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Background: Lipid-lowering recommendations for prevention of atherosclerotic cardiovascular disease rely principally on estimated 10-year risk. We sought to determine the optimal time for initiation of lipid lowering in younger adults as a function of expected 30-year benefit. Methods: Data from 3148 National Health and Nutrition Examination Survey (2009–2016) participants, age 30 to 59 years, not eligible for lipid-lowering treatment recommendation under the most recent US guidelines, were analyzed. We estimated the absolute and relative impact of lipid lowering as a function of age, age at initiation, and non–high-density lipoprotein cholesterol (HDL-C) level on the expected rates of atherosclerotic cardiovascular disease over the succeeding 30 years. We modeled expected risk reductions based on shorter-term effects observed in statin trials (model A) and longer-term benefits based on Mendelian randomization studies (model B). Results: In both models, potential reductions in predicted 30-year atherosclerotic cardiovascular disease risk were greater with older age and higher non–HDL-C level. Immediate initiation of lipid lowering (ie, treatment for 30 years) in 40- to 49-year-old patients with non–HDL-C ≥160 mg/dL would be expected to reduce their average predicted 30-year risk of 17.1% to 11.6% (model A; absolute risk reduction [ARR], 5.5%) or 6.5% (model B; ARR 10.6%). Delaying lipid lowering by 10 years (treatment for 20 years) would result in residual 30-year risk of 12.7% (A; ARR 4.4) or 9.9% (B; ARR 7.2%) and delaying by 20 years (treatment for 10 years) would lead to expected mean residual risk of 14.6% (A; ARR 2.6%) or 13.9% (B; ARR 3.2%). The slope of the achieved ARR as a function of delay in treatment was also higher with older age and higher non–HDL-C level. Conclusions: Substantial reduction in expected atherosclerotic cardiovascular disease risk in the next 30 years is achievable by intensive lipid lowering in individuals in their 40s and 50s with non–HDL-C ≥160 mg/dL. For many, the question of when to start lipid lowering might be more relevant than whether to start lipid lowering.

Background ApoAI (apolipoproteins AI) and apoAII (apolipoprotein AII) are structural and functional proteins of high‐density lipoproteins (HDL) which undergo post‐translational modifications at specific residues, creating distinct proteoforms. While specific post‐translational modifications have been reported to alter apolipoprotein function, the full spectrum of apoAI and apoAII proteoforms and their associations with cardiometabolic phenotype remains unknown. Herein, we comprehensively characterize apoAI and apoAII proteoforms detectable in serum and their post‐translational modifications and quantify their associations with cardiometabolic health indices. Methods and Results Using top‐down proteomics (mass‐spectrometric analysis of intact proteins), we analyzed paired serum samples from 150 CARDIA (Coronary Artery Risk Development in Young Adults) study participants from year 20 and 25 exams. Measuring 15 apoAI and 9 apoAII proteoforms, 6 of which carried novel post‐translational modifications, we quantified associations between percent proteoform abundance and key cardiometabolic indices. Canonical (unmodified) apoAI had inverse associations with HDL cholesterol and HDL‐cholesterol efflux, and positive associations with obesity indices (body mass index, waist circumference), and triglycerides, whereas glycated apoAI showed positive associations with serum glucose and diabetes mellitus. Fatty‐acid‒modified ApoAI proteoforms had positive associations with HDL cholesterol and efflux, and inverse associations with obesity indices and triglycerides. Truncated and dimerized proteoforms of apoAII were associated with HDL cholesterol (positively) and obesity indices (inversely). Several proteoforms had no significant associations with phenotype. Conclusions Associations between apoAI and AII and cardiometabolic indices are proteoform‐specific. These results provide “proof‐of‐concept” that precise chemical characterization of human apolipoproteins will yield improved insights into the complex pathways through which proteins signify and mediate health and disease.

Background Apolipoprotein B (apoB) is emerging as the lipoprotein entity that is critical for the role that lipoprotein lipids play in the aetiology of coronary heart disease (CHD). In this study, we explored effects of genetically-predicted apoB on endpoints in first-degree relatives. Methods Univariable Mendelian randomization (MR) used a weighted genetic instrument (229 SNPs) for apoB. For endpoints that apoB associated with at FDR Findings Parents were less likely to be alive with 10.7 months of life lost in fathers (95%CI: 7.6, 13.9; FDR-adjusted P=4.0×10−10) and 5.8 months of life lost in mothers (95%CI: 3.0, 8.52; FDR-adjusted P=1.7×10−4) per 1-SD higher apoB in offspring. Effects strengthened to ∼2 yrs of life lost in multivariable MR and replicated in conventional two-sample MR (OR surviving to 90th centile: 0.38; 95%CI: 0.22, 0.65). Genetically-elevated apoB caused higher risks of heart disease in all first-degree relatives and higher risk of stroke in mothers. Findings in first-degree relatives were replicated in two-sample multivariable MR which identified apoB to increase (OR 2.32; 95%CI: 1.49, 3.61) and LDL-C lower (OR 0.34; 95%CI: 0.21, 0.54) risk of T2D. Interpretation Higher apoB shortens the lifespan, and increases risks of heart disease and stroke. T2D effects may represent injurious effects of dyslipidaemia to pancreatic islets. Research in Context Evidence before this study Prior observational and Mendelian randomization studies have indicated that circulating concentrations of apoB are of critical importance to lipid-mediated atherogenesis, manifest as coronary heart disease. Added value of this study In this study, we explored the effects of genetically-predicted elevations in apoB on multiple endpoints occuring in first degree relatives including longevity and sought replication of findings using more conventional methods to exploit the statistical power from data available in large-scale GWAS consortia. We identified that apoB had a deleterious effect on longevity, shortening the lifespan by months to years. Furthermore, apoB caused higher risks of CHD and stroke in first degree relatives. Finally, apoB was identified to increase risk of T2D, in contradistinction to LDL-C which lowered risk of T2D, when employing multivairable MR methods. Implications of all the available evidence Our findings support apoB as being the major lipoprotein entity critical for CHD and stroke and extends this to identify higher apoB as negatively impacting longevity and increasing risk of T2D. These findings highlight the critical role of apoB in causing cardiometabolic disease, which collectively shortens the lifespan.

Introduction Dysbetalipoproteinaemia (HLP3) is a disorder characterized by excess cholesterol-enriched, triglyceride-rich lipoprotein remnants in genetically predisposed individuals that powerfully promote premature cardiovascular disease if untreated. The current prevalence of HLP3 is largely unknown. Material and methods We performed cross-sectional analysis of 128,485 U.S. adults from the Very Large Database of Lipids (VLDbL), using four algorithms to diagnose HLP3 employing three Vertical Auto Profile ultracentrifugation (UC) criteria and a previously described apolipoprotein B (apoB) method. We evaluated 4,926 participants from the 2011-2014 National Health and Nutrition Examination Survey (NHANES) with the apoB method. We examined demographic and lipid characteristics stratified by presence of HLP3 and evaluated lipid characteristics in those with HLP3 phenotype discordance and concordance as determined by apoB and originally defined UC criteria 1. Results In U.S. adults in VLDbL and NHANES, a 1.7-2.0% prevalence is observed for HLP3 with the novel apoB method as compared to 0.2-0.8% prevalence in VLDbL via UC criteria 1-3. Participants who were both apoB and UC criteria HLP3 positive had higher remnant particles as well as more elevated triglyceride/apoB and total cholesterol/apoB ratios (all p < 0.001) than those who were apoB method positive and UC criteria 1 negative. Conclusions HLP3 may be more prevalent than historically and clinically appreciated. The apoB method increases HLP3 identification via inclusion of milder phenotypes. Further work should evaluate the clinical implications of HLP3 diagnosis at various lipid algorithm cut-points to evaluate the ideal standard in the modern era.

Background Extended elevations of non–high-density lipoprotein cholesterol (non–HDL-C) across a lifespan are associated with increased risk of cardiovascular disease (CVD). However, optimal testing intervals to identify individuals with high lipid-related CVD risk are unknown. Objectives This study determined the extent to which lipid levels in young adulthood predict future lipid trajectories and associated long-term CVD risk. Methods A sample of 2,516 Framingham Offspring study participants 25 to 40 years of age free of CVD and diabetes had their non–HDL-C progression modeled over 8 study examinations (mean follow-up 32.6 years) using group-based methods. CVD risk based on 25 to 30 years of follow-up was evaluated using Kaplan-Meier analyses for those with mean non–HDL-C ≥160 mg/dl (“high”) and Results The trajectories of the lipid levels were generally stable over the 30-year life course; mean non–HDL-C measured in young adulthood were highly predictive of levels later in life. Individuals could be reliably assigned to high and low non–HDL-C groups based on 2 measurements collected between 25 to 40 years of age. Overall, 80% of those with non–HDL-C ≥160 mg/dl at the first 2 exams remained in the high group on subsequent 25-year testing, whereas 88% of those with non–HDL-C Conclusions Most adults with elevated non–HDL-C early in life continue to have high non–HDL-C over their life course, leading to significantly increased risk of CVD. The results demonstrate that early lipid monitoring before 40 years of age would identify a majority of those with a high likelihood for lifetime elevated lipid levels who also have a high long-term risk for CVD. This information could facilitate informed patient–provider discussion about the potential benefits of preventive lipid-lowering efforts during the early midlife period.

