A New Equation Based on the Standard Lipid Panel for Calculating Small Dense Low-Density Lipoprotein-Cholesterol and Its Use as a Risk-Enhancer Test.

BACKGROUND: Increased small dense low-density lipoprotein-cholesterol (sdLDL-C) is a risk factor for atherosclerotic cardiovascular disease (ASCVD) but typically requires advanced lipid testing. We describe two new equations, first one for calculating large buoyant LDL-C (lbLDL-C), based only upon results from the standard lipid panel, and the second one for sdLDL-C. METHODS: Equations for sdLDL-C and lbLDL-C were generated with least-squares regression analysis using the direct Denka sdLDL-C assay as reference (n = 20 171). sdLDL-C was assessed as a risk-enhancer test in the National Heart and Nutrition Examination Survey (NHANES), and for its association with ASCVD in the Multi-Ethnic Study of Atherosclerosis (MESA). RESULTS: The newly derived equations depend on two terms, namely LDL-C as determined by the Sampson equation, and an interaction term between LDL-C and the natural log of triglycerides (TG). The lbLDL-C equation (lbLDLC=1.43 × LDLC-0.14 ×(ln⁡(TG)× LDLC)- 8.99) was more accurate (R2 = 0.933, slope = 0.94) than the sdLDL-C equation (sdLDLC=LDLC- lbLDLC; R2 = 0.745, slope = 0.73). Using the 80th percentile (46 mg/dL) as a cut-point, sdLDL-C identified in NHANES additional high-risk patients not identified by other risk-enhancer tests based on TG, LDL-C, apolipoprotein B, and nonHDL-C. By univariate survival-curve analysis, estimated sdLDL-C was superior to other risk-enhancer tests in predicting ASCVD events in MESA. After multivariate adjustment for other known ASCVD risk factors, estimated sdLDL-C had the strongest association with ASCVD compared to other lipid parameters, including measured sdLDL-C. CONCLUSIONS: Estimated sdLDL-C could potentially be calculated on all patients tested with a standard lipid panel to improve ASCVD risk stratification.

A New Equation for Calculation of Low-Density Lipoprotein Cholesterol in Patients With Normolipidemia and/or Hypertriglyceridemia.

Importance: Low-density lipoprotein cholesterol (LDL-C), a key cardiovascular disease marker, is often estimated by the Friedewald or Martin equation, but calculating LDL-C is less accurate in patients with a low LDL-C level or hypertriglyceridemia (triglyceride [TG] levels ≥400 mg/dL). Objective: To design a more accurate LDL-C equation for patients with a low LDL-C level and/or hypertriglyceridemia. Design, Setting, and Participants: Data on LDL-C levels and other lipid measures from 8656 patients seen at the National Institutes of Health Clinical Center between January 1, 1976, and June 2, 1999, were analyzed by the ß-quantification reference method (18 715 LDL-C test results) and were randomly divided into equally sized training and validation data sets. Using TG and non-high-density lipoprotein cholesterol as independent variables, multiple least squares regression was used to develop an equation for very low-density lipoprotein cholesterol, which was then used in a second equation for LDL-C. Equations were tested against the internal validation data set and multiple external data sets of either ß-quantification LDL-C results (n = 28 891) or direct LDL-C test results (n = 252 888). Statistical analysis was performed from August 7, 2018, to July 18, 2019. Main Outcomes and Measures: Concordance between calculated and measured LDL-C levels by ß-quantification, as assessed by various measures of test accuracy (correlation coefficient [R2], root mean square error [RMSE], mean absolute difference [MAD]), and percentage of patients misclassified at LDL-C treatment thresholds of 70, 100, and 190 mg/dL. Results: Compared with ß-quantification, the new equation was more accurate than other LDL-C equations (slope, 0.964; RMSE = 15.2 mg/dL; R2 = 0.9648; vs Friedewald equation: slope, 1.056; RMSE = 32 mg/dL; R2 = 0.8808; vs Martin equation: slope, 0.945; RMSE = 25.7 mg/dL; R2 = 0.9022), particularly for patients with hypertriglyceridemia (MAD = 24.9 mg/dL; vs Friedewald equation: MAD = 56.4 mg/dL; vs Martin equation: MAD = 44.8 mg/dL). The new equation calculates the LDL-C level in patients with TG levels up to 800 mg/dL as accurately as the Friedewald equation does for TG levels less than 400 mg/dL and was associated with 35% fewer misclassifications when patients with hypertriglyceridemia (TG levels, 400-800 mg/dL) were categorized into different LDL-C treatment groups. Conclusions and Relevance: The new equation can be readily implemented by clinical laboratories with no additional costs compared with the standard lipid panel. It will allow for more accurate calculation of LDL-C level in patients with low LDL-C levels and/or hypertriglyceridemia (TG levels, ≤800 mg/dL) and thus should improve the use of LDL-C level in cardiovascular disease risk management.

