Subclassification of obesity for precision prediction of cardiometabolic diseases.

Obesity and cardiometabolic disease often, but not always, coincide. Distinguishing subpopulations within which cardiometabolic risk diverges from the risk expected for a given body mass index (BMI) may facilitate precision prevention of cardiometabolic diseases. Accordingly, we performed unsupervised clustering in four European population-based cohorts (N ≈ 173,000). We detected five discordant profiles consisting of individuals with cardiometabolic biomarkers higher or lower than expected given their BMI, which generally increases disease risk, in total representing ~20% of the total population. Persons with discordant profiles differed from concordant individuals in prevalence and future risk of major adverse cardiovascular events (MACE) and type 2 diabetes. Subtle BMI-discordances in biomarkers affected disease risk. For instance, a 10% higher probability of having a discordant lipid profile was associated with a 5% higher risk of MACE (hazard ratio in women 1.05, 95% confidence interval 1.03, 1.06, P = 4.19 × 10-10; hazard ratio in men 1.05, 95% confidence interval 1.04, 1.06, P = 9.33 × 10-14). Multivariate prediction models for MACE and type 2 diabetes performed better when incorporating discordant profile information (likelihood ratio test P < 0.001). This enhancement represents an additional net benefit of 4-15 additional correct interventions and 37-135 additional unnecessary interventions correctly avoided for every 10,000 individuals tested.

Healthy and unhealthy plant-based diets and the risk of cardiovascular diseases: The Rotterdam study and updated meta-analysis.

BACKGROUND: Consumption of more plant-based foods is gaining popularity, but the role of healthy versus unhealthy plant-based diets in cardiovascular disease (CVD) risk remains inconclusive. OBJECTIVES: We investigated associations of plant-based diet indices (PDIs) with incident CVDs in a prospective cohort study and conducted an updated meta-analysis. METHODS: We included 3507 men and 5345 women of the population-based Rotterdam Study. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) for CVD, coronary heart disease (CHD) and stroke with per SD increment of an overall PDI, healthy PDI (hPDI) and unhealthy PDI (uPDI), among men and women separately. We combined our findings with previously published effect estimates in an updated meta-analysis. RESULTS: We documented 2015 CVD cases (1231 CHD and 952 stroke) during 107,290 person-years follow-up. Among men, the PDI and hPDI were associated with a 7 % (HR 0.93, 95 % CI 0.87-0.99) and 8 % (HR 0.92, 95 % CI 0.86-0.98) lower CVD risk. Among women, there was evidence suggesting a U-shaped association of the PDI with stroke (pnon-linearity < 0.01). In meta-analyses including up to 43,067 incident CVD cases among 359,740 participants from nine studies, the PDI and hPDI, were associated with a lower CVD risk, while uPDI with a higher CVD risk (pooled HRs [95 % CI], per SD, PDI: 0.94 [0.91-0.97], I2 = 50.4 %; hPDI: 0.94 [0.91-0.98], I2 = 74.7 %; uPDI: 1.03 [1.01-1.06], I2 = 49.0 %). CONCLUSIONS: Our findings support recommendations to consume relatively more healthy plant-based foods for CVD prevention. Potential differences by sex and non-linear associations warrant further investigation.

Deep learning predicted perceived age is a reliable approach for analysis of facial ageing: A proof of principle study.

BACKGROUND: Perceived age (PA) has been associated with mortality, genetic variants linked to ageing and several age-related morbidities. However, estimating PA in large datasets is laborious and costly to generate, limiting its practical applicability. OBJECTIVES: To determine if estimating PA using deep learning-based algorithms results in the same associations with morbidities and genetic variants as human-estimated perceived age. METHODS: Self-supervised learning (SSL) and deep feature transfer (DFT) deep learning (DL) approaches were trained and tested on human-estimated PAs and their corresponding frontal face images of middle-aged to elderly Dutch participants (n = 2679) from a population-based study in the Netherlands. We compared the DL-estimated PAs with morbidities previously associated with human-estimated PA as well as genetic variants in the gene MC1R; we additionally tested the PA associations with MC1R in a new validation cohort (n = 1158). RESULTS: The DL approaches predicted PA in this population with a mean absolute error of 2.84 years (DFT) and 2.39 years (SSL). In the training-test dataset, we found the same significant (p < 0.05) associations for DL PA with osteoporosis, ARHL, cognition, COPD and cataracts and MC1R, as with human PA. We also found a similar but less significant association for SSL and DFT PAs (0.69 and 0.71 years per allele, p = 0.008 and 0.011, respectively) with MC1R variants in the validation dataset as that found with human, SSL and DFT PAs in the training-test dataset (0.79, 0.78 and 0.71 years per allele respectively; all p < 0.0001). CONCLUSIONS: Deep learning methods can automatically estimate PA from facial images with enough accuracy to replicate known links between human-estimated perceived age and several age-related morbidities. Furthermore, DL predicted perceived age associated with MC1R gene variants in a validation cohort. Hence, such DL PA techniques may be used instead of human estimations in perceived age studies thereby reducing time and costs.

