IMPORTANCE In clinical and research settings worldwide, low-density lipoprotein cholesterol (LDL-C) is typically estimated using the Friedewald equation. This equation assumes a fixed factor of 5 for ...the ratio of triglycerides to very low-density lipoprotein cholesterol (TG:VLDL-C); however, the actual TG:VLDL-C ratio varies significantly across the range of triglyceride and cholesterol levels. OBJECTIVE To derive and validate a more accurate method for LDL-C estimation from the standard lipid profile using an adjustable factor for the TG:VLDL-C ratio. DESIGN, SETTING, AND PARTICIPANTS We used a convenience sample of consecutive clinical lipid profiles obtained from 2009 through 2011 from 1 350 908 children, adolescents, and adults in the United States. Cholesterol concentrations were directly measured after vertical spin density-gradient ultracentrifugation, and triglycerides were directly measured. Lipid distributions closely matched the population-based National Health and Nutrition Examination Survey (NHANES). Samples were randomly assigned to derivation (n = 900 605) and validation (n = 450 303) data sets. MAIN OUTCOMES AND MEASURES Individual patient-level concordance in clinical practice guideline LDL-C risk classification using estimated vs directly measured LDL-C (LDL-CD). RESULTS In the derivation data set, the median TG:VLDL-C was 5.2 (IQR, 4.5-6.0). The triglyceride and non–high-density lipoprotein cholesterol (HDL-C) levels explained 65% of the variance in the TG:VLDL-C ratio. Based on strata of triglyceride and non–HDL-C values, a 180-cell table of median TG:VLDL-C values was derived and applied in the validation data set to estimate the novel LDL-C (LDL-CN). For patients with triglycerides lower than 400 mg/dL, overall concordance in guideline risk classification with LDL-CD was 91.7% (95% CI, 91.6%-91.8%) for LDL-CN vs 85.4% (95% CI, 85.3%-85.5%) for Friedewald LDL-C (LDL-CF) (P < .001). The greatest improvement in concordance occurred in classifying LDL-C lower than 70 mg/dL, especially in patients with high triglyceride levels. In patients with an estimated LDL-C lower than 70 mg/dL, LDL-CD was also lower than 70 mg/dL in 94.3% (95% CI, 93.9%-94.7%) for LDL-CN vs 79.9% (95% CI, 79.3%-80.4%) for LDL-CF in samples with triglyceride levels of 100 to 149 mg/dL; 92.4% (95% CI, 91.7%-93.1%) for LDL-CN vs 61.3% (95% CI, 60.3%-62.3%) for LDL-CF in samples with triglyceride levels of 150 to 199 mg/dL; and 84.0% (95% CI, 82.9%-85.1%) for LDL-CN vs 40.3% (95% CI, 39.4%-41.3%) for LDL-CF in samples with triglyceride levels of 200 to 399 mg/dL (P < .001 for each comparison). CONCLUSIONS AND RELEVANCE A novel method to estimate LDL-C using an adjustable factor for the TG:VLDL-C ratio provided more accurate guideline risk classification than the Friedewald equation. These findings require external validation, as well as assessment of their clinical importance. The implementation of these findings into clinical practice would be straightforward and at virtually no cost. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01698489
Objectives The aim of this study was to compare Friedewald-estimated and directly measured low-density lipoprotein cholesterol (LDL-C) values. Background LDL-C is routinely estimated by the ...Friedewald equation to guide treatment; however, compatibility with direct measurement has received relatively little scrutiny, especially at levels <70 mg/dl now targeted in high-risk patients. Methods We examined 1,340,614 U.S. adults who underwent lipid profiling by vertical spin density gradient ultracentrifugation (Atherotech, Birmingham, Alabama) from 2009 to 2011. Following standard practice, Friedewald LDL-C was not estimated if triglyceride levels were ≥400 mg/dl (n = 30,174), yielding 1,310,440 total patients and 191,333 patients with Friedewald LDL-C <70 mg/dl. Results Patients were 59 ± 15 years of age and 52% were women. Lipid distributions closely matched those in the National Health and Nutrition Examination Survey. A greater difference in the Friedewald-estimated versus directly measured LDL-C occurred at lower LDL-C and higher triglyceride levels. If the Friedewald-estimated LDL-C was <70 mg/dl, the median directly measured LDL-C was 9.0 mg/dl higher (5th to 95th percentiles, 1.8 to 15.4 mg/dl) when triglyceride levels were 150 to 199 mg/dl and 18.4 mg/dl higher (5th to 95th percentiles, 6.6 to 36.0 mg/dl) when triglyceride levels were 200 to 399 mg/dl. Of patients with a Friedewald-estimated LDL-C <70 mg/dl, 23% had a directly measured LDL-C ≥70 mg/dl (39% if triglyceride levels were concurrently 150 to 199 mg/dl; 59% if triglyceride levels were concurrently 200 to 399 mg/dl). Conclusions The Friedewald equation tends to underestimate LDL-C most when accuracy is most crucial. Especially if triglyceride levels are ≥150 mg/dl, Friedewald estimation commonly classifies LDL-C as <70 mg/dl despite directly measured levels ≥70 mg/dl, and therefore additional evaluation is warranted in high-risk patients.
