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  • 1.
    Bergqvist, Davis
    et al.
    Uppsala Universitet.
    Säwe, Juliette
    SBU, Stockholm.
    Wahlberg, Eric
    Linköping University, Department of Medical and Health Sciences, Vascular surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Benartärsjukdom – inget nytt sedan SBU-rapporten2011In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 108, no 8, p. 403-405Article in journal (Other academic)
    Abstract [en]

    In 2007 a report on leg ischemia was published by SBU (Board of Health Technology Assessment in Sweden). This paper summarizes the results of this report and analyzes further investigations of interest. No new open surgical or endovascular methods have been reported. Cilostazol has been approved to increase the walking distance in claudicants. Ongoing trials are evaluating the effect of stem cells and angiogenic factors to treat critical limb ischaemia.

  • 2.
    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.

  • 3.
    Dahl Jensen, Lasse
    et al.
    Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
    Cao, Ziquan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Nakamura, Masaki
    Karolinska Institute, Sweden .
    Yang, Yunlong
    Karolinska Institute, Sweden .
    Brautigam, Lars
    Karolinska Institute, Sweden .
    Andersson, Patrik
    Karolinska Institute, Sweden .
    Zhang, Yin
    Karolinska Institute, Sweden .
    Wahlberg, Eric
    Linköping University, Department of Medical and Health Sciences, Vascular surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Länne, Toste
    Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    Hosaka, Kayoko
    Karolinska Institute, Sweden .
    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, Stockholm, Sweden.
    Opposing Effects of Circadian Clock Genes Bmal1 and Period2 in Regulation of VEGF-Dependent Angiogenesis in Developing Zebrafish2012In: Cell Reports, ISSN 2211-1247, Vol. 2, no 2, p. 231-241Article in journal (Refereed)
    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.

  • 4.
    Dahl Jensen, Lasse
    et al.
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences.
    Rouhi, Pegah
    Karolinska Institute.
    Cao, Ziquan
    Karolinska Institute.
    Länne, Toste
    Linköping University, Department of Medical and Health Sciences, Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Thoracic and Vascular Surgery.
    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.
    Zebrafish Models to Study Hypoxia-Induced Pathological Angiogenesis in Malignant and Nonmalignant Diseases2011In: Birth Defects Research. Part C: Embryo Today Reviews, ISSN 1542-975X, Vol. 93, no 2, p. 182-193Article, review/survey (Refereed)
    Abstract [en]

    Most in vivo preclinical disease models are based on mouse and other mammalian systems. However, these rodent-based model systems have considerable limitations to recapitulate clinical situations in human patients. Zebrafish have been widely used to study embryonic development, behavior, tissue regeneration, and genetic defects. Additionally, zebrafish also provides an opportunity to screen chemical compounds that target a specific cell population for drug development. Owing to the availability of various genetically manipulated strains of zebrafish, immune privilege during early embryonic development, transparency of the embryos, and easy and precise setup of hypoxia equipment, we have developed several disease models in both embryonic and adult zebrafish, focusing on studying the role of angiogenesis in pathological settings. These zebrafish disease models are complementary to the existing mouse models, allowing us to study clinically relevant processes in cancer and nonmalignant diseases, which otherwise would be difficult to study in mice. For example, dissemination and invasion of single human or mouse tumor cells from the primary site in association with tumor angiogenesis can be studied under normoxia or hypoxia in zebrafish embryos. Hypoxia-induced retinopathy in the adult zebrafish recapitulates the clinical situation of retinopathy development in diabetic patients or age-related macular degeneration. These zebrafish disease models offer exciting opportunities to understand the mechanisms of disease development, progression, and development of more effective drugs for therapeutic intervention.

  • 5.
    Dong, Mei
    et al.
    Shandong University, Peoples R China .
    Yang, Xiaoyan
    Shandong University, Peoples R China .
    Lim, Sharon
    Karolinska Institute, Sweden .
    Cao, Ziquan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Honek, Jennifer
    Karolinska Institute, Sweden .
    Lu, Huixia
    Shandong University, Peoples R China .
    Zhang, Cheng
    Shandong University, Peoples R China .
    Seki, Takahiro
    Karolinska Institute, Sweden .
    Hosaka, Kayoko
    Karolinska Institute, Sweden .
    Wahlberg, Eric
    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.
    Yang, Jianmin
    Shandong University, Peoples R China .
    Zhang, Lei
    Shandong University, Peoples R China .
    Länne, Toste
    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.
    Sun, Baocun
    Tianjin Medical University, Peoples R China .
    Li, Xuri
    Sun Yat Sen University, Peoples R China .
    Liu, Yizhi
    Sun Yat Sen University, Peoples R China .
    Zhang, Yun
    Shandong University, Peoples R China .
    Cao, Yihai
    Karolinska Institute, Sweden .
    Cold Exposure Promotes Atherosclerotic Plaque Growth and Instability via UCP1-Dependent Lipolysis2013In: Cell Metabolism, ISSN 1550-4131, E-ISSN 1932-7420, Vol. 18, no 1, p. 118-129Article in journal (Refereed)
    Abstract [en]

