrease of the circulating level of the predominant thyroid hormone free thyroxine, but not the minimal isoform of triiodothyronine, suggesting that chronic anti-VEGF treatment impairs thyroid functions. Conversely, VEGFR-1-specific blockade produced virtually no obvious phenotypes. These findings provide structural and functional bases of anti-VEGF-specific drug-induced side effects in relation to vascular changes in healthy tissues. Understanding anti-VEGF drug-induced vascular alterations in healthy tissues is crucial to minimize and even to avoid adverse effects produced by currently used anti-VEGF-specific drugs.

    Place, publisher, year, edition, pages
    National Academy of Sciences, 2013
    Keywords
    angiogenesis, antiangiogenic therapy, off-tumor targets, vascular homeostasis, vessel regression
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-102114 (URN)10.1073/pnas.1301331110 (DOI)000322086100078 ()23818623 (PubMedID)
    Available from: 2013-12-01 Created: 2013-12-01 Last updated: 2017-12-06Bibliographically approved
    4. Opposing Effects of Circadian Clock Genes Bmal1 and Period2 in Regulation of VEGF-Dependent Angiogenesis in Developing Zebrafish
    Open this publication in new window or tab >>Opposing Effects of Circadian Clock Genes Bmal1 and Period2 in Regulation of VEGF-Dependent Angiogenesis in Developing Zebrafish
    Show others...
    2012 (English)In: Cell Reports, ISSN 2211-1247, Vol. 2, no 2, p. 231-241Article in journal (Refereed) Published
    Abstract [en]

    Molecular mechanisms underlying circadian-regulated physiological processes remain largely unknown. Here, we show that disruption of the circadian clock by both constant exposure to light and genetic manipulation of key genes in zebrafish led to impaired developmental angiogenesis. A bmal1-specific morpholino inhibited developmental angiogenesis in zebrafish embryos without causing obvious nonvascular phenotypes. Conversely, a period2 morpholino accelerated angiogenic vessel growth, suggesting that Bmal1 and Period2 display opposing angiogenic effects. Using a promoter-reporter system consisting of various deleted vegf-promoter mutants, we show that Bmal1 directly binds to and activates the vegf promoter via E-boxes. Additionally, we provide evidence that knockdown of Bmal1 leads to impaired Notch-inhibition-induced vascular sprouting. These results shed mechanistic insight on the role of the circadian clock in regulation of developmental angiogenesis, and our findings may be reasonably extended to other types of physiological or pathological angiogenesis.

    Place, publisher, year, edition, pages
    Elsevier (Cell Press), 2012
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-85304 (URN)10.1016/j.celrep.2012.07.005 (DOI)000309715100004 ()
    Note

    Funding Agencies|Swedish Research Council||Swedish Cancer Foundation||Karolinska Institute Foundation||Karolinska Institute||Tianjin Natural Science Foundation (CMM-Tianjin)|09ZCZDSF04400|Torsten Soderbergs Foundation||European Union|222741|European Research Council (ERC)|250021|

    Available from: 2012-11-16 Created: 2012-11-15 Last updated: 2017-03-27Bibliographically approved
  • 160.
    Cao, Ziquan
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Jensen, Lasse
    Karolinska Institute, Sweden.
    Rouhi, Pegah
    Karolinska Institute.
    Hosaka, Kayoko
    Karolinska Institute.
    Länne, Toste
    Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Steffensen, John F
    University of Copenhagen.
    Wahlberg, Eric
    Linköping University, Department of Medical and Health Sciences, Vascular surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Cao, Yihai
    Karolinska Institute.
    Hypoxia-induced retinopathy model in adult zebrafish2010In: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 5, no 12, p. 1903-1910Article in journal (Refereed)
    Abstract [en]

    Hypoxia-induced vascular responses, including angiogenesis, vascular remodeling and vascular leakage, significantly contribute to the onset, development and progression of retinopathy. However, until recently there were no appropriate animal disease models recapitulating adult retinopathy available. In this article, we describe protocols that create hypoxia-induced retinopathy in adult zebrafish. Adult fli1: EGFP zebrafish are placed in hypoxic water for 3-10 d and retinal neovascularization is analyzed using confocal microscopy. It usually takes 11 d to obtain conclusive results using the hypoxia-induced retinopathy model in adult zebrafish. This model provides a unique opportunity to study kinetically the development of retinopathy in adult animals using noninvasive protocols and to assess therapeutic efficacy of orally active antiangiogenic drugs.

  • 161.
    Cardona-Guarache, Ricardo
    et al.
    Univ Calif San Francisco, CA 94143 USA.
    Åström-Aneq, Meriam
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Oesterle, Adam
    Univ Calif San Francisco, CA 94143 USA.
    Asirvatham, Roshini
    Univ Calif San Francisco, CA 94143 USA.
    Svetlichnaya, Jana
    Kaiser Permanente, CA USA.
    Marcus, Gregory M.
    Univ Calif San Francisco, CA 94143 USA.
    Gerstenfeld, Edward P.
    Univ Calif San Francisco, CA 94143 USA.
    Klein, Liviu
    Univ Calif San Francisco, CA 94143 USA.
    Scheinman, Melvin M.
    Univ Calif San Francisco, CA 94143 USA.
    Atrial arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy: Prevalence, echocardiographic predictors, and treatment2019In: Cardiovascular Electrophysiology, ISSN 1045-3873, E-ISSN 1540-8167Article in journal (Refereed)
    Abstract [en]

    Introduction

    The clinical role of atrial arrhythmias (AA) in arrhythmogenic right ventricular cardiomyopathy (ARVC) and the echocardiographic variables that predict them are not well defined. We describe the prevalence, types, echocardiographic predictors, and management of AA in patients with ARVC.

    Methods

    We retrospectively evaluated medical records of 117 patients with definite ARVC (2010 Task Force Criteria) from two tertiary care centers. We identified those patients with sustained AA (>30 seconds), including atrial fibrillation (AF), atrial flutter (AFL), and atrial tachycardia (AT). We collected demographic, genetic, and clinical data. The median follow‐up was 3.4 years (interquartile range = 2.0‐5.7).

    Results

    Total 26 patients (22%) had one or more types of AA: AF (n = 19), AFL (n = 9), and AT (n = 8). We performed genetic testing on 84 patients with ARVC (71.8%). Two patients with AA (8%) had peripheral emboli, and one patient (4%) suffered inappropriate implantable cardioverter‐defibrillator shock. We performed catheter ablation of AA in eight patients (31%), with no procedural complications. Right atrial area and left atrial volume index were independently associated with increased odds of AA; odds ratio (OR), 1.1 (95% confidence interval [CI]:1.02‐1.16) (P = .01) and OR, 1.1 (95% CI:1.03‐1.15) (P = .003), respectively. An increase in tricuspid annular plane peak systolic excursion was independently associated with reduced odds; OR, 0.3 (95% CI: 0.1‐0.94) (P = .003).

    Conclusions

    Atrial arrhythmias (AA) are common in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Inappropriate shocks and systemic emboli may be associated with AA. Atrial size and right ventricular dysfunction may help identify patients with ARVC at increased odds of AA.

  • 162.
    Cardona-Guarache, Ricardo
    et al.
    Univ Calif San Francisco, CA 94143 USA.
    Åström-Aneq, Meriam
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Oesterle, Adam
    Univ Calif San Francisco, CA 94143 USA.
    Asirvatham, Roshini
    Univ Calif San Francisco, CA 94143 USA.
    Svetlichnaya, Jana
    Kaiser Permanente, CA USA.
    Marcus, Gregory M.
    Univ Calif San Francisco, CA 94143 USA.
    Gerstenfeld, Edward P.
    Univ Calif San Francisco, CA 94143 USA.
    Klein, Liviu
    Univ Calif San Francisco, CA 94143 USA.
    Scheinman, Melvin M.
    Univ Calif San Francisco, CA 94143 USA.
    Atrial arrhythmias in patients with arrhythmogenic right ventricular cardiomyopathy: Prevalence, echocardiographic predictors, and treatment2019In: Cardiovascular Electrophysiology, ISSN 1045-3873, E-ISSN 1540-8167Article in journal (Refereed)
    Abstract [en]

    Introduction

    The clinical role of atrial arrhythmias (AA) in arrhythmogenic right ventricular cardiomyopathy (ARVC) and the echocardiographic variables that predict them are not well defined. We describe the prevalence, types, echocardiographic predictors, and management of AA in patients with ARVC.

    Methods

    We retrospectively evaluated medical records of 117 patients with definite ARVC (2010 Task Force Criteria) from two tertiary care centers. We identified those patients with sustained AA (>30 seconds), including atrial fibrillation (AF), atrial flutter (AFL), and atrial tachycardia (AT). We collected demographic, genetic, and clinical data. The median follow‐up was 3.4 years (interquartile range = 2.0‐5.7).

    Results

    Total 26 patients (22%) had one or more types of AA: AF (n = 19), AFL (n = 9), and AT (n = 8). We performed genetic testing on 84 patients with ARVC (71.8%). Two patients with AA (8%) had peripheral emboli, and one patient (4%) suffered inappropriate implantable cardioverter‐defibrillator shock. We performed catheter ablation of AA in eight patients (31%), with no procedural complications. Right atrial area and left atrial volume index were independently associated with increased odds of AA; odds ratio (OR), 1.1 (95% confidence interval [CI]:1.02‐1.16) (P = .01) and OR, 1.1 (95% CI:1.03‐1.15) (P = .003), respectively. An increase in tricuspid annular plane peak systolic excursion was independently associated with reduced odds; OR, 0.3 (95% CI: 0.1‐0.94) (P = .003).

    Conclusions

    Atrial arrhythmias (AA) are common in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Inappropriate shocks and systemic emboli may be associated with AA. Atrial size and right ventricular dysfunction may help identify patients with ARVC at increased odds of AA.

  • 163.
    Carlsson, Axel C.
    et al.
    Karolinska Institute, Sweden; Uppsala University, Sweden.
    Östgren, Carl Johan
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in West Östergötland, "Primary Health Care in Motala".
    Nyström, Fredrik H
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Länne, Toste
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Thoracic and Vascular Surgery. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Jennersjö, Pär
    Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Community Medicine.
    Larsson, Anders
    Uppsala University, Sweden.
    Arnlov, Johan
    Uppsala University, Sweden; Dalarna University,Falun Sweden.
    Association of soluble tumor necrosis factor receptors 1 and 2 with nephropathy, cardiovascular events, and total mortality in type 2 diabetes2016In: Cardiovascular Diabetology, ISSN 1475-2840, E-ISSN 1475-2840, Vol. 15, no 1, p. 40-Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: Soluble tumor necrosis factor receptors 1 and 2 (sTNFR1 and sTNFR2) contribute to experimental diabetic kidney disease, a condition with substantially increased cardiovascular risk when present in patients. Therefore, we aimed to explore the levels of sTNFRs, and their association with prevalent kidney disease, incident cardiovascular disease, and risk of mortality independently of baseline kidney function and microalbuminuria in a cohort of patients with type 2 diabetes. In pre-defined secondary analyses we also investigated whether the sTNFRs predict adverse outcome in the absence of diabetic kidney disease. Methods: The CARDIPP study, a cohort study of 607 diabetes patients [mean age 61 years, 44 % women, 45 cardiovascular events (fatal/non-fatal myocardial infarction or stroke) and 44 deaths during follow-up (mean 7.6 years)] was used. Results: Higher sTNFR1 and sTNFR2 were associated with higher odds of prevalent kidney disease [odd ratio (OR) per standard deviation (SD) increase 1.60, 95 % confidence interval (CI) 1.32-1.93, p < 0.001 and OR 1.54, 95 % CI 1.21-1.97, p = 0.001, respectively]. In Cox regression models adjusting for age, sex, glomerular filtration rate and urinary albumin/creatinine ratio, higher sTNFR1 and sTNFR2 predicted incident cardiovascular events [hazard ratio (HR) per SD increase, 1.66, 95 % CI 1.29-2.174, p < 0.001 and HR 1.47, 95 % CI 1.13-1.91, p = 0.004, respectively]. Results were similar in separate models with adjustments for inflammatory markers, HbA1c, or established cardiovascular risk factors, or when participants with diabetic kidney disease at baseline were excluded (p < 0.01 for all). Both sTNFRs were associated with mortality. Conclusions/Interpretations: Higher circulating sTNFR1 and sTNFR2 are associated with diabetic kidney disease, and predicts incident cardiovascular disease and mortality independently of microalbuminuria and kidney function, even in those without kidney disease. Our findings support the clinical utility of sTNFRs as prognostic markers in type 2 diabetes.

