Olezarsen, Acute Pancreatitis, and Familial Chylomicronemia Syndrome.

BACKGROUND: Familial chylomicronemia syndrome is a genetic disorder associated with severe hypertriglyceridemia and severe acute pancreatitis. Olezarsen reduces the plasma triglyceride level by reducing hepatic synthesis of apolipoprotein C-III. METHODS: In a phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with genetically identified familial chylomicronemia syndrome to receive olezarsen at a dose of 80 mg or 50 mg or placebo subcutaneously every 4 weeks for 49 weeks. There were two primary end points: the difference between the 80-mg olezarsen group and the placebo group in the percent change in the fasting triglyceride level from baseline to 6 months, and (to be assessed if the first was significant) the difference between the 50-mg olezarsen group and the placebo group. Secondary end points included the mean percent change from baseline in the apolipoprotein C-III level and an independently adjudicated episode of acute pancreatitis. RESULTS: A total of 66 patients underwent randomization; 22 were assigned to the 80-mg olezarsen group, 21 to the 50-mg olezarsen group, and 23 to the placebo group. At baseline, the mean (±SD) triglyceride level among the patients was 2630±1315 mg per deciliter, and 71% had a history of acute pancreatitis within the previous 10 years. Triglyceride levels at 6 months were significantly reduced with the 80-mg dose of olezarsen as compared with placebo (-43.5 percentage points; 95% confidence interval [CI], -69.1 to -17.9; P<0.001) but not with the 50-mg dose (-22.4 percentage points; 95% CI, -47.2 to 2.5; P = 0.08). The difference in the mean percent change in the apolipoprotein C-III level from baseline to 6 months in the 80-mg group as compared with the placebo group was -73.7 percentage points (95% CI, -94.6 to -52.8) and between the 50-mg group as compared with the placebo group was -65.5 percentage points (95% CI, -82.6 to -48.3). By 53 weeks, 11 episodes of acute pancreatitis had occurred in the placebo group, and 1 episode had occurred in each olezarsen group (rate ratio [pooled olezarsen groups vs. placebo], 0.12; 95% CI, 0.02 to 0.66). Adverse events of moderate severity that were considered by a trial investigator at the site to be related to the trial drug or placebo occurred in 4 patients in the 80-mg olezarsen group. CONCLUSIONS: In patients with familial chylomicronemia syndrome, olezarsen may represent a new therapy to reduce plasma triglyceride levels. (Funded by Ionis Pharmaceuticals; Balance ClinicalTrials.gov number, NCT04568434.).

Olezarsen for Hypertriglyceridemia in Patients at High Cardiovascular Risk.

BACKGROUND: Reducing the levels of triglycerides and triglyceride-rich lipoproteins remains an unmet clinical need. Olezarsen is an antisense oligonucleotide targeting messenger RNA for apolipoprotein C-III (APOC3), a genetically validated target for triglyceride lowering. METHODS: In this phase 2b, randomized, controlled trial, we assigned adults either with moderate hypertriglyceridemia (triglyceride level, 150 to 499 mg per deciliter) and elevated cardiovascular risk or with severe hypertriglyceridemia (triglyceride level, ≥500 mg per deciliter) in a 1:1 ratio to either a 50-mg or 80-mg cohort. Patients were then assigned in a 3:1 ratio to receive monthly subcutaneous olezarsen or matching placebo within each cohort. The primary outcome was the percent change in the triglyceride level from baseline to 6 months, reported as the difference between each olezarsen group and placebo. Key secondary outcomes were changes in levels of APOC3, apolipoprotein B, non-high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. RESULTS: A total of 154 patients underwent randomization at 24 sites in North America. The median age of the patients was 62 years, and the median triglyceride level was 241.5 mg per deciliter. The 50-mg and 80-mg doses of olezarsen reduced triglyceride levels by 49.3 percentage points and 53.1 percentage points, respectively, as compared with placebo (P<0.001 for both comparisons). As compared with placebo, each dose of olezarsen also significantly reduced the levels of APOC3, apolipoprotein B, and non-HDL cholesterol, with no significant change in the LDL cholesterol level. The risks of adverse events and serious adverse events were similar in the three groups. Clinically meaningful hepatic, renal, or platelet abnormalities were uncommon, with similar risks in the three groups. CONCLUSIONS: In patients with predominantly moderate hypertriglyceridemia at elevated cardiovascular risk, olezarsen significantly reduced levels of triglycerides, apolipoprotein B, and non-HDL cholesterol, with no major safety concerns identified. (Funded by Ionis Pharmaceuticals; Bridge-TIMI 73a ClinicalTrials.gov number, NCT05355402.).

