Direct LDL Research Articles

Does friedewald formula underestimate the risk of ischemic heart disease?

Traditionally Friedewald formula has been used to calculate low density lipoprotein cholesterol (LDL-C) concentration though now direct homogenous methods for its measurement are also available. Clinical guidelines recommend the use of calculated LDL-C to guide therapy because the evidence base for cholesterol management is derived almost exclusively from trials that use calculated LDL, with direct measurement of LDL-C being reserved for those patients who are non fasting or with significant hypertriglyceridemia. In this study our aim was to compare calculated and direct LDL and their variation at different cholesterol and triglyceride levels. Fasting lipid profile estimation was done on 503 outpatients in a tertiary hospital. Both direct and calculated LDL were then compared. Mean fasting direct LDL was found to be higher than calculated LDL in 87.1% of subjects by 8.64±8.35mg/dl. This difference was seen a all levels of cholesterol and triglyceride. Using 130mg/dl LDL cholesterol as cut off fewer subjects were classified as high risk by calculated LDL than direct LDL. In conclusion, direct LDL is higher than calculated LDL. Compared with direct measurement, the Friedewald calculation underestimates the risk for ischemic heart disease.

The Role of the Total Cholesterol Level in the Assessment of the Severity of Myocardial Infarction

Cardiovascular diseases are the emerging causes of the mortality which is looming large in India also. Particularly, the Indian populations are genetically more susceptible to them [1]. Dyslipidaemia (especially high LDL-C levels) is the promoter of atherosclerosis, whereas the HDL-C fraction is protective [2]. The oxidatively modified LDL associated conversion of macrophages to foam cells is reportedly atherogenic [3]. The pro-inflammatory oxidative milieu favours this process [4]. The dyslipidaemia associated acute phase response was shown to develop a pro-inflammatory state which promoted atherosclerosis [5, 6]. The usual practice of assaying the entire lipid profile may not be cost effective for predicting the cardiovascular risk burden. Oxidized-LDL and/or malondialdehyde modified-LDL, appear as informative markers [7]. However, technically, they do not appear to be suitable for a routine clinical laboratory setting. Hence, there is an ardent need of reasonably effective and affordable tests. In this study, the plasma lipid profile parameters, namely HDL-C (high density lipoprotein), LDL-C (low density lipoprotein), TG (triglyceride) and TC (total cholesterol) were assessed in both myocardial infarction (MI) cases and in healthy controls; each parameter was correlated with the lipid peroxidative parameter, MDA to find out any possible single parameter which was most closely associated with its oxidative pathology, so as to draw any meaningful association for prognostic purposes. A case cohort was formed by selecting 42 clinically as well as electrocardiographically confirmed and previously untreated cases of MI (median age 58 years). Diabetes Mellitus, or any other major diseases and a past history of smoking were ruled out. Similarly, an age and sex matched cohort was formed by selecting 38 healthy volunteers from among the hospital staff (median age 54 years). Plasma samples were collected from all the individuals of both the groups after taking informed consents from them. The patients’ samples were collected within 12 hours of their admissions. Their lipid profiles, along with the direct LDL measurements, were assessed by using commercial kits as per the manufacturer’s protocol. The MDA estimation was done by a spectrophotometric method [8]. Except for HDL-C which was found to be significantly low in the cases, the mean levels of the lipid profile parameters in the cases were significantly high as compared to those in the corresponding control group; the MDA levels were also found to be significantly high among the cases [Table/Fig-1]. This showed a marked dyslipidaemia in the patient populace. Pearson’s correlation analysis showed a high degree of positive correlation between MDA and TC and also with LDL cholesterol (r = 0.79 and 0.72 respectively) in the MI cases. The positive correlation between MDA and the TG level was not comparably high. Similarly, the negative correlation between HDL-C and the MDA level was also not very significant. The control group parameters did not show any significant correlations. This result conformed to the view of the oxidative pathology being associated with such metabolic abnormalities. Total cholesterol and LDL-C, being significantly associated with lipid peroxidation in the cases, suggested a direct contribution of these fractions in the pathogenesis. However, in the general practice, LDL-C is calculated from the Friedwald’s formula and it may thus incorporate considerable error [9]. Moreover, the highest correlation value was observed between total cholesterol and MDA. This finding corroborated with that of an earlier study which reported a relative risk predictive efficacy of TC, which showed its direct association with the mortality in coronary heart disease [10, 11]. Hence, with the perspective of this small scale pilot type study (considering the huge prevalence of cardiovascular diseases in the general population), total cholesterol alone, as a single parameter, demands a large-scale multi-centric trial for being considered as an effective and an economic option for the prediction of the severity of cardiovascular health hazards in the MI cases. [Table/Fig-1]: Comparative display of lipid Profile parameters and malondialdehyde (MDA) in MI patients and control groups

