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Aims Currently, little evidence exists on survival and quality of care in cancer patients presenting with acute heart failure (HF). The aim of the study is to investigate the presentation and outcomes of hospital admission with acute HF in a national cohort of patients with prior cancer. Methods and results This retrospective, population-based cohort study identified 221 953 patients admitted to a hospital in England for HF during 2012–2018 (12 867 with a breast, prostate, colorectal, or lung cancer diagnosis in the previous 10 years). We examined the impact of cancer on (i) HF presentation and in-hospital mortality, (ii) place of care, (iii) HF medication prescribing, and (iv) post-discharge survival, using propensity score weighting and model-based adjustment. Heart failure presentation was similar between cancer and non-cancer patients. A lower percentage of patients with prior cancer were cared for in a cardiology ward [−2.4% age point difference (ppd) (95% CI −3.3, −1.6)] or were prescribed angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists (ACEi/ARB) for heart failure with reduced ejection fraction [−2.1 ppd (−3.3, −0.9)] than non-cancer patients. Survival after HF discharge was poor with median survival of 1.6 years in prior cancer and 2.6 years in non-cancer patients. Mortality in prior cancer patients was driven primarily by non-cancer causes (68% of post-discharge deaths). Conclusion Survival in prior cancer patients presenting with acute HF was poor, with a significant proportion due to non-cancer causes of death. Despite this, cardiologists were less likely to manage cancer patients with HF. Cancer patients who develop HF were less likely to be prescribed guideline-based HF medications compared with non-cancer patients. This was particularly driven by patients with a poorer cancer prognosis. more...

Supplementary Methods, Tables 1-3, Figure 1 from Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction

The use of omic modalities to dissect the molecular underpinnings of common diseases and traits is becoming increasingly common. But multi-omic traits can be genetically predicted, which enables highly cost-effective and powerful analyses for studies that do not have multi-omics1. Here we examine a large cohort (the INTERVAL study2; n = 50,000 participants) with extensive multi-omic data for plasma proteomics (SomaScan, n = 3,175; Olink, n = 4,822), plasma metabolomics (Metabolon HD4, n = 8,153), serum metabolomics (Nightingale, n = 37,359) and whole-blood Illumina RNA sequencing (n = 4,136), and use machine learning to train genetic scores for 17,227 molecular traits, including 10,521 that reach Bonferroni-adjusted significance. We evaluate the performance of genetic scores through external validation across cohorts of individuals of European, Asian and African American ancestries. In addition, we show the utility of these multi-omic genetic scores by quantifying the genetic control of biological pathways and by generating a synthetic multi-omic dataset of the UK Biobank3 to identify disease associations using a phenome-wide scan. We highlight a series of biological insights with regard to genetic mechanisms in metabolism and canonical pathway associations with disease; for example, JAK-STAT signalling and coronary atherosclerosis. Finally, we develop a portal ( https://www.omicspred.org/ ) to facilitate public access to all genetic scores and validation results, as well as to serve as a platform for future extensions and enhancements of multi-omic genetic scores. more...

Aims To assess the recording and accuracy of acute myocardial infarction (AMI) hospital admissions between two electronic health record databases within an English cancer population over time and understand the factors that affect case-ascertainment. Methods and results We identified 112 502 hospital admissions for AMI in England 2010–2017 from the Myocardial Ischaemia National Audit Project (MINAP) disease registry and hospital episode statistics (HES) for 95 509 patients with a previous cancer diagnosis up to 15 years prior to admission. Cancer diagnoses were identified from the National Cancer Registration Dataset (NCRD). We calculated the percentage of AMI admissions captured by each source and examined patient characteristics associated with source of ascertainment. Survival analysis assessed whether differences in survival between case-ascertainment sources could be explained by patient characteristics. A total of 57 265 (50.9%) AMI admissions in patients with a prior diagnosis of cancer were captured in both MINAP and HES. Patients captured in both sources were younger, more likely to have ST-segment elevation myocardial infarction and had better prognosis, with lower mortality rates up to 9 years after AMI admission compared with patients captured in only one source. The percentage of admissions captured in both data sources improved over time. Cancer characteristics (site, stage, and grade) had little effect on how AMI was captured. Conclusion MINAP and HES define different populations of patients with AMI. However, cancer characteristics do not substantially impact on case-ascertainment. These findings support a strategy of using multiple linked data sources for observational cardio-oncological research into AMI. more...

ObjectiveTo investigate percutaneous coronary intervention (PCI) practice in an international cohort of patients with spontaneous coronary artery dissection (SCAD). To explore factors associated with complications and study angiographic and longer term outcomes.MethodsSCAD patients (n=215, 94% female) who underwent PCI from three national cohort studies were investigated and compared with a matched cohort of conservatively managed SCAD patients (n=221).ResultsSCAD-PCI patients were high risk at presentation with only 8.8% undergoing PCI outside the context of ST-elevation myocardial infarction/cardiac arrest, thrombolysis in myocardial infarction (TIMI) 0/1 flow or proximal dissections. PCI complications occurred in 38.6% (83/215), with 13.0% (28/215) serious complications. PCI-related complications were associated with more extensive dissections (multiple vs single American Heart Association coronary segments, OR 1.9 (95% CI: 1.06–3.39),p=0.030), more proximal dissections (proximal diameter per mm, OR 2.25 (1.38–3.67), p=0.001) and dissections with no contrast penetration of the false lumen (Yip-Saw 2 versus 1, OR 2.89 (1.12–7.43), p=0.028). SCAD-PCI involved long lengths of stent (median 46mm, IQR: 29–61mm). Despite these risks, SCAD-PCI led to angiographic improvements in those with reduced TIMI flow in 84.3% (118/140). Worsening TIMI flow was only seen in 7.0% (15/215) of SCAD-PCI patients. Post-PCI major adverse cardiovascular and cerebrovascular events (MACCE) and left ventricular function outcomes were favourable.ConclusionWhile a conservative approach to revascularisation is favoured, SCAD cases with higher risk presentations may require PCI. SCAD-PCI is associated with longer stent lengths and a higher risk of complications but leads to overall improvements in coronary flow and good medium-term outcomes in patients. more...

