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Background and Objective: High Lp(a) levels are a risk factor for ASCVD, however Lp(a) ordering in clinical practice is low. This study examines how race/ethnicity and socioeconomic status influence Lp(a) ordering., Methods: This is a single center, retrospective study (2/1/2020-6/30/2023) using electronic medical records of adults with at least one personal ICD-10 diagnosis of ASCVD, aortic valve stenosis, resistant hypercholesterolemia (LDL-C >160 mg/dL on statin therapy), and family history of ASCVD or high Lp(a). We evaluated Lp(a) level differences among racial/ethnic groups and sexes. We also assessed associations between diagnosis type, diagnosis number, age at diagnosis, race/ethnicity, socioeconomic score (based on zip codes), public health coverage and the presence of Lp(a) orders., Results: 4 % of our cohort (N=2,249 in 56,833) had an Lp(a) order (17.3 % of whom identified as Hispanic, 8.7 % non-Hispanic Black, 47.5 % non-Hispanic White, and 27 % Asian/other). Non-Hispanic Black and Hispanic patients had lower rates of Lp(a) orders (0.17 % and 0.28 %, respectively) when compared to non-Hispanic White patients (2.35 %), p < 0.001, however, their median Lp(a) levels were higher, p < 0.001. Individuals on Medicaid or belonging to deprived socioeconomic groups were less likely to have an Lp(a) order (IRR = 0.40, p < 0.001 and IRR = 0.39, p < 0.001 respectively). Certain diagnosis (carotid stenosis, family history of ASCVD and FH) and multiple diagnoses (>2) resulted in more Lp(a) orders compared to only one diagnosis (p < 0.001)., Conclusions: Lp(a) ordering is low in patients with or at risk for ASCVD. Non-Hispanic Black and Hispanic patients are less likely to have an Lp(a) order. Individuals on Medicaid and residing in socioeconomically deprived neighborhoods are less like have an Lp(a) order. Lp(a) orders depend on the type and number of patients' diagnoses., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

Background: High Lp(a) levels contribute to atherosclerotic cardiovascular disease and are tightly regulated by the LPA gene . Lp(a) levels have an inverse correlation with LPA Kringle IV Type-2 (KIV-2) copy number (CN). Black (B) and Hispanic (H) individuals exhibit higher levels of Lp(a), and rates of CVD compared to non-Hispanic Whites (NHW). Therefore, we investigated genetic variations in the LPA KIV-2 region across three ancestries and their associations with metabolic risk factors., Methods: Using published pipelines, we analyzed a multi-ethnic whole exome dataset comprising 3,817 participants from the Washington Heights and Inwood Columbia Aging Project (WHICAP): 886 [NHW (23%), 1,811 Caribbean (C) H (47%), and 1,120 B individuals (29%). Rare and common variants (alternative allele carrier frequency, CF < 0.01 or > 0.99 and 0.01 < CF < 0.99, respectively) were identified and KIV-2 CN estimated. The associations of variants and CN with history of heart disease, hypertension (HTN), stroke, lipid levels and clinical diagnosis of Alzheimer's disease (AD) was assessed. A small pilot provided in-silico validation of study findings., Results: We report 1421 variants in the LPA KIV-2 repeat region, comprising 267 exonic and 1154 intronic variants. 61.4% of the exonic variants have not been previously described. Three novel exonic variants significantly increase the risk of HTN across all ethnic groups: 4785-C/A (frequency = 78%, odds ratio [OR] = 1.45, p = 0.032), 727-T/C (frequency = 96%, OR = 2.11, p = 0.032), and 723-A/G (frequency = 96%, OR = 1.97, p = 0.038). Additionally, six intronic variants showed associations with HTN: 166-G/A, 387-G/C, 402-G/A, 4527-A/T, 4541-G/A, and 4653-A/T. One intronic variant, 412-C/T, was associated with decreased blood glucose levels (frequency = 72%, β = -14.52, p = 0.02).Three of the associations were not affected after adjusting for LPA KIV-2 CN: 412-C/T (β = -14.2, p = 0.03), 166-G/A (OR = 1.41, p = 0.05), and 387-G/C (OR = 1.40, p = 0.05). KIV CN itself was significantly associated with 314 variants and was negatively correlated with plasma total cholesterol levels., Conclusions: In three ancestry groups, we identify novel rare and common LPA KIV-2 region variants. We report new associations of variants with HTN and Glucose levels. These results underscore the genetic complexity of the LPA KIV-2 region in influencing cardiovascular and metabolic health, suggesting potential genetic regulation of pathways that can be studied for research and therapeutic interventions.

Background: High lipoprotein (a) [Lp(a)] is associated with adverse limb events in patients undergoing lower extremity revascularization. Lp(a) levels are genetically pre-determined, with LPA gene encoding for two apolipoprotein (a) [apo(a)] isoforms. Isoform size variations are driven by the number of kringle IV type 2 (KIV-2) repeats. Lp(a) levels are inversely correlated with isoform size. In this study, we examined the role of Lp(a) levels, apo(a) size, and inflammatory markers with lower extremity revascularization outcomes., Methods: Twenty-five subjects with chronic peripheral arterial disease (PAD) underwent open or endovascular lower extremity revascularization (mean age, 66.7 ± 9.7 years; Female = 12; Male = 13; Black = 8; Hispanic = 5; and White = 12). Pre- and postoperative medical history, self-reported symptoms, ankle-brachial indices (ABIs), and lower extremity duplex ultrasounds were obtained. Plasma Lp(a), apoB100, lipid panel, and pro-inflammatory markers (IL-6, IL-18, hs-CRP, TNFα) were assayed preoperatively. Isoform size was estimated using gel electrophoresis and weighted isoform size ( wIS ) calculated based on % isoform expression. Firth logistic regression was used to examine the relationship between Lp(a) levels and wIS with procedural outcomes: symptoms (better/worse), early primary patency at 2 to 4 weeks, ABIs, and reintervention within 3 to 6 months. We controlled for age, sex, history of diabetes, smoking, statin, antiplatelet, and anticoagulation use., Results: Median plasma Lp(a) level was 108 (interrquartile range, 44-301) nmol/L. The mean apoB100 level was 168.0 ± 65.8 mg/dL. These values were not statistically different among races. We found no association between Lp(a) levels and w IS with measured plasma pro-inflammatory markers. However, smaller apo(a) wIS was associated with occlusion of the treated lesion(s) in the postoperative period (odds ratio, 1.97; 95% confidence interval, 1.01-3.86; P  < .05). The relationship of smaller apo(a) wIS with reintervention was not as strong (odds ratio, 1.57; 95% confidence interval, 0.96-2.56; P  = .07). We observed no association between wIS with patient reported symptoms or change in ABIs., Conclusions: In this small study, subjects with smaller apo(a) isoform size undergoing peripheral arterial revascularization were more likely to experience occlusion in the postoperative period and/or require reintervention. Larger cohort studies identifying the mechanism and validating these preliminary data are needed to improve understanding of long-term peripheral vascular outcomes., Competing Interests: None., (© 2024 The Author(s).)

