Can LDL cholesterol be too low? Possible risks of extremely low levels.

Following the continuous accumulation of evidence supporting the beneficial role of reducing low-density lipoprotein cholesterol (LDL-C) levels in the treatment and prevention of atherosclerotic cardiovascular disease and its complications, therapeutic possibilities now exist to lower LDL-C to very low levels, similar to or even lower than those seen in newborns and nonhuman species. In addition to the important task of evaluating potential side effects of such treatments, the question arises whether extremely low LDL-C levels per se may provoke adverse effects in humans. In this review, we summarize information from studies of human cellular and organ physiology, phenotypic characterization of rare genetic diseases of lipid metabolism, and experience from clinical trials. Specifically, we emphasize the importance of the robustness of the regulatory systems that maintain balanced fluxes and levels of cholesterol at both cellular and organismal levels. Even at extremely low LDL-C levels, critical capacities of steroid hormone and bile acid production are preserved, and the presence of a cholesterol blood-brain barrier protects cells in the central nervous system. Apparent relationships sometimes reported between less pronounced low LDL-C levels and disease states such as cancer, depression, infectious disease and others can generally be explained as secondary phenomena. Drug-related side effects including an increased propensity for development of type 2 diabetes occur during statin treatment, whilst further evaluation of more potent LDL-lowering treatments such as PCSK9 inhibitors is needed. Experience from the recently reported and ongoing large event-driven trials are of great interest, and further evaluation including careful analysis of cognitive functions will be important.

Comparison of amniotic fluid matrix metalloproteinase-8 and cathelicidin in the diagnosis of intra-amniotic infection.

OBJECTIVE: To evaluate the association of amniotic fluid (AF) matrix metalloproteinase-8 (MMP-8) and cathelicidin concentrations with microbial invasion of the amniotic cavity (MIAC) in pregnancies with preterm prelabor rupture of the membranes or intact membranes. STUDY DESIGN: Amniocentesis was performed in 54 singleton pregnancies between 22+0 and 34+2 gestational weeks with suspected intra-amniotic infection. AF-MMP-8 was analysed by immunoassay and AF-cathelicidin by commercial ELISA. Standard biochemical methods, molecular microbiology and culture techniques were used. RESULTS: MIAC was present in 18 (33%) women. The cutoff value for the diagnosis of MIAC was 41.5 ng ml-1 for AF-MMP-8, and 11.6 ng ml-1 for AF-cathelicidin. With these cutoff values AF-MMP-8 had a sensitivity of 100%, specificity of 69%, positive predictive value of 62% and negative predictive value of 100% for MIAC. The corresponding values for AF-cathelicidin were 89, 81, 70 and 94%. CONCLUSION: The performance of AF-cathelicidin in the prediction of MIAC is comparable to AF-MMP-8.

Amniotic fluid rapid biomarkers are associated with intra-amniotic infection in preterm pregnancies regardless of the membrane status.

OBJECTIVE: The objective of this study was to evaluate the association of amniotic fluid lactate dehydrogenase and glucose concentrations with microbial invasion of amniotic cavity and histologic chorioamnionitis before 37 pregnancy weeks in women with or without preterm premature rupture of membranes. STUDY DESIGN: Amniocentesis was performed on 70 women with suspected intra-amniotic infection. Standard biochemical methods, molecular microbiology and culture techniques were used. Histopathological examination of the placenta was performed. RESULTS: Thirty (48%) women had microbial invasion of the amniotic cavity (MIAC), 53 (76%) women had histological chorioamnionitis and 28 women had both. The cutoff values for MIAC and histological chorioamnionitis were 429 IU l(-1) for lactate dehydrogenase and 0.7 mmol l(-1) for glucose. Both end points occurred equally often regardless of the membrane status. CONCLUSION: Increased amniotic fluid lactate dehydrogenase and decreased glucose were associated with MIAC and histological chorioamnionitis. However, test performance was of limited value.

Long-term neurodevelopmental outcome of children from euploid pregnancies with increased nuchal translucency in the first trimester screening.