Background Plant-based diets are gaining attention globally due to their environmental benefits and perceived health-protective role. A vegan diet may have cardiovascular benefits; however, evidence remains conflicting and insufficiently assessed. Objectives We evaluated the utility of the vegan diet in cardiovascular disease (CVD) prevention. Methods We conducted a systematic review of studies evaluating the association between vegan diets and cardiovascular outcomes. We searched 5 databases (Ovid MEDLINE, EMBASE, Web of Science, Scopus, and OpenGrey) through 31 October 2020. Four investigators independently screened the full texts for inclusion, assessed quality, and extracted data from published reports. Results Out of the 5729 identified records, 7 were included, comprising over 73,000 participants, of whom at least 7661 were vegans. Three studies, with at least 73,426 individuals (including at least 7380 vegans), examined risks of primary cardiovascular events (total CVD, coronary heart disease, acute myocardial infarction, total stroke, hemorrhagic stroke, and ischemic stroke) in individuals who followed a vegan diet compared to those who did not. None of the studies reported a significantly increased or decreased risk of any cardiovascular outcome. One study suggested that vegans were at greater risk of ischemic stroke compared to individuals who consumed animal products (HR, 1.54; 95% CI, 0.95–2.48). Yet in another study, vegans showed lower common carotid artery intima-media thickness (0.56 ± 0.1 mm vs. 0.74 ± 0.1 mm in controls; P more...

In cross-platform analyses of 174 metabolites, we identify 499 associations (P

Funder: Medical Research Council (GB), Funder: British Heart Foundation; doi: http://dx.doi.org/10.13039/501100000274, Funder: Homerton College, University of Cambridge; doi: http://dx.doi.org/10.13039/501100008420, Funder: University of Cambridge, Purpose: Infertility is a global problem, but only a minority of couples access assisted reproductive technologies due to financial and sociocultural barriers. Complementary and alternative medicine are seen as another option. We aimed to determine the impact of complementary and alternative medicine on conception, miscarriage and live birth rates in couples not receiving assisted reproductive technology treatments. Methods: The electronic databases EMBASE, PubMed, Web of Science and the Allied and Complementary Medicine Database were systematically searched before March 24th 2020. Reference lists of eligible studies were searched for relevant studies. Eligible studies included trials and observational studies that assessed a complementary or alternative medicine and conception, miscarriage or live births in men or women not undergoing fertility treatment. Data were extracted by two independent reviewers using a pre-designed data collection form. The study protocol was published in the PROSPERO database (CRD42018086980). Results: Twenty randomized controlled trials were identified, including 2748 individuals. Most studies did not demonstrate any effect of a complementary or alternative medicine on pregnancy, live birth or miscarriage rates. Limited evidence was found for a positive effect of herbal therapies taken by women on conception rates. There was substantial diversity in quality across the studies. Conclusion: There is limited evidence of the effectiveness of complementary and alternative medicine on improving the chances of conception and live births, or increasing miscarriage risk. Owing to the generally sub-optimal quality and heterogeneous nature of the evidence, rigorous studies are needed to determine the impact of complementary and alternative medicine on fertility. more...

