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Objective: For decades, it has been suggested that small dense low‐density lipoprotein (sdLDL) may be particularly atherogenic. High levels of sdLDL are associated with an increased risk of ischemic heart disease; however, the association of sdLDL with ischemic stroke has not been explored in a large prospective study on the general population. We tested the hypothesis that high sdLDL cholesterol levels are associated with an increased risk of ischemic stroke. Methods: This prospective study included 38,319 individuals from the Copenhagen General Population Study with fresh sample measurements of sdLDL cholesterol. Median follow‐up time was 3.1 years. We observed 302 and 74 ischemic and hemorrhagic strokes from baseline in 2013 to 2017 to the end of follow‐up in 2018. For comparison, we included estimates for large buoyant LDL cholesterol and total LDL cholesterol. Results: Higher levels of sdLDL cholesterol were log‐linearly associated with increased risk of ischemic stroke. Compared with individuals with sdLDL cholesterol in the lowest tertile (≤0.60 mmol/l; ≤23 mg/dl) the multivariable adjusted hazard ratio for ischemic stroke was 1.79 (95% confidence interval = 1.31–2.43) for the highest tertile (≥0.86 mmol/l; ≥33 mg/dl). Multivariable adjusted hazard ratios for ischemic stroke per 1 mmol/l (38.7 mg/dl) higher levels were 1.69 (1.28–2.22) for sdLDL cholesterol, 0.95 (0.78–1.16) for large buoyant LDL cholesterol, and 1.08 (0.93–1.25) for total LDL cholesterol. Hazard ratios were similar when further adjusting for body mass index (BMI) and diabetes mellitus in the biological pathway in combination with related lipids and lipoproteins. Interpretation: Higher sdLDL cholesterol levels were robustly associated with increased risk of ischemic stroke. ANN NEUROL 2023;93:952–964 [ABSTRACT FROM AUTHOR]

This article discusses the results of six randomized trials that examined the effects of fibrates and gemfibrozil on the prevention of atherosclerotic cardiovascular disease (ASCVD). The trials showed inconsistent results, and the authors sought to understand these discrepancies by examining the effects of mass changes in remnant cholesterol and LDL cholesterol. Using the Copenhagen General Population Study (CGPS) to mimic the study population of these trials, the authors compared estimated changes in ASCVD risk through mass changes in cholesterol with the observed changes in the original trials. The results suggest that mass changes in total atherogenic cholesterol can explain the results of these trials, regardless of whether statins were used or not. The authors conclude that to reduce ASCVD, cholesterol-lowering agents should aim to reduce the total mass of atherogenic cholesterol. [Extracted from the article]

Background & Aims: Fatty liver disease has been associated with higher all‐cause as well as liver‐related, ischemic heart disease (IHD)‐related and extrahepatic cancer‐related mortality in observational epidemiological studies. We tested the hypothesis that fatty liver disease is a causal risk factor for higher mortality. Methods: We genotyped seven genetic variants known to be associated with fatty liver disease (in PNPLA3, TM6SF2, HSD17B13, MTARC1, MBOAT7, GCKR, and GPAM) in 110 913 individuals from the Danish general population. Hepatic steatosis was measured by hepatic computed tomography in n = 6965. Using a Mendelian randomization framework, we tested whether genetically proxied hepatic steatosis and/or elevated plasma alanine transaminase (ALT) was associated with liver‐related mortality. Results: During a median follow‐up of 9.5 years, 16 119 individuals died. In observational analyses, baseline elevated plasma ALT was associated with higher all‐cause (1.26‐fold), liver‐related (9‐fold), and extrahepatic cancer‐related (1.25‐fold) mortality. In genetic analyses, the risk alleles in PNPLA3, TM6SF2, and HSD17B13 were individually associated with higher liver‐related mortality. The largest effects were seen for the PNPLA3 and TM6SF2 risk alleles, for which homozygous carriers had 3‐fold and 6‐fold, respectively, higher liver‐related mortality than non‐carriers. None of the risk alleles, individually or combined into risk scores, were robustly associated with all‐cause, IHD‐related, or extrahepatic cancer‐related mortality. In instrumental variable analyses, genetically proxied hepatic steatosis and higher plasma ALT were associated with liver‐related mortality. Conclusions: Human genetic data support that fatty liver disease is a causal driver of liver‐related mortality. [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]

Background: Elevated remnant cholesterol causes ischemic heart disease.Objectives: We tested the hypothesis that the inclusion of elevated remnant cholesterol will lead to appropriate reclassification of individuals who later experience myocardial infarction and ischemic heart disease.Methods: For >10 years we followed up 41,928 white Danish individuals from the Copenhagen General Population Study without a history of ischemic cardiovascular disease, diabetes, and statin use. Using predefined cut points for elevated remnant cholesterol, we calculated net reclassification index (NRI) from below to above 5%, 7.5%, and/or 10% 10-year occurrence of myocardial infarction and ischemic heart disease defined as a composite of death from ischemic heart disease, myocardial infarction, and coronary revascularization.Results: For individuals with remnant cholesterol levels ≥95th percentile (≥1.6 mmol/L, 61 mg/dL), 23% (P < 0.001) of myocardial infarction and 21% (P < 0.001) of ischemic heart disease were reclassified correctly from below to above 5% for 10-year occurrence when remnant cholesterol levels were added to models based on conventional risk factors, whereas no events were reclassified incorrectly. Consequently, the addition of remnant cholesterol levels yielded NRI of 10% (95% CI: 1%-20%) for myocardial infarction and 5% (95% CI: -3% to 13%) for ischemic heart disease. Correspondingly, when reclassifications were combined from below to above 5%, 7.5%, and 10% risk of events, 42% (P < 0.001) of individuals with myocardial infarction and 41% (P < 0.001) with ischemic heart disease were reclassified appropriately, leading to NRI of respectively 20% (95% CI: 9%-31%) and 11% (95% CI: 2%-21%).Conclusions: Elevated remnant cholesterol levels considerably improve myocardial infarction and ischemic heart disease risk prediction. [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]

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]