Assessing the Accuracy of Estimated Lipoprotein(a) Cholesterol and Lipoprotein(a)‐Free Low‐Density Lipoprotein Cholesterol

Background Accurate measurement of the cholesterol within lipoprotein(a) (Lp[a]‐C) and its contribution to low‐density lipoprotein cholesterol (LDL‐C) has important implications for risk assessment, diagnosis, and treatment of atherosclerotic cardiovascular disease, as well as in familial hypercholesterolemia. A method for estimating Lp(a)‐C from particle number using fixed conversion factors has been proposed (Lp[a]‐C from particle number divided by 2.4 for Lp(a) mass, multiplied by 30% for Lp[a]‐C). The accuracy of this method, which theoretically can isolate “Lp(a)‐free LDL‐C,” has not been validated. Methods and Results In 177 875 patients from the VLDbL (Very Large Database of Lipids), we compared estimated Lp(a)‐C and Lp(a)‐free LDL‐C with measured values and quantified absolute and percent error. We compared findings with an analogous data set from the Mayo Clinic Laboratory. Error in estimated Lp(a)‐C and Lp(a)‐free LDL‐C increased with higher Lp(a)‐C values. Median error for estimated Lp(a)‐C <10 mg/dL was −1.9 mg/dL (interquartile range, −4.0 to 0.2); this error increased linearly, overestimating by +30.8 mg/dL (interquartile range, 26.1–36.5) for estimated Lp(a)‐C ≥50 mg/dL. This error relationship persisted after stratification by overall high‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol subtypes. Similar findings were observed in the Mayo cohort. Absolute error for Lp(a)‐free LDL‐C was +2.4 (interquartile range, −0.6 to 5.3) for Lp(a)‐C<10 mg/dL and −31.8 (interquartile range, −37.8 to −26.5) mg/dL for Lp(a)‐C≥50 mg/dL. Conclusions Lp(a)‐C estimations using fixed conversion factors overestimated Lp(a)‐C and subsequently underestimated Lp(a)‐free LDL‐C, especially at clinically relevant Lp(a) values. Application of inaccurate Lp(a)‐C estimations to correct LDL‐C may lead to undertreatment of high‐risk patients.

Baseline Low-Density-Lipoprotein Cholesterol Modifies the Risk of All-Cause Death Associated With Elevated Lipoprotein(a) in Coronary Artery Disease Patients

Background: The prognostic value of elevated lipoprotein(a) [Lp(a)] in coronary artery disease (CAD) patients is inconsistent in previous studies, and whether such value changes at different low-density-lipoprotein cholesterol (LDL-C) levels is unclear.Methods and Findings: CAD patients treated with statin therapy from January 2007 to December 2018 in the Guangdong Provincial People's Hospital (NCT04407936) were consecutively enrolled. Individuals were categorized according to the baseline LDL-C at cut-off of 70 and 100 mg/dL. The primary outcome was 5-year all-cause death. Multivariate Cox proportional models and penalized spline analyses were used to evaluate the association between Lp(a) and all-cause mortality. Among 30,908 patients, the mean age was 63.1 ± 10.7 years, and 76.7% were men. A total of 2,383 (7.7%) patients died at 5-year follow-up. Compared with Lp(a) &lt;50 mg/dL, Lp(a) ≥ 50 mg/dL predicted higher all-cause mortality (multivariable adjusted HR = 1.19, 95% CI 1.07–1.31) in the total cohort. However, when analyzed within each LDL-C category, there was no significant association between Lp(a) ≥ 50 mg/dL and higher all-cause mortality unless the baseline LDL-C was ≥ 100 mg/dL (HR = 1.19, 95% CI 1.04–1.36). The results from penalized spline analyses were robust.Conclusions: In statin-treated CAD patients, elevated Lp(a) was associated with increased risks of all-cause death, and such an association was modified by the baseline LDL-C levels. Patients with Lp(a) ≥ 50 mg/dL had higher long-term risks of all-cause death compared with those with Lp(a) &lt;50 mg/dL only when their baseline LDL-C was ≥ 100 mg/dL.

Genetic Predisposition to Low-Density Lipoprotein Cholesterol May Increase Risks of Both Individual and Familial Alzheimer's Disease

