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High-density lipoprotein (HDL) is commonly characterized by its cholesterol concentration (HDL-C) and inverse association with atherosclerotic cardiovascular disease.

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.

•7 % of US adults 40–59 years are eligible for primary prevention aspirin by USPSTF.•Higher proportional eligibility among men, older age (50–59 years), Black race.•30 % of individuals potentially eligible meet increased bleeding risk criteria.•Limited role of primary prevention aspirin in modern era under USPSTF guidelines.

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OBJECTIVE--To determine the association between circulating soluble receptor for advanced glycation end products (sRAGE) and coronary atherosclerosis. RESEARCH DESIGN AND METHODS--Using data from the Dallas Heart Study, a probability-based population [...]

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.

IMPORTANCE: Higher coronary artery calcium (CAC) identifies individuals at increased atherosclerotic cardiovascular disease (ASCVD) risk. Whether it can also identify individuals likely to derive net benefit from aspirin therapy is unclear. OBJECTIVE: To examine the association between CAC, bleeding, and ASCVD and explore the net estimated effect of aspirin at different CAC thresholds. DESIGN, SETTING, AND PARTICIPANTS: Prospective population-based cohort study of Dallas Heart Study participants, free from ASCVD and not taking aspirin at baseline. Data were analyzed between February 1, 2020, and July 15, 2020. EXPOSURES: Coronary artery calcium score in the following categories: 0, 1-99, and 100 or higher. MAIN OUTCOMES AND MEASURES: Major bleeding and ASCVD events were identified from International Statistical Classification of Diseases and Related Health Problems, Ninth Revision codes. Meta-analysis–derived aspirin effect estimates were applied to observed ASCVD and bleeding rates to model the net effect of aspirin at different CAC thresholds. RESULTS: A total of 2191 participants (mean [SD], age 44 [9.1] years, 1247 women [57%], and 1039 black individuals [47%]) had 116 major bleeding and 123 ASCVD events over a median follow-up of 12.2 years. Higher CAC categories (CAC 1-99 and ≥100 vs CAC 0) were associated with both ASCVD and bleeding events (hazard ratio [HR], 1.6; 95% CI, 1.1-2.4; HR, 2.6; 95% CI, 1.5-4.3; HR, 4.8; 95% CI, 2.8-8.2; P < .001; HR, 5.3; 95% CI, 3.6-7.9; P < .001), but the association between CAC and bleeding was attenuated after multivariable adjustment. Applying meta-analysis estimates, irrespective of CAC, aspirin use was estimated to result in net harm in individuals at low (<5%) and intermediate (5%-20%) 10-year ASCVD risk and net benefit in those at high (≥20%) ASCVD risk. Among individuals at lower bleeding risk, a CAC score of at least 100 identified individuals who would experience net benefit, but only in those at borderline or higher (≥5%) 10-year ASCVD risk. In individuals at higher bleeding risk, there would be net harm from aspirin irrespective of CAC and ASCVD risk. CONCLUSIONS AND RELEVANCE: Higher CAC is associated with both ASCVD and bleeding events, with a stronger association with ASCVD. A high CAC score identifies individuals estimated to derive net benefit from primary prevention aspirin therapy from those who would not, but only in the setting of lower bleeding risk and estimated ASCVD risk that is not low.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

Supplemental Digital Content is available in the text.

High-density lipoprotein (HDL) is a protein-lipid nanoparticle that has predominately been characterized by its cholesterol concentration (HDL-C). Recent studies have challenged the presumed inverse association between HDL-C and cardiovascular events, suggesting a more U-shaped association. This has opened new opportunities to evaluate more novel measures of HDL metabolism, such as HDL particle number (HDL-P) and one of HDL's key functions, cholesterol efflux. Both HDL-P and cholesterol efflux are inversely associated with incident cardiovascular events and may perhaps be better targets for intervention. This review includes recent research on the emerging U-shaped association between HDL-C and cardiovascular events, recent observational studies related to HDL-P, and the effects of established and novel interventions on cholesterol efflux.

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CVD Prevention – Primary and Secondary

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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.

Higher rates of dementia are reported in people with history of coronary artery disease. Smaller hippocampal volume (HV) is a risk factor for the development of dementia.

•GlycA more strongly predicted incident MI.•hsCRP more strongly predicted incident ischemic stroke.•GlycA may detect other inflammatory risk not captured by hsCRP

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.

