Quantitative analysis of ABCA1-dependent compartmentalization and trafficking of apolipoprotein A-I: implications for determining cellular kinetics of nascent high density lipoprotein biogenesis.

The molecular mechanisms underlying the apoA-I/ABCA1 endocytic trafficking pathway in relation to high density lipoprotein (HDL) formation remain poorly understood. We have developed a quantitative cell surface biotinylation assay to determine the compartmentalization and trafficking of apoA-I between the plasma membrane (PM) and intracellular compartments (ICCs). Here we report that (125)I-apoA-I exhibited saturable association with the PM and ICCs in baby hamster kidney cells stably overexpressing ABCA1 and in fibroblasts.

Effect of obesity on high-density lipoprotein metabolism.

Reduced levels of high-density lipoproteins (HDL) in non-obese and obese states are associated with increased risk for the development of coronary artery disease. Therefore, it is imperative to determine the mechanisms responsible for reduced HDL in obese states and, conversely, to examine therapies aimed at increasing HDL levels in these individuals. This paper examines the multiple causes for reduced HDL in obese states and the effect of exercise and diet--two non-pharmacologic therapies--on HDL metabolism in humans.

Sphingomyelin phosphodiesterase-1 (SMPD1) coding variants do not contribute to low levels of high-density lipoprotein cholesterol.

Background: Niemann-Pick disease type A and B is caused by a deficiency of acid sphingomyelinase due to mutations in the sphingomyelin phosphodiesterase-1 (SMPD1) gene. In Niemann-Pick patients, SMPD1 gene defects are reported to be associated with a severe reduction in plasma high-density lipoprotein (HDL) cholesterol.

Methods: Two common coding polymorphisms in the SMPD1 gene, the G1522A (G508R) and a hexanucleotide repeat sequence within the signal peptide region, were investigated in 118 unrelated subjects of French Canadian descent with low plasma levels of HDL-cholesterol (< 5th percentile for age and gender-matched subjects).

Hybrid sampling approach for imaging Fourier-transform spectrometry.

A new approach to interferogram sampling is demonstrated for Fourier-transform spectrometry. Sampling of the infrared channel is triggered at equidistant optical path differences while samples are time-referenced with a high-resolution digital clock. This hybrid method exploits the advantages of both time and position-sampling techniques.

Surgical strategies for severe calcification of the aorta (porcelain aorta) in two patients with homozygous familial hypercholesterolemia.

Homozygous familial hypercholesterolemia (HzFH) is a rare genetic defect caused predominantly by mutations at the low-density lipoprotein receptor. Until recent advances in the management of this complex disorder, patients affected by HzFH rarely survived beyond 30 years of age. Two patients with HzFH who survived to adulthood and developed cardiovascular complications requiring surgery are reported.

Carboxyl-terminal disulfide bond of acid sphingomyelinase is critical for its secretion and enzymatic function.

The human acid sphingomyelinase (ASM, EC 3.1.4.

Baseline characteristics of participants in the JUPITER trial, a randomized placebo-controlled primary prevention trial of statin therapy among individuals with low low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein.

The Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) is a randomized, double-blind, placebo-controlled primary prevention trial of statin therapy among persons with average to low levels of low-density lipoprotein (LDL) cholesterol who are at increased cardiovascular risk due to elevated plasma concentrations of the inflammatory biomarker high-sensitivity C-reactive protein (hs-CRP). A total of 17,802 persons with LDL cholesterol<130 mg/dl (3.36 mmol/L) and hs-CRP>or=2 mg/L were recruited from 26 countries and randomly allocated to 20 mg/day rosuvastatin or placebo.

Venous thromboembolism in association with features of the metabolic syndrome.

Background: Central obesity, diabetes mellitus, dyslipidaemia and chronic hypertension--features of the metabolic syndrome--have been individually associated with venous thromboembolism (VTE). However, whether each of these factors additively increases the risk of VTE is uncertain.

Aim: To determine whether features of the metabolic syndrome independently increase the risk of VTE.

Modulation of arterial reactivity using amlodipine and atorvastatin measured by ultrasound examination (MARGAUX).

Objective: To evaluate the effect of the calcium channel blocker amlodipine on endothelial function in normotensive patients with coronary disease taking concomitant atorvastatin therapy.

