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Studies of self-reported coffee consumption and smoking on risk of dementia have shown results conflicting with two-sample Mendelian randomization studies. We tested the hypotheses that coffee consumption and smoking influence risk of dementia using observational and one-sample Mendelian randomization designs with individual level data. We included 114,551 individuals from two Danish general population cohorts (median age 58 years). First, we tested whether high self-reported coffee consumption/smoking were associated with risk of dementia. Second, whether genetically predicted high coffee consumption/smoking due to variation near CYP1A1/AHR/CHRNA3 genes were associated with risk of dementia. We observed 3,784 dementia events. Moderate self-reported coffee consumption was associated with low risk of all dementia and non-Alzheimer's dementia, with a similar trend for Alzheimer's disease. Genetically predicted high coffee consumption was associated with high risk of all dementia (hazard ratio [95% confidence interval] per +1 cup/day: 1.20 [1.01–1.42]), with a similar trend for non-Alzheimer's dementia (1.23 [0.95–1.53]). High self-reported smoking was associated with high risk of non-Alzheimer's dementia. High genetically predicted smoking was associated with a trend towards high risk of all dementia and Alzheimer's disease (hazard ratios per +1 pack-year: 1.04 [0.96–1.11]) and 1.06 [0.97–1.16]). Moderate self-reported coffee consumption was associated with low risk of all and non-Alzheimer's dementia, while high genetically predicted coffee consumption was associated with a trend towards the opposite. High self-reported smoking was associated with high risk of non-Alzheimer's dementia, with a similar trend for genetically predicted smoking on all dementia and Alzheimer's disease. [Display omitted] • Moderate self-reported coffee consumption was associated with low risk of dementia. • High genetic coffee consumption showed a trend towards high risk of some dementia. • High self-reported smoking was associated with some dementia. • High genetic smoking showed a trend towards high risk of dementia. • High coffee consumption and smoking are unlikely to protect against dementia. [ABSTRACT FROM AUTHOR]

The joint consensus panel of the European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) recently addressed present and future challenges in the laboratory diagnostics of atherogenic lipoproteins. Total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, and calculated non-HDL cholesterol (=total – HDL cholesterol) constitute the primary lipid panel for estimating risk of atherosclerotic cardiovascular disease (ASCVD) and can be measured in the nonfasting state. LDL cholesterol is the primary target of lipid-lowering therapies. For on-treatment follow-up, LDL cholesterol shall be measured or calculated by the same method to attenuate errors in treatment decisions due to marked between-method variations. Lipoprotein(a)-cholesterol is part of measured or calculated LDL cholesterol and should be estimated at least once in all patients at risk of ASCVD, especially in those whose LDL cholesterol decline poorly upon statin treatment. Residual risk of ASCVD even under optimal LDL-lowering treatment should be also assessed by non-HDL cholesterol or apolipoprotein B, especially in patients with mild-to-moderate hypertriglyceridemia (2–10 mmol/L). Non-HDL cholesterol includes the assessment of remnant lipoprotein cholesterol and shall be reported in all standard lipid panels. Additional apolipoprotein B measurement can detect elevated LDL particle numbers often unidentified on the basis of LDL cholesterol alone. Reference intervals of lipids, lipoproteins, and apolipoproteins are reported for European men and women aged 20–100 years. However, laboratories shall flag abnormal lipid values with reference to therapeutic decision thresholds. Image 1 • Total cholesterol, triglycerides, HDL cholesterol, LDL cholesterol, and calculated non-HDL cholesterol (=total – HDL cholesterol) constitute the primary lipid panel for estimating risk of atherosclerotic cardiovascular disease (ASCVD) and can be measured in the nonfasting state. • LDL cholesterol is the primary target of lipid-lowering therapies. • Lipoprotein(a)-cholesterol is part of measured or calculated LDL cholesterol and lipoprotein(a) should be measured at least once in all patients. • Residual risk of ASCVD even under optimal LDL-lowering treatment should be also assessed by non-HDL cholesterol or apolipoprotein B, especially in patients with mild-to-moderate hypertriglyceridemia (2-10 mmol/L). • Non-HDL cholesterol includes the assessment of remnant lipoprotein cholesterol and shall be reported in all standard lipid panels. • Laboratories shall flag abnormal lipid values with reference to therapeutic decision thresholds. [ABSTRACT FROM AUTHOR]

The association between thyroid stimulating hormone (TSH) and cardiovascular disease has mainly been determined using clinical categories of disease. We tested the hypothesis that TSH on a continuous scale is associated with risk of atrial fibrillation (AF), myocardial infarction (MI), stroke, heart failure (HF), aortic valve stenosis (AVS), and major adverse cardiovascular events (MACE) and whether these associations are likely to be causal. We first tested whether plasma TSH on a continuous scale was observationally associated with incident cardiovascular events in a prospective cohort study of 105,224 individuals from the Copenhagen General Population Study followed for a median 7 years. Next, we tested whether a genetic risk score weighted on TSH was associated with cardiovascular endpoints. Finally, using Mendelian randomization, we tested whether the observed associations were likely to be causal. Using restricted cubic splines, lower concentrations of TSH relative to the population median (=1.53 mIU/L) were associated with higher risk of AF, MI, stroke, HF, AVS, and MACE. Comparing individuals with TSH ≤5th percentile (≤0.54 mIU/L) versus >50th percentile (>1.53 mIU/L), hazard ratios (HRs) ranged from 1.12 (1.00–1.26) for stroke to 1.27 (1.11–1.46) for HF. Genetic risk estimates per standard deviation decrease in TSH were 1.28 (1.08–1.52) for AF, 1.35 (1.06–1.71) for MI, 1.06 (0.89–1.26) for stroke, 1.19 (0.94–1.52) for HF, 1.53 (1.03–2.26) for AVS, and 1.09 (0.97–1.23) for MACE. In 105,224 individuals from the general population low plasma TSH was observationally and genetically associated with increased risk of AF, MI, and AVS suggesting that these observations may reflect causal pathways. [Display omitted] • We tested the hypothesis that TSH was associated with cardiovascular disease (CVD). • 105,224 individuals from the general population were followed for a median of 7 years. • Observationally, TSH below the median was associated with increased risk of CVD. • Genetically, Mendelian randomization suggested possible causal associations. [ABSTRACT FROM AUTHOR]