  • 164.
    Carlsson, Axel Carl
    et al.
    Division of Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden; Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden.
    Östgren, Carl Johan
    Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in West Östergötland, "Primary Health Care in Motala".
    Länne, Toste
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Larsson, Anders
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Nyström, Fredrik H
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Ärnlöv, Johan
    Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden; School of Health and Social Studies, Dalarna University, Falun, Sweden.
    The association between endostatin and kidney disease and mortality in patients with type 2 diabetes2016In: Diabetes & Metabolism, ISSN 1262-3636, E-ISSN 1878-1780, Vol. 42, no 5, p. 351-357Article in journal (Refereed)
    Abstract [en]

    AIM: Circulating endostatin, a biologically active derivate of collagen XVIII, is considered to be a marker of kidney disease and a risk factor for its related mortality. However, less is known of the role of endostatin in diabetes and the development of diabetic nephropathy. For this reason, our study investigated the associations between circulating endostatin and the prevalence and progression of kidney disease, and its mortality risk in patients with type 2 diabetes (T2D).

    METHODS: This was a cohort study of 607 patients with T2D (mean age: 61 years, 44% women). Estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation, was used to assess the patients' kidney function decline and mortality.

    RESULTS: Of the total study cohort, 20 patients declined by ≥20% in eGFR over 4 years, and 44 died during the follow-up (mean duration: 6.7 years). At baseline, participants with diabetic nephropathy (defined as eGFR<60mL/min/1.73m(2)) and/or microalbuminuria [defined as a urinary albumin-to-creatinine ratio (ACR)>3g/mol] had higher median levels of endostatin than those without nephropathy (62.7μg/L vs 57.4μg/L, respectively; P=0.031). In longitudinal analyses adjusted for age, gender, baseline eGFR and ACR, higher endostatin levels were associated with a higher risk of decline (≥20% in eGFR, OR per 1 SD increase: 1.73, 95% CI: 1.13-2.65) and a higher risk of mortality (HR per 1 SD increase: 1.57, 95% CI: 1.19-2.07).

    CONCLUSION: In patients with T2D, circulating endostatin levels can predict the progression of kidney disease and mortality independently of established kidney disease markers. The clinical usefulness of endostatin as a risk marker in such patients merits further studies.

  • 165.
    Carlsson, Hanna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Kalmar Cty Hosp, Sweden.
    Ekerfelt, Christina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Jonsson Henningsson, Anna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Brudin, Lars
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar Cty Hosp, Sweden.
    Tjernberg, Ivar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Kalmar Cty Hosp, Sweden.
    Subclinical Lyme borreliosis is common in south-eastern Sweden and may be distinguished from Lyme neuroborreliosis by sex, age and specific immune marker patterns2018In: Ticks and Tick-borne Diseases, ISSN 1877-959X, E-ISSN 1877-9603, Vol. 9, no 3, p. 742-748Article in journal (Refereed)
    Abstract [en]

    Background: Determinants of a subclinical course of Lyme borreliosis (LB) remain largely unknown. The aim of this study was to assess the extent, sex and age profiles of subclinical Borrelia seroconversion in a LB endemic area in Sweden and to map blood cellular Borrelia-specific immune marker patterns in individuals with a previous subclinical LB course compared with patients previously diagnosed with Lyme neuroborreliosis (LNB). Methods: A large group of 1113 healthy blood donors was screened for multiple IgG anti-Borrelia antibodies and asked to complete a health inquiry regarding previous LB. A group of subjects with anti-Borrelia-specific IgG antibodies but no previous history of LB (subclinical LB, n = 60) was identified together with 22 cases of previous LNB. Whole Borrelia spirochetes, strains B. afzelii ACA1 and B. garinii Ip90, were used for ex vivo whole blood stimulations, whereas outer surface protein enriched fractions of the same strains were used for stimulation of peripheral blood mononuclear cells (PBMCs). An extensive panel of immune markers was analysed in the supernatants after stimulation using multiplex bead arrays, and Borrelia-specific secretion was determined by subtracting the spontaneous secretion. Results: A total of 125/1113 blood donors reported previous clinical LB. In contrast, 66 donors denied previous LB but showed multiple IgG anti-Borrelia antibodies; these were defined as subclinical subjects, of whom 60 were available for further studies. The subclinical subjects consisted of significantly more men and had a younger age compared with the LNB patients (p amp;lt;= 0.01). Discriminant analysis revealed a distinct pattern of sex, age and PBMC B. garinii-specific levels of IL-10, IL-17A and CCL20 discriminating subclinical subjects from LNB patients. Conclusions: This study confirms that subclinical Borrelia seroconversion is common in south-eastern Sweden. The findings further suggest that male sex, younger age together with B. gariniii induced levels of IL-10, IL-17A and CCL20 may be associated with a subclinical course.

  • 166.
    Carlsson, Martin
    et al.
    Cty Hosp Kalmar, Sweden; Linnaeus Univ, Sweden.
    Brudin, Lars
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Cty Hosp Kalmar, Sweden.
    Wanby, Par
    Cty Hosp Kalmar, Sweden.
    Directly measured free 25-hydroxy vitamin D levels show no evidence of vitamin D deficiency in young Swedish women with anorexia nervosa2018In: Eating and Weight Disorders, ISSN 1124-4909, E-ISSN 1590-1262, Vol. 23, no 2, p. 247-254Article in journal (Refereed)
    Abstract [en]

    Purpose Anorexia nervosa (AN) is an eating disorder characterized by low fat mass complicated by osteoporosis. The role of circulating vitamin D in the development of bone loss in AN is unclear. Fat mass is known to be inversely associated with vitamin D levels measured as serum levels of total, protein-bound 25-hydroxyvitamin D, but the importance of directly measured, free levels of 25(OH)D has not been determined in AN. The aim of this study was to investigate vitamin D status, as assessed by serum concentrations of total and free serum 25(OH)D in patients with AN and healthy controls. Methods In female AN patients (n = 20), and healthy female controls (n = 78), total 25(OH)D was measured by LC-MS/MS, and free 25(OH)D with ELISA. In patients with AN bone mineral density (BMD) was determined with DEXA. Results There were no differences between patients and controls in total or free S-25(OH)D levels (80 +/- 31 vs 72 +/- 18 nmol/L, and 6.5 +/- 2.5 vs 5.6 +/- 1.8 pg/ml, respectively), and no association to BMD was found. In the entire group of patients and controls, both vitamin D parameters correlated with BMI, leptin, and PTH. Conclusions The current study did not demonstrate a vitamin D deficiency in patients with AN and our data does not support vitamin D deficiency as a contributing factor to bone loss in AN. Instead, we observed a trend toward higher vitamin D levels in AN subjects compared to controls. Measurement of free vitamin D levels did not contribute to additional information.

  • 167.
    Carlsson, Martin
    et al.
    County Hospital Kalmar, Sweden; Linnaeus University, Sweden.
    Nilsson, Ingela
    County Hospital Kalmar, Sweden.
    Brudin, Lars
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. County Hospital Kalmar, Sweden.
    Von, Siv-Ping
    County Hospital Kalmar, Sweden.
    Wanby, Par
    County Hospital Kalmar, Sweden.
    Erythrocyte fatty acid composition does not influence levels of free, bioavailable, and total 25-hydroxy vitamin D2017In: SCANDINAVIAN JOURNAL OF CLINICAL and LABORATORY INVESTIGATION, ISSN 0036-5513, Vol. 77, no 1, p. 45-52Article in journal (Refereed)
    Abstract [en]

    In vitro, mono- and polyunsaturated fatty acids (FAs) may decrease the binding affinity of vitamin D metabolites for vitamin D-binding protein, which in turn may influence their bioavailability. FAs incorporated as phospholipids in erythrocyte (ery-) cell membranes reflect dietary intake. The purpose of this study was to investigate ery-FA composition in relation to markers for vitamin D. In healthy females (age 22.6 +/- 2.0 years) total 25(OH)D was measured by LC-MS/MS (n=78), free 25(OH)D with ELISA (n=64 of 78), and bioavailable 25(OH)D was calculated. Analysis of ery-FA composition was by gas chromatography (n=56 of 78). A strong correlation between total 25(OH)D and free 25(OH)D was seen (r=.66, pamp;lt;.001), and between total-25(OH)D and bioavailable 25(OH)D (r=.68, pamp;lt;.001). No correlations between 25(OH)D fractions and specific fatty acids were found, and in particular, no associations with mono- and poly-unsaturated FA compositions. All 25(OH)D fractions were correlated with leptin (total 25(OH)D (r=-.33, pamp;lt;.003); bioavailable 25(OH)D (r=-.47, pamp;lt;.001); free 25(OH)D (r=-.44, pamp;lt;.001). Associations were found between PTH and total 25(OH)D (r=-.35, p=.002) and weaker between bioavailable 25(OH)D (r=-.35, p=.040) and free 25(OH)D (r=-.28, p=.079). All fractions of 25(OH)D appear to correlate in a similar way to PTH, BMI and body fat (leptin). No association was found between ery-FA composition and free/bioavailable 25(OH)D. It is unlikely that FAs are a strong uncoupling factor of DBP-bound 25(OH)D.

  • 168.
    Carlsson, Martin
    et al.
    County Hospital Kalmar, Sweden; Linnaeus University, Sweden.
    Wanby, Pär
    County Hospital Kalmar, Sweden.
    Brudin, Lars
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. County Hospital, Sweden.
    Lexne, Erik
    County Hospital Kalmar, Sweden.
    Mathold, Karin
    County Hospital Kalmar, Sweden.
    Nobin, Rebecca
    County Hospital Kalmar, Sweden.
    Ericson, Lisa
    Linnaeus University, Sweden.
    Nordqvist, Ola
    Kalmar County Council, Sweden.
    Petersson, Goran
    Linnaeus University, Sweden.
    Older Swedish Adults with High Self-Perceived Health Show Optimal 25-Hydroxyvitamin D Levels Whereas Vitamin D Status Is Low in Patients with High Disease Burden2016In: Nutrients, ISSN 2072-6643, E-ISSN 2072-6643, Vol. 8, no 11, article id 717Article in journal (Refereed)
    Abstract [en]

    Controversy pervades the definition of adequate and optimal vitamin D status. The Institutes of Medicine have recommended serum 25(OH) D levels above 50 nmol/L based upon evidence related to bone health, but some experts, including the Endocrine Society and International Osteoporosis Foundation, suggest a minimum serum 25(OH) D level of 75 nmol/L to reduce the risk of falls and fractures in older adults. In a cross-sectional study, we compared vitamin D status in people amp;gt;= 75 years selected from four groups with a frailty phenotype, combined with a control group free from serious illness, and who considered themselves completely healthy. Only 13% of the 169 controls were vitamin D deficient (S-25(OH) D) amp;lt; 50 nmol/L), in contrast with 49% of orthopedic patients with hip fractures (n = 133), 31% of stroke patients (n = 122), 39% of patients visiting the hospitals emergency department amp;gt;= 4 times a year (n = 81), and 75% of homebound adult residents in long-term care nursing homes (n = 51). The mean vitamin D concentration of the healthy control group (74 nmol/L) was similar to a suggested optimal level based on physiological data and mortality studies, and much higher than that of many officially recommended cut-off levels for vitamin D deficiency (amp;lt; 50 nmol/L). The present study provides a basis for planning and implementing public guidelines for the screening of vitamin D deficiency and vitamin D treatment for frail elderly patients.