    Molecular mechanisms underlying the cold-associated high cardiovascular risk remain unknown. Here, we show that the cold-triggered food-intake-independent lipolysis significantly increased plasma levels of small low-density lipoprotein (LDL) remnants, leading to accelerated development of atherosclerotic lesions in mice. In two genetic mouse knockout models (apolipoprotein E-/- [ApoE(-/-)] and LDL receptor(-/-) [Ldlr(-/-)] mice), persistent cold exposure stimulated atherosclerotic plaque growth by increasing lipid deposition. Furthermore, marked increase of inflammatory cells and plaque-associated microvessels were detected in the cold-acclimated ApoE(-/-) and Ldlr(-/-) mice, leading to plaque instability. Deletion of uncoupling protein 1 (UCP1), a key mitochondrial protein involved in thermogenesis in brown adipose tissue (BAT), in the ApoE(-/-) strain completely protected mice from the cold-induced atherosclerotic lesions. Cold acclimation markedly reduced plasma levels of adiponectin, and systemic delivery of adiponectin protected ApoE(-/-) mice from plaque development. These findings provide mechanistic insights on low-temperature-associated cardiovascular risks.

  • 6.
    Koraen, L.
    et al.
    Kärlkirurgiska Kliniken, Karolinska Universitetssjukhuset, Solna, Sweden, Institutionen för molekylärmedicin och kirurgi, Karolinska Institutet, Stockholm, Sweden.
    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.
    Claudicatio intermittens2010In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, no 29-31, p. 1774-1779Article in journal (Refereed)
    Abstract [en]

    [No abstract available]

  • 7.
    Letterstål, Anna
    et al.
    Section of Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
    Forsberg, Christina
    Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden.
    Olofsson, Pär
    Section of Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
    Wahlberg, Eric
    Section of Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
    Risk attitudes to treatment among patients with severe intermittent claudication2008In: Journal of Vascular Surgery, ISSN 0741-5214, E-ISSN 1097-6809, Vol. 47, no 5, p. 988-994Article in journal (Refereed)
    Abstract [en]

    Objectives

    To determine claudication patients' risk attitude to invasive treatment and whether this treatment is cost effective.

    Methods

    Quality of life and health state utility status of 50 consecutive patients with severe intermittent claudication was assessed and compared with ankle-brachial pressure index values (ABPI) and results from treadmill tests before and after endovascular or open revascularization. Health utility scores were then calculated and used in a cost-utility analysis.

    Results

    Before surgery, patients were assigned a utility score of 0.51 (EQ-5D index) for their disease, and the standard gamble (SG) and time trade-off (TTO) median scores were 0.88 and 0.70, respectively. Before treatment, a weak correlation (r = 0.43, P < .001) between having a high risk perception of treatment and patients' walking distance were observed, where patients able to walk short distances accepted a higher risk. After treatment, ABI (P = .003) and walking distance (P = .002) improved significantly as well the physical components of the quality of life instruments (P < .001). The surgical treatment generated an improvement in quality of life expressed in QALYs equivalent to 0.17. With an estimated survival of 5 years, it adds up to a value of 0.85, corresponding to a sum of 51,000 US$ gained.

    Conclusions

    Patients with severe intermittent claudication are risk-seeking when it comes to surgical treatment and their risk attitude is correlated to their walking ability and quality of life. The incremental QALYs gained by treatment are achieved at a reasonable cost and revascularization appears to be cost effective.

  • 8.
    Malmstedt, J
    et al.
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Wahlberg, Eric
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Jörneskog, G
    Danderyd University Hospital, Karolinska Institute, Stockholm, Sweden.
    Swedenborg, J
    Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Influence of perioperative blood glucose levels on outcome after infrainguinal bypass surgery in patients with diabetes2006In: British Journal of Surgery, ISSN 0007-1323, E-ISSN 1365-2168, Vol. 93, no 11, p. 1360-1367Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: High glucose levels are associated with increased morbidity and mortality after coronary surgery and in intensive care. The influence of perioperative hyperglycaemia on the outcome after infrainguinal bypass surgery among diabetic patients is largely unknown. The aim was to determine whether high perioperative glucose levels were associated with increased morbidity after infrainguinal bypass surgery.

