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Background and Aims Anti-inflammatory trials have shown considerable benefits for cardiovascular disease. High neutrophil counts, an easily accessible inflammation biomarker, are associated with atherosclerosis in experimental studies. This study aimed to investigate the associations between neutrophil counts and risk of nine cardiovascular endpoints using observational and genetic approaches. Methods Observational studies were conducted in the Copenhagen General Population Study (n = 101 730). Genetic studies were firstly performed using one-sample Mendelian randomization (MR) with individual-level data from the UK Biobank (n = 365 913); secondly, two-sample MR analyses were performed using summary-level data from the Blood Cell Consortium (n = 563 085). Outcomes included ischaemic heart disease, myocardial infarction, peripheral arterial disease, ischaemic cerebrovascular disease, ischaemic stroke, vascular-related dementia, vascular dementia, heart failure, and atrial fibrillation. Results Observational analyses showed associations between high neutrophil counts with high risks of all outcomes. In the UK Biobank, odds ratios (95% confidence intervals) per 1-SD higher genetically predicted neutrophil counts were 1.15 (1.08, 1.21) for ischaemic heart disease, 1.22 (1.12, 1.34) for myocardial infarction, and 1.19 (1.04, 1.36) for peripheral arterial disease; similar results were observed in men and women separately. In two-sample MR, corresponding estimates were 1.14 (1.05, 1.23) for ischaemic heart disease and 1.11 (1.02, 1.20) for myocardial infarction; multiple sensitivity analyses showed consistent results. No robust associations in two-sample MR analyses were found for other types of leucocytes. Conclusions Observational and genetically determined high neutrophil counts were associated with atherosclerotic cardiovascular disease, supporting that high blood neutrophil counts is a causal risk factor for atherosclerotic cardiovascular disease. [ABSTRACT FROM AUTHOR]

Aims It is unclear whether higher triglyceride metabolism per se contributes to mortality separate from elevated triglyceride-rich lipoproteins and body mass index. This study tested the hypotheses that higher triglyceride metabolism, measured as higher plasma glycerol and β-hydroxybutyrate, is associated with increased all-cause, cardiovascular, cancer, and other mortality. Methods and results This study included 30 000 individuals nested within 109 751 individuals from the Copenhagen General Population Study. During a median follow-up of 10.7 years, 9897 individuals died (2204 from cardiovascular, 3366 from cancer, and 2745 from other causes), while none were lost to follow-up. In individuals with glycerol >80 µ mol/L (highest fourth) vs. individuals with glycerol <52 µ mol/L (lowest fourth), the multivariable adjusted hazard ratio for all-cause mortality was 1.31 (95% confidence interval 1.22–1.40). In individuals with β-hydroxybutyrate >154 µ mol/L (highest fourth) vs. individuals with β-hydroxybutyrate <91 µ mol/L (lowest fourth), the multivariable adjusted hazard ratio for all-cause mortality was 1.18 (1.11–1.26). Corresponding values for higher plasma glycerol and β-hydroxybutyrate were 1.37 (1.18–1.59) and 1.18 (1.03–1.35) for cardiovascular mortality, 1.24 (1.11–1.39) and 1.16 (1.05–1.29) for cancer mortality, and 1.45 (1.28–1.66) and 1.23 (1.09–1.39) for other mortality, respectively. Results were robust to exclusion of first years of follow-up, to stratification for covariates including plasma triglycerides and body mass index, and to further adjustments. Conclusion This study observed an increased risk of all-cause, cardiovascular, cancer, and other mortality with higher triglyceride metabolism. This was not explained by higher plasma triglycerides and body mass index. The hypothesis studied in the present paper should be further validated by isotope flux studies. [ABSTRACT FROM AUTHOR]