Supplemental Digital Content is available in the text., Background: To optimize preventive strategies for coronary heart disease (CHD), it is essential to understand and appropriately quantify the contribution of its key risk factors. Our objective was to compare the associations of key modifiable CHD risk factors—specifically lipids, systolic blood pressure (SBP), diabetes mellitus, and smoking—with incident CHD events based on their prognostic performance, attributable risk fractions, and treatment benefits, overall and by age. Methods: Pooled participant-level data from 4 observational cohort studies sponsored by the National Heart, Lung, and Blood Institute were used to create a cohort of 22 626 individuals aged 45 to 84 years who were initially free of cardiovascular disease. Individuals were followed for 10 years from baseline evaluation for incident CHD. Proportional hazards regression was used to estimate metrics of prognostic model performance (likelihood ratio, C index, net reclassification, discrimination slope), hazard ratios, and population attributable fractions for SBP, non–high-density lipoprotein cholesterol (non–HDL-C), diabetes mellitus, and smoking. Expected absolute risk reductions for antihypertensive and lipid-lowering treatment were assessed. Results: Age, sex, and race capture 63% to 80% of the prognostic performance of cardiovascular risk models. In contrast, adding either SBP, non–HDL-C, diabetes mellitus, or smoking to a model with other risk factors increases the C index by only 0.004 to 0.013. However, primordial prevention could have a substantial effect as demonstrated by population attributable fractions of 28% for SBP≥130 mm Hg and 17% for non–HDL-C≥130 mg/dL. Similarly, lowering the SBP of all individuals to

Purpose of review The 2019 European Society of Cardiology/European Atherosclerosis Society Guidelines concluded that apolipoprotein B (apoB) was a more accurate measure of cardiovascular risk and a better guide to the adequacy of lipid lowering than low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (HDL-C). Also, they stated that apoB can be measured more accurately than LDL-C or non-HDL-C. This strong endorsement of the central role of apoB contrasts with the limited endorsement of apoB by the 2018 American College of Cardiology/American Heart Association Multisociety Guidelines. Nevertheless, both retained LDL-C as the primary metric to guide statin/ezetimibe/Proprotein convertase subtilisin/kexin type 9 (PCSK9) therapy. Recent findings This essay will review the most important recent advances in knowledge about apoB with particular emphasis on the results of Mendelian randomization studies and a new discordance analysis in subjects on statin therapy. We will also lay out why using LDL-C to guide the adequacy of lipid lowering therapy represents an interpretive error of the results of the statin/ezetimibe/PCSK9 inhibitor randomized clinical trials and therefore why apoB should be the primary metric to guide statin/ezetimibe/PCSK9 therapy. Summary There is now a robust body of evidence demonstrating the superiority of apoB over LDL-C and non-HDL-C as a clinical marker of cardiovascular risk. LDL-C is not the appropriate marker to assess the benefits of statin/ezetimibe/PCSK9 therapy.

IMPORTANCE: Lipid management typically focuses on levels of low-density lipoprotein cholesterol (LDL-C) and, to a lesser extent, triglycerides (TG). However, animal models and genetic studies suggest that the atherogenic particle subpopulations (LDL and very-low-density lipoprotein [VLDL]) are both important and that the number of particles is more predictive of cardiac events than their lipid content. OBJECTIVE: To determine whether common measures of cholesterol concentration, TG concentration, or their ratio are associated with cardiovascular risk beyond the number of apolipoprotein B (apoB)–containing lipoproteins. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort analysis included individuals from the population-based UK Biobank and from 2 large international clinical trials, FOURIER and IMPROVE-IT. The median (IQR) follow-up was 11.1 (10.4-11.8) years in UK Biobank and 2.5 (2.0-4.7) years in the clinical trials. Two populations were studied in this analysis: 389 529 individuals in the primary prevention group who were not taking lipid-lowering therapy and 40 430 patients with established atherosclerosis who were receiving statin treatment. EXPOSURES: ApoB, non–high-density lipoprotein cholesterol (HDL-C), LDL-C, and TG. MAIN OUTCOME AND MEASURES: The primary study outcome was incident myocardial infarction (MI). RESULTS: Of the 389 529 individuals in the primary prevention group, 224 097 (58%) were female, and the median (IQR) age was 56.0 (49.5-62.5) years. Of the 40 430 patients with established atherosclerosis, 9647 (24%) were female, and the median (IQR) age was 63 (56.2-69.0) years. In the primary prevention cohort, apoB, non–HDL-C, and TG each individually were associated with incident MI. However, when assessed together, only apoB was associated (adjusted hazard ratio [aHR] per 1 SD, 1.27; 95% CI, 1.15-1.40; P

Purpose of review This review summarizes the evidence that apolipoprotein B (apoB) integrates the conventional lipid markers - total cholesterol, triglycerides, LDL-cholesterol, and non-HDL-cholesterol - into a single index that accurately and simply quantitates the atherogenic risk due to the apoB lipoprotein particles. Recent findings Marked hypertriglyceridemia remains the essential signal for hyperchylomicronemia and potential pancreatitis. However, with the exception of Lp(a) and the abnormal cholesterol-enriched remnant particles that are the hallmark of type III hyperlipoproteinemia, recent evidence from discordance analyses and Mendelian randomization indicate that apoB integrates the risk due to the atherogenic lipoprotein particles because all LDL particles are, within the limits of our ability to measure any differences, equally atherogenic and all, except the largest VLDL particles are, within the limits of our ability to measure any differences, equally atherogenic. Summary Measuring apoB as well as the conventional lipids is essential for accurate diagnosis. For almost all follow-up, however, apoB is all that need be measured. ApoB is the Rosetta Stone of lipidology because dyslipoproteinemia cannot be understood unless apoB is measured.

BackgroundApolipoprotein B (apoB) is emerging as the lipoprotein entity that is critical for the role that lipoprotein lipids play in the aetiology of coronary heart disease (CHD). In this study, we explored effects of genetically-predicted apoB on endpoints in first-degree relatives.MethodsUnivariable Mendelian randomization (MR) used a weighted genetic instrument (229 SNPs) for apoB. For endpoints that apoB associated with at FDR FindingsParents were less likely to be alive with 10.7 months of life lost in fathers (95%CI: 7.6, 13.9; FDR-adjusted P=4.0×10−10) and 5.8 months of life lost in mothers (95%CI: 3.0, 8.52; FDR-adjusted P=1.7×10−4) per 1-SD higher apoB in offspring. Effects strengthened to ∼2 yrs of life lost in multivariable MR and replicated in conventional two-sample MR (OR surviving to 90thcentile: 0.38; 95%CI: 0.22, 0.65). Genetically-elevated apoB caused higher risks of heart disease in all first-degree relatives and higher risk of stroke in mothers.Findings in first-degree relatives were replicated in two-sample multivariable MR which identified apoB to increase (OR 2.32; 95%CI: 1.49, 3.61) and LDL-C lower (OR 0.34; 95%CI: 0.21, 0.54) risk of T2D.InterpretationHigher apoB shortens the lifespan, and increases risks of heart disease and stroke. T2D effects may represent injurious effects of dyslipidaemia to pancreatic islets.Research in ContextEvidence before this studyPrior observational and Mendelian randomization studies have indicated that circulating concentrations of apoB are of critical importance to lipid-mediated atherogenesis, manifest as coronary heart disease.Added value of this studyIn this study, we explored the effects of genetically-predicted elevations in apoB on multiple endpoints occuring in first degree relatives including longevity and sought replication of findings using more conventional methods to exploit the statistical power from data available in large-scale GWAS consortia. We identified that apoB had a deleterious effect on longevity, shortening the lifespan by months to years. Furthermore, apoB caused higher risks of CHD and stroke in first degree relatives. Finally, apoB was identified to increase risk of T2D, in contradistinction to LDL-C which lowered risk of T2D, when employing multivairable MR methods.Implications of all the available evidenceOur findings support apoB as being the major lipoprotein entity critical for CHD and stroke and extends this to identify higher apoB as negatively impacting longevity and increasing risk of T2D. These findings highlight the critical role of apoB in causing cardiometabolic disease, which collectively shortens the lifespan.

