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  • 1.
    Bergman, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Akhter, Tansim
    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.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Naessén, Tord
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Åkerud, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Plasma Levels of S100B in Preeclampsia and Association With Possible Central Nervous System Effects2014In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 27, no 8, p. 1105-1111Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    S100B is supposed to be a peripheral biomarker of central nervous system (CNS) injury. The purpose of this study was to compare levels of S100B in women with preeclampsia with levels in healthy pregnant control subjects and furthermore to analyze levels of S100B in relation to possible CNS effects.

    METHODS:

    A cross-sectional case-control study in antenatal care centers in Uppsala, Sweden, was performed. Fifty-three women with preeclampsia and 58 healthy pregnant women were recruited at similar gestational length; women with preeclampsia were recruited at time of diagnosis, and control subjects were recruited during their routine visit to an antenatal clinic. Plasma samples were collected, and levels of S100B were analyzed with an enzyme-linked immunosorbent assay. Information about demographic and clinical characteristics, including symptoms related to CNS affection, was collected from the medical records. The main outcome measures were plasma levels of S100B and possible CNS effects.

    RESULTS:

    Levels of S100B were significantly higher among women with preeclampsia than among control subjects (0.12 µg/L vs. 0.07 µg/L; P < 0.001). In preeclampsia, there was a significant association between high levels of S100B and visual disturbances (P < 0.05).

    CONCLUSIONS:

    S100B is increased among women with preeclampsia, and high levels of S100B associate with visual disturbances, which might reflect CNS affection in women with preeclampsia.

  • 2.
    Bergman, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Clin Res Ctr, Dalarna, Sweden..
    Åkerud, Helena
    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. Danderyd Hosp, Karolinska Inst, Dept Clin Sci, Stockholm, Sweden..
    Larsson, Marita
    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.
    Akhter, Tansim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Cerebral Biomarkers in Women With Preeclampsia Are Still Elevated 1 Year Postpartum2016In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 29, no 12, p. 1374-1379Article in journal (Refereed)
    Abstract [en]

    BACKGROUND There is evidence of cerebral involvement among women with preeclampsia. Levels of the cerebral biomarkers neuron-specific enolase (NSE) and S100B are elevated during pregnancy in women developing preeclampsia. It is although not known if these biomarkers return to normal range postpartum. The aim with this study was to compare levels of S100B and NSE during pregnancy and 1 year postpartum in women who have had preeclampsia to women with normal pregnancies. METHODS This study was a longitudinal study of cases (n = 53) with preeclampsia and controls (n = 58) consisted of normal pregnant women in matched gestational weeks. Plasma samples were collected at inclusion during pregnancy and 1 year postpartum. Plasma samples were analyzed for levels of S100B and NSE by enzyme-linked immunosorbent assays kits. RESULTS Levels of NSE and S100B in women with preeclampsia were higher during pregnancy than in women with normal pregnancies. One year postpartum, women who have had preeclampsia still had a higher median level of both NSE (5.07 vs. 4.28 mu g/l, P < 0.05) and S100B (0.07 vs. 0.06 mu g/l, P < 0.05) compared to women with previous normal pregnancies. High levels of NSE and S100B postpartum remained associated with previous preeclampsia after adjustment for confounding factors. Levels of NSE correlated to S100B during pregnancy and postpartum. CONCLUSIONS Levels of NSE and S100B are still elevated 1 year postpartum in women who have had preeclampsia in contrast to women with previous normal pregnancies. We hypothesize that there might be a persistent cerebral involvement among women with preeclampsia even 1 year postpartum.

  • 3.
    Bolin, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Wiberg-Itzel, Eva
    Department of Obstetrics and Gynaecology, Karolinska Institutet, Stockholm, Sweden.
    Wikström, Ann-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Goop, Margareta
    Department of Obstetrics and Gynaecology, Karlstad, Sweden.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Akerud, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Angiopoietin-1/angiopoietin-2 ratio for prediction of preeclampsia2009In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 22, no 8, p. 891-895Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A number of different biophysical and biochemical markers have been proposed as predictors of preeclampsia. Factors involved in the angiogenic balance are suggested as candidate markers. The purpose of this prospective, longitudinal cohort study was to determine whether a ratio between Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2) can be used to predict preeclampsia in a low-risk population. METHODS: A cohort of healthy pregnant women (n = 469) were enrolled at gestational weeks 8-12. Plasma samples were collected at gestational weeks 10, 25, 28, 33, and 37. By using commercially available enzyme-linked immunosorbent assay kits Ang-1 and Ang-2 were analyzed. RESULTS: The median Ang-1/Ang-2 ratio increased during pregnancy in all women, but the ratios were significantly lower at gestational weeks 25 and 28 in women who later developed preeclampsia than in normal pregnant women (1.49 compared to 2.19 and 2.12 compared to 3.54, P < 0.05 and P < 0.05). CONCLUSION: Our data indicate that in a low-risk population of women the Ang-1/Ang-2 ratio in plasma constitutes a possible biomarker for prediction of later onset of preeclampsia.

  • 4.
    Bolin, Marie
    et al.
    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.
    Wiberg-Itzel, Eva
    Department of Clinical Science and Education, Section of Obstetrics and Gynecology, Karolinska Institute, Södersjukhuset, Stockholm, Sweden.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ringvall, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sundström-Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Axelsson, Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i D län (CKFD).
    Thilaganathan, Basky
    Division of Clinical Development Sciences, Department of Obstetrics and Gynecology, St George’s University of London, England.
    Åkerud, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Prediction of Preeclampsia by Combining Serum Histidine-Rich Glycoprotein and Uterine Artery Doppler2012In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 25, no 12, p. 1305-1310Article in journal (Refereed)
    Abstract [en]

    Background

    Preeclampsia is associated with both maternal and perinatal morbidity and mortality. Histidine-rich glycoprotein (HRG) is a protein interacting with angiogenesis, coagulation, and inflammatory responses, processes known to be altered in preeclamptic pregnancies. Significantly lower levels of HRG have been demonstrated as early as in the first trimester in women later developing preeclampsia compared with normal pregnancies. The aim of this study was to investigate whether the combination of HRG and uterine artery Doppler ultrasonography can be used as a predictor of preeclampsia.

