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Het is belangrijk om te achterhalen welke ST-elevatiemyocardinfarctpatienten tot de laagrisicogroep behoren, zodat ze naar de huisarts terugverwezen kunnen worden. Wij onderzochten wat de prognose is van patienten met een ST-elevatiemyocardinfarct die na 1 jaar behandeling volgens een specifiek protocol naar de huisarts zijn terugverwezen.

Objective Thyroid hormones have been implicated to play a role in cardiovascular disease, along with studies linking thyroid hormone to kidney function. The aim of this study is to investigate whether kidney function modifies the association of subclinical thyroid dysfunction and the risk of cardiovascular outcomes. Methods In total, 5804 patients were included in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). For the current analysis, 426 were excluded because of overt thyroid disease at baseline or 6 months, 266 because of inconsistent thyroid function at baseline and 6 months, 294 because of medication use that could influence thyroid function, and 16 because of missing kidney or thyroid values. Participants with normal fT4 were classified, based on TSH both at inclusion and 6 months, into three groups: subclinical hypothyroidism (TSH >4.5 mIU/L); euthyroidism (TSH = 0.45–4.5 mIU/L); and subclinical hyperthyroidism (TSH 60 mL/min/1.73 m2. The primary endpoint consists of death from coronary heart disease, non-fatal myocardial infarction and (non)fatal stroke. Results Mean age was 75.3 years, and 49.0% patients were male. Mean follow-up was 3.2 years. Of all participants, 109 subjects (2.2%) had subclinical hypothyroidism, 4573 (94.0%) had euthyroidism, and 182 (3.7%) subclinical hyperthyroidism. For patients with subclinical hypothyroidism, euthyroidism, and subclinical hyperthyroidism, primary outcome occurred in 9 (8.3%), 712 (15.6%), and 23 (12.6%) patients, respectively. No statistically significant relationship was found between subclinical thyroid dysfunction and primary endpoint with adjusted hazard ratios of 0.51 (0.24–1.07) comparing subclinical hyperthyroidism and 0.90 (0.58–1.39) comparing subclinical hypothyroidism with euthyroidism. Neither was this relationship present in any of the strata of kidney function, nor did kidney function interact with subclinical thyroid dysfunction in the association with primary endpoint (P interaction = 0.602 for subclinical hyperthyroidism and 0.388 for subclinical hypothyroidism). Conclusions In this secondary analysis from PROSPER, we found no evidence that the potential association between thyroid hormones and cardiovascular disease is modified by kidney function in older patients with subclinical thyroid dysfunction.

Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes., Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.

Purpose To assess survival trends after ST-elevation myocardial infarction (STEMI) in patients with a prior cancer diagnosis and to evaluate the drivers of prognosis over a follow-up period of five years. Methods Patients with a known cancer diagnosis, admitted with STEMI between 2004–2014 and treated with primary PCI were recruited from the STEMI-clinical registry of our institution. Detailed information on cancer diagnosis, -stage, and treatment regimen were collected from the institutional and national cancer registry system and all patients were followed prospectively. Results In the 215 included patients the cumulative incidence of all-cause death after 5 years of follow-up was 38.2% (N=61). The cause of death was predominantly malignancy-related (N=29, 47.4% of deaths) and only 9 patients (14.8% of deaths) died of a cardiovascular cause. After correcting for age and sex – a recent cancer diagnosis (10 yr, HR 3.405 [95% CI: 1.552–7.470], p=0.002), distant metastasis at presentation (HR 2.603 [1.236–5.481], p=0.012), ongoing cancer treatment at presentation (HR 1.878 [1.015–3.475], p=0.045) and natural logarithm of maximum creatinine kinase level (HR 1.345 [1.044–1.733], p=0.022) were significant predictors of long-term mortality. While prevalent renal insufficiency showed significant association with all-cause mortality (HR 2.302 [1.289–4.111], p=0.005), other known determinants of long-term prognosis after STEMI – a history of diabetes mellitus (HR 1.250 [0.566–2.761], p=0.581), hypertension (HR 0.623 [0.393–1.085], p=0.150), and culprit vessel left anterior descending artery or left main artery (HR 1.066 [0.641–1.771], p=0.806) were not significantly associated with survival at 5-years follow-up. Conclusion Cancer patients admitted with STEMI have a poor survival with one third of patients died at 5 year follow up. Cancer was the most common cause of death and malignancy-related factors made a significant impact on prognosis, while most of the established cardiovascular determinants of prognosis were not significantly associated with long-term survival. Funding Acknowledgement Type of funding sources: None. Cumulative incidence curve

Introduction The aim in the diagnostic work-up of patients with an anomalous aortic origin of coronary arteries (AAOCA) is to determine whether the course of the coronary artery is benign or malignant. In patients with AAOCA with an interarterial course the guidelines on diagnostics are concise. Recommended CT-scan imaging does not evaluate stress-induced functional consequences like external compression by the pulmonary artery as the scan is performed in a resting state. Non-invasive ischemia detection techniques often lack sufficient sensitivity. To improve functional stratification, exploration of new diagnostic modalities in the diagnostic workup of AAOCA is mandatory. Purpose The purpose is to explore the potential role of intravascular ultrasound (IVUS) in the diagnostic workup of patients with AAOCA. Methods Nine patients with an anomalous right coronary artery with an interarterial course were analyzed. A cardiologist evaluated the complaints. Anatomical features of the AAOCA were assessed with CT-scan imaging. Further analyses included ischemia detection and coronary angiography. To assess stress-induced ischemia IVUS and invasive measurements – fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) – were performed at rest and during adrenaline-induced stress. A slit-like orifice was classified as a width/length (W/L) ratio of ≤0.50, an oval orifice as 0.51–0.9 and a round orifice as >0.91. Results Potential cardiac complaints were present in seven patients. In 8 (89%) patients CT-images showed an acute angle, in 8 (89%) proximal narrowing and an aortic take-off above the pulmonary valve in 4 (44%). In 7 (78%) patients a slit-like orifice and in two (22%) an oval orifice were observed (table 1). IVUS at rest showed a slit-like orifice in one patient classified as an oval orifice on the CT-images and vice versa in another patient (table 2). The patients classified as an oval orifice with IVUS showed no external compression during adrenaline-induced stress. In 4 (57%) out of 7 patients with an slit-like orifice on IVUS, the width remained unchanged or increased during adrenaline infusion. In 2 patients the width decreased slightly, however, these patients were asymptomatic and no ischemia was detected. In 1 (14%) patient the width remained 1.4mmm and the length increased from 3.2mm to 4.7mm. In this case the vessel ostium was fully engaged with the IVUS catheter, hence, the width could not decrease during adrenaline infusion. This was regarded as external compression. In addition, in this patient ischemia was detected. Conclusion(s) In two (22%) out of 9 patients IVUS gave a better insight of the shape of the orifice than CT. Additionally, the anatomic and functional-dynamic components of compression could be defined with adrenaline-induced stress. Therefore, IVUS can contribute to a better understanding of the functional consequences of the anatomical features and of potential stress-induced external compression. Funding Acknowledgement Type of funding sources: None. Table 1Table 2

Contains fulltext : 245649.pdf (Publisher’s version ) (Open Access) Recently, the European Society of Cardiology (ESC) has updated its guidelines for the management of patients with acute coronary syndrome (ACS) without ST-segment elevation. The current consensus document of the Dutch ACS working group and the Working Group of Interventional Cardiology of the Netherlands Society of Cardiology aims to put the 2020 ESC Guidelines into the Dutch perspective and to provide practical recommendations for Dutch cardiologists, focusing on antiplatelet therapy, risk assessment and criteria for invasive strategy.