ANGPTL3 and ApoC-III inhibitors for treating hypertriglyceridemia in context: horses for courses?

PURPOSE OF REVIEW: Hypertriglyceridemia (HTG) is an independent and casual risk factor for atherosclerotic cardiovascular disease (ASCVD). There is an unmet need for more effective treatments for patients with HTG. Angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C-III (apoC-III) are key regulators of triglyceride-rich lipoprotein (TRL) metabolism. We review recent clinical trials targeting ANGPTL3 and apoC-III with monoclonal antibody and nucleic acid therapies, including antisense oligonucleotides and small interfering RNA. RECENT FINDINGS: ANGPTL3 and apoC-III inhibitors are effective in lowering plasma triglycerides and TRLs, with possibly greater efficacy with the inhibition of apoC-III. By contrast to ANGPTL3 inhibition that has the advantage of greater lowering of plasma low-density lipoprotein (LDL)-cholesterol and apoB levels, apoC-III inhibition only has a modest or no effect in lowering plasma LDL-cholesterol and apoB concentrations. Therapeutic inhibition of ANGPTL3 and apoC-III can correct HTG possibly by reducing production and increasing catabolism of TRL particles, but this remains to be formally investigated in patients with HTG. SUMMARY: Novel agents targeting ANGPTL3 and apoC-III can correct HTG and potentially lower risk of ASCVD in patients with HTG. The long-term safety and cost-effectiveness of these agents await confirmation in ongoing and future studies.

Disease activity in patients with rheumatoid arthritis increases serum levels of apolipoprotein C-III.

OBJECTIVES: Rheumatoid arthritis (RA) has been unequivocally associated with an increased burden of accelerated atherosclerosis, which, at least in part, is a consequence of the inflammation present in the disease. Apolipoprotein C-III (ApoC3) is a key molecule in triglycerides metabolism that has been linked to cardiovascular (CV) disease. Our objective was to study how ApoC3 is related to the characteristics of RA, paying special attention to its relationship with the inflammatory activity of the disease. METHODS: Cross-sectional study that included 430 patients with RA. In these patients, data related to the disease, classic CV risk factors, complete lipid profile, and serum ApoC3 levels were evaluated. A multivariable regression analysis was performed to study the relationship of the characteristics of RA with ApoC3. RESULTS: Abdominal circumference, obesity, type 2 diabetes, and circulating triglycerides were significantly associated with higher ApoC3 serum levels. Furthermore, C-reactive protein and erythrocyte sedimentation rate, as well as the disease activity score -DAS28- were significantly related to a higher circulating ApoC3 after multivariable analysis. Patients included in the moderate or high disease activity groups had higher ApoC3 serum levels compared to those in remission (beta coefficient 1.28 [95% confidence interval 0.16-2.39] mg/dl, p=0.025) when adjusting for confounders. The use of prednisone, disease-modifying anti-rheumatic drugs and anti-tumour necrosis factor therapies was associated with lower values of ApoC3. CONCLUSIONS: The activity of the disease in patients with RA is independently associated with higher serum levels of ApoC3.

Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk.

BACKGROUND: High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels. METHODS: In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. RESULTS: Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, -25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease. CONCLUSIONS: Among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.).

