Association Of Low-density Lipoprotein Cholesterol Research Articles

Long-Term Association of Low-Density Lipoprotein Cholesterol With Cardiovascular Mortality in Individuals at Low 10-Year Risk of Atherosclerotic Cardiovascular Disease.

The associations of low-density lipoprotein cholesterol (LDL-C) with cardiovascular disease (CVD) and coronary heart disease mortality in an exclusively low estimated 10-year risk group are not well delineated. We sought to determine the long-term associations of various LDL-C and non-high-density lipoprotein cholesterol (HDL-C) thresholds and CVD and coronary heart disease mortality in a large, low 10-year risk cohort. The study sample included participants of the CCLS (Cooper Center Longitudinal Study) without a history of CVD or diabetes mellitus and defined as low risk (<7.5%) for 10-year atherosclerotic CVD events at baseline based on Pooled Cohort Risk Assessment Equations. The associations of fasting LDL-C and non-HDL-C with CVD mortality were tested with Cox proportional hazards models. In 36 375 participants (72% men, median age 42) followed for a median of 26.8 years, 1086 CVD and 598 coronary heart disease deaths occurred. Compared with LDL-C <100 mg/dL, LDL-C categories 100 to 129 mg/dL, 130 to 159 mg/dL, 160 to 189.9 mg/dL, and ≥190 mg/dL were associated with a significantly higher risk of CVD death, with hazard ratios of 1.4 (95% CI, 1.1-1.7), 1.3 (95% CI, 1.1-1.6), 1.9 (95% CI, 1.5-2.4), and 1.7 (95% CI, 1.3-2.3), and mean reductions in years free of CVD death of 1.8, 1.1, 4.3, and 3.9, respectively. After adjustment for atherosclerotic CVD risk factors, LDL-C categories 160 to 189 mg/dL and ≥190 mg/dL remained independently associated with CVD mortality, with hazard ratios of 1.7 (95% CI, 1.4-2.2) and 1.5 (95% CI, 1.2-2.1), respectively. In multivariable-adjusted models using non-HDL-C <130 mg/dL as the reference, non-HDL-C 160 to 189 mg/dL, 190 to 219 mg/dL, and ≥220 mg/dL were significantly associated with CVD death, with hazard ratios of 1.3 (95% CI, 1.1-1.6), 1.8 (95% CI, 1.4-2.2), and 1.5 (95% CI, 1.2-2.0), respectively. Restricting the cohort to those with 10-year risk <5% did not diminish the associations of LDL-C and non-HDL-C with CVD mortality. In a low 10-year risk cohort with long-term follow-up, LDL-C and non-HDL-C ≥160 mg/dL were independently associated with a 50% to 80% increased relative risk of CVD mortality. These findings may have implications for future cholesterol treatment paradigms.

Relation of Low-Density Lipoprotein Cholesterol to Ischemic Stroke in Patients With Nonvalvular Atrial Fibrillation

Low-density lipoprotein cholesterol (LDL-C) has been demonstrated as an independent risk factor of ischemic stroke, but the association of LDL-C with ischemic stroke in patients with nonvalvular atrial fibrillation (AF) remains uncertain. Our objective was to explore whether LDL-C could refine stroke stratification in patients with AF. A total of 424 nonvalvular patients with AF with ischemic stroke and 391 ones without ischemic stroke were enrolled. No patient had received antithrombotic therapy. Multivariate logistic regression analysis showed that LDL-C was an independent predictor of ischemic stroke in patients with AF, with the adjusted odds ratio of 2.004 (95% confidence interval 1.624 to 2.473; p <0.001). The receiver operating characteristic analysis revealed that the best cut-off value of LDL-C to predict ischemic stroke in patients with AF was 2.48mmol/L with 56.3% sensitivity and 66.3% specificity (area under the curve: 0.651, p <0.001). In the subgroup analysis based on different CHA2DS2-VASc scores, the predictive value of LDL-C remained significant in patients with a CHA2DS2-VASc score of ≤5. In conclusion, LDL-C was an independent predictor of ischemic stroke, which could potentially refine stroke stratification in patients with AF. A prospective study with a large number of patients is required to validate the current findings.