    METHODS: Ninety-one consecutive diabetic patients undergoing primary infrainguinal bypass surgery were identified from a prospective vascular registry. Risk factors, indication for surgery, operative details and outcome data were extracted from the medical records. Exposure to perioperative hyperglycaemia was measured using the area under the curve (AUC) method; the AUC was calculated using all blood glucose readings during the first 48 h after surgery.

    RESULTS: Multivariable analysis showed that the AUC for glucose (odds ratio (OR) 13.35, first versus fourth quartile), renal insufficiency (OR 4.77) and infected foot ulcer (OR 3.38) was significantly associated with poor outcome (death, major amputation or graft occlusion at 90 days). Similarly, the AUC for glucose (OR 14.45, first versus fourth quartile), female sex (OR 3.49) and tissue loss as indication (OR 3.30) was associated with surgical wound complications at 30 days.

    CONCLUSION: Poor perioperative glycaemic control was associated with an unfavourable outcome after infrainguinal bypass surgery in diabetic patients.

  • 9.
    Malmstedt, Jonas
    et al.
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Leander, Karin
    Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Wahlberg, Eric
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Karlström, Lars
    Department of Vascular Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Alfredsson, Lars
    Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Swedenborg, Jesper
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Outcome after leg bypass surgery for critical limb ischemia is poor in patients with diabetes2008In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 31, no 5, p. 887-892Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE—Our aim was to assess the risk of major amputation or death after leg bypass surgery for critical limb ischemia in patients with diabetes versus those without.

    RESEARCH DESIGN AND METHODS—We did a population-based cohort study by linking nationwide databases in Sweden. We identified 1,840 patients in the Swedish Vascular Registry who had their first leg bypass procedure for critical lower-limb ischemia between 1 January 2001 and 31 December 2003—742 with and 1,098 without diabetes. Our primary end point was first major amputation of the limb on which bypass was done or death. Individuals were followed up until 31 December 2005 through the National Hospital Patient Registry and the Cause-of-Death Registry.

    RESULTS—Incidence of ipsilateral amputation or death was higher in patients with diabetes than in patients without (30.2 vs. 22 events/100 person-years; crude hazard ratio [HR] 1.32 [95% CI 1.17–1.50]). Similarly, individuals with diabetes had a shorter amputation-free survival period than individuals without (2.3 years, range 1.9–2.8 vs. 3.4 years, range 3.1–3.7). Adjustment for demographic characteristics, comorbidities, and risk factors for amputation or death did not substantially affect the risk (HR 1.46 [95% CI 1.26–1.69]). The effect was more pronounced in male (1.75 [1.47–2.08]) than in female (1.35 [1.11–1.64]) patients after adjustment for age.

    CONCLUSIONS—Diabetes is associated with lower amputation–free survival after leg bypass for critical limb ischemia. Patients with diabetes and limb ischemia need intensified treatment of diabetes-related risk factors to improve outcome.

  • 10. Palmer-Kazen, U
    et al.
    Religa, P
    Wahlberg, Eric
    Linköping University, Department of Medicine and Health Sciences, Vascular surgery . Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery. Linköping University, Faculty of Health Sciences.
    Exercise in patients with intermittent claudication elicits signs of inflammation and angiogenesis.2009In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 38, p. 689-696Article in journal (Refereed)
    Abstract [en]

    Objectives

    Previous studies have demonstrated elevation of systemic levels of inflammatory cytokines after treadmill exercise in patients with intermittent claudication (IC), but it is unknown if growth factor expression also is stimulated. The aim of this study was to assess whether physical exercise-induced ischemia elicits an inflammatory response and increase in local and systemic vascular growth factor expression in patients with IC.

    Methods

    Nineteen patients with IC had plasma concentrations of inflammatory markers (IL-6, TNF-alpha, hs-CRP) and vascular growth factors (VEGF and FGF-2) measured before and at four time points after a treadmill exercise test. In 10 patients a gastrocnemius muscle biopsy was obtained to measure VEGF and FGF-2 mRNA. Plasma concentrations of vWF were also measured. Five patients who underwent the treadmill test without experiencing calf pain were enrolled as controls.

    Results

    Plasma concentrations of IL-6 increased after exercise (p = 0.004), while TNF-alpha and hs-CRP were unchanged (p = 0.191 and p = 0.709, respectively). Plasma concentrations of VEGF were similar (p = 0.151) at the different time points after exercise but FGF-2 levels decreased (p = 0.013). In biopsies after treadmill testing VEGF-A mRNA was increased (p = 0.043), but no change was observed for FGF-2 (p = 0.456).

