Small Dense Low-density Lipoprotein Cholesterol Research Articles

Why are Skipping Breakfast and Skipping Staple Foods Inappropriate Dietary Patterns? The Association with Small Dense Low-Density Lipoprotein Cholesterol Levels.

Why are Skipping Breakfast and Skipping Staple Foods Inappropriate Dietary Patterns? The Association with Small Dense Low-Density Lipoprotein Cholesterol Levels.

Management of Dyslipidemia in Patients with Diabetes Mellitus

Most patients with diabetes mellitus (DM) have dyslipidemia, which is characterized by increased triglycerides, decreased high-density lipoprotein cholesterol, and increased small dense low-density lipoprotein cholesterol (LDL-C). Dyslipidemia is an important modifiable risk factor for cardiovascular disease (CVD). Therefore active management is essential. Despite its increasing prevalence, the proportion of patients with adequately-controlled dyslipidemia is small, and efforts to improve this pattern are required. The Korean Diabetes Association guidelines recommend setting goals by evaluating each patient’s future CVD risk, including the presence or absence of CVD, target organ damage, major cardiovascular risk factors, and the duration of DM. The primary target is an LDL-C level below 55 mg/dL (and a reduction in LDL-C level by 50% or more from baseline), 70 mg/dL, and 100 mg/dL from the highest risk group to the lowest risk group, respectively. Statins are the first-line drug of choice, and if the LDL-C target is not reached by a maximum tolerable dose of statin, combination therapy with ezetimibe or proprotein convertase subtilisin/kexin type 9 inhibitors is recommended. In hypertriglyceridemia, lifestyle changes including weight loss and abstinence from alcohol are very important, along with glycemic control.

An increase in calculated small dense low-density lipoprotein cholesterol predicts new onset of hypertension in a Japanese cohort.

A disorder of lipid metabolism is involved in cardiovascular diseases including hypertension. A high level of small dense low-density lipoprotein cholesterol (sdLDL-C) is a strong risk factor for atherosclerotic cardiovascular disease. However, the association between sdLDL-C and hypertension has not been fully investigated. We investigated the associations between the development of hypertension during a 10-year period and levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides (TG), and LDL-C and sdLDL-C calculated by using the Sampson equations in 28,990 Japanese subjects who received annual health examinations. After exclusion of subjects with missing data, those with hypertension, and those with TG ≥ 800 mg/dL at baseline, a total of 15,177 subjects (men/women: 9374/5803, mean age: 46 years) were recruited. During the 10-year period, 2379 men (25.4%) and 724 women (12.5%) had new onset of hypertension. Multivariable Cox proportional hazard model analyses showed that levels of HDL-C, non-HDL-C, TG and sdLDL-C, but not levels of TC and LDL-C, were independent risk factors for the development of hypertension after adjustment of age, sex, family history of hypertension, systolic blood pressure, obesity, current smoking habit, alcohol drinking habit, estimated glomerular filtration rate, diagnosis of diabetes mellitus and use of lipid-lowering drugs and that the adjusted risk of sdLDL-C (per 1-standard deviation) was highest (hazard ratio [95% confidence interval: 1.09 [1.05-1.13]). The addition of sdLDL-C to traditional risk factors for hypertension significantly improved the discriminatory capability, which was better than that of other lipid fractions. In conclusion, a high level of calculated sdLDL-C predicts the development of hypertension.

Accuracy of Small Dense Low-density Lipoprotein-cholesterol Concentration Estimated via Sampson's Equation in Healthy Subjects and Patients with Diabetes.

