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Despite data suggesting that apolipoprotein B (apoB) measurement outperforms low-density lipoprotein cholesterol level measurement in predicting atherosclerotic cardiovascular disease risk, apoB measurement has not become widely adopted into routine clinical practice. One barrier for use of apoB measurement is lack of consistent guidance for clinicians on how to interpret and apply apoB results in clinical context. Whereas guidelines have often provided clear low-density lipoprotein cholesterol targets or triggers to initiate treatment change, consistent targets for apoB are lacking. In this review, we synthesize existing data regarding the epidemiology of apoB by comparing guideline recommendations regarding use of apoB measurement, describing population percentiles of apoB relative to low-density lipoprotein cholesterol levels, summarizing studies of discordance between low-density lipoprotein cholesterol and apoB levels, and evaluating apoB levels in clinical trials of lipid-lowering therapy to guide potential treatment targets. We propose evidence-guided apoB thresholds for use in cholesterol management and clinical care.

Low high-density lipoprotein cholesterol (HDL-C) characterizes an atherogenic dyslipidemia that reflects adverse lifestyle choices, impaired metabolism, and increased cardiovascular risk. Low HDL-C is also associated with increased risk of inflammatory disorders, malignancy, diabetes, and other diseases. This epidemiologic evidence has not translated to raising HDL-C as a viable therapeutic target, partly because HDL-C does not reflect high-density lipoprotein (HDL) function. Mendelian randomization analyses that have found no evidence of a causal relationship between HDL-C levels and cardiovascular risk have decreased interest in increasing HDL-C levels as a therapeutic target. HDLs comprise distinct subpopulations of particles of varying size, charge, and composition that have several dynamic and context-dependent functions, especially with respect to acute and chronic inflammatory states. These functions include reverse cholesterol transport, inhibition of inflammation and oxidation, and antidiabetic properties. HDLs can be anti-inflammatory (which may protect against atherosclerosis and diabetes) and proinflammatory (which may help clear pathogens in sepsis). The molecular regulation of HDLs is complex, as evidenced by their association with multiple proteins, as well as bioactive lipids and noncoding RNAs. Clinical investigations of HDL biomarkers (HDL-C, HDL particle number, and apolipoprotein A through I) have revealed nonlinear relationships with cardiovascular outcomes, differential relationships by sex and ethnicity, and differential patterns with coronary versus noncoronary events. Novel HDL markers may also have relevance for heart failure, cancer, and diabetes. HDL function markers (namely, cholesterol efflux capacity) are associated with coronary disease, but they remain research tools. Therapeutics that manipulate aspects of HDL metabolism remain the holy grail. None has proven to be successful, but most have targeted HDL-C, not metrics of HDL function. Future therapeutic strategies should focus on optimizing HDL function in the right patients at the optimal time in their disease course. We provide a framework to help the research and clinical communities, as well as funding agencies and stakeholders, obtain insights into current thinking on these topics, and what we predict will be an exciting future for research and development on HDLs.

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Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Introduction:HDL particles vary in size and concentration. Indices of overall HDL particle concentration (HDL-P) and the concentrations of different HDL size subspecies (small: H1-H3, medium: H4, H5, and large: H6, H7) have differential associations with near-term CVD events in middle-aged adults. It is unclear if measures of HDL particle concentration predict long-term ASCVD risk in young adults.Methods:Among CARDIA participants (ppts), NMR was used to measure HDL-P and HDL particle size subgroup H1-H7 concentrations. HDL cholesterol (HDL-C) was measured using standard assays. We stratified the ppts into 2 age windows: 20-30y (n= 1645) and 30-40y (n=2922). We used adjusted Cox proportional hazards models to assess the associations between a 1SD higher HDL-C, HDL-P, and HDL1-7 subgroups with incident ASCVD events. We added HDL-P, HDL H1-H7, and HDL-C separately to a modified Pooled Cohort Equation (PCE) model; model performance (discrimination and reclassification) was evaluated.Results:81 and 163 ASCVD events occurred over (median (IQR)) 31.8y (31.1-32.0y) for the 20-30y age window and over 26.8y (19.1-27.1y) for the 30-40y age window, respectively. In ppts age 20-30y, a higher HDL-P and HDL-C were not associated with ASCVD events, however a higher HDL H6 subgroup level was associated with lower risk for ASCVD in demographic adjusted models. In the age 30-40y group, higher HDL-P, HDL-C, and H6 subgroup were significantly associated with lower ASCVD risks in all models. There were no significant differences in c-statistics across PCE models. However, there were improvements in reclassification for all HDL measures when added to the PCE model in the 20-30y age window, and significant improvements in reclassification when HDL H1-7 were added to the PCE for the 30-40y age window.Conclusion:At younger ages (<40y) differences in HDL particle abundance, in particular large particles, may help reclassify long-term risk for ASCVD in some.

