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  • 1. Ahmad, S.
    et al.
    Demler, O.
    Sun, Q.
    Moorthy, M.V.
    Li, C.
    Lee, I.M.
    Ridker, P.M.
    Manson, J.E.
    Hu, F.B.
    Fall, T.
    Chasman, D.I.
    Cheng, S.
    Pradhan, A.D.
    Mora, S.
    Mediterranean Diet And Reduced Risk Of Diabetes: Potential Mediating Mechanisms2019In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 287, p. e43-e44Article in journal (Other academic)
  • 2.
    Akhter, Tansim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Obstetrics.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Marita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Naessén, Tord
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive biology.
    Sub-clinical atherosclerosis in the common carotid artery in women with/without previous pre-eclampsia: A seven-year follow-up2019In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 290, p. 206-213Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: Pre-eclampsia is associated with increased risk of cardiovascular disease and premature death. However, conventional common carotid artery intima-media thickness (CCA-IMT) measurement does not reflect this. In contrast, measurement of the individual CCA intima and media thicknesses clearly indicates increased vascular risk both at diagnosis and about one year after pre-eclampsia. This study examined whether individual CCA wall layers, risk factors for cardiovascular disease, and markers of endothelial dysfunction had normalized or remained unfavorable seven years after pre-eclampsia.

    METHODS: The individual CCA intima and media thicknesses were measured using 22 MHz ultrasound. Conventional cardiovascular risk factors were recorded. A thick intima, thin media and high intima/media thickness ratio (I/M) are signs of sub-clinical atherosclerosis.

    RESULTS: The median age of women with previous pre-eclampsia (cases = 23) or normal pregnancies (controls = 35) was 39/37 years. At follow-up (median about seven years), the intima remained thicker and the I/M was higher in cases than in controls [all p < 0.0001; p < 0.001 after adjustment for time to follow-up, body mass index (BMI), and mean arterial pressure (MAP)], whereas the CCA-IMT was illogically thinner. Further, BMI, MAP, hip circumference, abdominal height, serum endostatin and apolipoprotein B levels were higher in cases (all p < 0.05). Intima and I/M measurements were correlated with age, MAP, endostatin and apolipoprotein B, whereas no logical correlations were found for CCA-IMT.

    CONCLUSIONS: The arteries in cases but not controls were still adversely affected after seven years. Measuring intima thickness and I/M appears preferable to measuring CCA-IMT for demonstrating vascular risk after pre-eclampsia.

  • 3.
    Akhter, Tansim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Wikström, Gerhard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Larsson, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Naessén, Tord
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Dimethylarginines correlate to common carotid artery wall layer dimensions and cardiovascular risk factors in pregnant women with and without preeclampsia2018In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 275, p. E69-E70Article in journal (Other academic)
  • 4.
    Aldi, Silvia
    et al.
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Eriksson, Linnea
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Kronqvist, Malin
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Lengquist, Mariette
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Löfling, Marie
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Folkersen, Lasse
    Tech Univ Denmark, Ctr Biol Sequence Anal, Copenhagen, Denmark.
    Matic, Ljubica P.
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Maegdefessel, Lars
    Karolinska Inst, Dept Med Solna, S-17176 Stockholm, Sweden;Tech Univ Munich, Dept Vasc Surg, D-80333 Munich, Germany.
    Grinnemo, Karl-Henrik
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Österholm, C.
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Hedin, Ulf
    Karolinska Inst, Dept Mol Med & Surg, Bioclinicum J8 20, S-17164 Solna, Sweden.
    Dual roles of heparanase in human carotid plaque calcification2019In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 283, p. 127-136Article in journal (Refereed)
    Abstract [en]

    Background and aims: Calcification is a hallmark of advanced atherosclerosis and an active process akin to bone remodeling. Heparanase (HPSE) is an endo-beta-glucuronidase, which cleaves glycosaminoglycan chains of heparan sulfate proteoglycans. The role of HPSE is controversial in osteogenesis and bone remodeling while it is unexplored in vascular calcification. Previously, we reported upregulation of HPSE in human carotid endarterectomies from symptomatic patients and showed correlation of HPSE expression with markers of inflammation and increased thrombogenicity. The present aim is to investigate HPSE expression in relation to genes associated with osteogenesis and osteolysis and the effect of elevated HPSE expression on calcification and osteolysis in vitro.

    Methods: Transcriptomic and immunohistochemical analyses were performed using the Biobank of Karolinska Endarterectomies (BiKE). In vitro calcification and osteolysis were analysed in human carotid smooth muscle cells overexpressing HPSE and bone marrow-derived osteoclasts from HPSE-transgenic mice respectively.

    Results: HPSE expression correlated primarily with genes coupled to osteoclast differentiation and function in human carotid atheromas. HPSE was expressed in osteoclast-like cells in atherosclerotic lesions, and HPSE-transgenic bone marrow-derived osteoclasts displayed a higher osteolytic activity compared to wild-type cells. Contrarily, human carotid SMCs with an elevated HPSE expression demonstrated markedly increased mineralization upon osteogenic differentiation.

    Conclusions: We suggest that HPSE may have dual functions in vascular calcification, depending on the stage of the disease and presence of inflammatory cells. While HPSE plausibly enhances mineralization and osteogenic differentiation of vascular smooth muscle cells, it is associated with inflammation-induced osteoclast differentiation and activity in advanced atherosclerotic plaques.

  • 5.
    Balboa Ramilo, Amanda
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Becirovic Agic, Mediha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Petri, Marcelo Heron
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Mani, Kevin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Wanhainen, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery. Umeå Univ, Dept Surg & Perioperat Sci, Surg, Umeå, Sweden..
    Wågsäter, Dick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    The tyrosine kinase inhibitor Bosutinib does not inhibit angiotensin II-induced abdominal aortic aneurysm: Validation of the importance of PDGFR and c-Kit tyrosine kinases by Imatinib2022In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 340, p. 68-69Article in journal (Refereed)
  • 6.
    Bennet, A. M.
    et al.
    Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institute, Stockholm.
    Van Maarle, M.
    Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institute, Stockholm.
    Hallqvist, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Preventive Medicine.
    Morgenstern, R.
    Unit of Biochemical Toxicology, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
    Frostegård, J.
    Wiman, B.
    Division of Coagulation Research, Karolinska University Hospital, Stockholm, Sweden.
    Prince, J. A.
    de Faire, U.
    Association of TNF-α serum levels and TNFA promoter polymorohisms with risk of myocardial infarction2006In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 187, no 2, p. 408-414Article in journal (Refereed)
    Abstract [en]

    Elevated levels of tumor necrosis factor-alpha (TNF-α), and presence of polymorphisms of the TNFA gene have been implicated in cardiovascular disease pathogenesis. We explored the relationship between polymorphisms in the TNFA gene (−1031C/T, −863C/A −857T/C, −308G/A, −238G/A), protein levels of TNF-α and their association to myocardial infarction (MI) using a sample of 1213 post-MI patients and 1561 healthy controls. MI risk was higher among men with elevated TNF-α levels, with the highest compared to the lowest TNF-α quartile giving a 70% risk increase (OR [95% CI]: 1.7 [1.1; 2.6]). Obese subjects who also had elevated TNF-α levels were at even higher risk for MI (OR [95% CI]: 3.4 [2.1; 5.6]). Higher TNF-α levels were seen among smokers (but not among non-smokers) carrying the −857T allele. Furthermore, a rare haplotype occurred more frequently among the cases than the controls. Elevated TNF-α levels are associated with increased MI risk. Obese subjects with elevated TNF-a levels, and carriers of polymorphisms in or near TNFA are particularly susceptible to the hazards of smoking, results which may have implications for cardiovascular preventive measures.

  • 7.
    Bergstrom, Goran
    et al.
    Univ Gothenburg, Inst Med, Sahlgrenska Acad, Dept Mol & Clin Med, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Clin Physiol, Gothenburg, Sweden..
    Rosengren, Annika
    Univ Gothenburg, Inst Med, Sahlgrenska Acad, Dept Mol & Clin Med, Gothenburg, Sweden.;Sahlgrenska Univ Hosp Ostra Hosp, Dept Med Geriatr & Emergency Med, Gothenburg, Sweden..
    Brolin, Elin Bacsovics
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden.;Capio St Goran Hosp, Dept Radiol, Stockholm, Sweden..
    Brandberg, John
    Univ Gothenburg, Inst Clin Sci, Sahlgrenska Acad, Dept Radiol, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Dept Radiol, Gothenburg, Sweden..
    Cederlund, Kerstin
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Engstrom, Gunnar
    Lund Univ, Dept Clin Sci Malmö, Malmö, Sweden..
    Engvall, Jan E.
    Linköping Univ, Ctr Med Image Sci & Visualizat, CMIV, Linköping, Sweden.;Linköping Univ, Dept Clin Physiol, Linköping, Sweden.;Linköping Univ, Dept Hlth Med & Caring Sci, Linköping, Sweden..
    Eriksson, Maria J.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Physiol, Stockholm, Sweden..
    Goncalves, Isabel
    Skane Univ Hosp, Dept Cardiol, Malmö, Sweden.;Lund Univ, Dept Clin Sci Malmö, Cardiovasc Res Translat Studies, Malmö, Sweden..
    Hagström, Emil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR).
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR).
    Jernberg, Tomas
    Danderyd Hosp, Karolinska Inst, Dept Clin Sci, Stockholm, Sweden..
    Lilja, Mikael
    Umeå Univ, Östersund Hosp, Dept Publ Hlth & Clin Med, Unit Res Educ & Dev, Umeå, Sweden..
    Magnusson, Martin
    Lund Univ, Dept Clin Sci Malmö, Malmö, Sweden.;Skane Univ Hosp, Dept Cardiol, Malmö, Sweden.;Lund Univ, Wallenberg Ctr Mol Med, Lund, Sweden.;North West Univ, Hypertens Africa Res Team HART, Potchefstroom, South Africa..
    Persson, Anders
    Linköping Univ, Ctr Med Image Sci & Visualizat, CMIV, Linköping, Sweden.;Linköping Univ, Dept Hlth Med & Caring Sci, Linköping, Sweden.;Linköping Univ, Dept Radiol, Linköping, Sweden.;Karolinska Inst, Huddinge Univ Hosp, Dept Clin Sci, Stockholm, Sweden..
    Persson, Margaretha
    Lund Univ, Dept Clin Sci Malmö, Malmö, Sweden.;Skane Univ Hosp, Dept Internal Med, Malmö, Sweden..
    Sandstrom, Anette
    Umeå Univ, Heart Ctr, Umeå, Sweden.;Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden..
    Schmidt, Caroline
    Univ Gothenburg, Inst Med, Sahlgrenska Acad, Dept Mol & Clin Med, Gothenburg, Sweden..
    Larsson, Linn Skoglund
    Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden..
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Univ New South Wales, George Inst Global Hlth, Sydney, Australia..
    Swahn, Eva
    Linköping Univ, Dept Hlth Med & Caring Sci, Linköping, Sweden.;Linköping Univ, Dept Cardiol, Linköping, Sweden..
    Soderberg, Stefan
    Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden..
    Toren, Kjell
    Univ Gothenburg, Sahlgrenska Acad, Sch Publ Hlth & Community Med, Inst Med,Sect Occupat & Environm Med, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Dept Occupat & Environm Med, Gothenburg, Sweden..
    Ostgren, Carl Johan
    Linköping Univ, Ctr Med Image Sci & Visualizat, CMIV, Linköping, Sweden.;Linköping Univ, Dept Hlth Med & Caring Sci, Linköping, Sweden..
    Lampa, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Body weight at age 20 and in midlife is more important than weight gain for coronary atherosclerosis: Results from SCAPIS2023In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 373, p. 46-54Article in journal (Refereed)
    Abstract [en]

    Background and aims: Elevated body weight in adolescence is associated with early cardiovascular disease, but whether this association is traceable to weight in early adulthood, weight in midlife or to weight gain is not known. The aim of this study is to assess the risk of midlife coronary atherosclerosis being associated with body weight at age 20, body weight in midlife and body weight change.