Cholesterol efflux (CE) is a major athero-protective function of high density lipoproteins (HDL). HDL is a heterogeneous mixture of lipoproteins that contain apoA1, the prime protein of HDL, and may contain one or more of >200 other proteins. These other proteins cluster on subpopulations of HDL particles to form HDL subspecies. It is not entirely clear by simply measuring individual protein abundances what drives HDL function. We aimed to study the differential association of 7 HDL subspecies defined by presence or absence of a functional protein with extreme and persistent cholesterol efflux capacity (CEC). From ~3000 individuals in the multi-ethnic population-based DHS (Dallas Heart Study) cohort, people at the bottom 10% and top 90% of CEC were reassessed after 15 years resulting in 36 participants with extreme persistent high or low CEC for the present study. HDL with and without 7 individual proteins potentially relevant to HDL function were quantified using ELISA. Differences in association with CEC between HDL subspecies that contain or lack a defining protein were examined by heterogeneity test. In the low CEC group, HDL lacking apolipoprotein C3 (apoC3), complement C3, apoE (apolipoprotein E) and PLMG (plasminogen) were each associated positively with CEC while HDL subspecies containing these proteins were not positively associated with CEC. (Pearson correlation coefficient range 0.55369 to 0.66562 vs -0.08432 to -0.25198; p <0.05 for heterogeneity). In the high CEC group, no significant heterogeneity was found in association with CEC between HDL subspecies that contain or lack the same proteins. In people with extreme and persistent low CEC, HDL subspecies containing apoC3, complement C3, apoE and PLMG blunt the overall positive association between HDL and CEC. Our findings suggest that CEC of HDL in individuals with persistent and extreme low CEC is determined by the presence/absence of apoC3, complement C3, apoE and PLMG in HDL subspecies. Future studies involving manipulation of these proteins in HDL to investigate the effect on CE will provide deeper insight into functional speciation of HDL. This knowledge can be further applied to define biomarkers for altered CE in atherosclerotic cardiovascular diseases (ASCVD).

Reverse cholesterol transport is a main anti-atherosclerotic function of high-density lipoprotein (HDL), and cholesterol efflux capacity (CEC) is a key first step of this function. Inflammation and oxidation are metabolically linked to cholesterol transport but the relationships between these functions have not been well characterized. The objective of this study was to determine if extreme high or low CEC also had differences in inflammation and anti-oxidative functions. We hypothesized that inflammation and anti-oxidative functions of HDL are worse in those with extreme low vs. high CEC. Cholesterol efflux capacity was previously measured in 2,924 participants in the Dallas Heart Study, a multi-ethnic population-based cohort. Those below the 10thand above the 90thpercentile were recruited 15-17 years later, and those with persistent extreme high and low CEC were studied (N=36). Several inflammatory markers such as interleukin-1(IL-1), IL-6, IL-10, tumor necrosis factor α (TNF- α), vascular cell adhesion protein 1(VCAM-1), and serum amyloid A (SAA) were measured using MAGPIX instrument on whole EDTA plasma. The antioxidant levels of paraoxonase-1 (PON1) were measured based on arylesterase activity using ELISA kit on whole citrated plasma. We analyzed data in whole group and stratified by sex, race/ethnicity, and diabetes status. Despite a two-fold difference in CEC, there were no significant differences in inflammatory markers between extreme high vs. low CEC. In those with diabetes, SAA levels were significantly higher in those with low vs. high efflux (P=0.02). High CEC group showed the inverse association with inflammatory marker (IL-1) while direct association with anti-inflammatory marker (IL-10) performing Pearson Correlation Coefficient, R=1, P<0.0001. Activity of PON1 was lower in those with extreme low vs. high CEC, median (IQR) low vs. high: 76.7 (62.2-104.5) vs. 90.1 (82.6-102.0) U/L, (P=0.03). In conclusion, these findings suggest that a key measure of reverse cholesterol transport is more strongly related to anti-Oxidative function than systemic inflammation. Future studies are warranted to determine the complementary information these metabolic markers contribute for cardiovascular risk.