Purpose of Review: Transmembrane 6 superfamily member 2 ( TM6SF2 ) gene was identified through exome-wide studies in 2014. A genetic variant from glutamic acid to lysine substitution at amino acid position 167 (NM&#95;001001524.3:c.499G> A) (p.Gln167Lys/p.E167K, rs58542926) was discovered (p.E167K) to be highly associated with increased hepatic fat content and reduced levels of plasma triglycerides and LDL cholesterol. In this review, we focus on the discovery of TM6SF2 and its role in VLDL secretion pathways. Human data suggest TM6SF2 is linked to hepatic steatosis and cardiovascular disease (CVD), hence understanding its metabolic pathways is of high scientific interest., Recent Findings: Since its discovery, completed research studies in cell, rodent and human models have defined the role of TM6SF2 and its links to human disease. TM6SF2 resides in the endoplasmic reticulum (ER) and the ER-Golgi interface and helps with the lipidation of nascent VLDL, the main carrier of triglycerides from the liver to the periphery. Consistent results from cells and rodents indicated that the secretion of triglycerides is reduced in carriers of the p.E167K variant or when hepatic TM6SF2 is deleted. However, data for secretion of APOB, the main protein of VLDL particles responsible for triglycerides transport, are inconsistent., Summary: The identification of genetic variants that are highly associated with human disease presentation should be followed by the validation and investigation into the pathways that regulate disease mechanisms. In this review, we highlight the role of TM6SF2 and its role in processing of liver triglycerides., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: LCAT (lecithin cholesterol acyl transferase) catalyzes the conversion of unesterified, or free cholesterol, to cholesteryl ester, which moves from the surface of HDL (high-density lipoprotein) into the neutral lipid core. As this iterative process continues, nascent lipid-poor HDL is converted to a series of larger, spherical cholesteryl ester-enriched HDL particles that can be cleared by the liver in a process that has been termed reverse cholesterol transport., Methods: We conducted a randomized, placebocontrolled, crossover study in 5 volunteers with atherosclerotic cardiovascular disease, to examine the effects of an acute increase of recombinant human (rh) LCAT via intravenous administration (300-mg loading dose followed by 150 mg at 48 hours) on the in vivo metabolism of HDL APO (apolipoprotein)A1 and APOA2, and the APOB100-lipoproteins, very low density, intermediate density, and low-density lipoproteins., Results: As expected, recombinant human LCAT treatment significantly increased HDL-cholesterol (34.9 mg/dL; P ≤0.001), and this was mostly due to the increase in cholesteryl ester content (33.0 mg/dL; P =0.014). This change did not affect the fractional clearance or production rates of HDL-APOA1 and HDL-APOA2. There were also no significant changes in the metabolism of APOB100-lipoproteins., Conclusions: Our results suggest that an acute increase in LCAT activity drives greater flux of cholesteryl ester through the reverse cholesterol transport pathway without significantly altering the clearance and production of the main HDL proteins and without affecting the metabolism of APOB100-lipoproteins. Long-term elevations of LCAT might, therefore, have beneficial effects on total body cholesterol balance and atherogenesis., Competing Interests: Disclosures R. George was an employee of AstraZeneca during the time this study was conducted. H. Ginsberg has consulted for AstraZeneca intermittently, including on 2 occasions during the time period that this study was conducted. However, those consultations were not related to recombinant human lecithin cholesterol acyl transferase.

High levels of lipoprotein(a) [Lp(a)] are causal for atherosclerotic cardiovascular disease (ASCVD). Lp(a) is the most prevalent inherited dyslipidemia and strongest genetic ASCVD risk factor. This risk persists in the presence of at target, guideline-recommended, LDL-C levels and adherence to lifestyle modifications. Epidemiological and genetic evidence supporting its causal role in ASCVD and calcific aortic stenosis continues to accumulate, although various facets regarding Lp(a) biology (genetics, pathophysiology, and expression across race/ethnic groups) are not yet fully understood. The evolving nature of clinical guidelines and consensus statements recommending universal measurements of Lp(a) and the scientific data supporting its role in multiple disease states reinforce the clinical merit to start population screening for Lp(a) now. There is a current gap in the implementation of recommendations for primary and secondary cardiovascular disease (CVD) prevention in those with high Lp(a), in part due to a lack of protocols for management strategies. Importantly, targeted apolipoprotein(a) [apo(a)]-lowering therapies that reduce Lp(a) levels in patients with high Lp(a) are in phase 3 clinical development. This review focuses on the identification and clinical management of patients with high Lp(a). Specifically, we highlight the clinical value of measuring Lp(a) and its use in determining Lp(a)-associated CVD risk by providing actionable guidance, based on scientific knowledge, that can be utilized now to mitigate risk caused by high Lp(a)., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V.)

Background and Aims: High plasma lipoprotein (a) [Lp(a)] levels are associated with increased atherosclerotic cardiovascular disease (ASCVD), in part attributed to elevated inflammation. High plasma Lp(a) levels inversely correlate with apolipoprotein (a) [(APO(a)] isoform size. APO(a) isoform size is negatively associated with APO(a) production rate (PR) and positively associated with APO(a) fractional catabolic rate (FCR). We asked whether APO(a) PR and FCR (kinetics) are associated with plasma levels of interleukin (IL)-6 and IL-18, pro-inflammatory interleukins that promote ASCVD., Methods: We used samples from existing data of APO(a) kinetic studies from an ethnically diverse cohort (n = 25: 10 Black, 9 Hispanic, and 6 White subjects) and assessed IL-6 and IL-18 plasma levels. We performed multivariate linear regression analyses to examine the relationships between predictors APO(a) PR or APO(a) FCR, and outcome variables IL-6 or IL-18. In these analyses, we adjusted for parameters known to affect Lp(a) levels and APO(a) PR and FCR, including race/ethnicity and APO(a) isoform size., Results: APO(a) PR and FCR were positively associated with plasma IL-6, independent of isoform size, and dependent on race/ethnicity. APO(a) PR was positively associated with plasma IL-18, independent of isoform size and race/ethnicity. APO(a) FCR was not associated with plasma IL-18., Conclusions: Our studies demonstrate a relationship between APO(a) PR and FCR and plasma IL-6 or IL-18, interleukins that promote ASCVD. These studies provide new insights into Lp(a) pro-inflammatory properties and are especially relevant in view of therapies targeting APO(a) to decrease cardiovascular risk., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Lipoprotein (a) [Lp(a)] is an apoB100-containing lipoprotein with high levels being positively associated with atherosclerotic cardiovascular disease. Lp(a) levels are genetically determined. However, previous studies report a negative association between Lp(a) and saturated fatty acid intake. Currently, apoB100 lowering therapies are used to lower Lp(a) levels, and apheresis therapy is FDA approved for patients with extreme elevations of Lp(a). The current study analyzed the association of free-living diet components with plasma Lp(a) levels., Methods: Dietary composition data was collected during screening visits for enrollment in previously completed lipid and lipoprotein metabolism studies at Columbia University Irving Medical Center via a standardized protocol by registered dietitians using 24 hour recalls. Data were analyzed with the Nutrition Data System for Research (Version 2018). Diet quality was calculated using the Healthy Eating Index (HEI) score. Fasting plasma Lp(a) levels were measured via an isoform-independent ELISA and apo(a) isoforms were measured using gel electrophoresis., Results: We enrolled 28 subjects [Black (n = 18); Hispanic (n = 7); White (n = 3)]. The mean age was 48.3 ± 12.5 years with 17 males. Median level of Lp(a) was 79.9 nmol/L (34.4-146.0) and it was negatively associated with absolute (grams/day) and relative (percent of total calories) intake of dietary saturated fatty acids (SFA) (R = -0.43, P = 0.02, SFA …(% CAL): R = -0.38, P = 0.04), palmitic acid intake (R = -0.38, P = 0.05), and stearic acid intake (R = -0.40, P = 0.03). Analyses of associations with HEI score when stratified based on Lp(a) levels > or ≤ 100 nmol/L revealed no significant associations with any of the constituent factors., Conclusions: Using 24 hour recall, we confirm previous findings that Lp(a) levels are negatively associated with dietary saturated fatty acid intake. Additionally, Lp(a) levels are not related to diet quality, as assessed by the HEI score. The mechanisms underlying the relationship of SFA with Lp(a) require further investigation., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Therapeutic approaches to reduce atherogenic lipid and lipoprotein levels remain the most effective and assessable strategies to prevent and treat cardiovascular disease. The discovery of novel research targets linked to pathways associated with cardiovascular disease development has enhanced our ability to decrease disease burden; however, residual cardiovascular disease risks remain. Advancements in genetics and personalized medicine are essential to understand some of the factors driving residual risk. Biological sex is among the most relevant factors affecting plasma lipid and lipoprotein profiles, playing a pivotal role in the development of cardiovascular disease. This minireview summarizes the most recent preclinical and clinical studies covering the effect of sex on plasma lipid and lipoprotein levels. We highlight the recent advances in the mechanisms regulating hepatic lipoprotein production and clearance as potential drivers of disease presentation. We focus on using sex as a biological variable in studying circulating lipid and lipoprotein levels., Competing Interests: Disclosures None.