Sampson et al. proposed a method to calculate small dense low-density lipoprotein-cholesterol (sdLDL-C) concentrations using common lipid measurements, but its accuracy remains unresolved. We examined the difference between Sampson's equation and direct measurement in patients with diabetes. sdLDL-C was measured directly by our established homogeneous assay and estimated by Sampson's equation in patients with diabetes (n=1542) and healthy control subjects (n=673). Large-buoyant (lb)LDL-C was estimated using triglycerides and LDL-C, and sdLDL-C was obtained by subtracting lbLDL-C from LDL-C. The effect of fasting/nonfasting state or lipid-lowering drug therapy on sdLDL-C values was also examined in 30 and 43 patients with diabetes, respectively. The coefficient of determination (R 2 ) between calculated sdLDL-C and direct measurement was 0.73 and 0.61 for healthy controls and patients with diabetes, respectively. The R2 between calculated sdLDL-C and nonHDL-C or apolipoprotein B was 0.64 and 0.65, respectively. Calculated sdLDL-C was 4-5 mg/dl or 17%-18% higher than the direct measurement. The lower the plasma lipids, especially sdLDL-C, the greater the dissociation between the two methods. Sampson sdLDL-C was also found to give a positive bias when calculated for the nonfasting samples. Statins and pemafibrate significantly reduced sdLDL-C, but their therapeutic effect was underestimated by 5 mg/dl (24%) via Sampson's equation. The correlation between Sampson's equation and direct measurements of sdLDL-C was reduced in patients with diabetes. Furthermore, the correlations with nonHDL-C and apolipoprotein B were even higher than those with direct sdLDL-C. The accuracy of Sampson's equation decreased with lower sdLDL-C concentrations and was also influenced by diet.

Estimation of Small Dense LDL-Cholesterol Levels in Patients with Acute Coronary Syndrome.

Small dense LDL-cholesterol is an established risk factor for atherosclerosis, but it is not routinely measured in clinical practice, and its measurement has not yet been reimbursed. The Sampson equation that uses triglyceride and LDL-cholesterol levels has very recently been proposed to estimate small dense LDL-cholesterol levels. We validated its accuracy in patients with acute coronary syndrome.Serum samples were obtained on admission from hospitalized patients with acute coronary syndrome before heparinization. Small dense LDL-cholesterol levels were measured directly and were also estimated from triglyceride and LDL-cholesterol levels using the Sampson equation. The correlation between the Sampson's equation and direct measurement was investigated.A total of 55 patients were enrolled. The median age was 75 (65, 84) years old, and 35 (64%) were men. There was a moderate correlation between the two methods (r = 0.76, P < 0.001). A lower level of small dense LDL-cholesterol was independently associated with a greater overestimation of the Sampson equation.The Sampson equation is useful for estimating small dense LDL-cholesterol levels in patients with acute coronary syndrome. However, the estimated value may be overestimated in patients with low lipid profiles.

7-OR: Evaluation of Saroglitazar’s Effects on Small Dense LDL and Non-HDL Cholesterol Particles in Diabetic Dyslipidemia Patients

The dual PPAR α/γ agonist Saroglitazar is used to treat diabetic dyslipidemia (DD) that cannot be managed with statins. Due to its association with high triglycerides (TG), high small dense LDL (sdLDL), and low HDL-C, DD is extremely atherogenic. The efficacy and safety of saroglitazar have been assessed in this prospective multi-centric research in patients with type 2 diabetes and triglycerides (TG) 200 mg/dL following stable statin medication for at least 3 months and a steady lifestyle. A total of 104 patients (78% of whom were men) were enrolled, with a mean age of 59.1 ± 11.4 years. Saroglitazar 4 mg was administered to each subject once daily for 24 weeks. Using a paired t-test, the effects of saroglitazar were assessed after 24 weeks. 73 patients' six-month follow-up data are available. Non-HDL-C and sdLDL levels both significantly decreased at 24 weeks, with non-HDL-C dropping from 138 ± 51 mg/dL to 113 ± 44 mg/dL and from 31.7 ± 11.8 mg/dL to 26.0 ± 11.9 mg/dL, respectively. The values of HDL-C, TG, HbA1c and total cholesterol among the secondary end goals also considerably improved after 24 weeks (Table). No significant adverse event was reported during the investigation. This is the initial investigation on how saroglitazar affects sdLDL in DD patients. According to the findings, saroglitazar effectively lowers non-HDL-C and sdLDL particles while being safe and well tolerated. Disclosure J.Dinkar: None. R.Ranjan: None. A.Chandra: None.