    Methods

    A total of 175 women were randomly selected from a case-control study; 86 women had an uncomplicated pregnancy and 89 women later developed preeclampsia. Blood samples and pulsatility index (PI) were obtained from both cases and controls in gestational week 14.

    Results

    HRG levels were significantly lower in women who developed preterm preeclampsia compared with controls, but not for women developing preeclampsia in general. PI was significantly higher in the preeclampsia group compared with controls, especially in preterm preeclampsia. The combination of HRG and PI revealed a sensitivity of 91% and a specificity of 62% for preterm preeclampsia.

    Conclusions

    The combination of HRG and uterine artery Doppler may predict preterm preeclampsia in early pregnancy.

  • 5.
    Bolin, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Åkerud, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Hansson, Agneta
    Åkerud, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Histidine-Rich Glycoprotein as an Early Biomarker of Preeclampsia2011In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 24, no 4, p. 496-501Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Prediction of preeclampsia is of great interest and the coagulation system as well as the angiogenic pathway is known to be dysfunctional in preeclampsia. Histidine-rich glycoprotein (HRG) is a protein interacting with both these biological systems and the purpose of this prospective, longitudinal cohort study was to analyze whether there is a difference in circulating levels of HRG during pregnancy in women developing preeclampsia compared to normal healthy pregnancies. We furthermore wanted to evaluate whether HRG has the potential of being an early biomarker of preeclampsia. METHODS: A cohort of healthy pregnant women (n = 469) was enrolled at gestational weeks 8-12. Plasma samples were collected at gestational weeks 10, 25, 28, 33, and 37 and analyzed with an enzyme-linked immunosorbent assay. RESULTS: The levels of HRG decreased during pregnancy in all women, but the levels were significantly lower at gestational weeks 10, 25, and 28 in women who later developed preeclampsia than in normal pregnant women (P < 0.05, P < 0.05, and P < 0.05). CONCLUSION: Our data indicates that HRG levels in plasma might be a possible biomarker already in gestational week 10 for prediction of later onset of preeclampsia in a low risk population.

  • 6. Brguljan-Hitij, Jana
    et al.
    Thijs, Lutgarde
    Li, Yan
    Hansen, Tine W.
    Boggia, Jose
    Liu, Yan-Ping
    Asayama, Kei
    Wei, Fang-Fei
    Bjorklund-Bodegard, Kristina
    Gu, Yu-Mei
    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
    Wang, Jiguang
    O'Brien, Eoin
    Staessen, Jan A.
    Risk Stratification by Ambulatory Blood Pressure Monitoring Across JNC Classes of Conventional Blood Pressure2014In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 27, no 7, p. 956-965Article in journal (Refereed)
    Abstract [en]

    BACKGROUND Guidelines propose classification of conventional blood pressure (CBP) into normotension (<120/<80 mm Hg), prehypertension (120-139/80-89 mm Hg), and hypertension (>140/>90 mm Hg). METHODS To assess the potential differential contribution of ambulatory blood pressure (ABP) in predicting risk across CBP strata, we analyzed outcomes in 7,826 untreated people recruited from 11 populations. RESULTS During an 11.3-year period, 809 participants died (276 cardiovascular deaths) and 639, 383, and 225 experienced a cardiovascular, cardiac, or cerebrovascular event. Compared with normotension (n = 2,639), prehypertension (n = 3,076) carried higher risk (P <= 0.015) of cardiovascular (+ 41%) and cerebrovascular (+ 92%) endpoints; compared with hypertension (n = 2,111) prehypertension entailed lower risk (P <= 0.005) of total mortality (-14%) and cardiovascular mortality (-29%) and of cardiovascular (-34%), cardiac (-33%), or cerebrovascular (-47%) events. Multivariable-adjusted hazard ratios (HRs) for stroke associated with 24-hour and daytime diastolic ABP (+ 5 mm Hg) were higher (P <= 0.045) in normotension than in prehypertension and hypertension (1.98 vs. 1.19 vs. 1.28 and 1.73 vs. 1.09 vs. 1.24, respectively) with similar trends (0.03 <= P <= 0.11) for systolic ABP (+10 mm Hg). However, HRs for fatal endpoints and cardiac events associated with ABP did not differ significantly (P >= 0.13) across CBP categories. Of normotensive and prehypertensive participants, 7.5% and 29.3% had masked hypertension (daytime ABP >= 135/>= 85 mm Hg). Compared with true normotension (P <= 0.01), HRs for stroke were 3.02 in normotension and 2.97 in prehypertension associated with masked hypertension with no difference between the latter two conditions (P = 0.93). CONCLUSION ABP refines risk stratification in normotension and prehypertension mainly by enabling the diagnosis of masked hypertension.

  • 7.
    Gokturk, Camilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Sugimoto, Haruyo
    Blomgren, Bo
    Roomans, Godfried M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Sjöquist, Mats
    Macrovascular changes in mice overexpressing human semicarbazide-sensitive amine oxidase in smooth muscle cells2007In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 20, no 7, p. 743-750Article in journal (Refereed)
    Abstract [en]

    Background: The catalytic activity of semicarbazide-sensitive amine oxidase (SSAO) is increased in diabetes, as well as in other disorders of cardiovascular origin. Our hypothesis is that SSAO is involved in the synthesis or maturation of elastin in vascular tissue. An increased SSAO activity can thereby be involved in the development of vascular damage. Methods: Elastin quantification was performed in aorta of transgenic mice overexpressing the human form of SSAO, using electron microscopy. Furthermore, lung capacity was measured using a spirometry-mimicking method, developed for mice. The effect of vasoactive substances was estimated by measuring mean arterial pressure and pulse pressure under anesthesia. Results: No differences in elastin quantity or lung capacity could be observed between transgenic or nontransgenic littermates. Pulse pressure was higher in transgenic mice, and electron microscopy of aorta showed elastin fibers parallel with the aorta wall (ie, straight fibers instead of folded compared with control mice). No difference in the response to adrenaline or sodium chloride was observed between the transgenic and control mice. The control mice had a clear decrease in blood pressure (BP) with a longer duration as a response to injection of a nitric oxide (NO) donor, sodium nitroprusside, compared with transgenic mice where only a minor response was observed. The SSAO activity in serum of control mice was elevated in response to injection of the NO donor, but not in response to a ganglion blocker. Conclusions: An elevated pulse pressure, together with an abnormal elastin structure in the aorta, suggests a rigidity of large arteries as a result of an elevated SSAO activity as well as a physiologic role for SSAO in elastin maturation.