Guidelines propose using non-HDL cholesterol or apolipoprotein (apo) B as a secondary treatment target to reduce residual cardiovascular risk of LDL-targeted therapies. This review summarizes the strengths, weaknesses, opportunities, and threats (SWOT) of using apoB compared with non-HDL cholesterol. Non-HDL cholesterol, calculated as total-HDL cholesterol, includes the assessment of remnant lipoprotein cholesterol, an additional risk factor independent of LDL cholesterol. ApoB is a direct measure of circulating numbers of atherogenic lipoproteins, and its measurement can be standardized across laboratories worldwide. Discordance analysis of non-HDL cholesterol versus apoB demonstrates that apoB is the more accurate marker of cardiovascular risk. Baseline and on-treatment apoB can identify elevated numbers of small cholesterol-depleted LDL particles that are not reflected by LDL and non-HDL cholesterol. ApoB is superior to non-HDL cholesterol as a secondary target in patients with mild-to-moderate hypertriglyceridemia (175–880 mg/dL), diabetes, obesity or metabolic syndrome, or very low LDL cholesterol

Background The ESC/EAS Guidelines and the EAS/EFLM consensus reports state that apoB is a more accurate marker of cardiovascular risk than LDL-C or non-HDL-C and that apoB can be measured accurately and precisely than LDL-C or non-HDL-C. Nevertheless, EAS/EFLM called for a randomized clinical trial and a cost-effective analysis before widespread implementation of apoB. Objective To analyse these issues from the perspective of clinical utility as clinical utility would be considered by an informed patient and physician. Methods and results We highlight the biological inaccuracies as well as the laboratory inaccuracies of LDL-C/non-HDL-C versus apoB. We demonstrate why the biological variance in the cholesterol loading per apoB particle makes it impossible to design a randomized clinical trial to compare apoB to LDL-C/non-HDL-C. We further demonstrate that even in the context of the United States, adding apoB to a lipid panel would have only a trivial effect on costs. Conclusion We submit that no informed patient or physician would choose a less accurate test over a more accurate test if the more accurate test added only trivially to the total cost of care. For these reasons, the clinical utility of apoB far exceeds the clinical utility of LDL-C/non-HDL-C.

Supplemental Digital Content is available in the text., Background: Total cholesterol and high-density lipoprotein cholesterol (HDL-C) measurements are central to cardiovascular disease (CVD) risk assessment, but there is continuing debate around the utility of other lipids for risk prediction. Methods: Participants from UK Biobank without baseline CVD and not taking statins, with relevant lipid measurements (n=346 686), were included in the primary analysis. An incident fatal or nonfatal CVD event occurred in 6216 participants (1656 fatal) over a median of 8.9 years. Associations of nonfasting lipid measurements (total cholesterol, HDL-C, non–HDL-C, direct and calculated low-density lipoprotein cholesterol [LDL-C], and apolipoproteins [Apo] A1 and B) with CVD were compared using Cox models adjusting for classical risk factors, and predictive utility was determined by the C-index and net reclassification index. Prediction was also tested in 68 649 participants taking a statin with or without baseline CVD (3515 CVD events). Results: ApoB, LDL-C, and non–HDL-C were highly correlated (r>0.90), while HDL-C was strongly correlated with ApoA1 (r=0.92). After adjustment for classical risk factors, 1 SD increase in ApoB, direct LDL-C, and non–HDL-C had similar associations with composite fatal/nonfatal CVD events (hazard ratio, 1.23, 1.20, 1.21, respectively). Associations for 1 SD increase in HDL-C and ApoA1 were also similar (hazard ratios, 0.81 [both]). Adding either total cholesterol and HDL-C, or ApoB and ApoA, to a CVD risk prediction model (C-index, 0.7378) yielded similar improvement in discrimination (C-index change, 0.0084; 95% CI, 0.0065, 0.0104, and 0.0089; 95% CI, 0.0069, 0.0109, respectively). Once total and HDL-C were in the model, no further substantive improvement was achieved with the addition of ApoB (C-index change, 0.0004; 95% CI, 0.0000, 0.0008) or any measure of LDL-C. Results for predictive utility were similar for a fatal CVD outcome, and in a discordance analysis. In participants taking a statin, classical risk factors (C-index, 0.7118) were improved by non–HDL-C (C-index change, 0.0030; 95% CI, 0.0012, 0.0048) or ApoB (C-index change, 0.0030; 95% CI, 0.0011, 0.0048). However, adding ApoB or LDL-C to a model already containing non–HDL-C did not further improve discrimination. Conclusions: Measurement of total cholesterol and HDL-C in the nonfasted state is sufficient to capture the lipid-associated risk in CVD prediction, with no meaningful improvement from addition of apolipoproteins, direct or calculated LDL-C.

Cardiovascular risk is so high in type III hyperlipoproteinemia that type III, just like heterozygous familial hypercholesterolemia (FH)2, is a treat-on-diagnosis disorder (1–3). Tragically, although severe hypercholesterolemia is easy to recognize, type III hyperlipoproteinemia cannot be diagnosed using a conventional lipid panel (4) and the original diagnostic tools—electrophoresis and ultracentrifugation—are available in only a miniscule number of clinics (1). Thus, type III cannot be diagnosed in regular clinical care using regular diagnostic tools. Moreover, while the importance of FH is recognized by all the major lipid guidelines, even the existence of type III hyperlipoproteinemia is barely acknowledged, if at all, by the same groups. Consequently, those patients with type III are lumped and dumped with all the others with mixed hyperlipidemia and the result, tragically, can be no treatment when treatment is indicated. In a wonderful paper (3), Paul Hopkins and his colleagues referred to type III hyperlipoproteinemia as the “forgotten phenotype.” Nothing has changed and so the extended title of this editorial. In this issue of Clinical Chemistry , Boot et al. (5) present the advantages of the non-HDL cholesterol (non-HDL-C)/apoB ratio as a diagnostic tool for type III hyperlipoproteinemia. I congratulate them on their work, notwithstanding that their results and conclusions, using their approach, differ at the margins from our results and conclusions using our approach (4). On reflection, it may be that we were too rigid in one direction, while they may be too rigid in another. Nevertheless, what is most important is that the work is powerfully confirmatory of that of David Marais and his colleagues from South Africa, who diagnosed type III based on the total cholesterol (TC)/apoB ratio (6). I met Dr. Marais only once, and then only briefly, but his multiple contributions to the understanding of this disorder, while …

Aim This study aims to describe the variability of pre-dialysis troponin values in stable haemodialysis patients and compare the performance of single versus fluctuating or persistently elevated troponins in predicting a composite of mortality and cardiac arrest, myocardial infarction, or stroke. Methods 128 stable ambulatory chronic haemodialysis patients were enrolled. Pre-dialysis troponin I was measured for three consecutive months. The patients were followed for one year. A troponin elevation (>0.06 µg/L) was considered high risk, and patients were classified into 3 risk groups: 1) patients who had normal troponin levels on all three measurements; 2) patients with at least one elevated and one normal troponin value; 3) patients with elevated troponin values on all measurements. Results 81 patients had all three troponin values in the normal range; 29 had fluctuating values; 18 had all three values elevated. 27 deaths or composite events were observed: 8 in the first risk group, 10 in the second, and 9 in the third. Persistently elevated and fluctuating troponin values were associated with higher mortality and cardiovascular event rate. Serial troponin measurement had a higher sensitivity for the composite outcome than single troponin measurement when either fluctuating or persistently elevated values were considered to confer high risk. Conclusion Most haemodialysis patients do not have elevated troponin levels at baseline. Troponin levels that remain elevated or fluctuate are associated with worse outcomes. A serial troponin measurement strategy is associated with better sensitivity and higher negative predictive value compared with single troponin measurement.

Statins and PCSK9 inhibitors dramatically lower plasma LDL levels and dramatically increase LDL receptor number within hepatocyte cell membranes. It seems self-evident that total clearance of LDL particles from plasma and total delivery of cholesterol to the liver must increase in consequence. However, based on the results of stable isotope tracer studies, this analysis demonstrates the contrary to be the case. Statins do not change the production rate of LDL particles. Accordingly, at steady state, the clearance rate cannot change. Because LDL particles contain less cholesterol on statin therapy, the delivery of cholesterol to the liver must, therefore, be reduced. PCSK9 inhibitors reduce the production of LDL particles and this further reduces cholesterol delivery to the liver. With both agents, a larger fraction of a smaller pool is removed per unit time. These findings are inconsistent with the conventional model of cholesterol homeostasis within the liver, but are consistent with a new model of regulation, the multi-channel model, which postulates that different lipoprotein particles enter the hepatocyte by different routes and have different metabolic fates within the hepatocyte. The multi-channel model, but not the conventional model, may explain how statins and PCSK9 inhibitors can produce sustained increases in LDL receptor number.

