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Atherosclerosis manifests itself differently in men and women with respect to plaque initiation, progression and plaque composition. The observed delay in plaque progression in women is thought to be related to the hormonal status of women. Also features associated with the vulnerability of plaques to rupture seem to be less frequently present in women compared to men. Current invasive and non-invasive imaging modalities allow for visualization of plaque size, composition and high risk vulnerable plaque features. Moreover, image based modeling gives access to local shear stress and shear stress-related plaque growth. In this review, current knowledge on sex-related differences in plaque size, composition, high risk plaque features and shear stress related plaque growth in carotid and coronary arteries obtained from imaging are summarized.

Introduction: Acinetobacter baumannii , renowned for its exceptional multidrug resistance and its role as a prevalent nosocomial pathogen, poses a formidable challenge to conventional antibiotic therapies. The primary objective of this investigation was to evaluate the efficacy of Secapin, an antimicrobial peptide, against multidrug-resistant (MDR) baumannii . Furthermore, the mechanisms underlying Secapin's antibacterial and antibiofilm activities were elucidated.Methods: The antimicrobial and antibiofilm effectiveness of Secapin against MDR A. baumannii was assessed through a series of experiments. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of Secapin were determined using established protocols. Time-kill kinetic analysis was performed to assess the concentration-dependent bactericidal effect of Secapin. Additionally, the capacity of Secapin to impede biofilm formation and eradicate A. b aumannii biofilms was investigated. Hemolytic potential was evaluated using human red blood cells, while mammalian cell viability was examined at varying Secapin concentrations.Results: Secapin exhibited robust bactericidal activity at minimal concentrations, with an MIC of 5 µg/mL and an MBC of 10 µg/mL against MDR A. baumannii . The time-kill kinetic analysis confirmed the concentration-dependent efficacy of Secapin in diminishing bacterial viability. Moreover, Secapin demonstrated the ability to prevent biofilm formation and eliminate established A. baumannii biofilms. Notably, Secapin exhibited no hemolytic activity and preserved mammalian cell viability up to a concentration of 100 µg/mL.Conclusion: These findings underscore the substantial potential of Secapin as a potent agent against multidrug-resistant A. baumannii , showcasing its efficacy in both antibacterial and antibiofilm capacities. The favorable attributes of Secapin, characterized by its minimal hemolytic effects and high mammalian cell viability, position it as a prom, Hintergrund: Acinetobacter baumannii , bekannt für seine außergewöhnliche Multiresistenz und seine Rolle als häufiger nosokomialer Erreger, stellt eine Herausforderung für herkömmliche Antibiotikabehandlungen dar. Das Hauptziel dieser Studie war es, die Wirksamkeit von Secapin, einem antimikrobiellen Peptid, gegen multiresistente A. baumannii zu bewerten. Darüber hinaus wurden die Mechanismen, durch die Secapin seine antibakterielle und antibiofilmbildende Aktivitäten entfaltet, aufgeklärt.Methoden: Die antimikrobielle und antibiofilmbildende Wirksamkeit von Secapin gegen MDR A. baumannii wurde in einer Reihe von Experimenten untersucht. Die minimale Hemmkonzentration (MIC) und die minimale bakterizide Konzentration (MBC) von Secapin wurden unter Verwendung etablierter Protokolle bestimmt. Es wurde eine zeitabhängige Abtötungskinetik ermittelt, um die konzentrationsabhängige bakterizide Wirkung von Secapin zu bewerten. Darüber hinaus wurde die Fähigkeit von Secapin, die Bildung von Biofilmen zu hemmen und etablierte A. baumannii -Biofilme zu beseitigen, untersucht. Das hämolytische Potenzial wurde unter Verwendung von menschlichen roten Blutkörperchen bewertet, während die Lebensfähigkeit von Säugetierzellen bei verschiedenen Secapin-Konzentrationen untersucht wurde.Ergebnisse: Secapin zeigte eine starke bakterizide Aktivität bei geringen Konzentrationen mit einer MIC von 5 µg/mL und einer MBC von 10 µg/mL gegen MDR A. baumannii . Die zeitabhängige Abtötungskinetik bestätigte die konzentrationsabhängige Wirksamkeit von Secapin. Darüber hinaus zeigte Secapin die Fähigkeit, die Bildung von Biofilmen zu verhindern und etablierte A. baumannii -Biofilme zu eliminieren. Bemerkenswert ist, dass Secapin keine hämolytische Aktivität aufwies und die Lebensfähigkeit von Säugetierzellen bis zu einer Konzentration von 100 µg/mL aufrechterhielt.Fazit: Die Ergebnisse unterstreichen das erhebliche Potenzial von Secapin als wirksames Mittel gegen multiresistente A. baumannii sowohl