Lipoprotein(a) Levels Are Associated With Subclinical Calcific Aortic Valve Disease in White and Black Individuals: The Multi-Ethnic Study of Atherosclerosis.

OBJECTIVE: Lipoprotein(a) [Lp(a)] is a risk factor for calcific aortic valve disease (CAVD) but has not been evaluated across multiple races/ethnicities. This study aimed to determine whether Lp(a) cutoff values used in clinical laboratories to assess risk of cardiovascular disease identify subclinical CAVD and its severity and whether significant relations are observed across race/ethnicity. APPROACH AND RESULTS: Lp(a) concentrations were measured using a turbidimetric immunoassay, and subclinical CAVD was measured by quantifying aortic valve calcification (AVC) through computed tomographic scanning in 4678 participants of the Multi-Ethnic Study of Atherosclerosis. Relative risk and ordered logistic regression analysis determined cross-sectional associations of Lp(a) with AVC and its severity, respectively. The conventional 30 mg/dL Lp(a) clinical cutoff was associated with AVC in white (relative risk: 1.56; confidence interval: 1.24-1.96) and was borderline significant (P=0.059) in black study participants (relative risk: 1.55; confidence interval: 0.98-2.44). Whites with levels ≥50 mg/dL also showed higher prevalence of AVC (relative risk: 1.72; confidence interval: 1.36-2.17) than those below this level. Significant associations were observed between Lp(a) and degree of AVC in both white and black individuals. The presence of existing coronary artery calcification did not affect these associations of Lp(a) and CAVD. There were no significant findings in Hispanics or Chinese. CONCLUSIONS: Lp(a) cutoff values that are currently used to assess cardiovascular risk seem to be applicable to CAVD, but our results suggest race/ethnicity may be important in cutoff selection. Further studies are warranted to determine whether race/ethnicity influences Lp(a) and risk of CAVD incidence and its progression.

Race is a key variable in assigning lipoprotein(a) cutoff values for coronary heart disease risk assessment: the Multi-Ethnic Study of Atherosclerosis.

OBJECTIVE: We aimed to examine associations of lipoprotein(a) (Lp(a)) concentrations with coronary heart disease (CHD) and determine whether current Lp(a) clinical laboratory cut points identify risk of disease incidence in 4 races/ethnicities of the Multi-Ethnic Study of Atherosclerosis (MESA). APPROACH AND RESULTS: A subcohort of 1323 black, 1677 white, 548 Chinese American, and 1044 Hispanic MESA participants were followed up during a mean 8.5-year period in which 235 incident CHD events were recorded. Lp(a) mass concentrations were measured using a turbidimetric immunoassay. Cox regression analysis determined associations of Lp(a) with CHD risk with adjustments for lipid and nonlipid variables. Lp(a) concentrations were continuously associated with risk of CHD incidence in black (hazard ratio [HR], 1.49; 95% confidence interval [CI], 1.09-2.04] and white participants (HR, 1.22; 95% CI, 1.02-1.45). Examining Lp(a) risk by the 50 mg/dL cut point revealed higher risks of incident CHD in all races except Chinese Americans: blacks (HR, 1.69; 95% CI, 1.03-2.76), whites (HR, 1.82; 95% CI, 1.15-2.88); Hispanics (HR, 2.37; 95% CI, 1.17-4.78). The lower Lp(a) cut point of 30 mg/dL identified higher risk of CHD in black participants alone (HR, 1.87; 95% CI, 1.08-3.21). CONCLUSIONS: Our findings suggest that the 30 mg/dL cutoff for Lp(a) is not appropriate in white and Hispanic individuals, and the higher 50 mg/dL cutoff should be considered. In contrast, the 30 mg/dL cutoff remains suitable in black individuals. Further research is necessary to develop the most clinically useful Lp(a) cutoff values in individual races/ethnicities.