Perceived Stress, Hair Cortisol and Hair Cortisone in Relation to Appetite-Regulating Hormones in Patients with Obesity.

INTRODUCTION: Stress predicts unhealthy eating, obesity, and metabolic deterioration, likely mediated by altered levels of appetite- and metabolism-regulating hormones. Yet, evidence regarding the association between long-term stress and levels of appetite-regulating hormones in humans is lacking. METHODS: We included 65 patients with obesity (44 women) to investigate the cross-sectional association of biological stress (scalp hair cortisol and cortisone) and psychological stress (Perceived Stress Scale) with overnight-fasted serum levels of the hormonal appetite regulators leptin, adiponectin, insulin, pancreatic polypeptide, gastric-inhibitory peptide, peptide tyrosine-tyrosine, cholecystokinin and agouti-related protein, adjusted for age, sex and body-mass-index. RESULTS: Hair cortisone and, in trend, hair cortisol were positively associated with cholecystokinin (p=0.003 and p=0.058, respectively). No other associations between stress measures and hormonal appetite regulators were observed. CONCLUSION: Long-term biological stress, measured using scalp hair glucocorticoid levels, is associated with elevated levels of circulating cholecystokinin, indicating a link between long-term stress and hormonal appetite signaling.

Arteriosclerotic Calcification and Atrial Fibrillation in the General Population: The Rotterdam Study.

Limited population-based data on the gender differences and association between arteriosclerotic calcification at different sites and atrial fibrillation (AF) exist. We aimed to investigate the (gender-specific) associations between arteriosclerotic calcification at different sites with the risk of AF in the general population. Arteriosclerotic calcification was quantified using computed tomography examinations between 2003 and 2006 in 2,259 participants free of AF from the population-based Rotterdam Study. Cox proportional hazards models, adjusted for cardiovascular risk factors, were used to assess the associations of volumes of coronary artery calcification (CAC), aortic arch calcification (AAC), extracranial and intracranial carotid arteries, vertebrobasilar arteries, and the aortic valve with incident AF. During a median follow-up of 8.6 years, 182 incident AF cases occurred. A larger CAC was associated with incident AF (hazard ratio [HR], 95% confidence interval [CI] 1.25 1.09 to 1.44, p = 0.0019). The gender-stratified analyses showed that larger CAC in men (HR 1.43, 95% CI 1.10 to 1.86, p = 0.0068) and larger AAC in women were associated with incident AF (HR1.44, 95% CI 1.04 to 2.01, p = 0.0299). In conclusion, CAC in the general population, especially in men, and AAC in women were significantly associated with new-onset AF. Our findings imply that interventions to lower arteriosclerotic calcification, particularly, CAC, carry potential for the prevention of AF in the general population, especially in men.

Genome-Wide Interaction Analyses of Serum Calcium on Ventricular Repolarization Time in 125 393 Participants.