    Methods: We used data from 25,181 participants with no previous myocardial infarction or cardiac procedure in the Swedish CArdioPulmonary bioImage Study (SCAPIS, mean age 57 years, 51% women). Data on coronary atherosclerosis, self-reported body weight at age 20 and measured midlife weight were recorded together with potential confounders and mediators. Coronary atherosclerosis was assessed using coronary computed tomog-raphy angiography (CCTA) and expressed as segment involvement score (SIS).

    Results: The probability of having coronary atherosclerosis was markedly higher with increasing weight at age 20 and with mid-life weight (p < 0.001 for both sexes). However, weight increase from age 20 until mid-life was only modestly associated with coronary atherosclerosis. The association between weight gain and coronary atherosclerosis was mainly seen in men. However, no significant sex difference could be detected when adjusting for the 10-year delay in disease development in women.

    Conclusions: Similar in men and women, weight at age 20 and weight in midlife are strongly related to coronary atherosclerosis while weight increase from age 20 until midlife is only modestly related to coronary atherosclerosis.

    Download full text (pdf)
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  • 8.
    Bjerre, Mette
    et al.
    Medical Research Laboratory, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
    Hilden, Jørgen
    Department of Biostatistics, Institute of Public Health Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
    Winkel, Per
    The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
    Jensen, Gorm Boje
    Department of Cardiology, Hvidovre Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
    Kjøller, Erik
    The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital; Department of Cardiology, S, Herlev Hospital, University of Copenhagen.
    Sajadieh, Ahmad
    Department of Cardiology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.
    Kastrup, Jens
    Department of Cardiology, Rigshospitalet University of Copenhagen, Denmark.
    Kolmos, Hans Jørn
    Department of Clinical Microbiology, Odense University Hospital, Denmark.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ärnlöv, Johan
    Department of Neurobiology, Care Sciences and Society/Division of Family Medicine, Karolinska Institute; Department of Health and Social Sciences, Dalarna University, Falun.
    Jakobsen, Janus Christian
    The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Department of Cardiology, Holbæk Hospital, Holbæk, Denmark; Department of Regional Health Research, The Faculty of Health Sciences, University of Southern, Denmark.
    Gluud, Christian
    The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
    Serum osteoprotegerin as a long-term predictor for patients with stable coronary artery disease and its association with diabetes and statin treatment: A CLARICOR trial 10-year follow-up substudy2020In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 301, p. 8-14Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: Elevated circulating levels of osteoprotegerin (OPG) are known to add to the prediction of cardiovascular mortality. Our objective was to clarify the long-term risk associated with serum OPG and the possible influence of diabetes and statins on OPG levels in patients with stable coronary artery disease (CAD).

    METHODS: We assessed the placebo-treated group (n = 1998) from the CLARICOR trial (NCT00121550), a cohort with stable CAD. At entry, 15% of the participants had diabetes and 41% received statins. Serum OPG levels were measured in blood drawn at randomization. Participants were followed through public registers for 10 years.

    RESULTS: OPG levels correlated positively with diabetes status, age, CRP and female sex, but negatively with the use of statins. CAD participants with diabetes had significantly elevated serum OPG levels compared to participants without diabetes, p < 0.0001. The participants without diabetes treated with statins presented with significantly lower serum OPG levels than the corresponding non-statin-users (p < 0.0001). However, statin use showed no association with OPG levels in the participants with diabetes. High OPG levels at entry showed long-term associations with all-cause mortality and cardiovascular events (hazard ratio associated with factor 10 OPG increase 15.9 (95% CI 11.0-22.9) and 6.38 (4.60-8.90), p = 0.0001, even after adjustment for standard predictors (3.16 (1.90-5.25) and 2.29 (1.53-3.44), p < 0.0001).

    CONCLUSIONS: Circulating OPG holds long-term independent predictive ability for all-cause mortality and cardiovascular events in CAD participants. OPG levels were associated with diabetes, age, and female sex and statin treatment was associated with lower OPG levels in the absence of diabetes.

  • 9.
    Björck, Martin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Ravn, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Nilsson, T K
    Wanhainen, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Nilsson, P M
    Blood cell telomere length among patients with an isolated popliteal artery aneurysm and those with multiple aneurysm disease2011In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 219, no 2, p. 946-950Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    Short relative telomere length (RTL) is associated with vascular ageing, inflammation and cardiovascular risk factors. Previous studies have reported an association between abdominal aortic aneurysm and short RTL. The presence of atherosclerosis among patients with aneurysm disease may, however, be a confounder. The aim was to explore the associations between short RTL and aneurysm disease, by comparing patients with isolated popliteal artery aneurysms with those having multiple aneurysms.

    DESIGN AND PATIENTS:

    DNA was retrieved from 183 patients with popliteal artery aneurysm (PAA). They were all examined with ultrasound at the time of blood-sampling, and had a total of 423 aneurysms (range 1-7, mean 2.3/patient).

    METHODS:

    TL was measured with Real-Time PCR, RTL was calculated by comparing with three reference populations.

    RESULTS:

    Patients with bilateral PAAs had a mean RTL of 0.985 vs. 1.038 with unilateral PAAs (P=0.326). Patients with abdominal aortic aneurysm had RTL 1.035, vs. 0.999 without (P=0.513). No difference was seen with or without femoral or iliac aneurysms. Fifty-six patients with isolated PAA at surgery and at re-examination had RTL 0.974, vs. 1.033 who had >1 aneurysm (P=0.308). RTL was not associated with the number of aneurysms at re-examination (P=0.727, one-way ANOVA). There was a trend towards shorter RTL among active smokers (0.93 vs. 1.04, P=0.066).

    CONCLUSIONS:

    No association between short RTL and multiple aneurysm disease was found. The previously reported association between AAA and short RTL may be secondary to cardiovascular risk factors, rather than by aneurysm disease.

  • 10.
    Carlson, Lars A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine.
    Fröberg, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine.
    Oro, L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine.
    A case of massive hypertriglyceridemia corrected by nicotinic acid or nicotinamide therapy1972In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 16, no 3, p. 359-368Article in journal (Refereed)
    Abstract [en]

    A case of massive hypertriglyceridemia with fasting plasma triglycerides around 100 mmoles/l is described. Large amounts of chylomicra were present in fasting plasma and the amounts of low-density and high-density lipoproteins were very low. Postheparin plasma lipolytic activity was normal and intravenous heparin rapidly cleared the patient's abnormally prolonged alimentary lipemia with a concomitant rise in plasma free fatty acid levels.

    Nicotinic acid or nictotinamide given in doses of 3 g or more daily reduced plasma triglyceride levels to about 2–3 mmoles/1 and raised the reduced levels of low and high-density lipoproteins. The mode of onset of this therapeutic effect was slow and the effect persisted for several weeks after withdrawal of either nicotinic acid or nicotinamide.

    The pathogenesis of the hypertriglyceridemia as well as the mode of action of nicotinic acid and nicotinamide is discussed.

  • 11.
    Carlson, Lars A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine.
    Walldius, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine.
    Butcher, R.W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine.
    Effect of chlorophenoxyisobutyric acid (CPIB) on fat-mobilizing lipolysis and cyclic AMP levels in rat epididymal fat1972In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 16, no 3, p. 349-357Article in journal (Refereed)
    Abstract [en]

    High concentrations of chlorophenoxyisobutyric acid (CPIB) reduced basal glycerol release from rat epididymal fat pads in vitro and antagonized the lipolytic effects of noradrenaline. Furthermore, very high concentrations of CPIB significantly antagonized the effects or noradrenaline or ACTH on cyclic AMP accumulation by isolated rat adipocytes. These data are not incompatible with the hypothesis that a primary mechanism in the hypolipidemic action of CPIB is to lower the levels of cyclic AMP in adipose tissue, resulting in decreased hormone-sensitive lipase activity and/or increased lipoprotein lipase activity.

  • 12.
    Carlsson, Axel C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Centre for Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
    Jansson, Jan-Håkan
    Department of Public Health and Clinical Medicine, Research Unit Skellefteå, Umeå University, Umeå, Sweden.
    Söderberg, Stefan
    Department of Public Health and Clinical Medicine, Heart Centre, Umeå University, Umeå, Sweden.
    Ruge, Toralph
    Dept of Medicine Solna, Karolinska Institutet and Function of Emergency Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ärnlöv, Johan
    Centre for Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden; School of Health and Social Sciences, Dalarna University, Falun, Sweden.
    Levels of soluble tumor necrosis factor receptor 1 and 2, gender, and risk of myocardial infarction in Northern Sweden2018In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 272, p. 41-46Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS:

    Soluble receptors for tumor necrosis factor alpha (sTNFR1 and sTNFR2) have been associated with cardiovascular diseases, and some evidence points towards a difference in associated risk between men and women. We aimed to study the association between sTNFR1 and sTNFR2 and incident myocardial infarctions (MI) and to explore the influence of established cardiovascular risk factors in men and women.

    METHODS:

    We conducted a nested case control study in three large Swedish cohorts, including 533 myocardial infarction cases, and 1003 age-, sex- and cohort-matched controls. Odds ratios (OR) with 95% confidence intervals (CI) were calculated.

    RESULTS:

    An association between circulating sTNFR1 and sTNFR2 and an increased risk for MI was found when comparing cases and controls. The odds ratios were significant after adjustment for established cardiovascular risk factors and C-reactive protein in women (OR 1.44, 95% CI 1.08-1.93 for TNFR1, and 1.61, 95% CI 1.11-2.34 for TNFR2), but was abolished in men. Women with a combination of elevated CRP and values in the upper quartile of TNFR1 or TNFR2 had a 5-fold higher risk of myocardial infarction versus those with normal CRP and values in the lower three quartiles of TNFR1 or TNFR2.

    CONCLUSIONS:

    As the risk estimates for TNFR1 and TNFR2 were higher and remained significant after adjustments for established cardiovascular risk factors in women but not in men, a potential role for TNFR1 and TNFR2 in identifying women with a higher MI risk is possible. The future clinical role of TNFR1 and TNFR2 in combination with CRP to identify high risk patients for coronary heart disease has yet to be determined.

  • 13.
    Carlsson, Axel C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Juhlin, C Christofer
    Larsson, Tobias E
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Soluble tumor necrosis factor receptor 1 (sTNFR1) is associated with increased total mortality due to cancer and cardiovascular causes: Findings from two community based cohorts of elderly2014In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 237, no 1, p. 236-242Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Experimental evidence support soluble receptors for tumor necrosis factor alpha as important mediators of the underlying pathology leading to cardiovascular disease and cancer. However, prospective data concerning the relation between circulating soluble tumor necrosis factor receptor-1 (sTNFR1) and mortality in humans are lacking. We aimed to explore and validate the association between sTNFR1 and mortality, and to explore the influence of other established risk factors for mortality, including other inflammatory markers.

    METHODS: The association between serum sTNFR1and the risk for mortality was investigated in two community-based cohorts of elderly: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; women 50%, n = 1005, mean age 70 years, median follow-up 7.9 years) and the Uppsala Longitudinal Study of Adult Men (ULSAM, n = 775, mean age 77 years, median follow-up 8.1 years).

    RESULTS: In total, 101 participants in PIVUS and 274 in ULSAM died during follow-up. In multivariable Cox regression models adjusted for inflammation, lifestyle and established cardiovascular risk factors, one standard deviation (SD) higher sTNFR1 was associated with a hazard ratio (HR) for mortality of 1.37, 95% confidence interval (CI) 1.17-1.60, in PIVUS and HR 1.22, 95% CI 1.10-1.37 in ULSAM. Moreover, circulatingsTNFR1 was associated with cardiovascular mortality (HR per SD of sTNFR1, 1.24, 95% CI 1.07-1.44) and cancer mortality (HR per SD of sTNFR1, 1.32, 95% CI 1.11-1.57) in the ULSAM cohort. High levels of sTNFR1 identified individuals with increased risk of mortality among those with high as well as low levels of systemic inflammation.