High levels of lipoprotein(a) [Lp(a)] are causal for development of atherosclerotic cardiovascular disease and highly regulated by genetics. Levels are higher in Blacks compared to Whites, and in women compared to men. Lp(a)'s main protein components are apolipoprotein (apo) (a) and apoB100, the latter being the main component of Low-Density Lipoprotein (LDL) particles. Studies have identified Lp(a) to be associated with inflammatory, coagulation and wound healing pathways. Lack of validated and accepted assays to measure Lp(a), risk cutoff values, guidelines for diagnosis, and targeted therapies have added challenges to the field. Scientific efforts are ongoing to address these, including studies evaluating the cardiovascular benefits of decreasing Lp(a) levels with targeted apo(a) lowering treatments. This review will provide a synopsis of evidence-based effects of high Lp(a) on disease presentation, highlight available guidelines and discuss promising therapies in development. We will conclude with current clinical information and future research needs in the field., (Copyright © 2023. Published by Elsevier Ltd.)

Lipoprotein(a) [Lp(a)] has two main proteins, apoB100 and apo(a). High levels of Lp(a) confer an increased risk for atherosclerotic cardiovascular disease. Most people have two circulating isoforms of apo(a) differing in their molecular mass, determined by the number of Kringle IV Type 2 repeats. Previous studies report a strong inverse relationship between Lp(a) levels and apo(a) isoform sizes. The roles of Lp(a) production and fractional clearance and how ancestry affects this relationship remain incompletely defined. We therefore examined the relationships of apo(a) size with Lp(a) levels and both apo(a) fractional clearance rates (FCR) and production rates (PR) in 32 individuals not on lipid-lowering treatment. We determined plasma Lp(a) levels and apo(a) isoform sizes, and used the relative expression of the two isoforms to calculate a "weighted isoform size" (wIS). Stable isotope studies were performed, using D3-leucine, to determine the apo(a) FCR and PR. As expected, plasma Lp(a) concentrations were inversely correlated with wIS (R 2  = 0.27; P = 0.002). The wIS had a modest positive correlation with apo(a) FCR (R 2  = 0.10, P = 0.08), and a negative correlation with apo(a) PR (R 2  = 0.11; P = 0.06). The relationship between wIS and PR became significant when we controlled for self-reported race and ethnicity (SRRE) (R 2  = 0.24, P = 0.03); controlling for SRRE did not affect the relationship between wIS and FCR. Apo(a) wIS plays a role in both FCR and PR; however, adjusting for SRRE strengthens the correlation between wIS and PR, suggesting an effect of ancestry., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article, (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients with SARS-CoV-2 who present with gastrointestinal symptoms have a milder clinical course than those who do not. Risk factors for severe COVID-19 disease include increased adiposity and sarcopenia., Aims: To determine whether body composition risk factors are associated with worse outcomes among patients with gastrointestinal symptoms., Methods: This was a retrospective study of hospitalized patients with COVID-19 who underwent abdominal CT scan for clinical indications. Abdominal body composition measures including skeletal muscle index (SMI), intramuscular adipose tissue index (IMATI), visceral adipose tissue index (VATI), subcutaneous adipose tissue index (SATI), visceral-to-subcutaneous adipose tissue ratio (VAT/SAT ratio), and liver and spleen attenuation were collected. The association between body composition measurements and 30-day mortality was evaluated in patients with and without gastrointestinal symptoms at the time of positive SARS-CoV-2 test., Results: Abdominal CT scans of 190 patients with COVID-19 were evaluated. Gastrointestinal symptoms including nausea, vomiting, diarrhea, or abdominal pain were present in 117 (62%). Among patients without gastrointestinal symptoms, those who died had greater IMATI (p = 0.049), less SMI (p = 0.010), and a trend toward a greater VAT/SAT ratio. Among patients with gastrointestinal symptoms, those who died had significantly greater IMATI (p = 0.025) but no differences in other measures., Conclusions: Among patients with COVID-19, those without gastrointestinal symptoms showed the expected associations between mortality and low SMI, high IMATI, and trend toward higher VAT/SAT ratio, but those with gastrointestinal symptoms did not. Future studies should explore the mechanisms for the altered disease course in patients with COVID-19 who present with gastrointestinal symptoms., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

High levels of lipoprotein(a) [Lp(a)], an apoB100-containing lipoprotein, are an independent and causal risk factor for atherosclerotic cardiovascular diseases through mechanisms associated with increased atherogenesis, inflammation, and thrombosis. Lp(a) is predominantly a monogenic cardiovascular risk determinant, with ≈70% to ≥90% of interindividual heterogeneity in levels being genetically determined. The 2 major protein components of Lp(a) particles are apoB100 and apolipoprotein(a). Lp(a) remains a risk factor for cardiovascular disease development even in the setting of effective reduction of plasma low-density lipoprotein cholesterol and apoB100. Despite its demonstrated contribution to atherosclerotic cardiovascular disease burden, we presently lack standardization and harmonization of assays, universal guidelines for diagnosing and providing risk assessment, and targeted treatments to lower Lp(a). There is a clinical need to understand the genetic and biological basis for variation in Lp(a) levels and its relationship to disease in different ancestry groups. This scientific statement capitalizes on the expertise of a diverse basic science and clinical workgroup to highlight the history, biology, pathophysiology, and emerging clinical evidence in the Lp(a) field. Herein, we address key knowledge gaps and future directions required to mitigate the atherosclerotic cardiovascular disease risk attributable to elevated Lp(a) levels.

Background: Obesity has emerged as a risk factor for severe coronavirus disease 2019 (COVID-19) infection. To inform treatment considerations the relationship between obesity and COVID-19 complications and the influence of race, ethnicity, and socioeconomic factors deserves continued attention., Objective: To determine if obesity is an independent risk factor for severe COVID-19 complications and mortality and examine the relationship between BMI, race, ethnicity, distressed community index and COVID-19 complications and mortality., Methods: A retrospective cohort study of 1,019 SARS-CoV-2 positive adult admitted to an academic medical center (n = 928) and its affiliated community hospital (n-91) in New York City from March 1 to April 18, 2020., Results: Median age was 64 years (IQR 52-75), 58.7% were men, 23.0% were Black, and 52.8% were Hispanic. The prevalence of overweight and obesity was 75.2%; median BMI was 28.5 kg/m2 (25.1-33.0). Over the study period 23.7% patients died, 27.3% required invasive mechanical ventilation, 22.7% developed septic shock, and 9.1% required renal replacement therapy (RRT). In the multivariable logistic regression model, BMI was associated with complications including intubation (Odds Ratio [OR]1.03, 95% Confidence Interval [CI]1.01-1.05), septic shock (OR 1.04, CI 1.01-1.06), and RRT (OR1.07, CI 1.04-1.10), and mortality (OR 1.04, CI 1.01-1.06). The odds of death were highest among those with BMI ≥ 40 kg/m2 (OR 2.05, CI 1.04-4.04). Mortality did not differ by race, ethnicity, or socioeconomic distress score, though Black and Asian patients were more likely to require RRT., Conclusions and Relevance: Severe complications of COVID-19 and death are more likely in patients with obesity, independent of age and comorbidities. While race, ethnicity, and socioeconomic status did not impact COVID-19 related mortality, Black and Asian patients were more likely to require RRT. The presence of obesity, and in some instances race, should inform resource allocation and risk stratification in patients hospitalized with COVID-19., Competing Interests: Gabrielle Page-Wilson has served as a consultant for Strongbridge Biopharma and Adare Pharmaceuticals and has served on scientific advisory boards for Strongbridge Biopharma and Recordati Rare Diseases, Inc. Judith Korner MD, PhD is a consultant for Digma Medical, Found Health Inc. and a scientific advisory board member for GI Dynamics. We would like to confirm that these competing interests do not alter our adherence to all PLOS ONE policies on sharing data and materials.