BACKGROUND: Ventricular repolarization time (ECG QT and JT intervals) is associated with malignant arrhythmia. Genome-wide association studies have identified 230 independent loci for QT and JT; however, 50% of their heritability remains unexplained. Previous work supports a causal effect of lower serum calcium concentrations on longer ventricular repolarization time. We hypothesized calcium interactions with QT and JT variant associations could explain a proportion of the missing heritability. METHODS AND RESULTS: We performed genome-wide calcium interaction analyses for QT and JT intervals. Participants were stratified by their calcium level relative to the study distribution (top or bottom 20%). We performed a 2-stage analysis (genome-wide discovery [N=62 532] and replication [N=59 861] of lead variants) and a single-stage genome-wide meta-analysis (N=122 393, [European ancestry N=117 581, African ancestry N=4812]). We also calculated 2-degrees of freedom joint main and interaction and 1-degree of freedom interaction P values. In 2-stage and single-stage analyses, 50 and 98 independent loci, respectively, were associated with either QT or JT intervals (2-degrees of freedom joint main and interaction P value <5×10-8). No lead variant had a significant interaction result after correcting for multiple testing and sensitivity analyses provided similar findings. Two loci in the single-stage meta-analysis were not reported previously (SPPL2B and RFX6). CONCLUSIONS: We have found limited support for an interaction effect of serum calcium on QT and JT variant associations despite sample sizes with suitable power to detect relevant effects. Therefore, such effects are unlikely to explain a meaningful proportion of the heritability of QT and JT, and factors including rare variation and other environmental interactions need to be considered.

European Society of Cardiology: the 2023 Atlas of Cardiovascular Disease Statistics.

This report from the European Society of Cardiology (ESC) Atlas Project updates and expands upon the 2021 report in presenting cardiovascular disease (CVD) statistics for the ESC member countries. This paper examines inequalities in cardiovascular healthcare and outcomes in ESC member countries utilizing mortality and risk factor data from the World Health Organization and the Global Burden of Disease study with additional economic data from the World Bank. Cardiovascular healthcare data were collected by questionnaire circulated to the national cardiac societies of ESC member countries. Statistics pertaining to 2022, or latest available year, are presented. New material in this report includes contemporary estimates of the economic burden of CVD and mortality statistics for a range of CVD phenotypes. CVD accounts for 11% of the EU's total healthcare expenditure. It remains the most common cause of death in ESC member countries with over 3 million deaths per year. Proportionately more deaths from CVD occur in middle-income compared with high-income countries in both females (53% vs. 34%) and males (46% vs. 30%). Between 1990 and 2021, median age-standardized mortality rates (ASMRs) for CVD decreased by median >50% in high-income ESC member countries but in middle-income countries the median decrease was <12%. These inequalities between middle- and high-income ESC member countries likely reflect heterogeneous exposures to a range of environmental, socioeconomic, and clinical risk factors. The 2023 survey suggests that treatment factors may also contribute with middle-income countries reporting lower rates per million of percutaneous coronary intervention (1355 vs. 2330), transcatheter aortic valve implantation (4.0 vs. 153.4) and pacemaker implantation (147.0 vs. 831.9) compared with high-income countries. The ESC Atlas 2023 report shows continuing inequalities in the epidemiology and management of CVD between middle-income and high-income ESC member countries. These inequalities are exemplified by the changes in CVD ASMRs during the last 30 years. In the high-income ESC member countries, ASMRs have been in steep decline during this period but in the middle-income countries declines have been very small. There is now an important need for targeted action to reduce the burden of CVD, particularly in those countries where the burden is greatest.

Burden of risk factors in women and men with unrecognised myocardial infarction: a systematic review and meta-analysis.

AIMS: Unrecognised myocardial infarction (MI) is a MI that remains undetected in the acute phase and is associated with an unfavourable prognosis. With this systematic review and meta-analysis, we evaluated the burden of cardiovascular risk factors in individuals with unrecognised MI. METHODS AND RESULTS: We searched general population-based cohort studies diagnosing unrecognised MI by electrocardiogram or myocardial imaging up to 24 November 2023. Pooled mean differences (MD) or risk ratios (RR) with 95% confidence intervals (CI) were determined, and random-effects meta-analyses were performed. Fourteen cohort studies were included involving 200,450 individuals (mean age 62.8±9.9 years, 56.0% women), among which 4,322 (2.2%) experienced unrecognised MI (mean age 66.3±8.2 years, 47.8% women) and 4,653 (2.1%) recognised MI (mean age 68.5±7.3 years, 33.8% women). Compared to individuals without MI, those with unrecognised MI had higher body mass index (MD 0.27, 95% CI 0.16-0.39) and systolic blood pressure (MD 4.48, 95% CI 2.81-6.15), and higher prevalence of hypertension (RR 1.27, 95% CI 1.06-1.51) and diabetes mellitus (RR 1.67, 95% CI 1.36-2.06). Furthermore, individuals with unrecognised MI had lower prevalence of hypertension (RR 0.92, 95% CI 0.88-0.97) and diabetes mellitus (RR 0.80, 95% CI 0.70-0.92). CONCLUSION: Individuals with unrecognised MI are characterised by a substantial burden of metabolic risk factors. Our findings suggest insufficient recognition and management of cardiovascular risk factors among individuals with unrecognised MI.

