Identification of allele-specific KIV-2 repeats and impact on Lp(a) measurements for cardiovascular disease risk.

The abundance of Lp(a) protein holds significant implications for the risk of cardiovascular disease (CVD), which is directly impacted by the copy number (CN) of KIV-2, a 5.5 kbp sub-region. KIV-2 is highly polymorphic in the population and accurate analysis is challenging. In this study, we present the DRAGEN KIV-2 CN caller, which utilizes short reads. Data across 166 WGS show that the caller has high accuracy, compared to optical mapping and can further phase ~50% of the samples. We compared KIV-2 CN numbers to 24 previously postulated KIV-2 relevant SNVs, revealing that many are ineffective predictors of KIV-2 copy number. Population studies, including USA-based cohorts, showed distinct KIV-2 CN, distributions for European-, African-, and Hispanic-American populations and further underscored the limitations of SNV predictors. We demonstrate that the CN estimates correlate significantly with the available Lp(a) protein levels and that phasing is highly important.

Longitudinal increases in blood biomarkers of inflammation or cardiovascular disease and the incidence of venous thromboembolism.

Essentials Inflammatory and cardiac diseases are associated with increased venous thromboembolism (VTE) risk. Our prospective study assessed rise in inflammatory or cardiac biomarkers and VTE risk. A greater 6-year rise in N-terminal natriuretic peptide is associated with increased VTE incidence. Volume overload or impending cardiac disease may contribute to VTE occurrence. SUMMARY: Background We previously showed that participants in the population-based Atherosclerosis Risk in Communities (ARIC) cohort with elevated levels of blood biomarkers of inflammation or cardiac disease were at increased risk of venous thromboembolism (VTE). Objective We hypothesized that ARIC participants with larger 6-year increases in the levels of three biomarkers - C-reactive protein (CRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and troponin T - would also have an increased subsequent risk of VTE. Methods We measured changes in the levels of these biomarkers in 9844 participants from 1990-1992 to 1996-1998, and then identified VTEs through 2015. Results A greater 6-year rise in the level of NT-proBNP, but not in that of CRP or troponin T, was significantly associated with increased VTE incidence over a median of 17.6 years of follow-up. After adjustment for other VTE risk factors, those whose NT-proBNP level rose from < 100 pg mL-1 to ≥ 100 pg mL-1 had a hazard ratio for VTE of 1.44 (95% confidence interval [CI] 1.15-1.80), as compared with the reference group with an NT-proBNP level of < 100 pg mL-1 at both times. This hazard ratio was slightly higher (1.66, 95% CI 1.19-2.31) during the first 10 years of follow-up, but was attenuated (1.24, 95% CI 0.99-1.56) after adjustment for prevalent and incident coronary heart disease, heart failure, and atrial fibrillation. Conclusions The two most likely explanations for our results are that: (i) an increasing NT-proBNP level reflects increasing subclinical volume overload and potentially increased venous stasis or subclinical PE that had gone unrecognized over time; or (ii) an increasing NT-proBNP level is a risk marker for impending cardiac disease that places patients at risk of VTE.

Intermuscular and perimuscular fat expansion in obesity correlates with skeletal muscle T cell and macrophage infiltration and insulin resistance.