Item does not contain fulltext, Coronavirus disease 2019 (COVID-19) is reported to have long-term effects on cardiovascular health and physical functioning, even in the nonhospitalized population. The physiological mechanisms underlying these long-term consequences are however less well described. We compared cardiovascular risk factors, arterial stiffness, and physical functioning in nonhospitalized patients with COVID-19, at a median of 6 mo postinfection, versus age- and sex-matched controls. Cardiovascular risk was assessed using blood pressure and biomarker concentrations (amino-terminal pro-B-type-natriuretic-peptide, high-sensitive cardiac troponin I, C-reactive protein), and arterial stiffness was assessed using carotid-femoral pulse wave velocity. Physical functioning was evaluated using accelerometry, handgrip strength, gait speed and questionnaires on fatigue, perceived general health status, and health-related quality of life (hrQoL). We included 101 former patients with COVID-19 (aged 59 [interquartile range, 55-65] yr, 58% male) and 101 controls. At 175 [126-235] days postinfection, 32% of the COVID-19 group reported residual symptoms, notably fatigue, and 7% required post-COVID-19 care. We found no differences in blood pressure, biomarker concentrations, or arterial stiffness between both groups. Former patients with COVID-19 showed a higher handgrip strength (43 [33-52] vs. 38 [30-48] kg, P = 0.004) and less sleeping time (8.8 [7.7-9.4] vs. 9.8 [8.9-10.3] h/day, P < 0.001) and reported fatigue more often than controls. Accelerometry-based habitual physical activity levels, gait speed, perception of general health status, and hrQoL were not different between groups. In conclusion, one in three nonhospitalized patients with COVID-19 reports residual symptoms at a median of 6 mo postinfection, but we were unable to relate these symptoms to increases in cardiovascular risk factors, arterial stiffness, or physical dysfunction.NEW & NOTEWORTHY We examined cardiovascular and physical func

Contains fulltext : 292748.pdf (Publisher’s version ) (Open Access), BACKGROUND: Testosterone may be a possible modifiable risk factor for open-angle glaucoma (OAG) and intraocular pressure (IOP), but evidence has been scarce and conflicting. In this study we evaluated the association of testosterone and its genetic predisposition with incident (i) OAG, IOP, retinal nerve fiber layer (RNFL), and ganglion cell-inner plexiform layer (GCL +). METHODS: Participants aged 45-100 years were derived from the prospective, population-based Rotterdam Study. Ophthalmic examinations and serum testosterone measurements (including bioavailable and free testosterone) were performed from 1991 onwards. Follow-up took place every 4-5 years. A total of 187 out of 7898 participants were diagnosed with incident (i) OAG during follow-up. Genotyping was performed in 165 glaucoma cases and 6708 controls. We calculated sex-specific weighted genetic risk scores (GRS) for total and bioavailable testosterone. Associations with iOAG were analyzed using multivariable logistic regression. Associations with IOP, RNFL, and GCL + were analyzed with multivariable linear regression. Analyses were stratified on sex and adjusted for at least age, body mass index, and follow-up duration. RESULTS: In men, testosterone was not associated with iOAG. However, the GRS for higher total testosterone was associated with an increased iOAG risk (odds ratio [OR] with 95% confidence interval [95% CI]: 2.48 [1.18; 5.22], per unit). In women, higher values of bioavailable testosterone (2.05 [1.00; 4.18] per nmol/L) and free testosterone (1.79 [1.00; 3.20] per ng/dL) were significantly associated with increased risk of iOAG. Moreover, the GRS for higher bioavailable testosterone was associated with an increased iOAG risk (2.48 [1.09; 5.65], per unit). Higher bioavailable and free testosterone were adversely associated with IOP (0.58 [0.05; 1.10] per nmol/L and 0.47 [0.04; 0.90] per ng/dL). Higher total testosterone was inversely associated with peripapillary RNFL and GCL + (Beta [95% CI]