The EPIC-CVD project was supported by the European Union Framework 7 (HEALTH-F2-2012-279233), the European Research Council (268834), the UK Medical Research Council (G0800270, MR/L003120/1), the British Heart Foundation (SP/09/002, RG/08/014, RG13/13/30194), and the UK National Institute of Health Research (to EPIC-CVD). The establishment of the subcohort was supported by the EU Sixth Framework Programme (FP6) (grant LSHM_CT_2006_037197 to the InterAct project) and the Medical Research Council Epidemiology Unit (grants MC_ UU_12015/1 and MC_UU_12015/5). The national EPIC cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); Ministry of Health and Social Solidarity, Stavros Niarchos Foundation and Hellenic Health Foundation (Greece); Italian Association for Research on Cancer (AIRC) and National Research Council (Italy) and MIUR "Dipartimenti di Eccellenza"(Project D15D18000410001) to the Department of Medical Sciences; Dutch Ministry of Public Health, Welfare and Sports (VWS), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council and Regional Government of Skane and Vasterbotten (Sweden); and Cancer Research UK, Medical Research Council (United Kingdom). LIFE-Heart is funded by the Leipzig Research Center for Civilization Diseases (LIFE). LIFE is an organizational unit affiliated to the Medical Faculty of the University of Leipzig. LIFE is funded by means of the European Union, by the European Regional Development Fund (ERDF), and by funds of the Free State of Saxony within the framework of the excellence initiative. This work is supported by the Dutch Heart Foundation (2013T083 to V.D.), by a UK Medical Research Council Skills Development Fellowship (MR/P014550/1 to S.A.E.P.), and by a Sir Henry Dale Fellowship jointly funded by the Welcome Trust and the Royal Society (204623/Z/16/Z to S.B.). None of the funding sources had a role in the collection, analysis, and interpretation of the data, nor in the decision to submit the article for publication., Background: Accelerated reproductive aging, in women indicated by early natural menopause, is associated with increased coronary heart disease (CHD) risk in observational studies. Conversely, an adverse CHD risk profile has been suggested to accelerate menopause. Objectives: To study the direction and evidence for causality of the relationship between reproductive aging and (non-)fatal CHD and CHD risk factors in a bidirectional Mendelian randomization (MR) approach, using age at natural menopause (ANM) genetic variants as a measure for genetically determined reproductive aging in women. We also studied the association of these variants with CHD risk (factors) in men. Design: Two-sample MR, using both cohort data as well as summary statistics, with 4 methods: simple and weighted median-based, standard inverse-variance weighted (IVW) regression, and MR-Egger regression. Participants: Data from EPIC-CVD and summary statistics from UK Biobank and publicly available genome-wide association studies were pooled for the different analyses. Main Outcome Measures: CHD, CHD risk factors, and ANM. Results: Across different methods of MR, no association was found between genetically determined reproductive aging and CHD risk in women (relative risk estimateIVW = 0.99; 95% confidence interval (CI), 0.97-1.01), or any of the CHD risk factors. Similarly, no associations were found in men. Neither did the reversed analyses show evidence for an association between CHD (risk factors) and reproductive aging. Conclusion: Genetically determined reproductive aging is not causally associated with CHD risk (factors) in women, nor were the genetic variants associated in men. We found no evidence for a reverse association in a combined sample of women and men., European Commission HEALTH-F2-2012-279233 European Research Council (ERC) European Commission 268834, UK Research & Innovation (UKRI) Medical Research Council UK (MRC) G0800270 MR/L003120/1 British Heart Foundation SP/09/002 RG/08/014 RG13/13/30194, National Institute for Health Research (NIHR), EU Sixth Framework Programme (FP6) LSHM_CT_2006_037197, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) MC_ UU_12015/1 MC_UU_12015/5, Danish Cancer Society, Ligue Contre le Cancer (France), Institut Gustave Roussy (France), Mutuelle Generale de l'Education Nationale (France), Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe Federal Ministry of Education & Research (BMBF) Deutsches Krebsforschungszentrum (Germany), Ministry of Health and Social Solidarity (Greece) Stavros Niarchos Foundation (Greece) Hellenic Health Foundation (Greece), Fondazione AIRC per la ricerca sul cancro Consiglio Nazionale delle Ricerche (CNR) MIUR "Dipartimenti di Eccellenza" D15D18000410001, Dutch Ministry of Public Health, Welfare and Sports, LK Research Funds, Dutch Prevention Funds Netherlands Organization for Scientific Research (NWO), World Cancer Research Fund International (WCRF) ERC-2009-AdG 232997, Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway), Instituto de Salud Carlos III, Junta de Andalucia, Principality of Asturias, Regional Government of Basque Country (Spain) Regional Government of Murcia (Spain) Regional Government of Navarra (Spain), Instituto de Salud Carlos III RD06/0020, Swedish Cancer Society Swedish Scientific Council (Sweden) Regional Government of Skane and Vasterbotten (Sweden), Cancer Research UK UK Research & Innovation (UKRI) Medical Research Council UK (MRC), Leipzig Research Center for Civilization Diseases (LIFE), European Commission, Free State of Saxony, Netherlands Heart Foundation 2013T083, Medical Research Council UK (MRC) MR/P014550/1, Sir Henry Dale Fellowship - Welcome Trust 204623/Z/16/Z, Sir Henry Dale Fellowship - Royal Society 204623/Z/16/Z more...

Genetically predicted levels of multi-omic traits can uncover the molecular underpinnings of common phenotypes in a highly efficient manner. Here, we utilised a large cohort (INTERVAL; N=50,000 participants) with extensive multi-omic data for plasma proteomics (SomaScan, N=3,175; Olink, N=4,822), plasma metabolomics (Metabolon HD4, N=8,153), serum metabolomics (Nightingale, N=37,359), and whole blood Illumina RNA sequencing (N=4,136). We used machine learning to train genetic scores for 17,227 molecular traits, including 10,521 which reached Bonferroni-adjusted significance. We evaluated genetic score performances in external validation across European, Asian and African American ancestries, and assessed their longitudinal stability within diverse individuals. We demonstrated the utility of these multi-omic genetic scores by quantifying the genetic control of biological pathways and by generating a synthetic multi-omic dataset of UK Biobank to identify disease associations using a phenome-wide scan. Finally, we developed a portal (OmicsPred.org) to facilitate public access to all genetic scores and validation results as well as to serve as a platform for future extensions and enhancements of multi-omic genetic scores. more...