BACKGROUND It is uncertain whether measurement of circulating total atherogenic lipoprotein particle cholesterol mass [non–HDL cholesterol (nonHDLc)] or particle concentration [apolipoprotein B (apo B) and LDL particle concentration (LDLp)] more accurately reflects risk of incident coronary heart disease (CHD). We evaluated CHD risk among women in whom these markers where discordant. METHODS Among 27533 initially healthy women in the Women's Health Study (NCT00000479), using residuals from linear regression models, we compared risk among women with higher or lower observed particle concentration relative to nonHDLc (highest and lowest residual quartiles, respectively) to individuals with agreement between markers (middle quartiles) using Cox proportional hazards models. RESULTS Although all 3 biomarkers were correlated (r ≥ 0.77), discordance occurred in up to 20.2% of women. Women with discordant high particle concentration were more likely to have metabolic syndrome (MetS) and diabetes (both P < 0.001). Over a median follow-up of 20.4 years, 1246 CHD events occurred (514725 person-years). Women with high particle concentration relative to nonHDLc had increased CHD risk: age-adjusted hazard ratio (95% CI) = 1.77 (1.56–2.00) for apo B and 1.70 (1.50–1.92) for LDLp. After adjustment for clinical risk factors including MetS, these risks attenuated to 1.22 (1.07–1.39) for apo B and 1.13 (0.99–1.29) for LDLp. Discordant low apo B or LDLp relative to nonHDLc was not associated with lower risk. CONCLUSIONS Discordance between atherogenic particle cholesterol mass and particle concentration occurs in a sizeable proportion of apparently healthy women and should be suspected clinically among women with cardiometabolic traits. In such women, direct measurement of lipoprotein particle concentration might better inform CHD risk assessment.

BACKGROUND: Trapping of apoB lipoprotein particles within the arterial wall initiates and drives the atherosclerotic process from beginning to end. Very low-density lipoprotein particles (VLDL) contain most of the triglyceride in plasma whereas low-density lipoprotein particles (LDL) particles contain most of the cholesterol. Smaller numbers of chylomicron and Lp(a) particles are also present in plasma. All these particles have one molecule of apoB. Therefore, plasma apoB equals the total number of apoB particles. Because the lipid content of apoB particles is variable, plasma triglyceride and cholesterol are not always accurate-measures of the number of apoB particles. THE CHOLESTEROL MODEL OF ATHEROSCLEROSIS: The conventional model of atherosclerosis presumes that the mass of cholesterol within VLDL and LDL particles is the principal determinant of the mass of cholesterol that will be deposited within the arterial wall and will drive atherogenesis. But cholesterol can only enter the arterial wall within apoB particles and the mass of cholesterol that will be deposited is determined by the rate at which apoB particles are trapped within the arterial wall rather than passing harmless through. THE APOB PARTICLE MODEL OF ATHEROGENESIS: The number of apoB particles that enter and are trapped within the arterial wall is determined primarily by the number of apoB particles within the arterial lumen. However, once within the arterial wall, smaller cholesterol-depleted apoB particles have a greater tendency to be trapped than larger cholesterol-enriched apoB particles because they bind more avidly to the glycosaminoglycans within the subintimal space of the arterial wall. If so, a cholesterol-enriched particle would deposit more cholesterol than a cholesterol-depleted apoB particle. By contrast, more smaller apoB particles that enter the arterial wall will be trapped than larger apoB particles. The net result is, with the exceptions of the abnormal chylomicron remnants in type III hyperlipoproteinemia and Lp(a), all apoB particles are equally atherogenic. ApoB, therefore, unifies, amplifies, and simplifies the information from the conventional lipid markers as to the atherogenic risk attributable to the apoB lipoproteins.

Background The ODYSSEY OUTCOMES (Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome) trial demonstrated that alirocumab reduced major cardiovascular events. However, because of the hierarchical testing strategy used for the multiple outcomes examined, the observed reduction in all‐cause mortality was labeled “nominally significant” which has clouded its interpretation. Methods and Results We re‐analyzed data from ODYSSEY OUTCOMES using Bayesian methods and generated various prior probabilities by incorporating mortality data from previous similar PCSK 9 (proprotein convertase subtilisin‐kexin type 9) inhibitor trials. We first used data from the ODYSSEY OUTCOMES trial with a non‐informative prior, then sequentially added data from ODYSSEY LONG TERM and the FOURIER trial, giving FOURIER full weight, 50% weight and 10%. The posterior probability of a mortality reduction using only the ODYSSEY OUTCOMES data was hazard ratio 0.85 (95% CI 0.74–0.99) which corresponded to a 98.4% probability of a mortality benefit. When the ODYSSEY LONG TERM data were added to the analysis, the posterior probability was hazard ratio 0.84 (95% CI 0.72–0.97) with a 99.9% probability of mortality reduction, and when the FOURIER data were added to the analysis the posterior probability was hazard ratio 0.94 (95% CI 0.85–1.04) with an 89.1% probability of a mortality reduction. When the FOURIER trial was given only 50% or 10% weight, the probability of a mortality reduction rose 95.4% and 98.7%, respectively. We estimate that the probability of >1% absolute risk reduction ranges from 8% to 24%, while the probability of >0.5% absolute risk reduction ranges from 66% to 89%. Conclusions Our analysis demonstrates a high likelihood that alirocumab confers a reduction in all‐cause mortality, despite the equivocal interpretation of the data in the original ODYSSEY OUTCOMES publication.

Background There is a lack of evidence regarding the link between apolipoproteins and cancer mortality. Purpose By using two nationally representative samples of US adults, we prospectively evaluated the associations between apolipoprotein B (apoB) levels and apoB/apolipoprotein A-I (apoA-I) ratio with cancer mortality. We also examined the role of C-reactive protein (CRP) in these associations. Method Adults aged ≥20 years, enrolled in the Third National Health and Nutrition Examination Survey (NHANES-III, 1988–1994) and continuous NHANES (2005–2010), and followed up to December 31st 2011, were included in the present analysis. Multiple Cox regressionswere applied to evaluate the associations between the variables of interest and cancer mortality. Results Overall, 7,695 participants were included (mean age: 49.2 years; 50.4% men, median follow-up: 19.1 years). In the fully adjusted (for age, gender, race, poverty to income ratio, educational status, body mass index, alcohol and dietary intake, smoking, dyslipidemia, hypertension and diabetes) model, participants in the highest quartile (Q4) of apoB/apoA-I had a significantly greater risk for cancer mortality [hazard ratio (HR): 1.40, 95% confidence interval (CI): 1.25–1.93] compared with those in the first quartile (Q1) (Figure). In the same model, a positive and significant association between apoB levels and fatal cancer was observed for individuals in the Q3 (HR: 1.12, 95% CI: 1.09–1.16) and Q4 (HR: 1.17, 95% CI: 1.09–1.25) compared with those in the Q1. When CRP levels were added in the analysis, the apoB/apoA-I ratio, but not apoB levels, remained significantly related to cancer mortality (Q4= HR: 1.17, 95% CI 1.09–1.25). In contrast, CRP levels were not able to predict cancer death after correction for apoB/apoA-I ratio. Cancer death and quartiles of ApoB/ApoA1 Conclusions In a large representative sample of the US adult population, the apoB/apoA-I ratio and apoB levels significantly predicted cancer mortality, independently of several cardiometabolic risk factors. The predictive value of apoB/apoA-I, but not apoB levels, remained significant after taking into account CRP, whereas CRP was not associated with cancer mortality after adjustment for apoB/apoA-I ratio. If further evidence supports our findings, apoA-I and apoB measurements could be considered in general health-care policies. Acknowledgement/Funding None