New automated assay of small dense low-density lipoprotein cholesterol identifies risk of coronary heart disease: the Multi-ethnic Study of Atherosclerosis.

OBJECTIVE: Coronary heart disease (CHD) is the leading cause of death in the United States, yet assessing risk of its development remains challenging. The present study evaluates a new automated assay of small dense low-density lipoprotein cholesterol content (sdLDL-C) and whether sdLDL-C is a risk factor for CHD compared with LDL-C or small LDL particle concentrations derived from nuclear magnetic resonance spectroscopy. APPROACH AND RESULTS: sdLDL-C was measured using a new automated enzymatic method, and small LDL concentrations were obtained by nuclear magnetic resonance in 4387 Multi-Ethnic Study of Atherosclerosis participants. Cox regression analysis estimated hazard ratios for developing CHD for 8.5 years after adjustments for age, race, sex, systolic blood pressure, hypertension medication use, high-density lipoprotein cholesterol, and triglycerides. Elevated sdLDL-C was a risk factor for CHD in normoglycemic individuals. Those in the top sdLDL-C quartile showed higher risk of incident CHD (hazard ratio, 2.41; P=0.0037) compared with those in the bottom quartile and indicated greater CHD risk than the corresponding quartile of LDL-C (hazard ratio, 1.75; P=0.019). The association of sdLDL-C with CHD risk remained significant when LDL-C (<2.57 mmol/L) was included in a multivariate model (hazard ratio, 2.37; P=0.012). Nuclear magnetic resonance-derived small LDL concentrations did not convey a significant risk of CHD. Those with impaired fasting glucose or diabetes mellitus showed higher sdLDL-C and small LDL concentrations but neither was associated with higher CHD risk in these individuals. CONCLUSIONS: This new automated method for sdLDL-C identifies risk for CHD that would remain undetected using standard lipid measures, but only in normoglycemic, nondiabetic individuals.

Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular and liver-related mortality. NAFLD is characterized by both triglyceride and free cholesterol (FC) accumulation without a corresponding increment in cholesterol esters. The aim of this study was to evaluate the expression of cholesterol metabolic genes in NAFLD and relate these to disease phenotype. NAFLD was associated with increased SREBP-2 maturation, HMG CoA reductase (HMGCR) expression and decreased phosphorylation of HMGCR. Cholesterol synthesis was increased as measured by the circulating desmosterol:cholesterol ratio. miR-34a, a microRNA increased in NAFLD, inhibited sirtuin-1 with downstream dephosphorylation of AMP kinase and HMGCR. Cholesterol ester hydrolase was increased while ACAT-2 remained unchanged. LDL receptor expression was significantly decreased and similar in NAFLD subjects on or off statins. HMGCR expression was correlated with FC, histologic severity of NAFLD and LDL-cholesterol. These data demonstrate dysregulated cholesterol metabolism in NAFLD which may contribute to disease severity and cardiovascular risks.

High pre-beta1 HDL concentrations and low lecithin: cholesterol acyltransferase activities are strong positive risk markers for ischemic heart disease and independent of HDL-cholesterol.

BACKGROUND: We hypothesized that patients with high HDL-cholesterol (HDL-C) and ischemic heart disease (IHD) may have dysfunctional HDL or unrecognized nonconventional risk factors. METHODS: Individuals with IHD (Copenhagen University Hospital) and either high HDL-C (n = 53; women >or=735 mg/L; men >or=619 mg/L) or low HDL-C (n = 42; women