BACKGROUND:Recent recommendations favoring nonfasting lipid assessment may affect low-density lipoprotein cholesterol (LDL-C) estimation. The novel method of LDL-C estimation (LDL-CN) uses a flexible ...approach to derive patient-specific ratios of triglycerides to very low-density lipoprotein cholesterol. This adaptability may confer an accuracy advantage in nonfasting patients over the fixed approach of the classic Friedewald method (LDL-CF).
METHODS:We used a US cross-sectional sample of 1 545 634 patients (959 153 fasting ≥10–12 hours; 586 481 nonfasting) from the second harvest of the Very Large Database of Lipids study to assess for the first time the impact of fasting status on novel LDL-C accuracy. Rapid ultracentrifugation was used to directly measure LDL-C content (LDL-CD). Accuracy was defined as the percentage of LDL-CD falling within an estimated LDL-C (LDL-CN or LDL-CF) category by clinical cut points. For low estimated LDL-C (<70 mg/dL), we evaluated accuracy by triglyceride levels. The magnitude of absolute and percent differences between LDL-CD and estimated LDL-C (LDL-CN or LDL-CF) was stratified by LDL-C and triglyceride categories.
RESULTS:In both fasting and nonfasting samples, accuracy was higher with the novel method across all clinical LDL-C categories (range, 87%–94%) compared with the Friedewald estimation (range, 71%–93%; P≤0.001). With LDL-C <70 mg/dL, nonfasting LDL-CN accuracy (92%) was superior to LDL-CF accuracy (71%; P<0.001). In this LDL-C range, 19% of fasting and 30% of nonfasting patients had differences ≥10 mg/dL between LDL-CF and LDL-CD, whereas only 2% and 3% of patients, respectively, had similar differences with novel estimation. Accuracy of LDL-C <70 mg/dL further decreased as triglycerides increased, particularly for Friedewald estimation (range, 37%–96%) versus the novel method (range, 82%–94%). With triglycerides of 200 to 399 mg/dL in nonfasting patients, LDL-CN <70 mg/dL accuracy (82%) was superior to LDL-CF (37%; P<0.001). In this triglyceride range, 73% of fasting and 81% of nonfasting patients had ≥10 mg/dL differences between LDL-CF and LDL-CD compared with 25% and 20% of patients, respectively, with LDL-CN.
CONCLUSIONS:Novel adaptable LDL-C estimation performs better in nonfasting samples than the fixed Friedewald estimation, with a particular accuracy advantage in settings of low LDL-C and high triglycerides. In addition to stimulating further study, these results may have immediate relevance for guideline committees, laboratory leadership, clinicians, and patients.
CLINICAL TRIAL REGISTRATION:URLhttps://www.clinicaltrials.gov. Unique identifierNCT01698489.