OBJECTIVE: To assess the long-term neurodevelopmental outcome of children born from singleton euploid pregnancies with increased fetal nuchal translucency (NT) in the first trimester ultrasound screening and without structural anomalies in the second trimester ultrasound screening. STUDY DESIGN: This is a register-based retrospective cohort study carried out at a tertiary referral centre from 2002 to 2007. Children were followed up until 2012. All fetuses had increased NT (>95th percentile) at the first trimester ultrasound screening and normal findings in the second trimester ultrasound screening. Data about the neurodevelopmental outcome was retrieved from the hospital databases, The National Institute for Health and Welfare, and the Finnish Causes of Death Statistics Database. Information about received disability allowances was gathered from the Social Insurance Institute of Finland. RESULTS: The study population consists of 691 children. The mean follow-up time was 6.5 years. Neurodevelopmental disorders occurred in 29 children (4.2%). Twelve of these 29 children (1.7%) had severe neurodevelopmental impairment. CONCLUSIONS: The long-term neurodevelopmental outcome of children after increased fetal NT is reassuring. This information should be added to the parental counselling of such cases. © 2014 John Wiley & Sons, Ltd.

Systolic blood pressure and fatty acid-binding protein 4 predict pregnancy-induced hypertension in overweight nulliparous women.

INTRODUCTION: The insulin-sensitivity regulator adipocyte fatty acid-binding protein 4 (FABP4) integrates metabolic and inflammatory responses. We hypothesize that there is relationship between FABP4 and factors related to metabolic syndrome in pregnancy-induced hypertension (PIH). METHODS: In this prospective observational study, among the 72 relatively overweight (BMI ≥24 kg/m2) nulliparous women, 14 developed non-proteinuric PIH and 12 developed proteinuric PIH (preeclampsia), whereas 46 had normotensive pregnancies. Insulin sensitivity was assessed via the whole-body insulin sensitivity index (ISI) and the homeostatic model of assessment - insulin resistance (HOMA-IR) at 24 weeks of gestation. Maternal serum levels of FABP4, high-sensitive C-reactive protein (hs-CRP), total testosterone, and non-protein-bound calculated free testosterone (cfT) were determined at 24 and 32 weeks. RESULTS: Measures of ISI, HOMA-IR, hs-CRP, testosterone and lipids did not differ at 24 and/or at 32 weeks in women who were subsequently hypertensive. SBP was higher at all time points and FABP4 levels tended to be higher at 24 and 32 weeks in patients compared to controls. In logistic regression analysis, baseline FABP4 (OR [95% CI] 1.069 [1.020-1.121], P = 0.006) and SBP after 10 min standing (OR [95% CI] 1.087 [1.029-1.149], P = 0.003) were associated with the development of PIH. FABP4 levels at 24 weeks did not correlate with insulin sensitivity. Neither was correlation seen between FABP4 levels at 24 and 32 weeks, vs. those of hs-CRP and testosterone. DISCUSSION AND CONCLUSIONS: Serum FABP4 concentration and SBP after 10 min standing in an orthostatic test at 24 weeks are associated with subsequent development of PIH.

Blood pressure levels but not hypertensive complications have increased in Type 1 diabetes pregnancies during 1989-2010.

AIMS: The pre-pregnancy BMI and the third trimester HbA(1c) levels increased in Finnish parturients with Type 1 diabetes during 1989-2008. The aim of the present study was to investigate whether these trends have been accompanied by increases in blood pressure or hypertensive complications. Hypertension trends were analysed using the definitions of hypertension of both the American College of Obstetricians and Gynecologists and the American Diabetes Association. The associations of hypertension, as defined by the latter criteria, with perinatal complications were also studied. METHODS: The records of a cohort of 1007 consecutive patients with Type 1 diabetes with a singleton live childbirth during 1989-2010 at the Helsinki University Central Hospital were studied. RESULTS: The frequencies of hypertensive pregnancy complications did not change, but the mean diastolic blood pressure increased in normotensive parturients in all trimesters. The proportion of patients with systolic blood pressure > 130 mmHg or diastolic blood pressure > 80 mmHg in the first, second and third trimesters of pregnancy increased from 25 to 33%, from 26 to 35% and from 57 to 71%, respectively. Systolic blood pressure of 131-139 mmHg or diastolic blood pressure of 81-89 mmHg in the third trimester was associated with umbilical artery pH < 7.15. CONCLUSIONS: Blood pressure of patients with Type 1 diabetes during pregnancy is increasing. A growing proportion of women with Type 1 diabetes exceed the American Diabetes Association's definition of hypertension during pregnancy.