  • 8. Hänni, Arvo
    et al.
    Berglund, Lars
    Reneland, Richard
    Andersson, Per-Erik
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lithell, Hans
    The alterations in insulin sensitivity during angiotensin converting enzyme inhibitor treatment are related to changes in the calcium/magnesium balance1997In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 10, no 2, p. 145p. 145-151Article in journal (Other academic)
    Abstract [en]

    The present analysis was undertaken to investigate the relations between alterations in mineral factors, especially the balance between serum calcium and magnesium concentrations (S-Ca and S-Mg, respectively), and variables reflecting glucose and lipid metabolism during angiotensin converting enzyme (ACE) inhibitor treatment. A total of 96 patients with essential hypertension, participating in four double-blind studies with four different ACE inhibitors and similar protocols, were included. At the end of the initial placebo period and at the end of the period of active drug treatment, a hyperinsulinemic euglycemic clamp test was carried out, lipoprotein status was assessed, and the concentrations of serum electrolytes were measured. The serum ACE activity was determined in the group treated with fosinopril. Changes in insulin sensitivity index (M/I) were directly correlated to alterations in S-Mg (r = 0.24, P < .02), and inversely correlated to changes in S-Ca (r = -0.19, P = .07) and the ratio between serum calcium and magnesium concentrations (Ca/Mg) (r = -0.27, P < .008). The change in total serum triglycerides (S-Tg) was inversely correlated to the change in S-Mg (r = -0.35, P < .0005), and directly correlated to the change in Ca/Mg ratio (r = 0.36, P < .0004). The reduction in serum ACE activity correlated to a more pronounced increase in S-Mg r = -0.62, P < .002), and decrease in the Ca/Mg ratio (r = 0.73, P = .0002). We conclude that the changes in the studied metabolic variables and serum ACE activity during ACE inhibitor treatment are related to alterations in mineral status and the balance between calcium and magnesium concentrations in serum.

  • 9.
    Hänni, Arvo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Fugmann, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lithell, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Systolic blood pressure alterations during hyperinsulinemia are related to changes in ionized calcium status2001In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 14, no 11 Pt 1, p. 1106-1111Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A correlation between changes in ionized calcium status and changes in systolic blood pressure (BP) has previously been observed during induced euglycemic hyperinsulinemia in patients with essential hypertension. The objective of this study was to evaluate associations between alterations in ion status and BP changes during euglycemic hyperinsulinemia in healthy normotensive subjects. METHODS: Ion status in plasma and BP were measured before and at the end of euglycemic hyperinsulinemic clamp tests performed in 41 healthy normotensive volunteers. RESULTS: During euglycemic hyperinsulinemia plasma sodium increased by 1% (P < .0001), ionized calcium (iCa) by 5% (P < .0001), and ionized magnesium (iMg) by 4% (P < .01), whereas potassium decreased by 10% (P < .0001). The changes in plasma iCa and iMg correlated significantly to changes in systolic BP (r = -0.38, P < .02; r = -0.32, P < .05, respectively), but the correlation between changes in iMg and changes in systolic BP did not remain significant in a multiple regression model. The glucose infusion rate correlated inversely to the change in iMg (r = -0.39, P < .01). CONCLUSIONS: The group mean systolic BP was unaltered during induced euglycemic hyperinsulinemia in healthy normotensive subjects; however, a more pronounced increase in the circulating iCa concentration was associated with a greater decline in systolic BP, which is in accordance with previous observations in patients with essential hypertension. The group mean diastolic BP was decreased; however, the lowered diastolic BP was not correlated to changes in ion status.

  • 10.
    Junus, Katja
    et al.
    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.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Placental Expression of proBNP/NT-proBNP and Plasma Levels of NT-proBNP in Early- and Late-Onset Preeclampsia2014In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 27, no 9, p. 1225-1230Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Levels of plasma N-terminal pro B-type natriuretic peptide (NT-proBNP) are elevated in preeclampsia. In this study, the possibility that the placenta produces and releases proBNP/NT-proBNP was explored. Plasma levels of NT-proBNP in early- and late-onset preeclampsia were also measured.

    METHODS: Placental proBNP mRNA in early-onset preeclampsia (n = 7), late-onset preeclampsia (n = 8), and controls of similar gestational age (n = 10) was assessed by quantitative real-time polymerase chain reaction. ProBNP/NT-proBNP protein was studied in placental samples with immunohistochemistry (n = 8) and tissue culture (n = 2). Plasma levels of NT-proBNP were measured in early-onset preeclampsia (n = 18), late-onset preeclampsia (n = 20), and relevant controls (n = 36).

    RESULTS: Transcripts of proBNP mRNA were found in 20 out of 25 samples, there were no differences in expression between the groups. ProBNP/NT-proBNP protein was observed in maternal spiral arteries and in syncytiotrophoblasts in all placental samples. After placental tissue culture, there were measurable amounts of NT-proBNP in the culture media. Women with both early- (365 [14-9815] pg/ml) and late-onset preeclampsia (176 [33-2547] pg/ml) had higher levels of NT-proBNP than their controls (P < 0.001). There was a tendency toward higher levels of NT-proBNP in women with early-onset preeclampsia than in women with late-onset preeclampsia (P = 0.057).

    CONCLUSION: The results indicate possible placental production and release of proBNP/NT-proBNP into the maternal circulation.

  • 11.
    Kurland, Lisa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hallberg, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Liljedahl, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Hashemi, Nashmil
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kahan, Thomas
    The relationship between the plasma concentration of irbesartan and the antihypertensive response is disclosed by an angiotensin II type 1 receptor polymorphism: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs. Atenolol (SILVHIA) Trial2008In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 21, no 7, p. 836-839Article in journal (Refereed)
    Abstract [en]

    Background 

    The aim of this study was to investigate the effect of the plasma concentration of irbesartan, a specific angiotensin II type 1 receptor (AT1R) antagonist, and the blood pressure response in relation to AT1R gene polymorphisms.