Aims Whether high body mass index (BMI) causally influences development and prognosis of heart failure has implications for clinical practice. We tested the hypotheses that high BMI causally influences heart failure incidence and mortality. Methods and results Using observational and Mendelian randomization causal, genetic analyses, we studied 106 121 individuals from the Copenhagen General Population Study, 18 407 from the Copenhagen City Heart Study, and 977 323 from publicly available databases. In observational analyses in the Copenhagen studies with 10 years of median follow-up, multivariable adjusted hazard ratios per 1 kg/m2 increment of BMI were 1.06 (95% confidence interval: 1.05–1.07; P < 0.001; n = 124 528; events = 6589) for heart failure incidence, 1.04 (1.03–1.06; P < 0.001; n = 124 528; events = 1237) for heart failure mortality, and 1.01 (1.00–1.01; P < 0.001; n = 124 528; events = 24 144) for all-cause mortality. In genetic analyses in the Copenhagen studies, the age and sex adjusted causal risk ratios per 1 kg/m2 increment of BMI were 1.19 (1.05–1.36; P = 0.008; n = 118 200; events = 6541) for heart failure incidence, 1.27 (0.82–1.98; P = 0.28; n = 118 200; events = 889) for heart failure mortality, and 1.11 (1.02–1.22; P = 0.022; n = 118 200; events = 16 814) for all-cause mortality. Finally, combining genetic data from the Copenhagen studies, the Genetic Investigation of ANthropometric Traits, the Heart Failure Molecular Epidemiology for Therapeutic Targets, and the UK Biobank, the unadjusted causal risk ratios per 1 kg/m2 increment of BMI were 1.39 (1.27–1.52; P < 0.001; n = 1 095 523; events = 53 850) for heart failure incidence, 1.18 (1.00–1.38; P = 0.05; n = 576 853; events = 2373) for heart failure mortality, and 1.02 (1.00–1.04; P = 0.03; n = 576 853; events = 44 734) for all-cause mortality. Conclusion High BMI causally increases the risk of both heart failure incidence and mortality. [ABSTRACT FROM AUTHOR]

Background and Objective: High lipoprotein(a) is a genetically determined causal risk factor for cardiovascular disease, and 20% of the adult population has high levels (ie, >42 mg/dL, >88 nmol/L). We investigated whether early life lipoprotein(a) levels measured in cord blood may serve as a proxy for neonatal venous blood levels, whether lipoprotein(a) birth levels (ie, cord or venous) predict levels later in life, and whether early life and parental levels correlate. Methods: The Compare study is a prospective cohort study of newborns (N = 450) from Copenhagen, Denmark, including blood sampling of parents. Plasma lipoprotein(a) was measured in cord blood (N = 402), neonatal venous blood (N = 356), and at 2 (N = 320) and 15 months follow-up (N = 148) of infants, and in parents (N = 705). Results: Mean lipoprotein(a) levels were 2.2 (95% CI, 1.9-2.5), 2.4 (2.0-2.7), 4.1 (3.4-4.9), and 14.6 (11.4-17.9) mg/dL in cord, neonatal venous, and 2- and 15-month venous samples, respectively. Lipoprotein(a) levels in cord blood correlated strongly with neonatal venous blood levels (R² = 0.95, P < 0.001) and neonatal levels correlated moderately with 2- and 15-month levels (R² = 0.68 and 0.67, both P < 0.001). Birth levels ≥ 90th percentile predicted lipoprotein(a) > 42 mg/dL at 15 months with positive predictive values of 89% and 85% for neonatal venous and cord blood. Neonatal and infant levels correlated weakly with parental levels, most pronounced at 15 months (R² = 0.22, P < 0.001). Conclusions: Lipoprotein(a) levels are low in early life, cord blood may serve as a proxy for neonatal venous blood, and birth levels ≥ 90th percentile can identify newborns at risk of developing high levels. [ABSTRACT FROM AUTHOR]

Aims We tested the hypothesis that the contrasting results for the effect of high-dose, purified omega-3 fatty acids on the prevention of atherosclerotic cardiovascular disease (ASCVD) in two randomized trials, Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) vs. Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridaemia (STRENGTH), can be explained by differences in the effect of active and comparator oils on lipid traits and C-reactive protein. Methods and results In the Copenhagen General Population Study (CGPS) with 106 088 individuals, to mimic trial designs we analysed those who met key inclusion criteria in REDUCE-IT (n  = 5684; ASCVD = 852) and STRENGTH (n  = 6862; ASCVD = 697). Atherosclerotic cardiovascular disease incidence was followed for the median durations of REDUCE-IT and STRENGTH (4.9 and 3.5 years), respectively. When combining changes in plasma triglycerides, low-density lipoprotein cholesterol, and C-reactive protein observed in the active oil groups of the original studies, estimated hazard ratios for ASCVD in the CGPS were 0.96 [95% confidence interval 0.93–0.99] mimicking REDUCE-IT and 0.94 (0.91–0.98) mimicking STRENGTH. In the comparator oil groups, corresponding hazard ratios were 1.07 (1.04–1.10) and 0.99 (0.98–0.99). Combining these results, the active oil vs. comparator oil hazard ratio was 0.88 (0.84–0.93) in the CGPS mimicking REDUCE-IT compared to 0.75 (0.68–0.83) in the REDUCE-IT. The corresponding hazard ratio was 0.96 (0.93–0.99) in the CGPS mimicking STRENGTH compared to 0.99 (0.90–1.09) in STRENGTH. Conclusion The contrasting results of REDUCE-IT vs. STRENGTH can partly be explained by a difference in the effect of comparator oils (mineral vs. corn), but not of active oils [eicosapentaenoic acid (EPA) vs. EPA + docosahexaenoic acid], on lipid traits and C-reactive protein. The unexplained additional 13% risk reduction in REDUCE-IT likely is through other effects of EPA or mineral oil. [ABSTRACT FROM AUTHOR]