Background Sub‐optimal classification, interpretation and response to intrapartum electronic fetal monitoring using cardiotocography are known problems. Training is often recommended as a solution, but there is lack of clarity about the effects of training and which type of training works best. Objectives Systematic review of the effects of training healthcare professionals in intrapartum cardiotocography (PROSPERO protocol: CRD42017064525). Search strategy CENTRAL, Cochrane Library, MEDLINE, EMBASE, PsycINFO, British Nursing Database, CINAHL, ERIC, Scopus, Web of Science, ProQuest, grey literature and ongoing clinical trials were searched. Selection criteria Primary studies that reported impact of training healthcare professionals in intrapartum cardiotocography. Title/abstract, full‐text screening and quality assessment were conducted in duplicate. Data collection and analysis Data were synthesised both narratively and using meta‐analysis. Risk of bias and overall quality were assessed with the Mixed Methods Appraisal Tool and GRADE. Main results Sixty‐four studies were included. Overall, training and reporting were heterogeneous, the outcomes evaluated varied widely and study quality was low. Five randomised controlled trials reported that training improved knowledge of maternity professionals compared with no training, but evidence was of low quality. Evidence for the impact of cardiotocography training on neonatal and maternal outcomes was limited, showed inconsistent effects, and was of low overall quality. Evidence for the optimal content and method of delivery of training was very limited. Conclusions Given the scale of harm and litigation claims associated with electronic fetal monitoring, the evidence‐base for training requires improvement. It should address intervention design, evaluation of clinical outcomes and system‐wide contexts of sub‐optimal practice. Tweetable abstract Training in fetal monitoring: systematic review finds little evidence of impact on neonatal outcomes., Tweetable abstract Training in fetal monitoring: systematic review finds little evidence of impact on neonatal outcomes. more...

Introduction: Although studies have demonstrated a J-shaped association of parity with cardiovascular disease, the association with vascular disease is not fully understood. We examined the association between parity and carotid-femoral pulse wave velocity (cfPWV), a measure of arterial stiffness. Hypothesis: Women who were never pregnant or had no live births and women with 5+ live births would have higher cfPWV and 5-year cfPWV change compared to women with 1-2 live births. Materials and Methods: We included 1220 women (average age 73.7; 21.9% Black) from the Atherosclerosis Risk in Communities - Neurocognitive Study, a cohort of 15,792 adults enrolled in 1987-1989 from four communities: Forsyth Co., NC; Jackson, MS; Minneapolis, MN; and Washington Co., MD. Technicians measured cfPWV at visit 5 (2011-13) and visit 6 or 7 (2016-19). At visit 2 (1990-92), women self-reported parity (number of prior live births), which we categorized as never pregnant or pregnant but no live births, 1-2 (referent), 3-4, and 5+ live births. We used linear regression models to evaluate associations of parity with visit 5 cfPWV and 5-year cfPWV change, adjusting for years between visits 5 and 6 or 7, age, race-center, education, body mass index, heart rate, mean arterial pressure, hypertension medication, and diabetes. Results: Participants reported having had no (7.7%), 1-2 (38.7%), 3-4 (40.0%), or 5+ (13.6%) prior live births. Women with 5+ live births had a higher visit 5 cfPWV (β=50.6 cm/s, 95% confidence interval (CI): 3.6-97.7 cm/s; Table) as compared to those with 1-2 live births. No statistically significant associations were observed for other parity groups and visit 5 cfPWV or cfPWV change. Conclusions: In later life, women with 5+ live births had higher arterial stiffness than those with 1-2 live births, but the rate of cfPWV change did not differ by parity. Longitudinal arterial stiffness measurements at mid-life are needed to better understand the effect of pregnancy on the trajectory of arterial stiffness among women in later life. more...

Introduction: Early age at menopause is posited to increase cardiovascular disease (CVD) risk. However, studies examining the association with arterial stiffness, a predictor of CVD, are inconsistent and cross-sectional. Hypothesis: Earlier age at menopause and shorter reproductive years in women are associated with higher arterial stiffness and greater 5-year change at later life. Methods: We included 1,084 women in ARIC-NCS (mean 74 years at visit 5) with measures of arterial stiffness (carotid-femoral pulse wave velocity (cfPWV)) at visit 5 (2011-13) and visit 6 or 7 (2016-19). At visits 1-4, women self-reported age at first menses, age at menopause, and hysterectomy with and without bilateral oophorectomy. We defined menopause type as natural, surgical, and unknown, which included women with a hysterectomy, but unknown ovarian status. Multivariable linear regression was used to evaluate associations of age at menopause, early age at menopause ( Results: The average age at menopause was 46.2 years, and 319 (29.4%) women had early age at menopause. No statistically significant associations were observed for age at menopause and reproductive years with either visit 5 cfPWV or cfPWV change. However, the associations with cfPWV change differed by menopause type (Table). Age at menopause and reproductive years were inversely associated with cfPWV change in women with natural menopause but were positively associated with cfPWV change in women with surgical menopause. Conclusion: At later life, age at menopause and reproductive years are not strongly associated with arterial stiffness, although the change in arterial stiffness differs by menopause type. Longitudinal arterial stiffness measures among women at mid-life is needed to understand the effect of natural versus surgical menopause on arterial stiffness. more...

