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  • 1.
    Akhter, Tansim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Larsson, Marita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Wikström, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Naessén, Tord
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Individual Artery Wall Layer Dimensions Indicate Increased Cardiovascular Risk in Previous Severe Preeclampsia: An investigation using non-invasive high-frequency ultrasound2013In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563Article in journal (Refereed)
    Abstract [en]

    Preeclampsia, especially severe preeclampsia, is associated with an increased risk of cardiovascular disease later in life. However, ultrasound assessments of the common carotid artery intima-media thickness (CCA-IMT) do not convincingly demonstrate this. The aim of this study was to assess whether the individual thickness of the CCA intima and media layers and calculation of intima/media (I/M) ratio indicate an increased cardiovascular risk in women with previous severe PE. The thicknesses of the CCA intima and media layers were obtained by non-invasive high-frequency ultrasound (22 MHz) (Collagenoson, Meudt, Germany) in 42 women with previous severe preeclampsia and 44 women with previous normal pregnancies. A thick intima, thin media and high I/M ratio are signs of a less healthy artery wall. Women with previous severe preeclampsia had a thicker mean CCA intima and a higher I/M ratio than women with previous normal pregnancies (both p < 0.0001). CCA-IMT did not differ significantly between the groups. In receiver operating characteristic (ROC) curve analysis, both intima thickness and I/M ratio clearly discriminated between women with and without previous severe preeclampsia [area under the curve (AUC) about 0.95], whereas CCA-IMT did not (AUC 0.52). Estimation of the individual CCA intima and media layers using high-frequency ultrasound and calculation of the I/M ratio clearly demonstrated the well known increased cardiovascular risk in women with previous severe preeclampsia, whereas CCA-IMT did not. This method appears preferable to measuring CCA-IMT for imaging arterial effects and the increased cardiovascular risk in women with a history of previous severe preeclampsia.

  • 2. Asayama, Kei
    et al.
    Thijs, Lutgarde
    Li, Yan
    Gu, Yu-Mei
    Hara, Azusa
    Liu, Yan-Ping
    Zhang, Zhenyu
    Wei, Fang-Fei
    Lujambio, Ines
    Mena, Luis J.
    Boggia, Jose
    Hansen, Tine W.
    Björklund-Bodegård, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nomura, Kyoko
    Ohkubo, Takayoshi
    Jeppesen, Jorgen
    Torp-Pedersen, Christian
    Dolan, Eamon
    Stolarz-Skrzypek, Katarzyna
    Malyutina, Sofia
    Casiglia, Edoardo
    Nikitin, Yuri
    Lind, Lars
    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, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Luzardo, Leonella
    Kawecka-Jaszcz, Kalina
    Sandoya, Edgardo
    Filipovsky, Jan
    Maestre, Gladys E.
    Wang, Jiguang
    Imai, Yutaka
    Franklin, Stanley S.
    O'Brien, Eoin
    Staessen, Jan A.
    Setting Thresholds to Varying Blood Pressure Monitoring Intervals Differentially Affects Risk Estimates Associated With White-Coat and Masked Hypertension in the Population2014In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 64, no 5, p. 935-942Article in journal (Refereed)
    Abstract [en]

    Outcome-driven recommendations about time intervals during which ambulatory blood pressure should be measured to diagnose white-coat or masked hypertension are lacking. We cross-classified 8237 untreated participants (mean age, 50.7 years; 48.4% women) enrolled in 12 population studies, using >= 140/>= 90, >= 130/>= 80, >= 135/>= 85, and >= 120/>= 70 mm Hg as hypertension thresholds for conventional, 24-hour, daytime, and nighttime blood pressure. White-coat hypertension was hypertension on conventional measurement with ambulatory normotension, the opposite condition being masked hypertension. Intervals used for classification of participants were daytime, nighttime, and 24 hours, first considered separately, and next combined as 24 hours plus daytime or plus nighttime, or plus both. Depending on time intervals chosen, white-coat and masked hypertension frequencies ranged from 6.3% to 12.5% and from 9.7% to 19.6%, respectively. During 91 046 person-years, 729 participants experienced a cardiovascular event. In multivariable analyses with normotension during all intervals of the day as reference, hazard ratios associated with white-coat hypertension progressively weakened considering daytime only (1.38; P=0.033), nighttime only (1.43; P=0.0074), 24 hours only (1.21; P=0.20), 24 hours plus daytime (1.24; P=0.18), 24 hours plus nighttime (1.15; P=0.39), and 24 hours plus daytime and nighttime (1.16; P=0.41). The hazard ratios comparing masked hypertension with normotension were all significant (P<0.0001), ranging from 1.76 to 2.03. In conclusion, identification of truly low-risk white-coat hypertension requires setting thresholds simultaneously to 24 hours, daytime, and nighttime blood pressure. Although any time interval suffices to diagnose masked hypertension, as proposed in current guidelines, full 24-hour recordings remain standard in clinical practice.

  • 3. Boggia, Jose
    et al.
    Thijs, Lutgarde
    Hansen, Tine W.
    Li, Yan
    Kikuya, Masahiro
    Björklund-Bodegård, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Richart, Tom
    Ohkubo, Takayoshi
    Jeppesen, Jorgen
    Torp-Pedersen, Christian
    Dolan, Eamon
    Kuznetsova, Tatiana
    Olszanecka, Agnieszka
    Tikhonoff, Valerie
    Malyutina, Sofia
    Casiglia, Edoardo
    Nikitin, Yuri
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Maestre, Gladys
    Sandoya, Edgardo
    Kawecka-Jaszcz, Kalina
    Imai, Yutaka
    Wang, Jiguang
    Ibsen, Hans
    O'Brien, Eoin
    Staessen, Jan A.
    Ambulatory Blood Pressure Monitoring in 9357 Subjects From 11 Populations Highlights Missed Opportunities for Cardiovascular Prevention in Women2011In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 57, no 3, p. 397-405Article in journal (Refereed)
    Abstract [en]

    To analyze sex-specific relative and absolute risks associated with blood pressure (BP), we performed conventional and 24-hour ambulatory BP measurements in 9357 subjects (mean age, 52.8 years; 47% women) recruited from 11 populations. We computed standardized multivariable-adjusted hazard ratios for associations between outcome and systolic BP. During a course of 11.2 years (median), 1245 participants died, 472 of cardiovascular causes. The number of fatal combined with nonfatal events was 1080, 525, and 458 for cardiovascular and cardiac events and for stroke, respectively. In women and men alike, systolic BP predicted outcome, irrespective of the type of BP measurement. Women compared with men were at lower risk (hazard ratios for death and all cardiovascular events=0.66 and 0.62, respectively; P<0.001). However, the relation of all cardiovascular events with 24-hour BP (P=0.020) and the relations of total mortality (P=0.023) and all cardiovascular (P=0.0013), cerebrovascular (P=0.045), and cardiac (P=0.034) events with nighttime BP were steeper in women than in men. Consequently, per a 1-SD decrease, the proportion of potentially preventable events was higher in women than in men for all cardiovascular events (35.9% vs 24.2%) in relation to 24-hour systolic BP (1-SD, 13.4 mm Hg) and for all-cause mortality (23.1% vs 12.3%) and cardiovascular (35.1% vs 19.4%), cerebrovascular (38.3% vs 25.9%), and cardiac (31.0% vs 16.0%) events in relation to systolic nighttime BP (1-SD, 14.1 mm Hg). In conclusion, although absolute risks associated with systolic BP were lower in women than men, our results reveal a vast and largely unused potential for cardiovascular prevention by BP-lowering treatment in women.

  • 4. Boggia, Jose
    et al.
    Thijs, Lutgarde
    Li, Yan
    Hansen, Tine W.
    Kikuya, Masahiro
    Bjorklund-Bodegard, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ohkubo, Takayoshi
    Jeppesen, Jorgen
    Torp-Pedersen, Christian
    Dolan, Eamon
    Kuznetsova, Tatiana
    Stolarz-Skrzypek, Katarzyna
    Tikhonoff, Valerie
    Malyutina, Sofia
    Casiglia, Edoardo
    Nikitin, Yuri
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Schwedt, Emma
    Sandoya, Edgardo
    Kawecka-Jaszcz, Kalina
    Filipovsky, Jan
    Imai, Yutaka
    Wang, Jiguang
    Ibsen, Hans
    O'Brien, Eoin
    Staessen, Jan A.
    Risk Stratification by 24-Hour Ambulatory Blood Pressure and Estimated Glomerular Filtration Rate in 5322 Subjects From 11 Populations2013In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 61, no 1, p. 18-+Article in journal (Refereed)
    Abstract [en]

    No previous study addressed whether in the general population estimated glomerular filtration rate (eGFR [Chronic Kidney Disease Epidemiology Collaboration formula]) adds to the prediction of cardiovascular outcome over and beyond ambulatory blood pressure. We recorded health outcomes in 5322 subjects (median age, 51.8 years; 43.1% women) randomly recruited from 11 populations, who had baseline measurements of 24-hour ambulatory blood pressure (ABP(24)) and eGFR. We computed hazard ratios using multivariable-adjusted Cox regression. Median follow-up was 9.3 years. In fully adjusted models, which included both ABP(24) and eGFR, ABP(24) predicted (P <= 0.008) both total (513 deaths) and cardiovascular (206) mortality; eGFR only predicted cardiovascular mortality (P=0.012). Furthermore, ABP(24) predicted (P <= 0.0056) fatal combined with nonfatal events as a result of all cardiovascular causes (555 events), cardiac disease (335 events), or stroke (218 events), whereas eGFR only predicted the composite cardiovascular end point and stroke (P <= 0.035). The interaction terms between ABP(24) and eGFR were all nonsignificant (P >= 0.082). For cardiovascular mortality, the composite cardiovascular end point, and stroke, ABP(24) added 0.35%, 1.17%, and 1.00% to the risk already explained by cohort, sex, age, body mass index, smoking and drinking, previous cardiovascular disease, diabetes mellitus, and antihypertensive drug treatment. Adding eGFR explained an additional 0.13%, 0.09%, and 0.14%, respectively. Sensitivity analyses stratified for ethnicity, sex, and the presence of hypertension or chronic kidney disease (eGFR <60mL/min per 1.73 m(2)) were confirmatory. In conclusion, in the general population, eGFR predicts fewer end points than ABP(24). Relative to ABP(24), eGFR is as an additive, not a multiplicative, risk factor and refines risk stratification 2-to14-fold less.

  • 5.
    Carlsson, Axel C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ruge, Toralph
    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, Cardiovascular epidemiology.
    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.
    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 Public Health and Caring Sciences, Geriatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Association between circulating endostatin, hypertension duration, and hypertensive target-organ damage2013In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 62, no 6, p. 1146-1151Article in journal (Refereed)
    Abstract [en]

    Our aim is to study associations between circulating endostatin, hypertension duration, and hypertensive target-organ damage. Long-term hypertension induces cardiovascular and renal remodeling. Circulating endostatin, a biologically active derivate of collagen XVIII, has been suggested to be a relevant marker for extracellular matrix turnover and remodeling in various diseases. However, the role of endostatin in hypertension and hypertensive target-organ damage is unclear. Serum endostatin was measured in 2 independent community-based cohorts: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; women 51%; n=812; mean age, 75 years) and the Uppsala Longitudinal Study of Adult Men (ULSAM; n=785; mean age, 77.6 years). Retrospective data on blood pressure measurements and antihypertensive medication (PIVUS >5 years, ULSAM >27 years), and cross-sectional data on echocardiographic left ventricular mass, endothelial function (endothelium-dependent vasodilation assessed by the invasive forearm model), and urinary albumin/creatinine ratio were available. In PIVUS, participants with ≥5 years of history of hypertension portrayed 0.42 SD (95% confidence interval, 0.23-0.61; P<0.001) higher serum endostatin, compared with that of normotensives. This association was replicated in ULSAM, in which participants with 27 years hypertension duration had the highest endostatin (0.57 SD higher; 95% confidence interval, 0.35-0.80; P<0.001). In addition, higher endostatin was associated with higher left ventricular mass, worsened endothelial function, and higher urinary albumin/creatinine ratio (P<0.03 for all) in participants with prevalent hypertension. Circulating endostatin is associated with the duration of hypertension, and vascular, myocardial, and renal indices of hypertensive target-organ damage. Further studies are warranted to assess the prognostic role of endostatin in individuals with hypertension.

  • 6.
    Carlström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Response to Sex of the Animal Impacts Responses to Angiotensin II, Oxidative Stress Levels, and Nitric Oxide Bioavailability2011In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 57, no 5, p. E19-E19Article in journal (Refereed)
  • 7.
    Carlström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lai, En Yin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ma, Zufu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Steege, Andreas
    Patzak, Andreas
    Eriksson, Ulf J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lundberg, Jon O.
    Wilcox, Christopher S.
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Superoxide Dismutase 1 Limits Renal Microvascular Remodeling and Attenuates Arteriole and Blood Pressure Responses to Angiotensin II via Modulation of Nitric Oxide Bioavailability2010In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 56, no 5, p. 907-913Article in journal (Refereed)
    Abstract [en]

    Oxidative stress is associated with vascular remodeling and increased preglomerular resistance that are both implicated in the pathogenesis of renal and cardiovascular disease. Angiotensin II induces superoxide production, which is metabolized by superoxide dismutase (SOD) or scavenged by NO. We investigated the hypothesis that SOD1 regulates renal microvascular remodeling, blood pressure, and arteriolar responsiveness and sensitivity to angiotensin II using SOD1-transgenic (SOD1-tg) and SOD1-knockout (SOD1-ko) mice. Blood pressure, measured telemetrically, rose more abruptly during prolonged angiotensin II infusion in SOD1-ko mice. The afferent arteriole media: lumen ratios were reduced in SOD1-tg and increased in SOD1-ko mice. Afferent arterioles from nontreated wild types had graded contraction to angiotensin II (sensitivity: 10(-9) mol/L; responsiveness: 40%). Angiotensin II contractions were less sensitive (10(-8) mol/L) and responsive (14%) in SOD1-tg but more sensitive (10(-13) mol/L) and responsive (89%) in SOD1-ko mice. Arterioles from SOD1-ko had 4-fold increased superoxide formation with angiotensin II at 10(-9) mol/L. N-G-nitro-L-arginine methyl ester reduced arteriole diameter of SOD1-tg and enhanced angiotensin II sensitivity and responsiveness of wild-type and SOD1-tg mice to the level of SOD1-ko mice. SOD mimetic treatment with Tempol increased arteriole diameter and normalized the enhanced sensitivity and responsiveness to angiotensin II of SOD1-ko mice but did not affect wild-type or SOD1-tg mice. Neither SOD1 deficiency nor overexpression was associated with changes in nitrate/nitrite excretion or renal mRNA expression of NO synthase, NADPH oxidase, or SOD2/SOD3 isoforms and angiotensin II receptors. In conclusion, SOD1 limits afferent arteriole remodeling and reduces sensitivity and responsiveness to angiotensin II by reducing superoxide and maintaining NO bioavailability. This may prevent an early and exaggerated blood pressure response to angiotensin II.

  • 8.
    Carlström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Lai, En Yin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Steege, Andreas
    Sendeski, Mauricio
    Ma, Zufu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Zabihi, Sheller
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Eriksson, Ulf J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Patzak, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Nitric oxide deficiency and increased adenosine response of afferent arterioles in hydronephrotic mice with hypertension2008In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 51, no 5, p. 1386-1392Article, review/survey (Refereed)
    Abstract [en]

    Afferent arterioles were used to investigate the role of adenosine, angiotensin II, NO, and reactive oxygen species in the pathogenesis of increased tubuloglomerular feedback response in hydronephrosis. Hydronephrosis was induced in wild-type mice, superoxide dismutase-1 overexpressed mice (superoxide-dismutase-1 transgenic), and deficient mice (superoxide dismutase-1 knockout). Isotonic contractions in isolated perfused arterioles and mRNA expression of NO synthase isoforms, adenosine, and angiotensin II receptors were measured. In wild-type mice, N(G)-nitro-L-arginine methyl ester (L-NAME) did not change the basal arteriolar diameter of hydronephrotic kidneys (-6%) but reduced it in control (-12%) and contralateral arterioles (-43%). Angiotensin II mediated a weaker maximum contraction of hydronephrotic arterioles (-18%) than in control (-42%) and contralateral arterioles (-49%). The maximum adenosine-induced constriction was stronger in hydronephrotic (-19%) compared with control (-8%) and contralateral kidneys (+/-0%). The response to angiotensin II became stronger in the presence of adenosine in hydronephrotic kidneys and attenuated in contralateral arterioles. L-NAME increased angiotensin II responses of all of the groups but less in hydronephrotic kidneys. The mRNA expression of endothelial NO synthase and inducible NO synthase was upregulated in the hydronephrotic arterioles. No differences were found for adenosine or angiotensin II receptors. In superoxide dismutase-1 transgenic mice, strong but similar L-NAME response (-40%) was observed for all of the groups. This response was totally abolished in arterioles of hydronephrotic superoxide dismutase-1 knockout mice. In conclusion, hydronephrosis is associated with changes in the arteriolar reactivity of both hydronephrotic and contralateral kidneys. Increased oxidative stress, reduced NO availability, and stronger reactivity to adenosine of the hydronephrotic kidney may contribute to the enhanced tubuloglomerular feedback responsiveness in hydronephrosis and be involved in the development of hypertension.