IMPORTANCE: American College of Cardiology/American Heart Association cholesterol guidelines prioritize primary prevention statin therapy based on 10-year absolute risk (AR(10)) of atherosclerotic cardiovascular disease (ASCVD). However, given the same AR(10), patients with higher levels of low-density lipoprotein cholesterol (LDL-C) experience greater absolute risk reduction from statin therapy. OBJECTIVES: To estimate the cost-effectiveness of expanding preventive statin treatment eligibility from standard care to patients at borderline risk (AR(10), 5.0%-7.4%) for ASCVD and with high levels of LDL-C and to estimate cost-effectiveness of statin treatment across ranges of age, sex, AR(10), and LDL-C levels. DESIGN, SETTING, AND PARTICIPANTS: This study evaluated 100 simulated cohorts, each including 1 million ASCVD-free survey respondents (50% men and 50% women) aged 40 years at baseline. Cohorts were created by probabilistic sampling of the 1999-2014 US National Health and Nutrition Examination Surveys from the perspective of the US health care sector. The CVD Policy Model microsimulation version projected lifetime health and cost outcomes. Probability of first-ever coronary heart disease or stroke event was estimated by analysis of 6 pooled US cohort studies and recalibrated to match contemporary event rates. Other model variables were derived from national surveys, meta-analyses, and published literature. Data were analyzed from May 15, 2018, through June 10, 2019. EXPOSURES: Four statin treatment strategies were compared: (1) treat all patients with AR(10) of at least 7.5%, diabetes, or LDL-C of at least 190 mg/dL (standard care); (2) add treatment for borderline risk and LDL-C levels of 160 to 189 mg/dL; (3) add treatment for borderline risk and LDL-C levels of 130 to 159 mg/dL; and (4) add treatment for remainder of patients with AR(10) of at least 5.0%. Statin treatment was also compared with no statin treatment in age, sex, AR(10), and LDL-C strata. MAIN OUTCOMES AND MEASURES: Lifetime quality-adjusted life-years (QALYs) and costs (2019 US dollars) were projected and discounted 3.0% annually. The primary outcome was the incremental cost-effectiveness ratio. RESULTS: In these 100 simulated cohorts, each with 1 million patients aged 40 years at baseline (50% women and 50% men), adding preventive statins to individuals with borderline AR(10) and LDL-C levels of 160 to 189 mg/dL would be cost-saving; further treating borderline AR(10) and LDL-C levels of 130 to 159 mg/dL would also be cost-saving; and treating all individuals with AR(10) of at least 5.0% would be highly cost-effective ($33 558/QALY) and would prevent the most ASCVD events. Within age, AR(10), and sex categories, individuals with higher baseline LDL-C levels gained more QALYs from statin therapy. Cost-effectiveness increased with LDL-C level and AR(10). CONCLUSIONS AND RELEVANCE: In this study, lifetime statin treatment of patients in a hypothetical cohort with borderline ASCVD risk and LDL-C levels of 160 to 189 mg/dL was found to be cost-saving. Results suggest that treating all patients at borderline risk regardless of LDL-C level would likely be highly cost-effective.

Introduction: It is unclear if individuals with very low mean low-density lipoprotein cholesterol (LDL-C) during midlife experience significant absolute risk (AR) for coronary heart disease (CHD). Hypothesis: Individuals with LDL-C ≤80mg/dL from ages 20-60 years (y) do not develop significant AR for CHD over 30 y of follow-up. Methods: Our objective was to quantify and compare the 30-year AR for fatal or nonfatal CHD from index ages 20-40 y and 40-60 y in participants (ppts) with LDL-C ≤80, 81-130, and >130 mg/dL using data from the Lifetime Risk Pooling Project. We included ppts who were free from lipid lowering medications and CHD at baseline. Mean LDL-C was an average of multiple (2-5) fasting LDL-C measurements within 10 years prior to the baseline age. We used a modified Kaplan Meier analysis, adjusted for competing risks of death, to quantify the 30-year CHD AR by LDL-C strata. Results: 3,781 men and 4,995 women were followed for a combined 110,431 person*years and experienced 778 events. Among all ppts, tobacco use ranged from 20-40% and hypertension prevalence ranged from 13-40%. Non-lipid risk factor profiles were generally more favorable in the low-LDL-C strata. At index ages 20-40, men and women with LDL-C ≤80mg/dL did not experience risk for CHD over 20 and 25 years, respectively (Figure). A similar pattern was seen in the LDL-C 80-130mg/dL strata. At index ages 40-60, men and women with LDL-C ≤80mg/dL experienced no risk for CHD for 5 to 15 years, respectively. However, both sex groups saw a gradual increase in risk up to 13.7% (95% confidence interval [CI] 1.9-25.4%) for men and 5.2% (95% CI 2.0-8.4%) for women at year 30 of follow-up. Conclusion: Young ppts with LDL-C ≤80mg/dL had very low CHD risks across midlife despite significant risk factor burden. At older ages, ppts with low LDL-C develop modest AR for CHD suggesting adverse lipid changes over time or alternative mediators of CHD in this age group.

While there is no dispute that hypercholesterolemia increases the risk of cardiovascular disease, controversy as the importance of hypertriglyceridemia persists. Much of this relates to the fact that hypertriglyceridemia is not a single disorder but rather is a collection of disorders in which elevation of plasma triglycerides is due to the accumulation of different triglyceride-rich lipoproteins, some of which, such as remnant lipoprotein particles are ferociously atherogenic whereas others, such as intact chylomicrons, are not but do increase the risk of pancreatitis. Based on just the major lipoprotein lipids-cholesterol and triglycerides-the 6 major apoB dsylipoproteinemias cannot be separated and each identified. The apoB algorithm, which is based on total cholesterol, triglycerides and apoB, all three of which can be measured inexpensively in standard clinical laboratories, for the first time, allows all the specific apoB dyslipoproteinemias to be easily and accurately identified. By incorporating apoB into clinical care, we move from the lipid to the lipoprotein era with more precise identification of those who require pharmacological therapy and more rational and precise use of pharmacological agents to reduce their risk of cardiovascular disease.

Background— Current guidelines recommend statins in the primary prevention of cardiovascular disease on the basis of predicted cardiovascular risk without directly considering the expected benefits of statin therapy based on the available randomized, controlled trial evidence. Methods and Results— We included 2134 participants representing 71.8 million American residents potentially eligible for statins in primary prevention from the National Health and Nutrition Examination Survey for the years 2005 to 2010. We compared statin eligibilities using 2 separate approaches: a 10-year risk-based approach (≥7.5% 10-year risk) and an individualized benefit approach (ie, based on predicted absolute risk reduction over 10 years [ARR 10 ] ≥2.3% from randomized, controlled trial data). A risk-based approach led to the eligibility of 15.0 million (95% confidence interval, 12.7–17.3 million) Americans, whereas a benefit-based approach identified 24.6 million (95% confidence interval, 21.0–28.1 million). The corresponding numbers needed to treat over 10 years were 21 (range, 9–44) and 25 (range, 9–44). The benefit-based approach identified 9.5 million lower-risk (10 ) compared with higher-risk individuals. This lower-risk/acceptable-benefit group includes younger individuals (mean age, 55.2 versus 62.5 years; P P =0.01). Statin treatment in this group would be expected to prevent an additional 266 508 cardiovascular events over 10 years. Conclusions— An individualized statin benefit approach can identify lower-risk individuals who have equal or greater expected benefit from statins in primary prevention compared with higher-risk individuals. This approach may help develop guideline recommendations that better identify individuals who meaningfully benefit from statin therapy.

Background: High levels of apolipoprotein B (apoB) have been shown to predict atherosclerotic cardiovascular disease (CVD) in adults even in the context of low levels of low-density lipopro...

Several studies suggest differences between fibrates and statins in lowering plasma fibrinogen (Fib) concentrations, but the evidence is not definitive. Therefore, the aim of this meta-analysis of head-to-head randomized trials was to compare the efficacy of statins and fibrates on plasma Fib concentrations.The literature search included Medline, Scopus, and Web of Science up to February 1st, 2015, to identify head-to-head comparative randomized trials investigating the efficacy of fibrates vs statins on plasma Fib concentrations.In total 22 trials with 2762 participants were included to the meta-analysis. Random-effect meta-analysis suggested a significantly greater effect of fibrates vs statins in lowering plasma Fib concentrations (weighted mean difference [WMD]: -40.7mg/dL, 95% confidence interval [CI]: -55.2, -26.3, p0.001). When the analysis was stratified according to the type of fibrate administered, there were significant Fib-lowering effects with both bezafibrate (n=8 treatment arms; WMD: -23.7mg/dL, 95% CI: -41.8, -5.7, p=0.01) and fenofibrate (n=15 treatment arms; WMD: -43.7mg/dL, 95% CI: -61.3, -26.2, p0.001). Overall, there was a numerically greater effect in the subgroup of trials with ≥12 weeks duration (n=17 treatment arms; WMD: -42.7mg/dL, 95% CI: -60.3, -25.1, p0.001) compared with the subgroup of trials lasting12 weeks (n=7 treatment arms; WMD: -36.7mg/dL, 95% CI: -52.0, -21.4, p0.001).Monotherapy with either fibrates or statins suggested a significantly greater effect of fibrates in lowering plasma Fib concentrations. According to these findings, mechanisms associated with fibrinogen metabolism might be responsible for the distinct effects of statins and fibrates in reducing cardiovascular endpoints.

Background: An elevated troponin level is commonly found in asymptomatic patients on hemodialysis (HD) and is associated with higher risk of mortality and major adverse cardiovascular events. The underlying mechanism for the association between adverse outcomes and elevated troponin levels has not been elucidated. Methods: Two hundred thirty-six stable chronic HD patients from 2 tertiary care centers were enrolled in this study. We measured pre-dialysis troponin I levels with routine monthly bloods for 3 consecutive months. Troponin I was considered to be elevated if it exceeded the laboratory reference range of 0.06 μg/l. Results: The study population had a mean age of 67.5, 56% were male, 47% had diabetes and 28% had pre-existing coronary artery disease. Eighty-eight positive troponin values were recorded (13% of the available values) in 52 patients. In a repeated measures linear random effects model (univariate analysis), high ultrafiltration (UF), high inter-dialytic weight gain, and duration of the dialysis session, but not intra-dialytic hypotension, were associated with troponin I elevation. In the multivariate model, only high UF explained troponin I elevation (p = 0.04). The intraclass correlation coefficient was found to be 5.8%, suggesting that observed variability is within and not between subjects, with session-related parameters being more important than inter-individual differences. Conclusions: A high UF rate during HD is associated with a biochemical evidence of myocardial injury. If confirmed, efforts to avoid rapid UF, protect residual kidney function or minimize weight gain between sessions may impact cardiovascular outcomes in this high-risk population.