Challenges of Type 2 Diabetes in Patients With Alcohol Dependence

S.E., a 53-year-old Caucasian woman, was referred to the endocrinology clinic for management of type 2 diabetes. She was diagnosed 2 years ago and failed to achieve acceptable glycemic control with metformin and glipizide. Her glucose values ranged between 300 and 500 mg/dl. The patient expressed fear of not getting the care she needs to achieve her glycemic goal because of the stigma of alcohol dependence. S.E. had peripheral neuropathy but no history of nephropathy, retinopathy, or any macrovascular complications of diabetes. She has been drinking alcohol for the past 10 years. She reported that she has three 18-oz drinks per day, each composed of equal amounts of rum and regular cola. This is ~ 360 g of alcohol per day. She said she starts drinking from the time she wakes up until she goes to bed and has no intention of cutting back on the amount of drinking or enrolling in a detoxification program. On physical examination, her blood pressure was 147/82 mmHg and her BMI was 33 kg/m2. Her skin showed spider telangiectasia and no evidence of acanthosis nigricans or thyromegaly. Her abdomen was soft and non-tender, and she had no organomegaly. She was able to sense pressure from a 10-g monofilament in all of 10 points bilaterally. The rest of the examination was non-contributory. Laboratory results showed an A1C of 11%, creatinine of 1 mg/dl, albumin-to-creatinine ratio of 10.8 mg/g, aspartate transaminase of 113 IU/l, alanine aminotransferase of 69 IU/l, alkaline phosphatase of 276 IU/l, total bilirubin of 0.9 mg/dl, and thyroid-stimulating hormone of 2.04 μIU/ml. Her total cholesterol was 280 mg/dl, triglycerides were 805 mg/dl, HDL cholesterol was 15 mg/dl, and direct LDL cholesterol was 182 mg/dl. Her vitamin B12 level was > 1,500 pg/ml (reference range 250–900 pg/ml), and her folate level …

Abstract 3257: Prevalence and Correlates of PTSD After Stroke

Background Stroke survivors may be at increased risk for post-traumatic stress disorder (PTSD), yet detailed data on prevalence and contributing factors are lacking. Harlem residents and local researchers, alarmed by high rates of stroke in their community and frustrated by the difficulty of engaging stroke survivors in prevention programs, aimed to determine the prevalence and correlates of PTSD in a cohort of survivors of stroke and transient ischemic attack (TIA). Methods Harlem residents and researchers employed community-based participatory research to develop a recurrent stroke prevention intervention. English and Spanish speaking adults over 40 were eligible for inclusion if they reported a stroke or TIA within the past five years. Baseline assessments included blood pressure, direct LDL cholesterol and validated self-report scales for demographics, stroke impact (modified Rankin scale), medical co-morbidities (Charlson co-morbidity index), and the widely-used 17-item PTSD Checklist Specific for stroke (PCL-S). A PCL-S score of 25 connotes a positive screening test, while a score greater than 50 is highly specific for PTSD. We recruited participants from community and clinical sites. To create a model of correlates for PTSD (PCL-S score > 50), we used logistic regression. Results The 379 enrollees had a mean age of 64 years, 62% were women, 79% were Black or Latino, 28% never completed high school, and more than half earned under $15,000 yearly. Most (75%) had PCL-S scores greater than 25, including 69 (18%) who scored above 50. Using logistic regression, and controlling for gender, race, education, and income (c-statistic of 0.835, p<0.0001), PTSD was associated with younger age (odds ratio 0.94, 95% CI 0.91-0.97), increased disability post-stroke (OR 1.93, 95% CI 1.49-2.51), and greater burden of medical co-morbidities (OR 2.17, 95% CI 1.09-4.31). In addition, participants with PTSD were more likely to smoke (30% vs. 13%, p=0.0003) and have elevated LDL cholesterol > 100 mg/ dl (59% vs. 39%, p=0.003), both major risk factors for recurrent stroke. There was no significant difference in blood pressure control between the patients with and without PTSD. Conclusion PTSD is common after stroke, especially in younger people with more disability and more co-morbidity. We recommend that clinicians screen patients for PTSD after stroke and offer supportive therapy.