  • 9.
    Carlström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Important role of NAD(P)H oxidase 2 in the regulation of the tubuloglomerular feedback2009In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 53, no 3, p. 456-457Article in journal (Refereed)
  • 10.
    Carlström, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sällström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Skott, Ole
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Persson, Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Uninephrectomy in Young Age or Chronic Salt Loading Causes Salt-Sensitive Hypertension in Adult Rats2007In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 49, no 6, p. 1342-1350Article in journal (Refereed)
    Abstract [en]

    The importance of nephron endowment and salt intake for the development of hypertension is under debate. The present study was designed to investigate whether reduced nephron number, after completion of nephrogenesis, or chronic salt loading causes renal injury and salt-sensitive hypertension in adulthood. Rats were operated at 3 weeks of age (after completed nephrogenesis) and then subjected to either normal or high-salt diets for 6 to 8 weeks. Four different experimental groups were used: sham-operated animals raised with normal-salt diet (controls) or high-salt diet (HS) and uninephrectomized animals raised with normal-salt diet (UNX) or high-salt diet (UNX+HS). In the adult animals, renal and cardiovascular functions were evaluated and blood pressure recorded telemetrically under different sodium conditions (normal, high, and low). Hypertension was present in UNX+HS (122±9 mm Hg), UNX (101±3 mm Hg), and HS (96± 1 mm Hg) groups on normal-salt diets compared with the controls (84±2 mm Hg), and the blood pressure was salt sensitive (high- versus normal-salt diet; 23±3, 9±2, 7±2, and 1±1 mm Hg, respectively). The hypertensive groups (UNX+HS, UNX, and HS) had increased diuresis and reduced ability to concentrate urine. The glomerular filtration rate (milliliters per minute) in anesthetized rats was reduced in the UNX+HS (2.36±0.30) and UNX animals (2.00±0.31) compared with both HS animals (3.55±0.45) and controls (3.01±0.35). Hypertensive groups displayed reduced plasma renin concentrations during high sodium conditions and hypertrophic kidneys and hearts with various degrees of histopathologic changes. In conclusion, at a young age after completed nephrogenesis, uninephrectomy or chronic salt loading causes renal and cardiovascular injury with salt-sensitive hypertension.

  • 11.
    Cheng, Yi-Bang
    et al.
    Shanghai Jiao Tong Univ, Sch Med, Ctr Epidemiol Studies & Clin Trials, Shanghai, Peoples R China; Shanghai Jiao Tong Univ, Shanghai Inst Hypertens, Shanghai Key Lab Hypertens, Ctr Vasc Evaluat,Ruijin Hosp,Sch Med, Shanghai, Peoples R China.
    Thijs, Lutgarde
    Univ Leuven, Res Unit Hypertens & Cardiovasc Epidemiol, KU Leuven, Dept Cardiovasc Sci, Leuven, Belgium.
    Zhang, Zhen-Yu
    Univ Leuven, Res Unit Hypertens & Cardiovasc Epidemiol, KU Leuven, Dept Cardiovasc Sci, Leuven, Belgium.
    Kikuya, Masahiro
    Teikyo Univ, Dept Hyg & Publ Hlth, Sch Med, Tokyo, Japan.
    Yang, Wen-Yi
    Univ Leuven, Res Unit Hypertens & Cardiovasc Epidemiol, KU Leuven, Dept Cardiovasc Sci, Leuven, Belgium.
    Melgarejo, Jesus D.
    Univ Zulia, Lab Neurociencias, Maracaibo, Venezuela; Univ Zulia, Inst Enfermedades Cardiovasc, Maracaibo, Venezuela.
    Boggia, Jose
    Univ Republica, Hosp Clin, Ctr Nefrol, Montevideo, Uruguay; Univ Republica, Hosp Clin, Dept Fisiopatol, Montevideo, Uruguay.
    Wei, Fang-Fei
    Univ Leuven, Res Unit Hypertens & Cardiovasc Epidemiol, KU Leuven, Dept Cardiovasc Sci, Leuven, Belgium.
    Hansen, Tine W.
    Steno Diabet Ctr, Gentofte, Denmark;Ctr Hlth, Gentofte, Capital Region, Denmark.
    Yu, Cai-Guo
    Univ Leuven, Res Unit Hypertens & Cardiovasc Epidemiol, KU Leuven, Dept Cardiovasc Sci, Leuven, Belgium.
    Asayama, Kei
    Teikyo Univ, Dept Hyg & Publ Hlth, Sch Med, Tokyo, Japan;Tohoku Inst Management Blood Pressure, Dept Planning Drug Dev & Clin Evaluat, Sendai, Miyagi, Japan.
    Ohkubo, Takayoshi
    Teikyo Univ, Dept Hyg & Publ Hlth, Sch Med, Tokyo, Japan;Tohoku Inst Management Blood Pressure, Dept Planning Drug Dev & Clin Evaluat, Sendai, Miyagi, Japan.
    Dolan, Eamon
    Stroke & Hypertens Unit, Dublin, Ireland.
    Stolarz-Skrzypek, Katarzyna
    Jagiellonian Univ, Med Coll, Dept Cardiol Intervent Electrocardiol & Hypertens, Krakow, Poland.
    Malyutina, Sofia
    Russian Acad Sci, Inst Internal & Prevent Med, Inst Cytol & Genet, Siberian Branch, Novosibirsk, Russia.
    Casiglia, Edoardo
    Univ Padua, Dept Med, Padua, Italy.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics. Uppsala Univ, Sect Geriatr, Dept Publ Hlth & Caring Sci, Uppsala, Sweden.
    Filipovsky, Jan
    Charles Univ Prague, Fac Med, Plzen, Czech Republic.
    Maestre, Gladys E.
    Univ Zulia, Lab Neurociencias, Maracaibo, Venezuela; Univ Zulia, Inst Enfermedades Cardiovasc, Maracaibo, Venezuela; Univ Texas Rio Grande Valley, Sch Med, Dept Neurosci, Brownsville, TX USA; Univ Texas Rio Grande Valley, Sch Med, Dept Human Genet, Brownsville, TX USA.
    Imai, Yutaka
    Tohoku Inst Management Blood Pressure, Dept Planning Drug Dev & Clin Evaluat, Sendai, Miyagi, Japan.
    Kawecka-Jaszcz, Kalina
    Jagiellonian Univ, Med Coll, Dept Cardiol Intervent Electrocardiol & Hypertens, Krakow, Poland.
    Sandoya, Edgardo
    Asociac Espanola Primera Socorros Mutuos, Montevideo, Uruguay.
    Narkiewicz, Krzysztof
    Med Univ Gdansk, Dept Hypertens & Diabetol, Hypertens Unit, Gdansk, Poland.
    Li, Yan
    Shanghai Jiao Tong Univ, Sch Med, Ctr Epidemiol Studies & Clin Trials, Shanghai, Peoples R China; Shanghai Jiao Tong Univ, Shanghai Inst Hypertens, Shanghai Key Lab Hypertens, Ctr Vasc Evaluat,Ruijin Hosp,Sch Med, Shanghai, Peoples R China.
    O'Brien, Eoin
    Univ Coll Dublin, Conway Inst Biomol & Biomed Res, Dublin, Ireland.
    Wang, Ji-Guang
    Shanghai Jiao Tong Univ, Sch Med, Ctr Epidemiol Studies & Clin Trials, Shanghai, Peoples R China; Shanghai Jiao Tong Univ, Shanghai Inst Hypertens, Shanghai Key Lab Hypertens, Ctr Vasc Evaluat,Ruijin Hosp,Sch Med, Shanghai, Peoples R China.
    Staessen, Jan A.
    Univ Leuven, Res Unit Hypertens & Cardiovasc Epidemiol, KU Leuven, Dept Cardiovasc Sci, Leuven, Belgium; Maastricht Univ, Cardiovasc Res Inst Maastricht, Maastricht, Netherlands.
    Outcome-Driven Thresholds for Ambulatory Blood Pressure Based on the New American College of Cardiology/American Heart Association Classification of Hypertension2019In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 74, no 4, p. 776-783Article in journal (Refereed)
    Abstract [en]

    The new American College of Cardiology/American Heart Association guideline reclassified office blood pressure and proposed thresholds for ambulatory blood pressure (ABP). We derived outcome-driven ABP thresholds corresponding with the new office blood pressure categories. We performed 24-hour ABP monitoring in 11 152 participants (48.9% women; mean age, 53.0 years) representative of 13 populations. We determined ABP thresholds resulting in multivariable-adjusted 10-year risks similar to those associated with elevated office blood pressure (120/80 mm Hg) and stages 1 and 2 of office hypertension (130/80 and 140/90 mm Hg). Over 13.9 years (median), 2728 (rate per 1000 person-years, 17.9) people died, 1033 (6.8) from cardiovascular disease; furthermore, 1988 (13.8), 893 (6.0), and 795 (5.4) cardiovascular and coronary events and strokes occurred. Using a composite cardiovascular end point, systolic/diastolic outcome-driven thresholds indicating elevated 24-hour, daytime, and nighttime ABP were 117.9/75.2, 121.4/79.6, and 105.3/66.2 mm Hg. For stages 1 and 2 ambulatory hypertension, thresholds were 123.3/75.2 and 128.7/80.7 mm Hg for 24-hour ABP, 128.5/79.6 and 135.6/87.1 mm Hg for daytime ABP, and 111.7/66.2 and 118.1/72.5 mm Hg for nighttime ABP. ABP thresholds derived from other end points were similar. After rounding, approximate thresholds for elevated 24-hour, daytime, and nighttime ABP were 120/75, 120/80, and 105/65 mm Hg, and for stages 1 and 2, ambulatory hypertension 125/75 and 130/80 mm Hg, 130/80 and 135/85 mm Hg, and 110/65 and 120/70 mm Hg. Outcome-driven ABP thresholds corresponding to elevated blood pressure and stages 1 and 2 of hypertension are similar to those proposed by the current American College of Cardiology/American Heart Association guideline.

  • 12. Conen, David
    et al.
    Aeschbacher, Stefanie
    Thijs, Lutgarde
    Li, Yan
    Boggia, Jose
    Asayama, Kei
    Hansen, Tine W.
    Kikuya, Masahiro
    Bjorklund-Bodegard, Krishna
    Ohkubo, Takayoshi
    Jeppesen, Jorgen
    Gu, Yu-Mei
    Torp-Pedersen, Christian
    Dolan, Eamon
    Kuznetsova, Tatiana
    Stolarz-Skrzypek, Katarzyna
    Tikhonoff, Valerie
    Schoen, Tobias
    Malyutina, Sofia
    Casiglia, Edoardo
    Nikitin, Yuri
    Lind, Lars
    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, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sandoya, Edgardo
    Kawecka-Jaszcz, Kalina
    Mena, Luis
    Maestre, Gladys E.
    Filipovsky, Jan
    Imai, Yutaka
    O'Brien, Eoin
    Wang, Ji-Guang
    Risch, Lorenz
    Staessen, Jan A.
    Age-Specific Differences Between Conventional and Ambulatory Daytime Blood Pressure Values2014In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 64, no 5, p. 1073-1079Article in journal (Refereed)
    Abstract [en]

    Mean daytime ambulatory blood pressure (BP) values are considered to be lower than conventional BP values, but data on this relation among younger individuals <50 years are scarce. Conventional and 24-hour ambulatory BP were measured in 9550 individuals not taking antihypertensive treatment from 13 population-based cohorts. We compared individual differences between daytime ambulatory and conventional BP according to 10-year age categories. Age-specific prevalences of white coat and masked hypertension were calculated. Among individuals aged 18 to 30, 30 to 40, and 40 to 50 years, mean daytime BP was significantly higher than the corresponding conventional BP (6.0, 5.2, and 4.7 mm Hg for systolic; 2.5, 2.7, and 1.7 mm Hg for diastolic BP; all P<0.0001). In individuals aged 60 to 70 and >= 70 years, conventional BP was significantly higher than daytime ambulatory BP (5.0 and 13.0 mm Hg for systolic; 2.0 and 4.2 mm Hg for diastolic BP; all P<0.0001). The prevalence of white coat hypertension exponentially increased from 2.2% to 19.5% from those aged 18 to 30 years to those aged >= 70 years, with little variation between men and women (8.0% versus 6.1%; P=0.0003). Masked hypertension was more prevalent among men (21.1% versus 11.4%; P<0.0001). The age-specific prevalences of masked hypertension were 18.2%, 27.3%, 27.8%, 20.1%, 13.6%, and 10.2% among men and 9.0%, 9.9%, 12.2%, 11.9%, 14.7%, and 12.1% among women. In conclusion, this large collaborative analysis showed that the relation between daytime ambulatory and conventional BP strongly varies by age. These findings may have implications for diagnosing hypertension and its subtypes in clinical practice.

  • 13. Eriksson, Jan W.
    et al.
    Jansson, Per-Anders
    Carlberg, Bo
    Hägg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kurland, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Svensson, Maria K.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Ström, Conny
    Lönn, Lars
    Öjbrandt, Kristina
    Johansson, Lars
    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.
    Hydrochlorothiazide, but not Candesartan, aggravates insulin resistance and causes visceral and hepatic fat accumulation: the mechanisms for the diabetes preventing effect of Candesartan (MEDICA) Study2008In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 52, no 6, p. 1030-1037Article in journal (Refereed)
    Abstract [en]

    Treatment with angiotensin II receptor blockers is associated with lower risk for the development of type 2 diabetes mellitus compared with thiazide diuretics. The Mechanisms for the Diabetes Preventing Effect of Candesartan Study addressed insulin action and secretion and body fat distribution after treatment with candesartan, hydrochlorothiazide, and placebo. Twenty-six nondiabetic, abdominally obese, hypertensive patients were included in a multicenter 3-way crossover trial, and 22 completers (by predefined criteria; 10 men and 12 women) were included in the analyses. They underwent 12-week treatment periods with candesartan (C; 16 to 32 mg), hydrochlorothiazide (H; 25 to 50 mg), and placebo (P), respectively, and the treatment order was randomly assigned and double blinded. Intravenous glucose tolerance tests and euglycemic hyperinsulinemic (56 mU/m(2) per minute) clamps were performed. Intrahepatic and intramyocellular and extramyocellular lipid content and subcutaneous and visceral abdominal adipose tissue were measured using proton magnetic resonance spectroscopy and MRI. Insulin sensitivity (M-value) was reduced following H versus C and P (6.07+/-2.05, 6.63+/-2.04, and 6.90+/-2.10 mg/kg of body weight per minute, mean+/-SD; P<or=0.01). Liver fat content was higher (P<0.05) following H than both P and C. The subcutaneous to visceral abdominal adipose tissue ratio was reduced following H versus C and P (P<0.01). Glycosylated hemoglobin, alanine aminotransferase, aspartate aminotransferase, and high-sensitivity C-reactive protein levels were higher (P<0.05) after H, but not C, versus P. There were no changes in body fat, intramyocellular lipid, extramyocellular lipid, or first-phase insulin secretion. Blood pressure was reduced similarly by C and H versus P. In conclusion, visceral fat redistribution, liver fat accumulation, low-grade inflammation, and aggravated insulin resistance were demonstrated after hydrochlorothiazide but not candesartan treatment. These findings can partly explain the diabetogenic potential of thiazides.