The G188E, D9N, and N291S mutations in LPL increase TG, reduce HDL cholesterol, and increase risk of ischemic heart disease. The common S447X mutation may have opposite effects. We genotyped 8451 women and men from the Danish general population, and 854 women and men with ischemic heart disease. Participants carrying G188E, D9N, or N291S were excluded. Compared with non-carriers, female heterozygotes and homozygotes presented with a 0.11 and 0.18 mmol/l decrease in plasma TG (P=0.001 and P=0.37) and a 0.07 and 0.03 mmol/l increase in HDL cholesterol (P=0.001 and P=0.99). Male heterozygotes and homozygotes presented with a 0.20 and 0.41 mmol decrease in plasma TG (P<0.001 and P=0.06), which was twice that in women, and a 0.05 and 0.17 mmol/l increase in plasma HDL cholesterol (P=0.02 and P=0.04), respectively. In meta-analyses by gender, the S447X mutation was associated with a significant l7% reduction in risk of ischemic heart disease in men (OR=0.83; P=0.01), whereas risk was unaffected in women (OR=0.97; P=0.98). The S447X mutation is associated with anti-atherogenic effects on TG and HDL cholesterol in both genders, and with a moderate protective effect on risk of ischemic heart disease in men. [Copyright &y& Elsevier]

Sodium glucose co-transporter 2 (SGLT2)-inhibitors were developed as glucose-lowering drugs. Surprisingly, SGLT2-inhibitors also reduced risk of cardiovascular disease. The impact of SGLT2-inhibitors on lipids and lipoproteins is unclear, but an effect might contribute to the observed lower cardiovascular risk. We conducted a meta-analysis to examine this, overall and by dose, ethnicity, and drug type. PubMed, EMBASE and Web of Science were searched for randomized controlled trials examining all available SGLT2-inhibitors. Studies with available lipid measurements were included. Quantitative data synthesis was performed using random and fixed effects models. We identified 60 randomized trials, including 147,130 individuals. Overall, using random effects models, SGLT2-inhibitor treatment increased total cholesterol by 0.09 mmol/L (95% CI: 0.06, 0.13), low-density lipoprotein (LDL) cholesterol by 0.08 mmol/L (0.05, 0.10), and high-density lipoprotein (HDL) cholesterol by 0.06 mmol/L (0.05, 0.07), while it reduced triglycerides by 0.10 mmol/L (0.06, 0.14). Fixed effects estimates were similar but with smaller effect sizes for HDL cholesterol and triglycerides. For higher SGLT2-inhibitor doses, there was a nominally higher non-significant effect on lipids and lipoproteins. In Asian compared to non-Asian populations, a slightly larger increase in HDL cholesterol and a decrease in triglycerides were observed, but with similar results for total and LDL cholesterol. Treatment effects on lipids and lipoproteins were generally robust across different SGLT2-inhibitor drugs. In meta-analyses, SGLT2-inhibition increased total, LDL, and HDL cholesterol and decreased triglycerides. Effect sizes varied slightly by drug dose and ethnicity but were generally robust by drug type. [Display omitted] • SGLT2-inhibitor treatment increases total, LDL, and HDL cholesterol slightly. • SGLT2-inhibitor treatment lowers triglycerides slightly. • Higher vs. lower treatment dose had minimal influence on the results. • Results were generally robust across different types of SGLT2-inhibitors. • Overall, changes were modest and not likely to be of clinical relevance. [ABSTRACT FROM AUTHOR]