    Conclusion

    Exercise in IC triggers an inflammatory response as exemplified by elevated concentrations of IL-6. After exercise-induced pain, VEGF mRNA in calf muscle is increased. Therefore, it is plausible that angiogenesis is stimulated by exercise in IC.

  • 11.
    Påhlsson, Hans-Ivar
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Laskar, Carolina
    Karolinska Institute, Stockholm, Sweden.
    Stark, Karin
    Karolinska Institute, Stockholm, Sweden.
    Andersson, Anna
    Karolinska Institute, Stockholm, Sweden.
    Jogestrand, Tomas
    Karolinska Institute, Stockholm, Sweden.
    Wahlberg, Eric
    Karolinska Institute, Stockholm, Sweden.
    The optimal cuff width for measuring toe blood pressure2007In: Angiology, ISSN 0003-3197, E-ISSN 1940-1574, Vol. 58, no 4, p. 472-476Article in journal (Refereed)
    Abstract [en]

    To determine the optimal cuff width for measuring toe blood pressure in patients with lower limb ischemia, this experimental prospective study examined 20 patients with symptoms of peripheral arterial disease referred for vascular examination or vascular surgery. Toe blood pressure was measured hydrostatically by the pole test using cuffs of different widths. Pole test reflects the true physiological blood pressure value and was the reference method. Blood pressures obtained using the cuffs were related to this value and to patients' toe circumference. With the 2.5-cm cuff, the patients had a mean pole test toe blood pressure of 28 mm Hg (range, 6-55 mm Hg). Compared with pole test results, the toe blood pressure was 15.6 mm Hg (95% confidence interval [CI], 8-23 mm Hg) higher when measured using the 2.0-cm cuff (P < .001) and 4.5 mm Hg (95% CI, 0-9 mm Hg) higher when measured using the 2.5-cm cuff (P = .07). Using the 1.5-cm and 3.0-cm cuffs, the differences were 27.0 mm Hg (95% CI, 13-43 mm Hg) and -2.0 mm Hg (95% CI, -11 to 8 mm Hg), respectively. The cuff width greatly affects the obtained toe blood pressure value, and larger cuffs correspond better to the hydrostatic pressure. For clinical use and as a reporting standard, we propose that toe blood pressure measurements should be made using a 2.5-cm-wide cuff.

  • 12.
    Rouhi, Pegah
    et al.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Jensen, Lasse D
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Cao, Ziquan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Hosaka, Kayoko
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    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.
    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.
    Fleng Steffensen, John
    Marine Biological Laboratory, Biological Institute, University of Copenhagen, Helsingor, 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 Institutet, Stockholm, Sweden.
    Hypoxia-induced metastasis model in embryonic zebrafish2010In: Nature Protocols, ISSN 1754-2189, E-ISSN 1750-2799, Vol. 5, no 12, p. 1911-1918Article in journal (Refereed)
    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.

  • 13.
    Sartipy, Fredrik
    et al.
    Karolinska Inst, Sweden.
    Sigvant, Birgitta
    Uppsala Univ, Sweden.
    Lundin, Fredrik
    Cty Council Varmland, Sweden.
    Wahlberg, Eric
    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.
    Ten Year Mortality in Different Peripheral Arterial Disease Stages: A Population Based Observational Study on Outcome2018In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 55, no 4, p. 529-536Article in journal (Refereed)
    Abstract [en]

    Objective: The aim was to determine long-term mortality rates and the underlying cause of death for subjects with different peripheral arterial disease (PAD) stages in a population based setting. Methods: A randomly selected population sample of 5080 subjects was enrolled in the study in 2004-2005. Participants completed health state questionnaires and underwent ankle brachial index (ABI) measurements for classification into PAD severity stages and reference subjects. A follow-up was conducted by the end of 2015 using data from Swedish governmental national registers for cause of death, which was then compared with PAD stage determined at baseline in 2005. Results: The 10 year all cause mortality was 27% for reference cases, 56% for asymptomatic PAD (APAD), 63% for intermittent claudication (IC), and 75% for severe limb ischaemia (SLI). Among all PAD subjects, cardiovascular (CV) causes were the most common main cause of death (45%) and a CV event was present as either the main or one of the three most common contributing causes of death in 64% of the cases. The age adjusted hazard ratios for a main cause of death by a CV event were 1.9 (95% CI 1.5-2.3) for APAD, 2.6 (95% CI 2.1-3.4) for IC, and 3.5 (95% CI 2.3-5.2) for SLI. Conclusion: PAD subjects, including the APAD subjects, are still at high risk of CV death. The mortality risks are more than doubled in symptomatic PAD patients compared with reference subjects and increase by severity of PAD stage. Awareness and improved risk reduction management of PAD are still warranted. (C) 2018 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

