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ABSTRACT Low‐density lipoprotein cholesterol (LDL‐C) is known to be a causal substance of atherosclerosis, but its usefulness as a predictive biomarker for atherosclerotic cardiovascular disease (ASCVD) is limited. In patients with type 2 diabetes (T2D), LDL‐C concentrations do not markedly increase, while triglycerides (TG) concentrations are usually elevated. Although TG is associated with ASCVD risk, they do not play a direct role in the formation of atheromatous plaques. TG changes the risk of ASCVD in a way that is dependent on LDL‐C, and TG is the primary factor in reducing LDL particle size. Small dense (sd)LDL, a potent atherogenic LDL subfraction, best explains the “Atherogenic Duo” of TG and LDL‐C. Although hypertriglyceridemia is associated with small‐sized LDL, patients with severe hypertriglyceridemia and low LDL‐C rarely develop ASCVD. This suggests that quantifying sdLDL is more clinically relevant than measuring LDL size. We developed a full‐automated direct sdLDL‐C assay, and it was proven that sdLDL‐C is a better predictor of ASCVD than LDL‐C. The sdLDL‐C level is specifically elevated in patients with metabolic syndrome and T2D who have insulin resistance. Due to its clear link to metabolic dysfunction, sdLDL‐C could be named “metabolic LDL‐C.” Insulin resistance/hyperinsulinemia promotes TG production in the liver, causing steatosis and overproduction of VLDL1, a precursor of sdLDL. sdLDL‐C is closely associated with steatotic liver disease and chronic kidney disease, which are common complications in T2D. This review focuses on T2D and discusses the clinical significance of sdLDL‐C including its composition, pathophysiology, measurements, association with ASCVD, and treatments. [ABSTRACT FROM AUTHOR]

Objective: To compare serum small dense low-density lipoprotein cholesterol levels in coronary heart disease (CHD) patients and healthy controls. Study Design: Comparative cross-sectional study. Place and Duration of Study: Department of Chemical Pathology and Endocrinology, Armed Forces Institute of Pathology (AFIP), Rawalpindi Pakistan, in collaboration with AFIC Rawalpindi from Feb to Dec 2021. Methodology: A total of 220 participants were selected for the study, 120 healthy controls and 100 CHD patients. Fasting blood samples after 12 hours of fast were collected for lipid profile and small dense low-density lipoprotein cholesterol (sdLDL-C) levels. SdLDL-C levels were analyzed by automated, standardized enzymatic assay on Siemens Advia 1800 automated chemistry analyzer using Ex Denka Seiken kits. Results: Among the total participants, 154 (70%) were males, and 66(30%) were females. The median age of all participants was 55(IQR: 52 -56) years, while their median sdLDL-C was 0.93 (IQR: 0.56-1.08) mmol/L. Results showed that small, dense LDL cholesterol serum levels were significantly raised in CHD patients compared to healthy controls (p-value <0.05). Conclusion: The current study showed that patients with CHD had elevated small, dense LDL-C levels compared to the healthy control group. [ABSTRACT FROM AUTHOR]

Abstract Background Residual risk remained significant despite effective low density lipoprotein cholesterol (LDL-C) lowering treatment. Small dense low density lipoprotein cholesterol (sdLDL-C) as part of LDL-C has been found to be predictor of coronary heart disease (CHD) and cardiovascular (CV) events in patients with stable CHD independently of LDL-C. However, to date, few studies have explored the role of sdLDL-C in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI). Accordingly, this study aimed to evaluate the association of sdLDL-C with CV events in patients with ACS undergoing PCI. Methods Patients hospitalized with ACS undergoing PCI were enrolled and followed up for 18 months. The risk of sdLDL-C for CV events was compared according to sdLDL-C quartiles. The primary outcome was major cardiovascular and cerebrovascular adverse events (MACCE), which was the composite of all cause of death, nonfatal myocardial infarction (MI), nonfatal stroke or unplanned repeat revascularization. A Cox proportional hazards regression model was performed to estimate the risk of CV events. Subgroup analysis according to diabetes status and LDL-C were performed separately for MACCE. Results A total of 6092 patients were included in the analysis (age: 60.2 ± 10.13 years, male: 75.3%, BMI: 25.9 ± 3.33 kg/m2, dyslipidemia: 74.1% and diabetes: 44.5%). During 18 months of follow-up, 320 (5.2%) incident CV events occurred. Compared to the lowest sdLDL-C quartile group, patients in the highest quartile had a greater risk of CV events after multivariable adjustment (HR 1.92; 95% CI 1.37–2.70). In addition, it was mainly due to the increase of unplanned repeat revascularization. In the subgroup analyses, significant association was observed regardless of level of LDL-C and diabetes status. Conclusions Patients with elevated sdLDL-C have a higher risk of CV events in Chinese patients with ACS undergoing PCI, providing additional value for better risk assessment.

