Clinical Chemistry journal has contributed to progress in lipid and lipoprotein testing for fifty years.
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Chemistry, Clinical↗
Biomedical subjects
W Virgil Brown
Publications and source records attributed to W Virgil Brown.
Relationship between arterial stiffness and subclinical aortic atherosclerosis.
BACKGROUND: Noninvasive measures of arterial compliance may be useful for the detection of subclinical atherosclerosis. METHODS AND RESULTS: Measures of calf and thigh arterial compliance (MaxV50) were recorded in 267 subjects who also underwent MRI of the distal aorta to quantify distal aorta atherosclerosis. The average of calf and thigh MaxV50 was strongly predictive of extent of aortic atherosclerosis and risk of being in the top quartile of aortic atherosclerosis after adjustment for the Framingham Coronary Risk Score (FCRS) or the combination of the FCRS and C-reactive protein (P<0.0001). The areas under the receiver operating curves predicting the top quartile of gender-specific aortic atherosclerosis were 0.57, 0.60, and 0.75 for models containing the FCRS, the FCRS and C-reactive protein, and the FCRS, C-reactive protein, and the average of calf and thigh MaxV50. CONCLUSIONS: Lower-extremity arterial compliance may identify subjects with extensive subclinical atherosclerosis. Further studies examining the potential value of arterial stiffness as a screening tool to guide initiation of more aggressive preventive interventions are warranted.
Adult↗
Polyunsaturated fatty acids acutely suppress antibodies to malondialdehyde-modified lipoproteins in patients with vascular disease.
Antibodies to malondialdehyde (MDA)-modified low-density lipoprotein (LDL) are transiently reduced during the postprandial period in patients with atherosclerotic heart disease. Previous experiments using mixed meals high in fat have found reductions of approximately 20% within 2 hours. This study was designed to reveal if this phenomenon was due uniquely to saturated fats. Using a standardized immunoassay for the detection of circulating levels of autoantibodies (AAbs) against MDA-modified LDL, we examined the acute changes in AAb levels during 6 hours of postprandial lipemia in 10 men with known atherosclerotic heart disease. Each subject was given 4 meals 1 week apart. Three of the meals differed in content of saturated fat, monounsaturated fat, and polyunsaturated fat. A fat-free meal with equivalent carbohydrate and equivalent protein was also administered. The study was double blinded and the meals were administered in random order. Only the meal enriched with polyunsaturated fatty acids caused the reduction in antibodies to MDA-LDL. This decrease was statistically significant from baseline at 1 hour (p <0.05), 2 hours (p <0.004), and 3 hours (p <0.02), with the nadir occurring at 2 hours. Polyunsaturated fatty acids are the major stimulus for causing a reduction in the AAbs to MDA-LDL during postprandial lipemia. These results strongly suggest that fat in chylomicrons may be a major source of oxidized lipids in the blood of patients with arteriosclerosis.
Aged↗
Apolipoprotein C-III protein concentrations and gene polymorphisms in type 1 diabetes: associations with lipoprotein subclasses.
Serum apolipoprotein C-III (apoCIII) concentration and apoCIII gene polymorphisms have been shown to be a risk factor for cardiovascular disease; however, the underlying mechanisms remain unclear. In addition, no studies have been performed that address these issues in type 1 diabetes. The current study investigated apoCIII protein and apoCIII gene variation in a normotriglyceridemic (82 +/- 57 mg/dL) population of patients with type 1 diabetes, the Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications (DCCT/EDIC) cohort. Blood samples were obtained in 409 patients after an overnight fast. Serum apoCIII concentration was highly correlated with multiple changes in lipids and lipoproteins that resulted in an adverse cardiovascular disease risk profile. Higher apoCIII concentrations were associated (P < .0001) with increased triglycerides (r = 0.78), total (r = 0.61) and low-density lipoprotein (LDL) (r = 0.40) cholesterol, apoA-I (r = 0.26), and apoB (r = 0.50), and these relationships persisted after controlling for age, gender, body mass index (BMI), and hemoglobin A1c (HbA1c). Nuclear magnetic resonance (NMR) lipoprotein subclass analyses demonstrated that apoCIII was correlated with an increase in very-low-density lipoprotein (VLDL) subclasses (P = .0001). There also was a highly significant positive relationship between serum apoCIII concentration and the LDL particle concentration in both men (r = 0.49, P = .001) and women (r = 0.40, P = .001), and a highly significant negative relationship between serum apoCIII levels and average LDL particle size in both men (r = -0.37, P = .001) and women (r = -0.22, P = .001) due primarily to an augmentation in the small L1 subclass (r = 0.42, P = .0001). Neither the T(-455) --> C polymorphism affecting an insulin response element in the apoCIII gene promoter nor a SacI polymorphism in the 3'UTR were associated with any alterations in circulating apoCIII concentrations, serum lipids, apolipoprotein concentrations, lipoprotein composition, or parameters measured by NMR lipoprotein subclass analyses. In summary, elevated apoCIII concentration was associated with risk factors for cardiovascular disease in normolipidemic type 1 diabetic patients through associated changes in lipoprotein subfraction distributions, which were independent of apoCIII genotype.