Aims Angiopoietin-like protein 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase (LPL) and represent emerging drug targets to lower circulating triglycerides and reduce cardiovascular risk. To investigate the molecular effects of genetic mimicry of ANGPTL3 and ANGPTL4 inhibition and compare them to the effects of genetic mimicry of LPL enhancement. Methods and results Associations of genetic variants in ANGPTL3 (rs11207977-T), ANGPTL4 (rs116843064-A), and LPL (rs115849089-A) with an extensive serum lipid and metabolite profile (208 measures) were characterized in six cohorts of up to 61 240 participants. Genetic associations with anthropometric measures, glucose-insulin metabolism, blood pressure, markers of kidney function, and cardiometabolic endpoints via genome-wide summary data were also explored. ANGPTL4 rs116843064-A and LPL rs115849089-A displayed a strikingly similar pattern of associations across the lipoprotein and lipid measures. However, the corresponding associations with ANGPTL3 rs11207977-T differed, including those for low-density lipoprotein and high-density lipoprotein particle concentrations and compositions. All three genotypes associated with lower concentrations of an inflammatory biomarker glycoprotein acetyls and genetic mimicry of ANGPTL3 inhibition and LPL enhancement were also associated with lower C-reactive protein. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower waist-to-hip ratio, improved insulin-glucose metabolism, and lower risk of coronary heart disease and type 2 diabetes, whilst genetic mimicry of ANGPTL3 was associated with improved kidney function. Conclusions Genetic mimicry of ANGPTL4 inhibition and LPL enhancement have very similar systemic metabolic effects, whereas genetic mimicry of ANGPTL3 inhibition showed differing metabolic effects, suggesting potential involvement of pathways independent of LPL. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower risk of coronary heart disease and type 2 diabetes. These findings reinforce evidence that enhancing LPL activity (either directly or via upstream effects) through pharmacological approaches is likely to yield benefits to human health., Graphical Abstract more...

Funder: Homerton College, University of Cambridge (GB), Funder: National Institute for Health Research; doi: http://dx.doi.org/10.13039/501100000272, 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 I2 statistic and the Cochrane χ2 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] more...

Rationale This study assessed the associations between pregnancy loss (miscarriage, stillbirth and abortion) and future maternal cardiovascular diseases (CVD, myocardial infarction (MI), stroke, ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage) in women in the UK Biobank from 2006–2016. Cardiovascular diseases (CVDs) are a high priority public health issue, presenting a high disease burden. Pregnancy has been described as a stress test for women’s bodies, where complications with pregnancy, including pregnancy loss, may be an indicator of increased risk of future CVDs. However, findings regarding associations between pregnancy loss and future CVDs are mixed, with a scarcity of UK studies. Furthering understanding of female specific risk factors has the potential to increase the clinical utility of risk prediction and public health prevention. Methods A prospective cohort study was conducted, including women in the UK Biobank cohort with self-reported exposure status recorded at baseline (n=246,124), with a median follow up time of 7.03 years (IQR 6.36–7.75) and a total of 1,762,729 person-years. Cardiovascular outcomes were ascertained through linkage of participant healthcare records and UK mortality databases. Cox proportional hazards models were used to ascertain Hazard ratios (HR) and 95% confidence intervals (CI). Patient and participant involvement (PPI) was included to inform understanding of public health impacts of study findings. Results Within the study cohort, 79,482 (32.29%) women had experienced one or more pregnancy losses. During follow up 2,567 (1.04%) women developed CVD. A history of one or more stillbirths was associated with an increased risk of stroke (Adjusted HR 1.55, 95%CI 1.06–2.27), in particular subarachnoid haemorrhage (Adjusted HR: 1.52, 95%CI 0.62–3.74). Miscarriage was not consistently associated with an increased risk of any cardiovascular outcome and no association between a history of therapeutic abortion and increased risk of CVD was demonstrated. Conclusion Analyses of the relationship between pregnancy loss and subtypes of CVD indicated that the direction and magnitude of associations were not universal in women in the UK Biobank or across populations. There is evidence of association between some types of pregnancy loss are associated with an increased risk of CVDs, though further research into associations with haemorrhagic stroke, and the associations between abortion and CVD, are needed. History of miscarriage and/or stillbirth should be considered for inclusion in cardiovascular risk assessment tools, potential pooled with other pregnancy complications, to identify and target support for women at increased risk. more...

Risk factors for atrial fibrillation (AF), including type 2 diabetes and obesity, are highly prevalent in women with polycystic ovary syndrome (PCOS)1,2, an endocrinological condition affecting up to 18% of women2. Furthermore, raised levels of testosterone, a cardinal symptom of PCOS, are associated with a greater risk of AF and ischemic stroke in women3. We assessed the association between PCOS and AF risk using nationwide registries., This work was funded by the British Heart Foundation (RE/13/6/30180), a doctoral research grant to D.V. from the Faculty of Health and Medical Sciences, University of Copenhagen (Copenhagen, Denmark), a research fellowship to C.O. from Homerton College, University of Cambridge, a travel fellowship to C.O. from the European Society of Human Reproduction and Embryology and ReproUnion and this article is part of the ReproUnion collaborative study, co-financed by the European Union, Intereg V Öresund-Kattegat-Skagerrak. more...