  • 14. Franklin, Stanley S.
    et al.
    Thijs, Lutgarde
    Hansen, Tine W.
    Li, Yan
    Boggia, Jose
    Kikuya, Masahiro
    Björklund-Bodegård, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ohkubo, Takayoshi
    Jeppesen, Jorgen
    Torp-Pedersen, Christian
    Dolan, Eamon
    Kuznetsova, Tatiana
    Stolarz-Skrzypek, Katarzyna
    Tikhonoff, Valerie
    Malyutina, Sofia
    Casiglia, Edoardo
    Nikitin, Yuri
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sandoya, Edgardo
    Kawecka-Jaszcz, Kalina
    Imai, Yutaka
    Wang, Jiguang
    Ibsen, Hans
    O'Brien, Eoin
    Staessen, Jan A.
    Significance of White-Coat Hypertension in Older Persons With Isolated Systolic Hypertension: A Meta-Analysis Using the International Database on Ambulatory Blood Pressure Monitoring in Relation to Cardiovascular Outcomes Population2012In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 59, no 3, p. 564-571Article in journal (Refereed)
    Abstract [en]

    The significance of white-coat hypertension in older persons with isolated systolic hypertension remains poorly understood. We analyzed subjects from the population-based 11-country International Database on Ambulatory Blood Pressure Monitoring in Relation to Cardiovascular Outcomes database who had daytime ambulatory blood pressure (BP; ABP) and conventional BP (CBP) measurements. After excluding persons with diastolic hypertension by CBP (>= 90 mm Hg) or by daytime ABP (>= 85 mm Hg), a history of cardiovascular disease, and persons<18 years of age, the present analysis totaled 7295 persons, of whom 1593 had isolated systolic hypertension. During a median follow-up of 10.6 years, there was a total of 655 fatal and nonfatal cardiovascular events. The analyses were stratified by treatment status. In untreated subjects, those with white-coat hypertension (CBP >= 140/<90 mm Hg and ABP<135/<85 mm Hg) and subjects with normal BP (CBP<140/<90 mm Hg and ABP<135/<85 mm Hg) were at similar risk (adjusted hazard rate: 1.17 [95% CI: 0.87-1.57]; P=0.29). Furthermore, in treated subjects with isolated systolic hypertension, the cardiovascular risk was similar in elevated conventional and normal daytime systolic BP as compared with those with normal conventional and normal daytime BPs (adjusted hazard rate: 1.10 [95% CI: 0.79-1.53]; P = 0.57). However, both treated isolated systolic hypertension subjects with white-coat hypertension (adjusted hazard rate: 2.00; [95% CI: 1.43-2.79]; P<0.0001) and treated subjects with normal BP (adjusted hazard rate: 1.98 [95% CI: 1.49-2.62]; P<0.0001) were at higher risk as compared with untreated normotensive subjects. In conclusion, subjects with sustained hypertension who have their ABP normalized on antihypertensive therapy but with residual white-coat effect by CBP measurement have an entity that we have termed, "treated normalized hypertension." Therefore, one should be cautious in applying the term "white-coat hypertension" to persons receiving antihypertensive treatment.

  • 15. Franklin, Stanley S.
    et al.
    Thijs, Lutgarde
    Li, Yan
    Hansen, Tine W.
    Boggia, Jose
    Liu, Yanping
    Asayama, Kei
    Björklund-Bodegard, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ohkubo, Takayoshi
    Jeppesen, Jorgen
    Torp-Pedersen, Christian
    Dolan, Eamon
    Kuznetsova, Tatiana
    Stolarz-Skrzypek, Katarzyna
    Tikhonoff, Valerie
    Malyutina, Sofia
    Casiglia, Edoardo
    Nikitin, Yuri
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Sandoya, Edgardo
    Kawecka-Jaszcz, Kalina
    Filipovsky, Jan
    Imai, Yutaka
    Wang, Jiguang
    Ibsen, Hans
    O'Brien, Eoin
    Staessen, Jan A.
    Masked Hypertension in Diabetes Mellitus Treatment Implications for Clinical Practice2013In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 61, no 5, p. 964-+Article in journal (Refereed)
    Abstract [en]

    Although distinguishing features of masked hypertension in diabetics are well known, the significance of antihypertensive treatment on clinical practice decisions has not been fully explored. We analyzed 9691 subjects from the population-based 11-country International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcomes. Prevalence of masked hypertension in untreated normotensive participants was higher (P<0.0001) among 229 diabetics (29.3%, n=67) than among 5486 nondiabetics (18.8%, n=1031). Over a median of 11.0 years of follow-up, the adjusted risk for a composite cardiovascular end point in untreated diabetic-masked hypertensives tended to be higher than in normotensives (hazard rate [HR], 1.96; 95% confidence interval [CI], 0.97-3.97; P=0.059), similar to untreated stage 1 hypertensives (HR, 1.07; CI, 0.58-1.98; P=0.82), but less than stage 2 hypertensives (HR, 0.53; CI, 0.29-0.99; P=0.048). In contrast, cardiovascular risk was not significantly different in antihypertensive-treated diabetic-masked hypertensives, as compared with the normotensive comparator group (HR, 1.13; CI, 0.54-2.35; P=0.75), stage 1 hypertensives (HR, 0.91; CI, 0.49-1.69; P=0.76), and stage 2 hypertensives (HR, 0.65; CI, 0.35-1.20; P=0.17). In the untreated diabetic-masked hypertensive population, mean conventional systolic/diastolic blood pressure was 129.2 +/- 8.0/76.0 +/- 7.3 mm Hg, and mean daytime systolic/diastolic blood pressure 141.5 +/- 9.1/83.7 +/- 6.5 mm Hg. In conclusion, masked hypertension occurred in 29% of untreated diabetics, had comparable cardiovascular risk as stage 1 hypertension, and would require considerable reduction in conventional blood pressure to reach daytime ambulatory treatment goal. Importantly, many hypertensive diabetics when receiving antihypertensive therapy can present with normalized conventional and elevated ambulatory blood pressure that mimics masked hypertension.

  • 16. Franklin, Stanley S.
    et al.
    Thijs, Lutgarde
    Li, Yan
    Hansen, Tine W.
    Boggia, Jose
    Liu, Yanping
    Asayama, Kei
    Björklund-Bodegård, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ohkubo, Takayoshi
    Jeppesen, Jorgen
    Torp-Pedersen, Christian
    Dolan, Eamon
    Kuznetsova, Tatiana
    Stolarz-Skrzypek, Katarzyna
    Tikhonoff, Valerie
    Malyutina, Sofia
    Casiglia, Edoardo
    Nikitin, Yuri
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Sandoya, Edgardo
    Kawecka-Jaszcz, Kalina
    Filipovsky, Jan
    Imai, Yutaka
    Wang, Jiguang
    Ibsen, Hans
    O'Brien, Eoin
    Staessen, Jan A.
    Response to Masked Hypertension in Untreated and Treated Patients With Diabetes Mellitus: Attractive But Questionable Interpretations and Response to Is Masked Hypertension Related to Diabetes Mellitus?2013In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 62, no 4, p. E23-E25Article in journal (Refereed)
  • 17.
    Friederich-Persson, Malou
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Thorn, Erik
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Nangaku, Masaomi
    Levin, Max
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kidney Hypoxia, Attributable to Increased Oxygen Consumption, Induces Nephropathy Independently of Hyperglycemia and Oxidative Stress2013In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 62, no 5, p. 914-919Article in journal (Refereed)
    Abstract [en]

    Diabetic nephropathy is strongly associated with both increased oxidative stress and kidney tissue hypoxia. The increased oxidative stress causes increased kidney oxygen consumption resulting in kidney tissue hypoxia. To date, it has been difficult to determine the role of kidney hypoxia, per se, for the development of nephropathy. We tested the hypothesis that kidney hypoxia, without confounding factors such as hyperglycemia or elevated oxidative stress, results in nephropathy. To induce kidney hypoxia, dinitrophenol (30 mg per day per kg bodyweight by gavage), a mitochondrial uncoupler that increases oxygen consumption and causes kidney hypoxia, was administered for 30 consecutive days to rats. Thereafter, glomerular filtration rate, renal blood flow, kidney oxygen consumption, kidney oxygen tension, kidney concentrations of glucose and glycogen, markers of oxidative stress, urinary protein excretion, and histological findings were determined and compared with vehicle-treated controls. Dinitrophenol did not affect arterial blood pressure, renal blood flow, glomerular filtration rate, blood glucose, or markers of oxidative stress but increased kidney oxygen consumption, and reduced cortical and medullary concentrations of glucose and glycogen, and resulted in intrarenal tissue hypoxia. Furthermore, dinitrophenol treatment increased urinary protein excretion, kidney vimentin expression, and infiltration of inflammatory cells. In conclusion, increased mitochondrial oxygen consumption results in kidney hypoxia and subsequent nephropathy. Importantly, these results demonstrate that kidney tissue hypoxia, per se, without confounding hyperglycemia or oxidative stress, may be sufficient to initiate the development of nephropathy and therefore demonstrate a new interventional target for treating kidney disease.

  • 18.
    Gao, Xiang
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Yang, Ting
    Liu, Ming
    Peleli, Maria
    Zollbrecht, Christa
    Weitzberg, Eddie
    Lundberg, Jon O.
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlstrom, Mattias
    NADPH Oxidase in the Renal Microvasculature Is a Primary Target for Blood Pressure-Lowering Effects by Inorganic Nitrate and Nitrite2015In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 65, no 1, p. 161-+Article in journal (Refereed)
    Abstract [en]

    Renal oxidative stress and nitric oxide (NO) deficiency are key events in hypertension. Stimulation of a nitrate-nitrite-NO pathway with dietary nitrate reduces blood pressure, but the mechanisms or target organ are not clear. We investigated the hypothesis that inorganic nitrate and nitrite attenuate reactivity of renal microcirculation and blood pressure responses to angiotensin II (ANG II) by modulating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and NO bioavailability. Nitrite in the physiological range (10(-7)-10(-5) mol/L) dilated isolated perfused renal afferent arterioles, which were associated with increased NO. Contractions to ANG II (34%) and simultaneous NO synthase inhibition (56%) were attenuated by nitrite (18% and 26%). In a model of oxidative stress (superoxide dismutase-1 knockouts), abnormal ANG II-mediated arteriolar contractions (90%) were normalized by nitrite (44%). Mechanistically, effects of nitrite were abolished by NO scavenger and xanthine oxidase inhibitor, but only partially attenuated by inhibiting soluble guanylyl cyclase. Inhibition of NADPH oxidase with apocynin attenuated ANG II-induced contractility (35%) similar to that of nitrite. In the presence of nitrite, no further effect of apocynin was observed, suggesting NADPH oxidase as a possible target. In preglomerular vascular smooth muscle cells and kidney cortex, nitrite reduced both basal and ANG II-induced NADPH oxidase activity. These effects of nitrite were also abolished by xanthine oxidase inhibition. Moreover, supplementation with dietary nitrate (10(-2) mol/L) reduced renal NADPH oxidase activity and attenuated ANG II-mediated arteriolar contractions and hypertension (99+/-2-146+/-2 mm Hg) compared with placebo (100+/-3-168+/-3 mm Hg). In conclusion, these novel findings position NADPH oxidase in the renal microvasculature as a prime target for blood pressure-lowering effects of inorganic nitrate and nitrite.

  • 19. Graham, Lesley A
    et al.
    Padmanabhan, Sandosh
    Fraser, Niall J
    Kumar, Satish
    Bates, James M
    Raffi, Hajamohideen S
    Welsh, Paul
    Beattie, Wendy
    Hao, Shoujin
    Leh, Sabine
    Hultström, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Ferreri, Nicholas R
    Dominiczak, Anna F
    Graham, Delyth
    McBride, Martin W
    Validation of Uromodulin as a Candidate Gene for Human Essential Hypertension2014In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 63, no 3, p. 551-558Article in journal (Refereed)
    Abstract [en]

    A recent genome-wide association study identified a locus on chromosome 16 in the promoter region of the uromodulin (UMOD) gene that is associated with hypertension. Here, we examined the hypertension signal with functional studies in Umod knockout (KO) mice. Systolic blood pressure was significantly lower in KO versus wild-type (WT) mice under basal conditions (KO: 116.6±0.3 mm Hg versus WT: 136.2±0.4 mm Hg; P<0.0001). Administration of 2% NaCl did not alter systolic blood pressure in KO mice, whereas it increased in WT mice by ≈33%, P<0.001. The average 24-hour urinary sodium excretion in the KO was greater than that of WT mice (P<0.001). Chronic renal function curves demonstrate a leftward shift in KO mice, suggesting that the relationship between UMOD and blood pressure is affected by sodium. Creatinine clearance was increased during salt loading with 2% NaCl in the KO mice, leading to augmented filtered Na(+) excretion and further Na(+) loss. The difference in sodium uptake that exists between WT and KO strains was explored at the molecular level. Urinary tumor necrosis factor-α levels were significantly higher in KO mice compared with WT mice (P<0.0001). Stimulation of primary thick ascending limb of the loop of Henle cells with exogenous tumor necrosis factor-α caused a reduction in NKCC2A expression (P<0.001) with a concurrent rise in the levels of UMOD mRNA (P<0.001). Collectively, we demonstrate that UMOD regulates sodium uptake in the thick ascending limb of the loop of Henle by modulating the effect of tumor necrosis factor-α on NKCC2A expression, making UMOD an important determinant of blood pressure control.

  • 20. Gu, Yu-Mei
    et al.
    Thijs, Lutgarde
    Li, Yan
    Asayama, Kei
    Boggia, Jose
    Hansen, Tine W.
    Liu, Yan-Ping
    Ohkubo, Takayoshi
    Bjorklund-Bodegard, Krishna
    Jeppesen, Jorgen
    Dolan, Eamon
    Torp-Pedersen, Christian
    Kuznetsova, Tatiana
    Stolarz-Skrzypek, Katarzyna
    Tikhonoff, Valerie
    Malyutina, Sofia
    Casiglia, Edoardo
    Nikitin, Yuri
    Lind, Lars
    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, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sandoya, Edgardo
    Kawecka-Jaszcz, Kalina
    Imai, Yutaka
    Mena, Luis J.
    Wang, Jiguang
    O'Brien, Eoin
    Verhamme, Peter
    Filipovsky, Jan
    Maestre, Gladys E.
    Staessen, Jan A.
    Outcome-Driven Thresholds for Ambulatory Pulse Pressure in 9938 Participants Recruited From 11 Populations2014In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 63, no 2, p. 229-237Article in journal (Refereed)
    Abstract [en]

    Evidence-based thresholds for risk stratification based on pulse pressure (PP) are currently unavailable. To derive outcome-driven thresholds for the 24-hour ambulatory PP, we analyzed 9938 participants randomly recruited from 11 populations (47.3% women). After age stratification (<60 versus >= 60 years) and using average risk as reference, we computed multivariable-adjusted hazard ratios (IIRs) to assess risk by tenths of the PP distribution or risk associated with stepwise increasing (+1 mm Hg) PP levels. All adjustments included mean arterial pressure. Among 6028 younger participants (68 853 person-years), the risk of cardiovascular (HR, 1.58; P=0.011) or cardiac (HR, 1.52; P=0.056) events increased only in the top PP tenth (mean, 60.6 mm Hg). Using stepwise increasing PP levels, the lower boundary of the 95% confidence interval of the successive thresholds did not cross unity. Among 3910 older participants (39 923 person-years), risk increased (P <= 0.028) in the top PP tenth (mean, 76.1 mm Hg). HRs were 1.30 and 1.62 for total and cardiovascular mortality, and 1.52, 1.69, and 1.40 for all cardiovascular, cardiac, and cerebrovascular events. The lower boundary of the 95% confidence interval of the HRs associated with stepwise increasing PP levels crossed unity at 64 mm Hg. While accounting for all covariables, the top tenth of PP contributed less than 0.3% (generalized R-2 statistic) to the overall risk among the elderly. Thus, in randomly recruited people, ambulatory PP does not add to risk stratification below age 60; in the elderly, PP is a weak risk factor with levels below 64 mm Hg probably being innocuous.

  • 21. Gudbrandsen, Oddrun Anita
    et al.
    Hultström, Michael
    Leh, Sabine
    Monica Bivol, Liliana
    Vågnes, Øyvind
    Berge, Rolf K
    Iversen, Bjarne M
    Prevention of hypertension and organ damage in 2-kidney, 1-clip rats by tetradecylthioacetic acid.2006In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 48, no 3, p. 460-6Article in journal (Refereed)
    Abstract [en]

    Dietary lipids are reported to affect the blood pressure in both humans and experimental animal models with hypertension. In the present study, 2-kidney, 1-clip (2K1C) hypertensive rats were treated with the modified fatty acid tetradecylthioacetic acid (TTA) from the time of clipping or after hypertension was established. TTA treatment attenuated the development of hypertension and reduced established 2K1C hypertension. The mRNA level of renin in the clipped kidney and the plasma renin activity were markedly reduced, and the plasma angiotensin II level tended to decrease after TTA treatment. In addition, TTA reduced the mRNA level of angiotensinogen in white adipose tissue. Prevention of organ damage was demonstrated by normal urinary excretion of protein, maintained serum albumin, lower heart weight, and clearly reduced vascular, glomerular, and tubulointerstitial damage in the nonclipped kidney. Renal function was not affected as estimated by unchanged plasma creatinine. Furthermore, the serum levels of triacylglycerol and cholesterol were reduced by TTA. The serum fatty acid composition was changed, resulting in a favorable increase of oleic acid. However, the levels of all of the omega-3 fatty acids and of linoleic acid were reduced, and no change was seen in the level of arachidonic acid, but the urinary excretion of 8-iso-prostaglandin F2alpha was declined. In conclusion, TTA attenuated the development of hypertension, reduced established hypertension, and prevented the development of organ damage in 2K1C rats, possibly by reducing the amounts of the vasoconstrictors angiotensin II and 8-iso-prostaglandin F2alpha and by inducing a favorable increase of oleic acid in serum.

