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Aims Cholesterol carried in triglyceride-rich lipoproteins, also called remnant cholesterol, is being increasingly acknowledged as an important causal risk factor for atherosclerosis. Elevated remnant cholesterol, marked by elevated plasma triglycerides, is associated causally with an increased risk of atherosclerotic cardiovascular disease. The association with cause-specific mortality is, however, unclear. The aim of this study was to test the hypothesis that elevated remnant cholesterol and plasma triglycerides are associated with increased mortality from cardiovascular disease, cancer, and other causes. Methods and results Using a contemporary population-based cohort, 87 192 individuals from the Copenhagen General Population Study aged 20–69 years at baseline in 2003–2015 were included. During up to 13 years of follow-up, 687 individuals died from cardiovascular disease, 1594 from cancer, and 856 from other causes, according to the National Danish Causes of Death Registry. In individuals with remnant cholesterol ≥1.0 mmol/L (≥39 mg/dL; 22% of the population) compared with those with levels <0.5 mmol/L (<19 mg/dL), multivariable-adjusted mortality hazard ratios were 2.2 (95% confidence interval 1.3–3.5) for cardiovascular disease, 1.0 (0.7–1.3) for cancer, and 2.1 (1.4–3.3) for other causes. Exploratory analysis of the cause of death subcategories showed corresponding hazard ratios of 4.4 (1.6–11) for ischemic heart disease, 8.4 (2.0–34) for infectious diseases, and 9.1 (1.9–43) for endocrinological diseases. Results for plasma triglycerides >2 vs. <1 mmol/L (>177 vs. <89 mg/dL) were similar. Conclusion Remnant cholesterol of ≥1 mmol/L (39 mg/dL), present in 22% of the population, and plasma triglycerides of ≥2 mmol/L (177 mg/dL), present in 28% of the population, were associated with two-fold mortality from cardiovascular and other causes, but not from cancer. This novel finding should be confirmed in other cohorts. [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]

This commentary refers to 'Elevated remnant cholesterol, plasma triglycerides, and cardiovascular and non-cardiovascular mortality', by B.N. Wadström I et al i . https://doi.org/10.1093/eurheartj/ehac822 and the discussion piece 'Remnant cholesterol as a lipid-lowering target may have a long way to go', by Y.-X. In the PROMINENT trial, the remnant cholesterol-lowering effect was counteracted by an LDL cholesterol I increase i of similar magnitude in mg/dL, leading to an increase in apolipoprotein B as a marker of all atherogenic lipoproteins combined. In summary, to determine if remnant cholesterol-lowering therapy can lower residual ASCVD risk, randomized trials should include individuals with elevated remnant cholesterol levels and use a therapy that does not increase LDL cholesterol or apolipoprotein B as seen in the PROMINENT trial.[5] Since LDL cholesterol is the primary lipid target, remnant cholesterol-lowering therapy should be tested as add-on therapy in individuals receiving intensive LDL cholesterol-lowering treatment. [Extracted from the article]

Aims To identify individuals at high risk of atherosclerotic cardiovascular disease (ASCVD), who are not definite statin eligible according to the 2016 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines, based on high concentrations of plasma triglycerides. Methods and results From the Copenhagen General Population Study (2003-2015) 58 547 individuals aged 40-65 and free of ASCVD, diabetes, and statin use at baseline were included. Of these, 14% were definite statin eligible, 7% were not eligible and had triglycerides ≥3.0 mmol/L (264 mg/dL), and 79% were not statin eligible and had triglycerides <3.0 mmol/L (264 mg/dL). During 456 057 person-years of follow-up, 1770 individuals experienced a major adverse cardiovascular event (MACE) and 734 experienced a myocardial infarction (MI). The cumulative incidences of MACE at age 70 were 8.1% (95% confidence interval 7.3-8.9%) and 14.6% (12.6-16.8%) in statin non-eligible individuals with triglycerides <3.0 mmol/L (264 mg/dL) and ≥3.0 mmol/L (264 mg/dL), and 16.5% (14.0-19.3%) in statin eligible individuals. Corresponding cumulative incidences of MI were 3.0% (2.7-3.3%), 7.8% (6.4-9.5%), and 7.1% (5.9-8.4%), respectively. The estimated 10-year risks of MACE were 2.8% (2.6-3.0%) and 5.7% (4.9-6.6%) in statin non-eligible individuals with triglycerides <3.0mmol/L (264 mg/dL) and ≥3.0mmol/L (264mg/dL), and 7.6% (6.9-8.3%) in statin eligible individuals; the median age in these three groups were 51, 51, and 60 years, respectively. Corresponding risks of MI were 1.0% (0.9-1.1%), 3.0% (2.4-3.7%), and 3.3% (2.8-3.7%), respectively. Conclusion Statin non-eligible individuals with triglycerides ≥3.0 mmol/L (264 mg/dL) had risk of ASCVD similar to statin eligible individuals, defined according to the 2016 ESC/EAS guidelines. This illustrates an unmet need for primary prevention, calling for expansion of guidelines on statin eligibility, and the potential for placebo-controlled randomized clinical trials in individuals with hypertriglyceridaemia. [ABSTRACT FROM AUTHOR]