BACKGROUND/OBJECTIVES: Limited numbers of studies demonstrated obesity-induced macrophage infiltration in skeletal muscle (SM), but dynamics of immune cell accumulation and contribution of T cells to SM insulin resistance are understudied. SUBJECTS/METHODS: T cells and macrophage markers were examined in SM of obese humans by reverse transcription-PCR (RT-PCR). Mice were fed high-fat diet (HFD) for 2-24 weeks, and time course of macrophage and T-cell accumulation was assessed by flow cytometry and quantitative RT-PCR. Extramyocellular adipose tissue (EMAT) was quantified by high-resolution micro-computed tomography (CT), and correlation to T-cell number in SM was examined. CD11a-/- mice and C57BL/6 mice were treated with CD11a-neutralizing antibody to determine the role of CD11a in T-cell accumulation in SM. To investigate the involvement of Janus kinase/signal transducer and activator of transcription (JAK/STAT), the major pathway for T helper I (TH1) cytokine interferon-γ, in SM and adipose tissue inflammation and insulin resistance, mice were treated with a JAK1/JAK2 inhibitor, baricitinib. RESULTS: Macrophage and T-cell markers were upregulated in SM of obese compared with lean humans. SM of obese mice had higher expression of inflammatory cytokines, with macrophages increasing by 2 weeks on HFD and T cells increasing by 8 weeks. The immune cells were localized in EMAT. Micro-CT revealed that EMAT expansion in obese mice correlated with T-cell infiltration and insulin resistance. Deficiency or neutralization of CD11a reduced T-cell accumulation in SM of obese mice. T cells polarized into a proinflammatory TH1 phenotype, with increased STAT1 phosphorylation in SM of obese mice. In vivo inhibition of JAK/STAT pathway with baricitinib reduced T-cell numbers and activation markers in SM and adipose tissue and improved insulin resistance in obese mice. CONCLUSIONS: Obesity-induced expansion of EMAT in SM was associated with accumulation and proinflammatory polarization of T cells, which may regulate SM metabolic functions through paracrine mechanisms. Obesity-associated SM 'adiposopathy' may thus have an important role in the development of insulin resistance and inflammation.

Metabolic syndrome risk for cardiovascular disease and diabetes in the ARIC study.

OBJECTIVE: The metabolic syndrome is associated with increased risk for cardiovascular disease and diabetes. Several analyses from the Atherosclerosis Risk in Communities (ARIC) study have been performed to examine the role of the metabolic syndrome and its components in predicting risk for cardiovascular disease and diabetes. DESIGN AND SUBJECTS: The large, biracial, population-based ARIC study enrolled 15792 middle-aged Americans in four communities in the United States and has followed them for the development of cardiovascular disease and diabetes. MEASUREMENTS: Outcome parameters included prevalence of the metabolic syndrome and its individual components, carotid intima-media thickness, incident coronary heart disease, incident ischemic stroke and incident diabetes. RESULTS AND CONCLUSION: Several analyses from the ARIC study have shown that the metabolic syndrome, as well as individual metabolic syndrome components, is predictive of the prevalence and incidence of coronary heart disease, ischemic stroke, carotid artery disease and diabetes.

Glutamic acid decarboxylase antibodies are indicators of the course, but not of the onset, of diabetes in middle-aged adults: the Atherosclerosis Risk in Communities Study.

To efficiently examine the association of glutamic acid decarboxylase antibody (GADA) positivity with the onset and progression of diabetes in middle-aged adults, we performed a case-cohort study representing the ~9-year experience of 10,275 Atherosclerosis Risk in Communities Study participants, initially aged 45-64 years. Antibodies to glutamic acid decarboxylase (GAD65) were measured by radioimmunoassay in 580 incident diabetes cases and 544 non-cases. The overall weighted prevalence of GADA positivity (>or=1 U/mL) was 7.3%. Baseline risk factors, with the exception of smoking and interleukin-6 (P or=2.38 U/mL) of positivity. GADA-positive and GADA-negative non-diabetic individuals had similar risk profiles for diabetes, with central obesity and elevated inflammation markers, aside from glucose, being the main predictors. Among diabetes cases at study's end, progression to insulin treatment increased monotonically as a function of baseline GADA level. Overall, being GADA positive increased risk of progression to insulin use almost 10 times (HR = 9.9; 95%CI = 3.4, 28.5). In conclusion, in initially non-diabetic middle-aged adults, GADA positivity did not increase diabetes risk, and the overall baseline profile of risk factors was similar for positive and negative individuals. Among middle-aged adults, with the possible exception of those with the highest GADA levels, autoimmune pathophysiology reflected by GADA may become clinically relevant only after diabetes onset.

Meta-analysis of the cholesterol-lowering effect of ezetimibe added to ongoing statin therapy.