The PROMINENT trial, a cardiovascular outcome trial of the triglyceride- and remnant cholesterol-lowering agent pemafibrate, has shown neutral results despite reduction in plasma triglycerides and remnant cholesterol. We tested the hypothesis that absolute mass changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B explain the results of the PROMINENT trial. Among 108,431 individuals from the Copenhagen General Population Study (CGPS), those who met the key inclusion criteria of the PROMINENT trial were analyzed to mimic the trial design. Endpoint atherosclerotic cardiovascular disease (ASCVD) was cardiovascular death, myocardial infarction, ischemic stroke, and coronary revascularization as defined in PROMINENT. In the PROMINENT trial, treatment with pemafibrate resulted in -7 mg/dL (−0.18 mmol/L; -18 %) change in remnant cholesterol, +10 mg/dL (+0.26 mmol/L; +12 %) LDL cholesterol, and +5 mg/dL (+0.05 g/L; +5 %) apolipoprotein B. In the CGPS mimicking PROMINENT, the estimated hazard ratios for ASCVD were 0.97 (95 % confidence interval: 0.94–0.99) for a -7 mg/dL (−0.18 mmol/L) change in remnant cholesterol, 1.04 (1.01–1.07) for a +10 mg/dL (+0.26 mmol/L) change in LDL cholesterol, and 1.02 (1.01–1.03) for a +5 mg/dL (+0.05 g/L) change in apolipoprotein B. When combining absolute changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B, the estimated hazard ratio for ASCVD was 1.05 (0.96–1.14) in the CGPS mimicking PROMINENT compared to 1.03 (0.91–1.15) in the PROMINENT trial. Absolute mass changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B can explain results of the PROMINENT trial. The 3 mg/dL (0.08 mmol/L) higher total atherogenic cholesterol together with 5 mg/dL (0.05 g/L) higher apolipoprotein B seem to explain the trend toward more ASCVD in the pemafibrate arm. [Display omitted] • Absolute mass changes in remnant cholesterol, LDL cholesterol, and apo B can explain results of the PROMINENT trial. • To reduce ASCVD lipid lowering drugs, total atherogenic cholesterol and total number of atherogenic particles need to be reduced. • Understanding the potential for causing ASCVD, lipoproteins should be judged by their absolute mass of cholesterol content. [ABSTRACT FROM AUTHOR]

The apolipoprotein E(APOE) ϵ2/ϵ3/ϵ4 polymorphism plays a central role in lipid metabolism, vascular disease and dementia. The impact of the full range of structural genetic variation in APOE for lipids, lipoproteins and apolipoproteins and for vascular disease in the general population is not known. We systematically sequenced APOE in 10,296 individuals from the Copenhagen City Heart Study and genotyped nine rare variants (frequency≥2/10,296) in 95,227 individuals from the Copenhagen General Population Study. The UK Biobank was used for validation of common APOE variants. Rare mutations in APOE , predicted to be deleterious, are present in 1 in 257 individuals in the general population. In the meta-analysis, multifactorially adjusted hazard ratios (95% confidence intervals) for ϵ44 and ϵ22 versus ϵ33 were 1.15 (1.04–1.26) and 1.02 (0.83–1.24) for ischemic cerebrovascular disease (ICVD), 1.11 (1.04–1.19) and 0.94 (0.83–1.08) for ischemic heart disease (IHD) and 1.03 (0.89–1.17) and 1.49 (1.20–1.87) for peripheral arterial disease (PAD). A multifactorially and ϵ2/ϵ3/ϵ4 adjusted weighted allele score on the continuous scale including all common and rare structural variants showed that for individuals with genetically predicted high plasma apoE and remnant cholesterol the risk for PAD was increased. APOE variants with high apoE, triglycerides, and remnant cholesterol are associated with PAD, whereas common APOE variants with high LDL cholesterol, triglycerides and remnant cholesterol are associated with IHD. APOE variants with low apoE are associated with increased risk of ICVD. These findings highlight that both rare and common structural variations in APOE play a role in vascular disease. [Display omitted] • The APOE ϵ2/ϵ3/ϵ4 polymorphism plays a central role in lipid metabolism. • We sequenced APOE in 10,296 and genotyped rare variants in 95,227 individuals. • ϵ2-like variants are associated with peripheral arterial disease. • Variants with low apoE are associated with ischemic cerebrovascular disease. • Structural variations in APOE beyond the ϵ2 and ϵ4 alleles play a role. [ABSTRACT FROM AUTHOR]

Elevated remnant cholesterol and low-grade inflammation each cause atherosclerotic cardiovascular disease (ASCVD); however, it is unknown whether joint elevation of both factors confers the highest risk. We tested the hypothesis that dual elevated remnant cholesterol and low-grade inflammation marked by elevated C-reactive protein is associated with the highest risk of myocardial infarction, ASCVD, and all-cause mortality. The Copenhagen General Population Study randomly recruited white Danish individuals aged 20–100 years in 2003–2015 and followed them for a median 9.5 years. ASCVD was cardiovascular mortality, myocardial infarction, stroke, and coronary revascularization. In 103,221 individuals, we observed 2,454 (2.4%) myocardial infarctions, 5,437 (5.3%) ASCVD events, and 10,521 (10.2%) deaths. The hazard ratios increased with each of stepwise higher remnant cholesterol and stepwise higher C-reactive protein. In individuals with the highest tertile of both remnant cholesterol and C-reactive protein compared to individuals with the lowest tertile of both, the multivariable adjusted hazard ratios were 2.2 (95%CI:1.9–2.7) for myocardial infarction, 1.9 (1.7–2.2) for ASCVD, and 1.4 (1.3–1.5) for all-cause mortality. Corresponding values for only the highest tertile of remnant cholesterol were 1.6 (1.5–1.8), 1.4 (1.3–1.5), and 1.1 (1.0–1.1), and those for only the highest tertile of C-reactive protein were 1.7 (1.5–1.8), 1.6 (1.5–1.7), and 1.3 (1.3–1.4), respectively. There was no statistical evidence for interaction between elevated remnant cholesterol and elevated C-reactive protein on risk of myocardial infarction (p = 0.10), ASCVD (p = 0.40), or all-cause mortality (p = 0.74). Dual elevated remnant cholesterol and C-reactive protein confers the highest risk of myocardial infarction, ASCVD, and all-cause mortality, that is, compared to either of these two factors individually. [Display omitted] • Dual elevated remnant-C and CRP was associated with the highest risk of ASCVD. • ASCVD risk is particularly relevant if remnant-C is ≥ 0.8 mmol/L and CRP ≥1.5 mg/L. • ASCVD risk was double in the highest tertile of both compared to the lowest. [ABSTRACT FROM AUTHOR]