  • 169.
    Carlén, Anna
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Exercise Testing in Firefighters: Work Capacity and Cardiovascular Risk Assessment in a Low-Risk Population2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background. Firefighting is one of the most physically demanding occupations and it requires a high cardiorespiratory fitness level.

    Pre-duty medical evaluation of firefighters includes fitness testing and assessment of cardiac health to ensure that firefighters meet the minimum physical fitness standard and to ensure that they are not at increased risk of cardiac events. The medical evaluation methods for Swedish firefighters are regulated by the Swedish Work Environment Authority and include a 6 min constant workload treadmill (TM) test for fitness evaluation in which the firefighter wears full smoke diving equipment and a maximal effort exercise electrocardiography test (ExECG) at cycle ergometer (CE) for assessment of cardiac health. Previously, fitness was also evaluated by cycle ergometry.

    The standard parameter for evaluation of ischaemic heart disease (IHD) is exercise-induced ST depression. In general, exercise testing of asymptomatic low-risk individuals is discouraged due to low sensitivity and specificity for IHD, generating both false-positive and false-negative test results. Heart rate (HR) adjustment of the ST-segment response has been shown to be superior to simple ST depression to evaluate cardiac ischaemia in some populations, but has not been extensively evaluated in an occupational setting.

    Methods. We retrospectively analysed a cohort of 774 firefighters who were asymptomatic at the time of the testing.

    In paper I, test approval, HR response, and calculated oxygen uptake from TM tests and CE tests for 424 firefighters (44±10 years) were compared.

    Paper II methodologically described the process for data extraction, processing, and calculation of ExECG data from a clinical database. Procedures for noise assessment, error checking, and computerized calculation of ST/HR parameters were described.

    In paper III, ExECG and medical records of 521 male firefighters (44±10 years) were studied. During 8.4 ± 2.1 years of follow-up, IHD was verified angiographically in 12 subjects. The predictive value of HR-adjusted ST variables (ST/HR index, ST/HR slope, and ST/HR loop) for IHD was evaluated.

    In paper IV, subjects with objectively verified IHD were excluded and factors associated with exercise-induced nonischaemic ST depression were studied in the remaining 509 males (46±11 years).

     

    Results. The firefighters had an average maximal exercise capacity of 281 ± 36 W (range 186-467 W) achieved by incremental CE exercise. To enable comparison, the maximal workload was converted to the workload sustainable for 6 min. It was more common to pass the 6 min TM fitness test but to fail the supposedly equivalent CE test rather than vice versa.

    Twenty percent of the firefighters developed an ST depression of ≥o.1 mV in at least one lead during exercise and half of the firefighters had a horizontal or downsloping ST depression. While an abnormal ST response associated with an increased risk for IHD only in V4, both an abnormal ST/HR index and an abnormal ST/HR slope associated with IHD in three leads each. Clockwise rotation of the ST/HR loop was infrequent in all precordial leads (1%), but it associated with an increased risk for IHD.

    In the subgroup without evidence of coronary artery disease, age and the HR response associated with ST depression, whereas hypertension, hyperlipidaemia, diabetes, blood pressure response, and exercise capacity did not.

     

    Conclusions. Even though the calculated oxygen uptake was higher for the TM test than for the supposedly equivalent CE test, the higher treadmill approval rate may indicate that the fitness requirement for Swedish firefighters has been lowered by changing the test modality.

    Exercise-induced ST depression was common in asymptomatic physically active men, although there were only a few cases of IHD during follow-up. If performing ExECG in asymptomatic, low-risk populations, ST/HR analysis could be given more importance. However, the limited clinical value of ExECG in low-risk populations was emphasised and needs to be reconsidered.

    In asymptomatic, physically active men without coronary artery disease, false-positive ST depressions can be partially explained by HR variables rather than by common cardiovascular risk factors and blood pressure response to exercise.

    List of papers
    1. Loaded treadmill walking and cycle ergometry to assess work capacity: a retrospective comparison in 424 firefighters.
    Open this publication in new window or tab >>Loaded treadmill walking and cycle ergometry to assess work capacity: a retrospective comparison in 424 firefighters.
    2017 (English)In: Clinical Physiology and Functional Imaging, ISSN 1475-0961, E-ISSN 1475-097X, Vol. 37, no 1, p. 37-44Article in journal (Refereed) Published
    Abstract [en]

    The fitness of firefighters is regularly evaluated using exercise tests. We aimed to compare, with respect to age and body composition, two test modalities for the assessment work capacity. A total of 424 Swedish firefighters with cycle ergometer (CE) and treadmill (TM) tests available from Jan 2004 to Dec 2010 were included. We compared results from CE (6 min at 200 W, 250 W or incremental ramp exercise) with TM (6 min at 8° inclination, 4·5 km h(-1) or faster, wearing 24-kg protective equipment). Oxygen requirements were estimated by prediction equations. It was more common to pass the TM test and fail the supposedly equivalent CE test (20%), than vice versa (0·5%), P<0·001. Low age and tall stature were significant predictors of passing both CE and TM tests (P<0·05), while low body mass predicted accomplishment of TM test only (P = 0·006). Firefighters who passed the TM but failed the supposedly equivalent CE test within 12 months had significantly lower body mass, lower BMI, lower BSA and shorter stature than did those who passed both tests. Calculated oxygen uptake was higher in TM tests compared with corresponding CE tests (P<0·001). Body constitution affected approval differently depending on the test modality. A higher approval rate in TM testing suggests lower cardiorespiratory requirements compared with CE testing, even though estimated oxygen uptake was higher during TM testing. The relevance of our findings in relation to the occupational demands needs reconsidering.

    National Category
    Sport and Fitness Sciences
    Identifiers
    urn:nbn:se:liu:diva-120004 (URN)10.1111/cpf.12265 (DOI)000390688200006 ()26096157 (PubMedID)
    Note

    Funding agencies: ALF grants; County Council of Ostergotland, Sweden; Olav Axelssons memorial fund

    Available from: 2015-07-02 Created: 2015-07-02 Last updated: 2019-08-21
    2. ST/HR variables in firefighter exercise ECG: relation to ischemic heart disease
    Open this publication in new window or tab >>ST/HR variables in firefighter exercise ECG: relation to ischemic heart disease
    2019 (English)In: Physiological Reports, E-ISSN 2051-817X, Vol. 7, no 2, article id e13968Article in journal (Refereed) Published
    Abstract [en]

    Exercise electrocardiography (ExECG) is regularly performed by Swedish firefighters by law. Heart rate-corrected analysis of ST segment variables (ST/HR) has shown improved prediction of ischemic heart disease (IHD) compared to ST depression alone. This has not previously been extensively studied in asymptomatic persons with a low probability of IHD. We therefore evaluated the predictive performance of ST/HR analysis in firefighter ExECG. ExECG was studied in 521 male firefighters. During 8.4 ± 2.1 years, 2.3% (n = 12) were verified with IHD by catheterization or myocardial scintigraphy (age 51.5 ± 5.5 years) and were compared with firefighters without imaging proof of IHD (44.2 ± 10.1 years). The predictive value of ST depression, ST/HR index, ST/HR slope, and area and rotation of the ST/HR loop was calculated as age-adjusted odds ratios (OR), in 10 ECG leads. Predictive accuracy was analyzed with receiver operating characteristics (ROC) analysis. ST/HR index ≤-1.6 μV/bpm and ST/HR slope ≤-2.4 μV/bpm were associated with increased IHD risk in three individual leads (all OR > 1.0, P < 0.05). ST/HR loop area lower than the fifth percentile of non-IHD subjects indicated IHD risk in V4, V5, aVF, II, and -aVR (P < 0.05). ST depression ≤-0.1 mV was associated with IHD only in V4 (OR, 9.6, CI, 2.3-40.0). ROC analysis of each of these variables yielded areas under the curve of 0.72 or lower for all variables and leads. Clockwise-rotated ST/HR loops was associated with increased risk in most leads compared to counterclockwise rotation. The limited clinical value of ExECG in low-risk populations was emphasized, but if performed, ST/HR analysis should probably be given more importance.

    Place, publisher, year, edition, pages
    John Wiley & Sons, 2019
    Keywords
    Electrocardiography, ST depression, ST/HR variables, low risk
    National Category
    Cardiac and Cardiovascular Systems
    Identifiers
    urn:nbn:se:liu:diva-159752 (URN)10.14814/phy2.13968 (DOI)000457188800007 ()30688031 (PubMedID)2-s2.0-85060598157 (Scopus ID)
    Available from: 2019-08-20 Created: 2019-08-20 Last updated: 2019-08-26Bibliographically approved
    3. Exercise-induced ST depression in an asymptomatic population without coronary artery disease
    Open this publication in new window or tab >>Exercise-induced ST depression in an asymptomatic population without coronary artery disease
    2019 (English)In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 53, no 4, p. 206-212Article in journal (Refereed) Published
    Abstract [en]

    Objectives. Exercise electrocardiogram (ExECG) in low risk populations frequently generates false positive ST depression. We aimed to characterize factors that are associated with exercise-induced ST depression in asymptomatic men without coronary artery disease. Design. Cycle ergometer exercise tests from 509 male firefighters without imaging proof of significant coronary artery disease were analysed. Analysed test data included heart rate at rest before exercise, and workload, blood pressure, heart rate, ST depression and ST segment slope at peak exercise. ST depression of amp;gt;0.1 mV was considered significant (STdep). With a mean follow-up of 6.1 +/- 1.7 years, medical records were reviewed for cardiovascular diagnoses, hyperlipidemia and diabetes. Logistic regression analysis was used for risk assessment. Results. In total, 22% had STdep in amp;gt;= 1 lead. Subjects with STdep were older than those with normal ExECG (p amp;lt; .001). Downsloping STdep was more common in extremity leads (9%) than in precordial leads (2%). STdep was categorized according to location (precordial/extremity) and slope direction into eight categories. Larger age-adjusted heart rate increase predicted STdep in seven categories (p amp;lt; .05). Age-adjusted peak heart rate correlated with STdep in five categories, predominantly where the ST slope was positive. Peak blood pressure and exercise capacity were both associated with STdep in few categories. We found no association between STdep and hypertension, hyperlipidemia or diabetes (all p amp;gt; .05). Conclusions. In asymptomatic men with a physically demanding occupation and no coronary artery disease, both age and heart rate response were associated with ST depression, whereas common cardiovascular risk factors, blood pressure response and exercise capacity were not.

    Place, publisher, year, edition, pages
    Taylor & Francis, 2019
    Keywords
    Stress test; false positive; electrocardiography; heart rate; ST segment deviation; firefighters; low risk
    National Category
    Cardiac and Cardiovascular Systems
    Identifiers
    urn:nbn:se:liu:diva-158872 (URN)10.1080/14017431.2019.1626021 (DOI)000472278700001 ()31144537 (PubMedID)
    Note

    Funding Agencies|County Council of Ostergotland, Sweden [LIO-711261]; ALF grant [700731]

    Available from: 2019-07-15 Created: 2019-07-15 Last updated: 2019-11-07
  • 170.
    Carlén, Anna
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Gustafsson, Mikael
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Åström, Meriam
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Nylander, Eva
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Exercise-induced ST depression in an asymptomatic population without coronary artery disease2019In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 53, no 4, p. 206-212Article in journal (Refereed)
    Abstract [en]

    Objectives. Exercise electrocardiogram (ExECG) in low risk populations frequently generates false positive ST depression. We aimed to characterize factors that are associated with exercise-induced ST depression in asymptomatic men without coronary artery disease. Design. Cycle ergometer exercise tests from 509 male firefighters without imaging proof of significant coronary artery disease were analysed. Analysed test data included heart rate at rest before exercise, and workload, blood pressure, heart rate, ST depression and ST segment slope at peak exercise. ST depression of amp;gt;0.1 mV was considered significant (STdep). With a mean follow-up of 6.1 +/- 1.7 years, medical records were reviewed for cardiovascular diagnoses, hyperlipidemia and diabetes. Logistic regression analysis was used for risk assessment. Results. In total, 22% had STdep in amp;gt;= 1 lead. Subjects with STdep were older than those with normal ExECG (p amp;lt; .001). Downsloping STdep was more common in extremity leads (9%) than in precordial leads (2%). STdep was categorized according to location (precordial/extremity) and slope direction into eight categories. Larger age-adjusted heart rate increase predicted STdep in seven categories (p amp;lt; .05). Age-adjusted peak heart rate correlated with STdep in five categories, predominantly where the ST slope was positive. Peak blood pressure and exercise capacity were both associated with STdep in few categories. We found no association between STdep and hypertension, hyperlipidemia or diabetes (all p amp;gt; .05). Conclusions. In asymptomatic men with a physically demanding occupation and no coronary artery disease, both age and heart rate response were associated with ST depression, whereas common cardiovascular risk factors, blood pressure response and exercise capacity were not.