    Methods 

    Plasma irbesartan was analyzed in 42 patients with mild-to-moderate hypertension and left ventricular hypertrophy from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs. Atenolol (SILVHIA) trial, who were treated with irbesartan as monotherapy for 12 weeks. Blood pressure and irbesartan concentration were measured at trough, i.e., 24 ± 3 h after the last dose. Five AT1R gene polymorphisms were analyzed by minisequencing.

    Results 

    Neither the plasma concentration of irbesartan, nor any of the AT1R polymorphisms were associated with the blood pressure response to irbesartan treatment. However, the interaction term between the plasma concentration of irbesartan and the AT1R C5245T polymorphism was related to the reduction in systolic blood pressure after 12 weeks of treatment (P = 0.025). Furthermore, the plasma concentration of irbesartan was related to the change in systolic blood pressure in individuals homozygous for the AT1R 5245 T allele (r = -0.56, P = 0.030), but not for other genotypes.

    Conclusions 

    There was an association between plasma concentrations of irbesartan and the blood pressure response for hypertensive patients with AT1R 5245 TT. Because of the small sample size, this study needs to be viewed as hypothesis generating. This is the first study, to our knowledge, indicating that the concentration–response relationship of an antihypertensive drug may be genotype dependent.

  • 12.
    Kurland, Lisa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Liljedahl, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Karlsson, Julia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kahan, Thomas
    Malmqvist, Karin
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Angiotensinogen gene polymorphisms: relationship to blood pressure response to antihypertensive treatment. Results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA) trial2004In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 17, no 1, p. 8-13Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The renin-angiotensin-aldosterone system (RAAS) is important for the development of hypertension, and several antihypertensive drugs target this system. Our aim was to determine whether specific single nucleotide polymorphisms (SNPs) in RAAS genes were related to the blood pressure (BP) lowering effect of antihypertensive treatment. METHODS: Patients with mild to moderate primary hypertension and left ventricular hypertrophy were randomized in a double-blind fashion to treatment with either the angiotensin II type 1 receptor antagonist irbesartan (n = 48) or the beta(1)-adrenergic receptor blocker atenolol (n = 49) as monotherapy. A microarray-based minisequencing system was used to genotype 30 SNPs in seven genes in the RAAS. These polymorphisms were related to the antihypertensive response after 12 weeks treatment. RESULTS: The BP reductions were similar in the atenolol and the irbesartan groups. Presence of the angiotensinogen (AGT) -6A allele or the AGT 235T allele were both associated with the most pronounced systolic BP response to atenolol treatment (P =.001 when -6 AA+AG was compared with GG and P =.008 for presence of the 235T variant compared with 235 MM). CONCLUSIONS: We found that SNPs in the angiotensinogen gene were associated with the BP lowering response to atenolol. This study is limited by a relatively small sample size, and the results should therefore be viewed as preliminary. Despite this limitation, these results illustrate the potential of using SNP genotyping as a pharmacogenetic tool in antihypertensive treatment.

  • 13.
    Kurland, Lisa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Karlsson, Julia
    Kahan, Thomas
    Malmqvist, Karin
    Öhman, Peter
    Nyström, Fredrik
    Hägg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Aldosterone synthase (CYP11B2) -344 C/T polymorphism is related to antihypertensive response: result from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial2002In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 15, no 5, p. 389-93Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Our aim was to determine whether the aldosterone synthase (CYP11B2) -344 C/T polymorphism was associated with the blood pressure (BP)-lowering response to antihypertensive treatment. METHODS: Patients with mild-to-moderate primary hypertension and left ventricular hypertrophy were randomized in a double-blind study to receive treatment with either the angiotensin II type 1 (AT1) receptor antagonist irbesartan (n = 43), or the beta1-adrenergic receptor blocker atenolol (n = 43). The aldosterone synthase (CYP11B2) -344 C/T polymorphism was analyzed using solid-phase minisequencing and related to BP reduction after 3 months treatment. Serum aldosterone levels were measured. RESULTS: After 3 months treatment the mean reductions in BP were similar for both treatment groups. When assessing the systolic BP reduction in the irbesartan group, patients with the TT variant had a more pronounced reduction (-21 +/- 19 SD mm Hg, n = 17) than both the TC (-14 +/- 18 mm Hg, n= 18) and CC (0 +/- 17 mm Hg, n = 8) genotypes (P = .04). There was no association between this polymorphism and the diastolic BP response. The -344 C/T polymorphism was not associated with the BP response to atenolol. Nor was it related to the baseline serum aldosterone level. CONCLUSIONS: The aldosterone synthase -344 C/T polymorphism was related to the BP-lowering response in hypertensive patients treated with the AT1-receptor antagonist irbesartan.

  • 14.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hänni, Arvo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Lithell, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Hvarfner, A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sörensen, O.H.
    Ljunghall, Sverker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Vitamin D is related to blood pressure and other cardiovascular risk factors in middle-aged men1995In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 8, no 9, p. 894-901Article in journal (Refereed)
    Abstract [en]

    A previous study has shown that serum levels of the active vitamin D metabolite 1,25-(OH)2-vitamin D were inversely related to blood pressure levels while the prohormone 25-OH-vitamin D was found to be related to insulin metabolism. Also other clinical and experimental data support the view that vitamin D metabolism is involved in blood pressure regulation and other metabolic processes. The present study was conducted in order to see if the above mentioned relationships between the vitamin D endocrine system and blood pressure, as well as other cardiovascular risk factors, could be found in a cross-section population-based study. Serum levels of 1,25-(OH)2-vitamin D, 25-OH-vitamin D, and blood pressure were therefore measured in 34 middle-aged men and metabolic cardiovascular risk factors were evaluated by means of intravenous glucose and fat tolerance tests, euglycemic hyperinsulinemic clamp, lipoprotein measurements, and lipoprotein lipase activity determinations. Serum levels of 1,25-(OH)2-vitamin D were found to be inversely correlated to the blood pressure (r = -0.42, P < .02), VLDL triglycerides (r = -0.47, P < .005), and to triglyceride removal at the intravenous fat tolerance test (r = 0.34, P < .05), while serum levels of 25-OH-vitamin D were correlated to fasting insulin (r = -0.35, P < .05), insulin sensitivity during clamp (r = 0.54, P < .001), and lipoprotein lipase activity both in adiposal tissue (r = 0.48, P < .005) and skeletal muscle (r = 0.38, P < .03).(