BackgroundMitochondrial DNA (mtDNA) content might be involved in the risk of cardiovascular disease. We aimed to investigate the association of mtDNA copy number (mtDNA-CN), as a proxy of mtDNA content, and coronary artery disease (CAD) and heart failure (HF) using multivariable adjusted and Mendelian Randomizations (MR) analyses.MethodsMultivariable-adjusted analyses were conducted using Cox-proportional hazard models in 273,619 unrelated European descendants from UK Biobank (UKB). MtDNA-CN in peripheral blood cells was computed based on the weighted intensities of the mitochondrial genome probes. For the two-sample MR analyses, single nucleotide polymorphisms (SNPs) associated with mtDNA-CN were retrieved from genome-wide association studies in UKB. SNP-outcome associations were obtained for CAD from CARDIoGRAMplusC4D, UKB and FinnGen, comprising 902,538 participants (134,759 cases), and for HF from the HERMES consortium and FinnGen, collectively having data on 1,195,531 participants (70,706 cases). MR analyses were performed per database and results were subsequently meta analyzed using fixed-effects models per study.ResultsDuring a median follow-up of 11.8 years, participants in the lowest quintile of mtDNA-CN had higher risk for CAD (hazard ratio [95% CI]: 1.08 [1.03, 1.14]) and HF (hazard ratio [95% CI]: 1.15 [1.05, 1.24]) compared to those in the highest quintile. In MR analyses, the pooled odds ratios of genetically predicted per one-SD decrease in mtDNA were 1.16 (95% CI: 1.05, 1.27) for CAD and 1.00 (95% CI: 0.90, 1.10) for HF, respectively.ConclusionOur findings support a possible causal role of lower mtDNA-CN in higher CAD risk, but not in higher HF risk.

Among Ruffs Calidris pugnax migrating through the province of Friesland in The Netherlands in spring, some individuals have a remarkably plover-like, rustybrown neck collar. In this paper we explore the frequency of occurrence of this neck collar in 2,395 Ruffs in which the presence or absence was scored in yearround catches in Friesland between 2006 and 2019. Additionally, 49 nesting reeves in northern Finland and 73 skins of females (mostly in breeding plumage) in the Moscow Zoological Museum were checked for neck collars. The rustybrown neck collar was found in 395 Ruffs migrating through The Netherlands in spring. Among birds of known sex, age and morph (n = 2,098), the collar occurred in 14% of females, in 3.5% of faeders, and in 40% of satellite and 20% of independent males. However, among males, the rate dropped to zero by late April after the start of moult of the ruff and tuft feathers, and the occurrence was lower among second-calendar-year males (11%); no age effect was detected among females. Rusty-brown neck collars were rare among breeding females, with no cases in Finland, one possible case in the museum collection and one other case observed in Medusa Bay, north-central Siberia, Russia. The collar was also rare (0.4%) in non-breeding Ruffs caught in The Netherlands between June and February. The likely cause of the neck collar is staining by ferric oxide (Fe2O3) or ferrous oxide (FeO) as collar feathers tested positive for iron, while regular brown feathers tested negative. The presence in spring, but not after moult into the supplemental plumage or later, suggests that the birds acquire the ironbased collar in the wintering areas in West Africa or at stopover sites during northward migration.

The original version of this Article contained an error in Fig. 2, in which panels a and b were inadvertently swapped. This has now been corrected in the PDF and HTML versions of the Article.

Background: The benefits and risks of blood transfusion in patients with acute myocardial infarction who are anemic or who experience bleeding are debated. We sought to study the association between blood transfusion and ischemic outcomes according to haemoglobin nadir and bleeding status in patients with NST-elevation myocardial infarction (NSTEMI).Methods: The TAO trial randomized patients with NSTEMI and coronary angiogram scheduled within 72h to heparin plus eptifibatide versus otamixaban. After exclusion of patients who underwent coronary artery bypass surgery, patients were categorized according to transfusion status considering transfusion as a timevarying covariate. The primary ischemic outcome was the composite of all-cause death or MI within 180 days of randomization. Subgroup analyses were performed according to pre-transfusion hemoglobin nadir and bleeding status.Results: 12,547 patients were enrolled. Among these, blood transfusion was used in 489 (3.9%) patients. Patients who received transfusion had a higher rate of death or MI (29.9% vs. 8.1%, p 9.0 g/dl (HR 4.01; p-interaction 9.0g/dl. This suggests possible harm of transfusion in those groups. (C) 2020 Elsevier B.V. All rights reserved.

Background New ESC/EAS guidelines advise a low-density lipoprotein cholesterol (LDL-C) target level Aim To overcome these limitations, we performed a propensity score-matching (PSM) analysis of the ODYSSEY OUTCOMES trial, which compared the PCSK9 inhibitor alirocumab with placebo in 18,924 patients with recent ACS. Methods Patients on alirocumab were classified in 1 of 3 pre-specified categories according to Month 4 LDL-C 50 mg/dL (n=2197). Within each category, MACE after Month 4 was compared with patients on placebo using 1:1 PSM on demographic, clinical, and adherence variables. Because the trial design involved blinded substitution of placebo for alirocumab when consecutive LDL-C levels were Results Patients in the three achieved LDL-C categories of the alirocumab group differed by baseline age, sex, geographic region; history of diabetes, smoking, peripheral artery disease, cerebrovascular disease, coronary revascularization, heart failure, obstructive pulmonary disease, or malignancy; type of index ACS event; baseline LDL-C, lipoprotein(a), estimated glomerular filtration rate, body mass index, systolic blood pressure; use of intensive statin therapy; and adherence with study medication. After PSM, patients in each LDL-C category on alirocumab were well matched to patients on placebo for these characteristics. Treatment hazard ratios (HRs) for MACE (Figure) were similar in those with achieved LDL-C 50 mg/dL achieved less benefit. Patients who achieved consecutive LDL-C levels Conclusion After accounting for differences in baseline characteristics and adherence, reduction in risk of MACE with alirocumab was similar in patients who achieved LDL-C Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Sanofi and Regeneron Pharmaceuticals, Inc