Aortic stiffness: an age-related prognostic marker?

Aortic stiffness, a consequence of vascular aging, is an independent predictor of cardiovascular morbidity and mortality. However, the impact of age and sex on its predictive performance remains unclear. We have included 6046 individuals from the population-based Rotterdam study. Survival analyses were performed to investigate the impact of age and sex on the link between aortic stiffness and outcomes, including coronary heart disease (CHD), stroke, cardiovascular disease (CVD), cardiovascular and all-cause mortality. The added predictive value of aortic stiffness across age categories and by sex was assessed by using explained variation, Harrell's C index and Integrated Discrimination Improvement (IDI). Aortic stiffness was independently associated with all outcomes [hazard ratio (95% confidence interval; CI): 1.16 (1.04-1.22) for CHD, 1.09 (1.00-1.19) for stroke, 1.11 (1.05-1.18) for CVD, 1.14 (1.05-1.23) for cardiovascular mortality, 1.08 (1.03-1.13) for all-cause mortality]. The strength of the association between aortic stiffness and stroke, cardiovascular and all-cause mortality decreased significantly by advancing age. The variance of the outcome (R2) explained by aortic stiffness alone was noticeable in individuals younger than 60 years and negligible in the other age categories. The association of aortic stiffness and CHD was stronger in women than in men. Similarly, the difference in R2 between women and men was greater for CHD than for the other considered outcomes. Our findings suggest that the gain in explained variation caused by aortic stiffness for CVD and mortality might be limited to individuals younger than 60 years.

Antihypertensive Drugs for the Prevention of Atrial Fibrillation: A Drug Target Mendelian Randomization Study.

BACKGROUND: We investigated the potential impact of antihypertensive drugs for atrial fibrillation (AF) prevention through a drug target Mendelian randomization study to avoid the potential limitations of clinical studies. METHODS: Validated published single-nucleotide polymorphisms (SNPs) that mimic the action of 12 antihypertensive drug classes, including alpha-adrenoceptor blockers, adrenergic neuron blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, beta-adrenoceptor blockers, centrally acting antihypertensive drugs, calcium channel blockers, loop diuretics, potassium-sparing diuretics and mineralocorticoid receptor antagonists, renin inhibitors, thiazides and related diuretic agents, and vasodilators were used. We estimated, via their corresponding gene and protein targets, the downstream effect of these drug classes to prevent AF via systolic blood pressure using 2-sample Mendelian randomization analyses. The SNPs were extracted from 2 European genome-wide association studies for the drug classes (n=317 754; n=757 601) and 1 European genome-wide association study for AF (n=1 030 836). RESULTS: Drug target Mendelian randomization analyses supported the significant preventive causal effects of lowering systolic blood pressure per 10 mm Hg via alpha-adrenoceptor blockers (n=11 SNPs; odds ratio [OR], 0.34 [95% CI, 0.21-0.56]; P=2.74×10-05), beta-adrenoceptor blockers (n=17 SNPs; OR, 0.52 [95% CI, 0.35-0.78]; P=1.62×10-03), calcium channel blockers (n=49 SNPs; OR, 0.50 [95% CI, 0.36-0.70]; P=4.51×10-05), vasodilators (n=19 SNPs; OR, 0.53 [95% CI, 0.34-0.84]; P=7.03×10-03), and all 12 antihypertensive drug classes combined (n=158 SNPs; OR, 0.64 [95% CI, 0.54-0.77]; P=8.50×10-07) on AF risk. CONCLUSIONS: Our results indicated that lowering systolic blood pressure via protein targets of various antihypertensive drugs seems promising for AF prevention. Our findings inform future clinical trials and have implications for repurposing antihypertensive drugs for AF prevention.

The NOS1AP gene rs10494366 common genetic variant does not modify the risk of sudden cardiac death in users of digoxin.

