Publications
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Cauldwell M, Steer PJ, Swan L, et al., 2016, Pre-pregnancy counseling for women with heart disease: A prospective study., International Journal of Cardiology, Vol: 240, Pages: 374-378, ISSN: 0167-5273
BACKGROUND: Women with cardiac disease and their infants are at a greater risk of mortality and morbidity during pregnancy. Expert groups recommend preconception counseling (PCC) for all women with cardiac disease so they are made aware of these risks. We have run a specialist maternal cardiac clinic since 1996. The aim of this study was to evaluate the experience of women who have received PCC within an established multidisciplinary tertiary clinic and to establish their views regarding the counseling they received. METHODS: Single centre prospective study using a patient questionnaire was given to women attending a specialist cardiac preconception counseling clinic from November 2015 to August 2016, with analysis of descriptive data and free text comments from the questionnaire responders. RESULTS: 40/65 returned patient questionnaires. Prior to the consultation fewer than half felt well informed regarding how their heart disease could impact upon pregnancy but a similar proportion felt nonetheless that they would be able to have a healthy pregnancy. Women reported two main areas of concerns, their own health (whether they would survive a pregnancy) and the health of their child. 15% of women reported that these concerns had prevented them from pursuing a pregnancy. Women reported high satisfaction rates with the clinic. CONCLUSIONS: There is an increasing demand for PCC services for women with cardiac disease; our study is the first attempt to determine both the acceptability and the impact of PCC from the patient perspective. Patients reported a high level of satisfaction with the service provided.
van Hagen IM, Boersma E, Johnson MR, et al., 2016, Global cardiac risk assessment in the Registry Of Pregnancy And Cardiac disease: results of a registry from the European Society of Cardiology, European Journal of Heart Failure, Vol: 18, Pages: 523-533, ISSN: 1879-0844
AIMS: To validate the modified World Health Organization (mWHO) risk classification in advanced and emerging countries, and to identify additional risk factors for cardiac events during pregnancy. METHODS AND RESULTS: The ongoing prospective worldwide Registry Of Pregnancy And Cardiac disease (ROPAC) included 2742 pregnant women (mean age ± standard deviation, 29.2 ± 5.5 years) with established cardiac disease: 1827 from advanced countries and 915 from emerging countries. In patients from advanced countries, congenital heart disease was the most prevalent diagnosis (70%) while in emerging countries valvular heart disease was more common (55%). A cardiac event occurred in 566 patients (20.6%) during pregnancy: 234 (12.8%) in advanced countries and 332 (36.3%) in emerging countries. The mWHO classification had a moderate performance to discriminate between women with and without cardiac events (c-statistic 0.711 and 95% confidence interval (CI) 0.686-0.735). However, its performance in advanced countries (0.726) was better than in emerging countries (0.633). The best performance was found in patients with acquired heart disease from developed countries (0.712). Pre-pregnancy signs of heart failure and, in advanced countries, atrial fibrillation and no previous cardiac intervention added prognostic value to the mWHO classification, with a c-statistic of 0.751 (95% CI 0.715-0.786) in advanced countries and of 0.724 (95% CI 0.691-0.758) in emerging countries. CONCLUSION: The mWHO risk classification is a useful tool for predicting cardiac events during pregnancy in women with established cardiac disease in advanced countries, but seems less effective in emerging countries. Data on pre-pregnancy cardiac condition including signs of heart failure and atrial fibrillation, may help to improve preconception counselling in advanced and emerging countries.