Contains fulltext : 297328.pdf (Publisher’s version ) (Closed access), BACKGROUND: Reference intervals of thyroid-stimulating hormone (TSH) and free thyroxine (FT(4)) are statistically defined by the 2·5-97·5th percentiles, without accounting for potential risk of clinical outcomes. We aimed to define the optimal healthy ranges of TSH and FT(4) based on the risk of cardiovascular disease and mortality. METHODS: This systematic review and individual participant data (IPD) meta-analysis identified eligible prospective cohorts through the Thyroid Studies Collaboration, supplemented with a systematic search via Embase, MEDLINE (Ovid), Web of science, the Cochrane Central Register of Controlled Trials, and Google Scholar from Jan 1, 2011, to Feb 12, 2017 with an updated search to Oct 13, 2022 (cohorts found in the second search were not included in the IPD). We included cohorts that collected TSH or FT(4), and cardiovascular outcomes or mortality for adults (aged ≥18 years). We excluded cohorts that included solely pregnant women, individuals with overt thyroid diseases, and individuals with cardiovascular disease. We contacted the study investigators of eligible cohorts to provide IPD on demographics, TSH, FT(4), thyroid peroxidase antibodies, history of cardiovascular disease and risk factors, medication use, cardiovascular disease events, cardiovascular disease mortality, and all-cause mortality. The primary outcome was a composite outcome including cardiovascular disease events (coronary heart disease, stroke, and heart failure) and all-cause mortality. Secondary outcomes were the separate assessment of cardiovascular disease events, all-cause mortality, and cardiovascular disease mortality. We performed one-step (cohort-stratified Cox models) and two-step (random-effects models) meta-analyses adjusting for age, sex, smoking, systolic blood pressure, diabetes, and total cholesterol. The study was registered with PROSPERO, CRD42017057576. FINDINGS: We identified 3935 studies, of which 53 cohorts fulfilled the inclusion criteria and 26 co

BACKGROUND: Five modifiable risk factors are associated with cardiovascular disease and death from any cause. Studies using individual-level data to evaluate the regional and sex-specific prevalence of the risk factors and their effect on these outcomes are lacking. METHODS: We pooled and harmonized individual-level data from 112 cohort studies conducted in 34 countries and 8 geographic regions participating in the Global Cardiovascular Risk Consortium. We examined associations between the risk factors (body-mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, current smoking, and diabetes) and incident cardiovascular disease and death from any cause using Cox regression analyses, stratified according to geographic region, age, and sex. Population-attributable fractions were estimated for the 10-year incidence of cardiovascular disease and 10-year all-cause mortality. RESULTS: Among 1,518,028 participants (54.1% of whom were women) with a median age of 54.4 years, regional variations in the prevalence of the five modifiable risk factors were noted. Incident cardiovascular disease occurred in 80,596 participants during a median follow-up of 7.3 years (maximum, 47.3), and 177,369 participants died during a median follow-up of 8.7 years (maximum, 47.6). For all five risk factors combined, the aggregate global population-attributable fraction of the 10-year incidence of cardiovascular disease was 57.2% (95% confidence interval [CI], 52.4 to 62.1) among women and 52.6% (95% CI, 49.0 to 56.1) among men, and the corresponding values for 10-year all-cause mortality were 22.2% (95% CI, 16.8 to 27.5) and 19.1% (95% CI, 14.6 to 23.6). CONCLUSIONS: Harmonized individual-level data from a global cohort showed that 57.2% and 52.6% of cases of incident cardiovascular disease among women and men, respectively, and 22.2% and 19.1% of deaths from any cause among women and men, respectively, may be attributable to five modifiable risk factors. (Funded by the

Cardiovascular disease is the leading cause of death in women and men globally, with most due to atherosclerotic cardiovascular disease (ASCVD). Despite progress during the last 30 years, ASCVD mortality is now increasing, with the fastest relative increase in middle-aged women. Missed or delayed diagnosis and undertreatment do not fully explain this burden of disease. Sex-specific factors, such as hypertensive disorders of pregnancy, premature menopause (especially primary ovarian insufficiency), and polycystic ovary syndrome are also relevant, with good evidence that these are associated with greater cardiovascular risk. This position statement from the European Atherosclerosis Society focuses on these factors, as well as sex-specific effects on lipids, including lipoprotein(a), over the life course in women which impact ASCVD risk. Women are also disproportionately impacted (in relative terms) by diabetes, chronic kidney disease, and auto-immune inflammatory disease. All these effects are compounded by sociocultural components related to gender. This panel stresses the need to identify and treat modifiable cardiovascular risk factors earlier in women, especially for those at risk due to sex-specific conditions, to reduce the unacceptably high burden of ASCVD in women.