  • 22.
    Guimaraes, Drielle D.
    et al.
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden;Univ Fed Paraiba, Ctr Biotechnol, Joao Pessoa, Paraiba, Brazil.
    Cruz, Josiane C.
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden;Univ Fed Paraiba, Ctr Biotechnol, Joao Pessoa, Paraiba, Brazil.
    Carvalho-Galvao, Alynne
    Univ Fed Paraiba, Ctr Biotechnol, Joao Pessoa, Paraiba, Brazil.
    Zhuge, Zhengbing
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
    Marques, Stefanne M.
    Univ Fed Goias, Dept Physiol Sci, Goiania, Go, Brazil.
    Naves, Lara M.
    Univ Fed Goias, Dept Physiol Sci, Goiania, Go, Brazil.
    Persson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
    Weitzberg, Eddie
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
    Lundberg, Jon O.
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
    Balarini, Camille M.
    Univ Fed Paraiba, Ctr Biotechnol, Joao Pessoa, Paraiba, Brazil;Univ Fed Paraiba, Hlth Sci Ctr, Joao Pessoa, Paraiba, Brazil.
    Pedrino, Gustavo R.
    Univ Fed Goias, Dept Physiol Sci, Goiania, Go, Brazil.
    Braga, Valdir A.
    Univ Fed Paraiba, Ctr Biotechnol, Joao Pessoa, Paraiba, Brazil.
    Carlstrom, Mattias
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
    Dietary Nitrate Reduces Blood Pressure in Rats With Angiotensin II-Induced Hypertension via Mechanisms That Involve Reduction of Sympathetic Hyperactivity2019In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 73, no 4, p. 839-848Article in journal (Refereed)
    Abstract [en]

    Several experimental and clinical studies have shown that dietary nitrate supplementation can increase nitric oxide bioavailability. In the oral cavity, commensal bacteria reduce nitrate to nitrite, which is subsequently absorbed into the circulation where reduction to nitric oxide by enzymatic systems occur. Although it is well-known that boosting the nitrate-nitrite-nitric oxide pathway can improve cardiovascular, renal, and metabolic functions and that sympathoexcitation contributes to the development of the same disorders, the potential effects of dietary nitrate on sympathetic activity remain to be elucidated. In this study, we hypothesized that treatment with inorganic nitrate could prevent the increase in sympathetic nerve activity in an experimental model of Ang II (angiotensin II)-induced hypertension. Multiple in vivo approaches were combined, that is, Wistar rats orally treated with the nitric oxide synthase inhibitor L-NAME (N(G)-nitro-L-arginine methyl ester, 0.5 g/L) and implanted with subcutaneous osmotic minipump for continuous delivery of Ang II (120 ng/kg per minute; 14 days). Simultaneously, rats were supplemented with sodium nitrate (10 mmol/L) or placebo (sodium chloride; 10 mmol/L) in the drinking water. Blood pressure, heart rate, and renal sympathetic nerve activity were recorded. In placebo-treated rats, Ang II+ L-NAME treatment-induced arterial hypertension, which was linked with reduced spontaneous baroreflex sensitivity and increased renal sympathetic nerve activity, as well as upregulation of AT 1 Rs (Ang II type-1 receptors) in the rostral ventrolateral medulla. Supplementation with nitrate normalized the expression of AT 1 Rs in rostral ventrolateral medulla and reduced sympathetic nerve activity, which was associated with attenuated development of hypertension. In conclusion, chronic dietary nitrate supplementation blunted the development of hypertension via mechanisms that involve reduction of sympathetic outflow.

  • 23. Hansen, Tine W.
    et al.
    Thijs, Lutgarde
    Boggia, José
    Li, Yan
    Kikuya, Masahiro
    Björklund-Bodegård, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Richart, Tom
    Ohkubo, Takayoshi
    Jeppesen, Jørgen
    Torp-Pedersen, Christian
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sandoya, Edgardo
    Imai, Yutaka
    Wang, Jiguang
    Ibsen, Hans
    O'Brien, Eoin
    Staessen, Jan A.
    Prognostic value of ambulatory heart rate revisited in 6928 subjects from 6 populations2008In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 52, no 2, p. 229-235Article in journal (Refereed)
    Abstract [en]

    The evidence relating mortality and morbidity to heart rate remains inconsistent. We performed 24-hour ambulatory blood pressure monitoring in 6928 subjects (not on beta-blockers; mean age: 56.2 years; 46.5% women) enrolled in prospective population studies in Denmark, Belgium, Japan, Sweden, Uruguay, and China. We computed standardized hazard ratios for heart rate, while stratifying for cohort, and adjusting for blood pressure and other cardiovascular risk factors. Over 9.6 years (median), 850, 325, and 493 deaths accrued for total, cardiovascular, and noncardiovascular mortality, respectively. The incidence of fatal combined with nonfatal end points was 805, 363, 439, and 324 for cardiovascular, stroke, cardiac, and coronary events, respectively. Twenty-four-hour heart rate predicted total (hazard ratio: 1.15) and noncardiovascular (hazard ratio: 1.18) mortality but not cardiovascular mortality (hazard ratio: 1.11) or any of the fatal combined with nonfatal events (hazard ratio: < or =1.02). Daytime heart rate did not predict mortality (hazard ratio: < or =1.11) or any fatal combined with nonfatal event (hazard ratio: < or =0.96). Nighttime heart rate predicted all of the mortality outcomes (hazard ratio: > or =1.15) but none of the fatal combined with nonfatal events (hazard ratio: < or =1.11). The night:day heart rate ratio predicted total (hazard ratio: 1.14) and noncardiovascular mortality (hazard ratio: 1.12) and all of the fatal combined with nonfatal events (hazard ratio: > or =1.15) with the exception of stroke (hazard ratio: 1.06). Sensitivity analyses, in which we stratified by risk factors or from which we excluded 1 cohort at a time or the events occurring within 2 years of enrollment, showed consistent results. In the general population, heart rate predicts total and noncardiovascular mortality. With the exception of the night:day heart rate ratio, heart rate did not add to the risk stratification for fatal combined with nonfatal cardiovascular events. Thus, heart rate adds little to the prediction of cardiovascular risk.

  • 24. Hansen, Tine W.
    et al.
    Thijs, Lutgarde
    Li, Yan
    Boggia, José
    Kikuya, Masahiro
    Björklund-Bodegård, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Richart, Tom
    Ohkubo, Takayoshi
    Jeppesen, Jørgen
    Torp-Pedersen, Christian
    Dolan, Eamon
    Kuznetsova, Tatiana
    Stolarz-Skrzypek, Katarzyna
    Tikhonoff, Valérie
    Malyutina, Sofia
    Casiglia, Edoardo
    Nikitin, Yuri
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sandoya, Edgardo
    Kawecka-Jaszcz, Kalina
    Imai, Yutaka
    Wang, Jiguang
    Ibsen, Hans
    O'Brien, Eoin
    Staessen, Jan A.
    Prognostic value of reading-to-reading blood pressure variability over 24 hours in 8938 subjects from 11 populations2010In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 55, no 4, p. 1049-1057Article in journal (Refereed)
    Abstract [en]

    In previous studies, of which several were underpowered, the relation between cardiovascular outcome and blood pressure (BP) variability was inconsistent. We followed health outcomes in 8938 subjects (mean age: 53.0 years; 46.8% women) randomly recruited from 11 populations. At baseline, we assessed BP variability from the SD and average real variability in 24-hour ambulatory BP recordings. We computed standardized hazard ratios (HRs) while stratifying by cohort and adjusting for 24-hour BP and other risk factors. Over 11.3 years (median), 1242 deaths (487 cardiovascular) occurred, and 1049, 577, 421, and 457 participants experienced a fatal or nonfatal cardiovascular, cardiac, or coronary event or a stroke. Higher diastolic average real variability in 24-hour ambulatory BP recordings predicted (Por=1.07) with the exception of cardiac and coronary events (HR: or=0.58). Higher systolic average real variability in 24-hour ambulatory BP recordings predicted (P<0.05) total (HR: 1.11) and cardiovascular (HR: 1.16) mortality and all fatal combined with nonfatal end points (HR: >or=1.07), with the exception of cardiac and coronary events (HR: or=0.54). SD predicted only total and cardiovascular mortality. While accounting for the 24-hour BP level, average real variability in 24-hour ambulatory BP recordings added <1% to the prediction of a cardiovascular event. Sensitivity analyses considering ethnicity, sex, age, previous cardiovascular disease, antihypertensive treatment, number of BP readings per recording, or the night:day BP ratio were confirmatory. In conclusion, in a large population cohort, which provided sufficient statistical power, BP variability assessed from 24-hour ambulatory recordings did not contribute much to risk stratification over and beyond 24-hour BP.

  • 25.
    Hastie, Roxanne
    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. Mercy Hosp Women, Mercy Perinatal, Melbourne, Vic, Australia; Univ Melbourne, Dept Obstet & Gynaecol, Translat Obstet Grp, Heidelberg, Vic, Australia.
    Bergman, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna. 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. Stellenbosch Univ, Dept Obstet & Gynaecol, Cape Town, South Africa.
    Cluver, Catherin A.
    Univ Melbourne, Dept Obstet & Gynaecol, Translat Obstet Grp, Heidelberg, Vic, Australia; Stellenbosch Univ, Dept Obstet & Gynaecol, Cape Town, South Africa.
    Wikman, Anna
    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 Health.
    Hannan, Natalie J.
    Mercy Hosp Women, Mercy Perinatal, Melbourne, Vic, Australia; Univ Melbourne, Dept Obstet & Gynaecol, Translat Obstet Grp, Heidelberg, Vic, Australia.
    Walker, Susan P.
    Mercy Hosp Women, Mercy Perinatal, Melbourne, Vic, Australia.
    Wikström, Anna-Karin
    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.
    Tong, Stephen
    Mercy Hosp Women, Mercy Perinatal, Melbourne, Vic, Australia; Univ Melbourne, Dept Obstet & Gynaecol, Translat Obstet Grp, Heidelberg, Vic, Australia.
    Hesselman, Susanne
    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. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Center for Clinical Research Dalarna.
    Proton Pump Inhibitors and Preeclampsia Risk Among 157 720 Women: A Swedish Population Register-Based Cohort Study2019In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 73, no 5, p. 1097-1103Article in journal (Refereed)
    Abstract [en]

    Preeclampsia is a hypertensive disorder of pregnancy with a high rate of maternal and neonatal morbidity and mortality. The only definite treatment is delivery. Preclinical investigations have identified proton pump inhibitors (PPIs), which are commonly used to treat reflux during pregnancy, as a potential treatment for preeclampsia. The aim of this study was to determine the association between PPI use during pregnancy and preeclampsia risk in a population-based register cohort. Using the Swedish Pregnancy Register, we conducted a cohort study of nulliparous pregnant women delivering from January 2013 to July 2017. Associations between PPI use and preeclampsia were investigated using logistic regression analyses with risk estimates presented as crude and adjusted odds ratios (aOR) with 95% CI. Of 157 720 nulliparous pregnant women, 6051 (3.8%) reported PPI use during pregnancy. PPI use during any point of pregnancy was associated with an increased risk of overall preeclampsia (aOR of 1.17; 95% CI, 1.04-1.32) and preeclampsia at term (aOR of 1.20; 95% CI, 1.04-1.39). However, PPI use recorded after 28 gestational weeks was associated with a reduced risk of preterm (delivery <37 weeks) preeclampsia (aOR of 0.63; 95% CI, 0.41-0.96) and early (delivery <34 weeks) preeclampsia (aOR of 0.41; 95% CI, 0.20-0.82). These findings highlight the heterogeneity of this disease, with a potential role PPIs for preventing preterm preeclampsia when used in close proximity to disease onset. Targeting PPI use to women at greatest risk of preterm preeclampsia may help prevent this severe form of disease.

  • 26.
    Ho, C. L. B.
    et al.
    Univ Tasmania, Hobart, Tas, Australia..
    Doust, J.
    Bond Univ, Gold Coast, Qld, Australia..
    Jackson, R.
    Univ Auckland, Auckland, New Zealand..
    McManus, R. J.
    Univ Oxford, Oxford OX1 2JD, England..
    Reid, C. M.
    Monash Univ, Clayton, Vic, Australia.;Curtin Univ, Perth, WA 6845, Australia..
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Nelson, M. R.
    Univ Tasmania, Hobart, Tas, Australia..
    Should You Leave A Legacy?: Potential Effects Of Delayed Blood Pressure Lowering Pharmacotherapy In Individuals Stratified By Absolute Cardiovascular Disease Risk2016In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 67, no 5, p. E17-E18Article in journal (Other academic)
  • 27.
    Hutcheon, Jennifer A.
    et al.
    Univ British Columbia, Dept Obstet & Gynaecol, Vancouver, BC, Canada.
    Stephansson, Olof
    Dept Med, Clin Epidemiol Unit, Solna, Sweden;Karolinska Inst, Dept Womens & Childrens Hlth, Div Obstet & Gynaecol, Stockholm, Sweden.
    Cnattingius, Sven
    Dept Med, Clin Epidemiol Unit, Solna, Sweden.
    Bodnar, Lisa M.
    Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA.
    Wikström, Anna-Karin
    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.
    Johansson, Kari
    Dept Med, Clin Epidemiol Unit, Solna, Sweden.
    Pregnancy Weight Gain Before Diagnosis and Risk of Preeclampsia: A Population-Based Cohort Study in Nulliparous Women2018In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 72, no 2, p. 433-441Article in journal (Refereed)
    Abstract [en]

    Weight gain in early pregnancy may influence a woman's risk of developing preeclampsia. However, the consequences of weight gain throughout pregnancy up to the diagnosis of preeclampsia are unknown. The aim of this study was to determine whether pregnancy weight gain before the diagnosis of preeclampsia is associated with increased risks of preeclampsia (overall and by preeclampsia subtype). The study population included nulliparous pregnant women in the Swedish counties of Gotland and Stockholm, 2008 to 2013, stratified by early pregnancy body mass index category. Electronic medical records were linked with population inpatient and outpatient records to establish date of preeclampsia diagnosis (classified as any, early preterm <34 weeks, late preterm 34-36 weeks, or term 37 weeks). Antenatal weight gain measurements were standardized into gestational age-specific z scores. Among 62705 nulliparous women, 2770 (4.4%) developed preeclampsia. Odds of preeclampsia increased by approximate to 60% with every 1 z score increase in pregnancy weight gain among normal weight and overweight women and by 20% among obese women. High pregnancy weight gain was more strongly associated with term preeclampsia than early preterm preeclampsia (eg, 64% versus 43% increased odds per 1 z score difference in weight gain in normal weight women, and 30% versus 0% in obese women, respectively). By 25 weeks, the weight gain of women who subsequently developed preeclampsia was significantly higher than women who did not (eg, 0.43 kg in normal weight women). In conclusion, high pregnancy weight gain before diagnosis increases the risk of preeclampsia in nulliparous women and is more strongly associated with later-onset preeclampsia than early-onset preeclampsia.

  • 28. Laszlo, Krisztina D.
    et al.
    Liu, Xiao Qin
    Svensson, Tobias
    Wikström, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Li, Jiong
    Olsen, Jørn
    Obel, Carsten
    Vestergaard, Mogens
    Cnattingius, Sven
    Psychosocial Stress Related to the Loss of a Close Relative the Year Before or During Pregnancy and Risk of Preeclampsia2013In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 62, no 1, p. 183-189Article in journal (Refereed)
    Abstract [en]

    The role of stress in the pathogenesis of preeclampsia has only been investigated in a few studies, and the findings are not conclusive. We analyzed whether maternal bereavement shortly before or during pregnancy is associated with an increased risk of preeclampsia. We conducted a cohort study of singleton births in Denmark during 1978-2008 and in Sweden during 1973-2006 (n=4 122 490) by linking national population-based registers. Mothers were considered exposed to bereavement if they lost a parent, a sibling, a partner, or a child the year before or during pregnancy (n=124 553). The risk of preeclampsia was slightly increased for women who lost a close relative during the 6 months before conception (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.06-1.23) or during the first trimester of pregnancy (OR, 1.15; 95% CI, 1.03-1.29). Exposure during these periods tended to be more closely related to early preeclampsia (delivery before 34 weeks of gestation; OR, 1.37; 95% CI, 1.12-1.67) than to late preeclampsia (OR, 1.13; 95% CI, 1.06-1.20). The strongest association was observed between loss of a child and early preeclampsia when the exposure window was from 6 months before pregnancy until start of second trimester (OR, 4.03; 95% CI, 2.46-6.61). Our results related to timing of exposure suggest that severe stress may influence early placentation. However, the public health implications of our findings are limited in populations with a low prevalence of severe stress exposures.