Background: Previous observational studies provided conflicting results on the association between low-density lipoprotein cholesterol (LDL-C) level and the risk of Alzheimer's disease (AD).Objective: We used two-sample Mendelian randomization (MR) study to explore the causal associations between LDL-C level and the risks of individual, paternal, maternal, and family history of AD.Methods: Summary-level genetic data for LDL-C were acquired from results of the UK Biobank GWAS. Corresponding data for paternal, maternal, and family history of AD were obtained from the NHGRI-EBI Catalog of human genome-wide association studies. Data for individual AD were obtained from the MR-Base platform. A two-sample MR study was performed to explore the causal association between LDL-C level and the risks of individual, paternal, maternal, and family history of AD.Results: Genetically predicted LDL-C was positively associated with individual [Odds ratio (OR) = 1.509, 95% confidence interval (CI) = 1.140–1.999; P = 4.0 × 10−3], paternal [OR = 1.109, 95% CI = 1.053–1.168; P = 9.5 × 10−5], maternal [OR = 1.132, 95% CI = 1.070–1.199; P = 2.0 × 10−5], and family history of AD [OR = 1.124, 95% CI = 1.070–1.181; P = 3.7 × 10−6] in inverse variance weighted analysis. After performing weighted median and MR-Egger analysis, consistent results were observed. There was no horizontal pleiotropy in the two-sample MR analysis.Conclusions: High level of LDL-C may increase the risks of both individual and familial AD. Decreasing the LDL-C to a reasonable level may help to reduce the related risk.

Triglyceride/low-density-lipoprotein cholesterol ratio is the most valuable predictor for increased small, dense LDL in type 2 diabetes patients

Background Small, dense low-density lipoprotein (sd-LDL) increases in type 2 diabetes patients and causes arteriosclerosis. Non–high-density-lipoprotein cholesterol (non–HDL-C) is thought to be useful for predicting arteriosclerosis and sd-LDL elevation; however, there are no data about whether the triglyceride /low-density-lipoprotein cholesterol (TG/LDL-C) ratio is a valuable predictor for sd-LDL. Methods A total of 110 type 2 diabetes patients with hypertriglyceridemia were analyzed. No patients were treated with fibrates, but 47 patients were treated with statins. LDL-C was measured by the direct method. LDL-migration index (LDL-MI) using electrophoresis (polyacrylamide gel, PAG) was calculated, and a value ≥0.400 was determined to indicate an increase in sd-LDL. Simple regression analyses were carried out between LDL-MI and lipid markers. Receiver operating characteristic curves of lipid markers for predicting high LDL-MI were applied to determine the area under the curve (AUC), sensitivity, specificity, and cut-off point. Results LDL-MI correlated negatively with LDL-C (P = 0.0027) and PAG LDL fraction (P < 0.0001) and correlated positively with TGs, non–HDL-C, TG/LDL-C ratio, TG/HDL-C ratio, and non–HDL-C/HDL-C ratio among all study patients. Similar results were obtained for patients analyzed according to statin treatment. The AUCs (95% confidence interval) were 0.945 (0.884-1.000) for TG/LDL-C ratio and 0.614 (0.463-0.765) for non–HDL-C in patients without statins (P = 0.0002). The AUCs were 0.697 (0.507-0.887) for TG/LDL-C and 0.682 (0.500-0.863) for non–HDL-C in patients treated with statins. The optimal cut-off point for TG/LDL-C ratio for increased LDL-MI was 1.1 (molar ratio) regardless of statin treatment. The sensitivity and specificity of the TG/LDL-C ratio (90.0 and 93.9%, respectively) were higher than those of non–HDL-C (56.7 and 78.8%, respectively) in patients without statins. Conclusions The TG/LDL-C ratio is a reliable surrogate lipid marker of sd-LDL and superior to non–HDL-C in type 2 diabetes patients not treated with statins.

Prevalence and Correlates of Cardiovascular Calcification and Its Prognostic Effects Among Patients With Chronic Kidney Disease: Results From the C-STRIDE Study

Background and Aims: The purpose of this study was to identify the characteristics and risk factors for cardiovascular calcification, and its relationship to prognosis, in patients with chronic kidney disease (CKD) stages 1–4.Methods: Cardiovascular calcification was evaluated at baseline by lateral abdominal radiography to detect abdominal aortic calcifications (AAC), and by echocardiogram to detect cardiac valvular calcifications (CVC), respectively. Demographic and laboratory data were collected and analyzed. Univariate and multivariable logistic regression model was used to explore the factors associated with the indicators of cardiovascular calcification, while Cox proportional hazards regression was used to examine the association between AAC/CVC and incidence of cardiovascular events and all-cause mortality.Results: A subgroup of 2,235 patients with measurement of AAC in the C-STRIDE study and a subgroup of 2,756 patients with CVC were included in the analysis. AAC was present in 206 patients (9.22%) and CVC was present in 163 patients (5.91%). Age, gender, history of cardiovascular diseases, smoking, hypertension, diabetes, levels of hemoglobin, low-density lipoprotein cholesterol, and uric acid were associated with prevalence of AAC, while only age, history of cardiovascular diseases, levels of serum albumin and low-density lipoprotein cholesterol were associated with prevalence of CVC (all p &lt; 0.05).Survival analyses showed that cardiovascular events and all-cause mortality were significantly greater in patients with AACor with CVC (all p-values for log-rank tests &lt;0.05). After adjustment for age, sex and estimated glomerular filtration rate (eGFR), AAC was associated with increased risk of all-cause mortality (hazard ratio = 1.67[95% confidence interval: 0.99, 2.79]), while CVC associated with that of cardiovascular events only among patients with comparatively normal eGFR (≥45 ml/min/1.73m2) (hazard ratio = 1.99 [0.98, 4.03]).Conclusion: Demographic and traditional cardiovascular risk factors were associated with cardiovascular calcification, especially AAC. AAC may be associated with risk of death for patients CKD of any severity, while CVC as a possible risk factor for cardiovascular disease only among those with mild to moderate CKD. Assessments of vascular calcification are need to be advanced to patients in the early and middle stages of chronic kidney disease and to initiate appropriate preventive measures earlier.