The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines suggest statin therapy for primary prevention in patients with an estimated 10-year atherosclerotic cardiovascular disease risk ≥7.5%1 as calculated by the Pooled Cohorts Equation. We recently demonstrated that only 53% of individuals eligible for statins based on the ≥7.5% risk criterion would have been eligible for a statin randomized control trial (RCT) in which benefit was demonstrated.2 We sought (1) to evaluate whether the recently published HOPE-3 trial (Heart Outcomes Prevention Evaluation)3 improves the evidence base for the ACC/AHA guidelines and (2) to estimate whether HOPE-3 increases the number of individuals eligible for statins in primary prevention beyond those recommended by the ACC/AHA guidelines. Data from the National Health and Nutrition Examination Survey (NHANES) collected between 2005 and 2010 were used to create a sample of 2134 participants representing 71.8 million Americans without atherosclerotic cardiovascular disease who were not currently taking statins. Participants were categorized based on the following criteria: (1) a 10-year risk of ≥7.5% by Pooled Cohorts Equation; (2) an expected absolute risk reduction of ≥2.3% based on Pooled Cohorts Equation risk and individualized relative risk reductions, as previously described2; …

Importance A 10-year benefit-based approach to statin therapy in primary prevention includes younger individuals with higher low-density lipoprotein cholesterol (LDL-C) and prevents more cardiovascular events than a risk-based approach. However, a 10-year treatment duration likely underestimates the expected benefits of statins. Objective To model the impact of a 30-year benefit approach to select individuals for statin therapy. Design, Setting, and Participants This cross-sectional analysis of the National Health and Nutrition Survey (NHANES) data set included samples of the US population from the 2009-2010, 2011-2012, and 2013-2014 data collection cycles. Individuals between 40 to 60 years old who did not have atherosclerotic cardiovascular disease, diabetes, or LDL-C levels greater than 190 mg/dL and who were not taking statins were included. Data analysis took place from November 2017 to August 2018. Exposures We calculated 10-year risk of atherosclerotic cardiovascular disease and 10-year and 30-year absolute risk reduction (10-year ARR and 30-year ARR) of atherosclerotic cardiovascular disease for each individual. Main Outcomes and Measures Number of individuals meeting eligibility for statins based on 10-year (atherosclerotic) cardiovascular disease risk, 10-year ARR, or 30-year ARR. Results A total of 1688 individuals were included, representing 56.6 million US individuals. Statin eligibility based on 7.5% CVR 10 was 9.5%; based on 2.3% 10-year ARR, 13.0%, and based on 15% 30-year ARR, 17.5%. The 10-year risk, 10-year benefit, and 30-year benefit approaches all led to similar acceptable mean absolute risk reductions at 30 years, with the benefit-based approaches better able to avoid treatment of individuals with low expected benefit. Individuals who met statin eligibility based solely on the 30-year ARR threshold of 15% or greater were younger (mean age, 50 [95% CI, 48-52] years) and more likely to be women (43% [95% CI, 26%-59%]) than those recommended with a 10-year ARR threshold of 2.3% or greater (mean age, 56 [95% CI, 54-57] years; 22% [95% CI, 10%-34%] women). This group also had lower 10-year risk (mean risk, 4.7% [95% CI, 4.4%-5.1%]) and higher LDL-C levels (mean level, 149 mg/dL [95% CI, 142-155 mg/dL]) than those recommended with a 10-year ARR threshold of 2.3% or greater (mean risk, 9.3% [95% CI, 8.3%-10.2%]; mean LDL-C levels, 110 [103-118] mg/dL). Preventable atherosclerotic cardiovascular disease events in 10 and 30 years were highest using the 30-year benefit approach (296 000 at 10 years and 2.03 million at 30 years) and lowest based on 10-year risk (204 000 at 10 years and 1.18 million at 30 years). Conclusions and Relevance A long-term benefit approach to statin eligibility identifies nearly 1 in 6 individuals as having a high degree of expected long-term benefit of statins, with a number needed to treat of less than 7. This approach identifies younger individuals with higher LDL-C levels who would not be currently recommended for treatment and may provide a more optimal approach for determining statin eligibility in primary prevention.

A new paradigm for preventing atherosclerotic cardiovascular disease (ASCVD) is needed. The most recent US data show the long‐term decline in cardiovascular deaths has stopped, and has started to increase in the most at‐risk populations.1 Indeed, rising rates of obesity and diabetes mellitus in the setting of suboptimal risk factor control have resulted in a similar number of cardiovascular events occurring in those aged

Prevention of cardiovascular disease today is as different from Geoffrey Rose's day as day is to night. In his time, net benefit from medical therapy was uncertain because there were no therapies that had been proved to be safe, effective, and affordable. However, the evidence that therapies that lower blood pressure and cholesterol prevent cardiovascular events is now incontrovertible with the result that guidelines recommend medical treatment of a large segment of the population to prevent cardiovascular disease. Population prevention medicine is not something that may occur tomorrow. Population prevention medicine is being practiced today. Yet, much remains to be done. The medical treatments of hypertension and hyperlipidemia both take place within a medical model that was not designed to deal with the numbers that could benefit from preventive medical therapy, and we need to refine our present system of care to take the realities of population medicine into account.

Item does not contain fulltext BACKGROUND: Type III hyperlipoproteinemia is a highly atherogenic dyslipoproteinemia characterized by hypercholesterolemia and hypertriglyceridemia due to markedly increased numbers of cholesterol-enriched chylomicron and very-low-density lipoprotein (VLDL) remnant lipoprotein particles. Type III can be distinguished from mixed hyperlipidemia based on a simple diagnostic algorithm, which involves total cholesterol, triglycerides, and apolipoprotein B (apoB). However, apoB is not measured routinely. OBJECTIVE: The objective of the present study was to determine if patients with type III could be distinguished from mixed hyperlipidemia based on lipoprotein lipids. METHODS: Classification was based first on total cholesterol and triglyceride and then on the apoB diagnostic algorithm using apoB plus total cholesterol plus triglycerides, and validated by sequential ultracentrifugation. Four hundred and forty normals, 637 patients with hypertriglyceridemia, and 714 with hypertriglyceridemia and hypercholesterolemia were studied. Plasma lipoproteins were separated by sequential ultracentrifugation and heparin-manganese precipitation. Cholesterol, triglyceride, and apoB were measured in plasma and isolated lipoprotein fractions. RESULTS: Of the 1351 patients with hypertriglyceridemia, 49 had type III hyperlipoproteinemia, as diagnosed by the apoB algorithm and validated by ultracentrifugation. Plasma triglycerides were higher in the type III subjects: 4.16 mmol/L (3.35-6.08, 25th-75th percentile), but there was considerable overlap with the hypertriglyceridemic subjects 2.65 mmol/L (1.91-4.20, 25th-75th percentile) and the combined hyperlipidemic subjects 3.02 mmol/L (2.07-5.32, 25th-75th percentile). Similarly, total cholesterol was 4.79 mmol/L (4.31-5.58, 25th-75th percentile) for type III vs 5.5 mmol/L (4.64-5.78, 25th-75th percentile) and 7.02 mmol/L (6.39-7.96, 25th-75th percentile), respectively. By contrast, as identified by the apoB algorithm, the VLDL-C/TG, VLDL-C/VLDL-TG, VLDL-C/VLDL apoB, and VLDL apoB/LDL apoB ratios were all higher in type III than in the other hypertriglyceridemic dyslipoproteinemias with the exception of type V as diagnosed by the apoB algorithm. CONCLUSION: Cholesterol and triglycerides cannot reliably distinguish type III hyperlipoproteinemia from mixed hyperlipidemia. Adding apoB and applying the apoB algorithm makes reliable diagnosis possible and easy. However, unless apoB is introduced into routine clinical care, type III hyperlipoproteinemia will often not be recognized. Given the cardiovascular risk associated with type III and its responsiveness to treatment, this should not be acceptable.