  • 171.
    Carlén, Anna
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Nylander, Eva
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Åström Aneq, Meriam
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Gustafsson, Mikael
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    ST/HR variables in firefighter exercise ECG: relation to ischemic heart disease2019In: Physiological Reports, E-ISSN 2051-817X, Vol. 7, no 2, article id e13968Article in journal (Refereed)
    Abstract [en]

    Exercise electrocardiography (ExECG) is regularly performed by Swedish firefighters by law. Heart rate-corrected analysis of ST segment variables (ST/HR) has shown improved prediction of ischemic heart disease (IHD) compared to ST depression alone. This has not previously been extensively studied in asymptomatic persons with a low probability of IHD. We therefore evaluated the predictive performance of ST/HR analysis in firefighter ExECG. ExECG was studied in 521 male firefighters. During 8.4 ± 2.1 years, 2.3% (n = 12) were verified with IHD by catheterization or myocardial scintigraphy (age 51.5 ± 5.5 years) and were compared with firefighters without imaging proof of IHD (44.2 ± 10.1 years). The predictive value of ST depression, ST/HR index, ST/HR slope, and area and rotation of the ST/HR loop was calculated as age-adjusted odds ratios (OR), in 10 ECG leads. Predictive accuracy was analyzed with receiver operating characteristics (ROC) analysis. ST/HR index ≤-1.6 μV/bpm and ST/HR slope ≤-2.4 μV/bpm were associated with increased IHD risk in three individual leads (all OR > 1.0, P < 0.05). ST/HR loop area lower than the fifth percentile of non-IHD subjects indicated IHD risk in V4, V5, aVF, II, and -aVR (P < 0.05). ST depression ≤-0.1 mV was associated with IHD only in V4 (OR, 9.6, CI, 2.3-40.0). ROC analysis of each of these variables yielded areas under the curve of 0.72 or lower for all variables and leads. Clockwise-rotated ST/HR loops was associated with increased risk in most leads compared to counterclockwise rotation. The limited clinical value of ExECG in low-risk populations was emphasized, but if performed, ST/HR analysis should probably be given more importance.

  • 172.
    Carlén, Anna
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Åström Aneq, Meriam
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Nylander, Eva
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Gustafsson, Mikael
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Loaded treadmill walking and cycle ergometry to assess work capacity: a retrospective comparison in 424 firefighters.2017In: Clinical Physiology and Functional Imaging, ISSN 1475-0961, E-ISSN 1475-097X, Vol. 37, no 1, p. 37-44Article in journal (Refereed)
    Abstract [en]

    The fitness of firefighters is regularly evaluated using exercise tests. We aimed to compare, with respect to age and body composition, two test modalities for the assessment work capacity. A total of 424 Swedish firefighters with cycle ergometer (CE) and treadmill (TM) tests available from Jan 2004 to Dec 2010 were included. We compared results from CE (6 min at 200 W, 250 W or incremental ramp exercise) with TM (6 min at 8° inclination, 4·5 km h(-1) or faster, wearing 24-kg protective equipment). Oxygen requirements were estimated by prediction equations. It was more common to pass the TM test and fail the supposedly equivalent CE test (20%), than vice versa (0·5%), P<0·001. Low age and tall stature were significant predictors of passing both CE and TM tests (P<0·05), while low body mass predicted accomplishment of TM test only (P = 0·006). Firefighters who passed the TM but failed the supposedly equivalent CE test within 12 months had significantly lower body mass, lower BMI, lower BSA and shorter stature than did those who passed both tests. Calculated oxygen uptake was higher in TM tests compared with corresponding CE tests (P<0·001). Body constitution affected approval differently depending on the test modality. A higher approval rate in TM testing suggests lower cardiorespiratory requirements compared with CE testing, even though estimated oxygen uptake was higher during TM testing. The relevance of our findings in relation to the occupational demands needs reconsidering.

  • 173.
    Casas Garcia, Belén
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Towards Personalized Models of the Cardiovascular System Using 4D Flow MRI2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Current diagnostic tools for assessing cardiovascular disease mostly focus on measuring a given biomarker at a specific spatial location where an abnormality is suspected. However, as a result of the dynamic and complex nature of the cardiovascular system, the analysis of isolated biomarkers is generally not sufficient to characterize the pathological mechanisms behind a disease. Model-based approaches that integrate the mechanisms through which different components interact, and present possibilities for system-level analyses, give us a better picture of a patient’s overall health status.

    One of the main goals of cardiovascular modelling is the development of personalized models based on clinical measurements. Recent years have seen remarkable advances in medical imaging and the use of personalized models is slowly becoming a reality. Modern imaging techniques can provide an unprecedented amount of anatomical and functional information about the heart and vessels. In this context, three-dimensional, three-directional, cine phase-contrast (PC) magnetic resonance imaging (MRI), commonly referred to as 4D Flow MRI, arises as a powerful tool for creating personalized models. 4D Flow MRI enables the measurement of time-resolved velocity information with volumetric coverage. Besides providing a rich dataset within a single acquisition, the technique permits retrospective analysis of the data at any location within the acquired volume.

    This thesis focuses on improving subject-specific assessment of cardiovascular function through model-based analysis of 4D Flow MRI data. By using computational models, we aimed to provide mechanistic explanations of the underlying physiological processes, derive novel or improved hemodynamic markers, and estimate quantities that typically require invasive measurements. Paper I presents an evaluation of current markers of stenosis severity using advanced models to simulate flow through a stenosis. Paper II presents a framework to personalize a reduced-order, mechanistic model of the cardiovascular system using exclusively non-invasive measurements, including 4D Flow MRI data. The modelling approach can unravel a number of clinically relevant parameters from the input data, including those representing the contraction and relaxation patterns of the left ventricle, and provide estimations of the pressure-volume loop. In Paper III, this framework is applied to study cardiovascular function at rest and during stress conditions, and the capability of the model to infer load-independent measures of heart function based on the imaging data is demonstrated. Paper IV focuses on evaluating the reliability of the model parameters as a step towards translation of the model to the clinic.

    List of papers
    1. 4D Flow MRI-Based Pressure Loss Estimation in Stenotic Flows: Evaluation Using Numerical Simulations
    Open this publication in new window or tab >>4D Flow MRI-Based Pressure Loss Estimation in Stenotic Flows: Evaluation Using Numerical Simulations
    2016 (English)In: Magnetic Resonance in Medicine, ISSN 0740-3194, E-ISSN 1522-2594, Vol. 75, no 4, p. 1808-1821Article in journal (Refereed) Published
    Abstract [en]

    Purpose: To assess how 4D flow MRI-based pressure and energy loss estimates correspond to net transstenotic pressure gradients (TPG(net)) and their dependence on spatial resolution. Methods: Numerical velocity data of stenotic flow were obtained from computational fluid dynamics (CFD) simulations in geometries with varying stenosis degrees, poststenotic diameters and flow rates. MRI measurements were simulated at different spatial resolutions. The simplified and extended Bernoulli equations, Pressure-Poisson equation (PPE), and integration of turbulent kinetic energy (TKE) and viscous dissipation were compared against the true TPG(net). Results: The simplified Bernoulli equation overestimated the true TPG(net) (8.74 +/- 0.67 versus 6.76 +/- 0.54 mmHg). The extended Bernoulli equation performed better (6.57 +/- 0.53 mmHg), although errors remained at low TPG(net). TPG(net) estimations using the PPE were always close to zero. Total TKE and viscous dissipation correlated strongly with TPG(net) for each geometry (r(2) &gt; 0.93) and moderately considering all geometries (r(2) = 0.756 and r(2) = 0.776, respectively). TKE estimates were accurate and minorly impacted by resolution. Viscous dissipation was overall underestimated and resolution dependent. Conclusion: Several parameters overestimate or are not linearly related to TPG(net) and/or depend on spatial resolution. Considering idealized axisymmetric geometries and in absence of noise, TPG(net) was best estimated using the extended Bernoulli equation. (C) 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance.

    Place, publisher, year, edition, pages
    WILEY-BLACKWELL, 2016
    Keywords
    pressure loss; phase contrast magnetic resonance imaging; aortic valve disease; aortic coarctation
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-127426 (URN)10.1002/mrm.25772 (DOI)000372910900043 ()26016805 (PubMedID)
    Note

    Funding Agencies|European Research Council [310612]; Swedish Research Council

    Available from: 2016-05-01 Created: 2016-04-26 Last updated: 2018-10-10
    2. Bridging the gap between measurements and modelling: a cardiovascular functional avatar
    Open this publication in new window or tab >>Bridging the gap between measurements and modelling: a cardiovascular functional avatar
    Show others...
    2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 6214Article in journal (Refereed) Published
    Abstract [en]

    Lumped parameter models of the cardiovascular system have the potential to assist researchers and clinicians to better understand cardiovascular function. The value of such models increases when they are subject specific. However, most approaches to personalize lumped parameter models have thus far required invasive measurements or fall short of being subject specific due to a lack of the necessary clinical data. Here, we propose an approach to personalize parameters in a model of the heart and the systemic circulation using exclusively non-invasive measurements. The personalized model is created using flow data from four-dimensional magnetic resonance imaging and cuff pressure measurements in the brachial artery. We term this personalized model the cardiovascular avatar. In our proof-of-concept study, we evaluated the capability of the avatar to reproduce pressures and flows in a group of eight healthy subjects. Both quantitatively and qualitatively, the model-based results agreed well with the pressure and flow measurements obtained in vivo for each subject. This non-invasive and personalized approach can synthesize medical data into clinically relevant indicators of cardiovascular function, and estimate hemodynamic variables that cannot be assessed directly from clinical measurements.

    Place, publisher, year, edition, pages
    Nature Publishing Group, 2017
    National Category
    Biomedical Laboratory Science/Technology
    Identifiers
    urn:nbn:se:liu:diva-140069 (URN)10.1038/s41598-017-06339-0 (DOI)000406260100018 ()28740184 (PubMedID)2-s2.0-85025821468 (Scopus ID)
    Note

    Funding Agencies|European Research Council [310612]; Swedish Research Council [2014-6191]

    Available from: 2017-08-28 Created: 2017-08-28 Last updated: 2018-10-10Bibliographically approved
  • 174.
    Casas Garcia, Belén
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Lantz, Jonas
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Dyverfeldt, Petter
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV). Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Ebbers, Tino
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Science and Technology, Media and Information Technology. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Faculty of Science & Engineering. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    4D Flow MRI-Based Pressure Loss Estimation in Stenotic Flows: Evaluation Using Numerical Simulations2016In: Magnetic Resonance in Medicine, ISSN 0740-3194, E-ISSN 1522-2594, Vol. 75, no 4, p. 1808-1821Article in journal (Refereed)
    Abstract [en]

    Purpose: To assess how 4D flow MRI-based pressure and energy loss estimates correspond to net transstenotic pressure gradients (TPG(net)) and their dependence on spatial resolution. Methods: Numerical velocity data of stenotic flow were obtained from computational fluid dynamics (CFD) simulations in geometries with varying stenosis degrees, poststenotic diameters and flow rates. MRI measurements were simulated at different spatial resolutions. The simplified and extended Bernoulli equations, Pressure-Poisson equation (PPE), and integration of turbulent kinetic energy (TKE) and viscous dissipation were compared against the true TPG(net). Results: The simplified Bernoulli equation overestimated the true TPG(net) (8.74 +/- 0.67 versus 6.76 +/- 0.54 mmHg). The extended Bernoulli equation performed better (6.57 +/- 0.53 mmHg), although errors remained at low TPG(net). TPG(net) estimations using the PPE were always close to zero. Total TKE and viscous dissipation correlated strongly with TPG(net) for each geometry (r(2) &gt; 0.93) and moderately considering all geometries (r(2) = 0.756 and r(2) = 0.776, respectively). TKE estimates were accurate and minorly impacted by resolution. Viscous dissipation was overall underestimated and resolution dependent. Conclusion: Several parameters overestimate or are not linearly related to TPG(net) and/or depend on spatial resolution. Considering idealized axisymmetric geometries and in absence of noise, TPG(net) was best estimated using the extended Bernoulli equation. (C) 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance.