Abstract Background and aims We aimed to test the hypothesis that levels of total and low-density lipoprotein cholesterol are increased after Christmas and that the risk of hypercholesterolemia is increased after the Christmas holidays. Methods We conducted an observational study of 25,764 individuals from the Copenhagen General Population Study, Denmark, aged 20–100 years. Main outcome measures were mean total and LDL cholesterol levels. Hypercholesterolemia was defined as total cholesterol >5 mmol/L (>193 mg/dL) or LDL-cholesterol >3 mmol/L (>116 mg/dL). Results Mean levels of total and LDL cholesterol increased in individuals examined in summer through December and January. Compared with individuals examined in May–June, those examined in December–January had 15% higher total cholesterol levels (p < 0.001). The corresponding value for LDL cholesterol was 20% (p < 0.001). Of the individuals attending the study during the first week of January, immediately after the Christmas holidays, 77% had LDL cholesterol above 3 mmol/L (116 mg/dL) and 89% had total cholesterol above 5 mmol/L (193 mg/dL). In individuals attending the Copenhagen General Population Study in the first week of January, the multivariable adjusted odds ratio of hypercholesterolemia was 6.0 (95% confidence interval 4.2–8.5) compared with individuals attending the study during the rest of the year. Conclusions Celebrating Christmas is associated with higher levels of total and LDL cholesterol and a higher risk of hypercholesterolemia in individuals in the general population. Thus, a diagnosis of hypercholesterolemia should not be made around Christmas, and our results stress the need for re-testing such patients later and certainly prior to initiation of cholesterol-lowering treatment. Graphical abstract Image 1 Highlights • Celebrating Christmas is associated with higher levels of total and LDL cholesterol. • Celebrating Christmas is associated with a higher risk of hypercholesterolemia. • A diagnosis of hypercholesterolemia should not be made around Christmas. [ABSTRACT FROM AUTHOR]

In 2022, the European Atherosclerosis Society (EAS) published a new consensus statement on lipoprotein(a) [Lp(a)], summarizing current knowledge about its causal association with atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. One of the novelties of this statement is a new risk calculator showing how Lp(a) influences lifetime risk for ASCVD and that global risk may be underestimated substantially in individuals with high or very high Lp(a) concentration. The statement also provides practical advice on how knowledge about Lp(a) concentration can be used to modulate risk factor management, given that specific and highly effective mRNA-targeted Lp(a)-lowering therapies are still in clinical development. This advice counters the attitude: "Why should I measure Lp(a) if I can't lower it?". Subsequent to publication, questions have arisen relating to how the recommendations of this statement impact everyday clinical practice and ASCVD management. This review addresses 30 of the most frequently asked questions about Lp(a) epidemiology, its contribution to cardiovascular risk, Lp(a) measurement, risk factor management and existing therapeutic options. [Display omitted] [ABSTRACT FROM AUTHOR]

Background and aims We estimated the extent of undertreatment and overtreatment with cholesterol-lowering therapy according to European guidelines in individuals in the Danish general population without ischemic cardiovascular disease and diabetes. Methods We examined 92,348 such individuals aged 35–100 years recruited from 2004 through 2014 in the Copenhagen General Population Study. Each individual was assigned their 10-year risk of fatal cardiovascular disease according to the European SCORE chart based on age, sex, smoking, total cholesterol, and systolic blood pressure. European guidelines recommend cholesterol-lowering therapy definitely at ≥10% risk and LDL cholesterol ≥1.8 mmol/L, definitely at 5–9% risk and LDL cholesterol ≥2.5 mmol/L, possibly at 1–4% risk and LDL cholesterol ≥3 mmol/L, but not at <1% risk. Results 3858 individuals had ≥10% risk, 16,255 had 5–9% risk, 49,131 had 1–4% risk, and 23,104 had <1% 10-year risk of fatal cardiovascular disease. In these groups, 81%, 86%, 93%, and 99% did not receive cholesterol-lowering therapy. Definite undertreatment and overtreatment according to guidelines were found in 19% and 0.2% or in 187,660 and 1570 per million 35–100 year olds without ischemic cardiovascular disease and diabetes. If definite and possible undertreatment and overtreatment were combined, the corresponding numbers were 52% and 3% or 519,416 and 29,194 per million. Conclusions In the Danish general population, ∼190,000 per million 35–100 year olds without ischemic cardiovascular disease and diabetes are not treated to LDL cholesterol goals according to European guidelines. Conversely, ∼1600 per million received cholesterol-lowering therapy without endorsement in European guidelines. [ABSTRACT FROM AUTHOR]

