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The effects on lipid profiles of pharmacologic inhibition of ATP citrate lyase, an enzyme in the cholesterol–biosynthesis pathway upstream of HMGCR (the target of statins), are similar to those of statins. This inhibition may lower the risk of cardiovascular disease.

Vasomotor symptoms (hot flushes and night sweats) and other symptoms, including depression, anxiety and panic attacks, are commonly experienced by menopausal women and have been associated with an unfavourable cardiovascular risk profile. To investigate whether presence of menopausal symptoms is associated with the development of cardiovascular disease (CVD). Five electronic databases (Medline, EMBASE and Web of Science) were search until February 17th, 2015 to identify relevant studies. Observational cohort studies or randomised intervention studies were eligible for inclusion if they followed participants prospectively (at least 1 year of follow-up), and reported relevant estimates on the association of any vasomotor symptoms, or other menopausal symptoms, with risk of CVD, coronary heart disease (CHD), or stroke in perimenopausal, menopausal, or postmenopausal women. Data were extracted by two independent reviewers using a pre-designed data collection form. Separate pooled relative risks (RRs) for age and non-established cardiovascular risk factors (e.g., education, ethnicity) adjusted data and for established cardiovascular risk factors and potential mediators-adjusted data (e.g., smoking, body mass index, and hypertension) were calculated. Out of 9,987 initially identified references, ten studies were selected, including 213,976 women with a total of 10,037 cardiovascular disease outcomes. The age and non-established cardiovascular risk factors adjusted RRs) [95% confidence intervals] for development of CHD, Stroke and CVD comparing women with and without any menopausal symptoms were 1.34 [1.13-1.58], 1.30 [0.99-1.70], 1.48 [1.21-1.80] respectively, and the corresponding RRs adjusted for cardiovascular risk factors and potential mediators were 1.18 [1.03-1.35], 1.08 [0.89-1.32], 1.29 [0.98-1.71]. However, these analyses were limited by potential unmeasured confounding and the small number of studies on this topic. Presence of vasomotor symptoms and other menopausal symptoms are generally associated with an increased risk of cardiovascular disease, which is mainly explained by cardiovascular risk factors.

Circulating levels of glycine have previously been associated with lower incidence of coronary heart disease (CHD) and type 2 diabetes (T2D) but it remains uncertain if glycine plays an aetiological role. We present a meta-analysis of genome-wide association studies for glycine in 80,003 participants and investigate the causality and potential mechanisms of the association between glycine and cardio-metabolic diseases using genetic approaches. We identify 27 genetic loci, of which 22 have not previously been reported for glycine. We show that glycine is genetically associated with lower CHD risk and find that this may be partly driven by blood pressure. Evidence for a genetic association of glycine with T2D is weaker, but we find a strong inverse genetic effect of hyperinsulinaemia on glycine. Our findings strengthen evidence for a protective effect of glycine on CHD and show that the glycine-T2D association may be driven by a glycine-lowering effect of insulin resistance. Epidemiological studies have associated circulating levels of the amino acid glycine with cardiometabolic outcomes. Here, in a genome-wide meta-analysis of 80,003 individuals, Wittemans et al. identify 22 novel genetic loci for glycine and find a causal relationship with coronary heart disease using MR.

Background Hypertensive disorders of pregnancy are common pregnancy complications that are associated with greater cardiovascular disease risk for mothers. However, risk of cardiovascular disease subtypes associated with gestational hypertension or pre-eclampsia is unclear. The present study aims to compare the risk of cardiovascular disease outcomes for women with and without a history of gestational hypertension and pre-eclampsia using national hospital admissions data. Methods This was a retrospective cohort study of national medical records from all National Health Service hospitals in England. Women who had one or more singleton live births in England between 1997 and 2015 were included in the analysis. Risk of total cardiovascular disease and 19 pre-specified cardiovascular disease subtypes, including stroke, coronary heart disease, cardiomyopathy and peripheral arterial disease, was calculated separately for women with a history of gestational hypertension and pre-eclampsia compared to normotensive pregnancies. Results Amongst 2,359,386 first live births, there were 85,277 and 74,542 hospital admissions with a diagnosis of gestational hypertension and pre-eclampsia, respectively. During 18 years (16,309,386 person-years) of follow-up, the number and incidence of total CVD for normotensive women, women with prior gestational hypertension and women with prior pre-eclampsia were n = 8668, 57.1 (95% CI: 55.9–58.3) per 100,000 person-years; n = 521, 85.8 (78.6–93.5) per 100,000 person-years; and n = 518, 99.3 (90.9–108.2) per 100,000 person-years, respectively. Adjusted HRs (aHR) for total CVD were aHR (95% CI) = 1.45 (1.33–1.59) for women with prior gestational hypertension and aHR = 1.62 (1.48–1.78) for women with prior pre-eclampsia. Gestational hypertension was strongly associated with dilated cardiomyopathy, aHR = 2.85 (1.67–4.86), and unstable angina, aHR = 1.92 (1.33–2.77). Pre-eclampsia was strongly associated with hypertrophic cardiomyopathy, aHR = 3.27 (1.49–7.19), and acute myocardial infarction, aHR = 2.46 (1.72–3.53). Associations were broadly homogenous across cardiovascular disease subtypes and increased with a greater number of affected pregnancies. Conclusions Women with either previous gestational hypertension or pre-eclampsia are at greater risk of a range of cardiovascular outcomes. These women may benefit from clinical risk assessment or early interventions to mitigate their greater risk of various cardiovascular outcomes.