Trends in maternal BMI, glycaemic control and perinatal outcome among type 1 diabetic pregnant women in 1989-2008.

AIMS/HYPOTHESIS: Our objective was to examine the trends in prepregnancy BMI and glycaemic control among Finnish type 1 diabetic patients and their relation to delivery mode and perinatal outcome. METHODS: We analysed the obstetric records of 881 type 1 diabetic women with a singleton childbirth during 1989-2008. Maternal prepregnancy weight and height were obtained from the maternity cards, where they are recorded as reported by the mother. RESULTS: Maternal BMI increased significantly during 1989-2008 (p < 0.001). The mean HbA(1c) in the first trimester remained unchanged, but the midpregnancy and the last HbA(1c) before delivery increased (p = 0.009 and 0.005, respectively). Elective Caesarean sections (CS) decreased (p for trend <0.001), while emergency CS increased (p for trend <0.001). The mean umbilical artery (UA) pH decreased in vaginal deliveries (p for trend <0.001). The frequency of UA pH <7.15 and <7.05 increased (p for trend <0.001 and 0.008, respectively). The macrosomia rate remained at 32-40%. Neonatal intensive care unit (NICU) admissions increased (p for trend 0.03) and neonatal hypoglycaemia frequency decreased (p for trend 0.001). In multiple logistic regression analysis, maternal BMI was associated with macrosomia and NICU admission. The last HbA(1c) value before delivery was associated with delivery before 37 weeks' gestation, UA pH <7.15, 1 min Apgar score <7, macrosomia, NICU admission and neonatal hypoglycaemia. CONCLUSIONS/INTERPRETATION: Self-reported pregestational BMI has increased and glycaemic control during the second half of pregnancy has deteriorated. Poor glycaemic control seems to be associated with the observed increases in adverse obstetric and perinatal outcomes.

Rye bread intake improves oxidation resistance of LDL in healthy humans.

BACKGROUND: Oxidatively modified LDL particles contribute to atherogenic development and therefore dietary interventions for promoting oxidation resistance of LDL are of interest. The capacity of LDL to resist oxidation can be determined ex vivo by exposing isolated LDL particles to copper ions and measuring the formation of conjugated dienes by spectrophotometry. OBJECTIVE: The aim of this trial was to determine the effect of none versus high intake of rye bread on the oxidation resistance of LDL in healthy humans while otherwise on habitual diet. DESIGN: Sixty-three healthy subjects excluded rye products for one week (baseline), followed by a stepwise addition of rye bread from 99 g/d during the first two weeks to 198 g/d during the following two weeks. Additionally plant sterols were incorporated into the rye bread for half of the subjects to study cholesterol-lowering. The resistance of LDL against copper-induced oxidation was determined at baseline and at the end of the rye-period by monitoring formation of conjugated dienes. RESULTS: We observed a significant increase in the oxidation resistance of LDL, determined as a prolongation of the lag time (P < 0.001) and decrease in the slope of the propagation phase (P = 0.048) from baseline to the end of the rye-period without changes in vitamin E concentration. We observed no significant differences in the oxidation resistance of LDL between subjects who did or did not receive plant sterols. CONCLUSIONS: Rye bread intake improved significantly the oxidation resistance of LDL. Further studies are needed to clarify the protective mechanism(s).

The effect of high-fiber rye bread enriched with nonesterified plant sterols on major serum lipids and apolipoproteins in normocholesterolemic individuals.