AIMS: Common genetic variations in the nitric oxide synthase-1 adaptor protein (NOS1AP) gene are associated with QT-interval prolongation. In a previous study, we observed an association between the rs10494366 variant of this gene and an increased QT-interval shortening in digoxin users. As QT-interval shortening is a risk factor for sudden cardiac death (SCD), in this study, we investigated whether the association between digoxin use and risk of SCD differs in participants with different NOS1AP rs10494366 genotypes. METHODS: We included 11 377 individuals from the prospective population-based cohort of the Rotterdam Study. We used Cox proportional hazard regression analysis with digoxin as time-dependent exposure to estimate the associations between current digoxin use and the risk of SCD among different rs10494366 genotype groups in the adjusted models. We also studied whether such an association was dose-dependent, comparing high dosage (≥ 0.250 mg), moderate dosage (0.125 mg ≤ dose< 0.250 mg) and low dosage (< 0.125 mg) digoxin users with non-users. RESULTS: The median baseline age of the total study population was 62 (interquartile range [IQR] 58-71) years. The cumulative incidence of SCD was 4.1% (469 cases), and among them, 74 (15.7%) individuals were current digoxin users at the time of death, during a median follow-up of 11.5 (IQR 6.5-17) years. Current digoxin users had an increased risk of SCD (multivariable adjusted model hazard ratio [HR]: 3.07; 95% confidence interval [CI]: 2.38-3.98), with no significant differences between the three genotype groups. The adjusted HRs were 4.03 [95% CI: 1.98-8.21] in the minor homozygous GG, 3.46 [95% CI: 2.37-5.04] in the heterozygous TG and 2.56 [95%CI: 1.70-3.86] in the homozygous TT genotype groups. Compared to low- and moderate-dose, high-dose digoxin users with GG genotype had the highest risk of SCD (HR: 5.61 [95% CI: 1.34-23.47]). CONCLUSIONS: Current use of digoxin is associated with a significantly increased risk of SCD. The NOS1AP gene rs10494366 variant did not modify the digoxin-associated risk of SCD in a population of European ancestry.

Trends in population attributable fraction of modifiable risk factors for cardiovascular diseases across three decades.

AIMS: To evaluate temporal trends, across three decades, in the population attributable fractions (PAFs) of modifiable risk factors for 5-year risk of cardiovascular diseases (CVDs). METHODS AND RESULTS: Within population-based Rotterdam Study, we defined three time groups of individuals without established CVD at 'baseline' with a mean age of 70 years, and followed for five years: Epoch 1990s (1989-93, n = 6195), Epoch 2000s (1997-2001, n = 5572), and Epoch 2010s (2009-14, n = 5135). The prevalence of risk factors and related relative risks were combined to quantify PAFs. The PAF of the six risk factors combined for global CVD was 0.57 [95% confidence interval (CI) 0.47-0.65], 0.52 (0.39-0.62), and 0.39 (0.18-0.54) in three respective epochs. Hypertension contributed the highest PAF to global CVD in Epoch 1990s (0.37, 95% CI: 0.28-0.44) and 2000s (0.34, 95% CI: 0.22-0.43), while smoking was the largest contributor in Epoch 2010s (0.20, 95% CI: 0.06-0.32). Dyslipidaemia changed population-level coronary heart disease risk over time. For stroke, hypertension became a less significant contributor over time, but smoking became a larger contributor. For heart failure, all risk factors showed non-significant PAFs in Epoch 2010s. PAFs related to individual risk factor varied among women and men. CONCLUSION: Six modifiable risk factors to population-level global CVD risk decreased over time, but still explained 39% of total CVD in the latest decade. PAFs changed considerably for hypertension, dyslipidaemia, and smoking. Risk factors had different PAFs for different CVDs with pronounced sex differences.

The contribution of the individual cardiovascular risk factors to population cardiovascular disease (CVD) risk considerably changed over the past 3 decades, especially for hypertension, dyslipidaemia, and smoking.Traditional modifiable risk factors exerted declining contributions to population burden of total CVD over the past three decades, suggesting good progress in CVD prevention. Nonetheless, in the latest decade, unfavourable risk factors accounted for 39% of total CVD burden.Sex differences in the contributions of abdominal obesity, diabetes, and smoking to cardiovascular outcomes were observed.

Unraveling interindividual variation of trimethylamine N-oxide and its precursors at the population level.