Up to 40% of all dementia cases may be preventable, primarily by treating or acting on well-established cardiovascular risk factors such as diabetes, hypertension, smoking, and physical inactivity. Whether physical inactivity is associated with risk of non-Alzheimer's dementia – a disease influenced by cardiovascular risk factors – and whether a given association differs for physical activity in leisure time and at work remains unknown. We conducted a prospective cohort study including 117,616 individuals from the Copenhagen General Population Study and the Copenhagen City Heart Study with up to 43 years of follow-up. Multifactorially adjusted hazard ratios for low versus high physical activity at leisure time was 1.60 (95% confidence interval 1.40–1.83) for non-Alzheimer's dementia and 0.94 (0.80–1.11) for Alzheimer's disease. Corresponding values for non-Alzheimer's dementia after additional adjustment for physical activity at work or apolipoprotein E (APOE) genotype were 1.60 (1.40–1.83) and 1.82 (1.34–2.15). Multifactorially and APOE adjusted hazard ratios for high versus low physical activity at work were 1.50 (1.10–2.05) for non-Alzheimer's dementia and 1.62 (1.14–2.31) for Alzheimer's disease. When combining the two types of physical activity, physical activity in leisure time had the strongest relationship with risk of non-Alzheimer's dementia. Physical inactivity in leisure time was associated with increased risk of non-Alzheimer's dementia, independent of modifiable risk factors and physical activity at work. The present study thus provides evidence for public health advice on physical activity in leisure time for the vascular part of dementia. [Display omitted] • Prospective study including 117,616 individuals from the general Danish population. • Up to 43 years of follow-up with no losses to follow-up. • Low leisure physical activity associates with high risk of non-Alzheimer's dementia. • Leisure versus work physical activity is superior in predicting risk. • Public health advice on physical activity may prevent non-Alzheimer's dementia. [ABSTRACT FROM AUTHOR]

Background and aims Triglyceride-rich lipoproteins are causally associated with high risk of ischemic heart disease (IHD), and apolipoprotein E (apoE) has a central role in their plasma clearance. While both quantitative and qualitative changes of apoE are established causes of rare dyslipidemia syndromes, it remains unclear whether plasma levels of apoE are associated with risk of IHD in the general population. Methods We tested whether plasma levels of apoE at enrollment were associated with future risk of IHD and myocardial infarction (MI) in 91,695 individuals from the general population. Results Multifactorially adjusted hazard ratios (HRs) for highest versus lowest apoE tertile were 1.15 (1.04–1.27) for IHD and 1.16 (1.00–1.36) for MI in men, and 0.94 (0.84–1.05) and 1.04 (0.85–1.26) in women. These associations were attenuated by adjustments for triglyceride levels. Corresponding HRs for highest versus lowest apoE tertile in ε33 carriers were 1.18 (1.03–1.36) for IHD and 1.21 (0.98–1.49) for MI in men, and 0.91 (0.78–1.06) and 0.93 (0.71–1.21) in women. Thus, the present associations were independent of APOE genotype. Conclusion These findings suggest that high plasma levels of apoE are associated with IHD in men but not in women. Triglyceride-rich lipoproteins may partly explain these associations. [ABSTRACT FROM AUTHOR]

Elevated concentrations of Lipoprotein (a) [Lp(a)] is an inherited, causal risk factor for atherosclerotic cardiovascular disease (ASCVD). This study aims to investigate the clinical utility for patients, and the economic benefit to healthcare systems and society of measuring Lp(a) concentrations more widely today. We conducted a structured literature review to identify the economic and health benefits and costs of measuring the Lp(a) concentration, potential barriers hindering the uptake of the measure, and potential solutions to address them. These findings were then discussed in an advisory board attended by experts and patient organisations. It was found that if Lp(a) concentration is measured more widely today, patients, healthcare system and society would experience clinical and economic benefits even before specific Lp(a) lowering pharmacological treatments become available. Furthermore , a wider uptake of the Lp(a) measurement would support the development of epidemiological data. For Lp(a) measurement to be more widely used, key barriers which are hindering its uptake need to be addressed. These include i) the perception that the measure may have limited clinical value, ii) lack of awareness on Lp(a), iii) lack of data on the CV benefit of reducing Lp(a), iv) technical and clinical guidelines barriers, and v) healthcare system barriers. Scientific communities and industry should collaborate to address technical challenges and deficiencies in clinical guidelines. However, policy intervention will be crucial for national ASCVD plans to acknowledge the importance of Lp(a). [Display omitted] [ABSTRACT FROM AUTHOR]

We tested the hypotheses (i) that elevated lipoprotein(a) is causally associated with both mitral and aortic valve calcification and disease, and (ii) that aortic valve calcification mediates the effect of elevated lipoprotein(a) on aortic valve stenosis. From the Copenhagen General Population study, we included 12,006 individuals who underwent cardiac computed tomography to measure mitral and aortic valve calcification and 85,884 to examine risk of heart valve disease. Participants had information on plasma lipoprotein(a) and genetic instruments associated with plasma lipoprotein(a) to investigate potential causality. At age 70–79 years, 29% and 54% had mitral and aortic valve calcification, respectively. For 10-fold higher lipoprotein(a) levels, multifactorially adjusted odds ratios for mitral and aortic valve calcification were 1.26 (95% confidence interval: 1.13–1.41) and 1.62 (1.48–1.77). For mitral and aortic valve stenosis, corresponding hazard ratios were 0.93 (95%CI:0.40–2.15, 19 events) and 1.54 (1.38–1.71, 1158 events), respectively. For ≤23 versus ≥36 kringle IV type 2 number of repeats, the age and sex adjusted odds ratios for mitral and aortic valve calcification were 1.53 (1.18–1.99) and 2.23 (1.81–2.76). For carriers versus non-carriers of LPA rs10455872, odds ratios for mitral and aortic valve calcification were 1.33 (1.13–1.57) and 1.86 (1.64–2.13). For aortic valve stenosis, 31% (95%CI:16%–76%) of the effect of lipoprotein(a) was mediated through calcification. Elevated lipoprotein(a) was genetically and observationally associated with mitral and aortic valve calcification and aortic valve stenosis. Aortic valve calcification mediated 31% of the effect of elevated lipoprotein(a) on aortic valve stenosis. [Display omitted] • More than 12,000 individuals were CT scanned for heart valve calcification. • More than 85,000 individuals were followed in nationwide registries. • Lipoprotein(a) is causally associated with mitral valve calcification. • Lipoprotein(a) causes aortic valve stenosis but not mitral valve regurgitation. • Aortic valve calcification mediates 31% lipoprotein(a) effect on aortic stenosis. [ABSTRACT FROM AUTHOR]