The added value of incorporating information from repeated blood pressure and cholesterol measurements to predict cardiovascular disease (CVD) risk has not been rigorously assessed. We used data on 191,445 adults from the Emerging Risk Factors Collaboration (38 cohorts from 17 countries with data encompassing 1962-2014) with more than 1 million measurements of systolic blood pressure, total cholesterol, and high-density lipoprotein cholesterol. Over a median 12 years of follow-up, 21,170 CVD events occurred. Risk prediction models using cumulative mean values of repeated measurements and summary measures from longitudinal modeling of the repeated measurements were compared with models using measurements from a single time point. Risk discrimination (C-index) and net reclassification were calculated, and changes in C-indices were meta-analyzed across studies. Compared with the single-time-point model, the cumulative means and longitudinal models increased the C-index by 0.0040 (95% confidence interval (CI): 0.0023, 0.0057) and 0.0023 (95% CI: 0.0005, 0.0042), respectively. Reclassification was also improved in both models; compared with the single-time-point model, overall net reclassi- fication improvements were 0.0369 (95% CI: 0.0303, 0.0436) for the cumulative-means model and 0.0177 (95% CI: 0.0110, 0.0243) for the longitudinal model. In conclusion, incorporating repeated measurements of blood pressure and cholesterol into CVD risk prediction models slightly improves risk prediction. [ABSTRACT FROM AUTHOR]

Aims Ezetimibe reduces plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting Niemann-Pick C1-Like protein 1 (NPC1L1), the transporter responsible for cholesterol uptake fromthe intestine into enterocytes and fromthe bile into hepatocytes. We tested the hypothesis that genetic variation in NPC1L1, mimicking the effect of ezetimibe, was associated with reduced risk of ischaemic vascular disease (IVD) and with increased risk of symptomatic gallstone disease. METHODS AND RESULTS We included 67 385 individuals from the general population. Of these, 5255 and 3886 individuals developed IVD or symptomatic gallstone disease, respectively, during follow-up from 1977 to 2013. We genotyped four common NPC1L1 variants, previously associated with reduced LDL cholesterol levels, thus mimicking the effect of ezetimibe, and calculated a weighted genotype score. With increasing genotype score, LDL cholesterol decreased stepwise up to 3.5% (0.12 mmol/L) and total cholesterol up to 1.9% (0.11 mmol/L) (P-trend: 2 × 10(-12) and 2 × 10(-9)). The cumulative incidence by age of IVD decreased, while that of symptomatic gallstone disease increased as a function of increasing genotype score (P-trend: 0.005 and 0.01). Hazard ratios for genotype scores = 5.0 vs. <2.0 were 0.82 (95% confidence interval: 0.70-0.95) for IVD and 1.22 (0.99-1.49) for gallstone disease (P-trend across genotype scores: 0.004 and 0.01). Conclusion Genetic variation in NPC1L1 is associated with a reduction in risk of IVD, with a corresponding reduction in LDL cholesterol, but with a concomitant increased risk of gallstone disease. These data support the hypothesis that treatment with ezetimibe protects againstIVD but raise the question whether long-term treatment increases the risk of gallstone disease. [ABSTRACT FROM AUTHOR]

Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7-29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin rechallenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommendedlow-density lipoprotein cholesterol targets. ThePanel recommendsa structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential. [ABSTRACT FROM AUTHOR]