Genome wide association, epidemiological, and clinical studies have established high lipoprotein(a) [Lp(a)] as a causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Lp(a) is an apoB100 containing lipoprotein covalently bound to apolipoprotein(a) [apo(a)], a glycoprotein. Plasma Lp(a) levels are to a large extent determined by genetics. Its link to cardiovascular disease (CVD) may be driven by its pro-inflammatory effects, of which its association with oxidized phospholipids (oxPL) bound to Lp(a) is the most studied. Various inflammatory conditions, such as rheumatoid arthritis (RA), systemic lupus erythematosus, acquired immunodeficiency syndrome, and chronic renal failure are associated with high Lp(a) levels. In cases of RA, high Lp(a) levels are reversed by interleukin-6 receptor (IL-6R) blockade by tocilizumab, suggesting a potential role for IL-6 in regulating Lp(a) plasma levels. Elevated levels of IL-6 and IL-6R polymorphisms are associated with CVD. Therapies aimed at lowering apo(a) and thereby reducing plasma Lp(a) levels are in clinical trials. Their results will determine if reductions in apo(a) and Lp(a) decrease cardiovascular outcomes. As we enter this new arena of available treatments, there is a need to improve our understanding of mechanisms. This review will focus on the role of Lp(a) in inflammation and CVD., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose of Review: Lipoprotein(a) [Lp(a)] is a plasma circulating apoB100 (apoB) containing lipoprotein. It has a unique glycoprotein bound to the apoB100, apolipoprotein(a) [apo(a)]. The majority of the population expresses two apo(a) isoforms, when bound to apoB100 they create two circulating Lp(a) particles. Lp(a) levels are genetically determined and epidemiological studies have established elevated levels of Lp(a) to be a causal risk factor of cardiovascular disease (CVD). Lp(a) levels differ across racial groups and Blacks of Sub-Saharan decent have higher levels when compared to white. In comparison to white populations, studies in minorities are less represented in the published literature. Additionally, there is a lack of standardization in the commercial assays used to measured Lp(a) levels, and hence it is difficult to assess risk based on individual Lp(a) levels, but risk seems to occur in the upper percentiles of the population., Recent Findings: A recent study using data from the UK biobank highlights the racial differences in Lp(a) levels and the increase risk in CVD amongst all races., Summary: This review will highlight Lp(a) biology and physiology with a focus on available data from racially diverse cohorts. There is a need to perform studies in diverse populations to understand if they are at higher risk than whites are., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: The role of triglyceride-rich lipoproteins (TRLs) in the development of atherosclerotic cardiovascular disease (ASCVD) is at the forefront of current research and treatment development programs. Despite extreme lowering of LDL-cholesterol there remains a high risk of cardiovascular disease and mortality. Recent large epidemiological, genomic wide association studies and Mendelian randomization studies have identified novel mechanisms and targets regulating TRL. This review will focus on recent and ongoing clinical trials that aim to reduce cardiovascular risk by decreasing plasma levels of TRL., Recent Findings: Ongoing efforts of basic and clinical scientist have described novel TRL regulating mechanism. The concentration on lifestyle changes is key to prevention and treatment guidelines. There is continue evidence that supports previous guidelines using fibrates alone and in combination with niacin to reduce TRLs, in special cases. The recent results from the REDUCE-IT study support the use of eicosapentaenoic acid (EPA) for risk reduction and ASCVD, but recently presented data from the Long-Term Outcome Study to Assess Statin Residual Risk Reduction With Epanova in High Cardiovascular Risk Patients with Hypertriglyceridemia and Omega-3 Fatty Acids in Elderly Patients With Acute Myocardial Infarction studies do not support the use of combination EPA/docosahexaenoic acid. The latter highlights the need for further studies into the pathways regulating ASCVD risk reduction after EPA administration. The identification of novel targets, such as apolipoprotein C3 and angiopoietin-like protein-3, are driving the development of novel treatments, and is the focus of this review., Summary: The current management of elevated triglyceride levels and the effect on cardiovascular outcomes is an emerging area of research. New data from fish oil studies suggest differences in EPA vs. EPA/docosahexaenoic acid cardio protection outcomes. The preliminary data from ongoing clinical trials of novel triglyceride-lowering therapeutics are promising. These programs will ultimately provide foundations for future triglyceride-lowering guidelines., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

In this issue of the JCI, Kanter et al. make a strong case for implicating apolipoprotein C3 (APOC3) as a central player in atherosclerotic cardiovascular disease that is commonly seen in individuals with type 1 diabetes mellitus (T1DM). Kanter and colleagues suggest that insulin deficiency elevates plasma APOC3 as well as atherogenic triglyceride-rich (TG-rich) lipoproteins (TRLs). Using two mouse models of T1DM, the authors investigated APOC3-mediated inhibition of both TG hydrolysis by lipoprotein lipase and hepatic uptake of remnant lipoproteins. They suggest that poorly catabolized lipoproteins, enriched in both APOC3 and APOE content, are particularly atherogenic. Notably, treating both mouse models with an APOC3 antisense oligonucleotide lowered both plasma APOC3 and TRLs, and prevented atherosclerosis. These impactful mouse studies were supported by the initial finding that APOC3 predicted coronary artery disease events in participants of the prospective Coronary Artery Calcification in Type 1 Diabetes study with normal TG levels.

Objective- Apo (apolipoprotein) CIII inhibits lipoprotein lipase (LpL)-mediated lipolysis of VLDL (very-low-density lipoprotein) triglyceride (TG) and decreases hepatic uptake of VLDL remnants. The discovery that 5% of Lancaster Old Order Amish are heterozygous for the APOC3 R19X null mutation provided the opportunity to determine the effects of a naturally occurring reduction in apo CIII levels on the metabolism of atherogenic containing lipoproteins. Approach and Results- We conducted stable isotope studies of VLDL-TG and apoB100 in 5 individuals heterozygous for the null mutation APOC3 R19X (CT) and their unaffected (CC) siblings. Fractional clearance rates and production rates of VLDL-TG and apoB100 in VLDL, IDL (intermediate-density lipoprotein), LDL, apo CIII, and apo CII were determined. Affected (CT) individuals had 49% reduction in plasma apo CIII levels compared with CCs ( P<0.01) and reduced plasma levels of TG (35%, P<0.02), VLDL-TG (45%, P<0.02), and VLDL-apoB100 (36%, P<0.05). These changes were because of higher fractional clearance rates of VLDL-TG and VLDL-apoB100 with no differences in production rates. CTs had higher rates of the conversion of VLDL remnants to LDL compared with CCs. In contrast, rates of direct removal of VLDL remnants did not differ between the groups. As a result, the flux of apoB100 from VLDL to LDL was not reduced, and the plasma levels of LDL-cholesterol and LDL-apoB100 were not lower in the CT group. Apo CIII production rate was lower in CTs compared with CCs, whereas apo CII production rate was not different between the 2 groups. The fractional clearance rates of both apo CIII and apo CII were higher in CTs than CCs. Conclusions- These studies demonstrate that 50% reductions in plasma apo CIII, in otherwise healthy subjects, results in a significantly higher rate of conversion of VLDL to LDL, with little effect on direct hepatic uptake of VLDL. When put in the context of studies demonstrating significant protection from cardiovascular events in individuals with loss of function variants in the APOC3 gene, our results provide strong evidence that therapies which increase the efficiency of conversion of VLDL to LDL, thereby reducing remnant concentrations, should reduce the risk of cardiovascular disease.