Apolipoprotein C-III in patients with systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) has been associated with atherosclerotic cardiovascular disease (CV) and an altered lipid profile. High levels of apolipoprotein C-III (ApoC3) are associated with elevated triglyceride levels and an increased risk of CV. In the present study, we aimed to study circulating ApoC3 in patients with SLE and describe its relationship with the manifestations of the disease. METHODS: This is a cross-sectional study that included 186 patients with SLE. Disease-related data, CV comorbidity, full lipid profile, and serum levels of ApoC3 were assessed. A multivariable regression analysis was performed to study how ApoC3 was related to SLE features. RESULTS: Classic CV risk factors were significantly and strongly associated with circulating ApoC3. After a fully multivariable analysis that included classic CV risk factors and lipid profile molecules, SLICC damage (beta coef. 0.10 [95% CI 0.02-0.19] mg/dl, 0.020) and Katz severity (beta coef. 0.11 [95% CI 0.03-0.19] mg/dl, p = 0.011) indices and SLEDAI activity score (beta coef. 0.05 [95% CI 0.05-0.08] mg/dl, p = 0.004) were all independently associated with higher levels of circulating ApoC3. CONCLUSION: Among SLE patients, disease activity, severity, and disease damage are independently associated with higher ApoC3 serum levels.

Pharmacological Inhibition of CETP (Cholesteryl Ester Transfer Protein) Increases HDL (High-Density Lipoprotein) That Contains ApoC3 and Other HDL Subspecies Associated With Higher Risk of Coronary Heart Disease.

OBJECTIVE: Plasma total HDL (high-density lipoprotein) is a heterogeneous mix of many protein-based subspecies whose functions and associations with coronary heart disease vary. We hypothesize that increasing HDL by CETP (cholesteryl ester transfer protein) inhibition failed to reduce cardiovascular disease risk, in part, because it increased dysfunctional subspecies associated with higher risk such as HDL that contains apoC3. Approach and Results: We studied participants in 2 randomized, double-blind, placebo-controlled trials of a CETP inhibitor on a background of atorvastatin treatment: ACCENTUATE (The Addition of Evacetrapib to Atorvastatin Compared to Placebo, High Intensity Atorvastatin, and Atorvastatin With Ezetimibe to Evaluate LDL-C Lowering in Patients With Primary Hyperlipidemia; 130 mg evacetrapib; n=126) and ILLUMINATE (Phase 3 Multi Center, Double Blind, Randomized, Parallel Group Evaluation of the Fixed Combination Torcetrapib/Atorvastatin, Administered Orally, Once Daily [Qd], Compared With Atorvastatin Alone, on the Occurrence of Major Cardiovascular Events in Subjects With Coronary Heart Disease or Risk Equivalents; 60 mg torcetrapib; n=80). We measured the concentration of apoA1 in total plasma and 17 protein-based HDL subspecies at baseline and 3 months. Both CETP inhibitors increased apoA1 in HDL that contains apoC3 the most of all HDL subspecies (median placebo-adjusted percent increase: evacetrapib 99% and torcetrapib 50%). They also increased apoA1 in other HDL subspecies associated with higher coronary heart disease risk such as those involved in inflammation (α-2-macroglobulin and complement C3) or hemostasis (plasminogen), and in HDL that contains both apoE and apoC3, a complex subspecies associated with higher coronary heart disease risk. ApoA1 in HDL that contains apoC1, associated with lower risk, increased 71% and 40%, respectively. Only HDL that contains apoL1 showed no response to either drug. CONCLUSIONS: CETP inhibitors evacetrapib and torcetrapib increase apoA1 in HDL subspecies that contain apoC3 and other HDL subspecies associated with higher risk of coronary heart disease. Subspecies-specific effects shift HDL subspecies concentrations toward a profile associated with higher risk, which may contribute to lack of clinical benefit from raising HDL by pharmaceutical CETP inhibition.

PCSK9 Activity Is Potentiated Through HDL Binding.