BACKGROUND AND AIMS: Plant sterols are naturally occurring cholesterol-lowering compounds which are industrially incorporated in various foods. A novel food carrier is rye bread, the intake of which can be monitored in trials utilizing newly defined plasma biomarkers. Our aim was to determine the effects of plant sterols incorporated into high-fiber rye bread on serum total and LDL cholesterol, apoB/apoA1 and total cholesterol/HDL cholesterol ratios and lipophilic (pro)vitamins in healthy free-living normocholesterolemic individuals. METHODS AND RESULTS: In this double-blind, dietary intervention trial the subjects (n=68) were randomized to receive a rye bread (9.3g/d fiber) with added plant sterols (2g/d) (active) or without (control). In the second phase of the study the amount of rye bread was doubled providing 18.6g/d fiber and in the active group 4g/d plant sterols. Compliance was monitored utilizing 3-day food diaries and a novel rye fiber-derived biomarker in plasma. Intake of rye bread enriched with 2g/d of plant sterols during two weeks reduced significantly serum total and LDL cholesterol, apoB/apoA1 and total cholesterol/HDL cholesterol ratios by 5.1%, 8.1%, 8.3% and 7.2%, respectively, compared to controls. Correspondingly, the following two-week treatment with 4g/d of plant sterols resulted in 6.5%, 10.4%, 5.5% and 3.7% difference compared to controls, being most pronounced for LDL (0.33 mmol/L). The treatments did not affect lipophilic (pro)vitamin levels. CONCLUSION: Rye bread enriched with 2-4g/d of nonesterified plant sterols beneficially modifies cardiovascular lipid risk factors in normocholesterolemic subjects compared to controls.

Associations of Body Mass Index (Maternal BMI) and Gestational Diabetes Mellitus with Neonatal and Maternal Pregnancy Outcomes in a Multicentre European Database (Diabetes and Pregnancy Vitamin D and Lifestyle Intervention for Gestational Diabetes Mellitus Prevention).

Objective. Assess the impact of Gestational Diabetes Mellitus (GDM) and obesity on neonatal and maternal pregnancy outcomes. Methods. Cross-sectional data (3343 pregnancies) from seven European centres were included in a multilevel analysis of the association between GDM/obesity and caesarean section, macrosomia and neonatal morbidities. Results. Comparison of databases identified reporting differences between countries due to the inclusion of true population based samples or pregnancies from specialised tertiary centres, resulting in higher prevalences of GDM for some countries. The analysis showed that obesity and GDM were independent risk factors of perinatal complications. Only BMI had a dose-dependent effect on the risk of macrosomia and caesarean section. Both obesity (BMI > 30 kg/m(2)) and GDM were independent risk factors of neonatal morbidities. Conclusions. Obesity and GDM were independent risk factors of perinatal complications. The effect of the worldwide obesity and diabetes epidemic is extending to the next generation.

Hot flushes and biochemical markers for cardiovascular disease: a randomized trial on hormone therapy.

INTRODUCTION: Menopausal hot flushes may affect the responses of various vascular risk factors to hormone therapy (HT). We compared the responses of biochemical markers for cardiovascular diseases to HT in recently postmenopausal women with tolerable or intolerable hot flushes. METHODS: Healthy, non-smoking freshly postmenopausal women (n = 150) with no previous HT use were studied. Seventy-two women reported intolerable hot flushes (> or =7 moderate/severe episodes/day) and 78 women tolerable hot flushes (< or =3 mild episodes/day). The participants were treated in randomized order with either transdermal estradiol gel (1 mg), oral estradiol valerate (2 mg) with or without medroxyprogesterone acetate (5 mg), or placebo for 6 months. Treatment-induced changes in lipids, lipoproteins, apolipoproteins, sex hormone binding globulin (SHBG) and high-sensitivity C-reactive protein were compared. The trial is registered in the US National Institutes of Health Clinical Research Registry (no. NCT00668603). RESULTS: Pretreatment hot flush status was not related to the responses of these markers to different forms of HT. However, when all active regimens were evaluated together as a post-hoc analysis, 7/10 markers showed a tendency toward greater beneficial changes in women with intolerable hot flushes. Furthermore, in women with intolerable hot flushes and with HT use, the increases in SHBG (Spearman's rho = - 0.570, p < 0.001) were related to the reductions in hot flushes during the use of HT. CONCLUSIONS: Hot flushes appear to be no significant determinant for the responses of vascular markers to HT use.

Cardiovascular outcomes and their relationships to lipoprotein components in patients with and without chronic kidney disease: results from the IDEAL trial.