A Comparative And Correlative Study of Direct LDL Assay With Friedwald's Formula in Rural Kolar Population

A Comparative And Correlative Study of Direct LDL Assay With Friedwald's Formula in Rural Kolar Population

Abstract P198: Is Directly Measured LDL Clinically Equivalent to Calculated LDL

Background: LDL cholesterol can either be calculated or measured directly. Clinical guidelines recommend using calculated LDL to guide therapy, as the evidence base for lipid management is derived almost exclusively from trials using calculated LDL, with direct measurement of LDL being reserved for those not fasting or significant hypertriglyceridemia. Our aim was to determine the clinical equivalence of directly measured LDL and fasting calculated LDL. Design: Eighty-one subjects had at least 1 calculated and direct LDL performed simultaneously; 64 had a repeat lipid assessment after 4 to 6 weeks of therapy, resulting in 145 pairs of calculated and direct LDL. Correlation between direct and calculated LDL was determined using Pearson's correlation coefficient. The relationship between direct and calculated LDL was also evaluated from a clinical perspective. Direct and calculated LDL were considered “clinically concordant” when the difference between calculated and direct LDL fulfilled 3 criteria: 1) < 6% difference (incremental LDL lowering provided by 1 titration of statin dose, e.g. simvastatin 20 to 40 mg), 2) < 10 mg/dL difference, and 3) placement in the same ATP III LDL cut points (e.g. <100, 100-129). Direct and calculated LDL were considered “clinically discordant” when the difference between calculated and direct LDL fulfilled 3 criteria: 1) ≥ 12% difference (incremental LDL lowering provided by 2 statin titration steps, e.g. from simvastatin 20 to 80 mg), 2) ≥ 10 mg/dL difference, and 3) placement in different ATP III LDL cut points. Results: There was significant correlation between direct and calculated LDL(r=0.93). Clinical concordance between calculated and direct LDL was present in 40% of patients. Clinical discordance was noted in 25% of patients. One-third of patients had > 15 mg/dL difference between direct and calculated LDL, while 25% had > 20 mg/dL difference. In 47% of subjects, the difference between direct and calculated LDL at baseline and follow-up changed by a minimum of 10% or 10 mg/dL. Conclusion: Our findings suggest that directly measured LDL is not clinically equivalent to calculated LDL. This puts into question the current recommendation of using direct LDL in situations where calculated LDL would be inaccurate.

Non–HDL Cholesterol Shows Improved Accuracy for Cardiovascular Risk Score Classification Compared to Direct or Calculated LDL Cholesterol in a Dyslipidemic Population

Our objective was to evaluate the accuracy of cardiovascular disease (CVD) risk score classification by direct LDL cholesterol (dLDL-C), calculated LDL cholesterol (cLDL-C), and non-HDL cholesterol (non-HDL-C) compared to classification by reference measurement procedures (RMPs) performed at the CDC. We examined 175 individuals, including 138 with CVD or conditions that may affect LDL-C measurement. dLDL-C measurements were performed using Denka, Kyowa, Sekisui, Serotec, Sysmex, UMA, and Wako reagents. cLDL-C was calculated by the Friedewald equation, using each manufacturer's direct HDL-C assay measurements, and total cholesterol and triglyceride measurements by Roche and Siemens (Advia) assays, respectively. For participants with triglycerides<2.26 mmol/L (<200 mg/dL), the overall misclassification rate for the CVD risk score ranged from 5% to 17% for cLDL-C methods and 8% to 26% for dLDL-C methods when compared to the RMP. Only Wako dLDL-C had fewer misclassifications than its corresponding cLDL-C method (8% vs 17%; P<0.05). Non-HDL-C assays misclassified fewer patients than dLDL-C for 4 of 8 methods (P<0.05). For participants with triglycerides≥2.26 mmol/L (≥200 mg/dL) and<4.52 mmol/L (<400 mg/dL), dLDL-C methods, in general, performed better than cLDL-C methods, and non-HDL-C methods showed better correspondence to the RMP for CVD risk score than either dLDL-C or cLDL-C methods. Except for hypertriglyceridemic individuals, 7 of 8 dLDL-C methods failed to show improved CVD risk score classification over the corresponding cLDL-C methods. Non-HDL-C showed overall the best concordance with the RMP for CVD risk score classification of both normal and hypertriglyceridemic individuals.