Rationale: Proprotein convertase subtilisin/kexin type 9 (PCSK9) circulates in a free and lipoprotein-bound form, yet the functional consequence of the association between PCSK9 and high-density lipoprotein (HDL) remains unexplored. Objective: This study sought to interrogate the novel relationship between PCSK9 and HDL in humans. Methods and Results: Comparing lipoprotein and apolipoprotein profiles by nuclear magnetic resonance and targeted mass spectrometry measurements with PCSK9 levels in the community-based Bruneck (n=656) study revealed a positive association of plasma PCSK9 with small HDL, alongside a highly significant positive correlation between plasma levels of PCSK9 and apolipoprotein-C3, an inhibitor of lipoprotein lipase. The latter association was replicated in an independent cohort, the SAPHIR study (n=270). Thus, PCSK9-HDL association was determined during the postprandial response in two dietary studies (n=20 participants each, 8 times points). Peak triglyceride levels coincided with an attenuation of the PCSK9-HDL association, a loss of apolipoprotein-C3 from HDL and lower levels of small HDL as measured by nuclear magnetic resonance. Crosslinking mass spectrometry (XLMS) upon isolated HDL identified PCSK9 as a potential HDL-binding partner. PCSK9 association with HDL was confirmed through size-exclusion chromatography and immuno-isolation. Quantitative proteomics upon HDL isolated from patients with coronary artery disease (n=172) returned PCSK9 as a core member of the HDL proteome. Combined interrogation of the HDL proteome and lipidome revealed a distinct cluster of PCSK9, phospholipid transfer protein, clusterin and apolipoprotein-E within the HDL proteome, that was altered by sex and positively correlated with sphingomyelin content. Mechanistically, HDL facilitated PCSK9-mediated low-density lipoprotein receptor degradation and reduced low-density lipoprotein uptake through the modulation of PCSK9 internalisation and multimerisation. Conclusions: This study reports HDL as a binder of PCSK9 and regulator of its function. The combination of -omic technologies revealed postprandial lipaemia as a driver of PCSK9 and apolipoprotein-C3 release from HDL.

CREBH normalizes dyslipidemia and halts atherosclerosis in diabetes by decreasing circulating remnant lipoproteins.

Loss-of-function mutations in the transcription factor CREB3L3 (CREBH) associate with severe hypertriglyceridemia in humans. CREBH is believed to lower plasma triglycerides by augmenting the activity of lipoprotein lipase (LPL). However, by using a mouse model of type 1 diabetes mellitus (T1DM), we found that greater liver expression of active CREBH normalized both elevated plasma triglycerides and cholesterol. Residual triglyceride-rich lipoprotein (TRL) remnants were enriched in apolipoprotein E (APOE) and impoverished in APOC3, an apolipoprotein composition indicative of increased hepatic clearance. The underlying mechanism was independent of LPL, as CREBH reduced both triglycerides and cholesterol in LPL-deficient mice. Instead, APOE was critical for CREBH's ability to lower circulating remnant lipoproteins because it failed to reduce TRL cholesterol in Apoe-/- mice. Importantly, individuals with CREB3L3 loss-of-function mutations exhibited increased levels of remnant lipoproteins that were deprived of APOE. Recent evidence suggests that impaired clearance of TRL remnants promotes cardiovascular disease in patients with T1DM. Consistently, we found that hepatic expression of CREBH prevented the progression of diabetes-accelerated atherosclerosis. Our results support the proposal that CREBH acts through an APOE-dependent pathway to increase hepatic clearance of remnant lipoproteins. They also implicate elevated levels of remnants in the pathogenesis of atherosclerosis in T1DM.

Triglyceride-Rich Lipoproteins, Apolipoproteins, and Atherosclerotic Cardiovascular Events Among Patients with Diabetes Mellitus and End-Stage Renal Disease on Hemodialysis.