  • 14.
    Sigvant, B
    et al.
    Karolinska Institute.
    Henriksson, Martin
    Linköping University, Department of Medical and Health Sciences, Health Technology Assessment and Health Economics. Linköping University, Faculty of Health Sciences.
    Lundin, F
    Karlstad Hospital.
    Wahlberg, Eric
    Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Thoracic and Vascular Surgery in Östergötland. Linköping University, Department of Medical and Health Sciences, Thoracic Surgery.
    Asymptomatic peripheral arterial disease: is pharmacological prevention of cardiovascular risk cost-effective?2011In: EUROPEAN JOURNAL OF CARDIOVASCULAR PREVENTION and REHABILITATION, ISSN 1741-8267, Vol. 18, no 2, p. 254-261Article in journal (Refereed)
    Abstract [en]

    Peripheral arterial disease (PAD) is associated with an increased risk of early death in cardiovascular (CV) disease. The majority of PAD subjects are asymptomatic with a prevalence of 11 per cent among the elderly. Long-term drug prevention aiming to minimize disease progression and CV events in these subjects is probably beneficial, but expensive. The purpose of this analysis was to evaluate the cost-effectiveness of pharmacological risk reduction in subclinical PAD. Long-term costs and quality-adjusted life years (QALYs) were estimated by employing a decision-analytic model for ACE-inhibitor, statin, aspirin and non-aspirin anti-platelet therapy. Rates of CV events without treatment were derived from epidemiological studies and event rate reduction were retrieved from clinical trials. Costs and health-related quality of life estimates were obtained from published sources. All four drugs reduced CV events. Using ACE-inhibition resulted in a heart rate (HR) of 0.67 (95% CI: 0.55-0.79), statins 0.74 (0.70-0.79), and clopidogrel 0.72 (0.43-1.00). Aspirin had a HR of 0.87 and the 95% CI passed included one (0.72-1.03). ACE-inhibition was associated with the largest reduction in events leading to the highest gain in QALYs (7.95). Furthermore, ACE-inhibitors were associated with the lowest mean cost (sic)40.556. In conclusion, while all drugs reduced CV events, ACE-inhibition was the most cost-effective. These results suggest that we should consider efforts to identify patients with asymptomatic PAD and, when identified, offer ACE-inhibition.

  • 15.
    Sigvant, B.
    et al.
    Karolinska Institute, Sweden; Central Hospital Karlstad, Sweden; Karolinska Institute, Sweden.
    Lundin, F.
    Central Hospital Karlstad, Sweden.
    Wahlberg, Eric
    Region Östergötland, Heart and Medicine Center, Department of Thoracic and Vascular Surgery. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine.
    The Risk of Disease Progression in Peripheral Arterial Disease is Higher than Expected: A Meta-Analysis of Mortality and Disease Progression in Peripheral Arterial Disease2016In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 51, no 3, p. 395-403Article, review/survey (Refereed)
    Abstract [en]

    Objective: Peripheral arterial, disease (PAD) afflicts up to 20% of older people and is associated with a high risk of cardiovascular (CV) morbidity, but a rather low risk of progression of leg symptoms. These risk estimations are largely taken from cohort studies performed 20 years ago. To test the validity of this, available data were systematically reviewed and attempts were made to perform meta-analyses of CV risk and disease progression. Methods: A database literature search was conducted of the period 1990-2015 using related subject headings. Inclusion criteria were cohort studies for PAD, sample size &gt;100 subjects, follow up time &gt;= 1 year, and studies presenting endpoints covering mortality and/or CV events. Analyses were performed for a reference population, as well as groups with asymptomatic PAD (APAD), symptomatic PAD, and subjects with ankle brachial index &lt;0.9. Results: Of 354 identified articles, 35 were eligible for systematic review. Sample size varied between 109 and 16,440 subjects. Mean age in the cohorts ranged from 56 to 81 years (SD 10.8) and mean follow up was 6.3 years (range 1-13). Most included patients with symptomatic PAD had IC (91%). Symptomatic PAD subjects had higher 5 year cumulative CV mortality than the reference population, 13% versus 5%. During follow up, approximately 7% of APAD patients progressed to IC, and 21% of IC patients were diagnosed as having critical limb ischemia, with 4-27% undergoing amputations. Conclusion: The risk to the limb is underestimated in PAD patients, whereas the CV related morbidity is more moderate than stated in the guidelines. The latter observation is especially valid for IC patients. These findings should be considered when evaluating patients for treatment. (C) 2015 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