Background:Haptoglobin has three common genotypes: Hp 1-1, Hp 2-1, and Hp 2-2. The Hp 2-2 genotype, known to have poorer antioxidizing capacity, is associated with worse cardiovascular outcomes in select patients with diabetes. In this study, we explore the association between various cardiometabolic biomarker profiles and the three Hp genotypes in a multiethnic population.Methods:A cross-sectional analysis was performed for all participants with diabetes in the Dallas Heart Study and Multi-Ethnic Study of Atherosclerosis cohorts. Hp genotype was measured in 1,158 participants (399 from DHS and 759 from MESA) using ELISA technique (Savyon Diagnostics, Ltd). Associations between Hp genotype and 26 cardiometabolic circulating and imaging biomarkers were assessed by ANOVA and stratified by ethnicity.Results:The study included 51% women, 44% Black (513 of 1,158: Hp 1-1=45%, Hp 2-1=35%, Hp 2-2=20%), 26% Hispanic (300 of 1,158: Hp 1-1=25%, Hp 2-1=49%, Hp 2-2=26%), 20% White (237 of 1,158: Hp 1-1=16%, Hp 2-1=56%, Hp 2-2=28%), and 9.2% Asian/Pacific Islander/East Indian (107 of 1,158: Hp 1-1=15%, Hp 2-1=36%, Hp 2-2=49%) participants. Significant differences were seen in lipid metabolism as well as atherosclerosis, inflammatory, structural, and endothelial markers with no significant differences seen in imaging biomarkers. In White participants, Hp 1-1 was associated with elevated total cholesterol (p=0.016), LDL-p (p=0.001), and LDL-C (p=0.004). In Asian/Pacific Islander/East Indian participants, Hp 2-2 was associated with elevated systolic blood pressure (p=0.029), BMI (p=0.029), and inflammatory markers such as IL-6 (p=0.018) and D-dimer (p=0.027). In Black participants, Hp 2-2 was associated with elevated ICAM (p=0.048) and BMI (p=0.007). Lastly, in Hispanic participants, no significant associations were seen. In exploratory analysis, when comparing Hp 1-1 and Hp 2-1 with Hp 2-2, there was greater magnitude effect size of certain biomarkers in Black and Asian participants, suggesting potential differential effects by ethnicity.Conclusion:Associations between Hp genotype and various cardiometabolic biomarkers are varied and ethnicity dependent with further studies needed to investigate the underlying physiologic mechanisms.

IMPORTANCE Transthoracic echocardiography (TTE) accounts for almost half of all cardiac imaging services and is a widely available and versatile tool. Appropriate use criteria (AUC) for echocardiography were developed to improve patient care and health outcomes. Prior studies have shown that most TTEs are appropriate by AUC. However, the associations among TTE, AUC, and their clinical impact have not been well explored. OBJECTIVES To describe the proportion of TTEs that affect clinical care in an academic medical center overall and in subgroups defined as appropriate and inappropriate by AUC. DESIGN AND SETTING Retrospective review of medical records from 535 consecutive TTEs at an academic medical center was performed. The TTEs were classified according to 2011 AUC by 2 cardiologists blinded to clinical impact and were assessed for clinical impact by 2 cardiologists blinded to AUC. Clinical impact was assigned to 1 of the following 3 categories: (1) active change in care, (2) continuation of current care, or (3) no change in care. PARTICIPANTS Five hundred thirty-five patients undergoing TTE. EXPOSURE Transthoracic echocardiography. MAIN OUTCOMES AND MEASURES Prevalence of appropriate, inappropriate, and uncertain TTEs and prevalence of clinical impact subcategories. RESULTS Overall, 31.8% of TTEs resulted in an active change in care; 46.9%, continuation of current care; and 21.3%, no change in care. By 2011 AUC, 91.8% of TTEs were appropriate; 4.3%, inappropriate; and 3.9%, uncertain. We detected no statistically significant difference between appropriate and inappropriate TTEs in the proportion of TTEs that led to active change in care (32.2% vs 21.7%; P = .29). CONCLUSIONS AND RELEVANCE Although 9 in 10 TTEs were appropriate by 2011 AUC, fewer than 1 in 3 TTEs resulted in an active change in care, nearly half resulted in continuation of current care, and slightly more than 1 in 5 resulted in no change in care. The low rate of active change in care (31.8%) among TTEs mostly classified as appropriate (91.8%) highlights the need for a better method to optimize TTE utilization to use limited health care resources efficiently while providing high-quality care.

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.