3' Untranslated Regions↗
Study of lipid and apolipoprotein binding interactions using vesicle affinity capillary electrophoresis.
Vesicle affinity capillary electrophoresis (VCE), a newly developed technique, was designed to assess the effect of physicochemical properties of apolipoprotein (apo) on the binding to lipoproteins, under physiological conditions (phosphate-saline buffer system at pH 7.4 and 37 degrees C), using vesicle as a model. The technique results in similar lipid binding properties of apo CIII (CIII) and its peptides compared to other techniques. It also offers a fast and more sensitive tool in determining the lipid affinity of apos in a unique system simulating the dynamic binding properties of apo in vivo. A noncompetitive binding model is used to determine the multiple binding properties of CIII and its peptides to vesicle. The VCE binding constants are dependent on temperature, physicochemical properties of the protein (hydrophobicity and charge), and nature of the vesicle. The vesicles used in the VCE experiments described here have been fully characterized and found to be stable under different temperatures (4 and 37 degrees C) and voltage conditions. Migration behavior of CIII and related peptides is reported in terms of relative mobility in order to correct for variability in viscosity at different vesicle concentrations. The VCE method provides very precise data on the migration time from 0.1 to 3.3% RSD at the highest concentration of vesicle. The model and current data have been used to determine VCE binding constants and protein-to-lipid binding ratios. The model predicts that higher lipid affinity (K(B)), protein-lipid binding ratio (n), and lower protein concentration result in a shift of the binding isotherm toward a lower concentration range of vesicle. A higher vesicle mobility, reflecting the size and charge of the vesicle, results in a larger separation window between the migration time of the free protein and the complex. The value of VCE for structure-function studies and drug design for peptides and proteins that are strongly bound to lipids has been illustrated.
Apolipoproteins↗
Efficacy of rosuvastatin compared with other statins at selected starting doses in hypercholesterolemic patients and in special population groups.
A total of 5 randomized, double-blind trials in patients with hypercholesterolemia were prospectively designed to allow pooling of plasma lipid data after 12 weeks of treatment. The purpose was (1) to compare rosuvastatin 5 and 10 mg with atorvastatin 10 mg (data from 3 of the 5 trials); (2) to compare rosuvastatin 5 and 10 mg with simvastatin 20 mg and pravastatin 20 mg (data from 2 of the 5 trials); and (3) to summarize overall efficacy and subset analyses of rosuvastatin data from all 5 trials. Rosuvastatin 5 mg (n = 390) and 10 mg (n = 389) reduced low-density lipoprotein (LDL) cholesterol significantly more than did atorvastatin 10 mg (n = 393) (41.9% and 46.7% vs 36.4%, both p <0.001). Treatment with rosuvastatin 5 mg (n = 240) and 10 mg (n = 226) also resulted in significantly greater reductions in LDL cholesterol compared with both simvastatin 20 mg (n = 249) and pravastatin 20 mg (n = 252) (40.6% and 48.1% vs 27.1% and 35.7%, all p <0.001). Significant differences favoring rosuvastatin 10 mg were also observed for total cholesterol, high-density lipoprotein (HDL) cholesterol, non-HDL cholesterol, apolipoprotein (apo) B, and apo A-I versus atorvastatin 10 mg, and for total cholesterol, HDL cholesterol, triglycerides, non-HDL cholesterol, and apo B versus simvastatin 20 mg and pravastatin 20 mg. Analyses of all the rosuvastatin 10 mg data (n = 615) from the 5 trials in subgroups defined by age > or =65 years, female sex, postmenopausal status, hypertension, atherosclerosis, type 2 diabetes, and obesity showed that rosuvastatin had consistent efficacy across patient subgroups.
Adult↗
Importance of high-density lipoprotein cholesterol and triglyceride levels in coronary heart disease.
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Biomarkers↗
Cholesterol absorption inhibitors: defining new options in lipid management.