Hypertriglyceridemia may be implicated in the high atherosclerotic cardiovascular disease (ASCVD) risk experienced by patients with end-stage renal disease (ESRD). In this post-hoc analysis of the "Die Deutsche Diabetes Dialyse Studie (4D)" clinical trial, we examined incident ASCVD events, defined as myocardial infarction, ischemic stroke, or a coronary revascularization procedure, among 1255 participants with type 2 diabetes and ESRD treated with hemodialysis. Cox-regression methods were used to evaluate the association of triglycerides, very-low density lipoprotein cholesterol (VLDL-C), and apolipoproteins B (Apo B) and C-III (Apo C-III) with ASCVD. During a median follow-up time of 2.3 years, 340 (27%) participants experienced an ASCVD event. Higher concentrations of triglycerides were not associated with ASCVD risk: Hazard ratio (HR) 0.95; 95% CI (0.83, 1.10) per doubling concentration. Similarly, VLDL-C HR 1.01; 95% CI (0.90, 1.13); Apo B HR 1.04; 95% CI (0.93, 1.16); and Apo C-III HR 0.97; 95% CI (0.86, 1.09) (per one standard deviation higher concentrations), were not associated with ASCVD events. These associations did not differ by allocation to treatment to atorvastatin or by concentrations of markers of inflammation or malnutrition. In conclusion, we found no evidence that triglycerides, triglyceride-rich lipoproteins, or apolipoproteins B or C-III were associated with risk of ASCVD events among patients with type 2 diabetes and ESRD on hemodialysis. These results suggest that lowering triglycerides may not decrease atherosclerotic cardiovascular risk in this population.

Elevated Levels of Apolipoprotein CIII Increase the Risk of Postprandial Hypertriglyceridemia.

Background: To investigate possible mechanisms of postprandial hypertriglyceridemia (PPT), we analyzed serum lipid and apolipoprotein (Apo) AI, B, CII and CIII levels before and after a high-fat meal. Methods: The study has been registered with the China Clinical Trial Registry (registration number:ChiCTR1800019514; URL: http://www.chictr.org.cn/index.aspx). We recruited 143 volunteers with normal fasting triglyceride (TG) levels. All subjects consumed a high-fat test meal. Venous blood samples were obtained during fasting and at 2, 4, and 6 hours after the high-fat meal. PPT was defined as TG ≥2.5 mmol/L any time after the meal. Subjects were divided into two groups according to the high-fat meal test results: postprandial normal triglyceride (PNT) and PPT. We compared the fasting and postprandial lipid and ApoAI, ApoB, ApoCII and ApoCIII levels between the two groups. Results: Significant differences were found between the groups in fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), TG, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), TG-rich lipoprotein remnants (TRLRs), ApoB, ApoCIII, ApoAI/ApoB and ApoCII/ApoCIII. The insulin, HOMA-IR, TG, TC, LDL-C, non-HDL-C, TRLRs, ApoB, ApoCIII and ApoCII/ApoCIII values were higher in the PPT group, while the ApoAI/ApoB ratio was higher in the PNT group. The postprandial TG level peaked in the PNT group 2 hours after the meal but was significantly higher in the PPT group and peaked at 4 hours. TRLRs gradually increased within 6 hours after the high-fat meal in both groups. The area under the curve (AUC) of TG and TRLRs and the AUC increment were higher in the PPT group (P < 0.001). ApoCIII peaked in the PNT group 2 hours after the meal and gradually decreased. ApoCIII gradually increased in the PPT group within 6 hours after the meal, exhibiting a greater AUC increment (P < 0.001). Fasting ApoCIII was positively correlated with age, systolic and diastolic blood pressure, body mass index (BMI), waist circumference, TC, TG, LDL-C, non-HDL-C, TRLRs, and ApoB (P<0.05). ApoCIII was an independent risk factor of PPT after adjustment for BMI, waist circumference, TC, LDL-C, and ApoB (P < 0.001, OR=1.188). Conclusions: Elevated ApoCIII levels may cause PPT.

HDL Containing Apolipoprotein C-III is Associated with Insulin Sensitivity: A Multicenter Cohort Study.