The Risk Factors for Development of Type 2 Diabetes: Panasonic Cohort Study 4

(1) Background: As no study has evaluated the risk factors contributing to the development of type 2 diabetes according to body weight mass (BMI) categories in a large cohort and over a long period in a Japanese population, we aimed to assess them in 46,001 Japanese individuals; (2) Methods: This long-term retrospective cohort study included individuals who participated in a medical health checkup program at Panasonic Corporation from 2008 to 2018. In total, 3,208 participants developed type 2 diabetes. The BMI at 2008 were divided into 3 groups: BMI < 22 kg/m2, 22 ≤ BMI < 25 kg/m2, and BMI ≥ 25 kg/m2 to evaluate the risk factors for type 2 diabetes; (3) Results: Cox regression analyses revealed that the significant risk factors were age, BMI, systolic blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, fasting plasma glucose, current smoking status, and alcohol consumption in populations with BMI ≥ 25.0 kg/m2. The risk factors in the population with 22 ≤ BMI < 25 kg/m2 were identical to that of BMI ≥ 25.0 kg/m2 excluding systolic blood pressure, low-density lipoprotein cholesterol, and skipping breakfast. However, in the population with BMI < 22.0 kg/m2, no association was found as to BMI, SBP, LDL cholesterol level, and triglycerides; (4) Conclusions: The risk factors for developing diabetes were quite different between the population with BMI < 22 kg/m2 and the population with 22 ≤ BMI < 25 kg/m2 or BMI ≥ 25 kg/m2 in a Japanese population.

Bilirubin ameliorates murine atherosclerosis through inhibiting cholesterol synthesis and reshaping the immune system

Atherosclerosis is a chronic inflammatory disease caused mainly by lipid accumulation and excessive inflammatory immune response. Although the lipid-lowering and cardioprotective properties of bilirubin, as well as the negative relationship between bilirubin and atherosclerosis, were well documented, it is not yet clear whether bilirubin can attenuate atherosclerosis in vivo. In this study, we investigated the role of bilirubin in improving atherosclerosis. We found that mildly elevated bilirubin significantly reduced the risk factors of atherosclerosis, such as plasma glucose, total cholesterol, and low-density lipoprotein cholesterol, and the formation of atherosclerotic plaques, liver total cholesterol, and cholesterol ester concentration in apolipoprotein E-deficient (ApoE−/−) mice fed a western-type (high fat) diet. It was further found that bilirubin could promote the degradation of 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), a rate-limiting enzyme for endogenous cholesterol synthesis. Using mass cytometry-based high dimensional single cell analysis, we observed a decrease of natural killer cells and an increase of dendritic cells and myeloid-derived suppressor cells, which all are closely associated with atherosclerosis risk factors and contribute to the improvement of atherosclerosis, in ApoE−/− mice treated with bilirubin. By in-depth analysis, modulation of multiple spleen or peripheral blood T cell clusters exhibiting either positive or negative correlations with total cholesterol or low-density lipoprotein cholesterol was detected after bilirubin treatment. In this study, we demonstrate that bilirubin serves as a negative regulator of atherosclerosis and reduces atherosclerosis by inhibiting cholesterol synthesis and modulating the immune system.

Update on dyslipidemia in hypothyroidism

Hypothyroidism is often associated with elevated serum levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C) and triglycerides. Thyroid hormone (TH) affects the production, clearance and transformation of cholesterol, but current research shows that thyroid-stimulating hormone (TSH) also participates in lipid metabolism independently of TH. Therefore, the mechanism of hypothyroidism-related dyslipidemia is associated with the decrease of TH and the increase of TSH levels. Some newly identified regulatory factors, such as proprotein convertase subtilisin/kexin type 9 (PCSK9), angiogenin-like proteins (ANGPTL), and fibroblast growth factors (FGF) are the underlying causes of dyslipidemia in hypothyroidism. High-density lipoprotein (HDL) serum concentration changes were not consistent, and its function was reportedly impaired. The current review focuses on the updated understanding of the mechanism of hypothyroidism-related dyslipidemia.