Trimethylamine N-oxide (TMAO) is a circulating microbiome-derived metabolite implicated in the development of atherosclerosis and cardiovascular disease (CVD). We investigated whether plasma levels of TMAO, its precursors (betaine, carnitine, deoxycarnitine, choline), and TMAO-to-precursor ratios are associated with clinical outcomes, including CVD and mortality. This was followed by an in-depth analysis of their genetic, gut microbial, and dietary determinants. The analyses were conducted in five Dutch prospective cohort studies including 7834 individuals. To further investigate association results, Mendelian Randomization (MR) was also explored. We found only plasma choline levels (hazard ratio [HR] 1.17, [95% CI 1.07; 1.28]) and not TMAO to be associated with CVD risk. Our association analyses uncovered 10 genome-wide significant loci, including novel genomic regions for betaine (6p21.1, 6q25.3), choline (2q34, 5q31.1), and deoxycarnitine (10q21.2, 11p14.2) comprising several metabolic gene associations, for example, CPS1 or PEMT. Furthermore, our analyses uncovered 68 gut microbiota associations, mainly related to TMAO-to-precursors ratios and the Ruminococcaceae family, and 16 associations of food groups and metabolites including fish-TMAO, meat-carnitine, and plant-based food-betaine associations. No significant association was identified by the MR approach. Our analyses provide novel insights into the TMAO pathway, its determinants, and pathophysiological impact on the general population.

Plasma Extracellular MicroRNAs Associated With Cardiovascular Disease Risk Factors in Middle-Aged and Older Adults.

BACKGROUND: Extracellular microRNAs (miRNAs) are a class of noncoding RNAs that remain stable in the extracellular milieu, where they contribute to various physiological and pathological processes by facilitating intercellular signaling. Previous studies have reported associations between miRNAs and cardiovascular diseases (CVDs); however, the plasma miRNA signatures of CVD and its risk factors have not been fully elucidated at the population level. METHODS AND RESULTS: Plasma miRNA levels were measured in 4440 FHS (Framingham Heart Study) participants. Linear regression analyses were conducted to test the cross-sectional associations of each miRNA with 8 CVD risk factors. Prospective analyses of the associations of miRNAs with new-onset obesity, hypertension, type 2 diabetes, CVD, and all-cause mortality were conducted using proportional hazards regression. Replication was carried out in 1999 RS (Rotterdam Study) participants. Pathway enrichment analyses were conducted and target genes were predicted for miRNAs associated with ≥5 risk factors in the FHS. In the FHS, 6 miRNAs (miR-193b-3p, miR-122-5p, miR-365a-3p, miR-194-5p, miR-192-5p, and miR-193a-5p) were associated with ≥5 risk factors. This miRNA signature was enriched for pathways associated with CVD and several genes annotated to these pathways were predicted targets of the identified miRNAs. Furthermore, miR-193b-3p, miR-194-5p, and miR-193a-5p were each associated with ≥2 risk factors in the RS. Prospective analysis revealed 8 miRNAs associated with all-cause mortality in the FHS. CONCLUSIONS: These findings highlight associations between miRNAs and CVD risk factors that may provide valuable insights into the underlying pathogenesis of CVD.

Prediction of individual lifetime cardiovascular risk and potential treatment benefit: development and recalibration of the LIFE-CVD2 model to four European risk regions.

AIMS: The 2021 European Society of Cardiology prevention guidelines recommend the use of (lifetime) risk prediction models to aid decisions regarding initiation of prevention. We aimed to update and systematically recalibrate the LIFEtime-perspective CardioVascular Disease (LIFE-CVD) model to four European risk regions for the estimation of lifetime CVD risk for apparently healthy individuals. METHODS AND RESULTS: The updated LIFE-CVD (i.e. LIFE-CVD2) models were derived using individual participant data from 44 cohorts in 13 countries (687 135 individuals without established CVD, 30 939 CVD events in median 10.7 years of follow-up). LIFE-CVD2 uses sex-specific functions to estimate the lifetime risk of fatal and non-fatal CVD events with adjustment for the competing risk of non-CVD death and is systematically recalibrated to four distinct European risk regions. The updated models showed good discrimination in external validation among 1 657 707 individuals (61 311 CVD events) from eight additional European cohorts in seven countries, with a pooled C-index of 0.795 (95% confidence interval 0.767-0.822). Predicted and observed CVD event risks were well calibrated in population-wide electronic health records data in the UK (Clinical Practice Research Datalink) and the Netherlands (Extramural LUMC Academic Network). When using LIFE-CVD2 to estimate potential gain in CVD-free life expectancy from preventive therapy, projections varied by risk region reflecting important regional differences in absolute lifetime risk. For example, a 50-year-old smoking woman with a systolic blood pressure (SBP) of 140 mmHg was estimated to gain 0.9 years in the low-risk region vs. 1.6 years in the very high-risk region from lifelong 10 mmHg SBP reduction. The benefit of smoking cessation for this individual ranged from 3.6 years in the low-risk region to 4.8 years in the very high-risk region. CONCLUSION: By taking into account geographical differences in CVD incidence using contemporary representative data sources, the recalibrated LIFE-CVD2 model provides a more accurate tool for the prediction of lifetime risk and CVD-free life expectancy for individuals without previous CVD, facilitating shared decision-making for cardiovascular prevention as recommended by 2021 European guidelines.