Background: Residual risk remained significant despite effective low density lipoprotein cholesterol (LDL-C) lowering treatment. Small dense low density lipoprotein cholesterol (sdLDL-C) as part of LDL-C has been found to be predictor of coronary heart disease (CHD) and cardiovascular (CV) events in patients with stable CHD independently of LDL-C. However, to date, few studies have explored the role of sdLDL-C in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI). Accordingly, this study aimed to evaluate the association of sdLDL-C with CV events in patients with ACS undergoing PCI.Methods: Patients hospitalized with ACS undergoing PCI were enrolled and followed up for 18 months. The risk of sdLDL-C for CV events was compared according to sdLDL-C quartiles. The primary outcome was major cardiovascular and cerebrovascular adverse events (MACCE), which was the composite of all cause of death, nonfatal myocardial infarction (MI), nonfatal stroke or unplanned repeat revascularization. A Cox proportional hazards regression model was performed to estimate the risk of CV events. Subgroup analysis according to diabetes status and LDL-C were performed separately for MACCE.Results: A total of 6092 patients were included in the analysis (age: 60.2 ± 10.13 years, male: 75.3%, BMI: 25.9 ± 3.33 kg/m2, dyslipidemia: 74.1% and diabetes: 44.5%). During 18 months of follow-up, 320 (5.2%) incident CV events occurred. Compared to the lowest sdLDL-C quartile group, patients in the highest quartile had a greater risk of CV events after multivariable adjustment (HR 1.92; 95% CI 1.37-2.70). In addition, it was mainly due to the increase of unplanned repeat revascularization. In the subgroup analyses, significant association was observed regardless of level of LDL-C and diabetes status.Conclusions: Patients with elevated sdLDL-C have a higher risk of CV events in Chinese patients with ACS undergoing PCI, providing additional value for better risk assessment. [ABSTRACT FROM AUTHOR]

Abstract Background Small dense LDL cholesterol (sdLDL-c) has been established to be highly associated with metabolic disorder. However, the relationship between circulating sdLDL-c and the presence of metabolic syndrome (MetS) has not been fully established. Methods A total of 1065 Chinese males (45.07 ± 11.08 years old) without diabetes and general obesity was recruited into a population-based, cross-sectional study. The MetS was defined based on the updated National Cholesterol Education Program/ Adult Treatment Panel III criteria for Asian Americans. Serum sdLDL-c concentration was measured by a homogeneous assay method and its relationship with MetS and its traits was investigated. Results Serum sdLDL-c concentrations increased gradually with increasing numbers of MetS components (p

Aims: This preliminary randomized, parallel-group comparative study evaluated the efficacy of ipragliflozin for reduction of small dense low-density lipoprotein cholesterol (sd LDL-C) levels in Japanese patients with type 2 diabetes mellitus (T2DM). Methods: Sixty-two patients with T2DM (age, 56 ± 8 years; hemoglobin A1c levels, 8.1 ± 0.9%; BMI, 27.5 ± 3.3 kg/m2) were randomly assigned in a 2:1 ratio to receive ipragliflozin (50 mg/day) (treatment group; n = 40) or continued treatment (control group; n = 22) for 12 weeks. The primary endpoints were changes in sd LDL-C levels detected using the LipoPhor AS® system; the secondary endpoints included changes in the sd LDL-C/large buoyant LDL-C (lb LDL-C) ratio, a surrogate marker for LDL particle size, and percent changes in routine lipid parameters. Results: The treatment group exhibited a statistically significant reduction from baseline for LDL-C levels (−0.37 mg/dL vs. 14.4 mg/dL, p = 0.038), sd LDL-C levels (−1.28 mg/dL vs. 2.81 mg/dL, p = 0.012), and sd LDL-C/lb LDL-C ratio (−3.20% vs. 4.58%, p = 0.040) compared with the control group. Multiple regression analysis among all subjects revealed change in TG levels (p = 0.011) and LDL-C levels (p = 0.024) as well as change in body weight (p = 0.006) as independent factors contributing to the reduction in sd LDL-C. Conclusions: Ipragliflozin may have a potential for lowering sd LDL-C levels associated with increasing LDL particle size in Japanese patients with T2DM.

