Discordantly Elevated Apolipoprotein B versus Low-Density Lipoprotein Cholesterol is Associated with Remnant Lipoproteins and Increased Cardiovascular Events

Atherosclerotic cardiovascular disease is a result of low-density lipoprotein (LDL) particles becoming trapped in arterial walls and forming plaques which ultimately restrict blood-flow. LDL cholesterol (LDL-C) and apolipoprotein B (apoB) are highly correlated measures of plaque-causing LDL particles. Both have been shown to predict major adverse cardiac events (MACE). ApoB is also carried on remnant lipoproteins (RLP). RLP-cholesterol (RLP-C) is increasingly appreciated as a MACE risk-factor. This study aimed to define discordances between apoB and LDL-C in a large data set from a clinical reference laboratory. We then applied this definition to evaluate which measure predicted the risk of MACE in a patient cohort referred for coronary angiography with >10 years follow-up. LDL-C was measured by beta-quantification and RLP-C was defined as total cholesterol – LDL-C – HDL-C. Apo B discordance relative to LDL-C was determined by linear regression in a discovery cohort (n=17,203) using beta quantification. Discordance was defined by quartiles of the residual-apoB (expected–actual); discordant-low (<25th percentile), concordant (25th to 75th percentile) and discordant-high (>75th percentile). Associations with prevalence and incident of MACE were evaluated by odds-ratio and logistic regression. Risk of MACE was calculated based on the apoB-discordance and reported MACE events by several years follow up in a separate cohort (n=501). In the discovery cohort, age ranged from 18-95 years, 51% were female and mean (±SD) lipid values were: ApoB: 100.4 ± 30.0mg/dl, LDL-C: 121.7 ± 47.9mg/dl, and RLP-C: 17.2 ± 26.9mg/dl. Expected-apoB was described by the formula: (LDL-c X 0.6278 + 24.07, R=0.88). Residual-apoB (discordance) ranged from -1037 to 581.2 with a mean 0.01±18.6, and notably increased with triglyceride concentration (rho=0.65) and with RLP-C (rho=0.64), but was minimally influenced by apoB (rho=0.35) and LDL-C (rho=0.009) (p<0.001 all cases). In the clinical follow-up cohort, age ranged from 26-77 years, 42% were female, 64% were current/former smokers, and 28% were on lipid-lowering therapy. Mean (±SD) lipids were: apoB: 97.8 ± 20.9mg/dl, LDL-C: 124.6 ± 36.6mg/dl, and RLP-C: 34.9 ± 25.6mg/dl. Serum triglycerides among subjects discordant-low apoB, concordant and discordant-high apoB were 148mg/dL, 157mg/dL and 238mg/dL, respectively; similarly for RLP-C. A total of 192 events occurred during a mean of 9 years follow-up. Subjects with discordantly elevated apoB had a significantly higher incidence of MACE compared to those with concordant values (47% vs. 36%, p=0.03). There was no difference in MACE for subjects with discordantly low apoB (35% vs. 36%). These data support previous reports of an association between apoB and LDL-C and the superior performance of apoB when discordantly elevated. Our data expand on previous studies by applying an externally defined threshold for discordant-apoB. Our data indicate that triglycerides, RLP-C are associated with discordances and MACE.

The Importance of Lipoprotein Lipase Regulation in Atherosclerosis

Lipoprotein lipase (LPL) plays a major role in the lipid homeostasis mainly by mediating the intravascular lipolysis of triglyceride rich lipoproteins. Impaired LPL activity leads to the accumulation of chylomicrons and very low-density lipoproteins (VLDL) in plasma, resulting in hypertriglyceridemia. While low-density lipoprotein cholesterol (LDL-C) is recognized as a primary risk factor for atherosclerosis, hypertriglyceridemia has been shown to be an independent risk factor for cardiovascular disease (CVD) and a residual risk factor in Atherosclerosis development. In this review, we focus on the lipolysis machinery and discuss the potential role of triglycerides, remnant particles, and lipolysis mediators in the onset and progression of Atherosclerotic cardiovascular disease (ASCVD). This review details a number of important factors involved in the maturation and transportation of LPL to the capillaries, where the triglycerides are hydrolyzed, generating remnant lipoproteins. Moreover, LPL and other factors involved in intravascular lipolysis are also reported to impact the clearance of remnant lipoproteins from plasma and promote lipoprotein retention in capillaries. Apolipoproteins (Apo) and angiopoietin-like proteins (ANGPTLs) play a crucial role in regulating LPL activity and recent insights into LPL regulation may elucidate new pharmacological means to address the challenge of hypertriglyceridemia in Atherosclerosis development.

Increased particle size of triglyceride remnant lipoproteins, but not their plasma concentration or lipid content, augment risk prediction of incident diabetes: prospective results from ELSA-Brasil

Importance Predicting risk of Type 2 Diabetes Mellitus (T2DM) accurately allows allocation of resources to prevent its development. Fasting blood triglycerides are highly predictive for T2DM. Triglyceride remnant lipoproteins (TRL) more accurately reflect pathophysiological changes that underlie progression to T2DM, such as pancreatic steatosis and inflammation. We hypothesized TRL-related factors could improve risk prediction for development of T2DM. Methods We included individuals aged 35–74 years from the ELSA-Brasil cohort who had HbA1c and an oral glucose tolerance test at baseline. Regression models were used to predict incident T2DM, starting with medical history, metabolic syndrome traits (age, sex, hypertension, waist circumference [WC], HbA1c, triglycerides) and hsCRP, adding TRL-related measurements, including plasma concentration, particle size, as well as cholesterol and triglyceride content. TRL features were measured by NMR spectroscopy. Discrimination was assessed with area under receiver operator curves (AUROCs). Results Among 4,466 individuals at-risk, there were 353 new cases of T2DM after 3.7 (SD=0.6) years follow-up. We derived an 8-variable model with AUROC 0.891 (95% CI: 0.870–0.913). Overall TRL-related markers did not improve predictive capacity for T2DM. However, TRL particle diameter (TRLZ) increased AUROC, particularly in individuals without glucose abnormalities at baseline (Hba1c <5.7%). In this subgroup, AUROC increased from 0.761 (95% CI: 0.739–0.798 – Baseline-model) to 0.823 (95% CI: 0.783–0.862 – TRLZ model) (p-value=0.00006). Consistently, the net reclassification improvent (NRI) of the model with TRLZ improved by 10.27% (95% CI: 1.0–24.1, p=0.00041). In subjects with pre-diabetes at baseline, TRLZ is highly correlated with obesity, insulin resistance and inflammation (sum of z-scores for WC + HOMA-IR + hsPCR: R2=0.25), but this was less important in individuals with Hba1c <5.7% (R2=0.15). Sensitivity analyzes confirmed the results with different inclusion criteria (pre-diabetes defined with TTGO only) and excluding patients diagnosed with DM2 incident based only on fasting blood glucose. Conclusions TRL particle diameter improves prediction of T2DM, particularly in subjects with no glycemic abnormalities at baseline. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Brazilian Ministry of Health (Department of Science and Technology), Ministry of Science, Technology and Innovation, and the National Council for Scientific and Technological Development (CNPq)