Usefulness of Non–High-Density Lipoprotein Cholesterol as a Predictor of Cardiovascular Disease Mortality in Men in 22-Year Follow-Up

Non-high-density lipoprotein cholesterol (non-HDL-C) may be equivalent or superior to low-density lipoprotein cholesterol (LDL-C) for prediction of cardiovascular disease (CVD) risk. However, studies comparing the predictive values of LDL-C and non-HDL-C for CVD and total mortality in a long-term follow-up yielded conflicting results. The Cardiovascular Occupational Risk Factor Determination in Israel Study (CORDIS) is a prospective cohort study of a young industrial population of workers with a long-term follow-up. The initial phase of the study was carried out in 1985-1999. Interviews and physical examinations were conducted, and fasting blood samples, including lipid panels, were undertaken. In 2007, after a 22-year follow-up period, the baseline data were merged with data on all-cause and CVD mortality obtained from the Israeli National Death Registry. A total of 4,832 men were included in the analysis with a mean age of 42.1 ± 12.1years. Univariate analysis indicated a positive association between non-HDL-C and LDL-C levels and an increased risk for both all-cause and CVD mortality. Multiple regression analysis, following adjustment for potential confounders, resulted in attenuation of the association of both lipoproteins with total mortality. The adjusted association between non-HDL-C levels ≥190mg/dl and CVD mortality remained significant (hazard ratio 1.80, 95% confidence interval 1.10 to 2.96), but the association of LDL-C with CVD mortality was attenuated (hazard ratio 1.53, 95% confidence interval 0.98 to 2.39). In conclusion, non-HDL-C may be a more potent predictor of CVD mortality than LDL-C levels.

Association of low-density lipoprotein cholesterol within the normal range and NAFLD in the non-obese Chinese population: a cross-sectional and longitudinal study

ObjectivesThe relationship between normal low-density lipoprotein cholesterol (LDL-c) levels and non-alcoholic fatty liver disease (NAFLD) in non-obese individuals remains unclear. We aimed to investigate the precise prevalence and incidence of...

Moving beyond the "LDL hypothesis".

The term "LDL hypothesis" is frequently used to describe the association of low-density lipoprotein cholesterol (LDL-cholesterol, LDL-C) and cardiovascular (CV) events. Recent data from genetic studies prove a causal relation between serum LDL-C and CV events. These data are in agreement with mechanistic molecular studies and epidemiology. New randomised clinical trial data show that LDL-C lowering with statins and a non-statin drug, ezetimibe, reduces CV events. We therefore believe that the "LDL-hypothesis" has been proven; the term appears to be outdated and should be replaced by "LDL causality".

Plasma triglycerides predict incident albuminuria and progression of coronary artery calcification in adults with type 1 diabetes: the Coronary Artery Calcification in Type 1 Diabetes Study.

Coronary artery disease and diabetic nephropathy, which are thought to share pathogenic mechanisms, remain the most common causes of mortality in type 1 diabetes (T1D). Data from basic and clinical studies indicate that hypertriglyceridemia plays an important role in the pathogenesis of vascular complications, but the role of triglycerides (TG) in the normal range remains unresolved in T1D. We hypothesized that fasting TG would independently predict cardiorenal disease in adults with T1D and normal-to-low levels of TG. Subjects (N = 652) were 19 to 56 years old at baseline and reexamined 6 years later. Urinary albumin excretion was measured, and categorized as microalbuminuria or greater. Progression of coronary artery calcification (CACp), measured using electron beam computed tomography, was defined as a change in the square root transformed CAC volume ≥2.5. The association of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B, non-HDL-C, natural log triglyceride (lnTG), ln(TG/HDL-C) ratio with CACp and incident albuminuria were examined in logistic regression. The models were adjusted for age, sex, T1D duration, hemoglobin A1c, systolic blood pressure, diastolic blood pressure, blood pressure medications, statins, and smoking status. Integrated discrimination index and net reclassification improvement were used to examine prediction performance. Incident albuminuria was independently associated with CACp. lnTG independently predicted both incident albuminuria (odds ratio: 1.53, 1.02-2.30, P = .04) and CACp (1.41, 1.11-1.80, P = .006). The addition of lnTG to ABC risk factors (HbA1c, systolic blood pressure, diastolic blood pressure, and LDL-C) moderately improved discrimination and reclassification of CACp and incident albuminuria. In adults with T1D, fasting TG independently predicted cardiorenal disease over 6 years and improved reclassification of risk by conventional risk factors.

