Pregnancy insulin, glucose, and BMI contribute to birth outcomes in nondiabetic mothers.

OBJECTIVE: We investigated the effects of normal variations in maternal glycemia on birth size and other birth outcomes. RESEARCH DESIGN AND METHODS: Women in two unselected birth cohorts, one retrospective (n = 3,158) and one prospective (n = 668), underwent an oral glucose challenge at 28 weeks of gestation. In the retrospective study, glycemia was linked to routine birth records. In the prospective study, offspring adiposity was assessed by skinfold thickness from birth to age 24 months. RESULTS: In the retrospective study, within the nondiabetic range (2.1-7.8 mmol/l), each 1 mmol/l rise in the mother's 60-min glucose level was associated with a (mean +/- SEM) 2.1 +/- 0.8% (P = 0.006) rise in absolute risk of assisted vaginal delivery, a 3.4 +/- 0.8% (P 90th centile) was independently related to the mother's fasting glucose (odds ratio 2.61 per +1 mmol/l [95% CI 1.15-5.93]) and prepregnancy BMI (1.10 per +1 kg/m(2) [1.04-1.18]). The mother's higher fasting glycemia (P = 0.004), lower insulin sensitivity (P = 0.01), and lower insulin secretion (P = 0.02) were independently related to greater offspring adiposity at birth. During postnatal follow-up, the correlation between the mother's glycemia and offspring adiposity disappeared by 3 months, whereas prepregnancy BMI was associated with offspring adiposity that was only apparent at 12 and 24 months (both P < 0.05). CONCLUSIONS: Prepregnancy BMI, pregnancy glycemia, insulin sensitivity, and insulin secretion all contribute to offspring adiposity and macrosomia and may be separate targets for intervention to optimize birth outcomes and later offspring health

A Novel Risk Stratification Model for Patients with Non-ST Elevation Myocardial Infarction in the Korea Acute Myocardial Infarction Registry (KAMIR): Limitation of the TIMI Risk Scoring System

The Thrombolysis in Myocardial Infarction (TIMI) risk score (TRS) has proven value in predicting prognosis in unstable angina/non ST-elevation myocardial infarction (NSTEMI) as well as in ST-elevation myocardial infarction. The TRS system has little implication, however, in the extent of myocardial damage in high-risk patients with NSTEMI. A total of 1621 patients (63.6±12.2 years; 1043 males) with NSTEMI were enrolled in the Korea Acute Myocardial Infarction Registry (KAMIR). We analyzed the risk for major adverse cardiac events (MACE) during a 6-month follow-up period. The TRS system showed good correlation with MACE for patients in the low and intermediate groups but had poor correlation when the high-risk group was included (p=0.128). The MACE rate was 3.8% for TRS 1, 9.4% for TRS 2, 10.7% for TRS 3, and 12.3% for TRS 4 (HR=1.29, p=0.026). Among the biomarkers and clinical risk factors, elevated N-terminal pro-brain natriuretic peptide (NT-proBNP) (HR=2.61, p=0.001) and Killip class above III showed good correlation with MACE (HR=0.302, p<0.001). Therefore, we revised an alternative clinical scoring system by including these two variables that reflect left ventricular dysfunction: age > 65 years, history of ischemic heart disease, Killip class above III, and elevated pro-BNP levels above the 75th percentile. This modified scoring system, when tested for validity, showed good predictive value for MACE (HR=1.64, p<0.001). Compared with the traditional TRS, the novel alternative scoring system based on age, history of ischemic heart disease, Killip class, and NT-proBNP showed a better predictive value for 6-month MACE in high-risk patients with NSTEMI

Unusual towering elevation of troponin I after ST-elevation myocardial infarction and intensive monitoring with echocardiography post-percutaneous coronary intervention: a case report