OBJECTIVE: To review and analyse the evidence for the cholesterol-lowering effect of ezetimibe in adult patients with hypercholesterolaemia who are not at low-density lipoprotein cholesterol (LDL-C) goal on statin monotherapy. RESEARCH DESIGN: Systematic review and meta-analysis. METHODS: MEDLINE and EMBASE were searched to identify ezetimibe randomised controlled trials (RCTs) published between January 1993 and December 2005. The meta-analysis combined data from RCTs, with a minimum treatment duration of 6 weeks, that compared treatment with ezetimibe 10 mg/day or placebo added to current statin therapy. The difference between treatments was analysed for four co-primary outcomes: mean percentage change from baseline in total cholesterol (TC), LDL-C, and high-density lipoprotein cholesterol (HDL-C), and number of patients achieving LDL-C treatment goal. Meta-analysis results are presented for a modified version of the inverse variance random effects model. RESULTS: Five RCTs involving a total of 5039 patients were included in the meta-analysis. The weighted mean difference (WMD) between treatments significantly favoured the ezetimibe/statin combination over placebo/statin for TC (-16.1% (-17.3, -14.8); p < 0.0001), LDL-C (-23.6% (-25.6, -21.7); p < 0.0001) and HDL-C (1.7% (0.9, 2.5); p < 0.0001). The relative risk of reaching the LDL-C treatment goal was significantly higher for patients on ezetimibe/statin relative to those on placebo/statin (3.4 (2.0, 5.6); p < 0.0001). In pre-defined sub-group analyses of studies in patients with coronary heart disease, the WMD between treatments remained significantly in favour of ezetimibe/statin (p < 0.0001) for TC and LDL-C but was no longer significant for HDL-C. Elevations in creatine kinase, alanine aminotransferase or aspartate aminotransferase that were considered as an adverse effect did not differ significantly between treatments. CONCLUSIONS: The meta-analysis we performed included only five studies and was restricted to analysis of the changes in cholesterol levels relative to baseline. However, the results suggest that ezetimibe co-administered with ongoing statin therapy provides significant additional lipid-lowering in patients not at LDL-C goal on statin therapy alone, allowing more patients to reach their LDL-C goal.

Glutamic acid decarboxylase antibodies are indicators of the course, but not of the onset, of diabetes in middle-aged adults: the Atherosclerosis Risk in Communities Study

To efficiently examine the association of glutamic acid decarboxylase antibody (GADA) positivity with the onset and progression of diabetes in middle-aged adults, we performed a case-cohort study representing the ~9-year experience of 10,275 Atherosclerosis Risk in Communities Study participants, initially aged 45-64 years. Antibodies to glutamic acid decarboxylase (GAD65) were measured by radioimmunoassay in 580 incident diabetes cases and 544 non-cases. The overall weighted prevalence of GADA positivity (³1 U/mL) was 7.3 percent. Baseline risk factors, with the exception of smoking and interleukin-6 (P ú 0.02), were generally similar between GADA-positive and -negative individuals. GADA positivity did not predict incident diabetes in multiply adjusted (HR = 1.04; 95 percentCI = 0.55, 1.96) proportional hazard analyses. However, a small non-significant adjusted risk (HR = 1.29; 95 percentCI = 0.58, 2.88) was seen for those in the highest tertile (³2.38 U/mL) of positivity. GADA-positive and GADA-negative non-diabetic individuals had similar risk profiles for diabetes, with central obesity and elevated inflammation markers, aside from glucose, being the main predictors. Among diabetes cases at study's end, progression to insulin treatment increased monotonically as a function of baseline GADA level. Overall, being GADA positive increased risk of progression to insulin use almost 10 times (HR = 9.9; 95 percentCI = 3.4, 28.5). In conclusion, in initially non-diabetic middle-aged adults, GADA positivity did not increase diabetes risk, and the overall baseline profile of risk factors was similar for positive and negative individuals. Among middle-aged adults, with the possible exception of those with the highest GADA levels, autoimmune pathophysiology reflected by GADA may become clinically relevant only after diabetes onset.

Genetic variation and decreased risk for obesity in the Atherosclerosis Risk in Communities Study.