  • 15.
    Lind, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Wengle, B.
    Wide, L.
    Sörensen, O. H.
    Ljunghall, S.
    Hypertension in primary hyperparathyroidism--reduction of blood pressure by long-term treatment with vitamin D (alphacalcidol): A double-blind, placebo-controlled study1988In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 1, no 4 Pt 1, p. 397-402Article in journal (Refereed)
    Abstract [en]

    Patients with primary hyperparathyroidism (HPT) often have raised blood pressure but a simple cause-and-effect relationship has not been established. In 33 persons with probable primary HPT and mild hypercalcemia detected in a health survey, diastolic blood pressure (DBP) was significantly higher than among age- and sex-matched, normocalcemic, controls (89.4 +/- 9.8 (SD) v 85.2 +/- 8.9 mm Hg; P less than 0.05). Among the hypercalcemic individuals, DBP was, in a multivariate analysis, inversely related to the serum calcium and plasma-ionized calcium concentrations and to the serum levels of parathyroid hormone. A prospective, placebo-controlled, double-blind, study evaluating the effects of active vitamin D, alphacalcidol, (1 microgram daily) was carried out in the hypercalcemic patients over a six-month period. This treatment caused a slight further increase (0.05 mmol/L) of both serum calcium and plasma-ionized calcium concentrations. At the same time there was a significant reduction of DBP with a mean of 6.7 mm Hg compared with placebo (P less than 0.05). The hypotensive action of the vitamin D compound was inversely related to the pretreatment serum levels of 1,25(OH)2D3 and additive to concomitant, unchanged, antihypertensive medications. The negative correlation between serum calcium and blood pressure is similar to that obtained in normocalcemic individuals and suggests that raised blood pressure, at least in the milder forms of primary HPT, is only independently associated with the disease. Active vitamin D, although it raises serum calcium, can lower blood pressure also in hypercalcemic patients as previously demonstrated in normocalcemic individuals.

  • 16. Mason, R Preston
    et al.
    Kubant, Ruslan
    Jacob, Robert F
    Malinski, Peter
    Huang, Xiaoyan
    Louka, Febee R
    Borowiec, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Mizuno, Yoshiko
    Malinski, Tadeusz
    Loss of arterial and renal nitric oxide bioavailability in hypertensive rats with diabetes: effect of beta-blockers2009In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 22, no 11, p. 1160-1166Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Endothelial cell (EC) dysfunction contributes to hypertension and mechanisms of atherosclerosis. Agents that improve EC function may provide vascular protection, especially in patients with multiple risk factors. In this study, we examined the effects of beta(1)-selective antagonists, nebivolol and metoprolol, on vascular and renal EC function in spontaneously hypertensive (SH) rats with diabetes.

    METHODS:

    Male SH rats were treated with streptozotocin (STZ) to induce type 2 diabetes, followed by treatment with nebivolol or metoprolol at 2 mg/kg/day (vs. vehicle). After 4 weeks, aortic and glomerular ECs were isolated, stimulated with calcium ionophore (CaI), and assayed for nitric oxide (NO), and peroxynitrite (ONOO(-)) release using amperometric approaches.

    RESULTS:

    Glucose and mean blood pressure (BP) levels were significantly elevated in diabetic SH rats. In aortic ECs isolated from diabetic SH rats, NO production decreased by 20% whereas ONOO(-) increased by 16%, an effect linked to NAD(P)H oxidase and endothelial NO synthase (eNOS) uncoupling. Nebivolol treatment reduced glucose and BP levels and restored aortic EC function in diabetic SH rats, as indicated by a 30% increase and 23% decrease in NO and ONOO(-) levels, respectively. The NO/ONOO(-) ratio increased by more than twofold with nebivolol treatment in aortic and glomerular ECs. Despite similar reductions in glucose and mean BP levels, metoprolol had a smaller effect on the NO/ONOO(-) ratio in glomerular ECs but no effect in aortic ECs.

    CONCLUSIONS:

    Vascular and renal NO was significantly reduced in diabetic hypertensive rats and correlated with metabolic changes. Nebivolol reversed these effects in a manner consistent with enhanced endothelial function.

  • 17. Mena, Luis J.
    et al.
    Maestre, Gladys E.
    Hansen, Tine W.
    Thijs, Lutgarde
    Liu, Yanping
    Boggia, Jose
    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.
    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
    Wang, Jiguang
    O'Brien, Eoin
    Staessen, Jan A.
    How Many Measurements Are Needed to Estimate Blood Pressure Variability Without Loss of Prognostic Information?2014In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 27, no 1, p. 46-55Article in journal (Refereed)
    Abstract [en]

    BACKGROUND Average real variability (ARV) is a recently proposed index for short-term blood pressure (BP) variability. We aimed to determine the minimum number of BP readings required to compute ARV without loss of prognostic information.

    METHODS ARV was calculated from a discovery dataset that included 24-hour ambulatory BP measurements for 1,254 residents (mean age 56.6 years; 43.5% women) of Copenhagen, Denmark. Concordance between ARV from full (80 BP readings) and randomly reduced 24-hour BP recordings was examined, as was prognostic accuracy. A test dataset that included 5,353 subjects (mean age 54.0 years; 45.6% women) with at least 48 BP measurements from 11 randomly recruited population cohorts was used to validate the results.

    RESULTS In the discovery dataset, a minimum of 48 BP readings allowed an accurate assessment of the association between cardiovascular risk and ARV. In the test dataset, over 10.2 years (median), 806 participants died (335 cardiovascular deaths, 206 cardiac deaths) and 696 experienced a major fatal or nonfatal cardiovascular event. Standardized multivariable-adjusted hazard ratios (HRs) were computed for associations between outcome and BP variability. Higher diastolic ARV in 24-hour ambulatory BP recordings predicted (P < 0.01) total (HR 1.12), cardiovascular (HR 1.19), and cardiac (HR 1.19) mortality and fatal combined with nonfatal cerebrovascular events (HR 1.16). Higher systolic ARV in 24-hour ambulatory BP recordings predicted (P < 0.01) total (HR 1.12), cardiovascular (HR 1.17), and cardiac (HR 1.24) mortality.