<p>Abstract</p> <p>Introduction</p> <p>The elevation of troponin levels directly corresponds to the extent of myocardial injury. Here we present a case of a robust rise in cardiac biomarkers that correspond to extensive damage to the myocardium but did not spell doom for our patient. It is important to note that, to the best of our knowledge, this is the highest level of troponin I ever reported in the literature after a myocardial injury in an acute setting.</p> <p>Case presentation</p> <p>A 53-year-old African American man with an unknown medical history presented to the emergency room of our hospital with chest pain associated with diaphoresis and altered mental status. He required emergency intubation due to acute respiratory failure and circulatory collapse within 10 minutes of his arrival. He was started on heparin and eptifibatide (Integrilin) drips but he was taken immediately for cardiac catheterization, which showed a total occlusion of his proximal left anterior descending, diffuse left circumflex disease and severe left ventricular dysfunction with segmental wall motion abnormality. He remained hypotensive throughout the procedure and an intra-aortic balloon pump was inserted for circulatory support. His urinary toxicology examination result was positive for cocaine metabolites. Serial echocardiograms showed an akinetic apex, a severely hypokinetic septum, and severe systolic dysfunction of his left ventricle. Our patient stayed at the Coronary Care Unit for a total of 15 days before he was finally discharged.</p> <p>Conclusion</p> <p>Studies demonstrate that an increase of 1 ng/ml in the cardiac troponin I level is associated with a significant increase in the risk ratio for death. The elevation of troponin I to 515 ng/ml in our patient is an unusual robust presentation which may reflect a composite of myocyte necrosis and reperfusion but without short-term mortality. Nevertheless, prolonged close monitoring is required for better outcome. We also emphasize the need for the troponin assays to be standardized and have universal cutoffs for comparisons across available data.</p

Maternal rates of lipolysis and glucose production in late pregnancy are independently related to foetal weight.

OBJECTIVE: Associations between maternal glucose levels and increased foetal growth are well established, and independent relationships with maternal weight, weight gain and insulin resistance are also observed. The relative roles of lipolysis and glucose production in the determination of these observations remain unclear. DESIGN: We examined, through detailed physiological studies, the relationship between maternal late gestational energy substrate production (glucose and glycerol), maternal weight and weight gain, and estimated foetal size in the third trimester. PATIENTS: Twenty-one nulliparous pregnant women, without gestational diabetes (GDM) assessed at 28 weeks with oral glucose tolerance test, were recruited. MEASUREMENTS: Rates of hepatic glucose production (GPR) and rates of glycerol production (reflecting lipolysis) using [(13) C6 ]-glucose and [(2) H5 ]-glycerol were measured at 34-36 weeks of gestation. Respiratory quotient was assessed by indirect calorimetry and body composition by measurements of total body water (TBW; H2(18) O) and body density (BODPOD). Foetal weight was estimated from ultrasound measures of biparietal diameter, femoral length and abdominal circumference. RESULTS: At 34-36 weeks, bivariate analyses showed that GPR and lipolysis correlated with estimated foetal weight (r=.71 and .72, respectively) as well as with maternal weight, fat mass and fat-free mass, but not maternal weight gain. In multivariate analyses, rates of both glucose production (r=.42) and lipolysis (r=.47) were independently associated with foetal size explaining 63% of the variance. CONCLUSIONS: Both maternal rates of lipolysis and hepatic glucose production in late gestation are strongly related to estimated foetal weight.This project was supported by research grants from Diabetes UK and Funds and Friends of Addenbrooke's. Dr Diderholm was supported by the Throne-Holst Foundation, Uppsala University, Her Royal Highness the Crown Princess Lovisa's Foundation for Children's Health Care, the Wera Ekström Foundation, the Gillberg Foundation, the Swedish Society of Medical Research and the Swedish Society of Medicine

Convergence in insulin resistance between very severely obese and lean women at the end of pregnancy

AIMS: Disrupted intermediary metabolism may contribute to the adverse pregnancy outcomes in women with very severe obesity. Our aim was to study metabolism in such pregnancies. METHODS: We recruited a longitudinal cohort of very severely obese (n = 190) and lean (n = 118) glucose-tolerant women for anthropometric and metabolic measurements at early, mid and late gestation and postpartum. In case–control studies of very severely obese and lean women we measured glucose and glycerol turnover during low- and high-dose hyperinsulinaemic–euglycaemic clamps (HEC) at early and late pregnancy and in non-pregnant women (each n = 6–9) and body fat distribution by MRI in late pregnancy (n = 10/group). RESULTS: Although greater glucose, insulin, NEFA and insulin resistance (HOMA-IR), and greater weight and % fat mass (FM) was observed in very severely obese vs lean participants, the degree of worsening was attenuated in the very severely obese individuals with advancing gestation, with no difference in triacylglycerol (TG) concentrations between very severely obese and lean women at term. Enhanced glycerol production was observed in early pregnancy only in very severely obese individuals, with similar intrahepatic FM in very severely obese vs lean women by late gestation. Offspring from obese mothers were heavier (p = 0.04). CONCLUSIONS/INTERPRETATION: Pregnancies complicated by obesity demonstrate attenuation in weight gain and insulin resistance compared with pregnancies in lean women. Increased glycerol production is confined to obese women in early pregnancy and obese and lean individuals have similar intrahepatic FM by term. When targeting maternal metabolism to treat adverse pregnancy outcomes, therapeutic intervention may be most effective applied early in pregnancy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00125-015-3708-3) contains peer-reviewed but unedited supplementary material, which is available to authorised users