AIM: To investigate the effects of variation in the leptin [LEP (19A>G)] and melanocortin-4 receptor [MC4R (V103I)] genes on obesity-related traits in 13 405 African-American (AA) and white participants from the Atherosclerosis Risk in Communities (ARIC) Study. METHODS: We tested the association between the single-locus and multilocus genotypes and obesity-related measures [body mass index (BMI), body weight (BW), waist-hip ratio, waist circumference and leptin levels], adjusted for age, physical activity level, smoking status, diabetic status, prevalence of coronary heart disease, hypertension, stroke or transient ischaemic attack. RESULTS: AA and white female carriers of the MC4R I103 allele exhibited significantly lower BW than non-carriers of this allele (p < 0.05 and p < 0.01 respectively). AA female carriers of both the LEP A19 allele and the MC4R I103 allele were 63% [odds ratio (OR) = 0.37, 95% confidence interval (CI) (0.18-0.78)] less likely to be obese, and white female carriers of the same two alleles were 46% [OR = 0.54, 95% CI (0.32-0.91)] less likely to be obese, than non-carriers of the variant alleles. Female carriers of both the LEP A19 and MC4R I103 alleles had significantly lower BW (p < 0.05), BMI (p < 0.05) and plasma leptin (p < 0.01) than the non-carriers of both the alleles. Carriers of the two variant alleles had lower BMI over the 9-year course of the ARIC study and significantly lower weight gain from age 25 years. No significant joint effect of these two variants was observed in males. CONCLUSION: These results suggest that variation within the LEP and MC4R genes is associated with reduced risk for obesity in females.

Circulating oxidised low-density lipoprotein and intercellular adhesion molecule-1 and risk of type 2 diabetes mellitus: the Atherosclerosis Risk in Communities Study.

AIMS/HYPOTHESIS: To evaluate the role of oxidative stress and inflammation in the aetiology of type 2 diabetes, we examined the association of oxidised LDL (ox-LDL) and soluble intercellular adhesion molecule-1 (sICAM-1) levels with type 2 diabetes incidence over 9 years in the Atherosclerosis Risk in Communities Study. MATERIALS AND METHODS: In a large, prospective, case-cohort design, ox-LDL and sICAM-1 were measured in stored plasma samples collected at baseline in stratified samples of 581 diabetes cases and 572 non-cases selected from 10,275 middle-aged men and women without prevalent diabetes at baseline. RESULTS: Compared with non-cases, diabetes cases had significantly higher mean baseline levels of ox-LDL and sICAM-1. Elevated ox-LDL and sICAM-1 were both associated with increased risk of incident diabetes after adjustment for age, sex, race and centre, with hazard ratios for the highest vs lowest tertiles of 1.68 (95% CI 1.25-2.24) and 1.91 (95% CI 1.45-2.50), respectively. After additional adjustment for fasting glucose, waist circumference, HDL-cholesterol, triacylglycerol, hypertension and C-reactive protein, only sICAM-1 remained an independent predictor of incident diabetes (hazard ratio 1.50; 95% CI 1.02-2.23). CONCLUSIONS/INTERPRETATION: In this community-based cohort of middle-aged US adults, elevated plasma ox-LDL and sICAM-1 levels were associated with increased risk of type 2 diabetes. Measurement of ICAM-1 or ox-LDL, or other measures related to inflammation or oxidative stress, may be helpful in identifying those patient populations in which to test whether novel therapies that inhibit specific pathways related to inflammation or oxidative stress are beneficial in the prevention of diabetes in humans.

Leptin and incident type 2 diabetes: risk or protection?

AIMS/HYPOTHESIS: The aim of this study was to investigate the association of leptin levels with incident diabetes in middle-aged adults, taking into account factors purportedly related to leptin resistance. SUBJECTS AND METHODS: We conducted a case-cohort study (570 incident diabetes cases and 530 non-cases) representing the 9-year experience of 10,275 participants of the Atherosclerosis Risk in Communities Study. Plasma leptin was measured by direct sandwich ELISA. RESULTS: In proportional hazards models adjusting for age, study centre, ethnicity and sex, high leptin levels (defined by sex-specific cut-off points) predicted an increased risk of diabetes, with a hazard ratio (HR) comparing the upper with the lower quartile of 3.9 (95% CI 2.6-5.6). However, after further adjusting additionally for obesity indices, fasting insulin, inflammation score, hypertension, triglycerides and adiponectin, high leptin predicted a lower diabetes risk (HR=0.40, 95% CI 0.23-0.67). Additional inclusion of fasting glucose attenuated this protective association (HR=0.59, 95% CI 0.32-1.08, p<0.03 for linear trend across quartiles). In similar models, protective associations were generally seen across subgroups of sex, race, nutritional status and smoking, though not among those with lower inflammation scores or impaired fasting glucose (interaction p=0.03 for both). CONCLUSIONS/INTERPRETATION: High leptin levels, probably reflecting leptin resistance, predict an increased risk of diabetes. Adjusting for factors purportedly related to leptin resistance unveils a protective association, independent of adiponectin and consistent with some of leptin's described protective effects against diabetes.

Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel.

There is abundant evidence that the risk of atherosclerotic vascular disease is directly related to plasma cholesterol levels. Accordingly, all of the national and transnational screening and therapeutic guidelines are based on total or LDL cholesterol. This presumes that cholesterol is the most important lipoprotein-related proatherogenic risk variable. On the contrary, risk appears to be more directly related to the number of circulating atherogenic particles that contact and enter the arterial wall than to the measured concentration of cholesterol in these lipoprotein fractions. Each of the atherogenic lipoprotein particles contains a single molecule of apolipoprotein (apo) B and therefore the concentration of apo B provides a direct measure of the number of circulating atherogenic lipoproteins. Evidence from fundamental, epidemiological and clinical trial studies indicates that apo B is superior to any of the cholesterol indices to recognize those at increased risk of vascular disease and to judge the adequacy of lipid-lowering therapy. On the basis of this evidence, we believe that apo B should be included in all guidelines as an indicator of cardiovascular risk. In addition, the present target adopted by the Canadian guideline groups of an apo B <90 mg dL(-1) in high-risk patients should be reassessed in the light of the new clinical trial results and a new ultra-low target of <80 mg dL(-1) be considered. The evidence also indicates that the apo B/apo A-I ratio is superior to any of the conventional cholesterol ratios in patients without symptomatic vascular disease or diabetes to evaluate the lipoprotein-related risk of vascular disease.

Efficacy and safety of ezetimibe coadministered with statins: randomised, placebo-controlled, blinded experience in 2382 patients with primary hypercholesterolemia.

We assessed pooled safety and lipid-regulating efficacy data from four similarly designed trials of ezetimibe coadministered with statins in 2382 patients with primary hypercholesterolemia. Patients were randomised to one of the following double-blind treatments for 12 weeks: placebo; ezetimibe 10 mg; statin; or statin + ezetimibe. Statin doses tested were 10, 20, 40 mg/day (atorvastatin, simvastatin, pravastatin or lovastatin) or 80 mg/day (atorvastatin, simvastatin). Treatment with ezetimibe + statin led to significantly greater reductions in low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B and increases in HDL-C, compared to statin alone. At each statin dose, treatment with ezetimibe + statin led to a greater LDL-C reduction compared to the next highest statin monotherapy dose. Ezetimibe + statin had a safety profile similar to statin monotherapy. Coadministration of ezetimibe + statin offers a well-tolerated, highly efficacious new treatment strategy for patients with hypercholesterolemia.

Long-term safety and tolerability profile of ezetimibe and atorvastatin coadministration therapy in patients with primary hypercholesterolaemia.

Long-term safety and tolerability of ezetimibe plus atorvastatin (EZE + ATV) coadministration therapy were compared to those of ATV monotherapy in patients with primary hypercholesterolaemia. Upon completion of a 12 week randomised, double-blind, placebo-controlled study comparing EZE 10 mg; ATV 10, 20, 40 or 80 mg; EZE + ATV 10, 20, 40 or 80 mg or placebo, 246 patients were enrolled in a 12-month extension, with reassignment to double-blind EZE 10 mg (n = 201) or matching placebo (n = 45) coadministered daily with open-label ATV 10 mg. At intervals of 6 weeks, patients not at National Cholesterol Education Program Adult Treatment Panel II LDL-C goals were titrated to the next higher ATV dose. Safety evaluations included adverse event (AE) reports and laboratory test results. EZE + ATV and ATV monotherapy groups were similar with regard to incidence of all AEs (71 vs. 67%), treatment-related AEs (22 vs. 27%) and discontinuations due to AEs (9 vs. 7%) or treatment-related AEs (6 vs. 7%), respectively. Neither clinically significant elevations in hepatic transaminases or creatine kinase nor any cases of myopathy or rhabdomyolysis were observed in either group during the extension study. After 6 weeks, EZE + ATV 10mg produced greater reductions in low-density lipoprotein cholesterol (LDL-C; -53 vs. -37%), total cholesterol (TC; -38.8 vs. -26.0%) and triglycerides (TG; -28 vs. -12%) and similar increases in high-density lipoprotein cholesterol (4.6 vs. 4.5%) compared to ATV 10 mg, respectively, and these changes were maintained and significant at 1 year (p < 0.01 for LDL-C, TC and TG). More EZE + ATV patients achieved LDL-C goal than ATV patients at study endpoint (91 vs. 78%, respectively; p = 0.02). Thus, the coadministration of EZE + ATV for 12 months was well tolerated and more efficacious than ATV monotherapy.