Although many studies have documented that reduction of plasma cholesterol levels decreases the risk of coronary artery disease, it remains the most common cause of death in the Western world. Current therapeutic options are effective in lowering cholesterol, especially in clinical trials, but clinical application is not optimized for many reasons. Dietary restriction for long-term management of hypercholesterolemia is helpful but usually insufficient to reduce low-density lipoprotein cholesterol (LDL-C) to goal levels. Powerful drugs are available, but these are often insufficient to meet the clinical demands for cholesterol-lowering therapy. Phytosterols and phytostanols have been partially effective by providing some inhibition of absorption of cholesterol. Compounds that specifically and more effectively block intestinal absorption of dietary and biliary cholesterol should provide a significant new agent for altering lipoprotein concentrations favorably. Ezetimibe is the first of this class of compounds that act at the gut epithelium to reduce cholesterol absorption in the milligram dose range markedly. Clinical studies indicate that ezetimibe effectively decreases LDL-C by 15 to 20% as monotherapy, with a favorable safety profile. Moreover, results from preliminary clinical trials indicate that ezetimibe given concomitantly with a statin provides additive efficacy. The combination represents a new approach to lipid management, achieving greater LDL-C and triglyceride reductions and greater improvements in HDL-C than statin monotherapy. This could offer another important option in clinical practice for management of hypercholesterolemic patients.
Anticholesteremic Agents↗
Reaching goal: conquering the treatment gaps in dyslipidemia management.
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Cholesterol, LDL↗
Benefits of statin therapy in patients with special risks: coronary bypass surgery, stable coronary disease, and acute coronary syndromes.
Several major clinical studies have examined the impact of lipid lowering in patients with and without coronary heart disease and have demonstrated that lowering lipid levels can successfully and significantly delay the onset of cardiovascular events. Although epidemiologic studies and small clinical trials have suggested that more aggressive and sustained lowering of low-density lipoprotein cholesterol (LDL-C) to < 100 mg/dl (2.6 mmol/l) can result in reductions in cardiovascular events in these populations, reducing LDL-C to these concentrations has only recently been shown in larger clinical trials. However, few clinical trials have been conducted in patients with certain special high risks, such as those who have had a recent revascularization procedure or have experienced an acute coronary event. Three trials examined the short- and long-term clinical benefits of aggressive lipid lowering in patients who underwent coronary artery bypass surgery (Post-CABG), were candidates for angioplasty (AVERT), or were hospitalized for acute coronary syndromes (MIRACL).
Acute Disease↗
Arterial compliance adds to conventional risk factors for prediction of angiographic coronary artery disease.
BACKGROUND: Arterial compliance is related to left ventricular hypertrophy and risk for cardiovascular disease events; however, its association with coronary artery stenosis remains uncertain. We sought to assess the relation between lower extremity arterial compliance and presence of angiographically defined coronary artery disease. METHODS: Lower extremity arterial compliance was measured with the use of a noninvasive air plethysmography technique in 376 subjects undergoing routine diagnostic coronary angiography. RESULTS: Measures of calf arterial compliance were significantly associated with the presence of one or more stenoses > or =50% compared with no stenoses, even after adjustment for age, sex, smoking, diabetes, hypertension, hypercholesterolemia, and obesity (P =.03). Measures of thigh arterial compliance were also lower in subjects with disease, although this association did not reach statistical significance (P =.07). Receiver operator curves illustrate the incremental predictive ability of calf arterial compliance over and above age, sex, and conventional risk factors. CONCLUSIONS: Lower extremity arterial compliance is associated with presence of significant coronary stenoses in a cardiac catheterization laboratory referral population. This observation lends support for additional efforts to determine the utility of vascular stiffness measures in both clinical and pre-clinical populations to guide treatment and prevention efforts.
Adult↗
Ezetimibe.
Ezetimibe is the first of a new class of drugs that specifically reduces the intestinal absorption of cholesterol. The drug is absorbed into the intestinal epithelial cell and remains associated in great part with the apical cell membrane where it is believed to interfere with the putative sterol transporter system. This apparently prevents both free cholesterol and plant sterols (phytosterols) from being transported into the cell from the intestinal lumen. The mechanism is very different from the reduction produced by phytosterol esters and phytostanol esters that have been documented previously as interfering with the micellar presentation of sterols to the cell surface. The drug is rapidly absorbed and glucuronidated in the intestinal cell before secretion into the blood. Ezetimibe is avidly taken up by the liver from the portal blood and excreted into the bile, resulting in low peripheral blood concentrations. The glucuronide conjugate is hydrolyzed and absorbed and is equally effective in inhibiting sterol absorption. This enterohepatic recycling is responsible for a half-life in the body of more than 20 h. The principle medical benefit appears to be a reduction in low-density lipoprotein cholesterol (LDLc). There is also a reduction in the cholesterol content of chylomicrons, which may provide some reduction in the atherogenic potential of the plasma lipoprotein pool. Triglycerides fall moderately and a modest rise in high-density lipoprotein cholesterol (HDLc) has been consistently observed in groups of treated patients. The maximum mean reduction of LDL cholesterol is approximately 20-25% in small studies at the maximal dose tested of 40 mg/day and the reduction is usually in the 16-20% range at the dosage of 10 mg/day. Most subsequent studies have been completed with the 10 mg/day dose. The medication is effective as a single daily dose due to its long residence time in the body. Combinations of ezetimibe with all available statins have been completed and demonstrate LDLc reductions of approximately 25% as additive effects to any statin dose alone. There are also small additional increases in HDL (2-3%) and reductions in triglycerides (10-15%). Additive effects to statin therapy have also been documented in patients with homozygous familial hypercholesterolemia. Reduction of plant sterols has been demonstrated in phytosterolemia, offering the first drug treatment for this rare inherited disease.