  • 16.
    Sigvant, Birgitta
    et al.
    Karolinska Institute.
    Lundin, Fredrik
    Karlstad Hospital.
    Nilsson, Bo
    Karlstad Hospital .
    Bergqvist, David
    University Uppsala Hospital.
    Wahlberg, Eric
    Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Thoracic and Vascular Surgery in Östergötland. Linköping University, Department of Medical and Health Sciences, Thoracic Surgery.
    Differences in presentation of symptoms between women and men with intermittent claudication2011In: BMC Cardiovascular Disorders, ISSN 1471-2261, E-ISSN 1471-2261, Vol. 11, no 39Article in journal (Refereed)
    Abstract [en]

    Background: More women than men have PAD with exception for the stage intermittent claudication (IC). The purpose of this study was to evaluate differences in disease characteristics between men and women when using current diagnostic criteria for making the diagnosis IC, defined as ABI less than 0.9 and walking problems. Study Design: Cohort study Methods: 5040 elderly (median age 71) subjects participated in a point-prevalence study 2004. They had their ABI measured and filled out questionnaires covering medical history, current medication, PAD symptoms and walking ability. The prevalence of IC was 6.5% for women and 7.2% for men (P = 0.09). A subset of subjects with IC (N = 56) was followed up four years later with the same procedures. They also performed additional tests aiming to determine all factors influencing walking ability. Results: Men with IC had more concomitant cardiovascular disease and a more profound smoking history than women. Women, on the other hand, reported a lower walking speed (P less than 0.01) and more joint problems (P = 0.018). In the follow up cohort ABI, walking ability and amount of atherosclerosis were similar among the sexes, but women more often reported atypical IC symptoms. Conclusion: Sex differences in the description of IC symptoms may influence diagnosis even if objective features of PAD are similar. This may influence accuracy of prevalence estimates and selection to treatment.

  • 17.
    Sigvant, Birgitta
    et al.
    Central Hospital Karlstad, Sweden.
    Wiberg-Hedman, Katarina
    Central Hospital Karlstad, Sweden.
    Bergqvist, David
    Uppsala University Hospital, Sweden.
    Rolandsson, Olov
    Umeå University, Sweden.
    Andersson, Bob
    Skutskär Health Care Centre, Karolinska University Hospital and Institute, Malmö, Stockholm, Sweden.
    Persson, Elisabeth
    Rosengård Health Care Centre, Karolinska University Hospital and Institute, Malmö, Stockholm, Sweden.
    Wahlberg, Eric
    Karolinska University Hospital and Institute, Malmö, Stockholm, Sweden.
    A population-based study of peripheral arterial disease prevalence with special focus on critical limb ischemia and sex differences.2007In: Journal of Vascular Surgery, ISSN 0741-5214, E-ISSN 1097-6809, Vol. 45, no 6, p. 1185-1191Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: A population-based point-prevalence study was conducted to determine the prevalence of peripheral arterial disease (PAD) in Sweden, with special attention to critical limb ischemia and sex differences.

    METHODS: An age-standardized randomly selected population sample of 8000 women and men, aged 60 to 90 years, from four different regions in Sweden was invited to participate. The sample had the same age and gender distribution as the Swedish population in this age group. Participating subjects completed questionnaires on medical history, present medication, and symptoms, and their ankle-brachial index (ABI) was measured. Subjects were analyzed for presence of PAD according to reported symptoms and an ABI<0.9.

    RESULTS: A total of 5080 subjects were included, giving a participation rate of 64%. The prevalence of any PAD, asymptomatic PAD, intermittent claudication, and severe limb ischemia was, respectively, 18% (95% confidence interval [CI], 16% to 20%) 11% (9% to 13%), 7% (6.5 to 7%) and 1.2% (1% to 1.5%). Women had a higher prevalence than men when PAD was diagnosed with ABI only; that is, asymptomatic PAD (12.6% vs 9.4%, P=.03) and severe limb ischemia (1.5% vs 0.8%, P<.008). The prevalence of any PAD was 7.9% in the age group 60 to 65 years and increased to 47.2% among the age group 85 to 90 years. Severe limb ischemia occurred in 0.3% in the youngest age group, was highest in the age group 80 to 84 years at 3.3%, and declined to 2.5% among the oldest. The prevalence of PAD differed between regions (P<.0001).

    CONCLUSIONS: PAD is common in Sweden, and almost a fifth of all elderly individuals have some stage of this disease. Women are more often afflicted than men. The prevalence of severe ischemia, as a measure of critical limb ischemia, is about 1% the population.