Aims The underlying mechanisms of atrial fibrillation (AF) are largely unknown. Inflammation may underlie atrial remodelling. Autoimmune diseases, related to increased systemic inflammation, may therefore be associated with new-onset AF. Methods and results Participants from the population-based UK Biobank were screened for rheumatic fever, gastrointestinal autoimmune diseases, autoimmune diseases targeting the musculoskeletal system and connective tissues, and neurological autoimmune diseases. Between 2006 and 2022, participants were followed for incident AF. Cox proportional hazards regression analyses were performed to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) to quantify associations. 494 072 participants free from AF were included (median age 58.0 years, 54.8% women). After a median of 12.8 years, 27 194 (5.5%) participants were diagnosed with new-onset AF. Rheumatic fever without heart involvement (HR, 95% CI: 1.47, 1.26–1.72), Crohn’s disease (1.23, 1.05–1.45), ulcerative colitis (1.17, 1.06–1.31), rheumatoid arthritis (1.39, 1.28–1.51), polyarteritis nodosa (1.82, 1.04–3.09), systemic lupus erythematosus (1.82, 1.41–2.35), and systemic sclerosis (2.32, 1.57–3.44) were associated with a larger AF risk. In sex-stratified analyses, rheumatic fever without heart involvement, multiple sclerosis, Crohn’s disease, seropositive rheumatoid arthritis, psoriatic and enteropathic arthropathies, systemic sclerosis and ankylosing spondylitis were associated with larger AF risk in women, whereas only men showed a larger AF risk associated with ulcerative colitis. Conclusions Various autoimmune diseases are associated with new-onset AF, more distinct in women. Our findings elaborate on the pathophysiological differences in autoimmunity and AF risk between men and women.

Background and Aims: Fatty liver disease (FLD) has been associated with excess mortality. Screening for hepatic steatosis (HS) in patients with metabolic dysfunction is therefore recommended by several guidelines, despite a paucity of evidence on the clinical relevance of FLD in this specific subgroup. Approach and Results: We studied participants of an ongoing prospective cohort (the Rotterdam Study). Persons ≥65 years old were enrolled from 2009 to 2014 and were followed through 2018. Steatosis was assessed by ultrasound and liver stiffness (LS) by transient elastography. The association between HS and LS with mortality was assessed using Cox regression analysis adjusted for age, sex, education, smoking, individual components of metabolic syndrome (MetS), heart failure, coronary heart disease, and stroke. We included 4093 elderly participants (74.4 ± 6.6 years old; 42.7% male); 36.8% had ultrasound-based steatosis. During the median follow-up of 6.9 years, 793 participants died (29.6 per 1000 person-years). In the overall population, steatosis was not associated with mortality in multivariable analysis (adjusted HR [aHR], 0.87; 95% CI, 0.73–1.03). Findings were consistent across a range of clinically relevant subgroups, including age categories, sex, MetS, elevated liver enzymes, and cardiac disease. Sensitivity analyses showed similar results for mortality beyond 5 years of follow-up and cancer-related and cerebro-cardiovascular mortality. Furthermore, among participants with steatosis, higher LS (aHR, 1.04 per kPa; 95% CI, 0.95–1.14) was not associated with mortality. Conclusions: Presence of FLD was not associated with mortality in this cohort nor in a range of subgroups. This indicates that screening for FLD and/or fibrosis is unlikely to improve outcomes among the elderly population.