CONTEXT: High density lipoprotein (HDL) in humans is composed of a heterogeneous group of particles varying in protein composition as well as biological effects. OBJECTIVE: We investigated the prospective associations between HDL subspecies containing and lacking apolipoprotein (apo) C-III at baseline and insulin sensitivity at year 3. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study of 864 healthy volunteers drawn from the relationship between insulin sensitivity and cardiovascular disease (RISC) study, a multicenter European clinical investigation, whose recruitment initiated in 2002, with a follow-up of 3 years. MAIN MEASURES: Insulin sensitivity was estimated from an oral glucose tolerance test at baseline and year 3, and by euglycemic-hyperinsulinemic clamp at baseline only. The apolipoprotein concentrations were measured at baseline by a sandwich enzyme-linked immunosorbent assay (ELISA)-based method. RESULTS: The 2 HDL subspecies demonstrated significantly opposite associations with insulin sensitivity at year 3 (P-heterogeneity = 0.004). The highest quintile of HDL containing apoC-III was associated with a 1.2% reduction in insulin sensitivity (P-trend = 0.02), while the highest quintile of HDL lacking apoC-III was associated with a 1.3% increase (P-trend = 0.01), compared to the lowest quintile. No significant association was observed for total HDL, and very low density lipoprotein (VLDL) and low density lipoprotein (LDL) containing apoC-III. ApoC-III contained in HDL was associated with a decrease in insulin sensitivity even more strongly than plasma total apoC-III. CONCLUSION: Both HDL containing apoC-III and apoC-III in HDL adversely affect the beneficial properties of HDL on insulin response to glucose. Our results support the potential of HDL-associated apoC-III as a promising target for diabetes prevention and treatment.

Apolipoprotein C-III and cardiovascular diseases: when genetics meet molecular pathologies.

Cardiovascular diseases (CVD) have overtaken infectious diseases and are currently the world's top killer. A quite strong linkage between this type of ailments and elevated plasma levels of triglycerides (TG) has been always noticed. Notably, this risk factor is mired in deep confusion, since its role in atherosclerosis is uncertain. One of the explanations that aim to decipher this persistent enigma was provided by apolipoprotein C-III (apoC-III), a small protein historically recognized as an important regulator of TG metabolism. Preeminently, hundreds of studies have been carried out in order to explore the APOC3 genetic background, as well as to establish a correlation between its variants and dyslipidemia-related disorders, pointing to an earnest predictive power for future outcomes. Among several polymorphisms reported within the APOC3, the SstI site in its 3'-untranslated region (3'-UTR) was the most consistently and robustly associated with an increased CVD risk. As more genetic data supporting its importance in cardiovascular events aggregate, it was declared, correspondingly, that apoC-III exerts various atherogenic effects, either by intervening in the function and catabolism of many lipoproteins, or by inducing endothelial inflammation and smooth muscle cells (SMC) proliferation. This review was designed to shed the light on the structural and functional aspects of the APOC3 gene, the existing association between its SstI polymorphism and CVD, and the specific molecular mechanisms that underlie apoC-III pathological implications. In addition, the translation of all these gathered knowledges into preventive and therapeutic benefits will be detailed too.

The effects of KaiXinSan on depression and its association with lipid profiles: A randomized, double-blinded, placebo-controlled trial.

BACKGROUND: Traditional Chinese medicine (TCM) KaiXinSan (KXS) has been used to treat depressed patients for a long time, but its potential underlying mechanisms have not been fully understood. HYPOTHESIS: KXS could mitigate symptoms of patients with atypical depression at least partly via regulating lipid equilibrium. METHODS: Patients meeting DSM-IV criteria for mild or moderate depression were assigned into placebo (N = 68) or KXS 3.2 g/day (N = 66) groups in a randomized, double-blinded, placebo-controlled, parallel clinical trial to investigate the anti-depressive efficacy of KXS and its association with serum lipid profile. RESULTS: The HAMD score and SDS score at 8 weeks were significantly improved in KXS-treated patients the N-BACK accuracy rate was also increased after 8 weeks of KXS treatment compared with baseline. These results indicated that KXS not only improved the specific symptoms of depression, but also had a beneficial effect on cognitive function related working memory. More importantly, KXS treatment improved patients' lipid profile by reducing the ratios of LDL/HDL and ApoB/ApoA1 (p < 0.05), as well as ApoC3 level. Moreover, subgroup analysis found that HAMD score was significantly higher in patients with high lipid profile than in those with normal lipid profile, and lipid improvement after 8 weeks of KXS treatment was more obvious in depressed patients with high lipid profile than with normal lipid profile. CONCLUSION: KXS could mitigate symptoms of patients with minor and modest depression at least partly via regulating lipid equilibrium. Its might shed light that KXS may likely contributes to depressed patients with other cardio-metabolic diseases.