  • 29. Lauer, Dilyara
    et al.
    Slavic, Svetlana
    Sommerfeld, Manuela
    Thoene-Reineke, Christa
    Sharkovska, Yuliya
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Dahloef, Bjorn
    Kintscher, Ulrich
    Unger, Thomas
    Steckelings, Ulrike Muscha
    Kaschina, Elena
    AT2 Receptor Agonism Regulates TIMP1/MMP9 Axis in the Heart Preventing Cardiac Fibrosis and Improving Heart Function After Experimental Myocardial Infarction2013In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 62, no 3Article in journal (Other academic)
  • 30. Lauer, Dilyara
    et al.
    Slavic, Svetlana
    Sommerfeld, Manuela
    Thoene-Reineke, Christa
    Sharkovska, Yuliya
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Dahlof, Bjorn
    Kintscher, Ulrich
    Unger, Thomas
    Steckelings, Ulrike Muscha
    Kaschina, Elena
    Angiotensin Type 2 Receptor Stimulation Ameliorates Left Ventricular Fibrosis and Dysfunction via Regulation of Tissue Inhibitor of Matrix Metalloproteinase 1/Matrix Metalloproteinase 9 Axis and Transforming Growth Factor beta 1 in the Rat Heart2014In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 63, no 3, p. E60-E67Article in journal (Refereed)
  • 31.
    Lefranc, Clara
    et al.
    Sorbonne Univ, Ctr Rech Cordeliers, INSERM, Dept Physiol,UMRS 1138,Team 1, Paris, France.
    Friederich, Malou
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Braud, Laura
    Univ Paris Est Creteil, INSERM, Dept Pathophysiol Cardiovasc & Resp Dis, Dev & Senescence,U955,Team 12, Creteil, France.
    Palacios-Ramirez, Roberto
    Sorbonne Univ, Ctr Rech Cordeliers, INSERM, Dept Physiol,UMRS 1138,Team 1, Paris, France.
    Karlsson, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Boujardine, Nabiha
    Sorbonne Univ, Ctr Rech Cordeliers, INSERM, Dept Physiol,UMRS 1138,Team 1, Paris, France.
    Motterlini, Roberto
    Univ Paris Est Creteil, INSERM, Dept Pathophysiol Cardiovasc & Resp Dis, Dev & Senescence,U955,Team 12, Creteil, France.
    Jaisser, Frederic
    Sorbonne Univ, Ctr Rech Cordeliers, INSERM, Dept Physiol,UMRS 1138,Team 1, Paris, France.
    Cat, Aurelie Nguyen Dinh
    Sorbonne Univ, Ctr Rech Cordeliers, INSERM, Dept Physiol,UMRS 1138,Team 1, Paris, France.
    MR (Mineralocorticoid Receptor) Induces Adipose Tissue Senescence and Mitochondrial Dysfunction Leading to Vascular Dysfunction in Obesity2019In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 73, no 2, p. 458-468Article in journal (Refereed)
    Abstract [en]

    Adipose tissue (AT) senescence and mitochondrial dysfunction are associated with obesity. Studies in obese patients and animals demonstrate that the MR (mineralocorticoid receptor) contributes to obesity-associated cardiovascular complications through its specific role in AT. However, underlying mechanisms remain unclear. This study aims to elucidate whether MR regulates mitochondrial function in obesity, resulting in AT premature aging and vascular dysfunction. Obese (db/db) and lean (db/+) mice were treated with an MR antagonist or a specific mitochondria-targeted antioxidant. Mitochondrial and vascular functions were determined by respirometry and myography, respectively. Molecular mechanisms were probed by Western immunoblotting and real-time polymerase chain reaction in visceral AT and arteries and focused on senescence markers and redox-sensitive pathways. db/db mice displayed AT senescence with activation of the p53-p21 pathway and decreased SIRT (sirtuin) levels, as well as mitochondrial dysfunction. Furthermore, the beneficial anticontractile effects of perivascular AT were lost in db/db via ROCK (Rho kinase) activation. MR blockade prevented these effects. Thus, MR activation in obesity induces mitochondrial dysfunction and AT senescence and dysfunction, which consequently increases vascular contractility. In conclusion, our study identifies novel mechanistic insights involving MR, adipose mitochondria, and vascular function that may be of importance to develop new therapeutic strategies to limit obesity-associated cardiovascular complications.

  • 32. Li, Yan
    et al.
    Thijs, Lutgarde
    Boggia, Jose
    Asayama, Kei
    Hansen, Tine W.
    Kikuya, Masahiro
    Bjorklund-Bodegard, Kristina
    Ohkubo, Takayoshi
    Jeppesen, Jorgen
    Torp-Pedersen, Christian
    Dolan, Eamon
    Kuznetsova, Tatiana
    Stolarz-Skrzypek, Katarzyna
    Tikhonoff, Valerie
    Malyutina, Sofia
    Casiglia, Edoardo
    Nikitin, Yuri
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sandoya, Edgardo
    Kawecka-Jaszcz, Kalina
    Filipovsky, Jan
    Imai, Yutaka
    Ibsen, Hans
    O'Brien, Eoin
    Wang, Jiguang
    Staessen, Jan A.
    Blood Pressure Load Does Not Add to Ambulatory Blood Pressure Level for Cardiovascular Risk Stratification2014In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 63, no 5, p. 925-933Article in journal (Refereed)
    Abstract [en]

    Experts proposed blood pressure (BP) load derived from 24-hour ambulatory BP recordings as a more accurate predictor of outcome than level, in particular in normotensive people. We analyzed 8711 subjects (mean age, 54.8 years; 47.0% women) randomly recruited from 10 populations. We expressed BP load as percentage (%) of systolic/diastolic readings 135/85 mm Hg and 120/70 mm Hg during day and night, respectively, or as the area under the BP curve (mm Hgxh) using the same ceiling values. During a period of 10.7 years (median), 1284 participants died and 1109 experienced a fatal or nonfatal cardiovascular end point. In multivariable-adjusted models, the risk of cardiovascular complications gradually increased across deciles of BP level and load (P<0.001), but BP load did not substantially refine risk prediction based on 24-hour systolic or diastolic BP level (generalized R-2 statistic 0.294%; net reclassification improvement 0.28%; integrated discrimination improvement 0.001%). Systolic/diastolic BP load of 40.0/42.3% or 91.8/73.6 mm Hgxh conferred a 10-year risk of a composite cardiovascular end point similar to a 24-hour systolic/diastolic BP of 130/80 mm Hg. In analyses dichotomized according to these thresholds, increased BP load did not refine risk prediction in the whole study population (R(2)0.051) or in untreated participants with 24-hour ambulatory normotension (R(2)0.034). In conclusion, BP load does not improve risk stratification based on 24-hour BP level. This also applies to subjects with normal 24-hour BP for whom BP load was proposed to be particularly useful in risk stratification.

  • 33.
    Li, Yan
    et al.
    Shanghai Jiao Tong Univ, Sch Med, Ctr Epidemiol Studies, Shanghai, Peoples R China;Shanghai Jiao Tong Univ, Clin Trials & Ctr Vasc Evaluat, Shanghai Inst Hypertens, Shanghai Key Lab Hypertens,Ruijin Hosp, Shanghai, Peoples R China.
    Thijs, Lutgarde
    Univ Leuven, Dept Cardiovasc Sci, KU Leuven, Res Unit Hypertens & Cardiovasc Epidemiol, Leuven, Belgium.
    Zhang, Zhen-Yu
    Univ Leuven, Dept Cardiovasc Sci, KU Leuven, Res Unit Hypertens & Cardiovasc Epidemiol, Leuven, Belgium.
    Asayama, Kei
    Teikyo Univ, Sch Med, Dept Hyg & Publ Hlth, Tokyo, Japan;Tohoku Inst Management Blood Pressure, Sendai, Miyagi, Japan.
    Hansen, Tine W.
    Steno Diabet Ctr Copenhagen, Gentofte, Denmark.
    Boggia, Jose
    Univ Republica, Ctr Nefrol, Montevideo, Uruguay;Univ Republica, Dept Fisiopatol, Hosp Clin, Montevideo, Uruguay.
    Bjoerklund-Bodegard, Kristina
    Karolinska Inst, Div Cardiovasc Med, Dept Clin Sci, Danderyd Hosp, Stockholm, Sweden.
    Yang, Wen-Yi
    Univ Leuven, Dept Cardiovasc Sci, KU Leuven, Res Unit Hypertens & Cardiovasc Epidemiol, Leuven, Belgium.
    Niiranen, Teemu J.
    Natl Inst Hlth & Welf, Turku, Finland;Turku Univ Hosp, Dept Med, Turku, Finland;Univ Turku, Turku, Finland.
    Ntineri, Angeliki
    Univ Athens, Hypertens Ctr STRIDE 7, Sch Med, Sotiria Hosp,Dept Med 3, Athens, Greece.
    Wei, Fang-Fei
    Univ Leuven, Dept Cardiovasc Sci, KU Leuven, Res Unit Hypertens & Cardiovasc Epidemiol, Leuven, Belgium.
    Kikuya, Masahiro
    Teikyo Univ, Sch Med, Dept Hyg & Publ Hlth, Tokyo, Japan.
    Ohkubo, Takayoshi
    Teikyo Univ, Sch Med, Dept Hyg & Publ Hlth, Tokyo, Japan;Tohoku Inst Management Blood Pressure, Sendai, Miyagi, Japan.
    Dolan, Eamon
    Stroke & Hypertens Unit, Dublin, Ireland.
    Hozawa, Atsushi
    Tohoku Univ, Tohoku Med Megabank Org, Dept Prevent Med & Epidemiol, Sendai, Miyagi, Japan.
    Tsuji, Ichiro
    Tohoku Univ, Dept Publ Hlth, Grad Sch Med, Sendai, Miyagi, Japan.
    Stolarz-Skrzypek, Katarzyna
    Jagiellonian Univ, Dept Cardiol 1, Intervent Electrocardiol & Hypertens, Coll Med, Krakow, Poland.
    Huang, Qi-Fang
    Shanghai Jiao Tong Univ, Sch Med, Ctr Epidemiol Studies, Shanghai, Peoples R China;Shanghai Jiao Tong Univ, Clin Trials & Ctr Vasc Evaluat, Shanghai Inst Hypertens, Shanghai Key Lab Hypertens,Ruijin Hosp, Shanghai, Peoples R China.
    Melgarejo, Jesus D.
    Univ Zulia, Lab Neurociencias, Maracaibo, Venezuela;Univ Zulia, Inst Cardiovasc, Maracaibo, Venezuela.
    Tikhonoff, Valerie
    Univ Padua, Dept Med, Padua, Italy.
    Malyutina, Sofia
    Russian Acad Sci, Inst Internal & Prevent Med Internal & Prevent Me, Inst Cytol & Genet, Siberian Branch, Novosibirsk, Russia.
    Casiglia, Edoardo
    Univ Padua, Dept Med, Padua, Italy.
    Nikitin, Yuri
    Russian Acad Sci, Inst Internal & Prevent Med Internal & Prevent Me, Inst Cytol & Genet, Siberian Branch, Novosibirsk, Russia.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sandoya, Edgardo
    Asociac Espanola Primera Socorros Mutuos, Montevideo, Uruguay.
    Aparicio, Lucas
    Univ Buenos Aires, Hosp Italiano Buenos Aires, Dept Med, Buenos Aires, DF, Argentina.
    Barochiner, Jessica
    Univ Buenos Aires, Hosp Italiano Buenos Aires, Dept Med, Buenos Aires, DF, Argentina.
    Gilis-Malinowska, Natasza
    Med Univ Gdansk, Dept Hypertens, Gdansk, Poland.
    Narkiewicz, Krzysztof
    Med Univ Gdansk, Dept Hypertens, Gdansk, Poland.
    Kawecka-Jaszcz, Kalina
    Jagiellonian Univ, Dept Cardiol 1, Intervent Electrocardiol & Hypertens, Coll Med, Krakow, Poland.
    Maestre, Gladys E.
    Univ Zulia, Lab Neurociencias, Maracaibo, Venezuela;Univ Zulia, Inst Cardiovasc, Maracaibo, Venezuela;Univ Texas Rio Grande Valley, Dept Neurosci, Brownsville, TX USA;Univ Texas Rio Grande Valley, Dept Human Genet, Brownsville, TX USA.
    Jula, Antti M.
    Natl Inst Hlth & Welf, Turku, Finland.
    Johansson, Jouni K.
    Natl Inst Hlth & Welf, Turku, Finland.
    Kuznetsova, Tatiana
    Univ Leuven, Dept Cardiovasc Sci, KU Leuven, Res Unit Hypertens & Cardiovasc Epidemiol, Leuven, Belgium.
    Filipovsky, Jan
    Charles Univ Prague, Fac Med, Plzen, Czech Republic.
    Stergiou, George
    Univ Athens, Hypertens Ctr STRIDE 7, Sch Med, Sotiria Hosp,Dept Med 3, Athens, Greece.
    Wang, Ji-Guang
    Shanghai Jiao Tong Univ, Sch Med, Ctr Epidemiol Studies, Shanghai, Peoples R China;Shanghai Jiao Tong Univ, Clin Trials & Ctr Vasc Evaluat, Shanghai Inst Hypertens, Shanghai Key Lab Hypertens,Ruijin Hosp, Shanghai, Peoples R China.
    Imai, Yutaka
    Tohoku Inst Management Blood Pressure, Sendai, Miyagi, Japan.
    O'Brien, Eoin
    Univ Coll Dublin, Conway Inst, Dublin, Ireland.
    Staessen, Jan A.
    Univ Leuven, Dept Cardiovasc Sci, KU Leuven, Res Unit Hypertens & Cardiovasc Epidemiol, Leuven, Belgium;Maastricht Univ, Cardiovasc Res Inst Maastricht CARIM, Maastricht, Netherlands.
    Opposing Age-Related Trends in Absolute and Relative Risk of Adverse Health Outcomes Associated With Out-of-Office Blood Pressure2019In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 74, no 6, p. 1333-1342Article in journal (Refereed)
    Abstract [en]

    Participant-level meta-analyses assessed the age-specific relevance of office blood pressure to cardiovascular complications, but this information is lacking for out-of-office blood pressure. At baseline, daytime ambulatory (n=12 624) or home (n=5297) blood pressure were measured in 17 921 participants (51.3% women; mean age, 54.2 years) from 17 population cohorts. Subsequently, mortality and cardiovascular events were recorded. Using multivariable Cox regression, floating absolute risk was computed across 4 age bands (<= 60, 61-70, 71-80, and >80 years). Over 236 491 person-years, 3855 people died and 2942 cardiovascular events occurred. From levels as low as 110/65 mm Hg, risk log-linearly increased with higher out-of-office systolic/diastolic blood pressure. From the youngest to the oldest age group, rates expressed per 1000 person-years increased (P<0.001) from 4.4 (95% CI, 4.0-4.7) to 86.3 (76.1-96.5) for all-cause mortality and from 4.1 (3.9-4.6) to 59.8 (51.0-68.7) for cardiovascular events, whereas hazard ratios per 20-mm Hg increment in systolic out-of-office blood pressure decreased (P <= 0.0033) from 1.42 (1.19-1.69) to 1.09 (1.05-1.12) and from 1.70 (1.51-1.92) to 1.12 (1.07-1.17), respectively. These age-related trends were similar for out-of-office diastolic pressure and were generally consistent in both sexes and across ethnicities. In conclusion, adverse outcomes were directly associated with out-of-office blood pressure in adults. At young age, the absolute risk associated with out-of-office blood pressure was low, but relative risk high, whereas with advancing age relative risk decreased and absolute risk increased. These observations highlight the need of a lifecourse approach for the management of hypertension.

  • 34.
    Palm, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Connors, Stephanie G
    Mendonca, Margarida
    Welch, William J
    Wilcox, Christopher S
    Angiotensin II Type 2 Receptors and Nitric Oxide Sustain Oxygenation in the Clipped Kidney of Early Goldblatt Hypertensive Rats2008In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 51, no 2, p. 345-351Article in journal (Refereed)
    Abstract [en]

    Angiotensin-converting enzyme inhibitors (ACEIs) decrease the glomerular filtration rate and renal blood flow in the clipped kidneys of early 2-kidney, 1-clip Goldblatt hypertensive rats, but the consequences for oxygenation are unclear. We investigated the hypothesis that angiotensin II type 1 or angiotensin II type 2 receptors or NO synthase mediate renal oxygenation responses to ACEI. Three weeks after left renal artery clipping, kidney function, oxygen (O2) use, renal blood flow, renal cortical blood flow, and renal cortical oxygen tension (PO2) were measured after acute administration of an ACEI (enalaprilat) and after acute administration of ACEI following acute administration of an angiotensin II type 1 or angiotensin II type 2 receptor blocker (candesartan or PD-123,319) or an NO synthase blocker (NG-nitro-L-arginine methyl ester with control of renal perfusion pressure) and compared with mechanical reduction in renal perfusion pressure to the levels after ACEI. The basal renal cortical PO2 of clipped kidneys was significantly lower than contralateral kidneys (35±1 versus 51±1 mm Hg; n=40 each). ACEI lowered renal venous PO2, cortical PO2, renal blood flow, glomerular filtration rate, and cortical blood flow and increased the renal vascular resistance in the clipped kidney, whereas mechanical reduction in renal perfusion pressure was ineffective. PD-123,319 and NG-nitro-L-arginine methyl ester, but not candesartan, reduced the PO2 of clipped kidneys and blocked the fall in PO2 with acute ACEI administration. In conclusion, oxygen availability in the clipped kidney is maintained by angiotensin II generation, angiotensin II type 2 receptors, and NO synthase. This discloses a novel mechanism whereby angiotensin can prevent hypoxia in a kidney challenged with a reduced perfusion pressure.