OBJECTIVES: In Incremental Decrease in Endpoints through Aggressive Lipid-lowering (IDEAL), we compared cardiovascular outcomes in patients with and without chronic kidney disease (CKD) (estimated glomerular filtration rate <60 mL min(-1) 1.73 m(-2)) and analysed relationships between lipoprotein components (LC) and major coronary events (MCE) and other cardiovascular (CV) events. DESIGN: Exploratory analysis of CV endpoints in a randomized trial comparing high dose of atorvastatin to usual dose of simvastatin on MCE. SETTINGS: Patients with CKD were compared with the non-CKD patients. Cox regression models were used to study the relationships between on-treatment levels of LC and incident MCE. FINDINGS: Chronic kidney disease was strongly associated with cardiovascular end-points including total mortality. In patients with CKD, a significant benefit of high dose atorvastatin treatment was found for any CV events, stroke and peripheral artery disease, but not for MCE. However, all cardiovascular end-points except stroke and CV mortality were reduced in the non-CKD group. Differential changes in LC or relationships to LC could not explain the different treatment outcomes in MCE in the two groups. INTERPRETATION: Chronic kidney disease was a powerful risk factor for all cardiovascular end-points. The reason why the significant reductions achieved by high-dose statin treatment in most CV end-points in the non-CKD group were only in part matched by similar reductions in the CKD patients is not apparent. This difference did not result from differential changes in or relations to LC, but limited power may have increased the possibility of chance findings.

Safety assessment of common foods enriched with natural nonesterified plant sterols.

BACKGROUND/OBJECTIVES: To assess safety during a diet based on low-fat foods enriched with nonesterified wood-derived plant sterols and mineral nutrients related to serum phytosterol, sex hormone and fat-soluble vitamin metabolism. SUBJECTS/METHODS: Seventy-one study participants (52 women, 19 men) with mild-to-moderate hypercholesterolemia completed the double-blind, placebo-controlled feeding trial lasting for 15 weeks. The subjects were randomly allocated to the sterol group receiving food items enriched with mineral nutrients as well as with a total of 1.25, 2.5 and 5.0 g per day of plant sterols during the first, second and third 5-week periods, respectively, or to the placebo group receiving similar food items without plant sterols. This outpatient clinical trial with free-living subjects was carried out at two hospital clinics. RESULTS: Two significant findings were observed. Serum sitosterol concentrations increased from 2.84 to 5.35 mg l(-1) (P<0.004 vs placebo) but those of serum total plant sterols did not because of compensatory changes in other phytosterols. The highest plant sterol levels did not exceed 0.6% of total serum sterols. Serum alpha-tocopherol concentrations decreased in the sterol group by 10% (P<0.0002), but the between-group difference disappeared after adjusting for the change in the carrier (LDL cholesterol). CONCLUSIONS: Fifteen-week consumption of natural nonesterified plant sterol-enriched food does not cause any serious adverse effects during such a period. However, serum alpha-tocopherol levels were somewhat reduced in the sterol group suggesting that long-term effects of plant sterols on serum fat-soluble vitamin concentrations should be further explored, especially in relation to very low-fat diets.

Prediction of placental abruption by testing for C-reactive protein and chlamydial antibody levels in early pregnancy.

OBJECTIVE: Placental abruption may be a manifestation of acute and chronic inflammatory process. We wanted to assess the association of first-trimester serum C-reactive protein (CRP), Chlamydia pneumoniae antibodies, Chlamydia trachomatis antibodies or chlamydial heat-shock protein 60 (CHSP60) antibodies to placental abruption. DESIGN: Retrospective case-control study. SETTING: University Hospital. POPULATION: A total of 181 women with subsequent placental abruption and 261 control women with normal pregnancy. METHODS: Serum samples collected at first trimester (mean 10.4 gestational weeks) were analysed for CRP levels, C. pneumoniae-specific immunoglobulin G (IgG) and immunoglobulin A (IgA) antibodies and C. trachomatis-specific IgG, IgA and CHSP60 antibodies. MAIN OUTCOME MEASURE: Placental abruption. RESULTS: The levels of CRP showed no difference between the cases and the controls (median 2.35 mg/l [interquartile range {IQR} 1.09-5.93] versus 2.28 mg/l [IQR 0.92-5.01], not significant). C. pneumoniae-specific IgG and IgA as well as C. trachomatis-specific IgG, IgA and CHSP60 antibody frequencies were similar between the groups. There was no association between CRP levels and chlamydial antibodies. CONCLUSION: These markers of inflammation in early pregnancy failed to predict subsequent placental abruption.