Methods And Results: Atorvastatin was titrated (10-80 mg/day) to maintain LDL-C<2.5 mmol/L and patients were randomized to receive amlodipine (5-10mg/day, n=64) or placebo (n=70) for 12 months.

Identification of an ABCA1-dependent phospholipid-rich plasma membrane apolipoprotein A-I binding site for nascent HDL formation: implications for current models of HDL biogenesis.

It is well accepted that both apolipoprotein A-I (apoA-I) and ABCA1 play crucial roles in HDL biogenesis and in the human atheroprotective system. However, the nature and specifics of apoA-I/ABCA1 interactions remain poorly understood. Here, we present evidence for a new cellular apoA-I binding site having a 9-fold higher capacity to bind apoA-I compared with the ABCA1 site in fibroblasts stimulated with 22-(R)-hydroxycholesterol/9-cis-retinoic acid.

Fast line-shape correction procedure for imaging Fourier-transform spectrometers.

An instrument line-shape correction method adapted to imaging Fourier-transform spectrometers is demonstrated. The method calibrates all pixels on the same spectral grid and permits a direct comparison of the spectral features between pixels such as emission or absorption lines. Computation speed is gained by using matrix line-shape integration formalism rather than properly inverting the line shape of each pixel.

Parasitic diffuse reflection in a Fourier transform spectrometer yielding subharmonic ghosts and line-shape distortion.

When using a high-resolution Fourier transform spectrometer (FTS) in a cube-corner configuration, subharmonic ghosts are observed in the spectrum. These ghosts are attributable to parasitic diffuse reflections on the mirrors of the FTS arm. The reflected beams skip a part of the interferometer and travel a different path from the main beam thus experiencing a smaller optomechanical gain.

Subclinical inflammation and prothrombotic state in heart transplant recipients: impact of cyclosporin microemulsion vs. tacrolimus.

Background: Subclinical inflammation is related to adverse events in patients with coronary artery disease. In the present study, we determined the changes in hemostatic parameters and inflammatory markers in a large cohort of dyslipidemic cardiac transplant recipients compared with dyslipidemic healthy controls, and the effect of cyclosporin microemulsion (CsA) vs. tacrolimus immunoprophylaxis on these parameters.

Canadian Cardiovascular Society position statement--recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease.

Since the last publication of the recommendations for the management and treatment of dyslipidemia, new clinical trial data have emerged that support a more vigorous approach to lipid lowering in specific patient groups. The decision was made to update the lipid guidelines in collaboration with the Canadian Cardiovascular Society. A systematic electronic search of medical literature for original research consisting of blinded, randomized controlled trials was performed.

Combination of statin and ezetimibe for the treatment of dyslipidemias and the prevention of coronary artery disease.

The prevention of coronary artery disease (CAD) involves therapeutic lifestyle changes such as smoking cessation, diet, weight reduction and exercise. In patients with established CAD or atherosclerosis in other vascular beds, or in patients at high risk of developing CAD, lowering serum total and low-density lipoprotein cholesterol (LDL-C) has been associated with a reduction in cardiovascular morbidity and mortality, and total mortality. Recently, large-scale studies have shown that lowering the LDL-C to less than 2.

Correction of instrument line shape in Fourier transform spectrometry using matrix inversion.

A novel matrix inversion approach is proposed to correct several contributions to the instrument line shape (ILS) of a Fourier transform spectrometer. The matrix formalism for the ILS is first quickly reviewed. Formal inversion of the ILS matrix is next discussed, along with its limitations.

Impact of interferometer optical path difference speed profile on the Fourier-transform-spectrometry-derived spectrum of a telecommunications signal.

The impact of the interferometer optical path difference (OPD) speed profile on the spectrum, derived through the use of Fourier-transform spectrometry (FTS), of a synchronous optical network (SONET) signal is found. The SONET signal carries high-speed data traffic. It also may be modulated by low-frequency intensity or frequency modulation.

Genetics of high-density lipoproteins.

Purpose Of Review: High-density lipoproteins have multi-factorial anti-atherosclerosis properties: they have potent anti-oxidant effects and prevent the oxidation of low-density lipoproteins; they have anti-inflammatory effects; they modulate vascular endothelial cell function and transport cholesterol back to the liver for excretion into the bile - a process called reverse cholesterol transport. The present review focuses on genetic aspects of high-density lipoprotein metabolism, with genomic approaches used to identify genes that regulate high-density lipoproteins in humans.