Inflammation constitutes a complex, highly conserved cascade of molecular and cellular events. Inflammation has been labeled as “the fire within,” is highly regulated, and is critical to host defense ...and tissue repair. In general, inflammation is beneficial and has evolved to promote survival. However, inflammation can also be maladaptive when chronically activated and sustained, leading to progressive tissue injury and reduced survival. Examples of a maladaptive response include rheumatologic disease and atherosclerosis. Despite evidence gathered by Virchow over 100 years ago showing that inflammatory white cells play a role in atherogenesis, atherosclerosis was until recently viewed as a disease of passive cholesterol accumulation in the subendothelial space. This view has been supplanted by considerable basic scientific and clinical evidence demonstrating that every step of atherogenesis, from the development of endothelial cell dysfunction to foam cell formation, plaque formation and progression, and ultimately plaque rupture stemming from architectural instability, is driven by the cytokines, interleukins, and cellular constituents of the inflammatory response. Herein we provide an overview of the role of inflammation in atherosclerotic cardiovascular disease, discuss the predictive value of various biomarkers involved in inflammation, and summarize recent clinical trials that evaluated the capacity of various pharmacologic interventions to attenuate the intensity of inflammation and impact risk for acute cardiovascular events.
Electron microscopy touches on nearly every aspect of modern life, underpinning materials development for quantum computing, energy and medicine. We discuss the open, highly integrated and ...data-driven microscopy architecture needed to realize transformative discoveries in the coming decade.
Abstract Background and aims The effect of statin therapy on plasma adiponectin levels has not been conclusively studied. Therefore, we aimed to evaluate this effect through a systematic review and ...meta-analysis of available randomized controlled trials (RCTs). Methods Quantitative data synthesis was performed using a random-effects model with weighted mean difference (WMD) and 95% confidence interval (CI) as summary statistics. Results In 30 studies (43 study arms) with 2953 participants, a significant increase in plasma adiponectin levels was observed after statin therapy (WMD: 0.57 μg/mL, 95% CI: 0.18, 0.95, p = 0.004). In subgroup analysis, atorvastatin, simvastatin, rosuvastatin, pravastatin and pitavastatin were found to change plasma adiponectin concentrations by 0.70 μg/mL (95% CI: −0.26, 1.65), 0.50 μg/mL (95% CI: −0.44, 1.45), −0.70 μg/mL (95% CI: −1.08, −0.33), 0.62 μg/mL (95% CI: −0.12, 1.35), and 0.51 μg/mL (95% CI: 0.30, 0.72), respectively. With respect to duration of treatment, there was a significant increase in the subset of trials lasting ≥12 weeks (WMD: 0.88 μg/mL, 95% CI: 0.19, 1.57, p = 0.012) but not in the subset of <12 weeks of duration (WMD: 0.18 μg/mL, 95% CI: −0.23, 0.58, p = 0.390). Random-effects meta-regression suggested a significant association between statin-induced elevation of plasma adiponectin and changes in plasma low density lipoprotein cholesterol levels (slope: 0.04; 95% CI: 0.01, 0.06; p = 0.002). Conclusions The meta-analysis showed a significant increase in plasma adiponectin levels following statin therapy. Although statins are known to increase the risk for new onset diabetes mellitus, our data might suggest that the mechanism for this is unlikely to be due to a reduction in adiponectin expression.