Novel Antidiabetic Agents and Their Effects on Lipid Profile: A Single Shot for Several Cardiovascular Targets.

Type-2 diabetes mellitus (DM) represents one of the most important risk factors for cardiovascular diseases (CVD). Hyperglycemia and glycemic variability are not the only determinant of the increased cardiovascular (CV) risk in diabetic patients, as a frequent metabolic disorder associated with DM is dyslipidemia, characterized by hypertriglyceridemia, decreased high-density lipoprotein (HDL) cholesterol levels and a shift towards small dense low-density lipoprotein (LDL) cholesterol. This pathological alteration, also called diabetic dyslipidemia, represents a relevant factor which could promotes atherosclerosis and subsequently an increased CV morbidity and mortality. Recently, the introduction of novel antidiabetic agents, such as sodium glucose transporter-2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4i) and glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs), has been associated with a significant improvement in CV outcomes. Beyond their known action on glycemia, their positive effects on the CV system also seems to be related to an ameliorated lipidic profile. In this context, this narrative review summarizes the current knowledge regarding these novel anti-diabetic drugs and their effects on diabetic dyslipidemia, which could explain the provided global benefit to the cardiovascular system.

Hypertriglyceridemia contributes significantly to high prevalence of small dense LDL-cholesterol in patients with type 2 diabetes, even when LDL-C targets are achieved.

Small-dense (sd)LDL-cholesterol (C) is a potent risk factor for atherosclerotic cardiovascular disease (ASCVD) beyond LDL-C, and 35mg/dL has been proposed as a cut-off value for high-sdLDL-C. sdLDL-C levels are strongly regulated by triglycerides (TG) and LDL-C levels. LDL-C has detailed targets for the prevention of ASCVD, while TG is only defined as abnormal at ≥ 150mg/dL. We investigated the effect of hypertriglyceridemia on the prevalence of high-sdLDL-C in patients with type 2 diabetes and explored the optimal TG levels that would suppress high-sdLDL-C. Fasting plasma was obtained from 1569 patients with type 2 diabetes who were enrolled in the regional cohort study. sdLDL-C concentrations were measured by the homogeneous assay established by us. High-sdLDL-C was defined as ≤ 35mg/dL according to the Hisayama Study. Hypertriglyceridemia was defined as ≥ 150mg/dL. All lipid parameters except HDL-C were higher in the high-sdLDL-C group than in the normal-sdLDL-C group. The receiver operating characteristic (ROC) curves revealed that high sdLDL-C was identified sensitively by TG and LDL-C, with cut-off values of 115mg/dL for TG and 110mg/dL for LDL-C. The presence of hypertriglyceridemia increased the prevalence of high-sdLDL-C sixfold more than the normotriglyceridemic counterpart, regardless of statin use. This substantial influence of hypertriglyceridemia was found even within the control target of LDL-C levels (70-120mg/dL) for diabetic subjects. The TG cut-off for high-sdLDL-C was well below 150mg/dL in a diabetic population. Amelioration of hypertriglyceridemia is needed even when LDL-C targets for diabetes are achieved.

Abstract 458: A Study Of Short-term Low-saturated Fat Versus High-saturated Fat Diet In Atherothrombosis Risk Factors In Subjects With Hypertriglyceridemia