    CONCLUSIONS: An association between circulating sTNFR1 and an increased risk for mortality was found and validated in two independent community-based cohorts. The future clinical role of sTNFR1 to identify high risk patients for adverse outcomes and mortality has yet to be determined.

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  • 14. Delgado-Lista, J.
    et al.
    Perez-Martinez, P.
    Garcia-Rios, A.
    Phillips, C. M.
    Williams, C. M.
    Gulseth, H. L.
    Helal, O.
    Blaak, E. E.
    Kiec-Wilk, B.
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Oxidative Stress and Inflammation.
    Drevon, C. A.
    Defoort, C.
    Saris, W. H.
    Wybranska, I.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Lovegrove, J. A.
    Roche, H. M.
    Lopez-Miranda, J.
    Pleiotropic effects of TCF7L2 gene variants and its modulation in the metabolic syndrome: From the LIPGENE study2011In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 214, no 1, p. 110-116Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: Variants of the TCF7L2 gene predict the development of type 2 diabetes mellitus (T2DM). We investigated the associations between gene variants of TCF7L2 and clinical features of the metabolic syndrome (MetS) (an entity often preceeding T2DM), and their interaction with non-genetic factors, including plasma saturated fatty acids (SFA) concentration and insulin resistance (IR). Methods: Fasting lipid profiles, insulin sensitivity, insulin secretion, anthropometrics, blood pressure and 10 gene variations of the TCF7L2 gene were determined in 450 subjects with MetS. Results: Several single nucleotide polymorphisms (SNP) showed phenotypic associations independent of SFA or IR. Carriers of the rare T allele of rs7903146, and of three other SNPs in linkage disequilibrium with rs7903146, had lower blood pressure and insulin secretion. High IR and the presence of the T-allele of rs7903146 acted synergistically to define those with reduced insulin secretion. Carriers of the minor allele of rs290481 exhibited an altered lipid profile, with increased plasma levels of apolipoprotein B, non-esterified fatty acids, cholesterol and apolipoprotein B in triglyceride rich lipoproteins, and LDL cholesterol. Carriers of the minor allele of rs11196224 that had higher plasma SFA levels showed elevated procoagulant/proinflammatory biomarkers, impaired insulin secretion and increased IR, whereas carriers of the minor allele of rs17685538 with high plasma SFA levels exhibited higher blood pressure. Conclusions/interpretation: SNP in the TCF7L2 gene are associated with differences in insulin secretion, blood pressure, blood lipids and coagulation in MetS patients, and may be modulated by SFA in plasma or IR.

  • 15.
    den Hoed, Marcel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Strawbridge, Rona J
    Almgren, Peter
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Engström, Gunnar
    de Faire, Ulf
    Hedblad, Bo
    Humphries, Steve E
    Lindgren, Cecilia M
    Morris, Andrew P
    Östling, Gerd
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Tremoli, Elena
    Hamsten, Anders
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Melander, Olle
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    GWAS-identified loci for coronary heart disease are associated with intima-media thickness and plaque presence at the carotid artery bulb2015In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 239, no 2, p. 304-310Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Large-scale genome-wide association studies (GWAS) have so far identified 45 loci that are robustly associated with coronary heart disease (CHD) in data from adult men and women of European descent.

    OBJECTIVES: To examine whether the CHD-associated loci are associated with measures of atherosclerosis in data from up to 9582 individuals of European ancestry.

    METHODS: Forty-five SNPs representing the CHD-associated loci were genotyped in middle-aged to elderly individuals of European descent from four independent population-based studies (IMPROVE, MDC-CC, ULSAM and PIVUS). Intima-media thickness (IMT) was measured by external B-mode ultrasonography at the far wall of the bulb (sinus) and common carotid artery. Plaque presence was defined as a maximal IMT of the bulb >1.5 mm. We meta-analysed single-SNP associations across the four studies, and combined them in a genetic predisposition score. We subsequently examined the association of the genetic predisposition score with prevalent CHD and the three indices of atherosclerosis, adjusting for sex, age and Framingham risk factors.

    RESULTS: As anticipated, the genetic predisposition score was associated with prevalent CHD, with each additional risk allele increasing the odds of disease by 5.5% (p = 4.1 × 10(-6)). Moreover, each additional CHD-risk allele across the 45 loci was associated with a 0.24% increase in IMT (p = 4.0 × 10(-3)), and with a 2.8% increased odds of plaque presence (p = 7.4 × 10(-6)) at the far wall of the bulb. The genetic predisposition score was not associated with IMT of the common carotid artery (p = 0.47).

    CONCLUSIONS: Our results suggest that the association between the 45 previously identified loci and CHD at least partly acts through atherosclerosis.

  • 16. Digby, Janet E
    et al.
    McNeill, Eileen
    Dyar, Oliver J
    Lam, Vincent
    Greaves, David R
    Choudhury, Robin P
    Anti-inflammatory effects of nicotinic acid in adipocytes demonstrated by suppression of fractalkine, RANTES, and MCP-1 and upregulation of adiponectin.2010In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 209, no 1, p. 89-95Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: A major site of action for the atheroprotective drug nicotinic acid (NA) is adipose tissue, via the G-protein-coupled receptor, GPR109A. Since, adipose tissue is an active secretory organ that contributes both positively and negatively to systemic inflammatory processes associated with cardiovascular disease, we hypothesized that NA would act directly upon adipocytes to alter the expression of pro-inflammatory chemokines, and the anti-inflammatory adipokine adiponectin.

    METHODS AND RESULTS: TNF-alpha treatment (1.0ng/mL) of 3T3-L1 adipocytes resulted in an increase in gene expression of fractalkine (9+/-3.3-fold, P<0.01); monocyte chemoattractant protein-1 (MCP-1) (24+/-1.2-fold, P<0.001), 'regulated upon activation, normal T cell expressed and secreted' (RANTES) (500+/-55-fold, P<0.001) and inducible nitric oxide synthase (iNOS) (200+/-70-fold, P<0.05). The addition of NA (10(-4)M) to TNF-alpha-treated adipocytes attenuated expression of fractalkine (50+/-12%, P<0.01); MCP-1 (50+/-6%, P<0.01), RANTES (70+/-3%, P<0.01) and iNOS (60+/-16%). This pattern was mirrored in protein released from the adipocytes into the surrounding media. The effect on gene expression was neutralised by pre-treatment with pertussis toxin. NA attenuated macrophage chemotaxis (by 27+/-3.5%, P<0.001) towards adipocyte conditioned media. By contrast, NA, (10(-6)-10(-3)M) increased, in a dose-dependent manner, mRNA of the atheroprotective hormone adiponectin (3-5-fold n=6, P<0.01).

    CONCLUSIONS: NA suppresses pro-atherogenic chemokines and upregulates the atheroprotective adiponectin through a G-protein-coupled pathway. Since adipose tissue has the potential to contribute to both systemic and local (perivascular) inflammation associated with atherosclerosis our results suggest a new "pleiotropic" role for NA.

  • 17.
    Ebeling Barbier, Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Apolipoprotein B/A-I ratio related to visceral but not to subcutaneous adipose tissue in elderly Swedes2010In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 211, no 2, p. 656-659Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate whether the amount of visceral (VAT) or subcutaneous adipose tissue (SAT) independently of the other can determine the apolipoprotein (apo)B/A-I ratio. METHODS: VAT and SAT areas were assessed using magnetic resonance imaging in 247 randomly selected 70-year-old men and women who did not use lipid-lowering drugs. Their adipose tissue areas were compared to their apoB and apo A-I levels and to their apoB/A-I ratios. RESULTS: The VAT area and the gender were significantly related to the apoB/A-I ratio whereas the SAT area was not. There was a positive relationship between the VAT area and the apoB/A-I ratio. CONCLUSION: A positive relationship was established between the amount of VAT and the apoB/A-I ratio, whereas there was no relationship between the amount of SAT and the apoB/A-I ratio. This observation supports the notion that VAT is metabolically active.

  • 18.
    Eriksson, Jan W
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Burén, Jonas
    Svensson, Maria
    Olivecrona, Thomas
    Olivecrona, Gunilla
    Postprandial regulation of blood lipids and adipose tissue lipoprotein lipase in type 2 diabetes patients and healthy control subjects.2003In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 166, no 2, p. 359-67Article in journal (Refereed)
    Abstract [en]

    BACKGROUND/AIM: In type 2 diabetes and other insulin-resistant conditions, postprandial hypertriglyceridaemia is an important metabolic perturbation. To further elucidate alterations in the clearance of triglyceride-rich lipoproteins in type 2 diabetes we focused on the nutritional regulation of adipose tissue lipoprotein lipase (LPL).

    SUBJECTS AND METHODS: Eight subjects with type 2 diabetes and eight age-, sex- and body mass index (BMI)-matched control subjects underwent subcutaneous abdominal adipose tissue biopsies in the fasting state and 3.5 h following a standardized lipid-enriched meal. LPL activity and mass were measured in adipose tissue and also in plasma after an intravenous injection of heparin.

    RESULTS: Postprandial, but not fasting, triglycerides were significantly higher in the diabetic subjects than in the control subjects (3.0+/-0.4 vs 2.0+/-0.2 mmol/l, P=0.028). Adipose tissue LPL activity was increased following the meal test by approximately 35-55% (P=0.021 and 0.004, respectively). There was no significant difference between the groups in this respect. The specific enzyme activity of LPL was not altered in the postprandial state. Fasting and postprandial adipose tissue LPL activity as well as post-heparin plasma LPL activity tended to be lower among the diabetes patients (NS). There was a significant and independent inverse association between insulin resistance (homeostasis model assessment insulin resistance (HOMA-IR) index) vs post-heparin plasma LPL activity and postprandial triglyceride levels, respectively. Adipose tissue LPL activity was related to insulin action in vitro on adipocyte glucose transport, but not to HOMA-IR.

    CONCLUSION: Following food intake adipose tissue LPL activity is enhanced to a similar degree in patients with type 2 diabetes and in healthy control subjects matched for BMI, age and gender. If LPL dysregulation is involved in the postprandial hypertriglyceridaemia found in type 2 diabetes, it should occur in tissues other than subcutaneous fat.

  • 19.
    Feldreich, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. School of Health and Social Studies, Dalarna University, Falun, .
    Carlsson, Axel C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. School of Health and Social Studies, Dalarna University, Falun, .
    The association between serum cathepsin L and mortality in older adults2016In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 254, p. 109-116Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: Research suggests that the protease cathepsin L is causally involved in atherosclerosis. However, data on cathepsin L as a risk marker are lacking. Therefore, we investigated associations between circulating cathepsin L and cardiovascular mortality.

    METHODS: Two independent community-based cohorts were used: Uppsala Longitudinal Study of Adult Men (ULSAM); n = 776; mean age 77 years; baseline 1997-2001; 185 cardiovascular deaths during 9.7 years follow-up, and Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS); n = 993; 50% women; mean age 70 years; baseline 2001-2004; 42 cardiovascular deaths during 10.0 years follow-up.

    RESULTS: Higher serum cathepsin L was associated with an increased risk for cardiovascular mortality in age- and sex-adjusted models in both cohorts (ULSAM: hazard ratio (HR) for 1-standard deviation (SD) increase, 1.17 [95% CI, 1.01-1.34], p = 0.032 PIVUS: HR 1.35 [95% CI, 1.07-1.72], p = 0.013). When merging the cohorts, these associations were independent of inflammatory markers and cardiovascular risk factors, but non-significant adjusting for kidney function. Individuals with a combination of elevated cathepsin L and increased inflammation, kidney dysfunction, or prevalent cardiovascular disease had a markedly increased risk, while no increased risk was associated with elevated cathepsin L, in the absence of these disease states.