Low density lipoprotein‐cholesterol variability in patients with type 2 diabetes taking atorvastatin compared to simvastatin: justification for direct measurement?

The benefit of direct, as opposed to calculated, low density lipoprotein -cholesterol (LDL-C) measurement remains unclear. This study compared the biological variability of direct LDL in patients with type 2 diabetes (T2DM) on equivalent doses of the short half-life statin, simvastatin or the longer half-life statin, atorvastatin. A cross-over study of biological variation of lipids in 26 patients with T2DM taking either simvastatin 40 mg (n = 10) or atorvastatin 10 mg. After 3 months on one statin, fasting lipids were measured on 10 occasions over a 5-week period. The same procedure was then followed on the other statin. The variability of LDL-C was established using a Beckman direct assay. As a group, mean LDL was no different between statins (mean +/- s.d.) (1.69 +/- 0.60 mmol/l simvastatin vs. 1.67 +/- 0.60 mmol/l atorvastatin, p = 0.19). However, in all patients, the intraindividual biological variability of LDL while taking simvastatin was markedly higher than with atorvastatin (average s.d. = 0.17 mmol /l simvastatin vs. 0.01 mmol/l, p < 0.0001). Friedewald calculated LDL variability was no different between statins (average s.d. = 0.34 mmol /l simvastatin vs. 0.21 mmol/l atorvastatin, p = 0.19). In contrast to calculated values, direct measurement revealed LDL to be much more stable (the s.d. being an order of magnitude) in T2DM patients taking atorvastatin rather than simvastatin. This means LDL targets can be consistently met with less lipid monitoring using atorvastatin rather than simvastatin. Direct LDL measurement may therefore have a particular role in monitoring patients on statin treatment.

Abstract 4840: Are Statins Nephroprotective? A PCI Study to Explore for Possible Pleiotropism

HMG-CoA reductase inhibitors (statins) are used for dyslipidemia treatment and CAD prevention. Considerable controversy exists regarding statins’ possible pleiotropic effect with many vascular and nonvascular beds benefiting from their use. However, little data exists to support possible nephroprotective statins effect or their potential for ‘nephro-pleiotropism’. Hypothesis We hypothesize that pre-administration of statins in patients prior to undergoing percutaneous coronary intervention (PCI) may be beneficial in preventing contrast induced nephropathy (CIN) due to a pleiotropic effect. Methods A retrospective study of &gt;4000 patient charts who underwent PCI for routine clinical reasons was performed. Pts who developed CIN were selected based on serum creatinine (SCr) level elevation by ≥0.5mg/dL from baseline and further stratified into statin use (+/−) prior to PCI and by LDL level. Results SCr was measured within 1 week prior to or on day of PCI in 805 pts: 516 (64%) male, 289 (36%) female and within 1 week post PCI. Statin therapy was initiated in 328 (41%) pts ≥1 week prior to PCI. When classified by statin use (+/−), there was no difference in incidence of CIN (29 vs 39, p=0.8). However, there was a significant number of pts with SCr rise to &gt;2.5mg/dL in the statin(−) group (p&lt;0.05). When limited to absolute rise in SCr, the mean rise in SCr was 0.64 in statin(−) vs 0.16mg/dL in statin(+) subgroup, representing a 3-fold nephroprotective effect of statins (p&lt;0.001). Via multivariate analysis, neither age, gender, HTN, DM or contrast load was a significant predictor for the rise in SCr. In 44 pts (16 statin(+), 28 statin(−)) with recent LDL levels there was no difference in the mean LDL (99 vs 91mg/dL respectively, p=NS) and this pattern held true when categorized by LDL &lt;70, &lt;100, or &lt;130mg/dL (p=NS for all), again independent of all defined comorbidities. Conclusions Pre-PCI administration of statins is strongly nephroprotective. Multivariate analysis demonstrates the 3-fold nephroprotection is independent of common clinical high risk comorbidities. A more controversial finding implicates the lack of a direct anti-atherosclerotic LDL lowering effect as the genesis since LDL levels were nearly superimposable, implying substantial pleiotropism.