Recent advances in human genetics, together with a large body of epidemiologic, preclinical, and clinical trial results, provide strong support for a causal association between triglycerides (TG), TG-rich lipoproteins (TRL), and TRL remnants, and increased risk of myocardial infarction, ischaemic stroke, and aortic valve stenosis. These data also indicate that TRL and their remnants may contribute significantly to residual cardiovascular risk in patients on optimized low-density lipoprotein (LDL)-lowering therapy. This statement critically appraises current understanding of the structure, function, and metabolism of TRL, and their pathophysiological role in atherosclerotic cardiovascular disease (ASCVD). Key points are (i) a working definition of normo- and hypertriglyceridaemic states and their relation to risk of ASCVD, (ii) a conceptual framework for the generation of remnants due to dysregulation of TRL production, lipolysis, and remodelling, as well as clearance of remnant lipoproteins from the circulation, (iii) the pleiotropic proatherogenic actions of TRL and remnants at the arterial wall, (iv) challenges in defining, quantitating, and assessing the atherogenic properties of remnant particles, and (v) exploration of the relative atherogenicity of TRL and remnants compared to LDL. Assessment of these issues provides a foundation for evaluating approaches to effectively reduce levels of TRL and remnants by targeting either production, lipolysis, or hepatic clearance, or a combination of these mechanisms. This consensus statement updates current understanding in an integrated manner, thereby providing a platform for new therapeutic paradigms targeting TRL and their remnants, with the aim of reducing the risk of ASCVD. [ABSTRACT FROM AUTHOR]

Aims  We tested the hypothesis that high directly measured remnant cholesterol is associated with increased risk of ischaemic heart disease (IHD) and myocardial infarction (MI) in the general population. We also explored whether directly measured vs. calculated remnant cholesterol is superior in identifying individuals at increased risk. Methods and results  Overall, 16 207 individuals from the Copenhagen General Population Study with both directly measured and calculated remnant cholesterol, both representing cholesterol content in triglyceride-rich lipoproteins, were followed up for 14 years to analyse the risk for IHD and MI. For directly measured and calculated remnant cholesterol, hazard ratios for individuals with concentrations ≥95th percentile vs. <40th percentile were 1.75 (95% confidence interval 1.42–2.15) and 1.76 (1.42–2.17) for IHD and 2.05 (1.50–2.80) and 1.93 (1.40–2.66) for MI. Compared to individuals with both directly measured and calculated remnant cholesterol <80th percentile (75% of the whole population), those with only directly measured remnant cholesterol ≥80th percentile (5%) had hazard ratios of 1.42 (1.15–1.75) for IHD and 1.83 (1.35–2.47) for MI. Corresponding hazard ratios for individuals with only calculated remnant cholesterol ≥80th percentile (5%) were 1.14 (0.91–1.44) and 1.14 (0.80–1.62), respectively, and corresponding hazard ratios for individuals with both directly measured and calculated remnant cholesterol ≥80th percentiles (15%) were 1.48 (1.30–1.68) and 1.67 (1.38–2.01), respectively. In individuals with high directly measured or high calculated remnant cholesterol, the median directly measured remnant cholesterol was 1.9 and 1.5 mmol/L, the median plasma triglycerides were 2.0 and 2.7 mmol/L, and the median plasma apolipoprotein B was 132 and 142 mg/dL, respectively. Conclusions  Directly measured vs. calculated remnant cholesterol identifies 5% overlooked individuals in the general population with cholesterol-rich, triglyceride-poor remnants and 1.8-fold increased risk of MI. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide and challenges the capacity of health care systems globally. Atherosclerosis is the underlying pathophysiological entity in two-thirds of patients with CVD. When considering that atherosclerosis develops over decades, there is potentially great opportunity for prevention of associated events such as myocardial infarction and stroke. Subclinical atherosclerosis has been identified in its early stages in young individuals; however, there is no consensus on how to prevent progression to symptomatic disease. Given the growing burden of CVD, a paradigm shift is required—moving from late management of atherosclerotic CVD to earlier detection during the subclinical phase with the goal of potential cure or prevention of events. Studies must focus on how precision medicine using imaging and circulating biomarkers may identify atherosclerosis earlier and determine whether such a paradigm shift would lead to overall cost savings for global health. [Display omitted] • Early-stage subclinical atherosclerosis can be identified in young individuals, but evidence-based strategies are needed to prevent progression of disease and clinical events. • Precision medicine using imaging and circulating biomarkers could facilitate early identification of atherosclerosis and the development of curative interventions. • A paradigm shift based on these principles could reduce the global burden of CVD with enormous implications for population health. [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]