    CONCLUSIONS Forty-eight BP readings over 24 hours were observed to be adequate to compute ARV without meaningful loss of prognostic information.

  • 18.
    Nelander, Maria
    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), Obstetric research.
    Weis, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    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), Obstetric research.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    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), Obstetric research. Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Cerebral Magnesium Levels in Preeclampsia; A Phosphorus Magnetic Resonance Spectroscopy Study2017In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 30, no 7, p. 667-672Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Magnesium sulfate (MgSO4) is used as a prophylaxis for eclamptic seizures. The exact mechanism of action is not fully established. We used phosphorus magnetic resonance spectroscopy (31P-MRS) to investigate if cerebral magnesium (Mg2+) levels differ between women with preeclampsia, normal pregnant, and nonpregnant women.

    METHODS: This cross-sectional study comprised 28 women with preeclampsia, 30 women with normal pregnancies in corresponding gestational week (range: 23-41 weeks) and 11 nonpregnant healthy controls. All women underwent 31P-MRS from the parieto-occipital region of the brain and were interviewed about cerebral symptoms. Differences between groups were assessed by analysis of variance and Tukey's post-hoc test. Correlations between Mg2+ levels and specific neurological symptoms were estimated with Spearman's rank test.

    RESULTS: Mean maternal cerebral Mg2+ levels were lower in women with preeclampsia (0.12 mM ± 0.02) compared to normal pregnant controls (0.14 mM ± 0.03) (P = 0.04). Nonpregnant and normal pregnant women did not differ in Mg2+ levels. Among women with preeclampsia, lower Mg2+ levels correlated with presence of visual disturbances (P = 0.04). Plasma levels of Mg2+ did not differ between preeclampsia and normal pregnancy.

    CONCLUSIONS: Women with preeclampsia have reduced cerebral Mg2+ levels, which could explain the potent antiseizure prophylactic properties of MgSO4. Within the preeclampsia group, women with visual disturbances have lower levels of Mg2+ than those without such symptoms.

  • 19.
    Nelander, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Wikström, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Weis, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    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.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Sundström Poromaa, Inger
    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.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Cerebral osmolytes and plasma osmolality in pregnancy and preeclampsia: a proton magnetic resonance spectroscopy study2018In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 31, no 7, p. 847-853Article in journal (Refereed)
    Abstract [en]

    Background: Cerebral complications contribute substantially to mortality in preeclampsia. Pregnancy calls for extensive maternal adaptations, some associated with increased propensity for seizures, but the pathophysiology behind the eclamptic seizures is not fully understood. Plasma osmolality and sodium levels are lowered in pregnancy. This could result in extrusion of cerebral organic osmolytes, including the excitatory neurotransmitter glutamate, but this remains to be determined. The hypothesis of this study was that cerebral levels of organic osmolytes are decreased during pregnancy, and that this decrease is even more pronounced in women with preeclampsia.

    Method: We used proton magnetic resonance spectroscopy to compare levels of cerebral organic osmolytes, in women with preeclampsia (n=30), normal pregnancy (n=32) and non-pregnant controls (n=16). Cerebral levels organic osmolytes were further correlated to plasma osmolality, and plasma levels of glutamate and sodium.

    Results: Compared to non-pregnant women, women with normal pregnancy and preeclampsia had lower levels of the cerebral osmolytes myo-inositol, choline and creatine (p=0.001 or less), and all these metabolites correlated with each other (p<0.05). Women with normal pregnancies and preeclampsia had similar levels of osmolytes, except for glutamate, which was significantly lower in preeclampsia. Cerebral and plasma glutamate levels were negatively correlated with each other (p<0.008), and cerebral myo-inositol, choline and creatine levels were all positively correlated with both plasma osmolality and sodium levels (p<0.05).

    Conclusion: Our results indicate that pregnancy is associated with extrusion of cerebral organic osmolytes. This includes the excitatory neurotransmitter glutamate, which may be involved in the pathophysiology of seizures in preeclampsia.

  • 20.
    Oskarsson, Agneta
    et al.
    Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Uppsala, Sweden..
    Ullerås, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Andersson, Åsa Ohlsson
    Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Uppsala, Sweden..
    Acetaminophen Increases Aldosterone Secretion While Suppressing Cortisol and Androgens: A Possible Link to Increased Risk of Hypertension2016In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 29, no 10, p. 1158-1164Article in journal (Refereed)
    Abstract [en]

    Acetaminophen (paracetamol) is a widely used analgesic and antipyretic drug. Potential side effects are of public health concern, and liver toxicity from acute overdose is well known. More recently, a regular use of acetaminophen has been associated with an increased risk of hypertension. We investigated effects of acetaminophen on steroidogenesis as a possible mechanism for the hypertensive action by using the human adrenocortical cell line, H295R. Cells were treated with 0.1, 0.5, and 1mM of acetaminophen for 24 hours, and secretion of steroids and gene expression of key steps in the steroidogenesis were investigated. Progesterone and aldosterone secretion were increased dose dependently, while secretion of 17 alpha-OH-progesterone and cortisol as well as dehydroepiandrosterone and androstenedione was decreased. CYP17 alpha-hydroxylase activity, assessed by the ratio 17 alpha-OH-progesterone/progesterone, and CYP17-lyase activity, assessed by the ratio androstenedione/17 alpha-OH-progesterone, were both dose-dependently decreased by acetaminophen. No effects were revealed on cell viability. Treatment of cells with 0.5mM of acetaminophen did not cause any effects on the expression of 10 genes in the steroidogenic pathways. The pattern of steroid secretion caused by acetaminophen can be explained by inhibition of CYP17A1 enzyme activity. A decreased secretion of glucocorticoids and androgens, as demonstrated by acetaminophen, would, in an in vivo situation, induce adrenocorticotropic hormone release via negative feedback in the hypothalamic-pituitary-adrenal axis and result in an upregulation of aldosterone secretion. Our results suggest a novel possible mechanism for acetaminophen-induced hypertension, which needs to be further elucidated in clinical investigations.