    CONCLUSIONS: An association between higher serum cathepsin L and increased risk of cardiovascular mortality was found in two independent cohorts. Impaired kidney function appears to be an important moderator or mediator of these associations. Further studies are needed to delineate the underlying mechanisms and to evaluate whether the measurement of cathepsin L might have clinical utility.

  • 20.
    Feldreich, Tobias
    et al.
    Dalarna Univ, Educ Hlth & Social Studies, Falun, Sweden..
    Nowak, Christoph
    Karolinska Inst, Div Family Med & Primary Care, Dept Neurobiol Care Sci & Soc NVS, Alfred Nobels Alle 23, SE-14183 Huddinge, Sweden..
    Carlsson, Axel C.
    Karolinska Inst, Div Family Med & Primary Care, Dept Neurobiol Care Sci & Soc NVS, Alfred Nobels Alle 23, SE-14183 Huddinge, Sweden..
    ostgren, Carl-Johan
    Linköping Univ, Dept Hlth Med & Caring Sci, Linköping, Sweden..
    Nystrom, Fredrik H.
    Linköping Univ, Dept Hlth Med & Caring Sci, Linköping, Sweden..
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Carrero-Roig, Juan-Jesus
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Leppert, Jerzy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Hedberg, P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Cordeiro, Antonio
    Dante Pazzanese Inst Cardiol, Dept Hypertens & Nephrol, Sao Paulo, Brazil..
    arnlov, Johan
    Dalarna Univ, Educ Hlth & Social Studies, Falun, Sweden.;Karolinska Inst, Div Family Med & Primary Care, Dept Neurobiol Care Sci & Soc NVS, Alfred Nobels Alle 23, SE-14183 Huddinge, Sweden..
    The association between plasma proteomics and incident cardiovascular disease identifies MMP-12 as a promising cardiovascular risk marker in patients with chronic kidney disease2020In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 307, p. 11-15Article in journal (Refereed)
    Abstract [en]

    Background and aims: Previous proteomics efforts in patients with chronic kidney disease (CKD) have predominantly evaluated urinary protein levels. Therefore, our aim was to investigate the association between plasma levels of 80 cardiovascular disease-related proteins and the risk of major adverse cardiovascular events (MACE) in patients with CKD. Methods: Individuals with CKD stages 3-5 (eGFR below 60 ml min-1 [1.73 m]-2) from three community-based cohorts (PIVUS, ULSAM, SAVA), one diabetes cohort (CARDIPP) and one cohort with peripheral artery disease patients (PADVA) with information on 80 plasma protein biomarkers, assessed with a proximity extension assay, and follow-up data on incident MACE, were used as discovery sample. To validate findings and to asses generalizability to patients with CKD in clinical practice, an outpatient CKD-cohort (Malnutrition, Inflammation and Vascular Calcification (MIVC)) was used as replication sample. Results: In the discovery sample (total n = 1316), 249 individuals experienced MACE during 7.0 +/- 2.9 years (range 0.005-12.9) of follow-up, and in the replication sample, 71 MACE events in 283 individuals over a mean +/- SD change of 2.9 +/- 1.2 years (range 0.1-4.0) were documented. Applying Bonferroni correction, 18 proteins were significantly associated with risk of MACE in the discovery cohort, adjusting for age and sex in order of significance, GDF-15, FGF-23, REN, FABP4, IL6, TNF-R1, AGRP, MMP-12, AM, KIM-1, TRAILR2, TNFR2, CTSL1, CSF1, PlGF, CA-125, CCL20 and PAR-1 (p < 0.000625 for all). Only matrix metalloproteinase 12 (MMP-12) was significantly associated with an increased risk of MACE in the replication sample (hazard ratio (HR) per SD increase, 1.36, 95% CI (1.07-1.75), p = 0.013). Conclusions: Our proteomics analyses identified plasma MMP-12 as a promising cardiovascular risk marker in patients with CKD.

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  • 21. Ferguson, Jane F.
    et al.
    Phillips, Catherine M.
    McMonagle, Jolene
    Perez-Martinez, Pablo
    Shaw, Danielle I.
    Lovegrove, Julie A.
    Helal, Olfa
    Defoort, Catherine
    Gjelstad, Ingrid M. F.
    Drevon, Christian A.
    Blaak, Ellen E.
    Saris, Wim H. M.
    Leszczynska-Golabek, Iwona
    Kiec-Wilk, Beata
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Karlström, Brita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Lopez-Miranda, Jose
    Roche, Helen M.
    NOS3 gene polymorphisms are associated with risk markers of cardiovascular disease, and interact with omega-3 polyunsaturated fatty acids2010In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 211, no 2, p. 539-544Article in journal (Refereed)
    Abstract [en]

    Objective: Omega-3 polyunsaturated fatty acids (n-3 PUFA) may protect against the development of cardiovascular disease (CVD). Genotype at key genes such as nitric oxide synthase (NOS3) may determine responsiveness to fatty acids. Gene-nutrient interactions may be important in modulating the development of CVD, particularly in high-risk individuals with the metabolic syndrome (MetS). Methods: Biomarkers of CVD risk, plasma fatty acid composition, and NOS3 single nucleotide polymorphism (SNP) genotype (rs11771443, rs1800783, rs1800779, rs1799983, rs3918227, and rs743507) were determined in 450 individuals with the MetS from the LIPGENE dietary intervention cohort. The effect of dietary fat modification for 12 weeks on metabolic indices of the MetS was determined to understand potential NOS3 gene-nutrient interactions. Results: Several markers of inflammation and dyslipidaemia were significantly different between the genotype groups. A significant gene-nutrient interaction was observed between the NOS3 rs1799983 SNP and plasma n-3 PUFA status on plasma triacylglycerol (TAG) concentrations. Minor allele carriers (AC + AA) showed an inverse association with significantly higher plasma TAG concentrations in those with low plasma n-3 PUFA status and vice versa but the major allele homozygotes (CC) did not. Following n-3 PUFA supplementation, plasma TAG concentrations of minor allele carriers of rs1799983 were considerably more responsive to changes in plasma n-3 PUFA, than major allele homozygotes. Conclusions: Carriers of the minor allele at rs1799983 in NOS3 have plasma TAG concentrations which are more responsive to n-3 PUFA. This suggests that these individuals might show greater beneficial effects of n-3 PUFA consumption to reduce plasma TAG concentrations.

  • 22. Garcia-Rios, Antonio
    et al.
    Delgado-Lista, Javier
    Perez-Martinez, Pablo
    Phillips, Catherine M.
    Ferguson, Jane F.
    Gjelstad, Ingrid M. F.
    Williams, Christine M.
    Karlström, Brita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Kiec-Wilkh, Beata
    Blaak, Ellen E.
    Lairon, Denis
    Planells, Richard
    Malczewska-Malec, Malgorzata
    Defoort, Catherine
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Saris, Wim H. M.
    Lovegrove, Julie A.
    Drevon, Christian A.
    Roche, Helen M.
    Lopez-Miranda, Jose
    Genetic variations at the lipoprotein lipase gene influence plasma lipid concentrations and interact with plasma n-6 polyunsaturated fatty acids to modulate lipid metabolism2011In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 218, no 2, p. 416-422Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate whether seven common single nucleotide polymorphisms (SNPs) at the lipoprotein lipase (LPL) locus interact with total plasma fatty acids to modulate plasma lipid metabolism in metabolic syndrome (MetS) patients. Methods: Plasma fatty acid composition, plasma lipid concentrations and LPL SNPs were determined in 452 subjects with the MetS in the European LIPGENE human study and were repeated in 1754 subjects from the LIPGENE-SU.VI.MAX Study. Results: Triglycerides (TG) were lower, and HDL higher in the carriers of rs328 and rs1059611 in the SUVIMAX cohort (all P < 0.001), and these findings showed a similar, non-significant trend in LIPGENE cohort. In this last cohort, we found a gene-fatty acids interaction, as the carriers of the minor allele displayed a lower fasting TG and triglyceride rich lipoproteins-TG (TRL-TG) concentrations only when they had n-6 polyunsaturated fatty acids below the median (all P < 0.05). Moreover, subjects carrying the minor allele for rs328 SNP and with a low level of n-6 PUFA displayed higher nonesterified fatty acid (NEFA) plasma concentrations as compared with homozygous for the major allele (P = 0.034). Interestingly, the n-6 PUFA-dependent associations between those SNPs and TG metabolism were also replicated in subjects without MetS from the SU.VI.MAX cohort. Conclusion: Two genetic variations at the LPL gene (rs328 and rs1059611) influence plasma lipid concentrations and interact with plasma n-6 PUFA to modulate lipid metabolism. The knowledge of new genetic factors together with the understanding of these gene-nutrient interactions could help to a better knowledge of the pathogenesis in the MetS. 

  • 23. Gonzalez, Manuel
    et al.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Soderberg, Stefan
    Leptin and endothelial function in the elderly: The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study2013In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 228, no 2, p. 485-490Article in journal (Refereed)
    Abstract [en]

    Background: Leptin levels are elevated in obese humans. Several studies have shown an association between hyperleptinemia and development of atherosclerosis and cardiovascular disease (CVD), but the relationship between leptin and vascular function remains unclear. Aim: To evaluate associations between circulating plasma leptin and measures of vascular function in a large sample of elderly individuals from the community. Methods: This cross-sectional study included 1016 subjects aged 70 (50% women) from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). The invasive technique forearm plethysmography with intra-arterial infusions of acetylcholine and sodium nitroprusside was used for estimation of endothelial dependent vasodilatation (EDV) and endothelial independent vasodilatation (EIDV), respectively, in resistance arteries, and the non-invasive technique ultrasound assessed flow mediated vasodilation (FMD) in conduit arteries. The aortic augmentation index (AoAI), a surrogate measure of arterial stiffness, was evaluated by pulse wave analysis. Associations of vascular function, arterial stiffness and blood pressure with leptin were explored. Results: In sex-adjusted models, high levels of leptin were inversely associated with EDV and EIDV. These associations remained after stratification for sex, traditional risk factors of CVD and insulin resistance, but were attenuated after taking a measure of obesity (body mass index) into account. In addition, leptin associated with arterial stiffness and systolic and diastolic blood pressure. Conclusion: Hyperleptinemia associated inversely with vasodilatation in resistance arteries. Furthermore, hyperleptinemia associated with arterial stiffness and hypertension. These associations were attenuated after adjusting for body mass index suggesting that leptin may be the mediator between obesity and impaired vascular function.

  • 24.
    Hagström, Emil
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ahlström, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Uppsala Clinical Research Center (UCR).
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Parathyroid hormone and calcium are independently associated with subclinical vascular disease in a community-based cohort2015In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 238, no 2, p. 420-426Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    Diseases with abnormal levels of parathyroid hormone (PTH) and calcium, such as primary and secondary hyperparathyroidism, are associated with an increased risk of cardiovascular morbidity and mortality. However, there is paucity on the association between calcium, PTH and abnormalities in the vascular system in the general population.

    METHODS:

    In the PIVUS study (Prospective Investigation of the Vasculature in Uppsala Seniors), a community based cohort of 70-year old men and women (n = 1016), the associations between s-calcium, p-PTH and endothelial function, arterial stiffness and blood pressures were investigated, adjusting for cardiovascular risk factors and mineral metabolism.

    RESULTS:

    In multivariable linear regression models 1 SD increase in calcium was associated with 1.1 units decrease in the stroke volume/pulse pressure ratio and 0.06 decrease in common carotid artery distensibility (p < 0.001) indicative of increased arterial stiffness. Further, calcium was associated with increasing calculated central pulse pressure with 1.3 mmHg elevation per 1 SD increase in calcium (p < 0.05). 1 SD increase in PTH was associated with 1.9 and 1.0 mmHg increase in intra-arterially measured brachial artery systolic and diastolic blood pressures, respectively (p < 0.01), as well as 1.6 and 0.9 mmHg increase in calculated central systolic and diastolic blood pressures (p < 0.05). PTH was not associated with arterial stiffness, endothelial function or pulse pressure.