Background The adipocyte-derived hormone leptin has been associated with altered blood coagulation in in vitro studies. However, it is unclear whether this association is relevant in vivo and to what extent this association is influenced by total body fat. Therefore, we aimed to examine the association between serum leptin and blood coagulation while taking total body fat into account in a population-based cohort study. Methods We performed a cross-sectional analysis with baseline measurements of 5797 participants of the Netherlands Epidemiology of Obesity (NEO) study, a population-based cohort of middle-aged men and women. We examined associations between serum leptin concentration and coagulation factor concentrations and parameters of platelet activation in linear regression analyses. All analyses were adjusted for multiple covariates, including total body fat. Results In multivariable adjusted analyses a 1 μg/L higher serum leptin concentration was associated with a 0.22 IU/dL (95% CI: 0.11, 0.32) higher FVIII concentration and a 0.20 IU/dL (95% CI: 0.14, 0.27) higher FIX concentration (3.5 IU/dL FVIII and 3.2 IU/dL FIX per SD leptin). Serum leptin concentration was not associated with FXI, fibrinogen, platelet count, mean platelet volume and platelet distribution width in multivariable adjusted analyses. Discussion This study showed that serum leptin concentration was associated with higher concentrations of FVIII and FIX in an observational study, which could be clinically relevant.

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p

Contains fulltext : 220929.pdf (Publisher’s version ) (Open Access) An early invasive strategy in patients who have acute coronary syndrome without ST-elevation (NSTE-ACS) can improve clinical outcome in high-risk subgroups. According to the current guidelines of the European Society of Cardiology (ESC), the majority of NSTE-ACS patients are classified as "high-risk". We propose to prioritise patients with a global registry of acute coronary events (GRACE) risk score >140 over patients with isolated troponin rise or electrocardiographic changes and a GRACE risk score

On behalf of the Dutch ACS working group, we discuss the most important changes in recommendations in the 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation relevant for both the general and interventional cardiologist.

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, transethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N = 78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P

The significance of classical risk factors in coronary artery disease (CAD) remains unclear in older age due to possible changes in underlying disease pathologies. Therefore, we conducted Mendelian Randomization approaches to investigate the causal relationship between classical risk factors and primary CAD in different age groups. A Mendelian Randomization study was conducted in European-ethnicity individuals from the UK Biobank population. Analyses were performed using data of 22,313 CAD cases (71.6% men) and 407,920 controls (44.5% men). Using logistic regression analyses, we investigated the associations between standardized genetic risk score and primary CAD stratified by age of diagnosis. In addition, feature importance and model accuracy were assessed in different age groups to evaluate predictive power of the genetic risk scores with increasing age. We found age-dependent associations for all classical CAD risk factors. Notably, body mass index (OR 1.22 diagnosis 70 years), blood pressure (OR 1.12 70 years), LDL cholesterol (OR 1.16 70 years), and triglyceride levels (OR 1.11 70 years). In line with the Mendelian Randomization analyses, model accuracy and feature importance of the classical risk factors decreased with increasing age of diagnosis. Causal determinants for primary CAD are age dependent with classical CAD risk factors attenuating in relation with primary CAD with increasing age. These results question the need for (some) currently applied cardiovascular disease risk reducing interventions at older age. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-021-00498-9.

Contains fulltext : 182860.pdf (Publisher’s version ) (Open Access) Fractional flow reserve (FFR) guided percutaneous coronary intervention (PCI) is associated with favourable outcome compared with revascularization based on angiographic stenosis severity alone. The feasibility of the new image-based quantitative flow ratio (QFR) assessed from 3D quantitative coronary angiography (QCA) and thrombolysis in myocardial infarction (TIMI) frame count using three different flow models has been reported recently. The aim of the current study was to assess the accuracy, and in particular, the reproducibility of these three QFR techniques when compared with invasive FFR. QFR was derived (1) from adenosine induced hyperaemic coronary angiography images (adenosine-flow QFR [aQFR]), (2) from non-hyperemic images (contrast-flow QFR [cQFR]) and (3) using a fixed empiric hyperaemic flow [fixed-flow QFR (fQFR)]. The three QFR values were calculated in 17 patients who prospectively underwent invasive FFR measurement in 20 vessels. Two independent observers performed the QFR analyses. Mean difference, standard deviation and 95% limits of agreement (LOA) between invasive FFR and aQFR, cQFR and fQFR for observer 1 were: 0.01 +/- 0.04 (95% LOA: -0.07; 0.10), 0.01 +/- 0.05 (95% LOA: -0.08; 0.10), 0.01 +/- 0.04 (95% LOA: -0.06; 0.08) and for observer 2: 0.00 +/- 0.03 (95% LOA: -0.06; 0.07), -0.01 +/- 0.03 (95% LOA: -0.07; 0.05), 0.00 +/- 0.03 (95% LOA: -0.06; 0.05). Values between the 2 observers were (to assess reproducibility) for aQFR: 0.01 +/- 0.04 (95% LOA: -0.07; 0.09), for cQFR: 0.02 +/- 0.04 (95% LOA: -0.06; 0.09) and for fQFR: 0.01 +/- 0.05 (95% LOA: -0.07; 0.10). In a small number of patients we showed good accuracy of three QFR techniques (aQFR, cQFR and fQFR) to predict invasive FFR. Furthermore, good inter-observer agreement of the QFR values was observed between two independent observers.

Recent years have brought a significant amount of new results in the field of atherosclerosis. A better understanding of the role of different lipoprotein particles in the formation of atherosclerotic plaques is now possible. Recent cardiovascular clinical trials have also shed more light upon the efficacy and safety of novel compounds targeting the main pathways of atherosclerosis and its cardiovascular complications. In this review, we first provide a background consisting of the current understanding of the pathophysiology and treatment of atherosclerotic disease, followed by our future perspectives on several novel classes of drugs that target atherosclerosis. The focus of this update is on the pathophysiology and medical interventions of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG) and lipoprotein(a) (Lp(a)).