BACKGROUND The effect of postmenopausal hormone therapy (HT) on cardiovascular disease (CVD) risk remains controversial. OBJECTIVE AND RATIONALE We aimed to systematically review the evidence regarding the role of dose, route of hormone administration, timing of initiation and duration of HT on cardiovascular risk among postmenopausal women. SEARCH METHODS The electronic databases Medline Ovid, Web of Science and Cochrane Central were systematically searched to identify studies published before 30 January 2018. Reference lists, using Elsevier's Scopus, of the included studies were searched for further identification of relevant studies. Clinical trials and observational studies that assessed clinical and subclinical cardiovascular outcomes in relation to dose, route of administration, duration of use, or timing of HT initiation among postmenopausal women were included. Data were extracted by independent reviewers using a pre-designed data collection form. The Cochrane Collaboration's tool and the Newcastle-Ottawa Scale were used by two independent investigators to assess the risk of bias in RCTs and in prospective observational studies, respectively. OUTCOMES In total, 33 unique studies (6 trials and 27 prospective observational studies) were identified, including a total of 2 588 327 women. The synthesis of the existing knowledge on this topic was challenging due to inconsistent findings between some studies, caused by substantial diversity in scientific rigor and quality across the available literature. Overall, the evidence did not support the concerns that oral or transdermal HT increases heart disease risk. Contrary, observational data showed that a beneficial cardioprotective effect can be observed even with use of low doses of oral HT (effect of 0.3 mg/day of oral conjugated equine estrogen was similar to that seen with the standard dose of 0.625 mg/day), but clinical trials to support a cardioprotective benefit of HT in primary prevention have not been identified. Furthermore, the current data suggested that oral and transdermal HT, in dose-dependent manner and irrespective of HT formulation, may increase thromboembolic risk, as well as risk of stroke. However, transdermal estrogen with 10 years since the menopause onset (>60 years old), due to greater absolute risks of coronary heart disease, stroke and venous thromboembolism, HT should be used for the shortest time possible and in lowest possible dose and preferably transdermal administration should be recommended. However, an individualized treatment approach including baseline CVD risk assessment should be applied when prescribing HT. The majority of studies included in the current review are from North American and European populations, which might limit the generalizability of the findings of this review to the other populations. Finally, the quality of evidence included in this review was generally low or moderate, highlighting a need for more rigorous research to help us better understand HT and cardiovascular health. more...

Background This study aimed to assess how the prevalence and growth rates of small and medium abdominal aortic aneurysms (AAAs) (3·0–5·4 cm) have changed over time in men aged 65 years, and to evaluate long-term outcomes in men whose aortic diameter is 2·6–2·9 cm (subaneurysmal), and below the standard threshold for most surveillance programmes. Methods The Gloucestershire Aneurysm Screening Programme (GASP) started in 1990. Men aged 65 years with an aortic diameter of 2·6–5·4 cm, measured by ultrasonography using the inner to inner wall method, were included in surveillance. Aortic diameter growth rates were estimated separately for men who initially had a subaneurysmal aorta, and those who had a small or medium AAA, using mixed-effects models. Results Since 1990, 81 150 men had ultrasound screening for AAA (uptake 80·7 per cent), of whom 2795 had an aortic diameter of 2·6–5·4 cm. The prevalence of screen-detected AAA of 3·0 cm or larger decreased from 5·0 per cent in 1991 to 1·3 per cent in 2015. There was no evidence of a change in AAA growth rates during this time. Of men who initially had a subaneurysmal aorta, 57·6 (95 per cent c.i. 54·4 to 60·7) per cent were estimated to develop an AAA of 3·0 cm or larger within 5 years of the initial scan, and 28·0 (24·2 to 31·8) per cent to develop a large AAA (at least 5·5 cm) within 15 years. Conclusion The prevalence of screen-detected small and medium AAAs has decreased over the past 25 years, but growth rates have remained similar. Men with a subaneurysmal aorta at age 65 years have a substantial risk of developing a large AAA by the age of 80 years. more...

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. more...

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, Author summary Cardiovascular diseases (CVD) are the number one cause of death globally. Various metabolic biomarkers including lipid and lipoprotein particles have been implicated as risk factors for the development of CVD. Understanding how these biomarkers are regulated can lead to increased understanding of CVD aetiology and the potential identification of drug targets. Here we take advantage of high resolution measurements on a large cohort of 7,142 healthy blood donors with whole-exome and whole-genome sequencing data to explore the influence of rare variation on circulating metabolic biomarker levels. Using a novel approach leveraging the information gained from various measurements on the same participants we are able to identify a novel biological pathway involved in the regulation of intermediate-density and low-density lipoproteins as well as circulating cholesterol, confirm various established gene associations and identify potential novel gene associations that merit further replication. This work highlights the advantages that can be gained by combining high resolution genotypic and phenotypic measurements in one large cohort. more...