    CONCLUSION:

    In a large community-based sample of elderly, calcium was independently associated with increased arterial stiffness, and PTH independently to intra-arterial peripheral and calculated central blood pressures. The findings indicate a possible link between the vasculature and mineral metabolism.

  • 25.
    Hansen, Tomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Söderberg, S.
    Hulthe, J.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Visceral adipose tissue, adiponectin levels and insulin resistance are related to atherosclerosis as assessed by whole-body magnetic resonance angiography in an elderly population2009In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 205, no 1, p. 163-167Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The principal aim of this study was to determine whether the amount of visceral adipose tissue (VAT) is more related than subcutaneous adipose tissue (SAT) to atherosclerosis assessed by whole-body MRA (WBMRA). A further objective was to investigate whether traditional risk factors, inflammation, or adipokines could explain the hypothesized relationship between VAT and atherosclerosis. METHODS: Men and women aged 70 were recruited from the general population into the Prospective Investigation of The Vasculature in Uppsala Seniors (PIVUS) and 306 of them underwent WBMRA in a clinical 1.5-T scanner. The arterial tree was assessed for degree of stenosis or occlusion and a total atherosclerotic score (TAS) was established. Information on risk factors and BMI and on SAT and VAT, segmented on an axial MR scan was collected. Adiponectin, leptin, and high sensitive C-reactive protein (hsCRP) were measured in serum. HOMA index was used as a marker of insulin resistance. RESULTS: VAT was related to TAS independently of gender, total obesity (BMI), amount of SAT, hsCRP and also to the traditional risk factors included in the Framingham risk score (FRS) in an elderly population. Adiponectin or the HOMA insulin resistance, but not leptin or VAT, together with FRS was significantly related to TAS in a multiple censored regression model. CONCLUSION: Adiponectin attenuated the relationship between VAT and TAS, suggesting that adiponectin and insulin resistance is an important link between visceral adiposity and atherosclerosis.

  • 26.
    Hansen, Tomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Wanhainen, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Vascular Surgery.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lymph nodes as a potential pitfall in carotid plaque imaging with FDG-PET/CT2011In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 215, no 1, p. 247-248Article in journal (Refereed)
  • 27. Harrison, Seamus C.
    et al.
    Zabaneh, Delilah
    Asselbergs, Folkert W.
    Drenos, Fotios
    Jones, Gregory T.
    Shah, Sonia
    Gertow, Karl
    Sennblad, Bengt
    Strawbridge, Rona J.
    Gigante, Bruna
    Holewijn, Suzanne
    De Graaf, Jacqueline
    Vermeulen, Sita
    Folkersen, Lasse
    van Rij, Andre M.
    Baldassarre, Damiano
    Veglia, Fabrizio
    Talmud, Philippa J.
    Deanfield, John E.
    Agu, Obi
    Kivimaki, Mika
    Kumari, Meena
    Bown, Matthew J.
    Nyyssonen, Kristiina
    Rauramaa, Rainer
    Smit, Andries J.
    Franco-Cereceda, Anders
    Giral, Philippe
    Mannarino, Elmo
    Silveira, Angela
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    de Borst, Gert J.
    van der Graaf, Yolanda
    de Faire, Ulf
    Baas, Annette F.
    Blankensteijn, Jan D.
    Wareham, Nicholas J.
    Fowkes, Gerry
    Tzoulaki, Ionna
    Price, Jacqueline F.
    Tremoli, Elena
    Hingorani, Aroon D.
    Eriksson, Per
    Hamsten, Anders
    Humphries, Steve E.
    A gene-centric study of common carotid artery remodelling2013In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 226, no 2, p. 440-446Article in journal (Refereed)
    Abstract [en]

    Background: Expansive remodelling is the process of compensatory arterial enlargement in response to atherosclerotic stimuli. The genetic determinants of this process are poorly characterized. Methods: Genetic association analyses of inter-adventitial common carotid artery diameter (ICCAD) in the IMPROVE study (n = 3427) using the Illumina 200k Metabochip was performed. Single nucleotide polymorphisms (SNPs) that met array-wide significance were taken forward for analysis in three further studies (n = 5704), and tested for association with Abdominal Aortic Aneurysm (AAA). Results: rs3768445 on Chromosome 1q24.3, in a cluster of protein coding genes (DNM3, PIGC, C1orf105) was associated with larger ICCAD in the IMPROVE study. For each copy of the rare allele carried, ICCAD was on average 0.13 mm greater (95% CI 0.08-0.18 mm, P = 8.2 x 10(-8)). A proxy SNP (rs4916251, R-2 = 0.99) did not, however, show association with ICCAD in three follow-up studies (P for replication = 0.29). There was evidence of interaction between carotid intima-media thickness (CIMT) and rs4916251 on ICCAD in two of the cohorts studies suggesting that it plays a role in the remodelling response to atherosclerosis. In meta-analysis of 5 case-control studies pooling data from 5007 cases and 43,630 controls, rs4916251 was associated with presence of AAA 1.10, 95% CI 1.03-1.17, p = 2.8 x 10(-3), I-2 = 18.8, Q = 0.30). A proxy SNP, rs4916251 was also associated with increased expression of PIGC in aortic tissue, suggesting that this may the mechanism by which this locus affects vascular remodelling. Conclusions: Common variation at 1q24.3 is associated with expansive vascular remodelling and risk of AAA. These findings support a hypothesis that pathways involved in systemic vascular remodelling play a role in AAA development.

  • 28.
    Helmersson, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition Research.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Vessby, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition Research.
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition Research.
    Active smoking and a history of smoking are associated with enhanced prostaglandin F(2alpha), interleukin-6 and F(2)-isoprostane formation in elderly men2005In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 181, no 1, p. 201-207Article in journal (Refereed)
    Abstract [en]

    The underlying mechanisms by which smoking induces cardiovascular diseases are largely unknown. The effect of smoking status on the cyclooxygenase (COX)-mediated inflammatory indicator prostaglandin F(2alpha) (PGF(2alpha)) has never been studied. Associations of cytokines and antioxidants and smoking status, have shown conflicting results. Urinary 15-keto-dihydro-PGF(2alpha) (a major metabolite of PGF(2alpha)), serum interleukin-6 (IL-6) and high sensitivity C-reactive protein (hsCRP), serum amyloid protein A (SAA), urinary 8-iso-PGF(2alpha) (an F(2)-isoprostane, indicator of oxidative stress), and serum alpha-tocopherol were quantified in a population-based sample (n = 642) of 77-year old men without diabetes. Fifty-five men were current smokers and 391 former smokers. Inflammatory indicators were increased in current smokers (15-keto-dihydro-PGF(2alpha), P < 0.001; IL-6, P = 0.01) than non-smokers. 8-iso-PGF(2alpha) was increased (P < 0.01) and alpha-tocopherol reduced (P < 0.001) in current smokers. Further, former smokers had increased formation of 15-keto-dihydro-PGF(2alpha), IL-6 and 8-iso-PGF(2alpha) compared non-smokers. This is the first study to show that smokers have increased PGF(2alpha) formation, thus enhanced COX-mediated inflammation, in addition to elevated levels of cytokines and isoprostanes. Subclinical COX- and cytokine-mediated inflammation and oxidative stress are ongoing processes not only in active smokers but also in former smokers which may contribute to the accelerated atherosclerosis associated with smoking.

  • 29.
    Helmersson-Karlqvist, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Carlsson, Axel C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ingelsson, Erik
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Urinary neutrophil gelatinase-associated lipocalin (NGAL) is associated with mortality in a community-based cohort of older Swedish men2013In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 227, no 2, p. 408-413Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE

    Neutrophil gelatinase-associated lipocalin (NGAL) indicates tubular kidney damage, neutrophil activation and possibly atherogenesis, however the prospective association between urinary NGAL (u-NGAL) and cardiovascular death in the community is not known.

    METHODS

    This study evaluates the association between urinary and serum NGAL and mortality in a Swedish population of 597 men aged 78 years. During the study (median follow-up 8.1 years) 261 men died, 90 of cardiovascular causes.

    RESULTS

    U-NGAL was associated with increased all-cause and cardiovascular mortality (HR 2.0 for quartile 4 vs. quartile 1, 95% CI 1.0-4.0, P < 0.05) in Cox regression models independently of cardiovascular risk factors, CRP and cystatin C estimated glomerular filtration rate (eGFRCysC) but not urinary Albumin (u-Alb). A combination of low eGFRCysC (≤60 mL/min), high u-Alb (≥3 mg/mmol Cr) and high u-NGAL (≥1.19 μg/mmol Cr) was associated with a 9-fold increased cardiovascular mortality (P < 0.001) and a 3-fold increased all-cause mortality (P < 0.001). Serum NGAL was associated with increased all-cause mortality risk independent of other cardiovascular risk factors (HR 1.4 for quartile 4 vs.1, 95% CI 1.0-1.9, P < 0.05) but not after adjustment with CRP, eGFRCysC or u-Alb.

    CONCLUSION

    This community study is the first to show that the tubular kidney biomarker u-NGAL associated with increased cardiovascular and all-cause mortality independent of cardiovascular risk factors and glomerular filtration. Additional research is needed to evaluate the utility of NGAL in clinical practice.

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  • 30.
    Helmersson-Karlqvist, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Carlsson, Axel C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Härmä, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Increased urinary cystatin C indicated higher risk of cardiovascular death in a community cohort2014In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 234, no 1, p. 108-113Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Urinary cystatin C (u-CysC) is a new biomarker for acute tubular kidney dysfunction and may also indicate chronic tubular dysfunction. Chronic kidney disease is an important cardiovascular risk factor, however it is not known if u-CysC is a risk marker for cardiovascular death.

    METHODS: The association between u-CysC and cardiovascular mortality was investigated in a Swedish community-based cohort of 604 men aged 78 years. During follow-up (mean 6.7 years), 203 participants died, of which 90 due to cardiovascular causes.

    RESULTS: High u-CysC (>0.029 mg/mmol Cr) was associated with a more than 2-fold risk of cardiovascular death (multivariable hazard ratio for quintile 5 vs. 1: 2.5, 95% CI 1.2-5.2, P < 0.05) in Cox regression models independent of cardiovascular risk factors, glomerular filtration rate (eGFR) and urinary Albumin. Participants with low eGFR (≤60 mL/min), albuminuria (≥3 mg/mmol Cr) and high u-CysC (>0.029 mg/mmol Cr) combined had a significantly higher cardiovascular mortality risk compared to participants with one or two of these biomarkers normal (hazard ratio 15, 95% CI: 6.7-36, P < 0.001, compared to all three biomarkers normal).

    CONCLUSIONS: This study is the first to show that increased concentrations of the tubular kidney biomarker u-CysC indicated risk of cardiovascular death independently of other cardiovascular risk factors, glomerular filtration and albuminuria. Additional research is needed to further establish the usefulness of u-CysC in clinical practice.

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  • 31. Hoffmann, Christian J.
    et al.
    Hohberg, Margret
    Chlench, Sven
    Maroski, Julian
    Drab, Marek
    Siegel, Günter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Pries, Axel R.
    Zakrzewicz, Andreas
    Suppression of zinc finger protein 580 by high oxLDL/LDL-ratios is followed by enhanced expression of endothelial IL-82011In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 216, no 1, p. 103-108Article in journal (Refereed)
    Abstract [en]

    Objective: The Interleukin 8 (IL-8) response of endothelial cells to lipoproteins has well known implications for the development and progression of atherosclerosis. In this study we sought for the role of zinc finger protein 580 (ZNF580) in the endothelial IL-8 response to lipoproteins. Methods: In human umbilical vein endothelial cells (HUVEC) ZNF580 and IL-8 levels were examined by real-time-RT-PCR, immunoblotting and immunostaining or ELISA, respectively. Results: ZNF580 is located in the nucleus and regulated by LDL and HDL depending on the oxLDL/LDL-ratio but not by TNF alpha. IL-8 expression profiles are inversely influenced by the oxLDL/LDL-ratio, both in vitro and in vivo. Knock down of ZNF580 enhances the expression and release of IL-8 and increases monocyte arrest under flow conditions in vitro. Conclusions: ZNF580 is a novel factor in the lipoprotein-dependent regulation of IL-8 and monocyte arrest. Therefore it may be a new potential target for intervention in atherosclerosis.