Introduction Identifying ST-elevation myocardial infarction (STEMI) patients who can be referred back to the general practitioner (GP) can improve patient-tailored care. However, the long-term prognosis of patients who are returned to the care of their GP is unknown. Therefore, the aim of this study was to assess the long-term prognosis of patients referred back to the GP after treatment in accordance with a 1-year institutional guideline-based protocol. Methods All consecutive patients treated between February 2004 up to May 2013 who completed the 1‑year institutional MISSION! Myocardial Infarction (MI) follow-up and who were referred to the GP were evaluated. After 1 year of protocolised monitoring, asymptomatic patients with a left ventricular ejection fraction >45% on echocardiography were referred to the GP. Long-term prognosis was assessed with Kaplan-Meier curves and Cox proportional hazards analysis was used to identify independent predictors for 5‑year all-cause mortality and major adverse cardiovascular events (MACE). Results In total, 922 STEMI patients were included in this study. Mean age was 61.6 ± 11.7 years and 74.4% were male. Median follow-up duration after the 1‑year MISSION! MI follow-up was 4.55 years (interquartile range [IQR] 2.28–5.00). The event-free survival was 93.2%. After multivariable analysis, age, not using an angiotensin-converting enzyme (ACE) inhibitor/angiotensin-II (AT2) antagonist and impaired left ventricular function remained statistically significant predictors for 5‑year all-cause mortality. Kaplan-Meier curves revealed that 80.3% remained event-free for MACE after 5 years. Multivariable predictors for MACE were current smoking and a mitral regurgitation grade ≥2. Conclusion STEMI patients who are referred back to their GP have an excellent prognosis after being treated according to the 1‑year institutional MISSION! MI protocol.

Background Recent guidelines for cholesterol management recognize uncertainty regarding long-term efficacy and safety of prolonged very low levels of LDL-C on treatment with a PCSK9 inhibitor, including risk of new-onset diabetes. ODYSSEY OUTCOMES used a treat-to-target approach to demonstrate reduction of coronary heart disease death, non-fatal myocardial infarction, ischaemic stroke, or unstable angina (MACE) with the PCSK9 inhibitor alirocumab (ALI) vs placebo (PBO) in 18,924 patients with recent acute coronary syndrome and elevated LDL-C despite intensive statin therapy. ALI was blindly adjusted (75 or 150 mg dose) to target LDL-C 0.6–1.3 mmol/L (25–50 mg/dL). To avoid sustained very low LDL-C, blind substitution of PBO for ALI was intended if 2 consecutive LDL-C levels were Purpose We report the efficacy and safety of ALI in patients who reached very low LDL-C (consecutively Methods Of 9462 patients randomized to receive ALI, 730 (7.7%) reached very low LDL-C and had substitution of PBO a median 8.3 months after randomization. Using propensity score matching, they were compared (3:1) with 2152 patients initially assigned to PBO. Propensity score matching was also used to compare the incidence of new-onset diabetes in 525 patients without diabetes at baseline who had very low LDL-C levels on ALI with 1675 matched patients in the PBO group. Neurocognitive events and haemorrhagic stroke were also evaluated in relation to very low LDL-C. Results Overall, ALI reduced the incidence of MACE (9.5% vs 11.1%; HR 0.85, 95% CI 0.78–0.93; P Conclusions The overall efficacy of ALI on cardiovascular outcomes was not diminished by the patients who had blinded substitution of PBO for sustained very low LDL-C. Despite a short duration of active treatment, these patients had fewer MACE than matched controls from the PBO group. No adverse consequence of very low LDL-C was identified. However, because patients with sustained very low LDL-C were switched to PBO, the long-term safety of more prolonged very low LDL-C, including risk of new-onset diabetes, deserves further study. Acknowledgement/Funding Funded by Sanofi and Regeneron Pharmaceuticals

Background Statins are a cornerstone of therapy for coronary heart disease. We describe the effects of alirocumab (ALI) in patients (pts) with recent acute coronary syndrome (ACS) and dyslipidaemia per category of statin use. Methods ODYSSEY OUTCOMES compared ALI with placebo (PBO) in 18,924 pts with recent ACS and dyslipidaemia despite high-intensity/maximum tolerated statin (atorvastatin 40–80 mg/d or rosuvastatin 20–40 mg/d). Lower doses could be used if there were symptoms, laboratory abnormalities, or contraindications with higher doses. In cases of documented intolerance to ≥2 statins, pts could qualify on no statin treatment. Pts were randomized to ALI (75 mg SC Q2W, with possible uptitration to 150 mg Q2W) or PBO. Median follow-up was 2.8 years. Primary endpoint was major adverse cardiovascular events (MACE: CHD death, non-fatal MI, ischaemic stroke, or unstable angina requiring hospitalization). Pts were categorized by statin therapy at baseline: high intensity (88.8%), low or moderate intensity (8.7%), or no statin use (2.4%). In each category we determined the relative (hazard ratio [HR]) and absolute risk reductions (ARR) for MACE with ALI. Results Overall, ALI reduced MACE (HR 0.85, 95% CI 0.78–0.93; P LDL-C values and MACE events All patients High-intensity statin Low-/moderate-intensity statin No statin Interaction P-value N=18,924 (100%) N=16,811 (88.8%) N=1653 (8.7%) N=460 (2.4%) (treatment x statin category) PBO (N=9462) ALI (N=9462) PBO (N=8431) ALI (N=8380) PBO (N=804) ALI (N=849) PBO (N=227) ALI (N=233) LDL-C at baseline, mmol/L, mean (SE)* 2.39 (0.01) 2.39 (0.01) 2.35 (0.01) 2.35 (0.01) 2.41 (0.03) 2.43 (0.03) 3.76 (0.08) 3.82 (0.08) Change in LDL-C from baseline to Month 4, mmol/L, mean (SE) 0.03 (0.01) −1.4 (0.01) 0.03 (0.01) −1.37 (0.01) 0.01 (0.02) −1.47 (0.02) −0.004 (0.06) −2.27 (0.06) Conclusions In ODYSSEY OUTCOMES, patients unable to receive high-intensity statin treatment showed greater ARRs with ALI, consistent with higher baseline LDL-C concentration and greater absolute LDL-C reduction. Patients unable to receive high-intensity statin treatment are an important group to consider for treatment with ALI after ACS. Acknowledgement/Funding Funded by Sanofi and Regeneron Pharmaceuticals

Heart failure (HF) is a leading cause of morbidity and mortality worldwide1. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained2–4. We report the largest GWAS meta-analysis of HF to-date, comprising 47,309 cases and 930,014 controls. We identify 12 independent variant associations with HF at 11 genomic loci, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function suggesting shared genetic aetiology. Expression quantitative trait analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homeostasis (BAG3), and cellular senescence (CDKN1A). Using Mendelian randomisation analysis we provide new evidence supporting previously equivocal causal roles for several HF risk factors identified in observational studies, and demonstrate CAD-independent effects for atrial fibrillation, body mass index, hypertension and triglycerides. These findings extend our knowledge of the genes and pathways underlying HF and may inform the development of new therapeutic approaches.