Introduction: Dietary fat and composition may impact the risk of atherosclerotic cardiovascular disease (ASCVD) in subjects with hypertriglyceridemia (HTG). Hypothesis: We hypothesized that a low-saturated fat diet (LSFD), in contrast to a high-saturated fat diet (HSFD), improves blood lipid levels and reduces atherothrombosis risk factors in subjects with HTG. Method: Subjects with HTG and metabolic syndrome (n=19) were randomly placed on an LSFD (~25% of calories from fat, 5% from saturated fat) or an HSFD (~52% of calories from fat, 25% from saturated fat) for 4 days (day 1-4) and a breakfast on day 5 and then switched to the other diet after a 4- to 6-week washout period. Blood was collected on day 1 fasting before the start of the diet and on day 5 fasting and at 4 and 6 hours after breakfast. Lipid profiles and flow cytometry to measure monocyte intracellular lipid accumulation, monocyte expression of tissue factor (TF), and monocyte-platelet aggregates (MPAs) were performed. Results: On day 5, LSFD, compared to HSFD, induced lower plasma levels of postprandial total triglyceride and LDL-triglyceride and fasting and postprandial total cholesterol, non-HDL-cholesterol, LDL-cholesterol, and small dense LDL-cholesterol. Classical and intermediate monocytes with LSFD, in contrast to HSFD, exhibited reduced intracellular lipid accumulation indicated by decreases in cellular granularity and nile red staining examined by flow cytometry. LSFD vs. HSFD also reduced classical monocyte uptake of oxidized LDL ex vivo at 4 hours postprandially on day 5. Surface level of TF was higher on classical and intermediate monocytes than on nonclassical monocytes assessed by mean fluorescence intensity. Classical and intermediate monocytes, compared to nonclassical monocytes, were also more prone to form aggregates with platelets. However, there was no significant difference between LSFD and HSFD in TF levels on any monocyte subsets and in MPAs of any monocyte subsets at any time points recorded. Conclusion: In subjects with HTG and metabolic syndrome, short-term LSFD, in contrast to HSFD, reduced monocyte lipid accumulation and oxidized LDL uptake but did not induce significant differences in monocyte surface levels of TF and MPA formation.

Discordance between lipoprotein (a) and LDL-cholesterol levels in cardiovascular risk assessment in apparently healthy subjects

Background and aimsLipoprotein(a) is a recognized independent cardiovascular risk factor and apolipoprotein B (apoB) level better reflects the risk than LDL-cholesterol. Despite this cardiovascular prediction mostly relies on traditional risk factors. We evaluated the association between Lp(a) and lipid biomarkers of cardiovascular risk in relation to age and sex in apparently healthy individuals. Methods and results422 presumably healthy subjects aged 19–84 were included. Lipid profile, Lp(a), apoB and small dense low-density lipoprotein cholesterol (sdLDL-C) were assayed. Subjects were divided at desirable cut-points of apoB and LDL-C. A group with elevated apoB (≥100 mg/dL) at low LDL-C (≤115 mg/dL) was appointed as high-risk and a group with low apoB but elevated LDL-C as low-risk. Significantly elevated triglycerides, TG/HDL-C and sdLDL-C were found in high risk group, but Lp(a) levels were comparable. TG/HDL-C was the best predictor of high risk with a very good diagnostic accuracy (AUC = 0.85), whereas Lp(a) had no discriminatory power. Women aged ≤40 with low LDL-C ≤ 100 mg/dL and elevated Lp(a) ≥ 40 mg/dL had higher levels of apoB and sdLDL-C (p = 0.002; p = 0.07) than those with Lp(a) < 40 mg/dL, which was not observed in men. In young females increase of LDL-C and apoB significantly raised the risk of elevated Lp(a). ConclusionsWomen younger than 40 with low LDL-C may be at increased cardiovascular risk associated with elevated Lp(a) and apolipoprotein B levels. Inclusion of Lp(a) and apoB in the routine lipid testing providing information on an individual level may improve the prediction of cardiovascular risk in primary prevention.

Estimated small dense low-density lipoprotein-cholesterol and incident type 2 diabetes in Japanese people: Population-based Panasonic cohort study 13