Abstract 675: Contrasting Effects of Dietary Carbohydrate Compared to Mono-unsaturated Fat on Hepatic Production of ApoE and ApoC-III Containing VLDL, and Formation of LDL

The effects of substituting dietary carbohydrate (CHO) with mono-unsaturated fat (MUFA) on plasma apoB metabolism were evaluated in 12 adults: 6 with normal and 6 with high plasma triglyceride levels. They consumed for 3 weeks each time a high CHO diet (48% complex CHO, 8% MUFA) and a high MUFA diet (31% complex CHO, 24% MUFA). ApoB100 kinetic studies were performed at the end of each dietary intervention using stable isotope labeling with a bolus and a primed continuous infusion. Multiple VLDL, IDL, and LDL fractions were prepared according to their apoE and apoC-III content. Compared to the CHO diet, the MUFA diet increased the percentage of VLDL and IDL secreted with both apoE and apoC-III (45% on MUFA vs. 14% on CHO, p &lt; 0.01) and reduced the percentage of VLDL and IDL secreted without either apoE or apoC-III (MUFA 19% vs. CHO 40%, p = 0.02). Total liver secretion rates of apoB100 lipoproteins were similar between diets (MUFA 11.6 vs. CHO 11.3 mg·day −1 ·kg −1 , p = NS). The dietary change did not affect the fractional catabolic rates and flux patterns of the lipoproteins. On both diets, VLDL and IDL that had apoE were rapidly cleared from the circulation, limiting LDL formation; whereas lipoproteins that did not have apoE or apoCIII mostly underwent lipolysis with little direct clearance, and were the main precursors of LDL. As a result, increased secretion of VLDL and IDL containing apoE and apoC-III caused by the MUFA diet was associated with higher direct clearance and lower LDL production rates (p = 0.02 vs. CHO), while the CHO diet increased LDL production due to increased secretion of VLDL without apoE or apoC-III. In conclusion, our results reveal a strong dietary effect on the secretion pattern of apoB100 lipoproteins. Substituting dietary complex carbohydrate with mono-unsaturated fat selectively promotes liver secretion of VLDL and IDL containing both apoE and apoC-III while suppressing the secretion of VLDL and IDL without apoE or apoC-III. This leads to significant downstream effects on LDL formation due to differential effects of apoE and apoC-III on apoB lipoprotein metabolism, resulting in enhanced particle clearance and reduced LDL formation with the MUFA diet compared to the CHO diet.

A comparison of lipid and lipoprotein measurements in the fasting and nonfasting states in patients with type 2 diabetes

ABSTRACTBackground: Patients with diabetes often do not reach recommended lipid targets. This may be in part due to the difficulty of obtaining fasting measurements.Objective: To compare fasting and nonfasting low density lipoprotein cholesterol (LDLc), non-high density lipoprotein cholesterol (non-HDLc), and low density lipoprotein particle number (LDLP) patients with type 2 diabetes (T2DM) and to determine the effect on assessing treatment success.Research design and methods: Standard lipids and NMR lipoproteins were analyzed at baseline and following a standardized meal in patients with T2DM.Outcomes measures: Primary outcomes were agree­ment between fasting and nonfasting LDLc, non-HDLc, and LDLP and the agreement between these measures for determining fasting LDLc treatment success. Direct LDL cholesterol (DLDL) was a secondary outcome.Results: Of 31 patients, only 56% of LDLc measure­ments were equivalent in the fasting and nonfasting states, compared to 97% of DLDLc ( p < 0.0001), 94% of non-HDLc ( p < 0.001) and 77% of LDLP ( p < 0.01) measurements. Assessment of nonfasting lipid values would have resulted in misclassification by treatment target in 15% of LDLc, 3.2% of DLDLc assessments ( p < 0.05 vs. LDLc), and 0% of non-HDLc and LDLP assess­ments ( p < 0.01 vs. LDLc). Nonfasting LDLc, non-HDLc, LDLP, and DLDLc correctly identified fasting LDLc classification in 23/27 (85%), 26/30 (87%, p = NS vs. nonfasting LDLc), 16/30 (53%, p < 0.001 vs. nonfasting LDLc), and 24/30 (80%, p = NS vs. nonfasting LDLc), respectively.Conclusions: If confirmed in larger studies, nonfasting non-HDLc may be a suitable proxy for fasting LDLc in patients with T2DM.