The blood metabolome incorporates cues from the environment as well as the host’s genetic background, potentially offering a holistic view of an individual’s health status. We have compiled a vast resource of 1H-NMR metabolomics and phenotypic data encompassing over 25,000 samples derived from 26 community and hospital-based cohorts. Using this resource, we constructed a metabolomics-based age predictor (metaboAge) to calculate an individual’s biological age. Exploration in independent cohorts demonstrates that being judged older by one’s metabolome, as compared to one’s chronological age, confers an increased risk on future cardiovascular disease, mortality and functionality in older individuals. A web-based tool for calculating metaboAge (metaboage.researchlumc.nl) allows easy incorporation in other epidemiological studies. Access to data can be requested at bbmri.nl/samples-images-data. In summary, we present a vast resource of metabolomics data and illustrate its merit by constructing a metabolomics-based score for biological age that captures aspects of current and future cardio-metabolic health.

Background: \ud Characteristics and risk factors associated with electrocardiographic borderline Q-waves are not fully elucidated, especially in individuals without overt cardiovascular disease (CVD). Also, the relation of isolated and non-isolated borderline Q-waves with subclinical atherosclerosis and vascular stiffness is unknown.\ud \ud Methods and results: \ud We included 5746 Netherlands Epidemiology of Obesity study participants without overt CVD. Participants were divided in three groups: no Q-waves (93.7%), isolated (4.6%) and non-isolated borderline Q-waves (1.7%). Borderline Q-waves were defined as Minnesota Codes 1.2.x and 1.3.x and non-isolated as ≥1 of abnormal QRS axis, left ventricular hypertrophy or ST/T abnormalities. Several characteristics and measures of body fat were assessed. Vascular stiffness was assessed by pulse wave velocity (PWV) and subclinical atherosclerosis by carotid intima-media thickness (cIMT). Percentage of men, alcohol intake, blood pressure and fasting glucose concentrations were, compared with no Q-waves, higher in the isolated and highest in the non-isolated borderline Q-wave group. Isolated borderline Q-waves were associated with higher body mass index (difference compared with no Q-waves: 1.0 kg/m2; 95%CI: 0.3–1.7; p-value: 0.006), waist circumference (3.4 cm; 1.0–5.8; 0.005), and visceral adipose tissue (21.9 cm2; 7.4–36.3; 0.003) and differences were even larger for non-isolated borderline Q-waves. Compared with no Q-waves, non-isolated borderline Q-waves were associated with higher PWV (1.2 m/s; 0.4–2.0; 0.004) and cIMT (23.4 μm; 3.0–43.8; 0.024), whereas isolated borderline Q-waves were not.\ud \ud Conclusion: \ud Cardiovascular risk factors and measures of body fat, especially abdominal adiposity, were higher in participants with isolated borderline Q-waves, compared with no Q-waves, and highest in the non-isolated borderline Q-wave group. Non-isolated borderline Q-waves were associated with subclinical atherosclerosis and vascular stiffness. Future studies should investigate potential added value of borderline Q-waves in CVD prediction.

Publisher's version (útgefin grein), Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans., The work was supported by the following grants: National Institute of Health grants: R21HL123677, R21-HL140385, DK104806-01A1, R01-MD012765-01A1 (NF), National Institutes of Health awards R01HG009120, R01HG006399, U01CA194393, T32NS048004 (CG), the American Heart Association Grant #17POST33350042 (PV), the British Heart Foundation (RG/13/5/30112) and the National Institute for Health Research University College London Hospitals Biomedical Research Centre (RCL and RPH), the British Heart Foundation FS/14/55/30806 (JCH), the German Federal Ministry of Education and Research (BMBF) in the context of the e:Med program (e:AtheroSysMed), the DFG as part of the CRC 1123 (B3), and the FP7/2007-2103 European Union project CVgenes@target (grant agreement number Health-F2-2013-601456). We thank Li-Ming Gan for assistance with the STARNET study and Jon White for assistance with UCLEB analyses. Additional acknowledgements are included in Supplementary Note 2.

We aimed to investigate whether circulating leptin and body mass index (BMI) associate independently with cognitive function (decline) and brain volumes using magnetic resonance imaging (MRI) in older individuals at risk of cardiovascular disease. We studied the cross-sectional and longitudinal associations in participants enrolled in the PROSPER study (Prospective Study of Pravastatin in the Elderly at Risk). Cognitive function was tested at baseline and repeated during a mean follow-up time of 3.2 years. Analyses were performed with multivariable (repeated) linear regression models and adjusted for demographics, cardiovascular risk-factors, and stratified by sex. We included 5623 dementia-free participants (52 % female, mean age 75 years) with a mean BMI of 26.9 (SD = 4.1). In a sub-study, 527 participants underwent brain MRI. At baseline, individuals with a BMI > 30 had a worse performance on the Stroop test (beta 5.0 s, 95 %CI 2.6;7.5) and larger volumes of the amygdala (beta 234 mm(3), 95 %CI 3;464) and hippocampus (beta 590 mm(3), 95 %CI 181;999), independent of intracranial volume and serum leptin levels, compared with individuals with the reference BMI (BMI 18-25 kg/m(2)). Per log ng/mL higher serum leptin, independent of BMI, a 135 mm(3) (95 %CI 2;268) higher volume of the amygdala was found, but no association was observed with cognitive tests nor with other brain volumes. Stratification for sex did not materially change the results. Whereas higher BMI associated with worse cognitive function independent of leptin levels, our study provided evidence that leptin and BMI independently associate with amygdala volume suggesting potential distinct biological associations.

Aim Variations in treatment are the result of differences in demographic and clinical factors (e.g. anatomy), but physician and hospital factors may also contribute to treatment variation. The choice of treatment is considered important since it could lead to differences in long-term outcomes. This study explores the associations with stent choice: i.e. drug-eluting stent (DES) versus bare-metal stents (BMS) for Dutch patients diagnosed with stable or unstable coronary artery disease (CAD). Methods & results Associations with treatment decisions were based on a prospective cohort of 692 patients with stable or unstable CAD. Of those patients, 442 patients were treated with BMS or DES. Multiple logistic regression analyses were performed to identify variables associated with stent choice. Bivariate analyses showed that NYHA class, number of diseased vessels, previous percutaneous coronary intervention, smoking, diabetes, and the treating hospital were associated with stent type. After correcting for other associations the treating hospital remained significantly associated with stent type in the stable CAD population. Conclusions This study showed that several factors were associated with stent choice. While patients generally appear to receive the most optimal stent given their clinical characteristics, stent choice seems partially determined by the treating hospital, which may lead to differences in longterm outcomes.