  • 18.
    Tritsaris, Katerina
    et al.
    Panum Institute, University of Copenhagen, Denmark.
    Myren, Maja
    Panum Institute, University of Copenhagen, Denmark.
    Ditlev, Sisse B.
    Panum Institute, University of Copenhagen, Denmark.
    Hübschmann, Martin V.
    Panum Institute, University of Copenhagen, Denmark.
    van der Blom, Ida
    Novo Nordisk A/S, Måløv, Denmark.
    Hansen, Anker Jon
    Novo Nordisk A/S, Måløv, Denmark.
    Olsen, Uffe B.
    Novo Nordisk A/S, Måløv, Denmark.
    Cao, Renhai
    Karolinska Institutet, Stockholm, Sweden.
    Zhang, Junhang
    Karolinska Institutet, Stockholm, Sweden.
    Jia, Tanghong
    Shandong University, Jinan, China .
    Wahlberg, Eric
    Karolinska Institutet, Stockholm, Sweden.
    Dissing, Steen
    Panum Institute, University of Copenhagen, Denmark.
    Cao, Yihai
    Karolinska Institutet, Stockholm, Sweden.
    IL-20 is an arteriogenic cytokine that remodels collateral networks and improves functions of ischemic hind limbs2007In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 104, no 39, p. 15364-15369Article in journal (Refereed)
    Abstract [en]

    Successful therapeutic angiogenesis for the treatment of ischemic disorders relies on selection of optimal proangiogenic or arteriogenic agents that are able to promote establishment of functional collateral networks. Here, we show that IL-20, a pleiotropic inflammatory cytokine, displays an imperative effect on vascular remodeling. Stimulation of both large and microvascular endothelial cells with IL-20 leads to activation of receptor-dependent multiple intracellular signaling components, including increased phosphorylation levels of JAK2/STAT5, Erk1/2, and Akt; activation of small GTP-binding proteins Rac and Rho; and intracellular release of calcium. Surprisingly, IL-20 significantly promotes endothelial cell tube formation without affecting their proliferation and motility. These findings suggest that the vascular function of IL-20 involves endothelial cell organization, vessel maturation, and remodeling. Consistent with this notion, delivery of IL-20 to the ischemic muscle tissue significantly improves arteriogenesis and blood perfusion in a rat hind-limb model. Our findings provide mechanistic insights on vascular functions of IL-20 and define therapeutic implication of this cytokine for the treatment of ischemic disorders.

  • 19.
    Wahlberg, Eric
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Thoracic and Vascular Surgery.
    Hypertension in the Very Elderly - A Call to Improve Blood Pressure Management of Our PAD Patients2008In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 36, no 4, p. 407-408Other (Other academic)
    Abstract [en]

    [No abstract available]

  • 20.
    Wahlgren, Carl-Magnus
    et al.
    Department of Vascular Surgery, Karolinska University Hospital, Stockholm, Sweden.
    Wahlberg, Eric
    Department of Vascular Surgery, Karolinska University Hospital, Stockholm, Sweden.
    Olofsson, Pär
    Department of Vascular Surgery, Karolinska University Hospital, Stockholm, Sweden.
    Endovascular Treatment in Postthrombotic Syndrome2010In: Vascular and Endovascular Surgery, ISSN 1538-5744, Vol. 44, no 5, p. 356-360Article in journal (Refereed)
    Abstract [en]

    Background: The postthrombotic syndrome is a chronic complication of deep venous thrombosis that leads to considerable pain and suffering to patients. We evaluated our experience of endovascular treatment for patients with chronic postthrombotic femoroiliocaval venous disease.

    Materials and Methods: From January 2003 through December 2007, 50 patients (51 limbs; 60% women; mean age 45 years; range: 24-74 years) with chronic postthrombotic venous disease were referred to our institution for interventional assessment. All patients underwent duplex ultrasonography as well as ascending and descending venography. The CEAP (clinical, etiologic, anatomic, and pathophysiologic classification) clinical scores were class 0 (no signs) in 2% of limbs, class 3 (edema) in 63%, class 4a (pigmentation or eczema) in 18%, class 5 (healed venous ulcer) in 14%, and class 6 (active venous ulcer) in 4%. The etiology was secondary (postthrombotic) in all patients. The anatomical distribution of reflux and obstruction were deep veins in 63% and a combination of deep and superficial veins in 37%. The underlying pathophysiology due to obstruction of the deep venous outflow with no reflux was found in 25% of limbs, only reflux was found in 14%, and a combination of obstruction and reflux was found in 61%.