Matching-based preprocessing algorithms to the solution of saddle-point problems in large-scale nonconvex interior-point optimization

Interior-point methods are among the most efficient approaches for solving large-scale nonlinear programming problems. At the core of these methods, highly ill-conditioned symmetric saddle-point problems have to be solved. We present combinatorial methods to preprocess these matrices in order to establish more favorable numerical properties for the subsequent factorization. Our approach is based on symmetric weighted matchings and is used in a sparse direct LDL T factorization method where the pivoting is restricted to static supernode data structures. In addition, we will dynamically expand the supernode data structure in cases where additional fill-in helps to select better numerical pivot elements. This technique can be seen as an alternative to the more traditional threshold pivoting techniques. We demonstrate the competitiveness of this approach within an interior-point method on a large set of test problems from the CUTE and COPS sets, as well as large optimal control problems based on partial differential equations. The largest nonlinear optimization problem solved has more than 12 million variables and 6 million constraints.

Measurement and meaning of apolipoprotein AI and apolipoprotein B plasma levels

Apolipoproteins AI and B are structural components of lipoprotein particles, and also determinants of the metabolic fate of the encapsulated lipid, cholesterol and triglyceride. Development of accurate assays for these apolipoproteins has opened the way for their use as predictors of coronary heart disease risk. Interpretation of AI and apo B levels is best undertaken with background knowledge of the metabolic status of an individual, especially the lipolytic capacity as reflected in the triglyceride concentration. Those with raised triglyceride, in general, not only have an elevated apo B/apo AI ratio, but also apo B-containing lipoproteins with a prolonged residence time and hence ample opportunity for modification and damage. Assessment of apolipoprotein levels is an aid to risk prediction and can be useful in tailoring treatment.

Apolipoproteins AI and B as therapeutic targets

Currently the apolipoprotein B:AI ratio integrates information about the potential for cardiovascular disease (CVD) risk reduction better than any other lipid or lipoprotein index. Certainly it could, with benefit, replace serum cholesterol and HDL cholesterol in the estimation of CVD risk. Defining the therapeutic target of statin therapy in terms of serum apolipoprotein B (apo B) rather than LDL cholesterol could also help to optimize statin treatment. Deciding whether a therapeutic response is adequate also requires knowledge of whether there is persisting hypertriglyceridaemia, because this gives an indication of whether small dense LDL is likely to have been satisfactorily reduced. Raising low levels of HDL, probably best measured as apo AI, may also prove to be an important aim of treatment. This is, however, a more complex issue and also depends on the mechanism by which a particular therapy alters HDL levels and on whether the capacity of HDL to perform its anti-inflammatory and antioxidative functions is restored. A meta-analysis of randomized clinical trials of statins in which apo B and apo AI have been reported could provide valuable information.

C-reactive protein is more related to the metabolic syndrome than to atherosclerosis in 58-year old men