AimsThis study aimed to investigate the association between estimated small dense low-density lipoprotein (sd-LDL) and incident type 2 diabetes. MethodsWe analyzed the data from a health checkup under a program conducted by Panasonic Corporation between 2008 and 2018. A total of 120,613 participants were included, of whom 6,080 developed type 2 diabetes. Estimated large buoyant (lb)-LDL cholesterol and sd-LDL cholesterol was calculated by the formula using triglyceride and LDL cholesterol. Cox proportional hazard model and time-dependent receiver operating characteristic (ROC) analysis were used to evaluate the association between the lipid profiles and incident type 2 diabetes. ResultsMultivariate analysis showed that LDL cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, estimated large buoyant (lb)-LDL cholesterol, and estimated sd-LDL were associated with incident type 2 diabetes. Moreover, the area under the ROC curve and optimal cut-off values for estimated sd-LDL cholesterol for incident type 2 diabetes at 10 years were 0.676 and 35.9 mg/dL, respectively. The area under the curve of estimated sd-LDL cholesterol was higher than that of HDL cholesterol, LDL cholesterol, or estimated lb-LDL cholesterol. ConclusionThe estimated sd-LDL cholesterol was an important predictor of future incidence of diabetes within 10 years.

The influence of triglycerides on small dense low-density lipoprotein cholesterol levels is attenuated in low low-density lipoprotein-cholesterol range: Implications for the negative results of the PROMINENT trial.

The Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) trial failed to show the preventive effects of pemafibrate, a triglyceride (TG)-lowering drug, on atherosclerotic cardiovascular disease in patients with type 2 diabetes and dyslipidemia. We recently reported that TG-lowering with pemafibrate did not decrease the calculated small dense (sd) low-density lipoprotein cholesterol (LDL-C), and speculated that the effect of TG on sdLDL-C is attenuated in low LDL-C levels. This report examined this possibility in 1,508 patients with type 2 diabetes and 670 healthy controls. LDL-C ranges were classified as ≤69, 70-99, 100-139 and 140≤ mg/dL. The slope of the regression curve between sdLDL-C and TG was found to flatten as LDL-C decreased; 0.18, 0.13, 0.10 and 0.04 for controls, and 0.18, 0.13, 0.09 and 0.07 for diabetes patients. Correspondingly, the lower the LDL-C range, the lower the sdLDL-C/TG ratio. These results suggest that when LDL-C is tightly controlled, TG-lowering has only a weak inhibitory effect on sdLDL-C.

Analysis and correlation of small dense low-density lipoprotein-cholesterol (sdLDL-C) with various lipoproteins and cardiac markers in acute coronary syndrome patients associated with normal Low-density lipoprotein-cholesterol (LDL-C) level: A cross sectional study.

Title of the article: Analysis and correlation of small dense low-density lipoprotein-cholesterol (sdLDL-C) with various lipoproteins and cardiac markers in acute coronary syndrome patients associated with normal Low-density lipoprotein-cholesterol (LDL-C) level: A cross-sectional study. Aim: To analyze the levels of sdLDL cholesterol in acute coronary syndrome patients (ACS) with normal LDL cholesterol (LDL-C) and correlate with various lipoproteins and cardiac markers. Methodology: The present study included 100 patients diagnosed with ACS with normal LDL-C. Demographic details and cardiac markers were correlated with sdLDL levels. A detailed history was elicited from the patients and the details of clinical examination and laboratory findings such as cardiac Troponin, C- reactive protein, and CK-MB were obtained from patient case files. Results: The results are expressed in mean±sd. The mean age of study participants was 39.5±10.5yrs. The majority of the participants were men (69%) between the age group of 31-40 years. Mean values of total cholesterol, VLDL, sdLDL, Trop-I, CRP, and CKMB are at higher levels in men when compared to women. Whereas, mean values of triglycerides, LDL, and HDL are higher in women when compared to men. The majority of participants were having unstable angina (42%) followed by STEMI (33%) and NSTEMI (25%). Correlation between sdLDL and other parameters was carried out using Mann–Whitney–Wilcoxon test. The result showed a statistically significant correlation between sdLDL and VLDL, Trop-I, and CRP with p &lt;0.05. Patients with sdLDL of &gt; 25mg/dl had a higher incidence of unstable angina and STEMI. Conclusion: Our study result suggests that ACS with normolipidemic patients has a positive correlation with sdLDL levels and sdLDL can be a new diagnostic marker along with cardiac troponins in ACS.