Mendelian Randomization Analysis With Multiple Genetic Variants Using Summarized Data

Genome-wide association studies, which typically report regression coefficients summarizing the associations of many genetic variants with various traits, are potentially a powerful source of data for Mendelian randomization investigations. We demonstrate how such coefficients from multiple variants can be combined in a Mendelian randomization analysis to estimate the causal effect of a risk factor on an outcome. The bias and efficiency of estimates based on summarized data are compared to those based on individual-level data in simulation studies. We investigate the impact of gene–gene interactions, linkage disequilibrium, and ‘weak instruments’ on these estimates. Both an inverse-variance weighted average of variant-specific associations and a likelihood-based approach for summarized data give similar estimates and precision to the two-stage least squares method for individual-level data, even when there are gene–gene interactions. However, these summarized data methods overstate precision when variants are in linkage disequilibrium. If the P-value in a linear regression of the risk factor for each variant is less than , then weak instrument bias will be small. We use these methods to estimate the causal association of low-density lipoprotein cholesterol (LDL-C) on coronary artery disease using published data on five genetic variants. A 30% reduction in LDL-C is estimated to reduce coronary artery disease risk by 67% (95% CI: 54% to 76%). We conclude that Mendelian randomization investigations using summarized data from uncorrelated variants are similarly efficient to those using individual-level data, although the necessary assumptions cannot be so fully assessed.

Association of LDL Cholesterol, Non–HDL Cholesterol, and Apolipoprotein B Levels With Risk of Cardiovascular Events Among Patients Treated With Statins

The associations of low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B (apoB) levels with the risk of cardiovascular events among patients treated with statin therapy have not been reliably documented. To evaluate the relative strength of the associations of LDL-C, non-HDL-C, and apoB with cardiovascular risk among patients treated with statin therapy. Meta-analysis of individual patient data from randomized controlled statin trials in which conventional lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. Relevant trials were identified by a literature search updated through December 31, 2011. Investigators were contacted and individual patient data were requested and obtained for 62,154 patients enrolled in 8 trials published between 1994 and 2008. Hazard ratios (HRs) and corresponding 95% CIs for risk of major cardiovascular events adjusted for established risk factors by 1-SD increase in LDL-C, non-HDL-C, and apoB. Among 38,153 patients allocated to statin therapy, 158 fatal myocardial infarctions, 1678 nonfatal myocardial infarctions, 615 fatal events from other coronary artery disease, 2806 hospitalizations for unstable angina, and 1029 fatal or nonfatal strokes occurred during follow-up. The adjusted HRs for major cardiovascular events per 1-SD increase were 1.13 (95% CI, 1.10-1.17) for LDL-C, 1.16 (95% CI, 1.12-1.19) for non-HDL-C, and 1.14 (95% CI, 1.11-1.18) for apoB. These HRs were significantly higher for non-HDL-C than LDL-C (P = .002) and apoB (P = .02). There was no significant difference between apoB and LDL-C (P = .21). Among statin-treated patients, on-treatment levels of LDL-C, non-HDL-C, and apoB were each associated with risk of future major cardiovascular events, but the strength of this association was greater for non-HDL-C than for LDL-C and apoB.

Association of LDL Cholesterol and Inflammation With Cardiovascular Events and Mortality in Hemodialysis Patients With Type 2 Diabetes Mellitus