  • 32. Holme, Ingar
    et al.
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jardine, Alan
    Holdaas, Halvard
    Comparison of predictive ability of lipoprotein components to that of traditional risk factors of coronary events in renal transplant recipients2010In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 208, no 1, p. 234-239Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Risk factors for major adverse coronary events (MACE) in renal transplant recipients are often different from those of non-transplanted populations. We compared the predictive power of lipoprotein components (LC) to that of more traditional risk factors such as serum creatinine, diabetes and inflammation measured by C-reactive protein (CRP) in the assessment of lescol in renal transplantation (ALERT) trial population. METHODS: From the 2102 randomized patients in ALERT we selected 1734 patients with a complete set of risk and adjustment factors used in the study. Cox regression analysis was used to estimate relationships between baseline values of risk factors and first occurrence of MACE. Chi square statistics, receiver operating characteristics (ROC) and net reclassification improvement (NRI) were used to compare the information value of different risk factors. RESULTS: Atherogenic LC and especially non-high density cholesterol (nHDL-C) were as predictive as creatinine and nHDL-C was about as predictive as diabetes. CRP, body mass index, hypertension and glucose had less prediction ability than nHDL-C. The rank order of prediction was the same in the two treatment groups. By regression modelling the actual MACE risk reduction from 6 weeks onwards was well predicted from the difference in LC at 6 week. CONCLUSION: LC and especially nHDL-C predicted MACE at least as good as creatinine. Diabetes was about equally good as nHDL-C to predict MACE occurrence. Inflammation had less prediction ability than the other factors. Treated levels of atherogenic LC predicted MACE risk reduction well.

  • 33. Holmlund, A.
    et al.
    Hulthe, J.
    Millgård, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sarabi, Mahziar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kahan, Thomas
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Soluble intercellular adhesion molecule-1 is related to endothelial vasodilatory function in healthy individuals2002In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 165, no 2, p. 271-276Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate the associations between markers of systemic and vascular inflammation, and indicators of vascular morphology and function. METHODS: In 59 apparently healthy individuals, we measured serum levels of highly sensitive C-reactive protein (hsCRP), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. Endothelium-dependent (EDV) and -independent (EIDV) vasodilatation was evaluated in the forearm by venous occlusion plethysmography and local infusions of methacholine and sodium nitroprussid. Endothelial function index (EFI) was expressed as the EDV/EIDV ratio. The intima-media thickness (IMT) of the common carotid artery was investigated with ultrasound (far wall). RESULTS: EFI was inversely related only to ICAM-1 (r=-0.31, P<0.02) by univariate analysis. This association remained significant after adjustment for age, sex, blood pressure, smoking and serum cholesterol. EFI did not relate to hsCRP, VCAM-1 or E-selectin. Neither hsCRP, nor the adhesion molecules were significantly related to carotid artery IMT. CONCLUSION: ICAM-1 was related to endothelial vasodilatory function, but not to IMT, suggesting that endothelial inflammatory activation is related to an impaired vascular relaxation in apparently healthy individuals.

  • 34.
    Holmlund, Anders
    et al.
    Uppsala Univ Reg Gavleborg, Cty Hosp Gavle, Dept Periodontol, Ctr Res & Dev, Gavle, Sweden..
    Lampa, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Oral health and cardiovascular disease risk in a cohort of periodontitis patients2017In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 262, p. 101-106Article in journal (Refereed)
    Abstract [en]

    Background and aims: The aim of this study was to determine whether oral health is uniformly associated with three different cardiovascular diseases (CVDs), including myocardial infarction (MI), stroke, and heart failure (HF), which has not been studied previously. Methods: A full mouth investigation was performed in 8999 individuals referred to a specialized periodontology clinic between 1979 and 2012. The number of deepened pockets (NDP), number of teeth (NT), and bleeding on probing (BOP) were investigated. Incident CVD diagnosis was obtained from the Swedish cause of death and the hospital discharge registers. Results: During a median follow-up time of 15.8 years (153,103 person years at risk), 1338 incident cases of fatal/non-fatal CVD occurred (672 fatal/non-fatal MI, 545 stroke and 302 HF). When NT, BOP and NDP were all included in the same model with age, sex, smoking, calendar time, and education level, NT and NDP, but not BOP, were significantly related to future CVD (combined end-point, p=0.0003 for NT and p =0.007 for NDP). In similar analyses of 3 separate CVD outcomes, NT was significantly related to MI, with an incidence rate ratio (IRR) for a given interquartile range change of 0.90 (95% CI 0.82=0.99) and to HF, with an IRR of 0.87 (95% CI 0.77-0.99). However, NT was not significantly related to stroke. BOP and NDP were not significantly related to any of the three separate CVD outcomes. Conclusion: Oral health, mainly represented by NT, was related to incident MI and HF, but not to incident stroke. Therefore, oral health does not seem to relate to all major CV disorders in a similar fashion.

  • 35.
    Huang, Biying
    et al.
    Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, 300 Pasteur Dr, Stanford, CA 94304 USA.;Karolinska Inst, Dept Med, S-17176 Stockholm, Sweden..
    Svensson, Per
    Karolinska Inst, Dept Med, S-17176 Stockholm, Sweden..
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Dalarna Univ, Sch Hlth & Social Studies, S-79188 Falun, Sweden..
    Sundstrom, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, 300 Pasteur Dr, Stanford, CA 94304 USA.
    Effects of cigarette smoking on cardiovascular-related protein profiles in two community-based cohort studies2016In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 254, p. 52-58Article in journal (Refereed)
    Abstract [en]

    Background and aims: Cardiovascular diseases account for the largest fraction of smoking-induced deaths. Studies of smoking in relation to cardiovascular-related protein markers can provide novel insights into the biological effects of smoking. We investigated the associations between cigarette smoking and 80 protein markers known to be related to cardiovascular diseases in two community-based cohorts, the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS, n = 969, 50% women, all aged 70 years) and the Uppsala Longitudinal Study of Adult Men (ULSAM, n = 717, all men aged 77 years). Methods: Smoking status was self-reported and defined as current smoker, former smoker or never-smoker. Levels of the 80 proteins were measured using the proximity extension assay, a novel PCR-based proteomics technique. Results: We found 30 proteins to be significantly associated with current cigarette smoking in PIVUS (FDR<5%); and ten were replicated in ULSAM (p<0.05). Matrix metalloproteinase-12 (MMP-12), growth/differentiation factor 15 (GDF-15), urokinase plasminogen activator surface receptor (uPAR), TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2), lectin-like oxidized LDL receptor 1 (LOX-1), hepatocyte growth factor (HGF), matrix metalloproteinase-10 (MMP-10) and matrix metalloproteinase-1 (MMP-1) were positively associated, while endothelial cell-specific molecule 1 (ESM-1) and interleukin-27 subunit alpha (IL27-A) showed inverse associations. All of them remained significant in a subset of individuals without manifest cardiovascular disease. Conclusions: The findings of the present study suggest that cigarette smoking may interfere with several essential parts of the atherosclerosis process, as evidenced by associations with protein markers representing endothelial dysfunction, inflammation, neointimal formation, foam cell formation and plaque instability. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

  • 36.
    Ingelsson, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Vasan, Ramachandran S.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Blomhoff, Rune
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Circulating retinol-binding protein 4, cardiovascular risk factors and prevalent cardiovascular disease in elderly2009In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 206, no 1, p. 239-244Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Our aim was to examine relations of serum retinol-binding protein 4 (RBP4) to cardiovascular risk factors, and prevalent metabolic syndrome (MetS) and cardiovascular disease (CVD) in a large community-based sample of elderly. METHODS: We evaluated cross-sectional relations of serum RBP4 to cardiovascular risk factors including anthropometrical measures, blood pressure, lipid measures, fasting glucose and insulin, body fat distribution including truncal fat by dual-energy x-ray absorptiometry (DXA), homeostasis model assessment insulin resistance (HOMA-IR) and prevalent MetS in one thousand eight 70-year old participants (50% women) of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), and in five hundred seven 82-year old men from Uppsala Longitudinal Study of Adult Men (ULSAM). In ULSAM, we also examined associations with prevalent CVD. RESULTS: RBP4 concentrations were positively correlated with serum triglycerides (r=0.30; P<0.0001 in both samples), whereas correlations with body mass index (BMI), waist circumference, sagittal abdominal diameter, total and truncal fat mass, total cholesterol, fasting glucose and HOMA-IR were weak. In multivariable-adjusted models, RBP-4 was associated with MetS (odds ratio (OR), 1.16 and 1.33; 95% confidence interval (CI), 0.99-1.37 and 1.05-1.67 per 1-standard deviation (SD) increase in PIVUS and ULSAM, respectively), and prior cerebrovascular disease (OR, 1.37; 95% CI, 1.00-1.88 per 1-SD increase in ULSAM), but not with prior myocardial infarction. CONCLUSION: In elderly, RBP4 concentrations were associated with MetS and its components in both sexes, and prior cerebrovascular disease in men. These findings are consistent with the hypothesis that circulating RBP4 could be a marker of metabolic complications and possibly also atherosclerosis and overt CVD.

  • 37.
    Ingelsson, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Polymorphisms in the estrogen receptor alpha gene and endothelial function in resistance and conduit arteries in the elderly2008In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 199, no 1, p. 162-171Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Prior evidence suggests an important role for estrogen in the regulation of endothelium-dependent vasodilation, but the mechanisms modulating this are not known. Our aim was to examine the relations of single nucleotide polymorphisms (SNPs) in the estrogen receptor alpha gene (ESR1) to endothelium-dependent vasodilation.

    METHODS:

    We evaluated 959 70-year-old participants (51% men) of the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study, using invasive forearm technique with intra-brachial infusion of acetylcholine (EDV; reflecting vasodilation in resistance arteries), and brachial artery ultrasound to assess flow-mediated vasodilation (FMD; reflecting vasodilation in conduit arteries). We genotyped 25 common SNPs in the ESR1 gene, and related them to EDV and FMD using multivariable linear regression, adjusting for sex and other potential confounders, such as major cardiovascular risk factors and medications. Haplotypes were estimated using the PHASE software.

    RESULTS:

    We observed an association between rs1709183 in the ESR1 gene and EDV (nominal P=0.0012), with a lower EDV in carriers of the minor allele (C). This association remained significant after adjustment for multiple testing (empirical P=0.031, obtained using bootstrap re-sampling). Two ESR1 haplotypes in the block containing rs1709183 were associated with EDV (individual haplotype P=0.0015 and P=0.025); the directions of effect were consistent with individual SNP analyses. FMD was not associated with any of the ESR1 SNPs.

    CONCLUSIONS:

    In our community-based study of elderly, a polymorphism in the estrogen receptor alpha gene was associated with endothelium-dependent vasodilation in resistance, but not conduit arteries. Our findings should stimulate further exploration in other settings.