Preoperative plasma biomarkers associated with atrial fibrillation after coronary artery bypass surgery.

OBJECTIVES: Postoperative atrial fibrillation (POAF) is a common complication in coronary artery bypass grafting (CABG) procedures. This prospective study aimed to investigate predisposition of proteins and metabolites correlated to POAF after CABG and related cellular pathways. METHODS: Preoperative plasma samples from patients undergoing CABG procedures were prospectively collected. After CABG, the patients were grouped to POAF or sinus rhythm (N = 170; n = 90 in the discovery set and n = 80 in the validation set). The plasma samples were analyzed using proteomics, metabolomics, and bioinformatics to identify the differential proteins and differential metabolites. The correlation between differential proteins and POAF was also investigated by multivariable regression analysis and receiver operator characteristic analysis. RESULTS: In the POAF(+) group, 29 differential proteins and 61 differential metabolites were identified compared with the POAF(-) group. The analysis of integrated omics revealed that preoperative alteration of peroxisome proliferators-activated receptor α and glutathione metabolism pathways increased the susceptibility of POAF after CABG. There was a correlation between plasma levels of apolipoprotein-C3, phospholipid transfer protein, glutathione peroxidase 3, cholesteryl ester transfer protein, and POAF. CONCLUSIONS: The present study for first time at multi-omics levels explored the mechanism of POAF and validated the results in a new cohort of patients, suggesting preexisting differential proteins and differential metabolites in the plasma of patients prone to POAF after CABG. Dysregulation of peroxisome proliferators-activated receptor α and glutathione metabolism pathways related to metabolic remodeling and redox imbalance-associated electrical remodeling may play a key role in the pathogenesis of POAF. Lower plasma phospholipid transfer protein, apolipoprotein-C3, higher cholesteryl ester transfer protein and glutathione peroxidase 3 levels are linked with POAF. These proteins/metabolites may be developed as biomarkers to predict POAF.

Serum PCSK9 Correlates with PTX3 and Apolipoproteins B, A1, and C3 Concentrations in Patients with Type 2 Diabetes.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in the regulation of LDL metabolism. There is evidence that circulating PCSK9 is a cardiovascular risk factor. In this study, we determined factors associated with circulating PCSK9 in a group of patients with type 2 diabetes mellitus (DM2). Material included 116 consecutive patients with DM2 from outpatient diabetes clinic. Circulating PCSK9, PTX3, apolipoprotein (apo) B100, apo B48, and apo C3 levels were determined by ELISA, apo A1 by immunoturbidimetry. The mean (sd) age of patients was 59.1 (11.1) years, the mean (sd) values of serum PCSK9 were 255.4 (106.97) ng/ml. Circulating PCSK9 correlated negatively with age (r = -0.21, p < 0.05) and HbA1c (r = -0.21, p < 0.05) and positively with BMI (r = 0.21, p < 0.05), total cholesterol (r = 0.59), LDL-cholesterol (r = 0.50), triglyceride (r = 0.35), apo B100 (r = 0.43), apo A1 (r = 0.43) (p < 0.001 for all), apo C3 (r = 0.29, p < 0.01), and apo B48 (r = 0.25, p < 0.01) concentration and FLI (r = 0.26, p < 0.01). Strong correlation between PTX3 and PCSK9 levels was observed (r = 0.47, p < 0.001). Multiple stepwise backward regression analysis with PCSK9 as dependent variable revealed that PTX3, apo B100, apo A1, apo B48, and BMI were significantly positive and the presence of NAFLD and HbA1c negatively associated with PCSK9 concentrations. These variables together explain 57% of PCSK9 variability; the strongest relationship was observed between PCSK9 and PTX3 and apo B100. Our results indicate that circulating PCSK9 is significantly associated with inflammation marker PTX3 as well as atherogenic lipids and apolipoproteins C3, B100, and B48, which might be of value in understanding interactions between development of atherosclerosis and inflammatory state in DM2 patients.

Plasma proteome atlas for differentiating tumor stage and post-surgical prognosis of hepatocellular carcinoma and cholangiocarcinoma.