It is unclear whether elevated low-density lipoprotein (LDL) triglycerides are associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). This study tested the hypothesis that elevated LDL triglycerides are associated with an increased risk of ASCVD and of each ASCVD component individually. The study investigators used the Copenhagen General Population Study, which measured LDL triglycerides in 38,081 individuals with a direct automated assay (direct LDL triglycerides) and in another 30,208 individuals with nuclear magnetic resonance (NMR) spectroscopy (NMR LDL triglycerides). Meta-analyses aggregated the present findings with previously reported results. During a median follow-up of 3.0 and 9.2 years, respectively, 872 and 5,766 individuals in the 2 cohorts received a diagnosis of ASCVD. Per 0.1 mmol/L (9 mg/dL) higher direct LDL triglycerides, HRs were 1.26 (95% CI: 1.17-1.35) for ASCVD, 1.27 (95% CI: 1.16-1.39) for ischemic heart disease, 1.28 (95% CI: 1.11-1.48) for myocardial infarction, 1.22 (95% CI: 1.08-1.38) for ischemic stroke, and 1.38 (95% CI: 1.21-1.58) for peripheral artery disease. Corresponding HRs for NMR LDL triglycerides were 1.26 (95% CI: 1.20-1.33), 1.33 (95% CI: 1.25-1.41), 1.41 (95% CI: 1.31-1.52), 1.13 (95% CI: 1.05-1.23), and 1.26 (95% CI: 1.10-1.43), respectively. The foregoing results were not entirely statistically explained by apolipoprotein B levels. In meta-analyses for the highest quartile vs the lowest quartile of LDL triglycerides, random-effects risk ratios were 1.50 (95% CI: 1.35-1.66) for ASCVD (4 studies; 71,526 individuals; 8,576 events), 1.62 (95% CI: 1.37-1.93) for ischemic heart disease (6 studies; 107,538 individuals; 9,734 events), 1.30 (95% CI: 1.13-1.49) for ischemic stroke (4 studies; 78,026 individuals; 4,273 events), and 1.53 (95% CI: 1.29-1.81) for peripheral artery disease (4 studies; 107,511 individuals; 1,848 events). Elevated LDL triglycerides were robustly associated with an increased risk of ASCVD and of each ASCVD component individually in 2 prospective cohort studies and in meta-analyses of previous and present studies combined. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Women with previous preeclampsia have an increased risk of coronary artery disease later in life.Objectives: This study aimed to determine the prevalence of coronary atherosclerosis in younger women with previous preeclampsia in comparison with women from the general population.Methods: Women aged 40-55 years with previous preeclampsia were matched 1:1 on age and parity with women from the general population. Participants completed an extensive questionnaire, a clinical examination, and a coronary computed tomography angiography (CTA). The main study outcome was the prevalence of any coronary atherosclerosis on coronary CTA or a calcium score >0 in case of a nondiagnostic coronary CTA.Results: A total of 1,417 women, with a mean age of 47 years, were included (708 women with previous preeclampsia and 709 control subjects from the general population). Women with previous preeclampsia were more likely to have hypertension (284 [40.1%] vs 162 [22.8%]; P < 0.001), dyslipidemia (338 [47.7%] vs 296 [41.7%]; P = 0.023), diabetes mellitus (24 [3.4%] vs 8 [1.1%]; P = 0.004), and high body mass index (27.3 ± 5.7 kg/m2 vs 25.0 ± 4.2 kg/m2; P < 0.001). Cardiac computed tomography was performed in all women. The prevalence of any coronary atherosclerosis was higher in the preeclampsia group (193 [27.4%] vs 141 [20.0%]; P = 0.001) with an OR: 1.41 (95% CI: 1.08-1.85; P = 0.012) after adjustment for age, dyslipidemia, diabetes mellitus, smoking, body mass index, menopause, and parity.Conclusions: Younger women with previous preeclampsia had a slightly higher prevalence of coronary atherosclerosis compared with age- and parity-matched women from the general population. Preeclampsia remained an independent risk factor after adjustment for traditional cardiovascular risk factors. (The CoPenHagen PREeClampsia and cardIOvascUlar diSease study [CPH-PRECIOUS]; NCT03949829). [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]