  • 38.
    Larsson, Susanna C.
    et al.
    Karolinska Inst, Natl Inst Environm Med, Div Nutr Epidemiol, SE-17177 Stockholm, Sweden..
    Akesson, Agneta
    Karolinska Inst, Natl Inst Environm Med, Div Nutr Epidemiol, SE-17177 Stockholm, Sweden..
    Wolk, Alicja
    Karolinska Inst, Natl Inst Environm Med, Div Nutr Epidemiol, SE-17177 Stockholm, Sweden..
    Overall diet quality and risk of stroke: A prospective cohort study in women2014In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 233, no 1, p. 27-29Article in journal (Refereed)
    Abstract [en]

    Data on overall diet quality in relation to stroke risk are sparse. We examined the association between consumption of a diversity of recommended and non-recommended foods and risk of stroke. The study population comprised 33 911 Swedish women who had completed a questionnaire in 1997 and were free from cardiovascular disease and cancer. We calculated a Recommended Food Score (RFS) based on 25 healthy food items and a Non-Recommended Food Score (NRFS), consisting of 21 food items considered less healthy. Stroke cases were identified through linkage to Swedish registers. During 11 years of follow-up, we ascertained 1687 stroke cases. The multivariable relative risks of stroke for the highest versus lowest quintile were 0.80 (95% CI, 0.67-0.95) for RFS and 1.22 (95% CI, 1.02-1.46) for NRFS. In conclusion, these findings suggest that a diet including a variety of healthy foods and few less healthy foods may reduce stroke risk. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

  • 39.
    Larsson, Susanna C.
    et al.
    Karolinska Inst, Natl Inst Environm Med, Div Nutr Epidemiol, SE-17177 Stockholm, Sweden..
    Virtamo, Jarmo
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland..
    Wolk, Alicja
    Karolinska Inst, Natl Inst Environm Med, Div Nutr Epidemiol, SE-17177 Stockholm, Sweden..
    Dietary fats and dietary cholesterol and risk of stroke in women2012In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 221, no 1, p. 282-286Article in journal (Refereed)
    Abstract [en]

    Background: Whether intakes of dietary fat and cholesterol are associated with risk of stroke remain unclear. We examined the associations between intakes of total fat, specific types of fat, and cholesterol and risk of stroke in a prospective cohort of women. Methods: The study population consisted of 34,670 women, aged 49-83 years, in the Swedish Mammography Cohort who were free of cardiovascular disease and completed a food-frequency questionnaire in 1997. Cox proportional hazard regression models were used to estimate relative risks (RR) with 95% confidence intervals (CI). Results: During a mean follow-up of 10.4 years, we ascertained 1680 stroke events, including 1310 cerebral infarctions, 233 hemorrhagic strokes, and 137 unspecified strokes. After adjustment for other stroke risk factors, intake of long-chain omega-3 polyunsaturated fatty acids (PUFA) was inversely associated with risk of total stroke. The multivariable RR of total stroke for the highest compared with the lowest quintile of long-chain omega-3 PUFA intake was 0.84 (95% CI, 0.72-0.99; P for trend = 0.04). Dietary cholesterol was positively associated with risk of total stroke (highest versus lowest quintile: RR = 1.20; 95% CI, 1.00-1.44; P for trend = 0.01) and cerebral infarction (corresponding RR = 1.29; 95% CI, 1.05-1.58; P for trend = 0.004). Total fat, saturated fat, monounsaturated fat, polyunsaturated fat, alpha-linolenic acid, and omega-6 PUFA intakes were not associated with stroke. Conclusions: These findings suggest that intake of long-chain omega-3 PUFAs is inversely associated with risk of stroke, whereas dietary cholesterol is positively associated with risk. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

  • 40.
    Larsson, Susanna C.
    et al.
    Karolinska Inst, Natl Inst Environm Med, Div Nutr Epidemiol, S-17177 Stockholm, Sweden..
    Virtamo, Jarmo
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland..
    Wolk, Alicja
    Karolinska Inst, Natl Inst Environm Med, Div Nutr Epidemiol, S-17177 Stockholm, Sweden..
    Dietary protein intake and risk of stroke in women2012In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 224, no 1, p. 247-251Article in journal (Refereed)
    Abstract [en]

    Background: A high protein intake may reduce the risk of stroke but epidemiologic data on protein intake in relation to stroke risk are limited and inconsistent. Our objective was to test the hypothesis that protein intake would be inversely associated with risk of stroke. Methods and results: We conducted a population-based prospective cohort study consisting of 34,670 Swedish women who were free of cardiovascular disease and cancer in 1997. Diet was assessed with a food-frequency questionnaire. Incident cases of stroke were ascertained from the Swedish Hospital Discharge Registry. We estimated relative risks (RR) with 95% confidence intervals (CI) using Cox proportional hazard regression model. During 10.4 years of follow-up, 1680 stroke events were identified, including 1310 cerebral infarctions, 154 intracerebral hemorrhages, 79 subarachnoid hemorrhages, and 137 unspecified strokes. Intake of total and animal protein, but not vegetable protein, was statistically significantly inversely associated with risk of total stroke and cerebral infarction after adjustment for other risk factors for stroke. The multivariable RRs of total stroke for the highest versus lowest quintile of intake were 0.74 (95% CI: 0.61, 0.91; P for trend = 0.006) for total protein and 0.71 (95% CI: 0.57, 0.88; P for trend = 0.01) for animal protein. The associations were stronger in women with a history of hypertension (RR of total stroke = 0.56; 95% CI: 0.40, 0.78 for highest versus lowest quintile of total protein). Conclusion: These findings suggest that dietary protein intake is inversely associated with risk of stroke in women with hypertension. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

  • 41.
    Larsson, Susanna C.
    et al.
    Karolinska Inst, Natl Inst Environm Med, Div Nutr Epidemiol, SE-17177 Stockholm, Sweden..
    Virtamo, Jarmo
    Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland..
    Wolk, Alicja
    Karolinska Inst, Natl Inst Environm Med, Div Nutr Epidemiol, SE-17177 Stockholm, Sweden..
    Total and specific fruit and vegetable consumption and risk of stroke: A prospective study2013In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 227, no 1, p. 147-152Article in journal (Refereed)
    Abstract [en]

    Background: Fruit and vegetables is a heterogeneous food group with different content of dietary fiber, vitamins, minerals, carotenoids, and bioactive phytochemicals. Our objective was to examine the relation between specific consumption of fruit and vegetable subgroups and stroke risk in a cohort of Swedish women and men. Methods and results: We prospectively followed 74,961 participants (34,670 women and 40,291 men) who had completed a food frequency questionnaire in the autumn of 1997 and were free from stroke, coronary heart disease, and cancer at baseline. Diagnoses of stroke in the cohort during follow-up were ascertained from the Swedish Hospital Discharge Registry. A total of 4089 stroke cases, including 3159 cerebral infarctions, 435 intracerebral hemorrhages, 148 subarachnoid hemorrhages, and 347 unspecified strokes, were ascertained during 10.2 years of follow-up. The multivariable relative risk (RR) of total stroke for the highest vs. lowest category of total fruit and vegetable consumption was 0.87 (95% confidence interval [CI] 0.78-0.97; P for trend = 0.01). The association was confined to individuals without hypertension (corresponding RR, 0.81; 95% CI, 0.71-0.93; P for trend = 0.01). Among individual fruits and vegetable subgroups, inverse associations with total stroke were observed for apples/pears (RR, 0.89; 95% CI, 0.80-0.98; P for trend = 0.02) and green leafy vegetables (RR, 0.92; 95% CI, 0.81-1.04; P for trend = 0.03). Conclusion: This study shows an inverse association of fruit and vegetable consumption with stroke risk. Particularly consumption of apples and pears and green leafy vegetables was inversely associated with stroke. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

  • 42.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Arterial compliance influences the measurement of flow-mediated vasodilation, but not acetylcholine-mediated forearm blood flow. The prospective investigation of the vasculature in uppsala seniors (PIVUS) study2007In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 190, no 1, p. 212-215Article in journal (Refereed)
    Abstract [en]

    Objectives: Flow-mediated vasodilation (FMD) is low even in healthy elderly and therefore relations between FMD and cardiovascular risk factors might be hard to evaluate in the elderly. Using data from the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study, we investigated if a reduced arterial distensibility could influence FMD measurements. Methods: In the population-based PIVUS study (1016 subjects aged 70), assessments of arterial distensibility by ultrasound in the carotid artery (CCA) and FMD were performed. Endothelium-dependent vasodilation was also evaluated with the invasive forearm technique with acetylcholine (EDV) and by pulse wave analysis following terbutaline injection. A poor CCA distensibility was defined as <25th percentile in the healthy part of the population (n = 131). Results: FMD was significantly related to the Framingham risk score only in those with a good CCA distensibility (r = -0.16, p = 0.0081 versus r = -0.06, p = 0.17 in those with a poor CCA distensibility, p = 0.0001 for difference). In contrast, the relationship between EDV and coronary risk was not affected by CCA distensibility (r = -0.11, p = 0.018 versus r = -0.13, p = 0.027). Conclusions: A reduced CCA distensibility could in part explain the low FMD values in the elderly. FMD correlated to the Framingham risk score only in those with a good CCA distensibility, exemplifying a limitation of the use of FMD in elderly populations. On the contrary, EDV was not affected by arterial stiffness.

  • 43.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Effect of new statin treatment on carotid artery intima-media thickness: A real-life observational study over 10 years2020In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 306, p. 6-10Article in journal (Refereed)
    Abstract [en]

    Background and aims: Randomized clinical trials (RCT) have shown statin treatment to slow down the increase in carotid artery intima-media thickness (IMT) seen with ageing. However, those RCTs usually have a limited follow-up (1-3 years). Here an observational study was used to investigate the real-life effect of new statin treatment over a 10-year follow-up. Methods: In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, 954 individuals all aged 70 years at baseline were investigated regarding carotid artery IMT three times during 10 years (n = 771 at age 75, and n = 591 at age 80). Results: At age 70, 503 subjects were statin-naive and did not receive statin during the 10-year follow-up period (the never-statin group), while 197 subjects were statin-naive but received statins during the follow-up period (the received-statin group). Low-density lipoprotein (LDL)-cholesterol increased over time in the never-statin group (+0.1 mmol/l, p = 0.0012), but decreased in the group receiving statin treatment (-1.1 mmol/l, p < 0.0001). The never-statin group increased significantly in IMT over the 10 years (+0.07 mm, p < 0.0001), while the numerical increase seen in the received-statin group was not significant (+0.02 mm, p = 0.22) A significant difference in the change in IMT over time was seen between the received-statin group and the never-statin group (p < 0.0001 for interaction between time and group, adjusted for a propensity score). Conclusions: This real-life observational study showed that new statin treatment reduced the increase in IMT seen over 10 years compared to subjects not treated with statins.

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  • 44.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Endothelium-dependent vasodilation, insulin resistance and the metabolic syndrome in an elderly cohort: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study2008In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 196, no 2, p. 795-802Article in journal (Refereed)
    Abstract [en]

    Background: Only a few previous studies have investigated endothelium-dependent vasodilation in the metabolic syndrome (MetS). In the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study, different techniques to assess vasodilation in conduit and resistance arteries were evaluated in relation to the MetS and insulin resistance.

    Methods: In this population-based study, 1016 subjects aged 70 were evaluated by the invasive forearm technique with acetylcholine (EDV), brachial artery ultrasound to assess flow-mediated vasodilation (FMD) and pulse wave analysis with a beta-2 receptor agonist challenge, terbutaline.

    Results: EDV was lower in subjects with the MetS (NECP/ATP III-criteria, prevalence 23%) compared to those without (p < 0.0001), and declined with increasing number of MetS criteria (p < 0.0001), after adjustment for coronary heart disease, stroke and cardiovascular medication. Also a reduced pulse wave response (p=0.015), but not FMD (p=0.64), was seen in those with the MetS. EDV and the pulse wave response, but not FMD, were inversely related to insulin resistance evaluated by the HOMA index. Also endothelium-independent vasodilation (EIDV) induced by intra-brachial infusion of sodium nitroprusside was impaired in subjects with MetS and in insulin resistance.

    Conclusions: Vasodilation evaluated with the invasive forearm technique and pulse wave analysis with a beta-2 agonist, but not FMD, was reduced in elderly subjects with the MetS and was related to insulin resistance. Also EIDV showed the same pattern, suggesting a general deterioration in vasoreactivity mainly in resistance arteries in elderly subjects with the MetS.