  • 35.
    Palm, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Onozato, Maristela
    Georgetown University.
    Welch, William J
    Georgetown University.
    Wilcox, Christopher S
    Georgetown University.
    Blood pressure, blood flow, and oxygenation in the clipped kidney of chronic 2-kidney, 1-clip rats: effects of tempol and Angiotensin blockade2010In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 55, no 2, p. 298-304Article in journal (Refereed)
    Abstract [en]

    Angiotensin II maintains renal cortical blood flow and renal oxygenation in the clipped kidney of early 2-kidney, 1-clip Goldblatt hypertensive (2K,1C) rats. The involvement of Ang II is believed to decline, whereas oxidative stress increases during the progression of 2K,1C hypertension. We investigated the hypothesis that the acute administration of drugs to inhibit reactive oxygen species (Tempol), angiotensin II type 1 receptors (candesartan), or angiotensin-converting enzyme (enalaprilat) lowers mean arterial pressure and increases kidney blood flow and oxygenation in the clipped kidney of chronic 2K,1C rats in contrast to sham controls. Twelve months after left renal artery clipping or sham, mean arterial pressure, renal cortical blood flow, and renal cortical and medullary oxygen tension were measured after acute administration of Tempol followed by enalaprilat or candesartan followed by enalaprilat. The mean arterial pressure of the 2K,1C rat was reduced by candesartan (-9%) and, more effectively, by Tempol (-35%). All of the applied treatments had similar blood pressure-lowering effects in sham rats (average: -21%). Only Tempol increased cortical blood flow (+35%) and cortical and medullary oxygen tensions (+17% and +94%, respectively) in clipped kidneys of 2K,1C rats. Administration of enalaprilat had no additional effect, except for a modest reduction in cortical blood flow in the clipped kidney of 2K,1C rats when coadministered with candesartan (-10%). In conclusion, acute administration of Tempol is more effective than candesartan in reducing the mean arterial blood pressure and improving renal blood perfusion and oxygenation in the clipped kidney of chronic 2K,1C rats.

  • 36.
    Parikh, Nisha I.
    et al.
    Univ Calif San Francisco, Dept Med, Div Cardiol, San Francisco, CA 94143 USA..
    Norberg, Margareta
    Umea Univ, Dept Publ Hlth & Clin Med, Epidemiol & Global Hlth, S-90187 Umea, Sweden..
    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. Stanford Univ, Dept Med, Div Cardiovasc Med, Sch Med, Stanford, CA 94305 USA..
    Cnattingius, Sven
    Karolinska Inst, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden..
    Vasan, Ramachandran S.
    Boston Univ, Sch Med, Prevent Med Sect, Boston, MA 02215 USA.;Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02215 USA.;Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA..
    Domellof, Magnus
    Umea Univ, Pediat Unit, Dept Clin Sci, S-90187 Umea, Sweden..
    Jansson, Jan Hakan
    Umea Univ, Dept Publ Hlth & Clin Med, Res Unit Skelleftea, S-90187 Umea, Sweden..
    Bonamy, Anna-Karin Edstedt
    Karolinska Inst, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden.;Karolinska Inst, Dept Womens Childrens Hlth, Stockholm, Sweden..
    Association of Pregnancy Complications and Characteristics With Future Risk of Elevated Blood Pressure The Västerbotten Intervention Program2017In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 69, no 3, p. 475-483Article in journal (Refereed)
    Abstract [en]

    Pregnancy characteristics are associated with risk of cardiovascular diseases, but their independent associations with hypertension or blood pressure (BP) levels remain uncertain. We linked the Swedish Medical Birth Register with Vesterbotten Intervention Program data (Northern Sweden). Using linear and logistic regression, we related pregnancy factors in any prior pregnancy with BP and hypertension at 40 years of age in 15 896 parous women free of prepregnancy hypertension. Pregnancy factors included parity, age at first delivery, preeclampsia, gestational diabetes mellitus, placental abruption, shortest gestational age small for gestational age baby (<third percentile for birth weight) or stillbirth. We defined hypertension as systolic BP >= 140 mm Hg and diastolic BP >= 90 mm Hg or antihypertensive use. Multivariable models were adjusted for all pregnancy factors and potential lifestyle and sociodemographic confounders. At 40 years of age, 1535 women (9.6%) had hypertension. In multivariable models, lower parity, younger age at first birth, preeclampsia, small for gestational age, and placental abruption were independently associated with higher systolic and diastolic BP levels at 40 years of age. Younger age at first birth, preeclampsia, gestational age <32 versus >= 37 weeks, and small for gestational age were independently associated with hypertension. Our findings raise the possibility that earlier and more frequent BP screening may be desirable in women with these pregnancy characteristics.

  • 37.
    Persson, Patrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Fasching, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Teerlink, Tom
    Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.
    Hansell, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    L-Citrulline, But Not L-Arginine, Prevents Diabetes Mellitus–Induced Glomerular Hyperfiltration and Proteinuria in Rat2014In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 64, no 2, p. 323-329Article in journal (Refereed)
    Abstract [en]

    Diabetes mellitus–induced oxidative stress causes increased renal oxygen consumption and intrarenal tissue hypoxia. Nitric oxide is an important determinant of renal oxygen consumption and electrolyte transport efficiency. The present study investigates whether l-arginine or l-citrulline to promote nitric oxide production prevents the diabetes mellitus–induced kidney dysfunction. Glomerular filtration rate, renal blood flow, in vivo oxygen consumption, tissue oxygen tension, and proteinuria were investigated in control and streptozotocin-diabetic rats with and without chronic l-arginine or l-citrulline treatment for 3 weeks. Untreated and l-arginine–treated diabetic rats displayed increased glomerular filtration rate (2600±162 versus 1599±127 and 2290±171 versus 1739±138 µL/min per kidney), whereas l-citrulline prevented the increase (1227±126 versus 1375±88 µL/min per kidney). Filtration fraction was increased in untreated diabetic rats because of the increase in glomerular filtration rate but not in l-arginine– or l-citrulline–treated diabetic rats. Urinary protein excretion was increased in untreated and l-arginine–treated diabetic rats (142±25 versus 75±7 and 128±7 versus 89±7 µg/min per kidney) but not in diabetic rats administered l-citrulline (67±7 versus 61±5 µg/min per kidney). The diabetes mellitus–induced tissue hypoxia, because of elevated oxygen consumption, was unaltered by any of the treatments. l-citrulline administered to diabetic rats increases plasma l-arginine concentration, which prevents the diabetes mellitus–induced glomerular hyperfiltration, filtration fraction, and proteinuria, possibly by a vascular effect.

  • 38. Roberts, James M
    et al.
    Mascalzoni, Deborah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Ness, Roberta B
    Poston, Lucilla
    Collaboration to Understand Complex Diseases: Preeclampsia and Adverse Pregnancy Outcomes2016In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 67, no 4, p. 681-687Article, review/survey (Refereed)
  • 39. Rompe, Franziska
    et al.
    Artuc, Metin
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Alterman, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Stroeder, Katja
    Thoene-Reineke, Christa
    Reichenbach, Anne
    Schacherl, Jens
    Dahlöf, Björn
    Bader, Michael
    Alenina, Natalia
    Schwaninger, Markus
    Zuberbier, Torsten
    Funke-Kaiser, Heiko
    Schmidt, Cosima
    Schunck, Wolf-Hagen
    Unger, Thomas
    Steckelings, U. Muscha
    Direct Angiotensin II Type 2 Receptor Stimulation Acts Anti-Inflammatory Through Epoxyeicosatrienoic Acid and Inhibition of Nuclear Factor kappa B2010In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 55, no 4, p. 924-931Article in journal (Refereed)
    Abstract [en]

    Angiotensin II type 2 (AT(2)) receptors can be regarded as an endogenous repair system, because the AT(2) receptor is upregulated in tissue damage and mediates tissue protection. A potential therapeutic use of this system has only recently come within reach through synthesis of the first selective, orally active, nonpeptide AT(2) receptor agonist, compound 21 (C21; dissociation constant for AT(2) receptor: 0.4 nM; dissociation constant for angiotensin II type 1 receptor: >10 000 nM). This study tested AT(2) receptor stimulation with C21 as a potential future therapeutic approach for the inhibition of proinflammatory cytokines and of nuclear factor kappa B. C21 dose-dependently (1 nM to 1 mu mol/L) reduced tumor necrosis factor-alpha-induced interleukin 6 levels in primary human and murine dermal fibroblasts. AT(2) receptor specificity was controlled for by inhibition with the AT(2) receptor antagonist PD123319 and by the absence of effects in AT(2) receptor-deficient cells. AT(2) receptor-coupled signaling leading to reduced interleukin 6 levels involved inhibition of nuclear factor kappa B, activation of protein phosphatases, and synthesis of epoxyeicosatrienoic acid. Inhibition of interleukin 6 promoter activity by C21 was comparable in strength to inhibition by hydrocortisone. C21 also reduced monocyte chemoattractant protein 1 and tumor necrosis factor-alpha in vitro and in bleomycin-induced toxic cutaneous inflammation in vivo. This study is the first to show the anti-inflammatory effects of direct AT(2) receptor stimulation in vitro and in vivo by the orally active, nonpeptide AT(2) receptor agonist C21. These data suggest that pharmacological AT(2) receptor stimulation may be an orally applicable future therapeutic approach in pathological settings requiring the reduction of interleukin 6 or inhibition of nuclear factor kappa B.

  • 40. Skoglund, Per H.
    et al.
    Hoijer, Jonas
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Svensson, Per
    Amino-Terminal Pro-B-Type Natriuretic Peptide Improves Discrimination for Incident Atherosclerotic Cardiovascular Disease Beyond Ambulatory Blood Pressure in Elderly Men2015In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 66, no 3, p. 681-686Article in journal (Refereed)
    Abstract [en]

    Improvement of risk prediction for atherosclerotic cardiovascular disease (ASCVD) is needed. Both ambulatory blood pressure (ABP) and biomarkers amino-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein and cystatin C improve risk prediction but they have not been evaluated in relation to each other. We analyzed whether NT-proBNP, high-sensitivity C-reactive protein, or cystatin C improved risk prediction beyond traditional ASCVD risk factors combined with 24-hour systolic BP (SBP). Secondary aim was to evaluate whether ABP improved risk prediction when compared with models with the biomarkers. We followed up 907 70-year-old men, free of baseline disease, for incident ASCVD defined as fatal or nonfatal myocardial infarction or fatal or nonfatal stroke for a median of 10 years. Cox regression was used to estimate the association between variables in the models and incident ASCVD. Biomarkers were added to a model containing both traditional risk factors and ABP and the models were compared on C-statistics and net reclassification improvement. Twenty-four hour SBP improved discrimination for incident ASCVD when compared with office SBP in a traditional risk factor model (area under the receiver-operating characteristic curve, +2.4%). NT-proBNP further improved reclassification (+18.7%-19.9%; P<0.01) when added to ABP models, whereas high-sensitivity C-reactive protein and cystatin C did not. Twenty-four hour SBP significantly improved net reclassification when added to a traditional risk factor model that included NT-proBNP. The combination of 24-hour SBP and NT-proBNP improved discrimination and net reclassification for incident ASCVD when compared with office SBP in elderly men. NT-proBNP, but not high-sensitivity C-reactive protein or cystatin C, improved risk prediction and discrimination when added to a model that included ABP.