The study introduces LIFE-CVD2, a new tool that helps predict the risk of heart disease over a person's lifetime, and highlights how where you live in Europe can affect this risk.Using health information from over 687 000 people, LIFE-CVD2 looks at things like blood pressure and whether someone smokes to figure out their chance of having heart problems later in life. Health information from another 1.6 million people in seven different European countries was used to show that it did a good job of predicting who might develop heart disease.Knowing your heart disease risk over your whole life helps doctors give you the best advice to keep your heart healthy. Let us say there is a 50-year-old woman who smokes and has a bit high blood pressure. Right now, she might not look like she is in danger. But with the LIFE-CVD2 tool, doctors can show her how making changes today, like lowering her blood pressure or stopping smoking, could mean many more years without heart problems. These healthy changes can make a big difference over many years.

Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People With Type 2 Diabetes.

OBJECTIVE: To identify genetic risk factors for incident cardiovascular disease (CVD) among people with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We conducted a multiancestry time-to-event genome-wide association study for incident CVD among people with T2D. We also tested 204 known coronary artery disease (CAD) variants for association with incident CVD. RESULTS: Among 49,230 participants with T2D, 8,956 had incident CVD events (event rate 18.2%). We identified three novel genetic loci for incident CVD: rs147138607 (near CACNA1E/ZNF648, hazard ratio [HR] 1.23, P = 3.6 × 10-9), rs77142250 (near HS3ST1, HR 1.89, P = 9.9 × 10-9), and rs335407 (near TFB1M/NOX3, HR 1.25, P = 1.5 × 10-8). Among 204 known CAD loci, 5 were associated with incident CVD in T2D (multiple comparison-adjusted P < 0.00024, 0.05/204). A standardized polygenic score of these 204 variants was associated with incident CVD with HR 1.14 (P = 1.0 × 10-16). CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

Long-Term Glucocorticoid Exposure and Incident Cardiovascular Diseases-The Lifelines Cohort.

CONTEXT: Long-term glucocorticoid levels in scalp hair (HairGCs), including cortisol and the inactive form cortisone, represent the cumulative systemic exposure to glucocorticoids over months. HairGCs have repeatedly shown associations with cardiometabolic and immune parameters, but longitudinal data are lacking. DESIGN: We investigated 6341 hair samples of participants from the Lifelines cohort study for cortisol and cortisone levels and associated these to incident cardiovascular diseases (CVD) during 5 to 7 years of follow-up. We computed the odds ratio (OR) of HairGC levels for incident CVD via logistic regression, adjusting for classical cardiovascular risk factors, and performed a sensitivity analysis in subcohorts of participants < 60 years and ≥ 60 years of age. We also associated HairGC levels to immune parameters (total leukocytes and subtypes). RESULTS: Hair cortisone levels (available in n = 4701) were independently associated with incident CVD (P < .001), particularly in younger individuals (multivariate-adjusted OR 4.21, 95% CI 1.91-9.07 per point increase in 10-log cortisone concentration [pg/mg], P < .001). All immune parameters except eosinophils were associated with hair cortisone (all multivariate-adjusted P < .05). CONCLUSION: In this large, prospective cohort study, we found that long-term cortisone levels, measured in scalp hair, represent a relevant and significant predictor for future CVD in younger individuals. These results highlight glucocorticoid action as possible treatment target for CVD prevention, where hair glucocorticoid measurements could help identify individuals that may benefit from such treatments.

Association between BMD and coronary artery calcification: an observational and Mendelian randomization study.