The reference to the term acute coronary syndrome with normal or near-normal (non-obstructive) coronary arteries (ACSNNOCA) from Manolis et al. (2018) was inadvertently omitted to the original published article. Therefore, the following reference should be added to our paper:Manolis AS, Manolis AA, Manolis TA, Melita H. Acute coronary syndromes in patients with angiographically normal or near normal (non-obstructive) coronary arteries. Trends Cardiovasc Med. 2018;28(8):541–51. https://doi.org/10.1016/j.tcm. 2018.05.006. The authors would like to apologise for any inconvenience caused.

Under climate warming, migratory birds should align reproduction dates with advancing plant and arthropod phenology. To arrive on the breeding grounds earlier, migrants may speed up spring migration by curtailing the time spent en route, possibly at the cost of decreased survival rates. Based on a decades-long series of observations along an entire flyway, we show that when refuelling time is limited, variation in food abundance in the spring staging area affects fitness. Bar-tailed godwits migrating from West Africa to the Siberian Arctic reduce refuelling time at their European staging site and thus maintain a close match between breeding and tundra phenology. Annual survival probability decreases with shorter refuelling times, but correlates positively with refuelling rate, which in turn is correlated with food abundance in the staging area. This chain of effects implies that conditions in the temperate zone determine the ability of godwits to cope with climate-related changes in the Arctic., Advancing phenological timing is a risk for migratory birds, particularly in the Arctic where change is most rapid. Here, the authors show that bar-tailed godwits can adjust for phenological shifts by fuelling faster at staging areas to arrive at breeding sites in time.

Under climate warming, migratory birds should align reproduction dates with advancing plant and arthropod phenology. To arrive on the breeding grounds earlier, migrants may speed up spring migration by curtailing the time spent en route, possibly at the cost of decreased survival rates. Based on a decades-long series of observations along an entire flyway, we show that when refuelling time is limited, variation in food abundance in the spring staging area affects fitness. Bar-tailed godwits migrating from West Africa to the Siberian Arctic reduce refuelling time at their European staging site and thus maintain a close match between breeding and tundra phenology. Annual survival probability decreases with shorter refuelling times, but correlates positively with refuelling rate, which in turn is correlated with food abundance in the staging area. This chain of effects implies that conditions in the temperate zone determine the ability of godwits to cope with climate-related changes in the Arctic.

Events in the life cycle of migrant birds are generally time-constrained. Moult, together with breeding and migration, is the most energetically demanding annual cycle stages, but it is the only stage that can be scheduled at different times of the year. However, it is still not fully understood what factors determine this scheduling.We compare the timing of primary feather moult in relation to breeding and migration between two populations of Eurasian golden plover Pluvialis apricaria, the continental population breeding in Scandinavia and in N Russia that migrates to the Netherlands and southern Europe, and the Icelandic population that migrates mainly to Ireland and western UK. Moult was studied at the breeding grounds (N Sweden, N Russia, Iceland) and at stopover and wintering sites (S Sweden, the Netherlands). In both populations, primary moult overlapped with incubation and chick rearing, and females started on average 9 d later than males. Icelandic plovers overlapped moult with incubation to a larger extent and stayed in the breeding grounds until primary moult was completed. In contrast, continental birds only moulted the first 5-7 primaries at the breeding grounds and completed moult in stopover and wintering areas, such as S Sweden and the Netherlands.This overlap, although rare in birds, can be understood from an annual cycle perspective. Icelandic plovers presumably need to initiate moult early in the season to be able to complete it at the breeding grounds. The latter is not possible for continental plovers as their breeding season is much shorter due to a harsher climate. Additionally, for this population, moulting all the primaries at the stopover/wintering site is also not possible as too little time would remain to prepare for cold-spell movements. We conclude that environmental conditions and migration strategy affect the annual scheduling of primary feather moult in the Eurasian golden plover.