Background:The prevalence of type 2 diabetes is increasing rapidly, particularly among younger age groups. Estimates suggest that people with diabetes die, on average, 6 years earlier than people without diabetes. We aimed to provide reliable estimates of the associations between age at diagnosis of diabetes and all-cause mortality, cause-specific mortality, and reductions in life expectancy. Methods:For this observational study, we conducted a combined analysis of individual-participant data from 19 high-income countries using two large-scale data sources: the Emerging Risk Factors Collaboration (96 cohorts, median baseline years 1961–2007, median latest follow-up years 1980–2013) and the UK Biobank (median baseline year 2006, median latest follow-up year 2020). We calculated age-adjusted and sex-adjusted hazard ratios (HRs) for all-cause mortality according to age at diagnosis of diabetes using data from 1 515 718 participants, in whom deaths were recorded during 23·1 million person-years of follow-up. We estimated cumulative survival by applying age-specific HRs to age-specific death rates from 2015 for the USA and the EU. Findings: For participants with diabetes, we observed a linear dose–response association between earlier age at diagnosis and higher risk of all-cause mortality compared with participants without diabetes. HRs were 2·69 (95% CI 2·43–2·97) when diagnosed at 30–39 years, 2·26 (2·08–2·45) at 40–49 years, 1·84 (1·72–1·97) at 50–59 years, 1·57 (1·47–1·67) at 60–69 years, and 1·39 (1·29–1·51) at 70 years and older. HRs per decade of earlier diagnosis were similar for men and women. Using death rates from the USA, a 50-year-old individual with diabetes died on average 14 years earlier when diagnosed aged 30 years, 10 years earlier when diagnosed aged 40 years, or 6 years earlier when diagnosed aged 50 years than an individual without diabetes. Using EU death rates, the corresponding estimates

Item does not contain fulltext, Our purpose was to perform a systematic review to assess the prevalence of microvascular angina (MVA) among patients with stable symptoms in the absence of obstructive coronary artery disease (CAD). We performed a systematic review of the literature to group the prevalence of MVA, based on diagnostic pathways and modalities. We defined MVA using three definitions: (i) suspected MVA using non-invasive ischaemia tests; proportion of patients with non-obstructive CAD among patients with symptoms and a positive non-invasive ischaemia test result, (ii) suspected MVA using specific modalities for MVA; proportion of patients with evidence of impaired microvascular function among patients with symptoms and non-obstructive CAD, and (iii) definitive MVA; proportion of patients with positive ischaemia test results among patients with an objectified impaired microvascular dysfunction. We further examined the ratio of women-to-men for the different groups. Of the 4547 abstracts, 20 studies reported data on MVA prevalence. The median prevalence was 43% for suspected MVA using non-invasive ischaemia test, 28% for suspected MVA using specific modalities for MVA, and 30% for definitive MVA. Overall, more women were included in the studies reporting sex-specific data. The women-to-men ratio for included participants was 1.29. However, the average women-to-men ratio for the MVA cases was 2.50. In patients with stable symptoms of ischaemia in the absence of CAD, the prevalences of suspected and definitive MVA are substantial. The results of this study should warrant cardiologists to support, promote and facilitate the comprehensive evaluation of the coronary microcirculation for all patients with symptoms and non-obstructive CAD.

Contains fulltext : 282541.pdf (Publisher’s version ) (Open Access), AIMS: The contribution of sex hormones to micro- and macrovascular damage might differ among women and men. In particular, little is known about the association between sex hormones and small vessel disease. Therefore, we examined the association of total oestradiol, total testosterone, free-androgen index (FAI), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and androstenedione levels with micro- and macrovascular diseases. METHODS AND RESULTS: This cross-sectional study included 2950 women and 2495 men from the population-based Rotterdam Study. As proxy of microvascular damage, we measured diameters of retinal arterioles and venules. Markers of macrovascular damage included carotid intima-media thickness and carotid plaque, coronary artery calcification (CAC), and peripheral artery disease. Linear and logistic regression models were used and adjusted for age, cardiovascular risk factors, and years since menopause. Associations with microvasculature: In women, total testosterone [mean difference per 1-unit increase in natural-log transformed total testosterone (95% confidence interval, CI): 2.59 (0.08-5.09)] and androstenedione [4.88 (1.82-7.95)] and in men DHEAS [2.80 (0.23-5.37)] and androstenedione [5.83 (2.19-9.46)] were associated with larger venular caliber. Associations with markers of large vessel disease: In women, higher total testosterone [-0.29 (-0.56 to -0.03)], FAI [-0.33 (-0.56 to -0.10)], and androstenedione levels [-0.33 (-0.64 to -0.02)] were associated with lower CAC burden and FAI [odds ratio (95% CI): 0.82 (0.71-0.94)] was associated with lower prevalence of plaque. CONCLUSION: A more androgenic profile was associated with more microvascular damage in both women and men. Among women, however, higher androgen levels were also associated with less macrovascular damage. Our findings suggest that androgens might have distinct effects on the vasculature, depending on the vascular bed and stages of the atherosclerosis process.