  • 21. Perni, Uma C.
    et al.
    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.
    Cnattingius, Sven
    Villamor, Eduardo
    Interpregnancy Change in Smoking Habits and Risk of Preeclampsia: A Population-Based Study2012In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 25, no 3, p. 372-378Article in journal (Refereed)
    Abstract [en]

    BACKGROUND Maternal smoking has been associated with decreased risk of preeclampsia; however, it is uncertain whether this association is causal. An argument for causality would be strengthened if changes in smoking status across consecutive pregnancies were related to the risk of preeclampsia.

    METHODS We used data from the National Swedish Birth Register to ascertain the associations between changes in smoking status during the first two successive pregnancies and risk of preeclampsia in the second pregnancy in 371,627 women between 1992 and 2006. Multivariable logistic regression models were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI).

    RESULTS Compared to women who did not smoke in either pregnancy, the risk of preeclampsia was reduced in women who smoked in both pregnancies (adjusted OR = 0.54; 95% CI = 0.47, 0.63), in those who only smoked in second pregnancy (OR = 0.76; 95% CI = 0.58, 0.99) and, to a lesser extent, in women who smoked only in the first pregnancy (OR = 0.81; 95% CI = 0.70, 0.94). History of preeclampsia in the first pregnancy did not substantially modify these associations.

    CONCLUSION These data add support to a causal interpretation of the observed inverse association between smoking during pregnancy and risk of preeclampsia.

  • 22. Schneider, Jochen G.
    et al.
    Tilly, N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Hierl, Thomas
    Sommer, Ulrike
    Hamann, Andreas
    Dugi, Klaus
    Leidig-Bruckner, Gudrun
    Kasperk, Christian
    Elevated plasma endothelin-1 levels in diabetes mellitus2002In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 15, no 11, p. 967-72Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: This study compares plasma endothelin-1 (ET-1) levels in patients with diabetes mellitus or hypertension with healthy controls, and investigates whether ET-1 levels are correlated with glycemic control, metabolic parameters, and vascular complications. METHODS: The study population consisted of 103 patients with type 1 diabetes, 124 patients with type 2 diabetes, 35 hypertensive patients without diabetes mellitus, and 99 controls. RESULTS: Plasma ET-1 concentrations were significantly higher in patients with type 1 diabetes (0.28 +/- 0.34 fmol/mL, P =.001), type 2 diabetes (0.31 +/- 0.32 fmol/mL, P <.0001), and hypertension (0.35 +/- 0.26 fmol/mL, P <.0001) compared to controls (0.08 +/- 0.13 fmol/mL). Diabetic patients taking angiotensin converting enzyme (ACE) inhibitors had significantly lower plasma ET-1 levels than patients without (0.22 +/- 0.20 fmol/mL v 0.38 +/- 0.39 fmol/mL, P =.029). There were significant associations between ET-1 levels and age (r = 0.38, P <.05) and systolic blood pressure (BP) (r = 0.27, P <.05) in healthy controls. In diabetes we found only nonsignificant associations between ET-1 levels and age or vascular complications and a weak association between plasma ET-1 levels and glycemic control. CONCLUSIONS: Patients with diabetes or hypertension have elevated ET-1 levels, but do not exhibit positive correlations between ET-1 levels and BP, which was observed in healthy controls. Increased ET-1 levels do not induce hypertension in diabetes, but were lower in diabetic patients taking ACE inhibitors compared to those without ACE inhibitors. There is no significant association between ET-1 levels and vascular complications. These findings suggest that the plasma ET-1 level is not a marker of endothelial dysfunction but changes in plasma ET-1 levels may precede vascular complications associated with hypertension and diabetes.

  • 23. Schutte, Rudolph
    et al.
    Thijs, Lutgarde
    Asayama, Kei
    Boggia, Jose
    Li, Yan
    Hansen, Tine W.
    Liu, Yan-Ping
    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 Public Health and Caring Sciences.
    Sandoya, Edgardo
    Kawecka-Jaszcz, Kalina
    Filipovsky, Jan
    Imai, Yutaka
    Wang, Jiguang
    Ibsen, Hans
    O'Brien, Eoin
    Staessen, Jan A.
    Double Product Reflects the Predictive Power of Systolic Pressure in the General Population: Evidence from 9,937 Participants2013In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 26, no 5, p. 665-672Article in journal (Refereed)
    Abstract [en]

    BACKGROUND The double product (DP), consisting of the systolic blood pressure (SBP) multiplied by the pulse rate (PR), is an index of myocardial oxygen consumption, but its prognostic value in the general population remains unknown. METHODS We recorded health outcomes in 9,937 subjects (median age, 53.2 years; 47.3% women) randomly recruited from 11 populations and enrolled in the International Database on Ambulatory blood pressure in relation to Cardiovascular Outcomes (IDACO) study. We obtained the SBP, PR, and DP for these subjects as determined through 24-hour ambulatory monitoring. RESULTS Over a median period of 11.0 years, 1,388 of the 9,937 study subjects died, of whom 536 and 794, respectively, died of cardiovascular (CV) and non-CV causes, and a further 1,161, 658, 494, and 465 subjects, respectively, experienced a CV, cardiac, coronary, or cerebrovascular event. In multivariate-adjusted Cox models, not including SBP and PR, DP predicted total, CV, and non-CV mortality (standardized hazard ratio [HR], >= 1.10; P <= 0.02), and all CV, cardiac, coronary, and stroke events (HR, >= 1.21; P < 0.0001). For CV mortality (HR, 1.34 vs. 1.30; P = 0.71) and coronary events (1.28 vs. 1.21; P = 0.26), SBP and the DP were equally predictive. As compared with DP, SBP was a stronger predictor of all CV events (1.39 vs. 1.27; P = 0.002) and stroke (1.61 vs. 1.36; P < 0.0001), and a slightly stronger predictor of cardiac events (1.32 vs. 1.22; P = 0.06). In fully adjusted models, including both SBP and PR, the predictive value of DP disappeared for fatal endpoints (P >= 0.07), coronary events (P = 0.06), and stroke (P = 0.12), or DP was even inversely associated with the risk of all CV and cardiac events (both P <= 0.01). CONCLUSION In the general population, we did not observe DP to add to risk stratification over and beyond SBP and PR.