    Results: There were 21 limbs in 20 (38%) patients that underwent endovascular and/or surgical treatment. One limb underwent femoral endovenectomy and 1 limb superficial femoral vein to deep femoral vein transposition. In all, 19 limbs were scheduled for endovascular treatment. The technical success rate was 84%, 3 limbs with iliac vein occlusions could not be recanalized. A total of 11 patients (11 limbs) underwent solely endovascular intervention and 4 patients (5 limbs) underwent endovascular intervention combined with femoral endovenectomy. The endovascular and surgical procedures were performed with no perioperative or postoperative mortality as well as no major bleeding or cardiac, pulmonary, or renal 30-day complications. Early thrombosis (<30 days) of the stented iliac veins occurred in 3 limbs which were lysed and restented successfully. The mean follow-up time was 23 months (range: 1-69 months). Primary and assisted-primary/secondary patency rates at 12 months were 61% and 81%, respectively. The Venous Clinical Severity score was 9.1 (range: 5-15) before endovascular treatment and 6.0 (range: 3-13) after the treatment (P < .0001). There were 30 patients (62%) with symptoms attributable to venous dysfunction or with deep venous pathology that did not undergo interventional treatment after workup. These patients continued with appropriate thromboprophylaxis and elastic compression stockings.

    Conclusion: Endovascular treatment of chronic postthrombotic femoroiliocaval venous disease is a safe technique that can be performed with acceptable patency rates in this challenging patient population.

  • 21.
    Yang, Yunlong
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Zhang, Yin
    Karolinska Institute, Stockholm, Sweden.
    Cao, Ziquan
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Ji, Hong
    Karolinska Institute, Stockholm, Sweden.
    Yang, Xiaojuan
    Karolinska Institute, Stockholm, Sweden.
    Iwamoto, Hideki
    Karolinska Institute, Stockholm, Sweden.
    Wahlberg, Eric
    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.
    Länne, Toste
    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.
    Sun, Baocun
    Tianjin Medical University, China.
    Cao, Yihai
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Karolinska Institute, Stockholm, Sweden.
    Anti-VEGF- and anti-VEGF receptor-induced vascular alteration in mouse healthy tissues2013In: 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)
    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.

  • 22.
    Zhang, Junhang
    et al.
    Karolinska Institute.
    Cao, R
    Karolinska Institute.
    Zhang, Y
    Shandong University.
    Jia, T
    Shandong University.
    Cao, Y
    Karolinska Institute.
    Wahlberg, Eric
    Karolinska Institute.
    Differential roles of PDGFR-(alpha) and PDGFR-(beta) in angiogenesis and vessel stability2009In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 23, p. 153-163Article in journal (Refereed)
    Abstract [en]

    Preclinical and clinical evaluations of individual proangiogenic/arteriogenic factors for the treatment of ischemic myocardium and skeletal muscle have produced unfulfilled promises. The establishment of functional and stable arterial vascular networks may require combinations of different angiogenic and arteriogenic factors. Using in vivo angiogenesis and ischemic hind-limb animal models, we have compared the angiogenic and therapeutic activities of fibroblast growth factor 2 (FGF-2) in combinations with PDGF-AA and PDGF-AB, two members of the platelet-derived growth factor (PDGF) family, with distinct receptor binding patterns. We show that both PDGF-AA/FGF-2 and PDGF-AB/FGF-2 in combinations synergistically induce angiogenesis in the mouse cornea. FGF-2 up-regulates PDGFR- and -β expression levels in the newly formed blood vessels. Interestingly, PDGF-AB/FGF-2, but not PDGF-AA/FGF-2, is able to stabilize the newly formed vasculature by recruiting pericytes, and an anti-PDGFR-β neutralizing antibody significantly blocks PDGF-AB/FGF-2-induced vessel stability. These findings demonstrate that PDGFR-β receptor is essential for vascular stability. Similarly, PDGF-AB/FGF-2 significantly induces stable collateral growth in the rat ischemic hind limb. The high number of collaterals induced by PDGF-AB/FGF-2 leads to dramatic improvement of the paw’s skin perfusion. Immunohistochemical analysis of the treated skeletal muscles confirms that a combination of PDGF-AB and FGF-2 significantly induces arteriogenesis in the ischemic tissue. A combination of PDGF-AB and FGF-2 would be optimal proangiogenic agents for the treatment of ischemic diseases.—Zhang, J., Cao, R., Zhang, Y., Jia, T., Cao, Y., Wahlberg, E. Differential roles of PDGFR- and PDGFR-β in angiogenesis and vessel stability.

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