IntroductionRacial discrimination has been consistently linked to various health outcomes and health disparities, including studies associating racial discrimination with patterns of racial disparities in adverse pregnancy outcomes. To expand our knowledge, this systematic review and meta-analysis assesses all available evidence on the association between self-reported racial discrimination and adverse pregnancy outcomes.MethodsEight electronic databases were searched without language or time restrictions, through January 2022. Data were extracted using a pre-piloted extraction tool. Quality assessment was conducted using the Newcastle–Ottawa Scale (NOS), and across all included studies using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Random effects meta-analyses were performed on preterm birth and small for gestational age. Heterogenicity was assessed using Cochran’s χ2 test and I2 statistic.ResultsOf 13 597 retrieved records, 24 articles were included. Studies included cohort, case–control and cross-sectional designs and were predominantly conducted in the USA (n=20). Across all outcomes, significant positive associations (between experiencing racial discrimination and an adverse pregnancy event) and non-significant associations (trending towards positive) were reported, with no studies reporting significant negative associations. The overall pooled odds ratio (OR) for preterm birth was 1.40 (95% CI 1.17 to 1.68; 13 studies) and for small for gestational age it was 1.23 (95% CI 0.76 to 1.99; 3 studies). When excluding low-quality studies, the preterm birth OR attenuated to 1.31 (95% CI 1.08 to 1.59; 10 studies). Similar results were obtained across sensitivity and subgroup analyses, indicating a significant positive association.ConclusionThese results suggest that racial discrimination has adverse impacts on pregnancy outcomes. This is supported by the broader literature on racial discrimination as a risk factor for adverse health outcomes. To further explore this association and underlying mechanisms, including mediating and moderating factors, higher quality evidence from large ethnographically diverse cohorts is needed.

Cholesteryl ester transfer protein (CETP) inhibition reduces vascular event risk, but confusion surrounds its effects on low-density lipoprotein (LDL) cholesterol. Here, we clarify associations of genetic inhibition of CETP on detailed lipoprotein measures and compare those to genetic inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). We used an allele associated with lower CETP expression (rs247617) to mimic CETP inhibition and an allele associated with lower HMGCR expression (rs12916) to mimic the well-known effects of statins for comparison. The study consists of 65,427 participants of European ancestries with detailed lipoprotein subclass profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% reduction in relative risk of coronary heart disease (CHD). We also examined observational associations of the lipoprotein subclass measures with risk of incident CHD in 3 population-based cohorts totalling 616 incident cases and 13,564 controls during 8-year follow-up. Genetic inhibition of CETP and HMGCR resulted in near-identical associations with LDL cholesterol concentration estimated by the Friedewald equation. Inhibition of HMGCR had relatively consistent associations on lower cholesterol concentrations across all apolipoprotein B-containing lipoproteins. In contrast, the associations of the inhibition of CETP were stronger on lower remnant and very-low-density lipoprotein (VLDL) cholesterol, but there were no associations on cholesterol concentrations in LDL defined by particle size (diameter 18-26 nm) (-0.02 SD LDL defined by particle size; 95% CI: -0.10 to 0.05 for CETP versus -0.24 SD, 95% CI -0.30 to -0.18 for HMGCR). Inhibition of CETP was strongly associated with lower proportion of triglycerides in all high-density lipoprotein (HDL) particles. In observational analyses, a higher triglyceride composition within HDL subclasses was associated with higher risk of CHD, independently of total cholesterol and triglycerides (strongest hazard ratio per 1 SD higher triglyceride composition in very large HDL 1.35; 95% CI: 1.18-1.54). In conclusion, CETP inhibition does not appear to affect size-specific LDL cholesterol but is likely to lower CHD risk by lowering concentrations of other atherogenic, apolipoprotein B-containing lipoproteins (such as remnant and VLDLs). Inhibition of CETP also lowers triglyceride composition in HDL particles, a phenomenon reflecting combined effects of circulating HDL, triglycerides, and apolipoprotein B-containing particles and is associated with a lower CHD risk in observational analyses. Our results reveal that conventional composite lipid assays may mask heterogeneous effects of emerging lipid-altering therapies.