Migale R, MacIntyre DA, Cacciatore S, et al., 2016, Relative Contribution of Hormonal and Inflammatory Pathways to Uterine Transcriptome Dynamics in Term and Preterm Labor, 63rd Annual Scientific Meeting of the Society-for-Reproductive-Investigation, Publisher: SAGE PUBLICATIONS INC, Pages: 125A-125A, ISSN: 1933-7191
Cauldwell M, Steer PJ, Johnson M, et al., 2016, Counselling women with congenital cardiac disease, BMJ: British Medical Journal, Vol: 352, ISSN: 1756-1833
Nawathe AR, Christian M, Kim SH, et al., 2016, Insulin-like growth factor axis in pregnancies affected by fetal growth disorders, Clinical Epigenetics, Vol: 8, ISSN: 1868-7083
Cauldwell M, Von Klemperer K, Uebing A, et al., 2016, A cohort study of women with a Fontan circulation undergoing preconception counselling, Heart, Vol: 102, Pages: 534-540, ISSN: 1468-201X
Waldorf KMA, Singh N, Mohan AR, et al., 2015, Uterine overdistention induces preterm labor mediated by inflammation: observations in pregnant women and nonhuman primates, American Journal of Obstetrics and Gynecology, Vol: 213, Pages: 830.e1-830.e19, ISSN: 1097-6868
ObjectiveUterine overdistention is thought to induce preterm labor in women with twin and multiple pregnancies, but the pathophysiology remains unclear. We investigated for the first time the pathogenesis of preterm birth associated with rapid uterine distention in a pregnant nonhuman primate model.Study DesignA nonhuman primate model of uterine overdistention was created using preterm chronically catheterized pregnant pigtail macaques (Macaca nemestrina) by inflation of intraamniotic balloons (N = 6), which were compared to saline controls (N = 5). Cesarean delivery was performed due to preterm labor or at experimental end. Microarray, quantitative reverse transcriptase polymerase chain reaction, Luminex (Austin, TX), and enzyme-linked immunosorbent assay were used to measure messenger RNA (mRNA) and/or protein levels from monkey (amniotic fluid, myometrium, maternal plasma) and human (amniocytes, amnion, myometrium) tissues. Statistical analysis employed analysis of covariance and Wilcoxon rank sum. Biomechanical forces were calculated using the law of Laplace.ResultsPreterm labor occurred in 3 of 6 animals after balloon inflation and correlated with greater balloon volume and uterine wall stress. Significant elevations of inflammatory cytokines and prostaglandins occurred following uterine overdistention in an “inflammatory pulse” that correlated with preterm labor (interleukin [IL]-1β, tumor necrosis factor [TNF]-α, IL-6, IL-8, CCL2, prostaglandin E2, prostaglandin F2α, all P < .05). A similar inflammatory response was observed in amniocytes in vitro following mechanical stretch (IL1β, IL6, and IL8 mRNA multiple time points, P < .05), in amnion of women with polyhydramnios (IL6 and TNF mRNA, P < .05) and in amnion (TNF-α) and myometrium of women with twins in early labor (IL6, IL8, CCL2, all P < .05). Genes differentially expressed in the nonhuman primate after balloon inflation and in women with polyhydramnios
Gelson E, Curry R, Gatzoulis MA, et al., 2015, Maternal cardiac and obstetric performance in consecutive pregnancies in women with heart disease, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 122, Pages: 1552-1559, ISSN: 1470-0328
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- Citations: 6
Lei K, Georgiou EX, Chen L, et al., 2015, Progesterone and the Repression of Myometrial Inflammation: The Roles of MKP-1 and the AP-1 System, MOLECULAR ENDOCRINOLOGY, Vol: 29, Pages: 1454-1467, ISSN: 0888-8809
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- Citations: 29
Kim CH, Hvoslef-Eide M, Nilsson SRO, et al., 2015, The continuous performance test (rCPT) for mice: a novel operant touchscreen test of attentional function, Psychopharmacology, Vol: 232, Pages: 3947-3966, ISSN: 1432-2072
RationaleContinuous performance tests (CPTs) are widely used to assess attentional processes in a variety of disorders including Alzheimer’s disease and schizophrenia. Common human CPTs require discrimination of sequentially presented, visually patterned ‘target’ and ‘non-target’ stimuli at a single location.ObjectivesThe aims of this study were to evaluate the performance of three popular mouse strains on a novel rodent touchscreen test (rCPT) designed to be analogous to common human CPT variants and to investigate the effects of donepezil, a cholinesterase inhibitor and putative cognitive enhancer.MethodsC57BL/6J, DBA/2J and CD1 mice (n = 15–16/strain) were trained to baseline performance using four rCPT training stages. Then, probe tests assessed the effects of parameter changes on task performance: stimulus size, duration, contrast, probability, inter-trial interval or inclusion of flanker distractors. rCPT performance was also evaluated following acute administration of donepezil (0–3 mg/kg, i.p.).ResultsC57BL/6J and DBA/2J mice showed similar acquisition rates and final baseline performance following rCPT training. On probe tests, rCPT performance of both strains was sensitive to alteration of visual and/or attentional demands (stimulus size, duration, contrast, rate, flanker distraction). Relative to C57BL/6J, DBA/2J mice exhibited (1) decreasing sensitivity (d′) across the 45-min session, (2) reduced performance on probes where the appearance of stimuli or adjacent areas were changed (size, contrast, flanking distractors) and (3) larger dose- and stimulus duration-dependent changes in performance following donepezil administration. In contrast, CD1 mice failed to acquire rCPT (stage 3) and pairwise visual discrimination tasks.ConclusionsrCPT is a potentially useful translational tool for assessing attention in mice and for detecting the effects of nootropic drugs.