Anticholesteremic Agents↗
Efficacy and safety of rosuvastatin compared with pravastatin and simvastatin in patients with hypercholesterolemia: a randomized, double-blind, 52-week trial.
OBJECTIVE: The primary objective of this trial was to compare the efficacy of rosuvastatin with that of pravastatin and simvastatin for lowering low-density lipoprotein cholesterol (LDL-C) levels. METHODS: In this randomized, double-blind, multicenter trial, lipid levels were measured in 477 patients (baseline LDL-C > or =160 and <250 mg/dL) who received fixed doses of 5 mg of rosuvastatin, 10 mg of rosuvastatin, 20 mg of pravastatin, or 20 mg of simvastatin for 12 weeks. For an additional 40 weeks, individual daily doses were sequentially doubled to a maximum of 80 mg of rosuvastatin, 40 mg of pravastatin, and 80 mg of simvastatin, according to investigator discretion and if National Cholesterol Education Program Adult Treatment Panel II (ATP II) LDL-C goals were not achieved. RESULTS: At 12 weeks, percent LDL-C reductions after both 5-mg and 10-mg rosuvastatin treatment, which were 39.1% and 47.4%, respectively, were significantly different (P <.05) from LDL-C reductions after 20-mg pravastatin (26.5%) and 20-mg simvastatin (34.6%) treatment. After 52 weeks, more rosuvastatin-treated patients remained at their starting dose than did simvastatin or pravastatin patients. After dose titration, 88% and 87.5% of the rosuvastatin 5-mg and 10-mg groups, respectively, achieved their ATP II LDL-C goals, compared with 60% for pravastatin and 72.5% for simvastatin. All study treatments were well tolerated. CONCLUSION: Rosuvastatin reduced LDL-C levels more than pravastatin or simvastatin in patients with hypercholesterolemia in a 52-week dose-titration study.
Adult↗
Promising therapies for cholesterol reduction.
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Allylamine↗
Debate: "How low should LDL cholesterol be lowered for optimum prevention of vascular disease?" Viewpoint: "Below 100 mg/dl"
Arteriosclerotic vascular disease manifests as heart disease, stroke, aortic aneurysms, and peripheral vascular disease, and is a growing problem world-wide. The preventive efforts made so far have demonstrated that lowering LDL-C is one action that individuals and populations can do with significant success in delaying the onset of clinical events. Epidemiological studies and small clinical trials suggest that more aggressive and sustained lowering to LDL-C below 100 mg/dl could result in 50 to 70% reductions in vascular death. The full benefit of reducing LDL-C is only now being tested in adequate clinical trials.
Journal Article↗
Relationship of peripheral arterial compliance and standard cardiovascular risk factors.
Abnormalities of peripheral arterial compliance are clinically useful markers of atherosclerosis and risk of vascular events. Local peripheral arterial compliance can be easily and accurately assessed in the clinic by computer-controlled pulse volume recordings (air plethysmography). The purpose of this study was to investigate the relationship between clinical cardiovascular risk factors, a surrogate of atherosclerotic burden, and peripheral arterial compliance in the thigh and calf determined by quantification of local pulse volume recordings in patients undergoing coronary angiography. Peripheral arterial compliance in the thigh and calf was measured in 346 patients undergoing diagnostic cardiac catheterization at 4 centers. Demographic and cardiovascular risk factor data were collected, and their relationship to local arterial compliance examined using a new device that assesses maximal local arterial volume change in an extremity segment. Pulse volume recordings detected decreased local arterial compliance in the thigh associated with a history of hypertension (p < 0.0001), diabetes mellitus (p = 0.0001), and hyperlipidemia (p = 0.0007). In the calf, this arterial compliance measure was associated with a history of hypertension (p < 0.0001) and diabetes mellitus (p = 0.002). Females had lower arterial compliance than males in the thigh (p = 0.003) and calf (p < 0.0001). Limited evidence of lower arterial compliance in the thigh was found for those with obesity (p = 0.07). This procedure also demonstrated that subjects with multiple cardiovascular risk factors had lower arterial compliance in the thigh than subjects with no or 1 risk factor (p = 0.0001). Peripheral arterial compliance determined by air plethysmography is strongly associated with standard cardiovascular risk factors. The noninvasive measurement of local arterial compliance by regional pulse volume recording may be a useful adjunct for cardiovascular risk stratification early in the course of the disease as well as for monitoring vascular response to therapy.
Aged↗