Introduction: Individuals with no established cardiovascular disease (CVD) are currently recommended preventive statin therapy based on 10-year absolute risk (AR) of CVD, and individuals with a 10-year AR ≥7.5% are recommended statins. However, individuals with elevated LDL cholesterol experience greater absolute CVD absolute risk reduction (ARR) from statin therapy compared with those with the same 10-year AR but with lower LDL. A previous study showed that ARR-based statin treatment would prevent more CVD events than AR-based treatment in the 10 years following treatment initiation. Objective: This study aimed to quantify the long-term benefits of treating patients based on ARR rather than AR. Methods: A microsimulation version of the CVD Policy Model, a decision-analytic state transition model, simulated intermediate-strength statin therapy in 40,000 CVD-free US adults (50% female) under a variety of treatment strategies. The model predicts health outcomes for individuals based on their age, sex, and risk factor profile, accounting for the competing risk of non-CVD mortality. Individuals entered the model aged 40 years, and a time horizon of 40 years was employed. Life year gains and CVD events prevented compared to no treatment were estimated for a range of 10-year ARR and AR treatment initiation thresholds. Results: At the same numbers of patient-years of treatment (PYoT), ARR consistently produced more life year gains than AR (Figure). A 10-year ARR threshold of ≥2.62% would lead to approximately the same PYoT as standard of care (10-year AR ≥7.5%) while preventing 60 additional CVD events and producing 421 additional life year gains in the cohort. Conclusion: Treating patients with statins based on ARR would yield significant health gains in the U.S. population compared to standard AR-based treatment strategies. The ARR strategy may also achieve greater adherence and uptake as it focuses on individuals with elevated levels of a modifiable risk factor.

Objective— To reanalyze data from recent randomized trials of statins to assess whether the benefits and risks of statins are mediated primarily via their LDL-C (low-density lipoprotein cholesterol) lowering effects or via other mechanisms. Approach and Results— We adapted Egger regression, a technique frequently used in Mendelian randomization studies to detect genetic pleiotropy, to reanalyze the available randomized control trial data of statin therapy. For cardiovascular end points, each 1 mmol/L change in LDL-C with statin therapy was associated with a hazard ratio of 0.77 (95% confidence interval, 0.71–0.84) with an intercept that was indistinguishable from zero (intercept, −0.0032; [95% confidence interval, −0.090 to 0.084]; P =0.94), indicating no pleiotropy. For incident diabetes mellitus, a 1 mmol/L change in LDL-C with statin therapy was associated with a hazard ratio of 1.07 (95% confidence interval, 0.99–1.16) and an intercept nondistinguishable from zero (intercept, −0.015; [95% confidence interval, −0.30 to 0.27]; P =0.91), again indicating no pleiotropy. Conclusions— Our reanalysis of the randomized control trial data using Egger regression adds to the existing evidence that the cardiovascular benefits of statins and their association with incident diabetes mellitus are mediated primarily, if not entirely, via their LDL-C lowering properties rather than by any pleiotropic effects.

Background— The total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) ratio, estimated low-density lipoprotein cholesterol (LDL-C), and non–HDL-C are routinely available from the standard lipid profile. We aimed to assess the extent of patient-level discordance of TC/HDL-C with LDL-C and non–HDL-C, because discordance suggests the possibility of additional information. Methods and Results— We compared population percentiles of TC/HDL-C, Friedewald-estimated LDL-C, and non–HDL-C in 1 310 432 US adults from the Very Large Database of Lipids. Lipid testing was performed by ultracentrifugation (Vertical Auto Profile, Atherotech, AL). One in 3 patients had ≥25 percentile units discordance between TC/HDL-C and LDL-C, whereas 1 in 4 had ≥25 percentile units discordance between TC/HDL-C and non–HDL-C. The proportion of patients with TC/HDL-C > LDL-C by ≥25 percentile units increased from 3% at triglycerides non–HDL-C discordance by ≥25 percentile units increased from 6% to 21%. In those with 86% of the variance in percentile discordance between TC/HDL-C versus LDL-C and non–HDL-C. Conclusions— In this contemporary, cross-sectional, big data analysis of US adults who underwent advanced lipid testing, the extent of patient-level discordance suggests that TC/HDL-C may offer potential additional information to LDL-C and non–HDL-C. Future studies are required to determine the clinical implications of this observation. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01698489.

Background Relatives of people with coronary artery disease are at high risk of cardiovascular (CV) disease, but the effect of focused screening and treatment of this population is uncertain. Methods We searched the Cochrane Library, Medline, and Embase from inception until June 30, 2014 for articles that described screening strategies and primary prevention interventions targeting family members of patients with coronary artery disease to reduce CV risk. Results were pooled using a random-effects meta-analysis. Results We identified 18 studies that reported screening strategies and 15 reporting interventions to reduce CV risk. Proband willingness to refer relatives for screening was high (n = 6 studies, pooled rate = 87%; 95% confidence interval [CI], 80%-95%). Studies using a screening strategy in which the relative was contacted by health care professionals reported a pooled participation rate of 88% (95% CI, 78%-99%). The quality of interventional studies was highly variable. Random-effects meta-analysis of the highest quality randomized studies (n = 6) consisting of a specialized risk factor intervention compared with usual care was consistent with modest improvements in low-density lipoprotein cholesterol control (−0.18 mmol/L low-density lipoprotein cholesterol, 95% CI, −0.35 to −0.001; P = 0.048). Improvements in diet, smoking rates, exercise, and blood pressure were also observed with active intervention; however, reported outcomes were heterogeneous precluding a formal meta-analysis. Conclusions Screening strategies that target family members, particularly when led by a health care professional, achieve a high participation rate. Although the available evidence is of variable quality, interventions that target individuals with a family history of coronary artery disease appear to be feasible and might be effective in improving certain risk factors or health behaviours but their long-term CV benefits remain uncertain.

Background New cholesterol guidelines emphasize 10-year risk of cardiovascular disease (CVD) to identify adults eligible for statin therapy as primary prevention. Whether these CVD risk thresholds should be individualized by age and sex has not been explored. Objectives This study evaluated the potential impact of incorporating age- and sex-specific CVD risk thresholds into current cholesterol guidelines. Methods Using data from the Framingham Offspring Study, this study assessed current treatment recommendations among age- and sex-specific groups in 3,685 participants free of CVD. Then, it evaluated how varying age- and sex-specific 10-year CVD risk thresholds for statin treatment affect the sensitivity and specificity for incident 10-year CVD events. Results Basing statin therapy recommendations on a 10-year fixed risk threshold of 7.5% results in lower statin consideration among women than men (63% vs. 33%; p Conclusions Cholesterol treatment recommendations could be improved by using individualized age- and sex-specific CVD risk thresholds.

Background— Many young adults with moderate hyperlipidemia do not meet statin treatment criteria under the new American Heart Association/American College of Cardiology cholesterol guidelines because they focus on 10-year cardiovascular risk. We evaluated the association between years of exposure to hypercholesterolemia in early adulthood and future coronary heart disease (CHD) risk. Methods and Results— We examined Framingham Offspring Cohort data to identify adults without incident cardiovascular disease to 55 years of age (n=1478), and explored the association between duration of moderate hyperlipidemia (non–high-density lipoprotein cholesterol≥160 mg/dL) in early adulthood and subsequent CHD. At median 15-year follow-up, CHD rates were significantly elevated among adults with prolonged hyperlipidemia exposure by 55 years of age: 4.4% for those with no exposure, 8.1% for those with 1 to 10 years of exposure, and 16.5% for those with 11 to 20 years of exposure ( P Conclusions— Cumulative exposure to hyperlipidemia in young adulthood increases the subsequent risk of CHD in a dose-dependent fashion. Adults with prolonged exposure to even moderate elevations in non–high-density lipoprotein cholesterol have elevated risk for future CHD and may benefit from more aggressive primary prevention.

Analyses using conventional statistical methodologies have yielded conflicting results as to whether low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C) or apolipoprotein B (apoB) is the best marker of the apoB-associated risk of coronary heart disease. The aim of this study was to determine the additional value of apoB beyond LDL-C or non-HDL-C as a predictor of coronary heart disease.For each patient from the Framingham Offspring Cohort aged 40-75 years (n = 2966), we calculated the extent to which the observed apoB differed from the expected apoB based on their LDL-C or non-HDL-C. We added this difference to a Cox model predicting new onset coronary heart disease over a maximum of 20 years adjusting for standard risk factors plus LDL-C or non-HDL. The difference between observed and expected apoB over LDL-C or non-HDL-C was highly prognostic of future coronary heart disease events: adjusted hazard ratios 1.26 (95% confidence interval: 1.15, 1.37) and 1.20 (1.11, 1.29), respectively, for each standard deviation increase beyond expected apoB levels. When this difference between observed and expected apoB was added to standard coronary heart disease prediction models including LDL-C or non-HDL-C, prediction improved significantly (likelihood ratio test p-values0.0001) and discrimination c-statistics increased from 0.72 to 0.73. The corresponding relative integrated discrimination improvements were 11% and 8%, respectively.apoB improves risk assessment of future coronary heart disease events over and beyond LDL-C or non-HDL-C, which is consistent with coronary risk being more closely related to the number of atherogenic apoB particles than to the mass of cholesterol within them.