Lei K, Sooranna SR, Johnson MR, 2015, Expression data from primary culture human myometrial cells, Genomics Data, Vol: 6, Pages: 182-183, ISSN: 2213-5960
Inflammation plays a central role in many human diseases. Human parturition also resembles an inflammatory reaction, where progesterone (P4) and progesterone receptors (PRs) have already been demonstrated to suppress contraction-associated gene expression. In our previous studies, we have found that the progesterone actions, including progesterone-induced gene expression and progesterone's anti-inflammatory effect, are mediated by PR, GR or both. In this study, we used microarrays (GSE68171) to find P4 and IL-1β responsive genes and IL-1β responsive genes which were repressed by P4. These data may provide a broader view of gene networks and cellular functions regulated by P4 and IL-1β in human myometrial cells. These data will also help us understand the role of PR and GR in human parturition.
Salam AM, Ertekin E, van Hagen IM, et al., 2015, Atrial Fibrillation or Flutter During Pregnancy in Patients With Structural Heart Disease: Data From the ROPAC (Registry on Pregnancy and Cardiac Disease)., JACC Clin Electrophysiol, Vol: 1, Pages: 284-292
OBJECTIVES: Atrial fibrillation (AF)/atrial flutter (AFL) during pregnancy in these women is associated with adverse outcome of pregnancy. BACKGROUND: The incidence, timing, and consequences of AF or AFL during pregnancy in patients with heart disease are not well known. METHODS: Between January 2008 to June 2011, 60 hospitals in 28 countries prospectively enrolled 1,321 pregnant women with congenital heart disease, valvular heart disease, ischemic heart disease, or cardiomyopathy in the ROPAC (Registry of Pregnancy and Cardiac Disease). We studied the incidence, onset, and predictors of AF/AFL during pregnancy and assessed the pregnancy outcome. An overview of the existing literature is provided. RESULTS: Seventeen women (1.3%) developed AF/AFL during pregnancy, mainly in the second trimester (61.5%). Univariable analysis identified the following pre-pregnancy risk factors for AF/AFL in pregnancy: AF/AFL before pregnancy (odds ratio [OR]: 7.1, 95% confidence interval [CI]: 1.5 to 32.8); mitral valvular heart disease (OR: 6.9, 95% CI: 2.6 to 18.3); beta-blocker use (OR: 3.3, 95% CI: 1.2 to 9.0); and left-sided lesions (OR: 2.9, 95% CI: 1.0 to 8.3). Maternal mortality was higher in women with than in women without AF/AFL (11.8% vs. 0.9%; p = 0.01), although heart failure was not seen more often. Low birth weight (<2,500 g) occurred more often in women with than in women without AF/AFL (35% vs. 14%; p = 0.02). CONCLUSIONS: AF/AFL occurs in 1.3% of pregnant patients with structural heart disease with a peak at the end of the second trimester. AF/AFL during pregnancy in cardiac patients is associated with unfavorable maternal outcome and also has an impact on fetal birth weight.