Recent studies suggest that total high-density lipoprotein particle concentration (HDL-P) outperforms HDL cholesterol (HDL-C) in predicting atherosclerotic cardiovascular disease (ASCVD). Whether specific size-based HDL subspecies contribute to the atheroprotective effects of HDL-P remains unknown. Our objective was to assess size-based HDL subspecies for association with both incident myocardial infarction (MI) and ischemic stroke in a large, diverse cohort, expecting heterogeneous associations regarding subspecies and vascular endpoints.Participants without prior ASCVD enrolled in the Dallas Heart Study, MESA, ARIC, and PREVEND were included as a single pooled cohort (N=15,371). Seven HDL size-based subspecies were quantified by NMR (LP4 algorithm; H1=smallest; H7=largest). The primary adjudicated outcomes over an average of 8-10 years of follow up were first MI and first ischemic stroke. Cox proportional hazards models included traditional ASCVD risk factors (except HDL-C) and all seven HDL subspecies.As continuous variables, higher H1, H2 and H4 concentrations were associated with lower risk of MI (Panel A), whereas higher H2 and H4 concentrations were associated with lower risk of ischemic stroke (Panel B). The top vs bottom quartiles of H2 and H4 had 27-32% lower incidence of MI (HR Q4 vs. Q1 [95% CI]: H1 0.73 [0.58-0.91]; H2 0.69 [0.54-0.89]; H4 0.68 [0.54-0.86]) and no significant associations with ischemic stroke. Serial adjustment for HDL-C attenuated all associations with ischemic stroke. However, H1 and H4 retained significant inverse associations with MI adjusted for HDL-C (HR/SD [95% CI]: H1 0.88 [0.81-0.94]; H4 0.89 [0.82-0.97]).H1 (small HDL) and H4 (medium HDL), but no large subspecies, demonstrated inverse associations with MI in a large multi-ethnic pooled cohort. Next steps include assessment of interactions by sex and race as well as incremental clinical utility of H1 and H4 compared to both HDL-C and total HDL-P in predicting MI.

Introduction:The 2019 Primary Prevention Guideline suggests selective use of low-dose aspirin (ASA) for primary prevention of ASCVD given increased bleeding risk. Higher coronary calcium (CAC) may identify those more likely to benefit from ASA, but whether higher CAC also associates with more bleeding is unclear.Methods:Participants of the Dallas Heart Study, free from ASCVD and not on ASA at baseline were included. Fatal and non-fatal major bleeding events (gastrointestinal, intracranial, major other) were identified from ICD9 and 10 codes. Adjudicated ASCVD events (non-fatal MI, coronary heart disease death, non-fatal and fatal stroke) were identified using ICD codes and phone surveys. Multivariable Cox models were used to assess the independent association of CAC with incident bleeding and ASCVD events.Results:The cohort included 2184 participants (mean age 44y, 57% female, 33% black) with 109 major bleeding events and 123 ASCVD events over a median follow-up of 17 years. Older age, black race, diabetes, smoking, blood pressure, peptic ulcer disease, corticosteroid and antacid use were associated with bleeding. Higher CAC categories (0, 1-100, >100) were associated with both ASCVD and bleeding events (p<0.001 each; Figure). CAC better discriminated ASCVD risk (c-statistic 0.79, 95% CI 0.74 to 0.83) than bleeding risk (c-statistic 0.61, 95% CI 0.55 to 0.66), and CAC ?100 (vs. CAC=0) remained associated with ASCVD [HR, 95%CI 3.98 (2.07-7.64)], but not bleeding [HR-1.24 (0.68-2.27)] after multivariable adjustment . In exploratory analyses applying meta-analysis estimates of the effect of ASA, the absolute 10-year reduction of ASCVD would be 1.7% and absolute increased bleeding 2.2% in those with CAC ?100.Conclusions:Higher CAC is associated with both ASCVD and bleeding events, with a stronger association with ASCVD. Additional studies are warranted to determine if there are CAC thresholds with favorable net benefit of ASA for primary prevention of ASCVD.

Introduction:Impaired cholesterol efflux (CEC) from macrophages to apolipoprotein A-I is linked to coronary heart disease (CHD). Haptoglobin (Hp) binds to apolipoprotein A-I, and the Hp copy number variant designated by allele ?2? is linked to CEC and HDL dysfunction in diabetics. However, the direct effect of allele ?2? on CEC remains unknown. Given the effects of anacetrapib (ANA) on increased HDL-C, increased CEC, and reduced CHD, we hypothesized that allele ?2? would blunt the effect of ANA on CEC in diabetic patients.Objective:To determine how Hp CNV status impacts the effect of ANA on CEC in diabetics.Methods:This study included 332 participants with CHD and diabetes randomized to ANA 100mg vs. placebo in the DEFINE trial. BODIPY CEC from J774 macrophages to apo B-depleted plasma was measured at baseline and at 24 weeks. Hp CNV status was determined using a commercially available ELISA assay (Savyon Diagnostics, Ltd., St. Ashdod, Israel).Results:Among the 332 participants with diabetes, 51 had the 1-1, 162 had the 2-1, and 119 had the 2-2 Hp allele (194 Men and 138 Women). In unadjusted analyses, ANA was associated with a significant increase in CEC in those with the ?1? allele (18%; std beta = 0.42; p=0.0026) but not in those with the ?2? allele (11%; std beta = 0.08; p=0.16; p for interaction = 0.02; Figure). These findings remained significant adjusting for baseline risk factors and serial changes in lipids including apo AI and apo B (?1? allele: std beta = 0.55; p=0.05; ?2? allele: std beta = 0.19; p=0.18; p for interaction = 0.08). This effect modification by Hp genotype was consistent in both diabetic men and women but was not present in non-diabetics (p for interaction = 0.36).Conclusion:Among diabetic patients with CHD, the effect of ANA on raising CEC was blunted in those with a Hp CNV linked to dysfunctional HDL. These findings warrant validation and suggest a strategy to identify those most likely to benefit from interventions targeting reverse cholesterol transport.