Objective We tested the hypothesis that moderately elevated plasma creatinine levels and decreased levels of estimated glomerular filtration rate (eGFR) are associated with increased risk of myocardial infarction, ischemic heart disease, and early death in the general population. Methods We studied 10,489 individuals with a plasma creatinine measurement and calculated eGFR from the Danish general population, of which 1498 developed myocardial infarction, 3001 ischemic heart disease, and 7573 died during 32 years follow-up. Results Cumulative incidences of myocardial infarction and ischemic heart disease as a function of age increased with increasing levels of creatinine, and survival decreased (log-rank trends: <0.001). The median survival age was 78.7 (95%CI: 78.0–79.2) years for persons with creatinine levels <90th percentile, 78.1 (76.3–79.5) years for 90th–94th percentiles, and 74.8 (72.8–76.7) years for ≥95th percentile. Hazard ratios for myocardial infarction and plasma creatinine levels of 90th–94th percentiles and ≥95th percentile versus <50th percentile were 2.06 (95%CI: 1.67–2.56) and 1.90 (1.56–2.31) adjusted for gender and age, and 1.35 (1.09–1.68) and 1.11 (0.90–1.36) adjusted multifactorially, respectively. Corresponding estimates for creatinine and ischemic heart disease were 1.57 (1.33–1.85) and 1.64 (1.42–1.89) adjusted for gender and age, and 1.16 (0.98–1.37) and 1.11 (0.95–1.29) adjusted multifactorially. Finally, corresponding values for early death were 1.18 (1.06–1.32) and 1.43 (1.30–1.57), and 0.97 (0.87–1.09) and 1.13 (1.02–1.24), respectively. Low eGFR did not associate consistently with increased risk of these endpoints. Conclusion In the general population, moderately elevated plasma creatinine was associated with increased risk of myocardial infarction, ischemic heart disease, and early death, while low eGFR was not. [ABSTRACT FROM AUTHOR]

Apolipoprotein E (apoE) plays a crucial role in cholesterol metabolism, and high levels of apoE in plasma are associated with cardiovascular disease and all-cause mortality. We aimed to assess if HIV is independently associated with high plasma apoE and to determine HIV-related risk factors for high plasma apoE. We included 661 people with HIV (PWH) from the Copenhagen Comorbidity in HIV (COCOMO) study with available measurement of plasma apoE. COCOMO participants were frequency matched 1:1 on age and sex with controls from the Copenhagen General Population Study. High plasma apoE was defined as levels above the 90th percentile (66.2 mg/L). The association between HIV and high plasma apoE was assessed using logistic regression models. Among PWH, both linear and logistic regression models were used to determine HIV-specific risk factors for high plasma apoE. Mean age was 52 years and 89 % were male. Median plasma apoE was 49.0 mg/L in PWH and 43.3 mg/L in controls, p < 0.001. HIV was associated with higher plasma apoE after adjusting for potential confounders, including triglycerides (odds ratio 2.14 [95 % CI: 1.39–3.29], p < 0.001). In PWH, higher plasma apoE was associated with a previous AIDS-defining condition in linear models before adjustment for triglycerides and integrase strand transfer inhibitor use in fully adjusted linear models. PWH had higher plasma apoE than controls even after adjusting for triglycerides. Further studies are needed to elucidate the clinical impact of high plasma apoE in PWH. [Display omitted] • People with HIV had higher plasma apoE levels than controls from the general population. • Plasma apoE was consistently higher in people with HIV when stratifying by triglyceride levels. • People with HIV also had higher apoE/apoB ratio compared to controls. • Thus, the association between HIV status and apoE was independent of changes in other lipid parameters. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Zinc Finger Protein 202 (ZNF202) is a transcriptional repressor of genes affecting the vascular endothelium as well as lipid metabolism. A phenotype associated with genetic variation in ZNF202 is presently unknown. We tested the hypothesis that a common variant in ZNF202, A154V, predicts risk of ischemic heart disease (IHD), myocardial infarction (MI), and ischemic cerebrovascular disease (ICVD). Methods and results: We conducted a prospective study of more than 9000 individuals from the general population with 24 years follow-up. In women, age-adjusted hazard ratios in heterozygotes and homozygotes versus non-carriers were 1.2 (95% CI: 1.0–1.5, P =0.04) and 1.5 (1.1–2.1, P =0.007) for IHD, 1.5 (1.1–2.1; P =0.01) and 1.7 (1.1–2.8, P =0.02) for MI, and 1.3 (1.0–1.8, P =0.07) and 1.3 (0.8–2.1; P =0.33) for ICVD. Adjustments for lipids and lipoproteins did not alter these hazard ratios substantially. Genotype did not predict risk in men. Finally, results for IHD were borderline significant (P =0.06) in an independent case–control study including 933 patients and 8068 controls. Conclusion: This is the first study to suggest that ZNF202 could be a new candidate gene for IHD and MI in the general population. [Copyright &y& Elsevier]