Migale R, Herbert BR, Lee YS, et al., 2015, Specific Lipopolysaccharide Serotypes Induce Differential Maternal and Neonatal Inflammatory Responses in a Murine Model of Preterm Labor., American Journal of Pathology, Vol: 185, Pages: 2390-2401, ISSN: 1525-2191
Intrauterine inflammation is recognized as a key mediator of both normal and preterm birth but is also associated with neonatal neurological injury. Lipopolysaccharide (LPS) is often used to stimulate inflammatory pathways in animal models of infection/inflammation-induced preterm labor; however, inconsistencies in maternal and neonatal responses to LPS are frequently reported. We hypothesized that LPS serotype-specific responses may account for a portion of these inconsistencies. Four different Escherichia coli LPS serotypes (O111:B4, O55:B5, O127:B8, and O128:B12) were administered to CD1 mice via intrauterine injection at day 16 of gestation. Although control (phosphate-buffered saline)-treated animals were delivered at term approximately 60 ± 15 hours postinjection (p.i.), those administered with O111:B4 were delivered 7 ± 2 hours p.i., O55:B5 were delivered 10 ± 3 hours p.i., O127:B8 were delivered 16 ± 10 hours p.i., and O128:B12 were delivered 17 ± 2 hours p.i. (data are given as means ± SD). A correlation between the onset of preterm birth and myometrial activation of the inflammatory transcription factor, activator protein 1, but not NF-κB was observed. Specific LPS serotypes induced differential activation of downstream contractile and inflammatory pathways in both myometrium and neonatal pup brain. Our findings demonstrate functional disparity in inflammatory pathway activation in response to differing LPS serotypes. This may account for some reported differences in models of infection/inflammation-induced preterm labor. Selective use of LPS serotypes may represent a useful tool for targeting specific inflammatory response mechanisms in these models.
van Hagen IM, Roos-Hesselink JW, Ruys TPE, et al., 2015, Pregnancy in women with a mechanical heart valve. Data of the European Society of Cardiology Registry of Pregnancy and Cardiac Disease (ROPAC), Circulation, Vol: 132, Pages: 132-142, ISSN: 0009-7322
Background—Pregnant women with a mechanical heart valve (MHV) are at a heightened risk of a thrombotic event, and their absolute need for adequate anticoagulation puts them at considerable risk of bleeding and, with some anticoagulants, fetotoxicity.Methods and Results—Within the prospective, observational, contemporary, worldwide Registry of Pregnancy and Cardiac disease (ROPAC), we describe the pregnancy outcome of 212 patients with an MHV. We compare them with 134 patients with a tissue heart valve and 2620 other patients without a prosthetic valve. Maternal mortality occurred in 1.4% of the patients with an MHV, in 1.5% of patients with a tissue heart valve (P=1.000), and in 0.2% of patients without a prosthetic valve (P=0.025). Mechanical valve thrombosis complicated pregnancy in 10 patients with an MHV (4.7%). In 5 of these patients, the valve thrombosis occurred in the first trimester, and all 5 patients had been switched to some form of heparin. Hemorrhagic events occurred in 23.1% of patients with an MHV, in 5.1% of patients with a tissue heart valve (P<0.001), and in 4.9% of patients without a prosthetic valve (P<0.001). Only 58% of the patients with an MHV had a pregnancy free of serious adverse events compared with 79% of patients with a tissue heart valve (P<0.001) and 78% of patients without a prosthetic valve (P<0.001). Vitamin K antagonist use in the first trimester compared with heparin was associated with a higher rate of miscarriage (28.6% versus 9.2%; P<0.001) and late fetal death (7.1% versus 0.7%; P=0.016).Conclusions—Women with an MHV have only a 58% chance of experiencing an uncomplicated pregnancy with a live birth. The markedly increased mortality and morbidity warrant extensive prepregnancy counseling and centralization of care.