Significance of Circulating Remnant Lipoprotein Cholesterol Levels Measured by Homogeneous Assay in Patients with Type 2 Diabetes

Remnant lipoproteins (RLs), which are typically present at high concentrations in patients with type 2 diabetes mellitus (T2DM), are associated with cardiovascular disease (CVD). Although an RL cholesterol homogeneous assay (RemL-C) is available for the measurement of RL concentrations, there have been no studies of the relationship between RemL-C and clinical parameters in T2DM. Therefore, we evaluated the relationships between RemL-C and CVD-related parameters in patients with T2DM. We performed a cross-sectional study of 169 patients with T2DM who were hospitalized at Kumamoto University Hospital. Compared with those with low RemL-C, those with higher RemL-C had higher fasting plasma glucose, homeostasis model assessment for insulin resistance (HOMA-R), total cholesterol, triglyceride, small dense low-density lipoprotein cholesterol (sdLDL-C), and urinary albumin-creatinine ratio; and lower high-density lipoprotein cholesterol, adiponectin, and ankle brachial pressure index (ABI). Multivariate logistic regression analysis showed that sdLDL-C and ABI were significantly and independently associated with high RemL-C. Although LDL-C was lower in participants with CVD, there was no difference in RemL-C between participants with or without CVD. Thus, RemL-C may represent a useful index of lipid and glucose metabolism, and that may be a marker of peripheral atherosclerotic disease (PAD) in male patients with T2DM.

Abstract P555: Variants of Neurocan, a Nonalcoholic Fatty Liver Disease Risk Allele, Are Associated With Plaque Development in the Carotid Artery Over 5 Years

Introduction: Nonalcoholic fatty liver disease (NAFLD) genetic risk alleles are associated with lipid metabolism. However, the association between those variants and atherosclerosis has not yet been fully evaluated. Hypothesis: We hypothesized that NAFLD risk alleles are associated with the progression of atherosclerosis. Methods: A total of 1,050 Japanese men and women (median age 55 years and median body mass index 22.9 kg/m2) free of cardiovascular disease, dyslipidemia, hypertension, and diabetes were studied. . Among NAFLD risk SNPs, variants of patatin-like phospholipase domain containing 3 ( PNPLA3 ), transmembrane 6 superfamily member 2 ( TM6SF2 ), glucokinase regulator ( GCKR ), and neurocan ( NCAN ) were assessed. Plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C), small dense LDL-C, LDL-triglycerides, high-density lipoprotein cholesterol (HDL-C), HDL3-C, triglycerides, remnant-like particle cholesterol, lipoprotein(a), and adiponectin were also measured. At both baseline and after a five-year follow-up, carotid intima-media thickness (cIMT) was assessed. Atherosclerosis was defined as cIMT ≥ 1.1mm or the presence of a plaque. Univariate and multivariate analyses and chi-square and Fisher’s exact tests were performed to examine the associations between NAFLD risk SNPs, lipoproteins, and progression of atherosclerosis. Results: Both median and maximum cIMT of total participants did not differ between baseline and after a five-year follow-up. Among participants without atherosclerosis at baseline, the rate of plaque development was 13.8% (121/880) with the major allele (CC) of NCAN being significantly higher than other alleles. Variants of NCAN were associated with the development of plaque ( P = 0.04, Fisher’s exact test). Participants with the CT allele of NCAN had significantly lower RLP cholesterol at baseline than those with the CC allele (7.6 mg/dl vs. 10.5 mg/dl, P = 0.02). Variants of PNPLA3 , TM6SF2 , GCKR , and NCAN were not associated with changes in lipoproteins. Conclusions: A NCAN variant, one of the NAFLD risk SNPs, was associated with the development of plaque independent of lipoprotein alterations among healthy Japanese participants.

Association of Urinary Lead and Cadmium Levels, and Serum Lipids with Subclinical Arteriosclerosis: Evidence from Taiwan.