Individual differences in equol production capability modulate blood pressure in tibolone-treated postmenopausal women: lack of effect of soy supplementation.

OBJECTIVES: Equol, a gut bacterial metabolite of the isoflavone daidzein, has been associated with beneficial health effects. Recent studies indicate that women with intestinal capacity to convert daidzein to equol also have the capacity to alter steroid metabolism and bioavailability of estrogens. METHODS: We evaluated whether individual equol production capability, while not consuming soy supplement, was associated with lower blood pressure in postmenopausal women using tibolone. In addition, in a randomized, placebo-controlled, cross-over trial we assessed the effect of soy supplementation on blood pressure in both equol-producing (n = 20) and non-equol-producing (n = 20) women using tibolone. Blood pressure was recorded with a validated oscillometric technique. RESULTS: The circulating equol levels rose 20-fold in the equol producers and 1.9-fold in the non-equol producers. At baseline, systolic blood pressure (129.9 +/- 2.6 vs. 138.5 +/- 3.1 mmHg, p = 0.02), diastolic blood pressure (72.2 +/- 1.5 vs. 76.6 +/- 1.3 mmHg, p = 0.01) and mean arterial blood pressure (93.5 +/- 1.7 vs. 99.9 +/- 1.8 mmHg, p = 0.007) were lower in equol producers compared to non-equol producers. Soy supplementation had no effect on blood pressure in either group, whereas the baseline differences persisted. CONCLUSIONS: Postmenopausal women using tibolone characterized as equol producers had lower blood pressure compared to non-equol producers. Soy supplementation for 2 months had no blood pressure-lowering effect.

Erectile dysfunction as a risk factor for coronary heart disease: implications for prevention.

There is now mounting evidence that erectile dysfunction (ED) is an early predictor of coronary heart disease (CHD). Men presenting with ED but no other cardiovascular symptoms provide an opportunity for the treating physician to test for asymptomatic CHD and to reduce CHD risk factors.

Safety aspects and cholesterol-lowering efficacy of low fat dairy products containing plant sterols.

OBJECTIVE: The aim of this study was to investigate whether a plant sterol mixture would reduce serum cholesterol when added to low fat dairy products in subjects with hypercholesterolaemia, and to examine the effects of the mixture on the serum plant sterol and fat-soluble vitamin levels. DESIGN: A parallel, double-blind study. SETTING: The study was performed in three different locations in Finland. SUBJECTS: In total, 164 mildly or moderately hypercholesterolaemic subjects participated in the study. METHODS: The subjects were randomly divided into two groups: a plant sterol group and a control group. The subjects consumed the products for 6 weeks after a 3-week run-in period. The targeted plant sterol intake was 2 g/day in the sterol group. RESULTS: During the treatment period, there was a 6.5% reduction in serum total cholesterol in the sterol group while no change was observed in the control group (P<0.0005). Serum low-density lipoprotein (LDL) cholesterol was reduced by 10.4% in the sterol group and by 0.6% in the control group (P<0.00005). There was no change during the trial in serum high-density lipoprotein (HDL) cholesterol or triacylglycerol concentrations. The HDL/LDL cholesterol ratio increased by 16.1% in the sterol group and by 4.3% in the control group (P=0.0001). Serum plant sterol levels increased significantly (P=0.0001) in the sterol group. None of the fat-soluble vitamin levels decreased significantly when changes in serum total cholesterol were taken into account. The hypocholesterolaemic effect of sterol administration was not influenced by apolipoprotein E phenotype. CONCLUSIONS: Yoghurt, low-fat hard cheese and low-fat fresh cheese enriched with a plant sterol mixture reduced serum cholesterol in hypercholesterolaemic subjects and no adverse effects were noted in the dietary control of hypercholesterolaemia.