Roos-Hesselink J, Cornette J, Sliwa K, et al., 2015, Contraception and cardiovascular disease, EUROPEAN HEART JOURNAL, Vol: 36, Pages: 1728-U29, ISSN: 0195-668X
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- Citations: 48
Buckley SMK, Delhove JMKM, Perocheau DP, et al., 2015, In vivo bioimaging with tissue-specific transcription factor activated luciferase reporters, Scientific Reports, Vol: 5, ISSN: 2045-2322
The application of transcription factor activated luciferase reporter cassettes in vitro is widespread but potential for in vivo application has not yet been realized. Bioluminescence imaging enables non-invasive tracking of gene expression in transfected tissues of living rodents. However the mature immune response limits luciferase expression when delivered in adulthood. We present a novel approach of tissue-targeted delivery of transcription factor activated luciferase reporter lentiviruses to neonatal rodents as an alternative to the existing technology of generating germline transgenic light producing rodents. At this age, neonates acquire immune tolerance to the conditionally responsive luciferase reporter. This simple and transferrable procedure permits surrogate quantitation of transcription factor activity over the lifetime of the animal. We show principal efficacy by temporally quantifying NFκB activity in the brain, liver and lungs of somatotransgenic reporter mice subjected to lipopolysaccharide (LPS)-induced inflammation. This response is ablated in Tlr4−/− mice or when co-administered with the anti-inflammatory glucocorticoid analogue dexamethasone. Furthermore, we show the malleability of this technology by quantifying NFκB-mediated luciferase expression in outbred rats. Finally, we use somatotransgenic bioimaging to longitudinally quantify LPS- and ActivinA-induced upregulation of liver specific glucocorticoid receptor and Smad2/3 reporter constructs in somatotransgenic mice, respectively.
Sliwa K, Johnson MR, Zilla P, et al., 2015, Management of valvular disease in pregnancy: a global perspective, EUROPEAN HEART JOURNAL, Vol: 36, Pages: 1078-U20, ISSN: 0195-668X
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- Citations: 49
Anim-Nyame N, Gamble J, Sooranna SR, et al., 2015, Relationship between insulin resistance and tissue blood flow in preeclampsia, JOURNAL OF HYPERTENSION, Vol: 33, Pages: 1057-1063, ISSN: 0263-6352
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- Citations: 7
Karda R, Delhove JMKM, Buckley SMK, et al., 2015, Generation of Light-Emitting Somatic-Transgenic Mice for Disease Modelling of Hypoxic Ischaemic Encephalopathy, 18th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT), Publisher: NATURE PUBLISHING GROUP, Pages: S55-S55, ISSN: 1525-0016
Ruys TPE, Roos-Hesselink JW, Pijuan-Domenech A, et al., 2015, Is a planned caesarean section in women with cardiac disease beneficial?, HEART, Vol: 101, Pages: 530-536, ISSN: 1355-6037
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- Citations: 91
Cook JR, Macintyre DA, Samara E, et al., 2015, Exogenous oxytocin modulates human myometrial microRNAs, Publisher: WILEY-BLACKWELL, Pages: 226-226, ISSN: 1470-0328
Yulia A, Thomas S, Singh N, et al., 2015, Pregnancy outcome following the indication of cerclage, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 122, Pages: 226-227, ISSN: 1470-0328
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- Citations: 1
Nawathe A, Savvidou M, Christian M, et al., 2015, Differences in placental epigenetic regulation in pregnancies affected by fetal growth disorders, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 122, Pages: 62-62, ISSN: 1470-0328
Nawathe A, Savvidou M, Christian M, et al., 2015, Role of metformin and insulin in epigenetic regulation of IGF axis in women with gestational diabetes, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 122, Pages: 308-308, ISSN: 1470-0328
Parsonage W, Roos-Hesselink J, Johnson M, et al., 2015, The registry of pregnancy and cardiovascular disease: a global initiative of the EURObservational Research Programme, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 122, Pages: 270-271, ISSN: 1470-0328
Parsonage W, Hall R, Johnson M, et al., 2015, Pregnancy in women with artificial heart valves: outcomes from the registry of pregnancy and cardiovascular disease (ROPAC), BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 122, Pages: 284-284, ISSN: 1470-0328
Parsonage W, Hall R, Johnson M, et al., 2015, Pregnancy in women with artificial heart valves: outcomes from the registry of pregnancy and cardiovascular disease (ROPAC), BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 122, Pages: 355-355, ISSN: 1470-0328
Curry R, Gelson E, Gatzoulis M, et al., 2015, Pregnancy in women with valvular heart disease: maternal and perinatal outcomes, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 122, Pages: 22-23, ISSN: 1470-0328
Curry R, Gelson E, Gatzoulis M, et al., 2015, Pregnancy outcomes in women with pre-existing heart disease, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 122, Pages: 14-14, ISSN: 1470-0328
Curry R, Gelson E, Gatzoulis M, et al., 2015, Pregnancy in women with left ventricular outflow tract obstruction: maternal and perinatal outcomes, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 122, Pages: 25-26, ISSN: 1470-0328
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