Publisher's version (útgefin grein)., Background: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. Results: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction. Conclusions: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes., Funding This work was funded by a grant to YJ from the British Heart Foundation (PG/12/38/29615). AGES: This study has been funded by NIH contracts N01-AG-1-2100 and 271201200022C, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The study is approved by the Icelandic National Bioethics Committee, VSN: 00–063. The researchers are indebted to the participants for their willingness to participate in the study. ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Funding support for “Building on GWAS for NHLBI-diseases: the U.S. CHARGE consortium” was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). BRIGHT: The Exome Chip genotyping was funded by Wellcome Trust Strategic Awards (083948 and 085475). This work was also supported by the Medical Research Council of Great Britain (Grant no. G9521010D); and by the British Heart Foundation (Grant no. PG/02/128). AFD was supported by the British Heart Foundation (Grant nos. RG/07/005/23633 and SP/08/005/25115); and by the European Union Ingenious HyperCare Consortium: Integrated Genomics, Clinical Research, and Care in Hypertension (grant no. LSHM-C7–2006-037093). The BRIGHT study is extremely grateful to all the patients who participated in the study and the BRIGHT nursing team. We would also like to thank the Barts Genome Centre staff for their assistance with this project. CHS: This Cardiovascular Health Study (CHS) research was supported by NHLBI contracts HHSN268201800001C, HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants R01HL068986, U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and U01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. ERF: The ERF study as a part of EUROSPAN (European Special Populations Research Network) was supported by European Commission FP6 STRP grant number 018947 (LSHG-CT-2006-01947) and also received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013)/grant agreement HEALTH-F4–2007-201413 by the European Commission under the programme “Quality of Life and Management of the Living Resources” of 5th Framework Programme (no. QLG2-CT-2002-01254). The ERF study was further supported by ENGAGE consortium and CMSB. High-throughput analysis of the ERF data was supported by joint grant from Netherlands Organization for Scientific Research and the Russian Foundation for Basic Research (NWO-RFBR 047.017.043). We are grateful to all study participants and their relatives, general practitioners, and neurologists for their contributions to the ERF study and to P Veraart for her help in genealogy, J Vergeer for the supervision of the laboratory work, and P Snijders for his help in data collection. FHS: The Framingham Heart Study (FHS) research reported in this article was supported by a grant from the National Heart, Lung, and Blood Institute (NHLBI), HL120393. Generation Scotland: Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006). Genotyping of the Generation Scotland and Scottish Family Health Study samples was carried out by the Genetics Core Laboratory at the Clinical Research Facility, Edinburgh, Scotland and was funded by the UK’s Medical Research Council. GOCHA: The Genetics of Cerebral Hemorrhage with Anticoagulation was carried out as a collaborative study supported by grants R01NS073344, R01NS059727, and 5K23NS059774 from the NIH–National Institute of Neurological Disorders and Stroke (NIH-NINDS). GRAPHIC: The GRAPHIC Study was funded by the British Heart Foundation (BHF/RG/2000004). NJS and CPN are supported by the British Heart Foundation and is a NIHR Senior Investigator. This work falls under the portfolio of research supported by the NIHR Leicester Cardiovascular Biomedical Research. INGI-FVG: This study has been funded by Regione FVG (L.26.2008). INTER99: The Inter99 was initiated by Torben Jørgensen (PI), Knut Borch-Johnsen (co-PI), Hans Ibsen and Troels F. Thomsen. The steering committee comprises the former two and Charlotta Pisinger. The study was financially supported by research grants from the Danish Research Council, the Danish Centre for Health Technology Assessment, Novo Nordisk Inc., Research Foundation of Copenhagen County, Ministry of Internal Affairs and Health, the Danish Heart Foundation, the Danish Pharmaceutical Association, the Augustinus Foundation, the Ib Henriksen Foundation, the Becket Foundation, and the Danish Diabetes Association. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). JHS: We thank the Jackson Heart Study (JHS) participants and staff for their contributions to this work. The JHS is supported by contracts HHSN268201300046C, HHSN268201300047C, HHSN268201300048C, HHSN268201300049C, HHSN268201300050C from the National Heart, Lung, and Blood Institute and the National Institute on Minority Health and Health Disparities. Dr. Wilson is supported by U54GM115428 from the National Institute of General Medical Sciences. KORA: The KORA study was initiated and financed by the Helmholtz Zentrum München – German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. Korcula: This work was funded by the Medical Research Council UK, The Croatian Ministry of Science, Education and Sports (grant 216–1080315-0302), the Croatian Science Foundation (grant 8875), the Centre of Excellence in Personalized health care, and the Centre of Competencies for Integrative Treatment, Prevention and Rehabilitation using TMS. LifeLines: The LifeLines Cohort Study and generation and management of GWAS genotype data for the LifeLines Cohort Study are supported by The Netherlands Organization of Scientific Research NWO (grant 175.010.2007.006), the Economic Structure Enhancing Fund (FES) of the Dutch government, the Ministry of Economic Affairs, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the Northern Netherlands Collaboration of Provinces (SNN), the Province of Groningen, University Medical Center Groningen, the University of Groningen, Dutch Kidney Foundation, and Dutch Diabetes Research Foundation. Niek Verweij is supported by NWO-VENI (016.186.125) and Marie Sklodowska-Curie GF (call: H2020-MSCA-IF-2014, Project ID: 661395). UHP: Folkert W. Asselbergs is supported by UCL Hospitals NIHR Biomedical Research Centre. Ilonca Vaartjes is supported by a Dutch Heart Foundation grant DHF project “Facts and Figures.” MGH-CAMP: Dr. Patrick Ellinor is funded by NIH grants (2R01HL092577, 1R01HL128914, R01HL104156, and K24HL105780) and American Heart Association Established Investigator Award 13EIA14220013 (Ellinor). Dr. Steve Lubitz is funded by NIH grants K23HL114724 and a Doris Duke Charitable Foundation Clinical Scientist Development Award 2014105. NEO: The authors of the NEO study thank all individuals who participated in the Netherlands Epidemiology in Obesity study, all participating general practitioners for inviting eligible participants, and all research nurses for collection of the data. We thank the NEO study group, Pat van Beelen, Petra Noordijk, and Ingeborg de Jonge for the coordination, lab, and data management of the NEO study. We also thank Arie Maan for the analyses of the electrocardiograms. The genotyping in the NEO study was supported by the Centre National de Génotypage (Paris, France), headed by Jean-Francois Deleuze. The NEO study is supported by the participating Departments, the Division and the Board of Directors of the Leiden University Medical Center, and by the Leiden University, Research Profile Area Vascular and Regenerative Medicine. Dennis Mook-Kanamori is supported by Dutch Science Organization (ZonMW-VENI Grant 916.14.023). RS-I: The generation and management of the Illumina Exome Chip v1.0 array data for the Rotterdam Study (RS-I) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The Exome chip array dataset was funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, from the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO)-sponsored Netherlands Consortium for Healthy Aging (NCHA; project nr. 050–060-810); the Netherlands Organization for Scientific Research (NWO; project number 184021007); and by the Rainbow Project (RP10; Netherlands Exome Chip Project) of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL; www.bbmri.nl). We thank Ms. Mila Jhamai, Ms. Sarah Higgins, and Mr. Marijn Verkerk for their help in creating the exome chip database, and Carolina Medina-Gomez, MSc, Lennard Karsten, MSc, and Linda Broer PhD for QC and variant calling. Variants were called using the best practice protocol developed by Grove et al. as part of the CHARGE consortium exome chip central calling effort. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. The work of Bruno H. Stricker is supported by grants from the Netherlands Organization for Health Research and Development (ZonMw) (Priority Medicines Elderly 113102005 to ME and DoelmatigheidsOnderzoek 80–82500–98-10208 to BHS). The work of Mark Eijgelsheim is supported by grants from the Netherlands Organization for Health Research and Development (ZonMw) (Priority Medicines Elderly 113102005 to ME and DoelmatigheidsOnderzoek 80–82500–98-10208 to BHS). SHIP: SHIP is supported by the BMBF (grants 01ZZ9603, 01ZZ0103, and 01ZZ0403) and the German Research Foundation (Deutsche Forschungsgemeinschaft [DFG]; grant GR 1912/5–1). SHIP and SHIP-TREND are part of the Community Medicine Research net (CMR) of the Ernst-Moritz-Arndt University Greifswald (EMAU) which is funded by the BMBF as well as the Ministry for Education, Science and Culture and the Ministry of Labor, Equal Opportunities, and Social Affairs of the Federal State of Mecklenburg-West Pomerania. The CMR encompasses several research projects that share data from SHIP. The EMAU is a member of the Center of Knowledge Interchange (CKI) program of the Siemens AG. SNP typing of SHIP and SHIP-TREND using the Illumina Infinium HumanExome BeadChip (version v1.0) was supported by the BMBF (grant 03Z1CN22). We thank all SHIP and SHIP-TREND participants and staff members as well as the genotyping staff involved in the generation of the SNP data. TWINSUK: TwinsUK is funded by the Wellcome Trust, Medical Research Council, European Union, the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. UKBB: This research has been conducted using the UK Biobank Resource (application 8256 - Understanding genetic influences in the response of the cardiac electrical system to exercise) and is supported by Medical Research Council grant MR/N025083/1. We also wish to acknowledge the support of the NIHR Cardiovascular Biomedical Research Unit at Barts and Queen Mary University of London, UK. PD Lambiase acknowledges support from the UCLH Biomedicine NIHR. MO is supported by an IEF 2013 Marie Curie fellowship. JR acknowledges support from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007–2013) under REA grant agreement no. 608765. YFS: The Young Finns Study has been financially supported by the Academy of Finland: grants 286284, 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; and Diabetes Research Foundation of Finnish Diabetes Association. The expert technical assistance in the statistical analyses by Irina Lisinen is gratefully acknowledged. Cell culture and biochemistry: Funding was provided by the National Institutes of Health (Program of Excellence in Glycoscience award HL107147 to SSA and F32AR063548 to TJM) and the David and Lindsay Morgenthaler Postdoctoral Fellowship (to TJM) and by the Allen Distinguished Investigator Program, through support made by The Paul G. Allen Frontiers Group and the American Heart Association (to SSA). Mutant mouse model: Adamts6 mutant mice were generated and further propagated and analyzed by funding provided by NIH grants HL098180 and HL132024 (to CWL) and by the Allen Distinguished Investigator Program, through support made by The Paul G. Allen Frontiers Group and the American Heart Association (to SSA).