Aims The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) is underdiagnosed and undertreated. The second aim was to provide guidance for screening and treatment of FH, in order to prevent coronary heart disease (CHD). Methods and results Of the theoretical estimated prevalence of 1/500 for heterozygous FH, <1% are diagnosed in most countries. Recently, direct screening in a Northern European general population diagnosed approximately 1/200 with heterozygous FH. All reported studies document failure to achieve recommended LDL cholesterol targets in a large proportion of individuals with FH, and up to 13-fold increased risk of CHD. Based on prevalences between 1/500 and 1/200, between 14 and 34 million individuals worldwide have FH. We recommend that children, adults, and families should be screened for FH if a person or family member presents with FH, a plasma cholesterol level in an adult ≥8 mmol/L(≥310 mg/dL) or a child ≥6 mmol/L(≥230 mg/dL), premature CHD, tendon xanthomas, or sudden premature cardiac death. In FH, low-density lipoprotein cholesterol targets are <3.5 mmol/L(<135 mg/dL) for children, <2.5 mmol/L(<100 mg/dL) for adults, and <1.8 mmol/L(<70 mg/dL) for adults with known CHD or diabetes. In addition to lifestyle and dietary counselling, treatment priorities are (i) in children, statins, ezetimibe, and bile acid binding resins, and (ii) in adults, maximal potent statin dose, ezetimibe, and bile acid binding resins. Lipoprotein apheresis can be offered in homozygotes and in treatment-resistant heterozygotes with CHD. Conclusion Owing to severe underdiagnosis and undertreatment of FH, there is an urgent worldwide need for diagnostic screening together with early and aggressive treatment of this extremely high-risk condition. [ABSTRACT FROM PUBLISHER]

Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high-density lipoprotein cholesterol (HDL-C) as cardiovascular risk factors, and (ii) to advise on therapeutic strategies for management. Current evidence supports a causal association between elevated TRL and their remnants, low HDL-C, and cardiovascular risk. This interpretation is based on mechanistic and genetic studies for TRL and remnants, together with the epidemiological data suggestive of the association for circulating triglycerides and cardiovascular disease. For HDL, epidemiological, mechanistic, and clinical intervention data are consistent with the view that low HDL-C contributes to elevated cardiovascular risk; genetic evidence is unclear however, potentially reflecting the complexity of HDL metabolism. The Panel believes that therapeutic targeting of elevated triglycerides (≥1.7 mmol/L or 150 mg/dL), a marker of TRL and their remnants, and/or low HDL-C (<1.0 mmol/L or 40 mg/dL) may provide further benefit. The first step should be lifestyle interventions together with consideration of compliance with pharmacotherapy and secondary causes of dyslipidaemia. If inadequately corrected, adding niacin or a fibrate, or intensifying LDL-C lowering therapy may be considered. Treatment decisions regarding statin combination therapy should take into account relevant safety concerns, i.e. the risk of elevation of blood glucose, uric acid or liver enzymes with niacin, and myopathy, increased serum creatinine and cholelithiasis with fibrates. These recommendations will facilitate reduction in the substantial cardiovascular risk that persists in patients with cardiometabolic abnormalities at LDL-C goal. [ABSTRACT FROM PUBLISHER]

Background Low plasma levels of low-density lipoprotein (LDL) cholesterol are associated with an increased risk of cancer, but whether this association is causal is unclear. Methods We studied 10 613 participants in the Copenhagen City Heart Study (CCHS) and 59 566 participants in the Copenhagen General Population Study, 6816 of whom had developed cancer by May 2009. Individuals were genotyped for PCSK9 R46L (rs11591147), ABCG8 D19H (rs11887534), and APOE R112C (rs429358) and R158C (rs7412) polymorphisms, all of which are associated with lifelong reduced plasma LDL cholesterol levels. Plasma LDL cholesterol was calculated using the Friedewald equation in samples in which the triglyceride level was less than 354 mg/dL and measured directly by colorimetry for samples with higher triglyceride levels. Risk of cancer was estimated prospectively using Cox proportional hazards regression analyses and cross-sectionally by logistic regression analyses. Causality was studied using instrumental variable analysis. All statistical tests were two-sided. Results In the CCHS, compared with plasma LDL cholesterol levels greater than the 66th percentile (>158 mg/dL), those lower than the 10th percentile (<87 mg/dL) were associated with a 43% increase (95% confidence interval [CI] = 15% to 79% increase) in the risk of cancer. The polymorphisms were associated with up to a 38% reduction (95% CI = 36% to 41% reduction) in LDL cholesterol levels but not with increased risk of cancer. The causal odds ratio for cancer for a 50% reduction in plasma LDL cholesterol level due to all the genotypes in both studies combined was 0.96 (95% CI = 0.87 to 1.05), whereas the hazard ratio of cancer for a 50% reduction in plasma LDL cholesterol level in the CCHS was 1.10 (95% CI = 1.01 to 1.21) (P for causal odds ratio vs observed hazard ratio = .03). Conclusion Low plasma LDL cholesterol levels were robustly associated with an increased risk of cancer, but genetically decreased LDL cholesterol was not. This finding suggests that low LDL cholesterol levels per se do not cause cancer. [ABSTRACT FROM PUBLISHER]