  • 41.
    Wain, Louise V.
    et al.
    Univ Leicester, Dept Hlth Sci, Leicester, Leics, England..
    Vaez, Ahmad
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands.;Isfahan Univ Med Sci, Res Inst Primordial Prevent Noncommunicable Dis, Tehran, Iran..
    Jansen, Rick
    Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Neurosci Campus Amsterdam, Amsterdam, Netherlands..
    Joehanes, Roby
    Harvard Med Sch, Hebrew SeniorLife, Boston, MA USA.;Framingham Heart Dis Epidemiol Study, Natl Heart Lung & Blood Inst, Framingham, MA USA..
    van der Most, Peter J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Erzurumluoglu, A. Mesut
    Univ Leicester, Dept Hlth Sci, Leicester, Leics, England..
    O'Reilly, Paul F.
    Kings Coll London, Inst Psychiat Psychol & Neurosci, London, England. Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England..
    Cabrera, Claudia P.
    William Harvey Res Inst, Clin Pharmacol, London, England.;Queen Mary Univ London, NIHR Barts Cardiovasc Biomed Res Unit, Barts & London Sch Med & Dent, London, England..
    Warren, Helen R.
    William Harvey Res Inst, Clin Pharmacol, London, England.;Queen Mary Univ London, NIHR Barts Cardiovasc Biomed Res Unit, Barts & London Sch Med & Dent, London, England..
    Rose, Lynda M.
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA..
    Verwoert, Germaine C.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Hottenga, Jouke-Jan
    Vrije Univ, VU Univ Med Ctr, EMGO Inst, Dept Biol Psychol, Amsterdam, Netherlands..
    Strawbridge, Rona J.
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.;Karolinska Univ, Ctr Mol Med, Solna, Sweden..
    Esko, Tonu
    Childrens Hosp, Div Endocrinol, Boston, MA USA.;Broad Inst Harvard & MIT, Cambridge, MA USA..
    Arking, Dan E.
    Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Sch Med, Baltimore, MD USA..
    Hwang, Shih-Jen
    NHLBI, Populat Sci Branch, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA.;Framingham Heart Dis Epidemiol Study, Framingham, MA USA..
    Guo, Xiuqing
    Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Dept Pediat, Torrance, CA USA..
    Kutalik, Zoltan
    Univ Lausanne Hosp, Inst Social & Prevent Med, Lausanne, Switzerland.;Swiss Inst Bioinformat, Lausanne, Switzerland..
    Trompet, Stella
    Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands.;Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands.;Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands..
    Shrine, Nick
    Univ Leicester, Dept Hlth Sci, Leicester, Leics, England..
    Teumer, Alexander
    Univ Med Greifswald, Inst Community Med, Greifswald, Germany.;DZHK German Ctr Cardiovasc Res, Greifswald, Germany..
    Ried, Janina S.
    Helmholtz Zentrum Munchen, Inst Epidemiol 2, Munich, Germany..
    Bis, Joshua C.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA..
    Smith, Albert V.
    Icelandic Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Amin, Najaf
    Erasmus MC, Genet Epidemiol Unit, Dept Epidemiol, Rotterdam, Netherlands..
    Nolte, Ilja M.
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Lyytikainen, Leo-Pekka
    Fimlab Labs, Dept Clin Chem, Tampere, Finland.;Univ Tampere, Fac Med & Life Sci, Dept Clin Chem, Tampere, Finland..
    Mahajan, Anubha
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Wareham, Nicholas J.
    Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Inst Metab Sci, Cambridge, England..
    Hofer, Edith
    Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, Graz, Austria.;Med Univ Graz, Inst Med Informat Stat & Documentat, Graz, Austria..
    Joshi, Peter K.
    Univ Edinburgh, Ctr Global Hlth Res, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland..
    Kristiansson, Kati
    Dept Hlth, Helsinki, Finland. Chron Dis Prevent Unit, Helsinki, Finland. Natl Inst Hlth & Welf, Helsinki, Finland..
    Traglia, Michela
    Ist Sci San Raffaele, Div Genet & Cell Biol, Milan, Italy..
    Havulinna, Aki S.
    Dept Hlth, Helsinki, Finland. Chron Dis Prevent Unit, Helsinki, Finland. Natl Inst Hlth & Welf, Helsinki, Finland..
    Goel, Anuj
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England..
    Nalls, Mike A.
    NIA, Neurogenet Lab, Bethesda, MD 20892 USA.;Data Tecn Int, Glen Echo, MD USA..
    Sober, Siim
    Univ Tartu, Inst Biomed & Translat Med, Tartu, Estonia..
    Vuckovic, Dragana
    IRCCS Burlo Garofolo Children Hosp, Med Genet, Trieste, Italy.;Univ Trieste, Dept Med Surg & Hlth Sci, Trieste, Italy..
    Luan, Jian'an
    Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Inst Metab Sci, Cambridge, England..
    Del Greco M, Fabiola
    Univ Lubeck, Inst Biomed, Affiliated Inst, Eurac Res, Bolzano, Italy..
    Ayers, Kristin L.
    Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY USA.;Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY USA..
    Marrugat, Jaume
    IMIM, Cardiovasc Epidemiol & Genet, Barcelona, Spain.;CIBERCV, Barcelona, Spain..
    Ruggiero, Daniela
    CNR, Inst Genet & Biophys A Buzzati Traverso, Naples, Italy..
    Lopez, Lorna M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland.;Beaumont Hosp, Dept Psychiat, Royal Coll Surg Ireland, Educ & Res Ctr, Dublin, Ireland.;Univ Coll Dublin, UCD Conway Inst, Ctr Proteome Res, Belfield, Ireland.;Univ Coll Dublin, Sch Med, Conway Inst, Belfield, Ireland..
    Niiranen, Teemu
    Dept Hlth, Helsinki, Finland. Chron Dis Prevent Unit, Helsinki, Finland. Natl Inst Hlth & Welf, Helsinki, Finland..
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jackson, Anne U.
    Univ Michigan, Dept Biostat, Ann Arbor, MI USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI USA..
    Nelson, Christopher P.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Univ Leicester, NIHR Leicester Biomed Res Ctr, Leicester, Leics, England.;Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England.;Univ Edinburgh, Western Gen Hosp, MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland..
    Huffman, Jennifer E.
    Univ Edinburgh, MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Western Gen Hosp, MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland..
    Zhang, Weihua
    Imperial Coll London, Dept Epidemiol & Biostat, Sch Publ Hlth, London, England.;London North West Healthcare NHS Trust, Ealing Hosp, Dept Cardiol, Southall, Middx, England..
    Marten, Jonathan
    Univ Edinburgh, MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Western Gen Hosp, MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland..
    Gandin, Ilaria
    Univ Trieste, Dept Med Surg & Hlth Sci, Trieste, Italy..
    Harris, Sarah E.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Western Gen Hosp, MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Western Gen Hosp, Med Genet Sect, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Western Gen Hosp, MRC Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland..
    Zemunik, Tatijana
    London North West Healthcare NHS Trust, Dept Med Biol, Fac Med, Southall, Middx, England..
    Lu, Yingchang
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY USA..
    Evangelou, Evangelos
    Imperial Coll London, Dept Epidemiol & Biostat, Sch Publ Hlth, London, England.;Univ Ioannina, Dept Hyg & Epidemiol, Sch Med, Ioannina, Greece..
    Shah, Nabi
    Univ Dundee, Med Res Inst, Ninewells Hosp, Dundee, Scotland.;Univ Dundee, Sch Med, Dundee, Scotland.;COMSATS Inst Informat Technol, Dept Pharm, Abbottabad, Pakistan..
    de Borst, Martin H.
    Univ Groningen, Univ Med Ctr Groningen, Div Nephrol, Dept Internal Med, Groningen, Netherlands..
    Mangino, Massimo
    Natl Inst Hlth Res, Biomed Res Ctr, London, England..
    Prins, Bram P.
    Wellcome Trust Sanger Inst, Dept Human Genet, London, England..
    Campbell, Archie
    Univ Edinburgh, Med Genet Sect, Ctr Genom & Expt Med, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Med Genet Sect, Ctr Genom & Expt Med, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Generat Scotland, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland..
    Li-Gao, Ruifang
    Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands..
    Chauhan, Ganesh
    Bordeaux Populat Hlth Ctr, INSERM U 1219, Bordeaux, France.;Bordeaux Univ, Bordeaux, France..
    Oldmeadow, Christopher
    Hunter Med Res Inst, New Lambton, NSW, Australia..
    Abecasis, Goncalo
    Ctr Stat Genet, Dept Biostat, Ann Arbor, MI USA..
    Abedi, Maryam
    Isfahan Univ Med Sci, Dept Genet & Mol Biol, Esfahan, Iran..
    Barbieri, Caterina M.
    Ist Sci San Raffaele, Div Genet & Cell Biol, Milan, Italy..
    Barnes, Michael R.
    William Harvey Res Inst, Clin Pharmacol, London, England.;Queen Mary Univ London, NIHR Barts Cardiovasc Biomed Res Unit, Barts & London Sch Med & Dent, London, England..
    Batini, Chiara
    Univ Leicester, Dept Hlth Sci, Leicester, Leics, England..
    Beilby, John
    Busselton Populat Med Res Inst, Nedlands, WA, Australia.;PathWest Lab Med Western Australia, Nedlands, WA, Australia.;Univ Western Australia, Sch Pathol & Lab Med, Nedlands, WA, Australia..
    Blake, Tineka
    Univ Leicester, Dept Hlth Sci, Leicester, Leics, England..
    Boehnke, Michael
    Univ Michigan, Dept Biostat, Ann Arbor, MI USA.;Univ Michigan, Ctr Stat Genet, Ann Arbor, MI USA..
    Bottinger, Erwin P.
    Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY USA..
    Braund, Peter S.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Univ Leicester, NIHR Leicester Biomed Res Ctr, Leicester, Leics, England.;Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England.;Univ Edinburgh, Western Gen Hosp, MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland..
    Brown, Morris
    William Harvey Res Inst, Clin Pharmacol, London, England.;Queen Mary Univ London, NIHR Barts Cardiovasc Biomed Res Unit, Barts & London Sch Med & Dent, London, England..
    Brumat, Marco
    Univ Trieste, Dept Med Surg & Hlth Sci, Trieste, Italy..
    Campbell, Harry
    Univ Edinburgh, Ctr Global Hlth Res, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland..
    Chambers, John C.
    Imperial Coll London, Dept Epidemiol & Biostat, Sch Publ Hlth, London, England.;London North West Healthcare NHS Trust, Ealing Hosp, Dept Cardiol, Southall, Middx, England.;Imperial Coll Healthcare NHS Trust, London, England..
    Cocca, Massimiliano
    Univ Trieste, Dept Med Surg & Hlth Sci, Trieste, Italy..
    Collins, Francis
    NHGRI, Med Genom & Metab Genet Branch, Bethesda, MD 20892 USA..
    Connell, John
    Univ Dundee, Ninewells Hosp & Med Sch, Dundee, Scotland..
    Cordell, Heather J.
    Newcastle Univ, Inst Med Genet, Newcastle Upon Tyne, Tyne & Wear, England..
    Damman, Jeffrey J.
    Amsterdam Med Ctr, Dept Pathol, Amsterdam, Netherlands..
    Davies, Gail
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland..
    de Geus, Eco J.
    Vrije Univ, VU Univ Med Ctr, EMGO Inst, Dept Biol Psychol, Amsterdam, Netherlands..
    de Mutsert, Renee
    Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands..
    Deelen, Joris
    Leiden Univ, Med Ctr, Dept Mol Epidemiol, Leiden, Netherlands..
    Demirkale, Yusuf
    NIH, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA..
    Doney, Alex S. F.
    Univ Dundee, Med Res Inst, Ninewells Hosp, Dundee, Scotland.;Univ Dundee, Sch Med, Dundee, Scotland..
    Dorr, Marcus
    Univ Med Greifswald, Dept Internal Med, Greifswald, Germany.;Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany.;DZHK German Ctr Cardiovasc Res, Greifswald, Germany..
    Farrall, Martin
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England..
    Ferreira, Teresa
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Franberg, Mattias
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.;Karolinska Univ, Ctr Mol Med, Solna, Sweden.;Stockholm Univ, Dept Numer Anal & Comp Sci, Stockholm, Sweden..
    Gao, He
    Imperial Coll London, Dept Epidemiol & Biostat, Sch Publ Hlth, London, England..
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Gieger, Christian
    Forschungszentrum Gesundheit & Umwelt GmbH, Neuherberg, Germany..
    Giulianini, Franco
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA..
    Gow, Alan J.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland.;Heriot Watt Univ, Sch Social Sci, Dept Psychol, Edinburgh, Midlothian, Scotland..
    Hamsten, Anders
    Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden.;Karolinska Univ, Ctr Mol Med, Solna, Sweden..
    Harris, Tamara B.
    NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA..
    Hofman, Albert
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA..
    Holliday, Elizabeth G.
    Hunter Med Res Inst, New Lambton, NSW, Australia..
    Hui, Jennie
    Busselton Populat Med Res Inst, Nedlands, WA, Australia.;PathWest Lab Med Western Australia, Nedlands, WA, Australia.;Univ Western Australia, Sch Pathol & Lab Med, Nedlands, WA, Australia.;Univ Western Australia, Sch Populat & Global Hlth, Nedlands, WA, Australia..
    Jarvelin, Marjo-Riitta
    Imperial Coll London, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, Sch Publ Hlth, London, England.;Univ Oulu, Ctr Life Course Hlth Res, Oulu, Finland.;Univ Oulu, Bioctr Oulu, Oulu, Finland.;Oulu Univ Hosp, Unit Primary Care, Oulu, Finland..
    Johansson, Åsa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Johnson, Andrew D.
    Framingham Heart Dis Epidemiol Study, Natl Heart Lung & Blood Inst, Framingham, MA USA.;NHLBI, Cardiovasc Epidemiol & Human Genom Branch, Bldg 10, Bethesda, MD 20892 USA..
    Jousilahti, Pekka
    Dept Hlth, Helsinki, Finland. Chron Dis Prevent Unit, Helsinki, Finland. Natl Inst Hlth & Welf, Helsinki, Finland..
    Jula, Antti
    Dept Hlth, Helsinki, Finland. Chron Dis Prevent Unit, Helsinki, Finland. Natl Inst Hlth & Welf, Helsinki, Finland..
    Kahonen, Mika
    Tampere Univ Hosp, Dept Clin Physiol, Tampere, Finland.;Univ Tampere, Dept Clin Physiol, Fac Med & Life Sci, Tampere, Finland..
    Kathiresan, Sekar
    Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Ctr Human Genet, Boston, MA 02114 USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Khaw, Kay-Tee
    Univ Cambridge, Dept Publ Hlth & Primary Care, Inst Publ Hlth, Cambridge, England..
    Kolcic, Ivana
    Univ Split, Dept Publ Hlth, Fac Med, Split, Croatia..
    Koskinen, Seppo
    Dept Hlth, Helsinki, Finland. Chron Dis Prevent Unit, Helsinki, Finland. Natl Inst Hlth & Welf, Helsinki, Finland..
    Langenberg, Claudia
    Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Inst Metab Sci, Cambridge, England..
    Larson, Marty
    Framingham Heart Dis Epidemiol Study, Natl Heart Lung & Blood Inst, Framingham, MA USA..
    Launer, Lenore J.
    NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA..
    Lehne, Benjamin
    Imperial Coll London, Dept Epidemiol & Biostat, Sch Publ Hlth, London, England..
    Liewald, David C. M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland..
    Lin, Li
    Univ Hosp Geneva, Dept Med Specialties, Cardiol, Geneva, Switzerland..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Mach, Francois
    Univ Hosp Geneva, Dept Med Specialties, Cardiol, Geneva, Switzerland..
    Mamasoula, Chrysovalanto
    Newcastle Univ, Inst Hlth & Soc, Newcastle Upon Tyne, Tyne & Wear, England..
    Menni, Cristina
    Mifsud, Borbala
    William Harvey Res Inst, Clin Pharmacol, London, England..
    Milaneschi, Yuri
    Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Dept Psychiat, Amsterdam, Netherlands..
    Morgan, Anna
    Univ Trieste, Dept Med Surg & Hlth Sci, Trieste, Italy..
    Morris, Andrew D.
    Univ Edinburgh, Sch Mol Genet & Populat Hlth Sci, Sch Med, Teviot Pl, Edinburgh, Midlothian, Scotland..
    Morrison, Alanna C.
    Univ Texas Hlth Sci Ctr Houston, Dept Epidemiol Human Genet & Environm Sci, Sch Publ Hlth, Houston, TX USA..
    Munson, Peter J.
    NIH, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA..
    Nandakumar, Priyanka
    Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Sch Med, Baltimore, MD USA..
    Nguyen, Quang Tri
    Nutile, Teresa
    CNR, Inst Genet & Biophys A Buzzati Traverso, Naples, Italy..
    Oldehinkel, Albertine J.
    Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, Groningen, Netherlands..
    Oostra, Ben A.
    Erasmus MC, Genet Epidemiol Unit, Dept Epidemiol, Rotterdam, Netherlands..
    Org, Elin
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    Padmanabhan, Sandosh
    Univ Edinburgh, Generat Scotland, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland.;Univ Glasgow, British Heart Fdn, Glasgow Cardiovasc Res Ctr, Inst Cardiovasc & Med Sci,Coll Med Vet & Life Sci, Glasgow, Lanark, Scotland.;Univ Glasgow, Inst Cardiovasc & Med Sci, Fac Med, Glasgow, Lanark, Scotland..
    Palotie, Aarno
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland..
    Pare, Guillaume
    McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada..
    Pattie, Alison
    Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland..
    Penninx, Brenda W. J. H.
    Vrije Univ Amsterdam Med Ctr, EMGO Inst Hlth & Care Res, Dept Psychiat, Amsterdam, Netherlands..
    Poulter, Neil
    Imperial Coll London, Sch Publ Hlth, London, England..
    Pramstaller, Peter P.
    Univ Lubeck, Inst Biomed, Affiliated Inst, Eurac Res, Bolzano, Italy.;Dept Neurol, Gen Cent Hosp, Bolzano, Italy.;Univ Lubeck, Dept Neurol, Lubeck, Germany..
    Raitakari, Olli T.
    Turku Univ Hosp, Dept Clin Physiol & Nucl Med, Turku, Finland.;Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland..
    Ren, Meixia
    William Harvey Res Inst, Clin Pharmacol, London, England.;Fujian Med Univ, Fujian Prov Hosp, Dept Cardiol, Fuzhou, Fujian, Peoples R China..
    Rice, Kenneth
    Univ Washington, Dept Biostat, Seattle, WA 98195 USA..
    Ridker, Paul M.
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA..
    Riese, Harriette
    Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, Groningen, Netherlands..
    Ripatti, Samuli
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland..
    Robino, Antonietta
    Inst Maternal & Child Hlth IRCCS Burlo Garofolo, Trieste, Italy..
    Rotter, Jerome I.
    Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Dept Pediat & Med, LABioMed, Torrance, CA USA..
    Rudan, Igor
    Univ Edinburgh, Ctr Global Hlth Res, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland..
    Saba, Yasaman
    Med Univ Graz, Ctr Mol Med, Inst Mol Biol & Biochem, Graz, Austria..
    Saint Pierre, Aude
    Univ Lubeck, Inst Biomed, Affiliated Inst, Eurac Res, Bolzano, Italy.;INSERM U1078, Etab Francais Sang, Brest, France..
    Sala, Cinzia F.
    Ist Sci San Raffaele, Div Genet & Cell Biol, Milan, Italy..
    Sarin, Antti-Pekka
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland..
    Schmidt, Reinhold
    Med Univ Graz, Clin Div Neurogeriatr, Dept Neurol, Graz, Austria..
    Scott, Rodney
    Hunter Med Res Inst, New Lambton, NSW, Australia.;Univ Newcastle, Fac Hlth, Callaghan, NSW, Australia.;John Hunter Hosp, New Lambton, NSW, Australia..
    Seelen, Marc A.
    Univ Groningen, Univ Med Ctr Groningen, Div Nephrol, Dept Internal Med, Groningen, Netherlands..
    Shields, Denis C.
    Univ Coll Dublin, Sch Med, Conway Inst, Belfield, Ireland..
    Siscovick, David
    New York Acad Med, New York, NY USA..
    Sorice, Rossella
    CNR, Inst Genet & Biophys A Buzzati Traverso, Naples, Italy.;IRCCS Neuromed, Pozzilli, Isernia, Italy..
    Stanton, Alice
    Royal Coll Surgeons Ireland, Mol & Cellular Therapeut, Dublin 2, Ireland..
    Stott, David J.
    Univ Glasgow, Inst Cardiovasc & Med Sci, Fac Med, Glasgow, Lanark, Scotland..
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Swertz, Morris
    Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands..
    Taylor, Kent D.
    Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Los Angeles BioMed Res Inst, Torrance, CA USA.;Harbor UCLA Med Ctr, Div Genet Outcomes, Dept Pediat, Torrance, CA USA..
    Thom, Simon
    Imperial Coll London, Int Ctr Circulatory Hlth, London, England..
    Tzoulaki, Ioanna
    Imperial Coll London, Dept Epidemiol & Biostat, Sch Publ Hlth, London, England..
    Tzourio, Christophe
    Bordeaux Populat Hlth Ctr, INSERM U 1219, Bordeaux, France.;Bordeaux Univ, Bordeaux, France.;Bordeaux Univ Hosp, Dept Publ Hlth, Bordeaux, France.;Bordeaux Univ Hosp, Dept Neurol, Bordeaux, France..
    Uitterlinden, Andre G.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands.;Erasmus MC, Dept Internal Med, Rotterdam, Netherlands..
    Volker, Uwe
    Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany.;DZHK German Ctr Cardiovasc Res, Greifswald, Germany..
    Vollenweider, Peter
    Univ Lausanne Hosp, CHUV, Dept Internal Med, Lausanne, Switzerland..
    Wild, Sarah
    Univ Edinburgh, Ctr Global Hlth Res, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland..
    Willemsen, Gonneke
    Vrije Univ, VU Univ Med Ctr, EMGO Inst, Dept Biol Psychol, Amsterdam, Netherlands..
    Wright, Alan F.
    Univ Edinburgh, MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Western Gen Hosp, MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland..
    Yao, Jie
    Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Dept Pediat, Torrance, CA USA..
    Theriault, Sebastien
    McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON, Canada..
    Conen, David
    McMaster Univ, Populat Hlth Res Inst, Hamilton, ON, Canada..
    Attia, John
    Hunter Med Res Inst, New Lambton, NSW, Australia.;Univ Newcastle, Fac Hlth, Callaghan, NSW, Australia.;John Hunter Hosp, New Lambton, NSW, Australia..
    Sever, Peter
    Imperial Coll London, Natl Heart & Lung Inst, London, England..
    Debette, Stephanie
    Bordeaux Populat Hlth Ctr, INSERM U 1219, Bordeaux, France.;Bordeaux Univ, Bordeaux, France.;Bordeaux Univ Hosp, Dept Neurol, Bordeaux, France..
    Mook-Kanamori, Dennis O.
    Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands.;Leiden Univ, Med Ctr, Dept Publ Hlth & Primary Care, Leiden, Netherlands..
    Zeggini, Eleftheria
    Wellcome Trust Sanger Inst, Dept Human Genet, London, England..
    Spector, Tim D.
    van der Harst, Pim
    Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands..
    Palmer, Colin N. A.
    Univ Dundee, Med Res Inst, Ninewells Hosp, Dundee, Scotland.;Univ Dundee, Sch Med, Dundee, Scotland..
    Vergnaud, Anne-Claire
    Imperial Coll London, Dept Epidemiol & Biostat, Sch Publ Hlth, London, England..
    Loos, Ruth J. F.
    Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Inst Metab Sci, Cambridge, England.;Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY USA.;Icahn Sch Med Mt Sinai, Mindich Child Hlth Dev Inst, New York, NY USA..
    Polasek, Ozren
    Univ Split, Dept Publ Hlth, Fac Med, Split, Croatia..
    Starr, John M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh, Midlothian, Scotland..
    Girotto, Giorgia
    IRCCS Burlo Garofolo Children Hosp, Med Genet, Trieste, Italy.;Univ Trieste, Dept Med Surg & Hlth Sci, Trieste, Italy..
    Hayward, Caroline
    Univ Edinburgh, Generat Scotland, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, MRC, Human Genet Unit, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland..
    Kooner, Jaspal S.
    London North West Healthcare NHS Trust, Ealing Hosp, Dept Cardiol, Southall, Middx, England.;Imperial Coll Healthcare NHS Trust, London, England.;Imperial Coll London, Natl Heart & Lung Inst, Hammersmith Hosp Campus, London, England..
    Lindgren, Cecila M.
    Broad Inst Harvard & MIT, Cambridge, MA USA.;Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England..
    Vitart, Veronique
    Univ Edinburgh, MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Western Gen Hosp, MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland..
    Samani, Nilesh J.
    Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Univ Leicester, NIHR Leicester Biomed Res Ctr, Leicester, Leics, England.;Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England.;Univ Edinburgh, Western Gen Hosp, MRC Human Genet Unit, Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland..
    Tuomilehto, Jaakko
    Dasman Diabet Inst, Kuwait, Kuwait.;King Abdulaziz Univ, Diabet Res Grp, Jeddah, Saudi Arabia.;Danube Univ Krems, Dept Neurosci & Prevent Med, Krems An Der Donau, Austria. Univ Manchester, Div Cardiovasc Sci, Manchester, Lancs, England..
    Gyllensten, Ulf
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Knekt, Paul
    Dept Hlth, Helsinki, Finland. Chron Dis Prevent Unit, Helsinki, Finland. Natl Inst Hlth & Welf, Helsinki, Finland..
    Deary, Ian J.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland.;Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland..
    Ciullo, Marina
    CNR, Inst Genet & Biophys A Buzzati Traverso, Naples, Italy.;IRCCS Neuromed, Pozzilli, Isernia, Italy..
    Elosua, Roberto
    IMIM, Cardiovasc Epidemiol & Genet, Barcelona, Spain.;CIBERCV, Barcelona, Spain..
    Keavney, Bernard D.
    Cent Manchester Univ Hosp NHS Fdn Trust, Manchester, Lancs, England..
    Hicks, Andrew A.
    Univ Lubeck, Inst Biomed, Affiliated Inst, Eurac Res, Bolzano, Italy..
    Scott, Robert A.
    Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Inst Metab Sci, Cambridge, England..
    Gasparini, Paolo
    IRCCS Burlo Garofolo Children Hosp, Med Genet, Trieste, Italy.;Univ Trieste, Dept Med Surg & Hlth Sci, Trieste, Italy..
    Laan, Maris
    Univ Tartu, Inst Biomed & Translat Med, Tartu, Estonia..
    Liu, YongMei
    Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA..
    Watkins, Hugh
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Oxford, Div Cardiovasc Med, Radcliffe Dept Med, Oxford, England..
    Hartman, Catharina A.
    Univ Groningen, Univ Med Ctr Groningen, Interdisciplinary Ctr Psychopathol & Emot Regulat, Groningen, Netherlands..
    Salomaa, Veikko
    Dept Hlth, Helsinki, Finland. Chron Dis Prevent Unit, Helsinki, Finland. Natl Inst Hlth & Welf, Helsinki, Finland..
    Toniolo, Daniela
    Ist Sci San Raffaele, Div Genet & Cell Biol, Milan, Italy..
    Perola, Markus
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia.;Dept Hlth, Helsinki, Finland. Chron Dis Prevent Unit, Helsinki, Finland. Natl Inst Hlth & Welf, Helsinki, Finland.;Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland..
    Wilson, James F.
    Univ Edinburgh, Ctr Global Hlth Res, Usher Inst Populat Hlth Sci & Informat, Edinburgh, Midlothian, Scotland..
    Schmidt, Helena
    Med Univ Graz, Dept Neurol, Graz, Austria.;Med Univ Graz, Ctr Mol Med, Inst Mol Biol & Biochem, Graz, Austria..
    Zhao, Jing Hua
    Univ Cambridge, MRC Epidemiol Unit, Sch Clin Med, Inst Metab Sci, Cambridge, England..
    Lehtimaki, Terho
    Fimlab Labs, Dept Clin Chem, Tampere, Finland.;Univ Tampere, Fac Med & Life Sci, Dept Clin Chem, Tampere, Finland..
    van Duijn, Cornelia M.
    Erasmus MC, Genet Epidemiol Unit, Dept Epidemiol, Rotterdam, Netherlands..
    Gudnason, Vilmundur
    Icelandic Heart Assoc, Kopavogur, Iceland.;Univ Iceland, Fac Med, Reykjavik, Iceland..
    Psaty, Bruce M.
    Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA.;Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA.;Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA.;Kaiser Permanent, Washington Hlth Res Inst, Seattle, WA USA..
    Peters, Annette
    Helmholtz Zentrum Munchen, Inst Epidemiol 2, Munich, Germany..
    Rettig, Rainer
    Univ Med Greifswald, Inst Physiol, Karlsburg, Germany..
    James, Alan
    Univ Western Australia, Sch Med & Pharmacol, Nedlands, WA, Australia.;Sir Charles Gairdner Hosp, Dept Pulm Physiol & Sleep, Nedlands, WA, Australia..
    Jukema, J. Wouter
    Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands..
    Strachan, David P.
    St Georges Univ London, Populat Hlth Res Inst, London, England..
    Palmas, Walter
    Columbia Univ, Dept Med, Med Ctr, New York, NY USA..
    Metspalu, Andres
    Univ Tartu, Estonian Genome Ctr, Tartu, Estonia..
    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.
    Boomsma, Dorret I.
    Vrije Univ, VU Univ Med Ctr, EMGO Inst, Dept Biol Psychol, Amsterdam, Netherlands..
    Franco, Oscar H.
    Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
    Bochud, Murielle
    Univ Lausanne Hosp, Inst Social & Prevent Med, Lausanne, Switzerland..
    Newton-Cheh, Christopher
    Broad Inst Harvard & MIT, Cambridge, MA USA.;Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA.;Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA.;Broad Inst, Program Med & Populat Genet, Cambridge, MA USA..
    Munroe, Patricia B.
    William Harvey Res Inst, Clin Pharmacol, London, England.;Queen Mary Univ London, NIHR Barts Cardiovasc Biomed Res Unit, Barts & London Sch Med & Dent, London, England..
    Elliott, Paul
    Imperial Coll London, MRC PHE Ctr Environm & Hlth, Dept Epidemiol & Biostat, Sch Publ Hlth, London, England..
    Chasman, Daniel I.
    Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Med Sch, Boston, MA USA..
    Chakravarti, Aravinda
    Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Sch Med, Baltimore, MD USA..
    Knight, Joanne
    Univ Lancaster, Data Sci Inst, Lancaster, England.;Univ Lancaster, Lancaster Med Sch, Lancaster, England..
    Morris, Andrew P.
    Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England.;Univ Liverpool, Dept Biostat, Liverpool, Merseyside, England..
    Levy, Daniel
    NHLBI, Populat Sci Branch, Div Intramural Res, Bldg 10, Bethesda, MD 20892 USA.;Framingham Heart Dis Epidemiol Study, Framingham, MA USA..
    Tobin, Martin D.
    Snieder, Harold
    Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands..
    Caulfield, Mark J.
    William Harvey Res Inst, Clin Pharmacol, London, England.;Queen Mary Univ London, NIHR Barts Cardiovasc Biomed Res Unit, Barts & London Sch Med & Dent, London, England..
    Ehret, Georg B.
    Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Ctr Complex Dis Genom, Sch Med, Baltimore, MD USA.;Univ Hosp Geneva, Dept Med Specialties, Cardiol, Geneva, Switzerland..
    Alistair, T. Y.
    Betholdson, J. -P
    Xiao, Limin
    Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney2017In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 70, no 3, p. E4-e19Article in journal (Refereed)
    Abstract [en]

    Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA. Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation.

  • 42.
    Wei, Jin
    et al.
    Univ S Florida, Dept Mol Pharmacol & Physiol, Coll Med, Tampa, FL USA.
    Zhang, Jie
    Univ S Florida, Dept Mol Pharmacol & Physiol, Coll Med, Tampa, FL USA.
    Jiang, Shan
    Univ S Florida, Dept Mol Pharmacol & Physiol, Coll Med, Tampa, FL USA.
    Wang, Lei
    Univ S Florida, Dept Mol Pharmacol & Physiol, Coll Med, Tampa, FL USA.
    Persson, A. Erik G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Liu, Ruisheng
    Univ S Florida, Dept Mol Pharmacol & Physiol, Coll Med, Tampa, FL USA.
    High-Protein Diet-Induced Glomerular Hyperfiltration Is Dependent on Neuronal Nitric Oxide Synthase beta in the Macula Densa via Tubuloglomerular Feedback Response2019In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 74, no 4, p. 864-871Article in journal (Refereed)
    Abstract [en]

    It is well known that high protein intake increases glomerular filtration rate. Evidence from several studies indicated that NO and tubuloglomerular feedback (TGF) mediate the effect. However, a recent study with a neuronal NO synthase-alpha knockout model refuted this mechanism and concluded that neither neuronal NO synthase nor TGF response is involved in the protein-induced hyperfiltration. To examine the discrepancy, this study tested a hypothesis that neuronal NO synthase-beta in the macula densa mediates the high-protein diet-induced glomerular hyperfiltration via TGF mechanism. We examined the effects of high protein intake on NO generation at the macula densa, TGF response, and glomerular filtration rate in wild-type and macula densa-specific neuronal NO synthase KO mice. In wild-type mice, high-protein diet increased kidney weight, glomerular filtration rate, and renal blood flow, while reduced renal vascular resistance. TGF response in vivo and in vitro was blunted, and NO generation in the macula densa was increased following high-protein diet, associated with upregulations of neuronal NO synthase-beta expression and phosphorylation at Ser1417. In contrast, these high-protein diet-induced changes in NO generation at the macula densa, TGF response, renal blood flow, and glomerular filtration rate in wild-type mice were largely attenuated in macula densa-specific neuronal NO synthase KO mice. In conclusion, we demonstrated that high-protein diet-induced glomerular hyperfiltration is dependent on neuronal NO synthase beta in the macula densa via TGF response.

  • 43.
    Wikström, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Karolinska Univ Hosp & Inst, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden..
    Gunnarsdottir, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Nelander, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Simic, Marija
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Karolinska Univ Hosp & Inst, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden..
    Stephansson, Olof
    Karolinska Univ Hosp & Inst, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden.;Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA..
    Cnattingius, Sven
    Karolinska Univ Hosp & Inst, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden..
    Prehypertension in Pregnancy and Risks of Small for Gestational Age Infant and Stillbirth2016In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 67, no 3, p. 640-646Article in journal (Refereed)
    Abstract [en]

    It is not fully known whether maternal prehypertension is associated with increased risk of adverse fetal outcomes, and it is debated whether increases in blood pressure during pregnancy influence adverse fetal outcomes. We performed a population-based cohort study in nonhypertensive women with term (37 weeks) singleton births (n=157446). Using normotensive (diastolic blood pressure [DBP] <80 mmHg) women as reference, we calculated adjusted odds ratios with 95% confidence intervals between prehypertension (DBP 80-89 mmHg) at 36 gestational weeks (late pregnancy) and risks of a small-for-gestational-age (SGA) birth or stillbirth. We further estimated whether an increase in DBP from early to late pregnancy affected these risks. We found that 11% of the study population had prehypertension in late pregnancy. Prehypertension was associated with increased risks of both SGA birth and stillbirth; adjusted odds ratios (95% confidence intervals) were 1.69 (1.51-1.90) and 1.70 (1.16-2.49), respectively. Risks of SGA birth in term pregnancy increased by 2.0% (95% confidence intervals 1.5-2.8) per each mmHg rise in DBP from early to late pregnancy, whereas risk of stillbirth was not affected by rise in DBP during pregnancy. We conclude that prehypertension in late pregnancy is associated with increased risks of SGA birth and stillbirth. Risk of SGA birth was also affected by rise in DBT during pregnancy. Our findings provide new insight to the relationship between maternal blood pressure and fetal well-being and suggest that impaired maternal perfusion of the placenta contribute to SGA birth and stillbirth.

  • 44.
    Wikström, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Stephansson, Olof
    Cnattingius, Sven
    Tobacco Use During Pregnancy and Preeclampsia Risk: Effects of Cigarette Smoking and Snuff2010In: Hypertension, ISSN 0194-911X, E-ISSN 1524-4563, Vol. 55, no 5, p. 1254-1259Article in journal (Refereed)
    Abstract [en]

    Preeclampsia is a leading cause of maternal and infant mortality and morbidity worldwide. Both Swedish snuff and cigarette smoke include nicotine, but combustion products accompany only smoking. The aims of this study were to compare the effects of Swedish snuff and cigarette smoking on preeclampsia risk and to estimate whether changes in tobacco habits during pregnancy affect the risk of developing term preeclampsia. We used information from the Swedish Birth Register on all singleton births in Sweden during the years 1999-2006 (n=612 712). Compared with nontobacco users, women who used snuff in early pregnancy had an adjusted odds ratio (OR) for preeclampsia of 1.11 (95% CI: 0.97 to 1.28). The corresponding ORs for light and heavy smokers were 0.66 (95% CI: 0.61 to 0.71) and 0.51 (95% CI: 0.44 to 0.58), respectively, with ORs lower for term than preterm preeclampsia. Compared with nontobacco users, women who smoked in early pregnancy but had quit smoking before late pregnancy (weeks 30 to 32) had an adjusted OR for term preeclampsia of 0.94 (95% CI: 0.83 to 1.08). The corresponding OR for women who did not use tobacco in early pregnancy but had started to smoke before late pregnancy was 0.65 (95% CI: 0.50 to 0.85). We conclude that tobacco combustion products rather than nicotine are the probable protective ingredients against preeclampsia in cigarette smoke. Because change of smoking habits during pregnancy influence risk, we further conclude that it is the smoking habits in the middle or late rather than in the beginning of pregnancy that seem to affect the risk of preeclampsia. (Hypertension. 2010;55:1254-1259.)

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