Children with a growth trajectory of overweight have higher levels of cardiovascular disease (CVD) risk factors than children with a normal-weight trajectory. However, less is known about how trajectories of body mass index (BMI) across the rest of the BMI spectrum relate to CVD risk factors and whether adult BMI affects these associations. Our aim was to examine associations between childhood BMI trajectories and adult CVD risk factors. We included 2466 individuals with childhood weights and heights (ages 6–14) from the Copenhagen School Health Records Register and adult CVD risk factors (ages 20–81) from the Copenhagen City Heart Study. Associations between childhood BMI trajectories identified by latent class modelling and CVD risk factors were examined using generalized linear regression analyses with and without adjustment for adult BMI. Normal-weight and overweight were defined by growth references from the Centers for Disease Control and Prevention. We identified four childhood trajectories within the normal-weight spectrum and one trajectory of overweight. Compared to the trajectory with the lowest BMI level, several higher BMI trajectories were associated with worse circumference, HDL and glucose homeostasis in adulthood. The highest trajectory was additionally associated with higher total cholesterol and triglycerides. When adjusting for adult BMI, the higher BMI trajectories had lower waist circumference, blood pressure and triglycerides. Trajectories of BMI within the normal-weight range and in the overweight range are associated with a worse CVD risk profile than in the lowest BMI trajectory, and these associations are modifiable by growth after childhood. Image 1 • Five different trajectories of body mass index from ages 6-14 were identified in a population of 2466 Danish children. • The trajectory above overweight cutoffs was associated with the worst cardiovascular disease risk factor profile. • Even trajectories below overweight cutoffs had worse cardiovascular disease risk factor profiles than the lowest trajectory. • These associations appeared to be modifiable by body mass index development after age 14. [ABSTRACT FROM AUTHOR]

Smoking causes cardiovascular disease. AHRR hypomethylation at the cg05575921 site is associated with active and former smoking status at baseline, and cumulative amount of tobacco smoked. We tested the hypothesis that AHRR cg05575921 hypomethylation as an epigenetic marker of smoking history predicts the risk of myocardial infarction in former smokers. We included 10,510 individuals with methylation extent measurements and information on smoking status from the Copenhagen City Heart Study (CCHS), a prospective, cohort study of the general population carried out from 1991 to 2003. The endpoint myocardial infarction was retrieved from the national Danish Patient Registry and the national Danish Causes of Death Registry. For individuals in the 1st (lowest) quartile of AHRR cg05575921 methylation (≤49% methylation extent), 99% were ever smokers at baseline (active and former smokers combined) compared to 42% in the 4th (highest) quartile (>62% methylation extent). For former smokers, the cumulative incidence of myocardial infarction was higher in the lowest methylation extent (1st-50th percentile) compared to the highest methylation extent (51st-100th percentile). Compared to never smokers, the multivariable adjusted subhazard ratio for myocardial infarction was 1.09 (95%CI:0.88–1.35) for former smokers with the highest methylation degree, 1.38 (1.06–1.80) for active smokers with the highest methylation extent, 1.39 (1.08–1.78) for former smokers with the lowest methylation extent, and 1.61 (1.35–1.92) for active smokers with the lowest methylation extent. AHRR cg05575921 hypomethylation as an epigenetic marker of smoking history predicts risk of myocardial infarction, particularly in former smokers. Further, AHRR hypomethylation, regardless of smoking status, was associated with increased risk of myocardial infarction. Image 1 • AHRR cg05575921 hypomethylation is an epigenetic marker of smoking history. • AHRR cg05575921 hypomethylation predicted risk of myocardial infarction. • AHRR hypomethylation was associated with increased risk of myocardial infarction after adjustment for smoking. [ABSTRACT FROM AUTHOR]

During fat tolerance tests, plasma triglycerides increase while high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and intermediate-density lipoprotein (IDL) cholesterol decrease. However, it is unknown whether triglyceride content increases and cholesterol content decreases in HDL and LDL + IDL fractions following normal meals in the general population. Therefore, we tested the hypothesis that triglyceride content increases while cholesterol content decreases in HDL and LDL + IDL fractions following normal meals. In this cross-sectional study, we included 25,656 individuals aged 20–100 years, all without lipid-lowering therapy at examination and selected for metabolomic profiling from the Copenhagen General Population Study. Triglyceride and cholesterol content of 14 lipoprotein fractions weas measured using nuclear magnetic resonance (NMR) spectroscopy. Time since last meal was recorded by the examiner immediately before blood sampling. Following normal meals in age and sex-adjusted analyses and when compared with fasting levels, plasma triglycerides were higher for up to 5–6 h, and triglyceride content was higher for up to 6–7 h in HDL fractions, for up to 6–7 h in LDL + IDL fractions, and for up to 5–6 h in very-low-density lipoprotein (VLDL) fractions. Further, plasma cholesterol was lower for up to 2–3 h, and cholesterol content was lower for up to 0–1 h in HDL fractions and for up to 4–5 h in LDL + IDL fractions, while cholesterol content was higher for up to 4–5 h in VLDL fractions. Following normal meals, triglyceride content increases while cholesterol content decreases in HDL and LDL + IDL fractions. [Display omitted] • Following normal meals, triglyceride content increases in HDL and LDL + IDL fractions. • Following normal meals, cholesterol content decreases in HDL and LDL + IDL fractions. • Following normal meals, cholesterol content decreases in the smallest HDL fractions. • Following normal meals, cholesterol content increases in the largest VLDL fractions. • Results were similar in women and men, and in individuals with low and high BMI. [ABSTRACT FROM AUTHOR]