Circulating levels of small molecules or metabolites are highly heritable, but the impact of genetic differences in metabolism on human health is not well understood. In this cross-platform, genome-wide meta-analysis of 174 metabolite levels across six cohorts including up to 86,507 participants (70% unpublished data), we identify 499 (362 novel) genome-wide significant associations (p-10) at 144 (94 novel) genomic regions. We show that inheritance of blood metabolite levels in the general population is characterized by pleiotropy, allelic heterogeneity, rare and common variants with large effects, non-linear associations, and enrichment for nonsynonymous variation in transporter and enzyme encoding genes. The majority of identified genes are known to be involved in biochemical processes regulating metabolite levels and to cause monogenic inborn errors of metabolism linked to specific metabolites, such as ASNS (rs17345286, MAF=0.27) and asparagine levels. We illustrate the influence of metabolite-associated variants on human health including a shared signal at GLP2R (p.Asp470Asn) associated with higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes risk, and demonstrate beta-arrestin signalling as the underlying mechanism in cellular models. We link genetically-higher serine levels to a 95% reduction in the likelihood of developing macular telangiectasia type 2 [odds ratio (95% confidence interval) per standard deviation higher levels 0.05 (0.03-0.08; p=9.5×10-30)]. We further demonstrate the predictive value of genetic variants identified for serine or glycine levels for this rare and difficult to diagnose degenerative retinal disease [area under the receiver operating characteristic curve: 0.73 (95% confidence interval: 0.70-0.75)], for which low serine availability, through generation of deoxysphingolipids, has recently been shown to be causally relevant. These results show that integration of human genomic variation with circulating small molecule data obtained across different measurement platforms enables efficient discovery of genetic regulators of human metabolism and translation into clinical insights. more...

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., Inhibition of cholesteryl ester transfer protein does not affect size-specific low-density lipoprotein cholesterol, but may lower coronary heart disease risk by lowering cholesterol concentrations in other apolipoprotein-B containing atherogenic lipoproteins, and by lowering triglyceride content of high-density lipoprotein particles. more...

Introduction Hypertensive disorders of pregnancy, especially pre-eclampsia, are associated with greater cardiovascular disease risk. However, the risk of specific cardiovascular outcomes associated with pre-eclampsia or gestational hypertension is unclear. Methods Cox regression analysis compared rates of 19 cardiovascular outcomes in women with and without a history of pre-eclampsia and gestational hypertension, using electronic health records from women with one or more live births in England, 1997–2015. Results The cohort comprised 6,333,053 women, 276,389 and 223,715 pregnancies were complicated by gestational hypertension and pre-eclampsia, respectively. During 61.7 million person-years of follow-up, the incidence of any cardiovascular events for normotensive women, women with prior gestational hypertension and women with prior pre-eclampsia were: 39.95/100 000 person-years [95% CI, 39.05–40.87] (no. of CVD events=7,474), 62.24/100 000 person-years [95% CI, 56.67–68.20] (no. of CVD events= 469), and 73.72/100 000 person-years [95% CI, 67.20–80.71] (no. of CVD events=469), respectively. Compared with women with normotensive pregnancies, there was a greater risk of any cardiovascular event for women with previous gestational hypertension, adjusted HR (aHR) = 1.45 (1.31, 1.61), and pre-eclampsia, aHR = 1.69 (1.53–1.87). A history of gestational hypertension was most strongly associated with cardiomyopathy, aHR = 2.10 (1.52–2.89), and ischemic stroke, aHR = 1.79 (1.36–2.35). Women with two or more pregnancies with gestational hypertension were at greatest risk of stroke, aHR = 2.61 (1.91, 3.57), specifically ischemic stroke, aHR = 3.47 (2.38, 5.06). Women with a history of pre-eclampsia were at greatest risk of acute myocardial infarction, aHR = 3.08 (2.27, 4.16), and cardiomyopathy, aHR = 2.43 (1.78–3.31). Two or more pregnancies with pre-eclampsia was most strongly associated with ischemic stroke, aHR = 3.80 (2.53, 5.73) and acute myocardial infarction, aHR = 3.18 (1.91, 5.28). Conclusions This is the first study to compare the risk of a spectrum of CVD events for women with pre-eclampsia or gestational hypertension. Women with either previous gestational hypertension or pre-eclampsia are at increased risk of a range of cardiovascular outcomes compared to women with normotensive pregnancies. Associations were stronger with pre-eclampsia than gestational hypertension, and increased with a greater number of affected pregnancies. Gestational hypertension was most strongly associated with strokes, in particular ischemic stroke, and pre-eclampsia was most strongly associated with acute myocardial infarction and cardiomyopathy. Conflict of Interest None more...

Introduction The risk of cardiovascular outcomes associated with gestational hypertension is unclear. This study aimed to quantify the association between gestational hypertension and cardiovascular outcomes for women. Design Systematic review and meta-analysis. Data Sources PubMed, Embase and Web of Science. Eligibility Criteria Studies examining the association between gestational hypertension and any cardiovascular outcome, including cardiovascular disease, coronary heart disease, stroke and heart failure. Two reviewers independently assessed the abstracts and full-text articles. Study characteristics and the relative risk of cardiovascular outcomes associated with gestational hypertension were extracted from eligible studies. Where appropriate, estimates were pooled with inverse variance weighted random-effects meta-analysis, and the absolute risk increases were calculated using the European population as a reference, as the majority of studies came from Europe. Results Nineteen studies involving 3,601,192 women (128,445 with gestational hypertension) were identified. A history of one or more pregnancies affected by gestational hypertension was associated with an increased risk of cardiovascular disease (12 studies, relative risk 1.73, 95% confidence interval: 1.43–2.08), coronary heart disease (8 studies, 1.56, 1.35–1.81) and heart failure (4 studies, 1.70, 1.43–2.02). (See Figure) There was also evidence for an increased risk of stroke (9 studies, 1.66, 0.99–2.80). Among the outcomes examined, the highest absolute risk increase was for cardiovascular disease: 14.0 events/1000 person-years. Associations between gestational hypertension and cardiovascular disease were broadly consistent across subgroups, although there was evidence that high quality studies with a low risk of bias had lower effect estimates. When analyses were restricted to high quality studies, an increased risk was found for all outcomes: cardiovascular disease, (1.53, 1.25–1.88); coronary heart disease, (1.40, 1.26–1.54); stroke, (1.35, 1.14–1.60); and heart failure, (1.70, 1.43–2.02). Conclusion Gestational hypertension is associated with an increased risk of overall cardiovascular disease, coronary heart disease, stroke and heart failure. Only two studies evaluated risk associated with the number of pregnancies affected by gestational hypertension, therefore more research is needed to assess the presence of a dose-response relationship. Conflict of Interest None more...