Item does not contain fulltext, IMPORTANCE: Recent studies suggest that the diabetes drug metformin has a protective effect on open-angle glaucoma (OAG) and age-related macular degeneration (AMD). However, studies have not addressed the critical issue of confounding by indication, and associations have not been evaluated in a large prospective cohort. OBJECTIVE: To determine the association between diabetes medication and the common eye diseases OAG, AMD, and cataract and to evaluate their cumulative lifetime risks in a large cohort study. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included participants from 3 independent cohorts from the prospective, population-based Rotterdam Study between April 23, 1990, and June 25, 2014. Participants were monitored for incident eye diseases (OAG, AMD, cataract) and had baseline measurements of serum glucose. Data on diabetes medication use and data from ophthalmologic examinations were gathered. EXPOSURES: Type 2 diabetes (T2D) and the diabetes medications metformin, insulin, and sulfonylurea derivatives. MAIN OUTCOMES AND MEASURES: Diagnosis and cumulative lifetime risk of OAG, AMD, and cataract. RESULTS: This study included 11 260 participants (mean [SD] age, 65.1 [9.8]; 6610 women [58.7%]). T2D was diagnosed in 2406 participants (28.4%), OAG was diagnosed in 324 of 7394 participants (4.4%), AMD was diagnosed in 1935 of 10 993 participants (17.6%), and cataract was diagnosed in 4203 of 11 260 participants (37.3%). Untreated T2D was associated with a higher risk of OAG (odds ratio [OR], 1.50; 95% CI, 1.06-2.13; P = .02), AMD (OR, 1.35; 95% CI, 1.11-1.64; P = .003), and cataract (OR, 1.63; 95% CI, 1.39-1.92; P < .001). T2D treated with metformin was associated with a lower risk of OAG (OR, 0.18; 95% CI, 0.08-0.41; P < .001). Other diabetes medication (ie, insulin, sulfonylurea derivates) was associated with a lower risk of AMD (combined OR, 0.32; 95% CI, 0.18 to 0.55; P < .001). The cumulative lifetime risk of OAG was lower for individuals taking me

The current epidemics of cardiovascular and metabolic noncommunicable diseases have emerged alongside dramatic modifications in lifestyle and living environments. These correspond to changes in our ”modern” postwar societies globally characterized by rural-to-urban migration, modernization of agricultural practices, and transportation, climate change, and aging. Evidence suggests that these changes are related to each other, although the social and biological mechanisms as well as their interactions have yet to be uncovered. LongITools, as one of the 9 projects included in the European Human Exposome Network, will tackle this environmental health equation linking multidimensional environmental exposures to the occurrence of cardiovascular and metabolic noncommunicable diseases.

Background Both elevated and low resting heart rates are associated with atrial fibrillation (AF), suggesting a U-shaped relationship. However, evidence for a U-shaped causal association between genetically-determined resting heart rate and incident AF is limited. We investigated potential directional changes of the causal association between genetically-determined resting heart rate and incident AF. Method and results Seven cohorts of the AFGen consortium contributed data to this meta-analysis. All participants were of European ancestry with known AF status, genotype information, and a heart rate measurement from a baseline electrocardiogram (ECG). Three strata of instrumental variable-free resting heart rate were used to assess possible non-linear associations between genetically-determined resting heart rate and the logarithm of the incident AF hazard rate: <65; 65–75; and >75 beats per minute (bpm). Mendelian randomization analyses using a weighted resting heart rate polygenic risk score were performed for each stratum. We studied 38,981 individuals (mean age 59±10 years, 54% women) with a mean resting heart rate of 67±11 bpm. During a mean follow-up of 13±5 years, 4,779 (12%) individuals developed AF. A U-shaped association between the resting heart rate and the incident AF-hazard ratio was observed. Genetically-determined resting heart rate was inversely associated with incident AF for instrumental variable-free resting heart rates below 65 bpm (hazard ratio for genetically-determined resting heart rate, 0.96; 95% confidence interval, 0.94–0.99; p = 0.01). Genetically-determined resting heart rate was not associated with incident AF in the other two strata. Conclusions For resting heart rates below 65 bpm, our results support an inverse causal association between genetically-determined resting heart rate and incident AF.

Background: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. Objectives: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10−9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27). Results: Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. Conclusions: The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.

OBJECTIVE LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown. RESEARCH DESIGN AND METHODS We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses. RESULTS A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (b 5 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P 5 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P 5 0.04). CONCLUSIONS These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.