Elevated lipoprotein (a) [Lp(a)] levels increase the risk for CVD. Novel treatments that decrease LDL cholesterol (LDL-C) have also shown promise for reducing Lp(a) levels. Mipomersen, an antisense oligonucleotide that inhibits apoB synthesis, is approved for the treatment of homozygous familial hypercholesterolemia. It decreases plasma levels of LDL-C by 25% to 39% and lowers levels of Lp(a) by 21% to 39%. We examined the mechanisms for Lp(a) lowering during mipomersen treatment. We enrolled 14 healthy volunteers who received weekly placebo injections for 3 weeks followed by weekly injections of mipomersen for 7 weeks. Stable isotope kinetic studies were performed using deuterated leucine at the end of the placebo and mipomersen treatment periods. The fractional catabolic rate (FCR) of Lp(a) was determined from the enrichment of a leucine-containing peptide specific to apo(a) by LC/MS. The production rate (PR) of Lp(a) was calculated from the product of Lp(a) FCR and Lp(a) concentration (converted to pool size). In a diverse population, mipomersen reduced plasma Lp(a) levels by 21%. In the overall study group, mipomersen treatment resulted in a 27% increase in the FCR of Lp(a) with no significant change in PR. However, there was heterogeneity in the response to mipomersen therapy, and changes in both FCRs and PRs affected the degree of change in Lp(a) concentrations. Mipomersen treatment decreases Lp(a) plasma levels mainly by increasing the FCR of Lp(a), although changes in Lp(a) PR were significant predictors of reductions in Lp(a) levels in some subjects., (Copyright © 2018 by the American Society for Biochemistry and Molecular Biology, Inc.)

Pathophysiological, epidemiological, and genetic studies provide strong evidence that lipoprotein(a) [Lp(a)] is a causal mediator of cardiovascular disease (CVD) and calcific aortic valve disease (CAVD). Specific therapies to address Lp(a)-mediated CVD and CAVD are in clinical development. Due to knowledge gaps, the National Heart, Lung, and Blood Institute organized a working group that identified challenges in fully understanding the role of Lp(a) in CVD/CAVD. These included the lack of research funding, inadequate experimental models, lack of globally standardized Lp(a) assays, and inadequate understanding of the mechanisms underlying current drug therapies on Lp(a) levels. Specific recommendations were provided to facilitate basic, mechanistic, preclinical, and clinical research on Lp(a); foster collaborative research and resource sharing; leverage expertise of different groups and centers with complementary skills; and use existing National Heart, Lung, and Blood Institute resources. Concerted efforts to understand Lp(a) pathophysiology, together with diagnostic and therapeutic advances, are required to reduce Lp(a)-mediated risk of CVD and CAVD., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Lipoprotein (a) [Lp(a)] is characterized by apolipoprotein (a) [apo(a)] covalently bound to apolipoprotein B 100. It was described in human plasma by Berg et al. in 1963 and the gene encoding apo(a) ( LPA ) was cloned in 1987 by Lawn and colleagues. Epidemiologic and genetic studies demonstrate that increases in Lp(a) plasma levels increase the risk of atherosclerotic cardiovascular disease. Novel Lp(a) lowering treatments highlight the need to understand the regulation of plasma levels of this atherogenic lipoprotein. Despite years of research, significant uncertainty remains about the assembly, secretion, and clearance of Lp(a). Specifically, there is ongoing controversy about where apo(a) and apoB-100 bind to form Lp(a); which apoB-100 lipoproteins bind to apo(a) to create Lp(a); whether binding of apo(a) is reversible, allowing apo(a) to bind to more than one apoB-100 lipoprotein during its lifespan in the circulation; and how Lp(a) or apo(a) leave the circulation. In this review, we highlight past and recent data from stable isotope studies of Lp(a) metabolism, highlighting the critical metabolic uncertainties that exist. We present kinetic models to describe results of published studies using stable isotopes and suggest what future studies are required to improve our understanding of Lp(a) metabolism., (Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.)

Objective: Lp(a) [lipoprotein (a)] is composed of apoB (apolipoprotein B) and apo(a) [apolipoprotein (a)] and is an independent risk factor for cardiovascular disease and aortic stenosis. In clinical trials, anacetrapib, a CETP (cholesteryl ester transfer protein) inhibitor, causes significant reductions in plasma Lp(a) levels. We conducted an exploratory study to examine the mechanism for Lp(a) lowering by anacetrapib., Approach and Results: We enrolled 39 participants in a fixed-sequence, double-blind study of the effects of anacetrapib on the metabolism of apoB and high-density lipoproteins. Twenty-nine patients were randomized to atorvastatin 20 mg/d, plus placebo for 4 weeks, and then atorvastatin plus anacetrapib (100 mg/d) for 8 weeks. The other 10 subjects were randomized to double placebo for 4 weeks followed by placebo plus anacetrapib for 8 weeks. We examined the mechanisms of Lp(a) lowering in a subset of 12 subjects having both Lp(a) levels >20 nmol/L and more than a 15% reduction in Lp(a) by the end of anacetrapib treatment. We performed stable isotope kinetic studies using 2 H 3 -leucine at the end of each treatment to measure apo(a) fractional catabolic rate and production rate. Median baseline Lp(a) levels were 21.5 nmol/L (interquartile range, 9.9-108.1 nmol/L) in the complete cohort (39 subjects) and 52.9 nmol/L (interquartile range, 38.4-121.3 nmol/L) in the subset selected for kinetic studies. Anacetrapib treatment lowered Lp(a) by 34.1% ( P ≤0.001) and 39.6% in the complete and subset cohort, respectively. The decreases in Lp(a) levels were because of a 41% reduction in the apo(a) production rate, with no effects on apo(a) fractional catabolic rate., Conclusions: Anacetrapib reduces Lp(a) levels by decreasing its production., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00990808., (© 2017 The Authors.)

Cholesteryl ester transfer protein (CETP) mediates the transfer of HDL cholesteryl esters for triglyceride (TG) in VLDL/LDL. CETP inhibition, with anacetrapib, increases HDL-cholesterol, reduces LDL-cholesterol, and lowers TG levels. This study describes the mechanisms responsible for TG lowering by examining the kinetics of VLDL-TG, apoC-II, apoC-III, and apoE. Mildly hypercholesterolemic subjects were randomized to either placebo (N = 10) or atorvastatin 20 mg/qd (N = 29) for 4 weeks (period 1) followed by 8 weeks of anacetrapib, 100 mg/qd (period 2). Following each period, subjects underwent stable isotope metabolic studies to determine the fractional catabolic rates (FCRs) and production rates (PRs) of VLDL-TG and plasma apoC-II, apoC-III, and apoE. Anacetrapib reduced the VLDL-TG pool on a statin background due to an increased VLDL-TG FCR (29%; P = 0.002). Despite an increased VLDL-TG FCR following anacetrapib monotherapy (41%; P = 0.11), the VLDL-TG pool was unchanged due to an increase in the VLDL-TG PR (39%; P = 0.014). apoC-II, apoC-III, and apoE pool sizes increased following anacetrapib; however, the mechanisms responsible for these changes differed by treatment group. Anacetrapib increased the VLDL-TG FCR by enhancing the lipolytic potential of VLDL, which lowered the VLDL-TG pool on atorvastatin background. There was no change in the VLDL-TG pool in subjects treated with anacetrapib monotherapy due to an accompanying increase in the VLDL-TG PR., (Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.)