Characteristics of US adults with the metabolic syndrome and therapeutic implications.

BACKGROUND: The third Adult Treatment Panel (ATP III) of the National Cholesterol Education Program defines clinical criteria for diagnosis of the metabolic syndrome, which increases cardiovascular risk and is a target for therapy. AIM: We analysed the third National Health and Nutrition Examination Survey (NHANES III; 1988-94) to determine how many US adults meet these criteria and are recommended for lipid-modifying drug therapy by ATP III. METHODS: NHANES III data were used to estimate the number of individuals with the metabolic syndrome and the number recommended for treatment by ATP III, based on 1990 census data. RESULTS: An estimated 36.3 million (23%) US adults have the metabolic syndrome. Of these, 84% met the criterion for obesity, 76% for blood pressure, 75% for HDL-C, 74% for triglycerides and 41% for glucose. Most (54%) are in the higher risk categories of ATP III, yet only 39% overall are recommended for drug therapy by ATP III cutpoints; of these, most will achieve LDL-C targets with reductions of 35-40%. Of the 15.3 million individuals with the metabolic syndrome and triglycerides > or = 2.26 mmol/l (200 mg/dl), non-HDL-C is above ATP III recommendations in 11.6 million. CONCLUSIONS: Of the large number of Americans with the metabolic syndrome, ATP III recommends drug therapy for only a minority, because LDL-C typically is not substantially elevated. Instead, high triglycerides and low HDL-C are more common; clinical trial data are needed to determine whether optimal therapy should focus on reductions in LDL-C or on comprehensive improvements to the lipid profile.

Impact of weight loss on the metabolic syndrome.

AIM: Individuals with the metabolic syndrome (MS), a clustering of risk factors [triglycerides, glucose, high-density lipoprotein cholesterol, blood pressure (BP), abdominal obesity] defined by the National Cholesterol Education Program (NCEP), are at high risk for coronary heart disease and type 2 diabetes mellitus, and may benefit from aggressive lifestyle modification. METHODS: We reviewed 1 year of consecutive patients' charts to determine the prevalence of the MS in obese individuals enrolled in a medically supervised rapid weight loss programme, the correlation of weight change with the components of the MS, and response to diet-induced weight loss. RESULTS: Out of 185 individuals, 125 (68%) met the NCEP definition of the MS. A moderate decrease in weight (6.5%) induced by a very low calorie diet (VLCD) resulted in substantial reductions of systolic (11.1 mmHg) and diastolic (5.8 mmHg) blood pressure (BP), glucose (17 mg/dl), triglycerides (94 mg/dl) and total cholesterol (37 mg/dl) at 4 weeks (all p < 0.001). These improvements were sustained at the end of active weight loss (average 16.7 weeks; total weight loss 15.1%), with further significant reductions in BP and triglycerides. Weight loss was related to the changes in each criterion of the metabolic syndrome. CONCLUSIONS: The MS is prevalent in two-thirds of obese individuals enrolling in a structured weight loss programme. Moderate weight loss with a VLCD markedly improved all aspects of the MS.

Familial hypercholesterolaemia: optimum treatment strategies.