Background: Small dense LDL cholesterol (sdLDL-c) has been established to be highly associated with metabolic disorder. However, the relationship between circulating sdLDL-c and the presence of metabolic syndrome (MetS) has not been fully established. Methods: A total of 1065 Chinese males (45.07 ± 11.08 years old) without diabetes and general obesity was recruited into a population-based, cross-sectional study. The MetS was defined based on the updated National Cholesterol Education Program/ Adult Treatment Panel III criteria for Asian Americans. Serum sdLDL-c concentration was measured by a homogeneous assay method and its relationship with MetS and its traits was investigated. Results: Serum sdLDL-c concentrations increased gradually with increasing numbers of MetS components (p < 0.001) and the proportion of patients with MetS increased gradually with increasing sdLDL-c levels (p for trend< 0.001). For the second, third, and fourth sdLDL-c quartiles versus the first, the OR (95% CI) for MetS were 4.47(2.41,8.28), 5.47(2.97,10.07) and 8.39(4.58,15.38) (p < 0.001 for trend) after multivariate adjustment. The stratified analysis conducted according to LDL-c levels showed that the OR between serum sdLDL-c levels and MetS was greater in those LDL-c levels lower than 3.3 mmol/L (OR = 22.97; 95% CI, 7.64–69.09) than in those LDL-c levels higher than 3.3 mmol/L (OR = 17.49; 95% CI, 4.43–68.98). Mediation analysis showed sdLDL-c mediated 38.6% of the association of waist circumference with triglycerides, while the association between sdLDL-c and MetS components did not mediate by hsCRP. Conclusions: This study found that high sdLDL-c concentrations were associated with the presence of MetS independently of central obesity and inflammation. [ABSTRACT FROM AUTHOR]

Aim: We investigated the relationship between small dense low-density cholesterol (sdLDL-C) and risk of major adverse cardiovascular events (MACE) in patients treated with high- or low-dose statin therapy., Methods: This was a prospective case-cohort study within the Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study, a randomized trial of high- or low-dose (4 or 1 mg/d pitavastatin, respectively) statin therapy, in patients with stable coronary artery disease (CAD). Serum sdLDL-C was determined using an automated homogenous assay at baseline (randomization after a rule-in period, ＞1 month with 1 mg/d pitavastatin) and 6 months after randomization, in 497 MACE cases, and 1543 participants randomly selected from the REAL-CAD study population., Results: High-dose pitavastatin reduced sdLDL-C by 20% than low-dose pitavastatin (p for interaction ＜0.001). Among patients receiving low-dose pitavastatin, baseline sdLDL-C demonstrated higher MACE risk independent of LDL-C (hazard ratio [95% confidence interval], 4th versus 1st quartile, 1.67 [1.04-2.68]; p for trend=0.034). High-dose (versus low-dose) pitavastatin reduced MACE risk by 46% in patients in the highest baseline sdLDL-C quartile (＞34.3 mg/dL; 0.54 [0.36-0.81]; p=0.003), but increased relative risk by 40% in patients with 1st quartile (≤ 19.5 mg/dL; 1.40 [0.94-2.09]; p=0.099) and did not alter risk in those in 2nd and 3rd quartiles (p for interaction=0.002)., Conclusions: These findings associate sdLDL-C and cardiovascular risk, independent of LDL-C, in statin-treated CAD patients. Notably, high-dose statin therapy reduces this risk in those with the highest baseline sdLDL-C.

Dyslipidemia is a risk factor for cardiovascular disease (CVD), a major cause of death worldwide. Angiopoietin-like protein 3 (ANGPTL3), recognized as a new therapeutic target for dyslipidemia, regulates the metabolism of low-density lipoprotein-cholesterol (LDL-C) and triglycerides. Here, we design 3 epitopes (E1-E3) for use in development of a peptide vaccine targeting ANGPTL3 and estimate effects of each on obesity-associated dyslipidemia in B6.Cg- Lep ob /J ( ob/ob ) mice. Vaccination with the E3 ( 32 EPKSRFAMLD 41 ) peptide significantly reduces circulating levels of triglycerides, LDL-C, and small dense (sd)-LDL-C in ob/ob mice and decreases obese-induced fatty liver. Moreover, E3 vaccination does not induce cytotoxicity in ob/ob mice. Interestingly, the effect of E3 vaccination on dyslipidemia attenuates development of atherosclerosis in B6.KOR/StmSlc- Apoe shl mice fed a high-cholesterol diet, which represent a model of severe familial hypercholesterolemia (FH) caused by ApoE loss of function. Taken together, ANGPTL3 vaccination could be an effective therapeutic strategy against dyslipidemia and associated diseases., Competing Interests: The authors declare no competing interests., (© 2021.)