Bilirubin has antioxidant and anti-inflammatory properties; serum bilirubin levels have been known to be inversely associated with cardiovascular disease. However, the effects of different bilirubin subtypes on cardiometabolic traits are unknown. In this study, we aimed to determine whether direct bilirubin is more strongly correlated with small, dense low-density lipoprotein (sdLDL) compared to other bilirubin subtypes. We also investigated which LDL subfractions exhibited the highest correlation with direct bilirubin.A total of 288 overweight and centrally obese women were included in this study. The Pearson correlation and Steiger's Z test were used to compare the correlation coefficients between bilirubin subtypes and lipoproteins. Multiple linear regression analyses were used to evaluate the independent association between direct bilirubin and mean LDL particle size. Only direct bilirubin levels were significantly associated with the sdLDL subfraction and mean LDL particle size. Mean LDL particle size exhibited a significantly stronger correlation with direct bilirubin than sdLDL, percent sdLDL, and the sdLDL:large LDL ratio. Regression analysis showed that direct bilirubin was significantly associated with mean LDL particle size, according to both the stepwise method (β = 11.445, P value = 0.002) and the enter method (β = 11.655, P value = 0.002).Direct bilirubin is more strongly correlated with the sdLDL subfraction compared with total and indirect bilirubin, and is independently associated with mean LDL particle size in overweight and centrally obese women.

Reflex testing I: Algorithm for lipid and lipoprotein measurement in coronary heart disease risk assessment

We reviewed the current literature in order to construct a reflex testing algorithm that maximizes clinical utility and cost-effectiveness of lipid and lipoprotein testing. The algorithm was based on the 2nd Report of the National Cholesterol Education Program Adult Treatment Panel guidelines for use of total cholesterol (TC), triglycerides (TG), HDL-C, and LDL-C, and published reports describing the clinical use of apolipoprotein B and lipoprotein (a). The success of this algorithm was tested in a low-risk general and a high-risk hyperlipidemic patient population. Lipid data and non-lipid risk factors were obtained from a national database and from patients seen at two lipid clinics. A total of 16 968 individuals from the National Health and Nutrition Examination Survey III database comprised the low-risk group, and 239 patients examined in the Hartford Hospital and Washington University Lipid Clinics comprised the high-risk group. We found a solid scientific base to support the NCEP guidelines and reasonable support for limited testing of apoB and Lp(a). According to the algorithm, the direct LDL-C assay was deemed unnecessary in 98% and 91% of low- and high-risk subjects, respectively, if one assumes that the Friedewald equation is adequate with TG≤4.00 g/l. With a more conservative cutoff of TG≤2.50 g/l, the algorithm canceled 92% and 81% of direct LDL tests, respectively. The algorithm also limited TG to 20 and 64%, apoB to 6 and 20%, and Lp(a) to 15 and 56%, of low- and high-risk groups, respectively. Use of a comprehensive, reflex algorithm for coronary heart disease risk assessment will substantially reduce the utilization of laboratory services without diminishing the clinical value of these tests. The algorithm will prevent the overuse of certain expensive tests (direct LDL) while promoting the limited use of underutilized tests [apoB and Lp(a)].

Direct isolation of labeled low density lipoproteins for the determination of cholesteryl ester transfer protein activity

The measurement of the activity of cholesteryl ester transfer protein (CETP), is of high clinical interest and this study reports the use of a direct LDL isolation (d-LDL) technique to determine in one step the amount of radiolabeled cholesteryls esters ([ 3H]-CE) transferred from exogenous HDL 3 to LDL, avoiding the conveniences of the usually used ultracentrifugation or precipitation of apo-B containing lipoproteins in the CETP methodologies. The d-LDL technique providing a specific immunoprecipitation of VLDL, IDL and HDL allowed to directly determine the [ 3H]-CE transferred on LDL (d-[ 3H]-CE-LDL). Two methodologies were assayed for the CETP activityusing either exogenous or endogenous lipoproteins, and the results with the d-LDL technique were compared with those obtained using the ultracentrifugation (u-[3H]-CE-LDL) considered as the reference method. The intra- and inter-assays were similar in both techniques for the two CETP activity assays. Strong positive correlations were established between values obtained with d-[ 3H]-CE-LDL and u-[3H[-CE-LDL isolation procedures for CETP activities with exogenous or endogenous lipoproteins (r=0.972; p=0.0001 and r=0.965; p=0.0001 respectively). In conclusion, the d-LDL technique represents an easy and accurate procedure to measure directly, in normotriglyceridemic plasmas, the amount of [ 3H]-CE transferred from HDL to LDL by the CETP.