Exposure to lead and cadmium has been linked to changes in lipid metabolism and the development of arteriosclerosis, but the role of lipoprotein profiles in this relationship is not well understood, including the potential role of novel lipid biomarkers. In this study, we enrolled 736 young Taiwanese subjects aged 12 to 30 years to assess the correlation between urine levels of lead and cadmium, lipoprotein profiles, and carotid intima-media thickness (CIMT). Higher levels of lead and cadmium were significantly associated with higher levels of low-density lipoprotein cholesterol (LDL-C), small dense LDL-C (sdLDL-C), LDL-triglyceride (LDL-TG), and CIMT. Participants with higher levels of lead and cadmium had the highest mean values of CIMT, LDL-C, sdLDL-C, and LDL-TG. In a structural equation model, lead had a direct and indirect association with CIMT through LDL-C and sdLDL-C, whereas cadmium had a direct association with CIMT and an indirect association through LDL-C. Our results suggest higher levels of lead and cadmium are associated with abnormal lipid profiles and increased CIMT. These heavy metals could have additive effects on lipids and CIMT, and the relationship between them may be mediated by lipoprotein levels. Further research is needed to determine the causal relationship.

Atherosclerotic cardiovascular disease risk and small dense low-density lipoprotein cholesterol in men, women, African Americans and non-African Americans: The pooling project

Background and aimsElevated small dense low-density lipoprotein-cholesterol (sdLDL-C) has been reported to be associated with increased atherosclerotic cardiovascular disease (ASCVD) risk. Our aims were to determine whether direct and calculated sdLDL-C were significant independent ASCVD risk factors in sex and race subgroups. MethodsIn a total of 15,933 participants free of ASCVD at baseline (median age 62 years, 56.7% female, 19.7% African American) fasting plasma lipids and sdLDL-C were measured by standardized automated methods. All subjects were followed for 10 years for incident ASCVD, which developed in 9.7% of subjects. SdLDL-C values were also calculated. Univariate and multivariate analyses were carried out to assess for independent associations with incident ASCVD after adjustment for all standard risk factors. ResultsAll standard risk factors were significantly associated with incident ASCVD on univariate analysis, as were direct and calculated sdLDL-C. These latter parameters were also significant when added to the pooled cohort risk equation. However, associations were significantly stronger for direct sdLDL-C and were not significant for calculated values once direct values were in the model. In contrast to calculated values, top quartile direct sdLDL-C was significantly independently associated with incident ASCVD versus bottom quartile values in all subjects and subgroups, except African Americans (hazard ratios ≥1.50, p < 0.01). Subjects with direct values ≥ 50 mg/dL versus <25 mg/dL had significantly higher independent ASCVD risk in all groups (hazard ratios >1.49, all p < 0.01). ConclusionsHaving a direct small dense low-density lipoprotein cholesterol value ≥ 50 mg/dL is a significant independent ASCVD risk-enhancer.

Prognostic Implication of Small Dense LDL-Cholesterol Levels following Acute Coronary Syndrome.

Background and Objectives: Small dense LDL cholesterol is a strong risk factor for atherosclerosis. However, few studies have investigated the impacts of this specific lipid profile on the incident risk of adverse cardiovascular events in patients with acute coronary syndrome. Materials and Methods: Patients with acute coronary syndrome, who underwent revascularization, were included and followed for 2 years. The levels of small dense LDL cholesterol were measured at index discharge (day 0) in the setting of newly administered therapies for secondary prevention, including aspirin and statins, during the index hospitalization. The prognostic impact of small dense LDL-cholesterol levels on the risk of a primary composite endpoint, including cardiac death, non-fatal myocardial infarction, unstable angina pectoris, stroke, and heart failure, was investigated. Results: In total, 46 patients (median 75 (59, 83) years old, 63% men) were included. Median small dense LDL cholesterol was 19.4 (13.5, 23.8) mg/dL at index discharge. All patients initiated statin treatment before the index discharge, with a median LDL-cholesterol level of 77 (64, 109) mg/dL. Small dense LDL-cholesterol level was independently associated with an incremental risk for the primary endpoint (p &lt; 0.05 by adjusting for several potential risk factors, including LDL cholesterol) with a cutoff of 32.6 mg/dL. Conclusions: Small dense LDL-cholesterol level was a significant risk factor for cardiovascular events following presentations of acute coronary syndrome.