  • 175.
    Casas Garcia, Belén
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Lantz, Jonas
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Viola, Frederica
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Cedersund, Gunnar
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Bolger, Ann F.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. University of Calif San Francisco, CA USA.
    Carlhäll, Carljohan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Karlsson, Matts
    Linköping University, Department of Management and Engineering, Applied Thermodynamics and Fluid Mechanics. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Ebbers, Tino
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Bridging the gap between measurements and modelling: a cardiovascular functional avatar2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 6214Article in journal (Refereed)
    Abstract [en]

    Lumped parameter models of the cardiovascular system have the potential to assist researchers and clinicians to better understand cardiovascular function. The value of such models increases when they are subject specific. However, most approaches to personalize lumped parameter models have thus far required invasive measurements or fall short of being subject specific due to a lack of the necessary clinical data. Here, we propose an approach to personalize parameters in a model of the heart and the systemic circulation using exclusively non-invasive measurements. The personalized model is created using flow data from four-dimensional magnetic resonance imaging and cuff pressure measurements in the brachial artery. We term this personalized model the cardiovascular avatar. In our proof-of-concept study, we evaluated the capability of the avatar to reproduce pressures and flows in a group of eight healthy subjects. Both quantitatively and qualitatively, the model-based results agreed well with the pressure and flow measurements obtained in vivo for each subject. This non-invasive and personalized approach can synthesize medical data into clinically relevant indicators of cardiovascular function, and estimate hemodynamic variables that cannot be assessed directly from clinical measurements.

  • 176.
    Casas Garcia, Belén
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Viola, Frederica
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Cedersund, Gunnar
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Bolger, Ann F
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Univ Calif San Francisco, CA USA.
    Karlsson, Matts
    Linköping University, Department of Management and Engineering, Applied Thermodynamics and Fluid Mechanics. Linköping University, Faculty of Science & Engineering. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Carlhäll, Carljohan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Ebbers, Tino
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Non-invasive Assessment of Systolic and Diastolic Cardiac Function During Rest and Stress Conditions Using an Integrated Image-Modeling Approach2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 1515Article in journal (Refereed)
    Abstract [en]

    Background: The possibility of non-invasively assessing load-independent parameters characterizing cardiac function is of high clinical value. Typically, these parameters are assessed during resting conditions. However, for diagnostic purposes, the parameter behavior across a physiologically relevant range of heart rate and loads is more relevant than the isolated measurements performed at rest. This study sought to evaluate changes in non-invasive estimations of load-independent parameters of left-ventricular contraction and relaxation patterns at rest and during dobutamine stress. Methods: We applied a previously developed approach that combines non-invasive measurements with a physiologically-based, reduced-order model of the cardiovascular system to provide subject-specific estimates of parameters characterizing left ventricular function. In this model, the contractile state of the heart at each time point along the cardiac cycle is modeled using a time-varying elastance curve. Non-invasive data, including four-dimensional magnetic resonance imaging (4D Flow MRI) measurements, were acquired in nine subjects without a known heart disease at rest and during dobutamine stress. For each of the study subjects, we constructed two personalized models corresponding to the resting and the stress state. Results: Applying the modeling framework, we identified significant increases in the left ventricular contraction rate constant [from 1.5 +/- 0.3 to 2 +/- 0.5 (p = 0.038)] and relaxation constant [from 37.2 +/- 6.9 to 46.1 +/- 12 (p = 0.028)]. In addition, we found a significant decrease in the elastance diastolic time constant from 0.4 +/- 0.04 s to 0.3 +/- 0.03 s = 0.008). Conclusions: The integrated image-modeling approach allows the assessment of cardiovascular function given as model-based parameters. The agreement between the estimated parameter values and previously reported effects of dobutamine demonstrates the potential of the approach to assess advanced metrics of pathophysiology that are otherwise difficult to obtain non-invasively in clinical practice.

  • 177.
    Casimir Ahn, Henrik
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Granfeldt, Hans
    Linköping University, Department of Medical and Health Sciences, Thoracic Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Hübbert, Laila
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Peterzén, Bengt
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Long-term left ventricular support in patients with a mechanical aortic valve2013In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 47, no 4, p. 236-239Article in journal (Refereed)
    Abstract [en]

    Objectives. The presence of a mechanical prosthesis has been regarded as an increased risk of thromboembolic complications and as a relative contraindication for a left ventricular assist device (LVAD). Five patients in our center had a mechanical aortic valve at the time of device implantation and were studied regarding thromboembolic complications. Design. Five patients operated upon with an LVAD (1 HeartMate I (TM), 4 HeartMate II (TM)) between 2002 and 2011 had a mechanical aortic valve at the time of implantation. The first patient had a patch closure of the aortic valve. In four patients, the prosthesis was left in place. Anticoagulants included aspirin, warfarin, and clopidogrel. Results. The average and accumulated treatment times were 150 and 752 days, respectively. Three of the five patients showed early signs of valve thrombosis on echo with concomitant valve dysfunction. Four patients were transplanted without thromboembolic events during pump treatment. One patient died from a hemorrhagic stroke after 90 days on the LVAD. Conclusions. The strategy of leaving a mechanical heart valve in place at the time of LVAD implantation in five patients led to valvular thrombosis in three but did not provoke embolic events. It increased the complexity of postoperative anticoagulation.

  • 178.
    Cermakova, Pavla
    et al.
    Karolinska Institute, Sweden; Int Clin Research Centre, Czech Republic; St Annes University Hospital, Czech Republic.
    Lund, Lars H.
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Fereshtehnejad, Seyed-Mohammad
    Karolinska Institute, Sweden.
    Johnell, Kristina
    Karolinska Institute, Sweden; Stockholm University, Sweden.
    Winblad, Bengt
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Dahlström, Ulf
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Eriksdotter, Maria
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Religa, Dorota
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Heart failure and dementia: survival in relation to types of heart failure and different dementia disorders2015In: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844, Vol. 17, no 6, p. 612-619Article in journal (Refereed)
    Abstract [en]

    AimsHeart failure (HF) and dementia frequently coexist, but little is known about their types, relationships to each other and prognosis. The aims were to (i) describe patients with HF and dementia, assess (ii) the proportion of specific dementia disorders in types of HF based on ejection fraction and (iii) the prognostic role of types of HF and dementia disorders. Methods and resultsThe Swedish Heart Failure Registry (RiksSvikt) and The Swedish Dementia Registry (SveDem) were record-linked. Associations between dementia disorders and HF types were assessed with multinomial logistic regression and survival was investigated with Kaplan-Meier analysis and multivariable Cox regression. We studied 775 patients found in both registries (55% men, mean age 82years). Ejection fraction was preserved in 38% of patients, reduced in 34%, and missing in 28%. The proportions of dementia disorders were similar across HF types. Vascular dementia was the most common dementia disorder (36%), followed by other dementias (28%), mixed dementia (20%), and Alzheimer disease (16%). Over a mean follow-up of 1.5years, 76% of patients survived 1year. We observed no significant differences in survival with regard to HF type (P=0.2) or dementia disorder (P=0.5). After adjustment for baseline covariates, neither HF types nor dementia disorders were independently associated with survival. ConclusionsHeart failure with preserved ejection fraction was the most common HF type and vascular dementia was the most common dementia disorder. The proportions of dementia disorders were similar across HF types. Neither HF types nor specific dementia disorders were associated with survival.

  • 179.
    Cervin, A.
    et al.
    Uppsala University, Sweden; NU Hospital Org, Sweden.
    Tjarnstrom, J.
    Uppsala University, Sweden; NU Hospital Org, Sweden.
    Ravn, H.
    Uppsala University, Sweden; Lillebaelt Hospital, Denmark.
    Acosta, S.
    Malmö University Hospital, Sweden.
    Hultgren, R.
    Karolinska Institute, Sweden.
    Welander, Martin
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Bjorck, M.
    Uppsala University, Sweden.
    Treatment of Popliteal Aneurysm by Open and Endovascular Surgery: A Contemporary Study of 592 Procedures in Sweden2015In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 50, no 3, p. 342-350Article in journal (Refereed)
    Abstract [en]

    WHAT THIS STUDY ADDS Previous comparisons between open and endovascular repair of popliteal aneurysms have focused on asymptomatic patients, and have short follow up. This study is strengthened by the fact that it is contemporary, population based, without any selection bias, reporting on all kinds of presentations, and has approximately 90% 1 year follow up data. It shows that endovascular repair has significantly inferior results compared with open repair, in particular in the group of patients who present with acute ischaemia. We believe these results will make many vascular surgeons think twice before they treat patients endovascularly in the future. Background: Popliteal aneurysm (PA) is traditionally treated by open repair (OR). Endovascular repair (ER) has become more common. The aim was to describe time trends and compare results (OR/ER). Methods: The Swedish vascular registry, Swedvasc, has a specific PA module. Data were collected (2008-2012) and supplemented with a specific protocol (response rate 99.1%). Data were compared with previously published data (1994-2002) from the same database. Results: The number of operations for PA was 15.7/million person-years (8.3 during 1994-2001). Of 592 interventions for PA (499 patients), 174 (29.4%) were treated for acute ischaemia, 13 (2.2%) for rupture, 105 (17.7%) for other symptoms, and 300 (50.7%) were asymptomatic (31.5% were treated for acute ischaemia, 1994-2002, p = .58). There were no differences in background characteristics between OR and ER in the acute ischaennia group. The symptomatic and asymptomatic groups treated with ER were older (p = .006, p less than .001). ER increased 3.6 fold (4.7% 1994-2002, 16.7% 2008-2012, p = .0001). Of those treated for acute ischaemia, a stent graft was used in 27 (16.4%). Secondary patency after ER was 70.4% at 30 days and 47.6% at 1 year, versus 93.1% and 86.8% after OR (p = .001, less than .001). The amputation rate at 30 days was 14.8% after ER, 3.7% after OR (p = .022), and 17.4% and 6.8% at 1 year (p = .098). A stent graft was used in 18.3% for asymptomatic PA. Secondary patency after ER was 94.5% at 30 days and 83.7% at 1 year, compared with 98.8% and 93.5% after OR (p = .043 and 0.026). OR was performed with vein graft in 87.6% (395/451), with better primary and secondary patency at 1 year than prosthetic grafts (p = .002 and less than .001), and with a posterior approach in 20.8% (121/581). Conclusions: The number of operations for PA doubled while the indications remained similar. ER patency was inferior to OR, especially after treatment for acute ischaemia, and the amputation risk tended to be higher, despite similar pre-operative characteristics. (C) 2015 The Authors. Published by Elsevier Ltd on behalf of European Society for Vascular Surgery. This is an open access article under the CC BY-NC-SA license (http://creativecommons.org/licenses/by-nc-sa/4.0/).