Comparison of two assays for measuring LDL cholesterol

The purpose of this study was to evaluate the LipiDirect assay (L-LDL) against the Direct LDL immunoseparation method (D-LDL) and beta quantification (BQ-LDL) for measurement of LDL cholesterol (LDL-C) in patients with normo- and hypertriglyceridemia. Samples from 156 patients [triglyceride (Tg) range 0.61-9.95 g/L] were assayed for LDL-C concentrations with the three methods. An additional seven patients with type III hyperlipidemia and 25 paired sera from fasting and nonfasting individuals also were analyzed by the three methods. Both assays displayed excellent precision. The mean LDL-C value from L-LDL was significantly higher than BQ-LDL and D-LDL in normo- and hypertriglyceridemic samples (P < 0.001). The mean absolute bias of L-LDL vs BQ-LDL was 12.7% for Tg < 4 g/L and 30.6% for Tg > or = 4 g/L, compared with 6.2% and 12.5%, respectively, for D-LDL. L-LDL correctly classified only 68% of patients with LDL-C < 1.30 g/L and 57% of patients with LDL-C between 1.30-1.59 g/L as compared with 98% and 93%, respectively, for D-LDL (P < 0.001). In patients with type III hyperlipidemia, L-LDL had a 130% positive bias with BQ-LDL as compared with a 14% negative bias for D-LDL. With all three methods there were no significant differences between samples from fasting and nonfasting individuals. On the basis of these findings, the D-LDL assay appears to be superior to the L-LDL assay.

Variability in cholesterol measurements: comparison of calculated and direct LDL cholesterol determinations

Calculated low-density lipoprotein cholesterol (LDL-C) concentrations determined from the Friedewald equation have a large intraindividual CV, in part because the calculation incorporates the variability of cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglyceride measurements. We studied whether a new assay that measures LDL-C directly will reduce this variability and reduce the need for averaging serial specimens. Four blood samples were obtained 1 week apart from 35 mildly hypercholesterolemic subjects and analyzed for total cholesterol, triglycerides, and HDL-C. LDL-C was calculated by the Friedewald equation, and was also measured directly with a commercially available direct LDL-C assay. The intraindividual CV for the direct and calculated LDL-C assays were similar [CV of direct LDL-C assay (mean +/- SE): 6.8 +/- 0.5% vs calculated LDL-C: 7.3 +/- 0.6%; difference 0.44%, 95% confidence interval: -0.7-1.5%]. For both assays, at least two blood tests were required from each subject to reduce total variability of LDL-C to less than or equal to 5%. We conclude that the direct LDL-C assay did not reduce the variability in LDL-C compared with the conventional LDL-C calculation. However, it may have a specific role in lipid disorder evaluation and (or) monitoring when triglycerides are increased or the LDL-C value alone is needed.

Effects of Colestipol Alone and in Combination With Simvastatin on Apolipoprotein B Metabolism

The effects of colestipol therapy alone (20 g/d) or combined with simvastatin (20 mg/d) were examined in a group of eight male patients with primary moderate hypercholesterolemia (total cholesterol > or = 6.5 mmol/L [> or = 250 mg/dL]) who had undergone coronary artery bypass grafting more than 3 months previously. Colestipol therapy decreased total cholesterol by 14% (P < .001) and LDL cholesterol (LDL-C) by 23% (P < .001), while dual therapy decreased total cholesterol by 38% and LDL-C by 52% (both P < .001 versus baseline). No significant changes were observed in plasma triglyceride, VLDL cholesterol, or HDL cholesterol levels. VLDL subfraction turnovers were conducted at baseline and again on each regimen. ApoB kinetic parameters derived from a multicompartmental model suggested that colestipol therapy resulted in an expansion of the total VLDL apoB pool (36%, P < .05) that was largely due to a fall in the clearance rate of VLDL1 apoB (49%), while the LDL apoB pool decreased 23% as a result of diminished direct LDL input. The model used also revealed that addition of simvastatin to the resin therapy caused increases in the fractional transfer rates of VLDL2 to IDL and IDL to LDL together with a 37% increment in the LDL apoB fractional catabolic rate. Compared with baseline, combined therapy generated falls in both IDL (35%, P = .01) and LDL (37%, P < .04) apoB pools due to enhanced clearance of IDL (214%, P < .03) and reduced total input of LDL (39%, P < .003).