Background: Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), lowers plasma low-density lipoprotein (LDL) cholesterol and apolipoprotein B100 (apoB). Although studies in mice and cells have identified increased hepatic LDL receptors as the basis for LDL lowering by PCSK9 inhibitors, there have been no human studies characterizing the effects of PCSK9 inhibitors on lipoprotein metabolism. In particular, it is not known whether inhibition of PCSK9 has any effects on very low-density lipoprotein or intermediate-density lipoprotein (IDL) metabolism. Inhibition of PCSK9 also results in reductions of plasma lipoprotein (a) levels. The regulation of plasma Lp(a) levels, including the role of LDL receptors in the clearance of Lp(a), is poorly defined, and no mechanistic studies of the Lp(a) lowering by alirocumab in humans have been published to date., Methods: Eighteen (10 F, 8 mol/L) participants completed a placebo-controlled, 2-period study. They received 2 doses of placebo, 2 weeks apart, followed by 5 doses of 150 mg of alirocumab, 2 weeks apart. At the end of each period, fractional clearance rates (FCRs) and production rates (PRs) of apoB and apo(a) were determined. In 10 participants, postprandial triglycerides and apoB48 levels were measured., Results: Alirocumab reduced ultracentrifugally isolated LDL-C by 55.1%, LDL-apoB by 56.3%, and plasma Lp(a) by 18.7%. The fall in LDL-apoB was caused by an 80.4% increase in LDL-apoB FCR and a 23.9% reduction in LDL-apoB PR. The latter was due to a 46.1% increase in IDL-apoB FCR coupled with a 27.2% decrease in conversion of IDL to LDL. The FCR of apo(a) tended to increase (24.6%) without any change in apo(a) PR. Alirocumab had no effects on FCRs or PRs of very low-density lipoproteins-apoB and very low-density lipoproteins triglycerides or on postprandial plasma triglycerides or apoB48 concentrations., Conclusions: Alirocumab decreased LDL-C and LDL-apoB by increasing IDL- and LDL-apoB FCRs and decreasing LDL-apoB PR. These results are consistent with increases in LDL receptors available to clear IDL and LDL from blood during PCSK9 inhibition. The increase in apo(a) FCR during alirocumab treatment suggests that increased LDL receptors may also play a role in the reduction of plasma Lp(a)., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01959971., Competing Interests: Disclosures Gissette Reyes-Soffer: Research Support (Sanofi; Merck Inc.) Consultant (Merck) Marianna Pavlyha, Colleen Ngai, Tiffany Thomas, Stephen Holleran, Rajasekhar Ramakrishnan, Wahida Karmally, Renu Nandakumar, Nelson Fontanez, Joseph Obunike, Santica M. Marcovina, Alice Lichtenstein, Nirupa Rachel Matthan: None James Matta, Frederic Becue, Franck Poitiers, Brian Swanson, Lisa Cowan, Howard K. Surks: Employment (Sanofi) Magali Maroccia: Employment (contractor to Sanofi) William J. Sasiela: Employment (Regeneron Pharmaceuticals, Inc.) Henry N. Ginsberg: Research Support (Merck; Sanofi and Regeneron; Amgen), Consultant/Advisory Board (Amgen; AstraZeneca; Bristol Myers Squibb; GlaxoSmithKline; Ionis; Janssen; Kowa; Merck; Novartis; Sanofi; Regeneron; Pfizer; Resverlogix)., (© 2016 The Authors.)

Purpose of Review: Current preventive and treatment guidelines for type 2 diabetes have failed to decrease the incidence of comorbidities, such as dyslipidemia and ultimately heart disease. The goal of this review is to describe the physiological and metabolic lipid alterations that develop in patients with type 2 diabetes mellitus. Questions addressed include the differences in lipid and lipoprotein metabolism that characterize the dyslipidemia of insulin resistance and type 2 diabetes mellitus. We also examine the relevance of the new AHA/ADA treatment guidelines to dyslipidemic individuals., Recent Findings: In this review, we provide an update on the pathophysiology of diabetic dyslipidemia, including the role of several apolipoproteins such as apoC-III. We also point to new studies and new agents for the treatment of individuals with type 2 diabetes mellitus who need lipid therapies. Type 2 diabetes mellitus causes cardiovascular disease via several pathways, including dyslipidemia characterized by increased plasma levels of apoB-lipoproteins and triglycerides, and low plasma concentrations of HDL cholesterol. Treatments to normalize the dyslipidemia and reduce the risk for cardiovascular events include the following: lifestyle and medication, particularly statins, and if necessary, ezetimibe, to significantly lower LDL cholesterol. Other treatments, more focused on triglycerides and HDL cholesterol, are less well supported by randomized clinical trials and should be used on an individual basis. Newer agents, particularly the PCSK9 inhibitors, show a great promise for even greater lowering of LDL cholesterol, but we await the results of ongoing clinical trials.

Objective: Anacetrapib (ANA), an inhibitor of cholesteryl ester transfer protein (CETP) activity, increases plasma concentrations of high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-I (apoA)-I, apoA-II, and CETP. The mechanisms responsible for these treatment-related increases in apolipoproteins and plasma CETP are unknown. We performed a randomized, placebo (PBO)-controlled, double-blind, fixed-sequence study to examine the effects of ANA on the metabolism of HDL apoA-I and apoA-II and plasma CETP., Approach and Results: Twenty-nine participants received atorvastatin (ATV) 20 mg/d plus PBO for 4 weeks, followed by ATV plus ANA 100 mg/d for 8 weeks (ATV-ANA). Ten participants received double PBO for 4 weeks followed by PBO plus ANA for 8 weeks (PBO-ANA). At the end of each treatment, we examined the kinetics of HDL apoA-I, HDL apoA-II, and plasma CETP after D3-leucine administration as well as 2D gel analysis of HDL subspecies. In the combined ATV-ANA and PBO-ANA groups, ANA treatment increased plasma HDL-C (63.0%; P<0.001) and apoA-I levels (29.5%; P<0.001). These increases were associated with reductions in HDL apoA-I fractional clearance rate (18.2%; P=0.002) without changes in production rate. Although the apoA-II levels increased by 12.6% (P<0.001), we could not discern significant changes in either apoA-II fractional clearance rate or production rate. CETP levels increased 102% (P<0.001) on ANA because of a significant reduction in the fractional clearance rate of CETP (57.6%, P<0.001) with no change in CETP production rate., Conclusions: ANA treatment increases HDL apoA-I and CETP levels by decreasing the fractional clearance rate of each protein., (© 2016 American Heart Association, Inc.)

Low levels of high-density lipoprotein cholesterol (HDL-C) and high triglyceride levels contribute to the excess rate of cardiovascular events seen in subjects with type 2 diabetes. Fenofibrate treatment partially reverses dyslipidemia in these subjects. However, a paradoxical marked reduction in HDL-C and HDL's major protein, apolipoprotein A-I, is a complication of fenofibrate in combination with rosiglitazone, an insulin-sensitizing agent. Risk factors for this condition, termed hypoalphalipoproteinemia, have yet to be identified. Using a case-control study design with subjects enrolled in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, we tested the hypothesis that alterations in HDL's protein cargo predispose diabetic subjects to fenofibrate/rosiglitazone-induced hypoalphalipoproteinemia. HDL was isolated from blood obtained from controls (no decreases or increase in HDL-C while receiving fenofibrate/rosiglitazone therapy) and cases (developed hypoalphalipoproteinemia after fenofibrate/rosiglitazone treatment) participating in the ACCORD study before they began fenofibrate/rosiglitazone treatment. HDL proteins were quantified by targeted parallel reaction monitoring (PRM) and selected reaction monitoring (SRM) with isotope dilution. This approach demonstrated marked increases in the relative concentrations of paraoxonase/arylesterase 1 (PON1), apolipoprotein C-II (APOC2), apolipoprotein C-I, and apolipoprotein H in the HDL of subjects who developed hypoalphalipoproteinemia. The case and control subjects did not differ significantly in baseline HDL-C levels or other traditional lipid risk factors. We used orthogonal biochemical techniques to confirm increased levels of PON1 and APOC2. Our observations suggest that an imbalance in HDL proteins predisposes diabetic subjects to develop hypoalphalipoproteinemia on fenofibrate/rosiglitazone therapy., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

Mipomersen is a 20mer antisense oligonucleotide (ASO) that inhibits apolipoprotein B (apoB) synthesis; its low-density lipoprotein (LDL)-lowering effects should therefore result from reduced secretion of very-low-density lipoprotein (VLDL). We enrolled 17 healthy volunteers who received placebo injections weekly for 3 weeks followed by mipomersen weekly for 7 to 9 weeks. Stable isotopes were used after each treatment to determine fractional catabolic rates and production rates of apoB in VLDL, IDL (intermediate-density lipoprotein), and LDL, and of triglycerides in VLDL. Mipomersen significantly reduced apoB in VLDL, IDL, and LDL, which was associated with increases in fractional catabolic rates of VLDL and LDL apoB and reductions in production rates of IDL and LDL apoB. Unexpectedly, the production rates of VLDL apoB and VLDL triglycerides were unaffected. Small interfering RNA-mediated knockdown of apoB expression in human liver cells demonstrated preservation of apoB secretion across a range of apoB synthesis. Titrated ASO knockdown of apoB mRNA in chow-fed mice preserved both apoB and triglyceride secretion. In contrast, titrated ASO knockdown of apoB mRNA in high-fat-fed mice resulted in stepwise reductions in both apoB and triglyceride secretion. Mipomersen lowered all apoB lipoproteins without reducing the production rate of either VLDL apoB or triglyceride. Our human data are consistent with long-standing models of posttranscriptional and posttranslational regulation of apoB secretion and are supported by in vitro and in vivo experiments. Targeting apoB synthesis may lower levels of apoB lipoproteins without necessarily reducing VLDL secretion, thereby lowering the risk of steatosis associated with this therapeutic strategy., (Copyright © 2016, American Association for the Advancement of Science.)