BACKGROUND: Subclinical hypothyroidism is common in older people and its contribution to health and disease needs to be elucidated further. Observational and clinical trial data on the clinical effects of subclinical hypothyroidism in persons aged 80 years and over is inconclusive, with some studies suggesting harm and some suggesting benefits, translating into equipoise whether levothyroxine therapy provides clinical benefits. This manuscript describes the study protocol for the Institute for Evidence-Based Medicine in Old Age (IEMO) 80-plus thyroid trial to generate the necessary evidence base.METHODS: The IEMO 80-plus thyroid trial was explicitly designed as an ancillary experiment to the Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism randomised placebo controlled Trial (TRUST) with a near identical protocol and shared research infrastructure. Outcomes will be presented separately for the IEMO and TRUST 80-plus groups, as well as a pre-planned combined analysis of the 145 participants included in the IEMO trial and the 146 participants from the TRUST thyroid trial aged 80 years and over. The IEMO 80-plus thyroid trial is a multi-centre randomised double-blind placebo-controlled parallel group trial of levothyroxine treatment in community-dwelling participants aged 80 years and over with persistent subclinical hypothyroidism (TSH ≥4.6 and ≤ 19.9 mU/L and fT4 within laboratory reference ranges). Participants are randomised to levothyroxine 25 or 50 micrograms daily or matching placebo with dose titrations according to TSH levels, for a minimum follow-up of one and a maximum of three years. Primary study endpoints: hypothyroid physical symptoms and tiredness on the thyroid-related quality of life patient-reported outcome (ThyPRO) at one year. Secondary endpoints: generic quality of life, executive cognitive function, handgrip strength, functional ability, blood pressure, weight, body mass index, and mortality. Adverse events will be recorded with specific interest on cardiovascular endpoints such as atrial fibrillation and heart failure.DISCUSSION: The combined analysis of participants in the IEMO 80-plus thyroid trial with the participants aged over 80 in the TRUST trial will provide the largest experimental evidence base on multimodal effects of levothyroxine treatment in 80-plus persons to date.TRIAL REGISTRATION: Nederlands (Dutch) Trial Register: NTR3851 (12-02-2013), EudraCT: 2012-004160-22 (17-02-2013), ABR-41259.058.13 (12-02-2013).

In essence, pharmacogenetic research is aimed at discovering variants of importance to gene-treatment interaction. However, epidemiological studies are rarely set up with this goal in mind. It is therefore of great importance that researchers clearly communicate which assumptions they have had to make, and which inherent limitations apply to the interpretation of their results. This review discusses considerations of, and the underlying assumptions for, utilizing different response phenotypes and study designs popular in pharmacogenetic research to infer gene-treatment interaction effects, with a special focus on those dealing with of clinical effects of drug treatment.

MotivationGenome-wide association studies have had great success in identifying human genetic variants associated with disease, disease risk factors, and other biomedical phenotypes. Many variants are associated with multiple traits, even after correction for trait-trait correlation. Discovering subsets of variants associated with a shared subset of phenotypes could help reveal disease mechanisms, suggest new therapeutic options, and increase the power to detect additional variants with similar pattern of associations. Here we introduce two methods based on a Bayesian framework, SNP And Pleiotropic PHenotype Organization (SAPPHO), one modeling independent phenotypes (SAPPHO-I) and the other incorporating a full phenotype covariance structure (SAPPHO-C). These two methods learn patterns of pleiotropy from genotype and phenotype data, using identified associations to discover additional associations with shared patterns.ResultsThe SAPPHO methods, along with other recent approaches for pleiotropic association tests, were assessed using data from the Atherosclerotic Risk in Communities (ARIC) study of 8,000 individuals, whose gold-standard associations were provided by meta-analysis of 40,000 to 100,000 individuals from the CHARGE consortium. Using power to detect gold-standard associations at genome-wide significance (0.05 family-wise error rate) as a metric, SAPPHO performed best. The SAPPHO methods were also uniquely able to select the most significant variants in a parsimonious model, excluding other less likely variants within a linkage disequilibrium block. For meta-analysis, the SAPPHO methods implement summary modes that use sufficient statistics rather than full phenotype and genotype data. Meta-analysis applied to CHARGE detected 16 additional associations to the gold-standard loci, as well as 124 novel loci, at 0.05 false discovery rate. Reasons for the superior performance were explored by performing simulations over a range of scenarios describing different genetic architectures. With SAPPHO we were able to learn genetic structures that were hidden using the traditional univariate tests.Availabilityhttps://bitbucket.org/baderlab/fast/wiki/Home. SAPPHO software is available under the GNU General Public License, v2.

Sulfonylureas, a commonly-used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In eleven ethnically diverse cohorts that included 71 857 European, African American, and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT, and QRS intervals. In ancestry-specific meta-analyses, 8 novel pharmacogenomic loci met the threshold for genome-wide significance (P < 5 x 10−8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.

Breeding Pacific Golden-Plovers (Pluvialis fulva) cover 140 longitudinal degrees of Arctic tundra. Having examined 557 museum skins from across this huge distributional range, we conclude that Pacific Golden-Plovers breeding in Alaska are structurally larger than those breeding in Siberia, especially in wing length. Birds from Alaska also have more pointed wings and almost always postpone the initiation of primary molt until they reach their winter quarters, whereas many Siberian birds start primary molt in the breeding areas. These differences could have been favored by the longer transoceanic flights followed by the Alaskan populations to nonbreeding destinations in the Pacific Islands. We propose that the Alaskan and Siberian breeding birds be distinguished as distinct flyway populations to be used in conservation assessments by the international conservation community.