Familial hypercholesterolaemia (FH) is a hereditary metabolic disorder characterised by defects in the low-density lipoprotein (LDL) receptor, elevated LDL cholesterol (LDL-C) levels and an extremely high risk for premature cardiovascular disease. Heterozygous FH occurs in about one of every 500 individuals in the United States and Europe. The high prevalence of FH and associated morbidity and mortality strongly support aggressive screening and treatment. There are two major barriers to effective management of FH: 1) the failure to screen for this disease in people who may be at increased risk for it; and 2) the inability of most available therapies to enable achievement of LDL-C goals. More aggressive screening, coupled with new genetic screening techniques, and more powerful 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have the potential to overcome these limitations. Automated genetic assays are now available for detection of common LDL receptor mutations in individuals at risk for FH, and they have been used effectively to identify patients with this condition. Recent clinical trial results with the new synthetic statin rosuvastatin (Crestor; AstraZeneca, Alderley Park, Macclesfield, Cheshire, UK; licensed from Shionogi & Co, Ltd, Osaka, Japan) in patients with heterozygous FH have shown that it decreased LDL-C by 58% and increased high-density lipoprotein cholesterol (HDL-C) by 12%. Rosuvastatin was significantly superior to high-dose atorvastatin in improving these lipid parameters as well as total cholesterol, apolipoprotein (apo) B, apo A-I, and the LDL-C/HDL-C ratio. Thus, new screening tools and medical therapies have the potential to significantly improve management and reduce cardiovascular disease risk for patients with FH.

Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S.

BACKGROUND: Patients with low HDL cholesterol (HDL-C) and elevated triglyceride had an increased risk for coronary heart disease (CHD) events and received the greatest benefit with fibrate therapy in substudy analyses of the Helsinki Heart Study and the Bezafibrate Infarction Prevention Study. METHODS AND RESULTS: In this post hoc analysis of the Scandinavian Simvastatin Survival Study, which enrolled patients with elevated LDL cholesterol (LDL-C) and CHD, subgroups defined by HDL-C and triglyceride quartiles were compared to examine the influence of HDL-C and triglyceride on CHD events and response to therapy. Patients in the lowest HDL-C (<1.00 mmol/L [39 mg/dL]) and highest triglyceride (>1.80 mmol/L [159 mg/dL]) quartiles (lipid triad; n=458) had increased proportions of other features of the metabolic syndrome (increased body mass index, hypertension, diabetes), men, prior myocardial infarction, prior revascularization, and beta-blocker use than patients in the highest HDL-C (>1.34 mmol/L [52 mg/dL]) and lowest triglyceride (<1.11 mmol/L [98 mg/dL]) quartiles (isolated LDL-C elevation; n=545). The major coronary event rate was highest in lipid triad patients on placebo (35.9%), and this subgroup had the greatest event reduction (relative risk 0.48, 95% CI 0.33 to 0.69); a significant treatment-by-subgroup interaction (P=0.03) indicated a greater treatment effect in the lipid triad subgroup than the isolated LDL-C elevation subgroup. CONCLUSIONS: Patients with elevated LDL-C, low HDL-C, and elevated triglycerides were more likely than patients with isolated LDL-C elevation to have other characteristics of the metabolic syndrome, had increased risk for CHD events on placebo, and received greater benefit with simvastatin therapy.

Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients.

BACKGROUND: Sirolimus (Rapamune, rapamycin, RAPA) is a potent immunosuppressive drug that has reduced the rate of acute rejection episodes by more than 40% in phase III trials when added to an immunosuppression regimen of cyclosporine (CsA) and prednisone. However, RAPA treatment tends to increase lipid levels, particularly among patients with pre-existing hyperlipidemia. METHODS: To identify the metabolic pathway(s) leading to RAPA-mediated hyperlipidemia, five patients with renal transplants maintained on CsA+/-prednisone+/- azathioprine (AZA) were studied before and after 6 weeks of treatment with RAPA (off RAPA and on RAPA, respectively). Each study patient was infused with a single bolus of [2H4]-lysine to derive metabolic parameters for apoB100-containing lipoproteins by using kinetic analysis based upon quantitation of isotopic enrichment by gas chromatography-mass spectrometry. RESULTS: Serial lipid measurements revealed that four patients displayed increased plasma triglyceride levels after RAPA treatment, which coincided with significantly higher plasma VLDL-apoB100 concentrations (21.7+/-12.1 mg/dl off RAPA vs. 38.7+/-14.8 mg/dl on RAPA, mean+/-SD, P<0.05). Kinetic analysis showed that the RAPA-induced increase in VLDL-apoB100 concentrations was due to a significant reduction in the fractional catabolic rate (FCR) of very low-density lipoprotein (VLDL) apoB100 (0.83+/-0.65 off RAPA vs. 0.24+/-0.10 on RAPA, mean+/-SD, P<0.05), rather than an enhanced VLDL-apoB100 synthesis. In one patient, RAPA treatment induced hypercholesterolemia but not hypertriglyceridemia. This hypercholesterolemia was due to elevated low-density lipoprotein (LDL) cholesterol levels, which coincided with a decreased FCR of LDL-apoB100. Heparin-induced lipoprotein lipase activity was significantly lower in the immunosuppressed hyperlipidemic patients than in normolipidemic controls. However, RAPA treatment did not significantly alter basal lipoprotein lipase activity in renal transplant patients in this study. CONCLUSIONS: This study indicates that for renal transplant patients in whom RAPA treatment induces hyperlipidemia, this effect is the result of reduced catabolism of apoB100-containing lipoproteins.

Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Despite consensus on the need for blood cholesterol reductions to prevent coronary heart disease (CHD), available evidence on optimal cholesterol levels or the added predictive value of additional lipids is sparse. METHODS AND RESULTS: After 10 years follow-up of 12 339 middle-aged participants free of CHD in the Atherosclerosis Risk in Communities Study (ARIC), 725 CHD events occurred. The lowest incidence was observed in those at the lowest LDL cholesterol (LDL-C) quintile, with medians of 88 mg/dL in women and 95 mg/dL in men, and risk accelerated at higher levels, with relative risks (RRs) for the highest quintile of 2.7 in women and 2.5 in men. LDL-C, HDL-C, lipoprotein(a) [Lp(a)], and in women but not men, triglycerides (TG) were all independent CHD predictors, providing an RR, together with blood pressure, smoking, and diabetes, of 13.5 in women and 4.9 in men. Lp(a) was less significant in blacks than whites. Prediction was not enhanced by HDL-C density subfractions or apolipoproteins (apo) A-I or B. Despite strong univariate associations, apoB did not contribute to risk prediction in subgroups with elevated TG, with lower LDL-C, or with high apoB relative to LDL-C. CONCLUSIONS: Optimal LDL-C values are <100 mg/dL in both women and men. LDL-C, HDL-C, TG, and Lp(a), without additional apolipoproteins or lipid subfractions, provide substantial CHD prediction, with much higher RR in women than men.

Achieving and maintaining National Cholesterol Education Program low-density lipoprotein cholesterol goals with five statins.

PURPOSE: Most patients fail to achieve and maintain low-density lipoprotein (LDL) cholesterol goals established by the National Cholesterol Education Program (NCEP). The Atorvastatin Comparative Cholesterol Efficacy and Safety Study (ACCESS) was a randomized study comparing the efficacy and safety of five statins and their ability reduce LDL cholesterol to the NCEP target level. SUBJECTS AND METHODS: Of 7542 patients screened, 3916 hypercholesterolemic patients were randomly assigned to treatment with a statin, beginning with the lowest recommended dose (atorvastatin, pravastatin, and simvastatin, 10 mg; fluvastatin and lovastatin, 20 mg). If the NCEP target was not achieved, the dose was titrated up to the recommended maximum (atorvastatin, fluvastatin, and lovastatin, 80 mg; pravastatin and simvastatin, 40 mg). The total duration of treatment was 54 weeks. RESULTS: Atorvastatin achieved the greatest mean reduction in LDL cholesterol: 36% +/- 11% at 6 weeks (initial dose) and 42% +/- 13% at 54 weeks. More patients receiving atorvastatin at its initial dose (53%, 997 of 1888) achieved their NCEP target levels than patients receiving simvastatin (38%, 174 of 462), lovastatin (28%, 134 of 472), pravastatin (15%, 71 of 461), or fluvastatin (15%, 69 of 474) at the initial dose. Atorvastatin-treated patients were more likely to maintain their target levels from week 6 to week 54. The percent reduction in LDL cholesterol achieved at the initial dose correlated strongly with the proportion of patients who maintained their goals at 54 weeks (r = -0.84). CONCLUSION: For patients treated with statins, providing a greater margin between the NCEP target level and the achieved LDL cholesterol level enhances the likelihood of maintaining NCEP goal levels.