  • 180.
    Chaireti, Roza
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine. Karolinska Univ Hosp, Coagulat Unit, Div Haematol, Dept Med, Stockholm, Sweden.
    Rajani, Rupesh
    Division of Gastroenterology & Hepatology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Bergquist, Annika
    Division of Gastroenterology & Hepatology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Melin, Tor
    Division of Gastroenterology & Hepatology, University Hospital, Lund, Sweden.
    Friis-Liby, Inga-Lill
    Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Kapraali, Marjo
    Karolinska Institutet, Department of Clinical Sciences Danderyd Hospital, Division of Medicine, Stockholm, Sweden.
    Kechagias, Stergios
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Gastroentorology.
    Lindahl, Tomas L.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Almer, Sven
    Division of Gastroenterology & Hepatology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; Karolinska Inst, Dept Med, Solna, Sweden.
    Increased thrombin generation in splanchnic vein thrombosis is related to the presence of liver cirrhosis and not to the thrombotic event2014In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 134, no 2, p. 455-461Article in journal (Refereed)
    Abstract [en]

    Background: In recent years there have been increasing evidence associating liver disease with hypercoagulability, rather than bleeding.

    Aims: To evaluate the haemostatic potential in patients with liver disease.

    Methods: We measured thrombin generation in the presence and absence of thrombomodulin in patients with portal vein thrombosis (PVT, n=47), Budd-Chiari syndrome (BCS, n=15) and cirrhosis (n=24) and compared the results to those obtained from healthy controls (n=21). Fifteen patients with PVT and 10 patients with BCS were treated with warfarin and were compared with an equal number of patients with atrial fibrillation matched for prothrombin time-international normalized ratio. We assessed resistance to thrombomodulin by using ratios [marker measured in the presence]/[marker measured in the absence of thrombomodulin].

    Results: There were no differences between patients with BCS, patients on warfarin treatment and controls. Cirrhotic patients generated more thrombin in the presence of thrombomodulin and exhibited thrombomodulin resistance compared with controls [p=0.006 for endogenous thrombin potential (ETP) and p<0.001 for peak thrombin. P<0.001 for both ratios ETP and peak] and patients with non-cirrhotic PVT (p=0.001, p=0.006, p<0.001, p<0.001 for ETP, peak, ratio ETP, ratio peak). The patients with cirrhotic PVT exhibited higher ETP (p=0.044) and peak (p=0.02) in the presence of thrombomodulin than controls, as well as thrombomodulin resistance (ETP ratio: p=0.001, peak ratio: p=0.001).

    Conclusions: Hypercoagulability and thrombomodulin resistance in patients with cirrhosis were independent of the presence of splanchnic vein thrombosis. The hypercoagulability in patients with cirrhotic PVT could have implications for considering longer treatment with anticoagulants in this group.

  • 181.
    Charitakis, Emmanouil
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Neurohormonal activation, Symptoms and health-related quality of life in patients with atrial fibrillation eligible for radiofrequency ablation2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Atrial fibrillation (AF) is the most common cardiac arrhythmia. In order to improve the management of patients with AF, a better understanding of patients’ arrhythmia-related symptoms and health-related quality of life (HRQoL), as well as a finer grasp of the effect of AF initiation and the revolutionary treatment of radiofrequency ablation (RFA) on neurohormonal balance are of great importance.

    The aim of this dissertation was to study the effects of RFA and AF initiation on four different neurohormonal systems represented by two cardiac biomarkers: the N-terminal fragment of the proB-type natriuretic peptide (NT-proBNP), the mid-regional fragment of the N-terminal of pro-atrial natriuretic peptide (MR-proANP); and two extra-cardiac biomarkers: the C-terminal fragment of the prodromal molecule of arginine vasopressin (copeptin) and the mid-regional portion of pro-adrenomedullin (MR-proADM). Furthermore, we aimed to correlate objective indicators with the variety of arrhythmiarelated symptoms and HRQoL in patients with AF.

    We studied 192 consecutive AF patients, eligible for RFA, referred to the University Hospital, Linköping, Sweden between January 2012 and April 2014. Forty-five patients, out of the initially selected sample, were included in the interventional part of the study. Biomarkers were collected from the femoral vein (fv), the coronary sinus (CS) and the left atrium (LA), and from fv immediately and the day after RFA. With regard to the interventional part of the study, 36 patients were randomized to AF initiation and 19 to control group. Biomarkers were retrieved from fv, CS and LA prior to AF initiation (baseline) and 30 minutes later. The Arrhythmia-Specific questionnaire in Tachycardia and Arrhythmia (ASTA) symptom scale was used in order to assess patients’ arrhythmiarelated symptoms. The ASTA HRQoL scale and the generic short-form 36 (SF-36) physical and mental component summaries were used in order to express patients’ disease-specific and overall HRQoL respectively.

    While analysing the effect of RFA on biomarkers, it was noticed that the level of NTproBNP decreased the day after RFA in participants in AF, compared with the participants in sinus rhythm who showed a slight increase. Regardless of the actual rhythm, the level of MR-proANP showed an increase immediately after RFA was carried out, followed by a decrease the day after. The copeptin level showed a six-fold increase, compared with baseline, immediately after the RFA procedure, while the MR-proADM level increased the day after. The levels of copeptin and MR-proADM were similar in the CS compared to peripheral blood.

    When it came to the effects of AF initiation on biomarkers, compared with the control group, MR-proANP and NT-proBNP concentrations were increased. Copeptin levels in patients without ischemic heart disease were decreased after the initiation of AF.

    We also found that signs of anxiety, low-grade inflammation (defined by high-sensitive C-reactive protein levels>3mg/l) and LA dilatation significantly predicted arrhythmiarelated symptoms. Probable depression was the most important predictor of arrhythmiaspecific HRQoL, and obesity and signs of anxiety were the most important predictors of the physical and mental component summaries respectively.

    AF is a complex arrhythmia that affects the cardiac and extra-cardiac neurohormonal balance directly after its initiation. RFA causes a neurohormonal imbalance not only due to secondary myocardial injury, but also due to other factors such as patient’s actual rhythm, volume overload and procedural stress. Treatable factors such as anxiety, depression and obesity, which can affect HRQoL and symptoms in patients with AF, should be addressed, and possibly a more intensive life style factor modification can be of value.

    List of papers
    1. Symptom burden, Metabolic profile, Ultrasound findings, Rhythm, neurohormonal activation, haemodynamics and health-related quality of life in patients with atrial Fibrillation (SMURF): a protocol for an observational study with a randomised interventional component
    Open this publication in new window or tab >>Symptom burden, Metabolic profile, Ultrasound findings, Rhythm, neurohormonal activation, haemodynamics and health-related quality of life in patients with atrial Fibrillation (SMURF): a protocol for an observational study with a randomised interventional component
    Show others...
    2015 (English)In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 5, no 12, article id e008723Article in journal (Refereed) Published
    Abstract [en]

    INTRODUCTION: Atrial fibrillation (AF) is the most common cardiac arrhythmia, with an estimated prevalence of 1.5-2%. It is an independent risk factor for ischaemic stroke and is estimated to cause about 20-25% of all stroke cases. AF has a great impact on health-related quality of life (HRQoL); however, one unresolved issue related to AF is the wide variation in its symptoms.

    METHODS AND ANALYSIS: The symptom burden, metabolic profile, ultrasound findings, rhythm, neurohormonal activation, haemodynamics and HRQoL in patients with AF (Symptom burden, Metabolic profile, Ultrasound findings, Rhythm, neurohormonal activation, haemodynamics and health-related quality of life in patients with atrial Fibrillation, SMURF) study is a prospective observational, cohort study, with a randomised interventional part. The aim of the study is to investigate, in patients with AF, the relationship between symptom burden and metabolic aspects, atrial function and different neurohormones, and the effect of radiofrequency ablation (RFA). The interventional part of the study will give an insight into the neurohormonal and intracardiac pressure changes directly after initiation of AF. Consecutive patients with symptomatic AF accepted for treatment with RFA for the first time at Linköping University Hospital are eligible for participation. The enrolment started in January 2012, and a total of 200 patients are to be included into the study, with 45 of them being enrolled into the interventional study with initiation of AF. The sample size of the interventional study is based on a small pilot study with 5 patients induced to AF while 2 served as controls. The results indicated that, in order to find a statistically significant difference, there was a need to include 28 patients; for safety reasons, 45 patients will be included.

    ETHICS AND DISSEMINATION: The SMURF study is approved by the Regional Ethical Review Board at the Faculty of Health Sciences, Linköping, Sweden. The results will be presented through peer-review journals and conference presentation.

    TRIAL REGISTRATION NUMBER: NCT01553045; Pre-results.

    Place, publisher, year, edition, pages
    BMJ Publishing Group, 2015
    National Category
    Cardiac and Cardiovascular Systems
    Identifiers
    urn:nbn:se:liu:diva-124290 (URN)10.1136/bmjopen-2015-008723 (DOI)000368839100047 ()26692555 (PubMedID)
    Note

    Funding agencies: ALF grants (County Council of Ostergotland); Carldavid Jonsson Research Foundation; Heart Foundation; Linkoping University; Biosense Webster; Johnson and Johnson

    Available from: 2016-01-25 Created: 2016-01-25 Last updated: 2017-11-30
    2. Short‐Term Influence of Radiofrequency Ablation on NT‐proBNP, MR‐proANP, Copeptin, and MR‐proADM in Patients With Atrial Fibrillation: Data From the Observational SMURF Study
    Open this publication in new window or tab >>Short‐Term Influence of Radiofrequency Ablation on NT‐proBNP, MR‐proANP, Copeptin, and MR‐proADM in Patients With Atrial Fibrillation: Data From the Observational SMURF Study
    2016 (English)In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 5, no 9Article in journal (Refereed) Published
    Abstract [en]

    Background There is limited knowledge on the short‐term influence of radiofrequency ablation (RFA) of atrial fibrillation (AF) on 2 cardiac biomarkers; the N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and the midregional fragment of the N‐terminal of pro‐ANP (MR‐proANP) and 2 extracardiac biomarkers; the c‐terminal provasopressin (copeptin) and the midregional portion of proadrenomedullin (MR‐proADM). There are also limited data concerning cardiac production of the latter two.

    Methods and Results We studied 192 consecutive patients eligible for RFA of AF referred to the University Hospital, Linköping, Sweden. NT‐proBNP, MR‐proANP, copeptin, and MR‐proADM levels were measured in peripheral blood, the coronary sinus (CS), and the left atrium before ablation, and in peripheral blood immediately and the day after RFA. The level of NT‐proBNP decreased the day after RFA in participants in AF at the time of RFA, compared to the participants in sinus rhythm who showed a slight increase (P<0.001). Furthermore, regardless of the actual rhythm, the level of MR‐proANP showed an increase immediately after RFA (P<0.001), followed by a decrease the day after ablation (P<0.001). Copeptin level showed a 6‐fold increase immediately after RFA compared to baseline (P<0.001), whereas MR‐proADM level increased the day after RFA (P<0.001). Levels of copeptin and MR‐proADM were not higher in the CS compared to peripheral blood.

    Conclusions RFA of AF is a strong stimulus with a significant and direct impact on different neurohormonal systems. We found no sign of a cardiac release of MR‐proADM or copeptin.