  • 45.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Flow-mediated vasodilation over five years in the general elderly population and its relation to cardiovascular risk factors2014In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 237, no 2, p. 666-670Article in journal (Refereed)
    Abstract [en]

    Background: Flow-mediated vasodilation (FMD) has previously been shown to be related to cardiovascular risk factors in cross-sectional studies. The present study aims to investigate how FMD changes over time, and determine whether this change is paralleled by changes in cardiovascular risk factors. Methods: Of the participants in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, 750 individuals had measurements made of FMD in the brachial artery both at the ages of 70 and 75 years. In addition, the change over the 5 years in carotid artery intima-media thickness (IMT) was monitored, as well as traditional cardiovascular risk factors. Results: While no significant change in FMD occurred during the 5-year period (+0.1%, p = 0.53), large changes could be seen at the individual level. The Framingham risk score (excluding the age-variable) increased during the follow-up period (+0.54, p < 0.001). This change was inversely related to the individual change in FMD (beta -0.15, 95% CI -0.29 to 0.0059, p = 0.041). Of the eight individual CV risk factors tested, the change in FMD was only related to the change in LDL-cholesterol (inversely, p = 0.0028). The change in FMD was not related to the change in IMT seen over the 5-year period (p = 0.41). Conclusion: While no change was seen in the mean FMD over a five-year period in elderly subjects attending both examinations despite ageing and a change in several risk factors, the individual change was mainly related to the change in LDL-cholesterol, further emphasizing the important role of lipids to determine vasoreactivity.

  • 46.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    The metabolomic profile of carotid artery intima-media thickness and echogenicity2021In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 335, p. 142-147Article in journal (Refereed)
    Abstract [en]

    Background and aims: Nuclear magnetic resonance (NMR)-based metabolomics analyses have defined the lipoprotein profile of carotid artery intima-media thickness (IMT) in detail. In this study, the aim was to use multi-modal mass spectroscopy (MS) to relate multiple metabolites from different chemical classes to IMT and also to the echogenicity of the intima-media complex (IM-GSM).

    Method: Multi-modal MS with 791 annotated non-xenobiotic metabolites was measured in two different population-based samples (PIVUS at age 80, n = 586 and POEM at age 50, n = 495) in which also carotid IMT and IM-GSM have been assessed by ultrasound.

    Results: Four metabolites were significantly (false discovery rate, FDR<0.05) related to IMT in a meta-analysis of POEM and PIVUS. The top finding was adenosine 3',5'-cyclic monophosphate (cAMP), being inversely related to IMT. Fifty metabolites were significantly related to IM-GSM in a meta-analysis of POEM and PIVUS. The top findings were branched-chained amino acids (BCAA), fructosyllysine, metabolonic lactone sulfate, a ceramide together with some sphingomyelins and phosphatidylcholines. All these top findings represented inverse relationships. Two metabolites identified by lasso regression in PIVUS increased discrimination of an echolucent IM-GSM by 3.3% in POEM compared to traditional cardiovascular risk factors (p = 0.020).

    Conclusions: IMT, especially IM-GSM, was related to multiple metabolites from different chemical classes. Although such metabolites improved the discrimination of an echolucent IM-GSM, it remains to be investigated if any of those metabolites are involved in the pathogenesis of carotid arteriopathy.

  • 47.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Vasodilation in resistance arteries is related to the apolipoprotein B/A1 ratio in the elderly: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study2007In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 190, no 2, p. 378-384Article in journal (Refereed)
    Abstract [en]

    Background: Recent studies have shown the apolipoprotein B to apolipoprotein A1 ratio (apoB/A1) to be superior to LDL-cholesterol measurements to predict cardiovascular events. The present study aims to relate apoB/A1 to endothelium-dependent vasodilation, an early marker of atherosclerosis, in the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study. Methods and results: In this population-based study, 1016 subjects aged 70 years were evaluated by the invasive forearm technique with acetylcholine (EDV), brachial artery ultrasound to assess flow-mediated vasodilation (FMD) and pulse wave analysis with a beta-2 receptor agonist challenge, terbutaline. EDV and the pulse wave response, but not FMD, were related to apoB/A1 levels (r = -0.11, p = 0.0038 for EDV, r = -0.16, p < 0.0001 for the pulse wave analysis and r = 0.01, p = 0.65 for FMD). Neither LDL-cholesterol, nor non-HDL-cholesterol, was significantly related to the measurements of endothelium-dependent vasodilation. Also endothelium-independent vasodilation (EIDV) evaluated by the invasive forearm technique with sodium nitroprusside was related to apoB/A1 levels (r = -0.12, p < 0.0016). Conclusion: The apoB/A1 levels, but not LDL-cholesterol, were inversely related to endothelium-dependent vasodilation evaluated by EDV and pulse wave analysis, but not by FMD. Also EIDV showed the same pattern, suggesting a general deterioration in vasoreactivity mainly in resistance arteries in elderly subjects with high apoB/A1 levels.

  • 48.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Andersson, Jessika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rönn, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gustavsson, Tomas
    The echogenecity of the intima-media complex in the common carotid artery is closely related to the echogenecity in plaques.2007In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 195, no 2, p. 411-414Article in journal (Refereed)
    Abstract [en]

    Objective

    The echogenecity measured by ultrasound of atherosclerotic plaques is related to future cardiovascular events. The aim of the present study is to relate the grey scale median of the intima–media complex (IM-GSM) of the common carotid artery (CCA) to the echogenecity of carotid plaques.

    Material and results

    In the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study, a population-based study of 1016 subjects aged 70, carotid artery intima–media thickness (IMT) and IM-GSM were evaluated by ultrasound and computerized analysis. Also the occurrence of plaque and plaque GSM were measured. The echogenecity of the plaques was also visually estimated by the Gray-Weale classification.

    In subjects with a carotid plaque (n=582), IM-GSM in CCA was correlated to GSM in the plaque (r=0.60, p<0.0001) independently of plaque size and IMT. IM-GSM in CCA was also correlated to the visually estimated echogenecity (p<0.0001 for trend).

    Conclusion

    IM-GSM of the CCA is closely related to the echogenecity in overt carotid plaques, regardless if evaluated by the same computerized method or evaluated visually. This finding suggests that IM-GSM of CCA could be an important and easily measurable characteristic of the carotid artery wall that could be obtained in almost all subjects and not only those with an overt plaque.

  • 49.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Gigante, Bruna
    Karolinska Inst, Dept Med, Bruna Gigante Unit Cardiovasc Med, Huddinge, Sweden.
    Borne, Yan
    Lund Univ, Yan Borne Dept Clin Sci Malmo, Lund, Sweden.
    Mälarstig, Anders
    Karolinska Inst, Dept Med, Bruna Gigante Unit Cardiovasc Med, Huddinge, Sweden.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology. Univ New South Wales, George Inst Global Hlth, Sydney, NSW, Australia.
    Ärnlöv, Johan
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Family Med & Primary Care, Huddinge, Sweden;Dalarna Univ, Sch Hlth & Social Sci, Falun, Sweden.
    Ingelsson, Erik
    Stanford Univ, Stanford Diabet Res Ctr, Stanford Cardiovasc Inst, Dept Med,Div Cardiovasc Med, Stanford, CA 94305 USA.
    Baldassarre, Damiano
    Univ Milan, Dept Med Biotechnol & Translat Med, Milan, Italy;IRCCS, Ctr Cardiol Monzino, Milan, Italy.
    Tremoli, Elena
    IRCCS, Ctr Cardiol Monzino, Milan, Italy.
    Veglia, Fabrizio
    IRCCS, Ctr Cardiol Monzino, Milan, Italy.
    Hamsten, Anders
    Karolinska Inst, Dept Med, Bruna Gigante Unit Cardiovasc Med, Huddinge, Sweden.
    Orho-Melander, Marju
    Lund Univ, Yan Borne Dept Clin Sci Malmo, Lund, Sweden.
    Nilsson, Jan
    Lund Univ, Yan Borne Dept Clin Sci Malmo, Lund, Sweden.
    Melander, Olle
    Lund Univ, Yan Borne Dept Clin Sci Malmo, Lund, Sweden.
    Engström, Gunnar
    Lund Univ, Yan Borne Dept Clin Sci Malmo, Lund, Sweden.
    The plasma protein profile and cardiovascular risk differ between intima-media thickness of the common carotid artery and the bulb: A meta-analysis and a longitudinal evaluation2020In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 295, p. 25-30Article in journal (Refereed)
    Abstract [en]

    Background and aims: Genetic loci associated with CHD show different relationships with intima-media thickness in the common carotid artery (IMT-CCA) and in the bulb (IMT-bulb). We evaluated if IMT-CCA and IMT-bulb differ also with respect to circulating protein profiles and risk of incident atherosclerotic disease.

    Methods: In three Swedish cohorts (MDC, IMPROVE, PIVUS, total n > 7000), IMT-CCA and IMT-bulb were assessed by ultrasound at baseline, and 86 cardiovascular-related proteins were analyzed. In the PIVUS study only, IMT-CCA and IMT-bulb were investigated in relation to incident atherosclerotic disease over 10 years of follow-up.

    Results: In a meta-analysis of the analysis performed separately in the cohorts, three proteins, matrix metalloproteinase-12 (MMP-12), hepatocyte growth factor (HGF) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), were associated with IMT-CCA when adjusted for traditional cardiovascular risk factors. Five proteins were associated with IMT-bulb (MMP-12, growth/differentiation factor 15 (GDF-15), osteoprotegerin, growth hormone and renin). Following adjustment for cardiovascular risk factors, IMT-bulb was significantly more closely related to incident stroke or myocardial infarction (total number of cases, 111) than IMT-CCA in the PIVUS study (HR 1.51 for 1 SD, 95%CI 1.21-1.87, p < 0.001 vs HR 1.17, 95%CI 0.93-1.47, p = 0.16). MMP-12 levels were related to this combined end-point (HR 1.30, 95%CI 1.08-1.56, p = 0.0061).

    Conclusions: Elevated levels of MMP-12 were associated with both IMT-CCA and IMT-bulb, but other proteins were significantly related to IMT in only one of these locations. The finding that IMT-bulb was more closely related to incident atherosclerotic disease than IMT-CCA emphasizes a difference between these measurements of IMT.

  • 50.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Hulthe, Johannes
    von Below, Catrin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Vasodilation and visceral fat in elderly subjects: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study2007In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 194, no 2, p. e64-e71Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Although obesity has long been recognised as a cardiovascular risk factor, only in recent years has the role of visceral adipose tissue (VAT) been evaluated. In the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study, we related VAT and other obesity indices to endothelium-dependent vasodilation in both capacitance and resistance arteries. METHODS AND RESULTS: In this population-based study, 1016 subjects aged 70 were evaluated by the invasive forearm technique with acetylcholine (EDV) and brachial artery ultrasound to assess flow-mediated vasodilation (FMD). Intra-abdominal visceral (VAT) and subcutaneous adipose tissue (SAT) were determined by magnetic resonance imaging in a random sample of 287 subjects. EDV, but not FMD, was inversely related to VAT, SAT, BMI and the waist/hip ratio (r=-0.23, -0.16, -0.21 and -0.11, respectively, p=0.05-0.001 after adjustment for gender). In multiple regression analysis however, only VAT was an independent predictor of EDV. Similar results were obtained for endothelium-independent vasodilation (EIDV, infusion of sodium nitroprusside in the brachial artery). CONCLUSIONS: Both endothelium-dependent and independent vasodilation in the forearm resistance arteries, but not FMD in the brachial artery, was reduced in elderly subjects with increased intra-abdominal adipose tissue mass. This finding suggests deterioration in general vasoreactivity mainly in resistance arteries in elderly subjects with intra-abdominal obesity.

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