  • 24.
    Sohlberg, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Stephansson, Olof
    Department of Medicine, Clinical Epidemiology Unit at Karolinska Institutet, Stockholm, Sweden.
    Cnattingius, Sven
    Department of Medicine, Clinical Epidemiology Unit at Karolinska Institutet, Stockholm, Sweden.
    Wikström, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Maternal Body Mass Index, Height, and Risks of Preeclampsia2012In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 25, no 1, p. 120-125Article in journal (Refereed)
    Abstract [en]

    Background

    There is an association between maternal body mass index (BMI) and preeclampsia, but if BMI has an effect on preeclampsia of all severities is debated. If there is an association between maternal height and preeclampsia of all severities is unknown.

    Methods

    In this population-based cohort study including 503,179 nulliparous women, we estimated risks of preeclampsia of different severity in short (<164 cm) and tall (≥172 cm) women, using women of average height (164-171 cm) as reference, and in underweight (BMI: ≤18.4kg/m(2)), overweight (BMI: 25.0-29.9 kg/m(2)), obese class I (BMI: 30.0-34.9kg/m(2)) and obese class II-III (BMI: ≥35.0 kg/m(2)) women, using women with normal weight (BMI: 18.5-24.9kg/m(2)) as reference. Severity of preeclampsia was classified as early (<32 weeks), moderately early (32-36 weeks), and late (≥37 weeks) preeclampsia, or severe preeclampsia and mild to moderate preeclampsia, as defined by diagnostic codes.

    Results

    Short women had increased risks of all types of preeclampsia, but especially of early disease (adjusted odds ratio (OR) 1.3; 95% confidence interval (CI) 1.2-1.5). The risks of all preeclampsia types increased with BMI, but seemed higher for milder than more severe types of preeclampsia. Obesity class II-III was associated with a four-fold increased risk of mild to moderate preeclampsia (adjusted OR 4.0; 95% CI 3.7-4.4).

    Conclusion

    A short maternal stature and a high BMI increase risks of preeclampsia of all severities. The associations seem especially strong between short stature and severe types of preeclampsia, and high BMI and mild types of preeclampsia.

  • 25.
    Sällström, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Carlström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Jensen, Boye L
    Skøtt, Ole
    Brown, Russell D
    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.
    Neuronal nitric oxide synthase-deficient mice have impaired renin release but normal blood pressure2008In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 21, no 1, p. 111-116Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Nitric oxide deficiency is involved in the development of hypertension, but the mechanisms are currently unclear. This study was conducted to further elucidate the role of neuronal nitric oxide synthase (nNOS) in blood pressure regulation and renin release in relation to different sodium loads. METHODS: Blood pressure and heart rate were measured telemetrically and assessed during periods of physical activity and inactivity. Urinary solute excretion was measured by metabolism cages and plasma renin concentration (PRC) was determined by radioimmunoassay; all in nNOS knockout (nNOS(-/-)) and wild-type (nNOS(+/+)) mice after 10 days of low (0.01% NaCl) and high (4% NaCl) sodium diets. RESULTS: The resting heart rate was reduced in nNOS(-/-) mice, but the two genotypes had similar blood pressure during the low (nNOS(+/+) 104 +/- 2 mm Hg; nNOS(-/-) 103 +/- 2 mm Hg) and high (nNOS(+/+) 107 +/- 3 mm Hg; nNOS(-/-) 108 +/- 2 mm Hg) sodium diets. During the high sodium diet, PRC did not differ between the genotypes (nNOS(+/+) 743 +/- 115 10(-5) Goldblatt units; nNOS(-/-) 822 +/- 63 10(-5) Goldblatt units), but during the low sodium diet, nNOS(-/-) mice failed to increase PRC (nNOS(+/+) 2164 +/- 220 10(-5) Goldblatt units; nNOS(-/-) 907 +/- 101 10(-5) Goldblatt units) and renal renin mRNA. On the low sodium diet, nNOS(-/-) mice also showed increased urine flow rate and osmolar excretion, observations not made during a high sodium diet. CONCLUSIONS: Our results show that nNOS is necessary for stimulation of renin in response to sodium restriction. Furthermore, nNOS(-/-) mice are normotensive, and their blood pressure responds normally to an increased dietary sodium intake, indicating that nNOS deficiency does not cause salt-sensitive hypertension.

  • 26.
    Sällström, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Jensen, Boye
    Physiology and Pharmacology, University of Southern Denmark.
    Skøtt, Ole
    Physiology and Pharmacology, University of Southern Denmark.
    Xiang, Gao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Persson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrativ Fysiologi.
    Neuronal nitric oxide synthase supports renin release during sodium restriction through inhibition of phosphodiesterase 32010In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 23, no 11, p. 1241-1246Article in journal (Refereed)
    Abstract [en]

    Background: Mice with targeted deletion of neuronal nitric oxide synthase (nNOS‑/‑) display inability to increase plasma renin concentration (PRC) in response to sodium restriction. nNOS has a distinct expression at the macula densa, and it has been hypothesized that nNOS supports renin release by cGMP-mediated inhibition of cAMP-specific phosphodiesterase 3 (PDE3) in juxtaglomerular cells.

    Objective: To test the hypothesis that nNOS-derived NO supports renin release by inhibition of PDE3.

    Methods: The experiments were performed in conscious nNOS-/- and wild types after ten days on a low sodium diet by acute treatment with the PDE3 inhibitor milrinone, the PDE5 inhibitor zaprinast, or vehicle, using a crossover study protocol. PRC was measured with the antibody-trapping technique and blood pressure with telemetry. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were estimated by measurements of inulin- and Para-Amino Hippuric acid clearances, respectively.

    Results: The basal PRC was reduced in nNOS-/- compared to the wild types. Administration of milrinone caused a more pronounced PRC increase in nNOS-/-, resulting in normalized renin levels, while PDE5 inhibition did not affect PRC in any genotype. The blood pressure was similar in both genotypes, and milrinone did not affect blood pressure compared to vehicle. GFR and RPF were similar at baseline and were reduced by milrinone.

    Conclusions: The present study provides in vivo evidence supporting the view that NO, selectively derived from nNOS, mediates renin release during sodium restriction by inhibiting PDE3, which would increase renin release by elevating cAMP levels in the juxtaglomerular cells.

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