    Place, publisher, year, edition, pages
    Wiley-Blackwell Publishing Inc., 2016
    Keywords
    Atrial fibrillation, biomarkers, catheter ablation
    National Category
    Cardiac and Cardiovascular Systems Public Health, Global Health, Social Medicine and Epidemiology
    Identifiers
    urn:nbn:se:liu:diva-132725 (URN)10.1161/JAHA.116.003557 (DOI)000386716900022 ()27633393 (PubMedID)
    Note

    Funding agencies: ALF grants (County Council of Ostergotland); Carldavid Jonsson Research Foundation; Heart Foundation; Linkoping University; Biosense Webster; Johnson Johnson

    Available from: 2016-11-21 Created: 2016-11-21 Last updated: 2017-11-29Bibliographically approved
  • 182.
    Charitakis, Emmanouil
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Barmano, Neshro
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Department of Internal Medicine, County Hospital Ryhov, Jönköping, Sweden.
    Walfridsson, Ulla
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Walfridsson, Håkan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Factors Predicting Arrhythmia-Related Symptoms and Health-Related Quality of Life in Patients Referred for Radiofrequency Ablation of Atrial Fibrillation: An Observational Study (the SMURF Study)2017In: JACC: Clinical Electrophysiology, ISSN 2405-500X, Vol. 3, no 5, p. 9p. 497-502Article in journal (Refereed)
    Abstract [en]

    Conclusions Anxiety, depression, and low-grade inflammation were the factors that predicted both arrhythmia-related symptoms and HRQoL in patients with AF. Obesity was the most significant predictor of patient general physical status. These factors need to be addressed in patients with AF to improve management of their disease. Intensive risk factor modification can be of great importance. (Reasons for Variations in Health Related Quality of Life and Symptom Burden in Patients With Atrial Fibrillation [SMURF]; NCT01553045)

  • 183.
    Charitakis, Emmanouil
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Walfridsson, Håkan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Alehagen, Urban
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Short‐Term Influence of Radiofrequency Ablation on NT‐proBNP, MR‐proANP, Copeptin, and MR‐proADM in Patients With Atrial Fibrillation: Data From the Observational SMURF Study2016In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 5, no 9Article in journal (Refereed)
    Abstract [en]

    Background There is limited knowledge on the short‐term influence of radiofrequency ablation (RFA) of atrial fibrillation (AF) on 2 cardiac biomarkers; the N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and the midregional fragment of the N‐terminal of pro‐ANP (MR‐proANP) and 2 extracardiac biomarkers; the c‐terminal provasopressin (copeptin) and the midregional portion of proadrenomedullin (MR‐proADM). There are also limited data concerning cardiac production of the latter two.

    Methods and Results We studied 192 consecutive patients eligible for RFA of AF referred to the University Hospital, Linköping, Sweden. NT‐proBNP, MR‐proANP, copeptin, and MR‐proADM levels were measured in peripheral blood, the coronary sinus (CS), and the left atrium before ablation, and in peripheral blood immediately and the day after RFA. The level of NT‐proBNP decreased the day after RFA in participants in AF at the time of RFA, compared to the participants in sinus rhythm who showed a slight increase (P<0.001). Furthermore, regardless of the actual rhythm, the level of MR‐proANP showed an increase immediately after RFA (P<0.001), followed by a decrease the day after ablation (P<0.001). Copeptin level showed a 6‐fold increase immediately after RFA compared to baseline (P<0.001), whereas MR‐proADM level increased the day after RFA (P<0.001). Levels of copeptin and MR‐proADM were not higher in the CS compared to peripheral blood.

    Conclusions RFA of AF is a strong stimulus with a significant and direct impact on different neurohormonal systems. We found no sign of a cardiac release of MR‐proADM or copeptin.

  • 184.
    Charitakis, Emmanouil
    et al.
    Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Walfridsson, Håkan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Nylander, Eva
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Alehagen, Urban
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Neurohormonal Activation After Atrial Fibrillation Initiation in Patients Eligible for Catheter Ablation: A Randomized Controlled Study2016In: JOURNAL OF THE AMERICAN HEART ASSOCIATION, ISSN 2047-9980, Vol. 5, no 12, article id e003957Article in journal (Refereed)
    Abstract [en]

    Background-Biomarker activation in atrial fibrillation (AF) has been widely studied, but the immediate effect of AF initiation remains unclear. We studied the effect of AF initiation on 2 cardiac biomarkers: the N-terminal fragment of the proB-type natriuretic peptide (NT-proBNP), the midregional fragment of the N-terminal of pro-atrial natriuretic peptide (MR-proANP), and 2 extracardiac biomarkers-the copeptin and the midregional portion of proadrenomedullin (MR-proADM). Methods and Results-This was a randomized controlled study, including 45 patients with AF who had been referred for radiofrequency ablation to the University Hospital, Link_ oping, Sweden, between February 2012 and April 2014. Freedom from AF during the 4 days prior to radiofrequency ablation was confirmed by transtelephonic ECGs. Biomarkers were collected from the femoral vein (fv), coronary sinus (CS), and left atrium (LA) prior to AF initiation (baseline) and 30 minutes later. The MR-proANP and NT-proBNP concentrations increased in the intervention group compared with the control group 30 minutes after the initiation of AF (MR-proANP: P-fvamp;lt;0.001, P-CSamp;lt;0.001, P-LAamp;lt;0.001; NT-proBNP: P-LAamp;lt;0.001). Copeptin levels in patients without ischemic heart disease were decreased after the initiation of AF (P-fv= 0.003, P-CS= 0.015, P-LA= 0.011). Conclusions-AF is a strong stimulus that results in immediate activation of different biomarkers.

  • 185.
    Charitakis, Emmanouil
    et al.
    Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Walfridsson, Ulla
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Nyström, Fredrik H
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Endocrinology.
    Nylander, Eva
    Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    Strömberg, Anna
    Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping. Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences.
    Alehagen, Urban
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Walfridsson, Håkan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Symptom burden, Metabolic profile, Ultrasound findings, Rhythm, neurohormonal activation, haemodynamics and health-related quality of life in patients with atrial Fibrillation (SMURF): a protocol for an observational study with a randomised interventional component2015In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 5, no 12, article id e008723Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Atrial fibrillation (AF) is the most common cardiac arrhythmia, with an estimated prevalence of 1.5-2%. It is an independent risk factor for ischaemic stroke and is estimated to cause about 20-25% of all stroke cases. AF has a great impact on health-related quality of life (HRQoL); however, one unresolved issue related to AF is the wide variation in its symptoms.

    METHODS AND ANALYSIS: The symptom burden, metabolic profile, ultrasound findings, rhythm, neurohormonal activation, haemodynamics and HRQoL in patients with AF (Symptom burden, Metabolic profile, Ultrasound findings, Rhythm, neurohormonal activation, haemodynamics and health-related quality of life in patients with atrial Fibrillation, SMURF) study is a prospective observational, cohort study, with a randomised interventional part. The aim of the study is to investigate, in patients with AF, the relationship between symptom burden and metabolic aspects, atrial function and different neurohormones, and the effect of radiofrequency ablation (RFA). The interventional part of the study will give an insight into the neurohormonal and intracardiac pressure changes directly after initiation of AF. Consecutive patients with symptomatic AF accepted for treatment with RFA for the first time at Linköping University Hospital are eligible for participation. The enrolment started in January 2012, and a total of 200 patients are to be included into the study, with 45 of them being enrolled into the interventional study with initiation of AF. The sample size of the interventional study is based on a small pilot study with 5 patients induced to AF while 2 served as controls. The results indicated that, in order to find a statistically significant difference, there was a need to include 28 patients; for safety reasons, 45 patients will be included.

    ETHICS AND DISSEMINATION: The SMURF study is approved by the Regional Ethical Review Board at the Faculty of Health Sciences, Linköping, Sweden. The results will be presented through peer-review journals and conference presentation.

    TRIAL REGISTRATION NUMBER: NCT01553045; Pre-results.

  • 186.
    Chen, Xiaoyun
    et al.
    Sun Yat Sen University, Peoples R China; Karolinska Institute, Sweden.
    Wang, Jian
    Karolinska Institute, Sweden; Shandong University, Peoples R China.
    Cao, Ziquan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Hosaka, Kayoko
    Karolinska Institute, Sweden.
    Jensen, Lasse
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Yang, Huasheng
    Sun Yat Sen University, Peoples R China.
    Sun, Yuping
    Shandong University, Peoples R China.
    Zhuang, Rujie
    Chinese Medical University, Peoples R China.
    Liu, Yizhi
    Sun Yat Sen University, Peoples R China.
    Cao, Yihai
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden; University of Leicester, England; Glenfield Hospital, England.
    Invasiveness and metastasis of retinoblastoma in an orthotopic zebrafish tumor model2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, no 10351Article in journal (Refereed)
    Abstract [en]

    Retinoblastoma is a highly invasive malignant tumor that often invades the brain and metastasizes to distal organs through the blood stream. Invasiveness and metastasis of retinoblastoma can occur at the early stage of tumor development. However, an optimal preclinical model to study retinoblastoma invasiveness and metastasis in relation to drug treatment has not been developed. Here, we developed an orthotopic zebrafish model in which retinoblastoma invasion and metastasis can be monitored at a single cell level. We took the advantages of immune privilege and transparent nature of developing zebrafish embryos. Intravitreal implantation of color-coded retinoblastoma cells allowed us to kinetically monitor tumor cell invasion and metastasis. Further, interactions between retinoblastoma cells and surrounding microvasculatures were studied using a transgenic zebrafish that exhibited green fluorescent signals in blood vessels. We discovered that tumor cells invaded neighboring tissues and blood stream when primary tumors were at the microscopic sizes. These findings demonstrate that retinoblastoma metastasis occurs at the early stage and antiangiogenic drugs such as Vegf morpholino and sunitinib could potentially interfere with tumor invasiveness and metastasis. Thus, this orthotopic retinoblastoma model offers a new and unique opportunity to study the early events of tumor invasion, metastasis and drug responses.

  • 187.
    Chisalita, Ioana Simona
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Health Care in Linköping.
    Dahlström, Ulf
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Arnqvist, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Endocrinology.
    Alehagen, Urban
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Proinsulin and IGFBP-1 predicts mortality in an elderly population2014In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 174, no 2, p. 260-267Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    High IGFBP-1 in elderly subjects is related to all-cause and cardiovascular (CV) mortality. We studied the relation of IGFBP-1 to cardiometabolic risk factors and cardiovascular and all-cause mortality, and also the impact of proinsulin and insulin on this association in an unselected elderly primary health care population.

    HYPOTHESIS:

    Our hypothesis was that proinsulin and insulin may have an impact on the association of high IGFBP-1 levels with all-cause and CV-mortality in elderly.

    DESIGN, SETTING AND PARTICIPANTS:

    A cross-sectional and prospective study was carried out in a rural Swedish population. 851 persons aged 66-81 years were evaluated by medical history, clinical examination, electrocardiography, echocardiography, and fasting plasma samples, and were followed prospectively for up to 12 years.

    RESULTS:

    At baseline, in a multivariate analysis, IGFBP-1 was associated with gender, N-terminal proBNP (NT pro-BNP), blood glucose, body mass index (BMI), insulin and proinsulin, estimated glomerular filtration rate (eGFR) and haemoglobin (Hb). During the follow-up period there were 230 deaths (27%), of which 134 (16%) were due to CV mortality. When divided into tertiles there was a significant difference for CV mortality and all-cause mortality between tertiles of IGFBP-1 and proinsulin. For insulin there was a significant difference only for all-cause mortality. After adjustment for well-known risks factors, proinsulin and IGFBP-1 had significant impact on all-cause mortality but only proinsulin on CV mortality.

    CONCLUSION:

    Only proinsulin is an independent predictor for both all-cause mortality and CV mortality when comparing IGFBP-1, insulin, and proinsulin as prognostic biomarkers for CV and all-cause mortality in an elderly population.

  • 188.
    Chung, Rosanna
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Jonasson, Lena
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Pigment hade antiinflammatoriska effekter vid kranskärlssjukdom2017In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 114, no 33-34Article in journal (Refereed)
    Abstract [en]

    [No abstract available]

  • 189.
    Chung, Rosanna
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Leanderson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Gustafsson, Nelly
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Jonasson, Lena
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Liberation of lutein from spinach: Effects of heating time, microwavereheating and liquefaction2019In: Food Chemistry, ISSN 0308-8146, E-ISSN 1873-7072, Vol. 277, p. 573-578Article in journal (Refereed)
    Abstract [en]

    Lutein, abundant in dark leafy vegetables, has been associated with several health promoting effects. Still, to what extent different preparation conditions and practices affect the liberation of lutein from food is not fully understood. Here, we compared a range of domestic methods under realistic conditions to prepare spinach, the most common lutein-rich vegetable. After preparations, samples were processed by in vitro digestion and lutein was quantified by HPLC. Data indicate that short-term and medium-term heating of spinach, independent of heating method, substantially reduced liberated lutein and reduction was most pronounced after long boiling times. Interestingly, the loss of lutein in heated samples was partly compensated when samples were reheated in the microwave. However, the highest yield of liberated lutein was obtained from liquefied spinach. Additional dairy enhanced the liquefaction effect. Thus, for optimal liberation of lutein, liquefaction of raw spinach appears to be the method of choice.