Increased concentrations of calculated remnant cholesterol in triglyceride-rich lipoproteins are observationally and genetically, causally associated with increased risk of ischemic heart disease; however, when measured directly, the fraction of plasma cholesterol present in remnant particles is unclear. We tested the hypothesis that a major fraction of plasma cholesterol is present in remnant lipoproteins in individuals in the general population. We examined 9293 individuals from the Copenhagen General Population Study using nuclear magnetic resonance spectroscopy measurements of total cholesterol, free- and esterified cholesterol, triglycerides, phospholipids, and particle concentration. Fourteen subclasses of decreasing size and their lipid constituents were analysed: six subclasses were very low-density lipoprotein (VLDL), one intermediate-density lipoprotein (IDL), three low-density lipoprotein (LDL), and four subclasses were high-density lipoprotein (HDL). Remnant lipoproteins were VLDL and IDL combined. Mean nonfasting cholesterol concentration was 1.84 mmol/L (72 mg/dL) for remnants, 2.01 mmol/L (78 mg/dL) for LDL, and 1.83 mmol/L (71 mg/dL) for HDL, equivalent to remnants containing 32% of plasma total cholesterol. Of 14 lipoprotein subclasses, large LDL and IDL were the ones containing most of plasma cholesterol. The plasma concentration of remnant cholesterol was from ∼1.4 mmol/L (54 mg/dL) at age 20 to ∼1.9 mmol/L (74 mg/dL) at age 60. Corresponding values for LDL cholesterol were from ∼1.5 mmol/L (58 mg/dL) to ∼2.1 mmol/L (81 mg/dL). Using direct measurements, one third of total cholesterol in plasma was present in remnant lipoproteins, that is, in the triglyceride-rich lipoproteins IDL and VLDL. Image 1 • Using NMR, a third of plasma cholesterol was present in remnant lipoproteins. • Of 14 lipoprotein subclasses, large LDL and IDL were containing most cholesterol. • Directly measured remnant cholesterol was highest in older individuals. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To compare the new Patient Rule Induction Method (PRIM) Score and common clinical practice with the Framingham Point Score for classification of individuals with respect to coronary heart disease (CHD) risk. Methods and results: PRIM Score and the Framingham Point Score were estimated for 11,444 participants from the Copenhagen City Heart Study. Gender specific cumulative incidences and 10 year absolute CHD risks were estimated for subsets defined by age, total cholesterol, high-density lipoprotein (HDL) cholesterol, blood pressure, diabetes and smoking categories. PRIM defined seven mutually exclusive subsets in women and men, with cumulative incidences of CHD from 0.01 to 0.22 in women, and from 0.03 to 0.26 in men. PRIM versus Framingham Point Score found 11% versus 4% of all women, and 31% versus 35% of all men to have 10 year CHD risks>20%. Among women≥65 years with hypertension and/or with diabetes, 10 year CHD risk>20% was found for 100% with PRIM scoring but for only 18% with the Framingham Point Score. Conclusion: Compared to the PRIM Score, common clinical practice with the Framingham Point Score underestimates CHD risk in women, especially in women≥65 years with hypertension and/or with diabetes. [ABSTRACT FROM AUTHOR]

Abstract: Objective: We tested the hypotheses that Prothrombin G20210A heterozygosity associate with increased risk of venous thromboembolism (VTE), ischemic heart disease (IHD), and ischemic cerebrovascular disease (ICVD) in the general population and re-tested risk of IHD and ICVD in two case-control studies. Methods: 9231 individuals from the Danish general population were followed for VTE (VTE=DVT+PE), deep venous thrombosis (DVT), pulmonary embolism (PE), IHD, myocardial infarction (MI), ICVD, and ischemic stroke (IS) for a median of 24 years. Case-control studies included 2461 IHD cases and 867 ICVD cases. Results: In the general population, Prothrombin G20210A heterozygotes had1.3 (95% CI:0.6–2.9) fold risk for VTE, 0.6 (0.2–2.0) for DVT, 1.7(0.6–4.8) for PE, 1.5(1.1–2.1) for IHD, 1.7(1.1–2.7) for MI, 1.1(0.6–1.9) for ICVD, and 1.1(0.5–2.1) for IS compared to non-carriers. Double heterozygotes for Prothrombin G20210A and Factor V Leiden versus double non-carriers had a multifactorially adjusted hazard ratio for IHD of 6.0(2.0–19). In case-control studies, multifactorially adjusted odds ratios for Prothrombin G20210A heterozygotes versus non-carriers were 2.0(1.1–3.4) for IHD, 2.0(1.0–3.8) for MI, 1.4(0.7–3.1) for ICVD, and 2.1(0.8–5.4) for IS. Conclusion: Prothrombin G20210A heterozygosity alone and in combination with Factor V Leiden R506Q heterozygosity predicts 1.5 and 6.0 fold risk of IHD compared to non-carriers. [Copyright &y& Elsevier]