Circulating metabolite levels are biomarkers for cardiovascular disease (CVD). Here we studied, association of rare variants and 226 serum lipoproteins, lipids and amino acids in 7,142 (discovery plus follow-up) healthy participants. We leveraged the information from multiple metabolite measurements on the same participants to improve discovery in rare variant association analyses for gene-based and gene-set tests by incorporating correlated metabolites as covariates in the validation stage. Gene-based analysis corrected for the effective number of tests performed, confirmed established associations at APOB, APOC3, PAH, HAL and PCSK (p<1.32x10-7) and identified novel gene-trait associations at a lower stringency threshold with ACSL1, MYCN, FBXO36 and B4GALNT3 (p<2.5x10-6). Regulation of the pyruvate dehydrogenase (PDH) complex was associated for the first time, in gene-set analyses also corrected for effective number of tests, with IDL and LDL parameters, as well as circulating cholesterol (pMETASKAT<2.41x10-6). In conclusion, using an approach that leverages metabolite measurements obtained in the same participants, we identified novel loci and pathways involved in the regulation of these important metabolic biomarkers. As large-scale biobanks continue to amass sequencing and phenotypic information, analytical approaches such as ours will be useful to fully exploit the copious amounts of biological data generated in these efforts.

Background Cardiovascular disease (CVD) is the leading cause of death in women, responsible for approximately a third of all female deaths. Pregnancy complications are known to be associated with a greater risk of incident CVD in mothers. However, the relationships between pregnancy loss due to miscarriage, stillbirth, or therapeutic abortion, and future maternal cardiovascular health are under-researched. This study seeks to provide an up-to-date systematic review and meta-analysis of the relationship between these three forms of pregnancy loss and the subsequent development of CVD. Methods This systematic review will follow the Preferred Reporting Items for Systematic Review and Meta-Analysis checklist (PRISMA) and the Meta-analyses Of Observational Studies in Epidemiology (MOOSE) Checklist. A systematic search will be undertaken using publications identified in MEDLINE (PubMed), Scopus, Web of Knowledge, the CINAHL Nursing Database, and the Cochrane Library. The eligibility of each publication will be determined by predefined selection criteria. The quality of the included studies will be rated using the Newcastle-Ottawa Scale. Pooled measures of association will be computed using random-effects model meta-analyses. Between-study heterogeneity will be assessed using the I 2 statistic and the Cochrane χ 2 statistic. Small study effects will be evaluated for meta-analyses with sufficient studies through the use of funnel plots and Egger’s test. Discussion The results of this systematic review will discuss the long-term risks of multiple types of cardiovascular disease in women who have experienced miscarriage, stillbirth, and/or therapeutic abortion. It will contribute to the growing field of cardio-obstetrics as the first to consider the full breadth of literature regarding the association between all forms of pregnancy loss and future maternal cardiovascular disease. Systematic review registration PROSPERO registration number [CRD42020167587]

[This corrects the article DOI: 10.1371/journal.pbio.3000572.].

Numerous studies have demonstrated that therapeutic termination of pregnancy (abortion) is associated with an increased risk of subsequent preterm birth. However, the literature is inconsistent, and methods of abortion have changed dramatically over the last 30 years. We hypothesized that the association between previous abortion and the risk of preterm first birth changed in Scotland between 1 January 1980 and 31 December 2008. We studied linked Scottish national databases of births and perinatal deaths. We analysed the risk of preterm birth in relation to the number of previous abortions in 732,719 first births (≥24 wk), adjusting for maternal characteristics. The risk (adjusted odds ratio [95% CI]) of preterm birth was modelled using logistic regression, and associations were expressed for a one-unit increase in the number of previous abortions. Previous abortion was associated with an increased risk of preterm birth (1.12 [1.09-1.16]). When analysed by year of delivery, the association was strongest in 1980-1983 (1.32 [1.21-1.43]), progressively declined between 1984 and 1999, and was no longer apparent in 2000-2003 (0.98 [0.91-1.05]) or 2004-2008 (1.02 [0.95-1.09]). A statistical test for interaction between previous abortion and year was highly statistically significant (p<0.001). Analysis of data for abortions among nulliparous women in Scotland 1992-2008 demonstrated that the proportion that were surgical without use of cervical pre-treatment decreased from 31% to 0.4%, and that the proportion of medical abortions increased from 18% to 68%. Previous abortion was a risk factor for spontaneous preterm birth in Scotland in the 1980s and 1990s, but the association progressively weakened and disappeared altogether by 2000. These changes were paralleled by increasing use of medical abortion and cervical pre-treatment prior to surgical abortion. Although it is plausible that the two trends were related, we could not test this directly as the data on the method of prior abortions were not linked to individuals in the cohort. However, we speculate that modernising abortion methods may be an effective long-term strategy to reduce global rates of preterm birth.