Background: Individuals treated with the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib exhibit a reduction in both LDL cholesterol and apolipoprotein B (ApoB) in response to monotherapy or combination therapy with a statin. It is not clear how anacetrapib exerts these effects; therefore, the goal of this study was to determine the kinetic mechanism responsible for the reduction in LDL and ApoB in response to anacetrapib., Methods: We performed a trial of the effects of anacetrapib on ApoB kinetics. Mildly hypercholesterolemic subjects were randomized to background treatment of either placebo (n = 10) or 20 mg atorvastatin (ATV) (n = 29) for 4 weeks. All subjects then added 100 mg anacetrapib to background treatment for 8 weeks. Following each study period, subjects underwent a metabolic study to determine the LDL-ApoB-100 and proprotein convertase subtilisin/kexin type 9 (PCSK9) production rate (PR) and fractional catabolic rate (FCR)., Results: Anacetrapib markedly reduced the LDL-ApoB-100 pool size (PS) in both the placebo and ATV groups. These changes in PS resulted from substantial increases in LDL-ApoB-100 FCRs in both groups. Anacetrapib had no effect on LDL-ApoB-100 PRs in either treatment group. Moreover, there were no changes in the PCSK9 PS, FCR, or PR in either group. Anacetrapib treatment was associated with considerable increases in the LDL triglyceride/cholesterol ratio and LDL size by NMR., Conclusion: These data indicate that anacetrapib, given alone or in combination with a statin, reduces LDL-ApoB-100 levels by increasing the rate of ApoB-100 fractional clearance., Trial Registration: ClinicalTrials.gov NCT00990808., Funding: Merck & Co. Inc., Kenilworth, New Jersey, USA. Additional support for instrumentation was obtained from the National Center for Advancing Translational Sciences (UL1TR000003 and UL1TR000040).

Autophagy is an essential cellular pathway by which protein aggregates, long-lived proteins, or defective organelles are sequestered in double membrane vesicles and then degraded upon fusion of those vesicles with lysosomes. Although autophagy plays a critical role in maintaining intracellular homeostasis and keeping the cell in a healthy state, this key pathway can become dysregulated in various cardiometabolic disorders, such as; obesity, dyslipidemia, inflammation, and insulin resistance. In these conditions, autophagy may actually worsen the pathological state instead of protecting the cell or organism. In this review, we discuss how dysregulated autophagy may be linked to increases in cardiovascular risk factors, and how manipulation of the autophagic machinery might reduce those risks.

Background: For a more complete understanding of pharmacodynamic, metabolic, and pathophysiologic effects, protein kinetics, such as production rate and fractional catabolic rate, can offer substantially more information than protein concentration alone. Kinetic experiments with stable isotope tracers typically require laborious sample preparation and are most often used for studying abundant proteins. Here we describe a practical methodology for measuring isotope enrichment into low-abundance proteins that uses an automated procedure and immunoaffinity enrichment (IA) with LC-MS. Low-abundance plasma proteins cholesteryl ester transfer protein (CETP) and proprotein convertase subtilisin/kexin type 9 (PCSK9) were studied as examples., Methods: Human participants (n = 39) were infused with [(2)H(3)]leucine, and blood samples were collected at multiple time points. Sample preparation and analysis were automated and multiplexed to increase throughput. Proteins were concentrated from plasma by use of IA and digested with trypsin to yield proteotypic peptides that were analyzed by microflow chromatography-mass spectrometry to measure isotope enrichment., Results: The IA procedure was optimized to provide the greatest signal intensity. Use of a gel-free method increased throughput while increasing the signal. The intra- and interassay CVs were <15% at all isotope enrichment levels studied. More than 1400 samples were analyzed in <3 weeks without the need for instrument stoppages or user interventions., Conclusions: The use of automated gel-free methods to multiplex the measurement of isotope enrichment was applied to the low-abundance proteins CETP and PCSK9., (© 2014 American Association for Clinical Chemistry.)

LC/MS quantification of multiple plasma proteins that differ by several orders of magnitude in concentration from a single sample is challenging. We present a strategy that allows the simultaneous determination of the concentration and turnover kinetics of higher and lower abundant proteins from a single digestion mixture. Our attention was directed at a cluster of proteins that interact to affect the absorption and interorgan lipid trafficking. We demonstrate that apos involved in TG metabolism such as apoC2, C3, E, and A4 (micromolar concentration), and apoB48 and apoA5 (single-digit nanomolar concentration) can be quantified from a single digestion mixture. A high degree of correlation between LC/MS and immunobased measurements for apoC2, C3, E, and B48 was observed. Moreover, apoA5 fractional synthesis rate was measured in humans for the first time. Finally, the method can be directly applied to studies involving nonhuman primates because peptide sequences used in the method are conserved between humans and nonhuman primates., (Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.)

Purpose of Review: To provide an update on recent mechanistic and clinical trial data related to the actions and efficacy of niacin., Recent Findings: Recent mechanistic studies have provided novel insights regarding the mechanism of action of niacin. Studies of the purported niacin receptor, GPR109A, indicate that niacin-mediated fatty acid-lowering and flushing are dependent on niacin binding to this receptor, whereas the lipid-altering effects of niacin may be independent of the interaction of niacin with the receptor. Two cardiovascular outcome trials - Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health trial and HPS2-THRIVE - were both negative., Summary: Niacin has been used to treat dyslipidemia for almost 60 years. Recent studies have provided clues to niacin's broad lipid-altering efficacy, but more work is required to fully understand its mechanisms of action. The failure of niacin to reduce cardiovascular events in two recent placebo-controlled trials of high-risk patients with LDL-cholesterol levels less than 70 mg/dl on statins was surprising based on prior outcome and surrogate studies. We await publication of subgroup analyses to allow full assessment of those trials. In the meantime, we should not forget that niacin is an effective LDL-cholesterol-lowering drug in patients with high LDL levels despite statin treatment.

Rationale: Apolipoprotein(a) [apo(a)] is the defining protein component of lipoprotein(a) [Lp(a)], an independent risk factor for cardiovascular disease. The regulation of Lp(a) levels in blood is poorly understood in part due to technical challenges in measuring Lp(a) kinetics. Improvements in the ability to readily and reliably measure the kinetics of apo(a) using a stable isotope labeled tracer is expected to facilitate studies of the role of Lp(a) in cardiovascular disease. Since investigators typically determine the isotopic labeling of protein-bound amino acids following acid-catalyzed hydrolysis of a protein of interest [e.g., apo(a)], studies of protein synthesis require extensive protein purification which limits throughput and often requires large sample volumes. We aimed to develop a rapid and efficient method for studying apo(a) kinetics that is suitable for use in studies involving human subjects., Methods: Microfluidic device and tandem mass spectrometry were used to quantify the incorporation of [(2)H3]-leucine tracer into protein-derived peptides., Results: We demonstrated that it is feasible to quantify the incorporation of [(2)H3]-leucine tracer into a proteolytic peptide from the non-kringle repeat region of apo(a) in human subjects. Specific attention was directed toward optimizing the multiple reaction monitoring (MRM) transitions, mass spectrometer settings, and chromatography (i.e., critical parameters that affect the sensitivity and reproducibility of isotopic enrichment measurements). The results demonstrated significant advantages with the use of a microfluidic device technology for studying apo(a) kinetics, including enhanced sensitivity relative to conventional micro-flow chromatography, a virtually drift-free elution profile, and a stable and robust electrospray., Conclusions: The technological advances described herein enabled the implementation of a novel method for studying the kinetics of apo(a) in human subjects infused with [(2)H3]-leucine., (Copyright © 2013 John Wiley & Sons, Ltd.)