Although mass spectrometry-based plasma proteomics enables sensitive and large-scale discovery and validation of biomarkers for various diseases, its integrative application to hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) is not well investigated. Therefore, we analyzed albumin- and immunoglobulin G-depleted plasma samples from 148 and 60 patients with HCC and CCA, respectively, using liquid chromatography-tandem mass spectrometry. The algorithm used to measure the content of each protein was the percentage of exponentially modified protein abundance index. From 5320 proteins assayed in plasma, 53 and 25 biomarker candidates were identified for HCC and CCA, respectively. The abundance of six and two HCC markers particularly protruded in stage II and III, respectively, whereas plasma serine protease inhibitor was the sole marker the level of which steadily decreased with CCA progression. From a prognostic facet, we showed candidate markers and their cutoff levels for evaluating probability of tumor recurrence and patient survival period. Combination Kaplan-Meier models showed that HCC stage III or IV and both the content of alpha-2-HS-glycoprotein and apolipoprotein CIII <0.2% exhibited the poorest post-surgical recurrence-free and overall survivals. Furthermore, the content of afamin ≥0.2% played a significant role on the poor prognosis in patients with CCA. Our findings, taken together, characterized novel plasma biomarker signatures in dissecting tumor stages and post-surgical outcomes of HCC and CCA.

Association of Apolipoprotein E in Lipoprotein Subspecies With Risk of Dementia.

Importance: The ε4 allele of the apolipoprotein E (APOE) gene and lower apolipoprotein E (apoE) protein levels in plasma are risk factors for Alzheimer disease, but the underlying biological mechanisms are not fully understood. Half of plasma apoE circulates on high-density lipoproteins (HDLs). Higher apoE levels in plasma HDL were previously found to be associated with lower coronary heart disease risk, but the coexistence of another apolipoprotein, apoC3, modified this lower risk. Objective: To investigate associations between the presence of apoE in different lipoproteins with cognitive function, particularly the risk of dementia. Design, Setting, and Participants: This prospective case-cohort study embedded in the Ginkgo Evaluation of Memory Study (2000-2008) analyzed data from 1351 community-dwelling participants 74 years and older. Of this group, 995 participants were free of dementia at baseline (recruited from September 2000 to June 2002) and 521 participants were diagnosed with incident dementia during follow-up until 2008. Data analysis was performed from January 2018 to December 2019. Exposures: Enzyme-linked immunosorbent assay-measured concentration of apoE in whole plasma, HDL-depleted plasma (non-HDL), HDL, and HDL subspecies that contain or lack apoC3 or apoJ. Main Outcomes and Measures: Adjusted hazard ratios for risk of dementia and Alzheimer disease during follow-up and adjusted differences (ß coefficients) in Alzheimer Disease Assessment-Cognitive Subscale (ADAS-cog) and Modified Mini-Mental State Examination scores at baseline. Results: Among 1351 participants, the median (interquartile range) age was 78 (76-81) years; 639 (47.3%) were women. The median (interquartile range) follow-up time was 5.9 (3.7-6.5) years. Higher whole plasma apoE levels and higher apoE levels in HDL were associated with better cognitive function assessed by ADAS-cog (whole plasma, ß coefficient, -0.15; 95% CI, -0.24 to -0.06; HDL, ß coefficient, -0.20; 95% CI, -0.30 to -0.10) but were unassociated with dementia or Alzheimer disease risk. When separated by apoC3, a higher apoE level in HDL that lacks apoC3 was associated with better cognitive function (ADAS-cog per SD: ß coefficient, 0.17; 95% CI, -0.27 to -0.07; Modified Mini-Mental State Examination score per SD: ß coefficient, 0.25; 95% CI, 0.07 to 0.42) and lower risk of dementia (hazard ratio per SD, 0.86; 95% CI, 0.76 to 0.99). In contrast, apoE levels in HDL that contains apoC3 were unassociated with any of these outcomes. Conclusions and Relevance: In a prospective cohort of older adults with rigorous follow-up of dementia, the apoE level in HDL that lacked apoC3 was associated with better cognitive function and lower dementia risk. This finding suggests that the cardioprotective associations of this novel lipoprotein extend to dementia.