Abstract Objective Raised plasma endothelin-1 (ET-1) levels may be a risk factor for vascular dysfunction and cardiovascular (CV) disease. This meta-analysis assessed the effect of statins on ...circulating ET-1 concentrations. Methods and results The search included PUBMED, Cochrane Library, Web of Science, Scopus, and EMBASE up to September 30, 2014 to identify randomized controlled trials (RCTs) with ET-1 measurement during statin therapy. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference (WMD) and 95% confidence interval (CI) as summary statistics. Data from 15 RCTs showed that statin therapy significantly reduces plasma ET-1 concentrations (WMD: −0.30 pg/mL, 95%CI: −0.47, −0.13; p < 0.01). This effect was robust in sensitivity analysis, and not largely affected by the duration of statin therapy (<12 weeks – WMD: −0.51 pg/mL, 95%CI: −0.89, −0.14, p < 0.01; >12 week –WMD: −0.19 pg/mL, 95%CI: −0.36, −0.02; p < 0.05) or by dose of statins (<40 mg/day – WMD: −0.27 pg/mL, 95%CI: −0.49, −0.05; p = 0.01; >40 mg/day – WMD: −0.38 pg/mL, 95%CI: −0.68, −0.08; p = 0.01). Lipophilic (atorvastatin, simvastatin, fluvastatin, and cerivastatin – WMD: −0.34 pg/mL, 95%CI: −0.55, −0.13; p < 0.01), but not a hydrophilic statin (pravastatin – WMD: −0.18 pg/mL, 95%CI: −0.44 −0.08; p > 0.05) had a significant effect in promoting ET-1 reduction. Conclusions Statin therapy significantly reduces circulating ET-1 concentrations, regardless of treatment duration or dose of statins. This effect of statins may be influenced by statin lipophilicity. There is a need to establish whether lowering ET-1 levels has a beneficial effect on CV events.
Coronary heart disease (CHD) is the leading cause of morbidity and mortality world-wide and has been characterized as a chronic immunoinflammatory, fibroproliferative disease fueled by lipids. Great ...advances have been made in elucidating the complex mechanistic interactions among risk factors associated with CHD, yielding abundant success towards preventive measures and the development of pharmaceuticals to prevent and treat CHD via attenuation of lipoprotein-mediated risk. However, significant residual risk remains. Several potentially modifiable CHD risk factors ostensibly contributing to this residual risk have since come to the fore, including systemic inflammation, diabetes mellitus, high-density lipoprotein, plasma triglycerides (TG) and remnant lipoproteins (RLP), lipoprotein(a) (Lpa), and vascular endothelial dysfunction (ED). Herein, we summarize the body of evidence implicating each of these risk factors in residual CHD risk.
This study aims to broadly examine how commonly various conceptualizations of the definite integral are drawn on by students as they attempt to explain the meaning of integral expressions. Previous ...studies have shown that certain conceptualizations, such as the area under a curve or the values of an anti-derivative, may be less productive in making sense of contextualized integrals. On the other hand, interpreting the integral using Riemann sum-based conceptions proves much more productive for understanding contextualized integrals. This study investigates how frequently students from a US calculus population drew on these three conceptualizations (as well as others) to interpret the meaning of definite integrals. The results were achieved by asking a large sample of students from two US colleges (n = 150) four open-ended questions regarding the underlying meaning of definite integrals. Data from the student responses show a high prevalence of area and anti-derivative ideas and a relatively low occurrence of multiplicatively based summation ideas for interpreting these integrals. Possible reasons for and implications of the results are discussed.
Abstract Objective While nonalcoholic fatty liver disease (NAFLD) is associated with the metabolic syndrome, it is not known if NAFLD plays an independent role in the atherogenic dyslipidemia ...phenotype. Methods and results The Multi-Ethnic Study of Atherosclerosis (MESA) is a population-based prospective cohort study of adults free of clinical cardiovascular disease at enrollment. We tested for a relationship between NAFLD, defined as a liver/spleen (L/S) attenuation ratio of <1 on a non-contrast cardiac CT scan, and multiple measures of fasting serum lipoprotein size, cholesterol and particle concentrations. NAFLD was present in 569 (17%) of 3362 participants. After adjustment for multiple metabolic risk factors, adiposity and measures of insulin resistance (HOMA-IR), NAFLD was independently associated with higher fasting serum triglycerides and lower serum HDL-C. Despite a lack of association with LDL-C, NAFLD was associated with higher LDL particle concentration and lower LDL particle size. Modeling the L/S ratio as a continuous variable, a severity dependent association was observed between atherogenic lipoprotein abnormalities and NAFLD. Conclusion In a large, multi-ethnic, gender balanced cohort, CT-diagnosed NAFLD was associated with the atherogenic dyslipidemia phenotype in a dose dependent fashion. These relationships persisted after adjustment for several metabolic risk factors and HOMA-IR, suggesting a possible independent pathophysiologic role between NAFLD and dyslipidemia.
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