Modifying effect of dual antiplatelet therapy on incidence of stent thrombosis according to implanted drug-eluting stent type

Aim To investigate the putative modifying effect of dual antiplatelet therapy (DAPT) use on the incidence of stent thrombosis at 3 years in patients randomized to Endeavor zotarolimus-eluting stent (E-ZES) or Cypher sirolimus-eluting stent (C-SES). Methods and results Of 8709 patients in PROTECT, 4357 were randomized to E-ZES and 4352 to C-SES. Aspirin was to be given indefinitely, and clopidogrel/ticlopidine for ≥3 months or up to 12 months after implantation. Main outcome measures were definite or probable stent thrombosis at 3 years. Multivariable Cox regression analysis was applied, with stent type, DAPT, and their interaction as the main outcome determinants. Dual antiplatelet therapy adherence remained the same in the E-ZES and C-SES groups (79.6% at 1 year, 32.8% at 2 years, and 21.6% at 3 years). We observed a statistically significant (P = 0.0052) heterogeneity in treatment effect of stent type in relation to DAPT. In the absence of DAPT, stent thrombosis was lower with E-ZES vs. C-SES (adjusted hazard ratio 0.38, 95% confidence interval 0.19, 0.75; P = 0.0056). In the presence of DAPT, no difference was found (1.18; 0.79, 1.77; P = 0.43). Conclusion A strong interaction was observed between drug-eluting stent type and DAPT use, most likely prompted by the vascular healing response induced by the implanted DES system. These results suggest that the incidence of stent thrombosis in DES trials should not be evaluated independently of DAPT use, and the optimal duration of DAPT will likely depend upon stent type (Clinicaltrials.gov number NCT00476957

Does metformin reduce excess birthweight in offspring of obese pregnant women? A randomised controlled trial of efficacy, exploration of mechanisms and evaluation of other pregnancy complications

BackgroundMaternal obesity is associated with high birthweight, obesity and premature mortality in adult offspring, probably as a result of maternal hyperglycaemia and insulin resistance. We present the results of a trial designed to test the hypothesis that metformin will improve insulin sensitivity in obese pregnant women, thereby reducing the incidence of high-birthweight babies.ObjectiveTo determine the efficacy of metformin (up to 2500 mg daily) given to obese pregnant women in reducing the gestational age-, parity- and sex-adjusted birthweight centile of the baby.DesignDouble-blind, placebo-controlled, randomised controlled trial with embedded substudies.SettingFifteen NHS hospitals in the UK.ParticipantsPregnant women aged ≥ 16 years with a singleton fetus and a body mass index of ≥ 30 kg/m2.InterventionMetformin tablets (or placebo) administered between 12 and 16 weeks’ gestation until delivery of the baby.Main outcome measuresThe primary outcome measure was z-score corresponding to the gestational age-, parity- and sex-adjusted birthweight centile of live-born babies delivered at ≥ 24 weeks’ gestation. The main secondary outcome was maternal insulin resistance at 36 weeks’ gestation. Embedded substudies were included to assess the effect of metformin on insulin sensitivity using the hyperinsulinaemic–euglycaemic clamp; endothelial function; maternal and fetal fat distribution using magnetic resonance imaging; placental expression of 11β-hydroxysteroid dehydrogenase types 1 and 2 and glucocorticoid receptor; and myometrial contractility and glycogen storage.ResultsWe randomised 449 women to either placebo (n = 223) or metformin (n = 226), of whom 434 were included in the final intention-to-treat analysis. Mean birthweight at delivery was 3463 g [standard deviation (SD) 660 g] in the placebo group and 3462 g (SD 548 g) in the metformin group. The estimated effect size of metformin on the primary outcome was non-significant [adjusted mean difference in z-score –0.029, 95% confidence interval (CI) –0.217 to 0.158; p = 0.7597]. There was no evidence of a reduction in the main secondary outcome of homeostatic model assessment – insulin resistance (HOMA-IR) at 36 weeks’ gestation (mean HOMA-IR 5.98 and 6.30 molar units in the placebo and metformin groups, respectively; adjusted mean ratio 0.974, 95% CI 0.865 to 1.097). Metformin had no effect on the combined adverse outcome of miscarriage, termination of pregnancy, stillbirth or neonatal death. Subjects taking metformin demonstrated increased insulin sensitivity [glucose disposal per unit plasma insulin difference between means during high-dose insulin 0.02 mg/kg, 95% CI 0.001 to 0.03 mg/kg (fat-free mass)/minute/µIU/l; p = 0.04] compared with those taking placebo and enhanced endogenous glucose production [difference between means 0.54 mg/kg, 95% CI 0.08 to 1.00 mg/kg (fat-free mass)/minute; p = 0.02]. There were no differences in endothelial function, maternal or fetal body fat distribution, placental expression of 11β-hydroxysteroid dehydrogenase types 1 and 2 and glucocorticoid receptor, or myometrial contractility and glycogen storage.ConclusionsMetformin has no clinically significant effect on birthweight centile in obese pregnant women. Follow-up studies of the children born to participants in the trial are required to determine whether or not there are any longer-term benefits or harms of maternal metformin for offspring weight, fat mass or metabolism.Trial registrationCurrent Controlled Trials ISRCTN51279843.FundingThis project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership

Perinatal Energy Substrate Metabolism : Glucose Production and Lipolysis in Pregnant Women and Newborn Infants with Particular Reference to Intrauterine Growth Restriction (IUGR)

Glucose is the most important fetal nutrient and the production of this substrate increases in the pregnant woman. In the last trimester the increased insulin resistance directs energy substrates to the fetus. Fetal growth is sometimes disturbed, often without an obvious explanation. After birth the newborn infant must produce its own glucose, primarily for the brain. Fatty acids from lipolysis are also important energy substrates. Hypoglycaemia can be a problem, occurring frequently in preterm infants and infants born small for gestational age (SGA). In addition, SGA infants are at risk of developing the metabolic syndrome in adulthood. Neonatal medication can influence energy metabolism. One such medication is theophylline, administered in preterm infants to prevent apnoea. We investigated energy substrate production in women with normal and IUGR pregnancies, in preterm neonates, before and after theophylline treatment and in newborn SGA infants, using stable isotope-labelled compounds and gas chromatography-mass spectrometry. We found that late pregnancy was associated with an almost twofold increase in the rate of lipolysis. This provides substrates for maternal energy metabolism, which may spare glucose for the fetus. Even though glucose production was comparable in the two groups of pregnant women, those with IUGR had a lower rate of lipolysis. A reduced supply of energy substrates could be one factor underlying IUGR. In spite of the insulin resistance of late pregnancy, insulin still had a regulatory role in energy substrate production in the women with normal pregnancies, but not in those with IUGR. Although infants born preterm and/or SGA have limited energy stores, we demonstrated that they are capable of both lipolysis and glucose production. Theophylline had no adverse effects on energy substrate production. Data on insulin and IGFBP-1 in the SGA infants indicate that in such infants insulin sensitivity is increased peripherally but reduced in the liver

Early Invasive Strategy in Unstable Coronary Artery Disease : Outcome in Relation to Risk Stratification

In unstable coronary artery disease (CAD) it still is a matter of debate which patients should undergo early revascularisation. In the FRISC II study (n=2457) an early invasive strategy was, compared to a primarily non-invasive strategy, associated with reduced mortality and myocardial infarction (MI) rates. However, in this heterogeneous group of patients, tools for an appropriate selection to revascularisation are needed. From the FRISC II study we evaluated the prognosis, the angiographic extent of CAD and the effects of an early invasive strategy in relation to risk variables on admission. The occurrence of ST depression and/or elevated levels of Troponin T were associated with a higher risk for death and MI, more severe CAD and also with a reduction of death or MI by the early invasive strategy. Elevated levels of the inflammatory markers C-reactive protein (CRP) and interleukin-6 (Il-6) were associated with a higher mortality but an unchanged MI rate. Elevated levels of Il-6, but not CRP, identified patients with a large reduction of mortality by the invasive strategy. Age ≥ 70 years, male gender, diabetes, previous MI, ST depression and elevated levels of troponin and markers of inflammation were independently associated with an adverse outcome. The FRISC-score was constructed using these 7 variables. At FRISC-score ≥ 5 an early invasive strategy markedly reduced mortality and MI, at FRISC–score 3-4 death/MI was reduced, whereas in patients with a FRISC-score 0-2 neither mortality nor death/MI was influenced. In unstable CAD, a non-invasive strategy seems justified only for patients at low risk, i.e. FRISC score &lt; 2. In patients with intermediate and high risk, i.e. FRISC-score ≥ 3, an early invasive strategy is recommended