  • 190.
    Chung, Rosanna W S
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Leandersson, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Occupational and Environmental Medicine Center.
    Lundberg, Anna K
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Jonasson, Lena
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Lutein exerts anti-inflammatory effects in patients with coronary artery disease.2017In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 262, p. 87-93, article id S0021-9150(17)30197-1Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: Many coronary artery disease (CAD) patients exhibit chronic low-grade inflammation. Carotenoids are anti-oxidants with potential anti-inflammatory properties. Here, we first assessed relationships between interleukin (IL)-6 and individual carotenoids in plasma from CAD patients. Based on the results, we proceeded to assess anti-inflammatory effects of one carotenoid, lutein, in peripheral blood mononuclear cells (PBMCs) from CAD patients.

    METHODS: Lutein + zeaxanthin (isomers with lutein being dominant), β-cryptoxanthin, lycopene, α- and β-carotene and IL-6 were measured in plasma from 134 patients with stable angina (SA) and 59 patients with acute coronary syndrome. In 42 patients, plasma measurements were also performed 3 months after coronary intervention. PBMCs from SA patients were pre-treated with lutein (1, 5 and 25 μM) for 24 h followed by 24 h incubation ± lipopolysaccharide (LPS). Cell pellets were collected for IL-6, IL-1β and TNF mRNA and intracellular lutein. Cytokine secretion was measured in cell media.

    RESULTS: Only lutein + zeaxanthin were inversely correlated with IL-6 in SA patients at baseline (r = -0.366, p < 0.001) and follow-up (r = -0.546, p < 0.001). Ex vivo, lutein was taken up by PBMCs from SA patients in a dose- and time-dependent manner. Pre-treatment with lutein dose-dependently lowered LPS-induced secretion of IL-6, IL-1β (p < 0.01) and TNF (p < 0.05), and also reduced IL-6, IL-1β and TNF mRNA expression (p < 0.05).

    CONCLUSIONS: Clinical findings highlighted the inverse association between lutein and IL-6 in CAD patients. Anti-inflammatory effects of lutein in PBMCs from CAD patients were consolidated in ex vivo experiments. Taken together, these results show that lutein has the potential to play a role in resolution of chronic inflammation in CAD patients.

  • 191.
    Cibis, Merih
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Bustamante, Mariana
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Eriksson, Jonatan
    Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Carlhäll, Carljohan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Ebbers, Tino
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Creating Hemodynamic Atlases of Cardiac 4D Flow MRI2017In: Journal of Magnetic Resonance Imaging, ISSN 1053-1807, E-ISSN 1522-2586, Vol. 46, no 5, p. 1389-1399Article in journal (Refereed)
    Abstract [en]

    Purpose: Hemodynamic atlases can add to the pathophysiological understanding of cardiac diseases. This study proposes a method to create hemodynamic atlases using 4D Flow magnetic resonance imaging (MRI). The method is demonstrated for kinetic energy (KE) and helicity density (Hd). Materials and Methods: Thirteen healthy subjects underwent 4D Flow MRI at 3T. Phase-contrast magnetic resonance cardioangiographies (PC-MRCAs) and an average heart were created and segmented. The PC-MRCAs, KE, and Hd were nonrigidly registered to the average heart to create atlases. The method was compared with 1) rigid, 2) affine registration of the PC-MRCAs, and 3) affine registration of segmentations. The peak and mean KE and Hd before and after registration were calculated to evaluate interpolation error due to nonrigid registration. Results: The segmentations deformed using nonrigid registration overlapped (median: 92.3%) more than rigid (23.1%, P amp;lt; 0.001), and affine registration of PC-MRCAs (38.5%, P amp;lt; 0.001) and affine registration of segmentations (61.5%, P amp;lt; 0.001). The peak KE was 4.9 mJ using the proposed method and affine registration of segmentations (P50.91), 3.5 mJ using rigid registration (P amp;lt; 0.001), and 4.2 mJ using affine registration of the PC-MRCAs (P amp;lt; 0.001). The mean KE was 1.1 mJ using the proposed method, 0.8 mJ using rigid registration (P amp;lt; 0.001), 0.9 mJ using affine registration of the PC-MRCAs (P amp;lt; 0.001), and 1.0 mJ using affine registration of segmentations (P50.028). The interpolation error was 5.262.6% at mid-systole, 2.863.8% at early diastole for peak KE; 9.669.3% at mid-systole, 4.064.6% at early diastole, and 4.964.6% at late diastole for peak Hd. The mean KE and Hd were not affected by interpolation. Conclusion: Hemodynamic atlases can be obtained with minimal user interaction using nonrigid registration of 4D Flow MRI. Level of Evidence: 2 Technical Efficacy: Stage 1

  • 192.
    Cibis, Merih
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
    Ebbers, Tino
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Karlsson, Lars
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Carlhäll, Carljohan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Left Atrial 4D Blood Flow Dynamics and Hemostasis following Electrical Cardioversion of Atrial Fibrillation2017In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 8, article id 1052Article in journal (Refereed)
    Abstract [en]

    Background: Electrical cardioversion in patients with atrial fibrillation is followed by a transiently impaired atrial mechanical function, termed atrial stunning. During atrial stunning, a retained risk of left atrial thrombus formation exists, which may be attributed to abnormal left atrial blood flow patterns. 4D Flow cardiovascular magnetic resonance (CMR) enables blood flow assessment from the entire three-dimensional atrial volume throughout the cardiac cycle. We sought to investigate left atrial 4D blood flow patterns and hemostasis during left atrial stunning and after left atrial mechanical function was restored. Methods: 4D Flow and morphological CMR data as well as blood samples were collected in fourteen patients at two time-points: 2-3 h (Time-1) and 4 weeks (Time-2) following cardioversion. The volume of blood stasis and duration of blood stasis were calculated. In addition, hemostasis markers were analyzed. Results: From Time-1 to Time-2: Heart rate decreased (61 +/- 7 vs. 56 +/- 8 bpm, p = 0.01); Maximum change in left atrial volume increased (8 +/- 4 vs. 22 +/- 15%, p = 0.009); The duration of stasis (68 +/- 11 vs. 57 +/- 8%, p = 0.002) and the volume of stasis (14 +/- 9 vs. 9 +/- 7%, p = 0.04) decreased; Thrombin-antithrombin complex (TAT) decreased (5.2 +/- 3.3 vs. 3.3 +/- 2.2it.g/L, p = 0.008). A significant correlation was found between TAT and the volume of stasis (r(2) = 0.69, p amp;lt; 0.001) at Time-1 and between TAT and the duration of stasis (r(2) = 0.34, p = 0.04) at Time-2. Conclusion: In this longitudinal study, left atrial multidimensional blood flow was altered and blood stasis was elevated during left atrial stunning compared to the restored left atrial mechanical function. The coagulability of blood was also elevated during atrial stunning. The association between blood stasis and hypercoagulability proposes that assessment of left atrial 4D flow can add to the pathophysiological understanding of thrombus formation during atrial fibrillation related atrial stunning.

  • 193.
    Cibis, Merih
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Erasmus MC, Netherlands.
    Potters, Wouter V.
    Academic Medical Centre, Netherlands.
    Gijsen, Frank J.
    Erasmus MC, Netherlands.
    Marquering, Henk
    Academic Medical Centre, Netherlands; AMC, Netherlands.
    van Ooij, Pim
    Academic Medical Centre, Netherlands.
    I vanBave, Ed
    AMC, Netherlands.
    Wentzel, Jolanda J.
    Erasmus MC, Netherlands.
    Nederveen, Aart J.
    Academic Medical Centre, Netherlands.
    The Effect of Spatial and Temporal Resolution of Cine Phase Contrast MRI on Wall Shear Stress and Oscillatory Shear Index Assessment2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 9, p. e0163316-Article in journal (Refereed)
    Abstract [en]

    Introduction Wall shear stress (WSS) and oscillatory shear index (OSI) are associated with atherosclerotic disease. Both parameters are derived from blood velocities, which can be measured with phase-contrast MRI (PC-MRI). Limitations in spatiotemporal resolution of PC-MRI are known to affect these measurements. Our aim was to investigate the effect of spatiotemporal resolution using a carotid artery phantom. Methods A carotid artery phantom was connected to a flow set-up supplying pulsatile flow. MRI measurement planes were placed at the common carotid artery (CCA) and internal carotid artery (ICA). Two-dimensional PC-MRI measurements were performed with thirty different spatiotemporal resolution settings. The MRI flow measurement was validated with ultrasound probe measurements. Mean flow, peak flow, flow waveform, WSS and OSI were compared for these spatiotemporal resolutions using regression analysis. The slopes of the regression lines were reported in %/mm and %/100ms. The distribution of low and high WSS and OSI was compared between different spatiotemporal resolutions. Results The mean PC-MRI CCA flow (2.5 +/- 0.2mL/s) agreed with the ultrasound probe measurements (2.7 +/- 0.02mL/s). Mean flow (mL/s) depended only on spatial resolution (CCA:-13%/ mm, ICA:-49%/mm). Peak flow (mL/s) depended on both spatial (CCA:-13%/mm, ICA:17%/ mm) and temporal resolution (CCA:-19%/100ms, ICA:-24%/100ms). Mean WSS (Pa) was in inverse relationship only with spatial resolution (CCA:-19%/mm, ICA:-33%/mm). OSI was dependent on spatial resolution for CCA (-26%/mm) and temporal resolution for ICA (-16%/100ms). The regions of low and high WSS and OSI matched for most of the spatiotemporal resolutions (CCA: 30/30, ICA: 28/30 cases for WSS; CCA: 23/30, ICA: 29/30 cases for OSI). Conclusion We show that both mean flow and mean WSS are independent of temporal resolution. Peak flow and OSI are dependent on both spatial and temporal resolution. However, the magnitude of mean and peak flow, WSS and OSI, and the spatial distribution of OSI and WSS did not exhibit a strong dependency on spatiotemporal resolution.

  • 194.
    Cinthio, Magnus
    et al.
    Lund Univ, Sweden.
    Albinsson, John
    Lund Univ, Sweden.
    Erlov, Tobias
    Lund Univ, Sweden.
    Bjarnegård, Niclas
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Länne, Toste
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Ryden Ahlgren, Asa
    Lund Univ, Sweden.
    LONGITUDINAL MOVEMENT OF THE COMMON CAROTID ARTERY WALL: NEW INFORMATION ON CARDIOVASCULAR AGING2018In: Ultrasound in Medicine and Biology, ISSN 0301-5629, E-ISSN 1879-291X, Vol. 44, no 11, p. 2283-2295Article in journal (Refereed)
    Abstract [en]

    Putative changes in the multiphasic pattern of longitudinal movement of the common carotid artery wall in the normal aging process are unknown. The aim of this study was to explore the phases, and resulting patterns, of the longitudinal movement of the intima-media complex of the human common carotid artery with respect to age and gender. One hundred thirty-five healthy non-smoking patients of different ages were investigated using in-house-developed ultrasound methods. The patterns of longitudinal movement seen in middle-aged and older patients were markedly different from those commonly seen in young patients, including the appearance of two additional phases of motion and, thus, new complex patterns. The displacement and maximum velocity of one of the phases, occurring at the time of aortic valve closure, increased quadratically with age in both men and women. (C) 2018 World Federation for Ultrasound in Medicine amp; Biology. All rights reserved.