Endurance running ability at adolescence as a predictor of blood pressure levels and hypertension in men: a 25-year follow-up study.

The aim was to study whether aerobic fitness measured by a maximal endurance running test at adolescence predicts prevalence of hypertension or blood pressure levels in adulthood. From the 413 (197 slow runners and 216 fast runners) participating in a 2000-meter running test at adolescence in 1976 and responding to a health and fitness questionnaire in 2001, 29 subjects (15 very slow runners and 14 very fast runners) participated in a clinical follow-up study in 2001. Compared to those who were fast runners in adolescence, those who were slow runners tended to have higher age-adjusted risk of hypertension at follow-up (OR 2.7, 95 % CI 0.9 to 7.5; p=0.07). The result persisted after further adjustment for body mass index at follow-up (OR 2.9, 95 % CI 1.0 to 8.3; p=0.05). Diastolic blood pressure was higher for very slow runners at adolescence compared to very fast runners, the age-adjusted mean diastolic blood pressure being 90 mm Hg (95 % CI 86 to 93) vs. 83 mm Hg (95 % CI 80 to 87), age-adjusted p=0.013. High endurance type fitness in adolescence predicts low risk of hypertension and low resting diastolic blood pressure levels in adult men.

Effects of vitamin E on the toxicity of oxidized LDL on endothelial cells in vitro in smokers vs nonsmokers on diets rich in fish.

OBJECTIVE: To clarify whether supplementation of vitamin E can alter the low density lipoprotein (LDL) oxidation properties and thereby affect endothelial cell function and prostacyclin production in smokers compared to nonsmokers on diets rich in fish in a pilot study. DESIGN: The LDL of six smokers and six nonsmokers on habitual high fish diet was isolated before and after an 8-week supplementation of vitamin E (800 IU/day). LDL was oxidized by incubation with CuSO4. Cytotoxicity of LDL oxidized to different degrees on endothelial cells was investigated in vitro in these two groups. SETTING: Helsinki University Central Hospital; Institute of Biomedicine, Pharmacology, University of Helsinki. RESULTS: At baseline, the rate of oxidation was higher in nonsmokers than in smokers. The lag phase increased significantly after the supplementation of vitamin E both in smokers and nonsmokers. Native LDL dose dependently tended to reduce the viability of endothelial cells in vitro more markedly when isolated from smokers than from nonsmokers. Vitamin E supplementation had no beneficial effect on the cytotoxicity of oxidized LDLs in endothelial cell culture. On the other hand, simultaneous administration of Trolox, the water-soluble analogue of vitamin E, attenuated the LDL cytotoxicity on endothelial cells. The vitamin E supplementation to LDL donors attenuated the increase in prostacyclin production both in smokers and nonsmokers. CONCLUSION: Supplementation of LDL donors (healthy male volunteers on habitual fish diet) with vitamin E increased the lag phase of LDL oxidation, but, on the other hand, did not influence in vitro cytotoxicity of LDL, or prostacyclin production.

Effects of oral and transdermal estradiol administration on levels of sex hormone-binding globulin in postmenopausal women with and without a history of intrahepatic cholestasis of pregnancy.

SHBG, the most important transport protein for sex steroids, is produced in the liver under the control of estrogen action. In a randomized, double-blind, prospective crossover study we compared basal levels of serum SHBG and their responses to increasing doses of oral and transdermal estradiol (E2), followed by E2 plus oral progestin (medroxyprogesterone acetate [MPA]), in 40 postmenopausal women with or without a history of intrahepatic cholestasis of pregnancy (ICP), which could affect the synthesis of SHBG. Serum samples collected at baseline, on the last day of each E2 period, and on the last day of the E2 plus MPA combination were assayed for SHBG and E2. Basal levels of SHBG showed no difference between the study groups. Oral but not transdermal E2 increased SHBG concentrations by 67-171% in the control group, but the response was smaller (42-121%) in the ICP group. Addition of MPA decreased SHBG levels by 14-18% in both groups during both treatments. In conclusion, a history of ICP is associated with blunted responses of SHBG to oral estrogen.