Infertility is a global problem, but only a minority of couples access assisted reproductive technologies due to financial and sociocultural barriers. Complementary and alternative medicine are seen as another option. We aimed to determine the impact of complementary and alternative medicine on conception, miscarriage and live birth rates in couples not receiving assisted reproductive technology treatments. The electronic databases EMBASE, PubMed, Web of Science and the Allied and Complementary Medicine Database were systematically searched before March 24th 2020. Reference lists of eligible studies were searched for relevant studies. Eligible studies included trials and observational studies that assessed a complementary or alternative medicine and conception, miscarriage or live births in men or women not undergoing fertility treatment. Data were extracted by two independent reviewers using a pre-designed data collection form. The study protocol was published in the PROSPERO database (CRD42018086980). Twenty randomized controlled trials were identified, including 2748 individuals. Most studies did not demonstrate any effect of a complementary or alternative medicine on pregnancy, live birth or miscarriage rates. Limited evidence was found for a positive effect of herbal therapies taken by women on conception rates. There was substantial diversity in quality across the studies. There is limited evidence of the effectiveness of complementary and alternative medicine on improving the chances of conception and live births, or increasing miscarriage risk. Owing to the generally sub-optimal quality and heterogeneous nature of the evidence, rigorous studies are needed to determine the impact of complementary and alternative medicine on fertility. more...

Background Earlier age at menopause has been associated with increased risk of coronary heart disease (CHD), but the shape of association and role of established cardiovascular risk factors remain unclear. Therefore, we examined the associations between menopausal characteristics and CHD risk; the shape of the association between age at menopause and CHD risk; and the extent to which these associations are explained by established cardiovascular risk factors. Methods We used data from EPIC-CVD, a case–cohort study, which includes data from 23 centres from 10 European countries. We included only women, of whom 10 880 comprise the randomly selected sub-cohort, supplemented with 4522 cases outside the sub-cohort. We conducted Prentice-weighted Cox proportional hazards regressions with age as the underlying time scale, stratified by country and adjusted for relevant confounders. Results After confounder and intermediate adjustment, post-menopausal women were not at higher CHD risk compared with pre-menopausal women. Among post-menopausal women, earlier menopause was linearly associated with higher CHD risk [HRconfounder and intermediate adjusted per-year decrease = 1.02, 95% confidence interval (CI) = 1.01–1.03, p = 0.001]. Women with a surgical menopause were at higher risk of CHD compared with those with natural menopause (HRconfounder-adjusted = 1.25, 95% CI = 1.10–1.42, p Conclusions Earlier and surgical menopause were associated with higher CHD risk. These associations could partially be explained by differences in conventional cardiovascular risk factors. These women might benefit from close monitoring of cardiovascular risk factors and disease. more...

BACKGROUND: ATP citrate lyase is an enzyme in the cholesterol–biosynthesis pathway upstream of 3-hydroxy-3-methylglutaryl–coenzyme A reductase (HMGCR), the target of statins. Whether the genetic inhibition of ATP citrate lyase is associated with deleterious outcomes and whether it has the same effect, per unit decrease in the low-density lipoprotein (LDL) cholesterol level, as the genetic inhibition of HMGCR is unclear. METHODS: We constructed genetic scores composed of independently inherited variants in the genes encoding ATP citrate lyase (ACLY) and HMGCR to create instruments that mimic the effect of ATP citrate lyase inhibitors and HMGCR inhibitors (statins), respectively. We then compared the associations of these genetic scores with plasma lipid levels, lipoprotein levels, and the risk of cardiovascular events and cancer. RESULTS: A total of 654,783 participants, including 105,429 participants who had major cardiovascular events, were included in the study. The ACLY and HMGCR scores were associated with similar patterns of changes in plasma lipid and lipoprotein levels and with similar effects on the risk of cardiovascular events per decrease of 10 mg per deciliter in the LDL cholesterol level: odds ratio for cardiovascular events, 0.823 (95% confidence interval [CI], 0.78 to 0.87; P = 4.0×10(−14)) for the ACLY score and 0.836 (95% CI, 0.81 to 0.87; P= 3.9×10(−19)) for the HMGCR score. Neither lifelong genetic inhibition of ATP citrate lyase nor lifelong genetic inhibition of HMGCR was associated with an increased risk of cancer. CONCLUSIONS: Genetic variants that mimic the effect of ATP citrate lyase inhibitors and statins appeared to lower plasma LDL cholesterol levels by the same mechanism of action and were associated with similar effects on the risk of cardiovascular disease per unit decrease in the LDL cholesterol level. (Funded by Esperion Therapeutics and others.) more...

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. more...