In the general population, C-reactive protein (CRP) in addition to low-density lipoprotein (LDL) cholesterol level is useful in predicting cardiovascular events. In hemodialysis patients, the additive value is unknown. The association between LDL cholesterol level and outcome previously was suggested to be inverse and confounded by inflammation. Prospective cohort study. 1,255 hemodialysis patients with type 2 diabetes mellitus randomly assigned to atorvastatin versus placebo in the German Diabetes Dialysis Study. Baseline LDL cholesterol level. Combined vascular end point (cardiac death, myocardial infarction, and stroke), mortality, myocardial infarction, sudden death, and stroke. During 4 years, 465 combined vascular events, 612 deaths, 160 sudden deaths, 200 myocardial infarctions, and 99 strokes occurred. Median LDL cholesterol level was 123 mg/dL. LDL cholesterol level (millimoles per liter and quartiles) was not predictive of outcome. This was analyzed further in patients with and without inflammation. In patients with inflammation (CRP level > 5 mg/L), the adjusted relative risk of combined vascular events was 29% greater compared with those without inflammation and a low LDL cholesterol level (LDL cholesterol < or = 123 mg/dL). This was irrespective of whether LDL cholesterol level was low or high (hazard ratio [HR] for LDL < 123 mg/dL [HR (for LDL< or =123 mg/dL)], 1.29, with 95% confidence interval [CI], 0.98 to 1.70; HR(LDL>123 mg/dL), 1.29, with 95% CI, 0.99 to 1.69). Similar results were found for all-cause death (HR(LDL< or =123 mg/dL), 1.47 [95% CI, 1.16 to 1.86]; HR(LDL>123 mg/dL), 1.48 [95% CI, 1.16 to 1.88]), sudden death (HR(LDL< or =123 mg/dL), 1.98 [95% CI, 1.23 to 3.20]; HR(LDL>123 mg/dL), 1.66 [95% CI, 1.01 to 2.75]), and myocardial infarction (HR(LDL< or =123 mg/dL), 1.74 [95% CI, 1.14 to 2.66]; HR(LDL>123 mg/dL), 1.54 [95% CI, 0.99 to 2.38]). In patients without inflammation, the respective risks did not differ significantly between patients with varying LDL cholesterol levels. However, there was a trend toward an increased risk of myocardial infarction (HR(LDL>123 mg/dL), 1.45 [95% CI, 0.95 to 2.21]) in patients with high compared with low LDL cholesterol levels. P values for the interaction between CRP and LDL cholesterol levels were 0.9 (composite vascular end point), 0.5 (mortality), 0.9 (sudden death), 0.09 (stroke), and 0.2 (myocardial infarction). Selected patient cohort, post hoc analysis. Because CRP level more than LDL cholesterol level determined outcome, the value of regular LDL cholesterol measurements in long-term hemodialysis patients with type 2 diabetes needs reassessment.

Abstract 5054: Apolipoprotein B, but not Low-Density Lipoprotein Cholesterol is Associated with Coronary Atherosclerosis Beyond Total Cholesterol in Diabetics and Non-Diabetics

Introduction: Accumulating evidence suggests that apolipoprotein B (apoB) is superior to low-density lipoprotein cholesterol (LDL-C) in prediction of cardiovascular events. Yet, an important outstanding question is whether apoB, relative to LDL, is an enhanced marker for subclinical atherosclerosis, particularly in diabetics where LDL levels may underestimate atherogenic lipid burden due to increased proportion of small, dense LDL. Hypothesis: We hypothesized that plasma apoB would be a better predictor than LDL-C of coronary artery calcification (CAC) scores in type 2 diabetics and non-type 2 diabetics. Methods: We performed cross-sectional analyses of asymptomatic Caucasians in (1) The Study of Inherited Risk of Coronary Atherosclerosis (434 men and 383 women; median age 48, non-diabetics) and (2) The Penn Diabetes Heart Study (580 men and 261 women; median age 60, type 2 diabetics). Results: Levels of apoB and LDL-C were correlated in diabetics (r=0.78, p&lt;0.001) and non-diabetics (r=0.77, p&lt;0.001). There was no association between LDL-C and CAC in diabetics. In non-diabetics, an association of LDL-C was lost after adjustment for total cholesterol. In contrast, after controlling for age, gender, statin therapy, and total cholesterol, levels of apoB were positively associated with CAC in diabetics [tobit regression ratio for 30 mg/dl increase in apoB 2.94 (95% CI 1.62 – 5.53), p=0.001) and had a more modest association with CAC in non-diabetics [1.67 (95% CI 1.16 – 2.32), p=0.005]. Conclusions: ApoB, but not LDL-C, predicted CAC scores, a measure of coronary atherosclerotic burden. The strength of this association was greater in diabetics than non-diabetics. Relative to LDL-C, plasma apoB levels may be particularly useful in assessing CVD risk in type 2 diabetes.