Observational studies have reported inconsistent associations between bone mineral density (BMD) and coronary artery calcification (CAC). We examined the observational association of BMD with CAC in 2 large population-based studies and evaluated the evidence for a potential causal relation between BMD and CAC using polygenic risk scores (PRS), 1- and 2-sample Mendelian randomization (MR) approaches. Our study populations comprised 1414 individuals (mean age 69.9 yr, 52.0% women) from the Rotterdam Study and 2233 individuals (mean age 56.5 yr, 50.9% women) from the Framingham Heart Study with complete information on CAC and BMD measurements at the total body (TB-), lumbar spine (LS-), and femoral neck (FN-). We used linear regression models to evaluate the observational association between BMD and CAC. Subsequently, we compared the mean CAC across PRSBMD quintile groups at different skeletal sites. In addition, we used the 2-stage least squares regression and the inverse variance weighted (IVW) model as primary methods for 1- and 2-sample MR to test evidence for a potentially causal association. We did not observe robust associations between measured BMD levels and CAC. These results were consistent with a uniform random distribution of mean CAC across PRSBMD quintile groups (P-value > .05). Moreover, neither 1- nor 2-sample MR supported the possible causal association between BMD and CAC. Our results do not support the contention that lower BMD is (causally) associated with an increased CAC risk. These findings suggest that previously reported epidemiological associations of BMD with CAC are likely explained by unmeasured confounders or shared etiology, rather than by causal pathways underlying both osteoporosis and vascular calcification processes.

Decreased bone mineral density, the determinant of osteoporosis, and increased coronary artery calcification are common in people at an advanced age and share some common risk factors. Some studies have reported a higher risk for coronary artery calcification in people with osteoporosis than in people without, whereas others failed to find evidence for this relationship. Recently, Mendelian randomization has emerged as an important epidemiological tool that offers a simple way to distinguish causation, minimizing the confounding present in observational studies, leveraging individual genetic data and the findings from robust genome-wide association studies. We combined data from the participants of both the Rotterdam Study and the Framingham Heart Study, and did not observe sufficient evidence for the association between bone mineral density at different skeletal sites and coronary artery calcification. Also, when using Mendelian randomization, we concluded there was no causal relation between bone deterioration and the build-up of calcium in the coronary arteries. Although more research is needed, we conclude that the associations between decreased bone mineral density and increased coronary artery calcification reported in previous studies are likely attributed to other confounders rather than a causal relationship between these traits.

Lifetime prevalence and associated factors of itch with skin conditions: atopic dermatitis, psoriasis and dry skin in individuals aged > 50†years.

BACKGROUND: Itch, common in dermatological conditions, is often accompanied by psychological distress and reduced quality of life. However, research on the prevalence and associated factors of itch with skin conditions in general populations is limited. OBJECTIVES: This cross-sectional study aimed to determine the lifetime prevalence of itch with skin conditions and to identify its associated factors in individuals aged > 50 years. METHODS: Participants from the Rotterdam Study, a population-based cohort, were interviewed to assess whether they had ever had an itchy skin condition, defining lifetime itch with skin conditions. Over 20 demographic, lifestyle, dermatological and nondermatological factors were recorded. Multivariable logistic regression analysis explored associations between these factors and itch with skin conditions, reported as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: In total, 5246 eligible participants were included (age range 51-100 years, median age 67; 56.0% women). The results revealed a -lifetime prevalence of 33.7% for itch with skin conditions. Factors significantly associated with itch were female sex (OR 1.26, 95% CI 1.11-1.43), body mass index (1.02, 1.01-1.03), self-reported atopic dermatitis (4.29, 3.74-4.92), presence of atopic dermatitis (1.97, 1.60-2.43), self--reported psoriasis (2.31, 1.77-3.01), presence of psoriasis (2.11, 1.55-2.87), self-reported dry skin (1.95, 1.73-2.20), self-reported asthma (1.40, 1.08-1.83), renal impairment (1.45, 1.17-1.79), and clinically relevant depressive (1.85, 1.52-2.25) and anxiety symptoms (1.36, 1.11-1.66). CONCLUSIONS: This study reveals a substantial one-third lifetime prevalence of itch with skin conditions in individuals aged > 50 years. Significant associations with diverse lifestyle, demographic, dermatological and, intriguingly, nondermatological factors, including renal impairment, imply additional contributors to induction or persistence of itch in individuals with skin conditions.