Validation of Estimated Small Dense Low-Density Lipoprotein Cholesterol Concentration in a Japanese General Population.

A high level of directly measured small dense low-density lipoprotein cholesterol (sdLDL-C) is a strong risk factor for atherosclerotic cardiovascular disease. A method for estimating sdLDL-C by using Sampson's equation that includes levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C), non-HDL-C and triglycerides (TG) has recently been proposed. We investigated the validation and exploration of estimated sdLDL-C level. The associations between measured and estimated sdLDL-C levels were investigated in 605 Japanese subjects (men/women: 280/325; mean age: 65±15 years) who received annual health check-ups in the Tanno-Sobetsu Study, a population-based cohort. Estimated sdLDL-C level was highly correlated with measured sdLDL-C level in all subjects (R2=0.701), nondiabetic subjects without any medication (n=254, R2=0.686) and subjects with diabetes mellitus (n=128, R2=0.721). Multivariable regression analysis showed that levels of non-HDL-C, TG and γ-glutamyl transpeptidase (γGTP) were independent predictors of measured sdLDL-C level. In a stratification of the LDL window, all of the subjects with a combination of high non-HDL-C (≥ 170 mg/dL) and high TG (≥ 150 mg/dL) had high levels of measured and estimated sdLDL-C (≥ 35 mg/dL). Furthermore, machine learning-based estimation of sdLDL-C level by artificial intelligence software, Prediction One, was substantially improved by using components of Sampson's equation (R2=0.803) and by using those components with the addition of γGTP and deletion of TC (R2=0.929). sdLDL-C level estimated by Sampson's equation can be used instead of measured sdLDL-C level in general practice. By building multiple machine learning models of artificial intelligence, a more accurate and practical estimation of sdLDL-C level might be possible.

PS-BPB03-5: DEVELOPMENT OF A THERAPEUTIC VACCINE FOR DYSLIPIDEMIA AND RELATED DISEASES TARGETING ANGIOPOIETIN-LIKE PROTEIN 3 (ANGPTL3).

Background: Dyslipidemia is a major factor in the development and progression of atherosclerotic diseases. Among dyslipidemias, familial hypercholesterolemia (FH) is a genetic disorder affecting approximately 34 million people worldwide, with 300,000 patients in Japan. Since homozygous FH in particular is resistant to existing therapies, there is an urgent need to develop new therapies to reduce the risk of cardiovascular disease (CVD) in patients with FH. Design and Method: We focused on angiopoietin-like protein 3 (ANGPTL3) as a novel therapeutic target for dyslipidemia. ANGPTL3 is known to inhibit lipoprotein lipase as well as angiogenesis. Mutations of this gene in humans were reported to have no apparent pathogenic effects and have been reported to reduce triglyceride (TG) and LDL cholesterol (LDL-C) levels in the blood and the risk of developing CVD. We have developed a peptide vaccine that induces anti-ANGPTL3 antibodies and produces a potent therapeutic effect on dyslipidemia. We vaccinated ob/ob mice, an obese mouse model of type 2 diabetes, with a total of three doses of vaccine every two weeks and analyzed the results. Results: The vaccine group (n = 12) showed significant reductions in blood TG concentration by 52%, LDL-C concentration by 41%, and small dense LDL-C concentration by 49% compared to the control group (n = 10). In addition, histologically fatty liver was improved, and analysis of TG accumulation in hepatocytes showed a 47% reduction in the vaccine group. Furthermore, vaccination reduced dyslipidemia and atherosclerosis in ApoE function-deficient mice, a model of severe familial hypercholesterolemia. Notability, the vaccine did not induce cytotoxic immunity against the mouse liver and ANGPTL3-producing organs. Conclusions: Based on these results, this vaccine is expected to be one of the effective treatments for atherosclerotic diseases.