Aim: The present study aims to investigate the association between serum small dense low-density lipoprotein (sdLDL) cholesterol level and the development of coronary heart disease (CHD) in subjects at high cardiovascular risk., Methods: A total of 3,080 participants without prior cardiovascular disease (CVD), aged ≥ 40 years, were followed up for a median of 8.3 years, which were divided into two groups, those with serum sdLDL cholesterol levels of ＜35 mg/dL or ≥ 35 mg/dL. Then, subjects were stratified by the status of diabetes, CVD-related comorbidities (defined as the presence of diabetes, chronic kidney disease, or peripheral artery disease), and the CVD risk assessment according to the Japan Atherosclerosis Society Guidelines. The hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using a Cox proportional hazards model., Results: During the follow-up, 79 subjects developed CHD. The risk for incident CHD was higher in subjects with serum sdLDL cholesterol of ≥ 35 mg/dL than those with sdLDL cholesterol of ＜35 mg/dL (HR 2.09, 95%CI 1.26-3.45) after adjusting for traditional risk factors. In the subgroup analyses, the multivariable-adjusted HR for incident CHD increased significantly in those with serum sdLDL cholesterol of ≥ 35 mg/dL among subjects with diabetes (HR 2.76, 95%CI 1.09-7.01), subjects with CVD-related comorbidities (HR 2.60, 95%CI 1.21-5.58), and high-risk category defined as the presence of CVD-related comorbidities or a Suita score of ≥ 56 points (HR 1.93, 95%CI 1.02-3.65)., Conclusions: Elevated serum sdLDL cholesterol was associated with the development of CHD even in subjects at high cardiovascular risk.

Aim: The association between small dense low-density lipoprotein cholesterol (sdLDL-C) levels and carotid intimal medial thickness (cIMT) progression has not been evaluated fully. We assessed specialized lipoproteins, including sdLDL-C, with regard to cIMT progression in a prospective observational study in Japan., Methods: Plasma total cholesterol, direct LDL-C, sdLDL-C, LDL-triglycerides (LDL-TG), high-density lipoprotein cholesterol (HDL-C), HDL2-C, HDL3-C, triglycerides, Lp(a), and adiponectin were measured in 2,030 men and women (median age 59 years, free of cardiovascular disease (CVD) and off cholesterol lowering medication). At both baseline and after a five-year follow-up, cIMT was assessed. Univariate, multivariate regression, and least square analyses were performed to examine the relationships between direct LDL-C, sdLDL-C, and other lipoproteins with cIMT progression., Results: The median cIMT at baseline was 0.63 mm and five-year progression was 0.18 mm. After adjustment for standard CVD risk factors, including age, gender, systolic blood pressure, total cholesterol, HDL-C, smoking, diabetes, and hypertension treatment, only direct LDL-C, sdLDL-C, and the sdLDL-C/LDL-C ratio were associated with cIMT progression. Even in subjects with direct LDL-C ＜100 mg/dL, who were considered at low CVD risk, elevated sdLDL-C were associated with cIMT progression (P for trend=0.009) in a model with established CVD risk factors, although the sdLDL-C/LDL-C ratio did not. Those correlations did not change by including triglycerides as a controlling factor or excluding premenopausal women from the analyzed population., Conclusions: Small dense LDL-C has a stronger relationship with cIMT progression than LDL-C does; therefore, measuring sdLDL-C may allow for the formulation of optimal therapy for CVD prevention.

Aims: This study aims to investigate the association between serum small dense low-density lipoprotein (sdLDL) cholesterol level and the development of coronary heart disease (CHD) in a Japanese community., Methods: A total of 3,080 participants without prior cardiovascular disease, aged 40 years or older, were followed up for 8 years. The participants were divided into the quartiles of serum sdLDL cholesterol levels. The risk estimates were computed using a Cox proportional hazards model., Results: During the follow-up period, 79 subjects developed CHD. Subjects in the highest quartile had a 5.41- fold (95% confidence interval, 2.12-13.82) higher risk of CHD than those in the lowest quartile after controlling for confounders. In the analysis classifying the participants into four groups according to the levels of serum sdLDL cholesterol and serum low-density lipoprotein (LDL) cholesterol levels, the risk of CHD almost doubled in subjects with sdLDL cholesterol of ≥ 32.9 mg/dL (median), regardless of serum LDL cholesterol levels, as compared with subjects with serum sdLDL cholesterol of ＜32.9 mg/dL and serum LDL cholesterol of ＜120.1 mg/dL (median). When serum sdLDL cholesterol levels were incorporated into a model with known cardiovascular risk factors, c-statistics was significantly increased (from 0.77 to 0.79; p=0.02), and the net reclassification improvement was also significant (0.40; p＜0.001)., Conclusions: The present findings suggest that the serum sdLDL cholesterol level is a relevant biomarker for the future development of CHD that offers benefit beyond the serum LDL cholesterol level and a possible therapeutic target to reduce the burden of CHD in a Japanese community.