Objective: The Action to Control Cardiovascular Risk in Diabetes lipid study (ACCORD Lipid), which compared the effects of simvastatin plus fenofibrate (FENO-S) versus simvastatin plus placebo (PL-S) on cardiovascular disease outcomes, measured only fasting triglyceride (TG) levels. We examined the effects of FENO-S on postprandial (PP) lipid and lipoprotein levels in a subgroup of ACCORD Lipid subjects., Research Design and Methods: We studied 139 subjects (mean age of 61 years, 40% female, and 76% Hispanic or black) in ACCORD Lipid, from a total 529 ACCORD Lipid subjects in the Northeast Clinical Network. PP plasma TG, apolipoprotein (apo)B48, and apoCIII were measured over 10 h after an oral fat load., Results: The PP TG incremental area under the curve (IAUC) above fasting (median and interquartile range [mg/dL/h]) was 572 (352-907) in the FENO-S group versus 770 (429-1,420) in the PL-S group (P = 0.008). The PP apoB48 IAUC (mean ± SD [μg/mL/h]) was also reduced in the FENO-S versus the PL-S group (23.2 ± 16.3 vs. 35.2 ± 28.6; P = 0.008). Fasting TG levels on the day of study were correlated with PP TG IAUC (r = 0.73 for FENO-S and r = 0.62 for PL-S; each P < 0.001). However, the fibrate effect on PP TG IAUC was a constant percentage across the entire range of fasting TG levels, whereas PP apoB48 IAUC was only reduced when fasting TG levels were increased., Conclusions: FENO-S lowered PP TG similarly in all participants compared with PL-S. However, levels of atherogenic apoB48 particles were reduced only in individuals with increased fasting levels of TG. These results may have implications for interpretation of the overall ACCORD Lipid trial, which suggested benefit from FENO-S only in dyslipidemic individuals.

Background: Heart failure (HF) is characterized by inflammation, insulin resistance, and progressive catabolism. We hypothesized that patients with advanced HF also develop adipose tissue inflammation associated with impaired adipokine signaling and that hemodynamic correction through implantation of ventricular assist devices (VADs) would reverse adipocyte activation and correct adipokine signaling in advanced HF., Methods and Results: Circulating insulin, adiponectin, leptin, and resistin levels were measured in 36 patients with advanced HF before and after VAD implantation and 10 healthy control subjects. Serum adiponectin was higher in HF patients before VAD implantation compared with control subjects (13.3±4.9 versus 6.4±2.1 μg/mL, P=0.02). VAD implantation (mean, 129±99 days) reduced serum adiponectin (7.4±3.4 μg/mL, P<0.05) and improved insulin resistance (Homeostasis Assessment Model of insulin resistance: 7.6±7.7-4.5±3.6; P=0.012). [corrected] Adiponectin expression in adipose tissue decreased after VAD implantation (-65%; P<0.03). Adiponectin receptor expression was suppressed in the failing myocardium compared with control subjects and increased after mechanical unloading. Histomorphometric analysis of adipose tissue specimens revealed reduced adipocyte size in patients with advanced HF compared with control subjects (2105±585 μm(2) [corrected] versus 5583±142 μm(2) in control subjects; P<0.05), which increased after VAD placement. Of note, macrophage infiltration in adipose tissue was higher in advanced HF patients compared with control subjects (+25%; P<0.01), which normalized after VAD implantation., Conclusions: Adipose tissue inflammation and adiponectin resistance develop in advanced HF. Mechanical unloading of the failing myocardium reverses adipose tissue macrophage infiltration, inflammation, and adiponectin resistance in patients with advanced HF.

Introduction: People with insulin resistance/metabolic syndrome (IR/MS) and/or type 2 diabetes mellitus (T2DM) have increased rates of cardiovascular disease (CVD) even when low-density lipoprotein cholesterol levels are at or near target levels. Contributors to this problem are the high triglyceride (TG) levels and low levels of high-density lipoprotein cholesterol (HDLC) that are commonly present in this population, even with statin therapy., Areas Covered: This review focuses on the use of a combination of statins with fibrates, which lower TG and raise HDLC concentrations and, therefore, have the potential to further lower rates of CVD more in people with IR/MS and/or T2DM. Treatment with this combination is uncommon because doctors and patients are fearful of muscle, liver and renal complications and because the evidence that the combination will actually reduce risk has been lacking. In this review, the authors examine the efficacy and safety of the statin-fibrate combination, particularly fenofibrate and simvastatin, the combination used in the ACCORD trial., Expert Opinion: The authors' opinion is that this combination of fenofibrate and statin is as safe as either drug alone and, in patients with significant dyslipidemia, is likely to reduce CVD. Concerns remain concerning fenofibrate-associated increases in serum creatinine levels and the significant heterogeneity in the reduction in CVD by the combination in women. A trial of statin + fenofibrate in people with IR/MS and/or T2DM who also have significant dyslipidemia is needed.

The goal of this study was to determine if individuals with coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM) had greater endothelial dysfunction (ED) than individuals with only CAD. Flow-mediated dilation (FMD), calculated as percentage increase in brachial artery diameter in response to postischemic blood flow, was measured after an overnight fast in 2 cohorts. The first cohort included 76 participants in the Northern Manhattan Study with CAD; 25 also had T2DM. The second cohort was composed of 27 individuals with both T2DM and CAD who were participants in a study of postprandial lipemia. Combined, we analyzed 103 patients with CAD: 52 with T2DM (T2DM+) and 51 without T2DM (T2DM-). The 52 CAD T2DM+ subjects had a mean FMD of 3.9% +/- 3.2%, whereas the 51 CAD T2DM- subjects had a greater mean FMD of 5.5% +/- 4.0% (P < .03). An investigation of various confounders known to affect FMD identified age and body mass index as the only significant covariates in a multiple regression model. Adjusting for age and body mass index, we found that FMD remained lower in T2DM+ subjects compared with T2DM- subjects (difference, -1.99%; P < .03). In patients with CAD, the concomitant presence of T2DM is independently associated with greater ED, as measured by FMD. This finding may be relevant to the greater early and late morbidity and mortality observed in patients with both CAD and T2DM., (Copyright 2010 Elsevier Inc. All rights reserved.)

Individuals with type 2 diabetes mellitus (DM) characteristically have elevated fasting and postprandial (PP) plasma triglycerides (TG). Previous case-control studies indicated that PPTG levels predict the presence of coronary artery disease (CAD) in people without DM; however, the data for patients with DM are conflicting. Therefore, we conducted a case-control study in DM individuals, 84 with (+) and 80 without (-) CAD. Our hypothesis was that DM individuals with or without CAD would have similar PPTG levels, but CAD+ individuals would have more small d<1.006 g/L lipoprotein particles. Several markers of PP lipid metabolism were measured over 10 h after a fat load. PP lipoprotein size and particle number were also determined. There was no significant difference in any measure of PP lipid metabolism between CAD+ and CAD-, except for apoB48, which was actually higher in CAD-. We followed 69 CAD- participants for a mean 8.7 years; 33 remained free of any cardiovascular event. There were no PP differences at baseline between these 33 who remained CAD- and either the 36 original CAD- who subsequently developed CAD or the original CAD+ group.PP measurements of TG-rich lipoproteins do not predict the presence of CAD in individuals with DM.