Hyperglycaemia, hypercholesterolaemia and the risk for developing gastric dysplasia

Background/goals Gastric dysplasia is believed to be the penultimate stage of gastric carcinogenesis. Few studies have evaluated whether there is a relationship between such risk factors and gastric dysplasia. This case–control study was conducted to investigate the associations between obesity, serum glucose, lipids and gastric dysplasia. Study Endoscopic findings and pathology specimens were reviewed from 1 July 1997 to 31 December 2006 in the Health Promotion Center. One hundred thirty patients have the dysplasia in the stomach during screening endoscopy. The same number of controls was evaluated and matched to the gastric dysplasia group for age and gender. Result The univariate analysis showed that the dysplasia risk was slightly increased among persons with a higher low-density lipoprotein, lower high-density lipoprotein, impaired fasting glucose and higher total cholesterol. However, a higher body mass index and higher triglyceride level were not associated with the diagnosis of gastric dysplasia. In the multivariate-adjusted model, a higher low-density lipoprotein cholesterol and glucose were strongly associated with an increased risk of dysplasia compared to the controls. However, the body mass index, triglyceride and total cholesterol were not associated with the risk for dysplasia. Conclusion Hyperglycaemia and low-density lipoprotein cholesterol appear to be associated with the risk for gastric dysplasia. Further epidemiologic studies including a large cohort of patients with gastric dysplasia and adenocarcinoma are needed to clarify the association of low-density lipoprotein cholesterol, serum glucose and gastric carcinogenesis.

Cholesterol levels in small LDL particles predict the risk of coronary heart disease in the EPIC-Norfolk prospective population study

To evaluate the association of low-density lipoprotein cholesterol (LDL-C) levels in small and large LDL particles with risk of incident coronary heart disease (CHD). We performed a prospective case-control study nested in the EPIC-Norfolk cohort. Cases were apparently healthy men and women aged 45-79 years who developed fatal or non-fatal CHD (n = 1035), and who were matched by age, gender, and enrollment time to 1920 controls who remained free of CHD. Electrophoretic characteristics of LDL particles were measured using 2-16% polyacrylamide gradient gel electrophoresis. Concentrations of LDL-C(<255 A) were higher in cases than controls in men (1.34 +/- 0.88 vs. 1.15 +/- 0.80 mmol/L, P < 0.001) as well as in women (1.12 +/- 0.84 vs. 0.94 +/- 0.74 mmol/L, P < 0.001). The unadjusted odds ratio (OR) for future CHD in men of the top tertile of LDL-C(<255 A) was 1.68 (95% CI, 1.33-2.13; P < 0.001) whereas in women the unadjusted OR was 1.53 (95% CI, 1.13-2.07; P < 0.001). However, after further adjustments for confounding variables, the association between LDL-C(<255 A) and CHD was no longer significant in men and in women. Cholesterol concentrations in different LDL subclasses show different relationships with CHD risk in this European cohort.

Modifying Plasma Low-Density Lipoprotein and High-Density Lipoprotein Cholesterol: What Combinations Are Available in the Future?

Despite a growing body of research on the benefit of combination drug therapy for dyslipidemia in the metabolic syndrome or diabetes mellitus, there are insufficient outcome data on the use of combination therapy as well as inadequate data to compare certain combination regimens. The focus of the therapeutic approach in treating the metabolic syndrome has been almost exclusively on low-density lipoprotein (LDL) cholesterol for approximately the past 10 years, and specifically on statin therapy. Although results of epidemiologic studies as well as clinical trials using angiographic and clinical end points confirm the association of LDL cholesterol and risk of coronary artery disease, data are lacking regarding the effects of combination therapy in the management of coronary artery disease. Management of the metabolic syndrome focusing on the modification of plasma LDL as well as high-density lipoprotein cholesterol is reviewed. Future management strategies with the use of novel combination therapy is also discussed.