Background The World Heart Federation has undertaken an initiative to develop a series of Roadmaps. Objectives The aim of these is to promote development of national policies and health systems approaches and identify potential roadblocks on the road to effective prevention, detection and management of cardiovascular disease (CVD) in low-and middle-income countries (LMIC), and strategies for overcoming these. This Roadmap focuses on elevated blood cholesterol, a leading risk factor for myocardial infarction, stroke, and peripheral arterial disease. Methods Through a review of published guidelines and research papers, and consultation with a committee composed of experts in clinical management of cholesterol and health systems research in LMIC, this Roadmap identifies (1) key interventions for primordial, primary and secondary prevention of CVD through detection, treatment, and management of elevated cholesterol and familial hypercholesterolemia (FH); (2) gaps in implementation of these interventions (knowledge-practice gaps); (3) health system roadblocks to treatment of elevated cholesterol in LMIC; and (4) potential strategies for overcoming these. Results Despite strong evidence of the importance of cholesterol levels in primary or secondary prevention of CVD, and the effectiveness of statin therapy for cholesterol lowering and reduction of CVD risk, gaps exist in the detection, treatment, and management of high cholesterol globally. Some potential roadblocks include poor access to laboratory facilities or trained professionals for cholesterol management, low awareness of FH among the general population and health professionals, unaffordability of statins for patient households, and low awareness of the importance of persistent adherence to lipid-lowering medication. Potential solutions include point-of-care testing, provision of free or subsidized lipid-lowering medication, and treatment adherence support using text message reminders. Conclusions Known effective strategies for detection, treatment, and management of elevated cholesterol and FH exist, but there are barriers to their implementation in many low-resource settings. Priorities for health system intervention should be identified at the national level, and the feasibility and effectiveness of proposed solutions should be assessed in specific contexts. Many solutions proposed in this Roadmap may apply to other cardiovascular conditions and present opportunities for integration of CVD care in LMIC.

Background— The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines expanded eligibility criteria for statins. We examined race and socioeconomic differences associated with these changes. Methods and Results— This was an observational study of adults between 40 and 75 years of age using data from the National Health and Nutrition Examination Surveys between 2005 and 2012. Change in eligibility for statins was assessed based on the third adult treatment panel criteria and the 2013 ACC/AHA guidelines. Differences relating to self-reported race, income, education, and insurance status were assessed in models that were adjusted for age and each of the other factors. Statin eligibility increased among all race, education, and income groups. Becoming newly eligible for statins was more likely for black people (25.8% newly eligible; adjusted odds ratio, 3.8; P P P =0.001), and those with no health insurance (17.6%; adjusted odds ratio, 1.5; P Conclusions— The 2013 ACC/AHA guidelines increase statin eligibility most among adults with nonwhite race, socioeconomic disadvantage, and no health insurance. Without improving access to healthcare, the potential gains from expanding indications for cardioprotective medications will not be realized.

All current guidelines use the 10-year risk of a cardiovascular event to select subjects for statin primary preventive therapy. Benefit from therapy is stated to be determined by risk with the result that statin primary preventive therapy is initiated only when the risk of a cardiovascular event over the next decade exceeds a specified level. Thus all current guidelines are based primarily on the Risk-Benefit paradigm of primary prevention. The recent American Heart Association/American College of Cardiology guidelines differ from others in basing selection for statin therapy virtually exclusively on risk except for those few subjects with markedly elevated levels of low-density lipoprotein cholesterol (LDL-C). The Causal Exposure paradigm differs from the Risk-Benefit paradigm in that the objective of therapy is to prevent the anatomic disease within arterial walls that produces cardiovascular risk. Moreover, the anatomic disease and, therefore, the cardiovascular risk, is a function of the injurious action of the causal factors of vascular disease, such as blood pressure and LDL, on the arterial wall over long periods. In this article, we explain the strengths and weaknesses of both paradigms to provide a more secure framework to compare the strengths and weaknesses in the different cholesterol guidelines with particular emphasis on the evidence that the cardiovascular risk and the benefit from statin therapy is related to the level of LDL.

Background Glucose, the conventional osmotic agent in peritoneal dialysis (PD) solutions, may contribute to atherogenic dyslipoproteinemia and increased cardiovascular risk. Objective To determine whether a low-glucose PD regimen may improve the serum lipid and lipoprotein profile in patients with diabetes. Methods A prospective, open-label, parallel group, multinational, randomized, controlled trial with a 6-month follow-up, comprising 251 patients with diabetes receiving PD. Patients were randomized to a low-glucose PD regimen (dextrose-based PD solution plus icodextrin, a starch polymer, and amino acids) or a conventional PD regimen (dextrose PD solutions). Serum lipid and apolipoprotein profiles were determined at baseline and 3 and 6 months. Results Serum triglycerides, very low-density-lipoprotein cholesterol, and apolipoprotein B (apoB) decreased significantly in the intervention group at both 3 and 6 months compared with baseline (serum triglycerides: median change at 3 months −0.5 mmol/L, P .001, at 6 months −0.3 mmol/L, P .001; very low-density-lipoprotein cholesterol: −0.3 mg/dL, P .001; −0.3 mg/dL, P .001; and apoB: −8.5 mg/dL, P .001; −3.6 mg/dL, P = .043, respectively) and also compared with the control group. In contrast, apoB levels increased significantly in the control group at 3 and 6 months compared with baseline (5.3 mg/dL, P = .041; 5.2 mg/dL, P = .007, respectively). Percentage of patients on lipid-lowering medications at baseline and intensity of therapy was equivalent in each group. The apoB decrease was not affected by lipid-lowering medications in the intervention group. Conclusion A low glucose-PD regimen significantly improved the atherogenic lipoprotein phenotype compared with PD patients treated with a conventional glucose regimen.

The severe hypercholesterolemia phenotype includes all patients with marked elevation of low-density lipoprotein cholesterol (LDL-C) levels. The most common cause is autosomal dominant hypercholesterolemia, an inherited disorder caused by mutations either in LDL receptor , apolipoprotein B ( APOB ), or proprotein convertase subtilisin kexin type 9 ( PCSK9 ) genes. However, it is now known that many subjects with severe inherited hypercholesterolemia have no defects in these genes. These cases are caused either by mutations in genes yet to be identified or are consequences of polygenic, epigenetic, or acquired defects. Because the clinical consequences of extreme hypercholesterolemia are the same no matter the cause, the focus should be on the identification of subjects with severe hypercholesterolemia, followed by phenotypic screening of family members. Genetic screening is not necessary to diagnose or initiate treatment for the severe hypercholesterolemia phenotype. Management of severe hypercholesterolemia is based on risk factor modification and use of multiple lipid-lowering medications. Lipoprotein apheresis is indicated for coronary artery disease (CAD) patients taking maximally tolerated therapy and with LDL-C levels >200 mg/dl (>300 mg/dl if without CAD). A microsomal triglyceride transfer protein inhibitor and an antisense oligonucleotide against APOB have recently been approved for use in subjects with clinically diagnosed homozygous familial hypercholesterolemia. PCSK9 inhibitors, currently in phase II and III trials, lower LDL-C up to an additional 70% in the setting of maximally tolerated medical therapy and have the potential to reduce LDL-C to

Why South Asians are at increased risk of premature atherosclerotic cardiovascular diseases compared with other ethnic groups is not fully understood. Atherogenic dyslipoproteinemia - hypertriglyceridemia, elevated numbers of low-density lipoprotein (LDL) particles and low high-density lipoprotein cholesterol (HDL-C) - is more common in South Asians but the mechanisms responsible have not been explicated. Here we examined whether the circulating lipid transfer protein, cholesteryl ester transfer protein (CETP), plays a role in the pathogenesis of the atherogenic dyslipoproteinemia among South Asians.CETP activity was determined by exogenous substrate assay in the serum of healthy, metabolically well-characterized individuals of South Asian and European descent (N = 244 and 238, respectively). Serum and lipoprotein lipids and apolipoproteins were measured and lipoprotein particle number and size were quantified via nuclear magnetic resonance spectroscopy. All the elements of the atherogenic dyslipoproteinemia were more severe in South Asians and CETP activity was significantly greater by 30% in South Asians compared with Europeans, adjusted for age, sex, body mass index and waist circumference (p 0.0001). CETP activity was directly associated with serum triglycerides and inversely with HDL-C in the whole population. CETP activity was also directly related to apoB and LDL particle number. Finally, increased CETP activity was associated with pro-atherogenic reductions in HDL and LDL particle size.We identified novel associations between elevated CETP activity and the triad of quantitative and qualitative lipoprotein abnormalities in the atherogenic dyslipidemia in South Asians, a major contributor of increased atherosclerotic cardiovascular diseases in South Asians.