Recent Findings: Disorders of the many genes that code for proteins, including transporters, enzymes, receptors, transfer proteins and lipases, involved in high-density lipoprotein metabolism have been identified in humans as causing extremes of high-density lipoprotein cholesterol, and provide potential novel therapeutic avenues.

New insights into the biogenesis of human high-density lipoproteins.

Purpose Of Review: The interest for the human HDL system was recently revived by the identification of the ABCA1 as a critical component in the formation and maintenance of plasma HDL levels. The present review focuses on recent progress in our understanding of the basic mechanisms underlying HDL biogenesis pathways.

Recent Findings: Several novel mechanisms governing ABCA1/apoA-I interactions have recently been identified: apolipoprotein A-I activates ABCA1 phosphorylation through the cAMP/protein kinase A-dependent pathway; the majority of ABCA1 exists as a tetramer in human living cell, supporting the concept that the homotetrameric ABCA1 complex constitutes the minimum functional unit for the formation of nascent HDL particles; apolipoprotein A-I has been shown to have a recycling retroendocytic pathway with uptake and resecretion of the lipidated nascent HDL particles by the cell, most likely through the ABCA1 transporter pathway; there is evidence that the speciation of nascent HDL into pre-beta and alpha-HDL is linked to specific cell lines, and occurs by both ABCA1-dependent and independent pathways.

Identification of a novel C5L2 variant (S323I) in a French Canadian family with familial combined hyperlipemia.

Objective: A functional acylation stimulating protein (ASP) receptor, C5L2, has been recently identified in ASP-responsive cells. Impaired ASP-mediated triglyceride synthesis has previously been described in a subset of hyperapolipoprotein B/familial combined hyperlipidemia subjects.

Methods And Results: DNA sequencing of C5L2 coding region in 61 unrelated probands identified a heterozygous variant (G968-->T) in 1 subject, resulting in Ser323-->Ile substitution in the carboxyl terminal region.

Homocysteine lowering with folic acid and B vitamins in vascular disease.

Background: In observational studies, lower homocysteine levels are associated with lower rates of coronary heart disease and stroke. Folic acid and vitamins B6 and B12 lower homocysteine levels. We assessed whether supplementation reduced the risk of major cardiovascular events in patients with vascular disease.

Cellular cholesterol homeostasis in vascular endothelial cells.

Atherosclerosis is a disease of blood vessel walls that is thought to be initiated as a reaction of insults to the endothelium. The complex sequence of cellular events that begins with focal inflammation leads to the accumulation of leukocytes in the subendothelial layer and unrestricted uptake of oxidized lipoproteins by macrophages and smooth muscle cells, leading to foam cell formation. Vascular endothelial cells do not undergo the foam cell transformation and do not accumulate cholesterol in atherosclerotic plaques to the same extent as macrophages or smooth muscle cells.

Matrix form for the instrument line shape of Fourier-transform spectrometers yielding a fast integration algorithm to theoretical spectra.

The instrument line shape (ILS) of a Fourier-transform spectrometer is expressed in a matrix form. For all line shape effects that scale with wavenumber, the ILS matrix is shown to be transposed in the spectral and interferogram domains. The novel representation of the ILS matrix in the interferogram domain yields an insightful physical interpretation of the underlying process producing self-apodization.

Rationale, design and baseline characteristics of a large, simple, randomized trial of combined folic acid and vitamins B6 and B12 in high-risk patients: the Heart Outcomes Prevention Evaluation (HOPE)-2 trial.

Background: Epidemiological studies suggest that mild to moderate elevation in plasma homocysteine concentration is associated with increased risk of atherothrombotic cardiovascular (CV) disease. Simple, inexpensive and nontoxic therapy with folic acid and vitamins B6 and B12 reduces plasma homocysteine levels by approximately 25% to 30% and may reduce CV events. Therefore, a large, randomized clinical trial--the Heart Outcomes Prevention Evaluation (HOPE)-2 study--is being conducted to evaluate this therapy in patients at high risk for CV events.

Elevated homocysteine reduces apolipoprotein A-I expression in hyperhomocysteinemic mice and in males with coronary artery disease.

Hyperhomocysteinemia, a risk factor for cardiovascular disease, is caused by nutritional or genetic disturbances in homocysteine metabolism. A polymorphism in methylenetetrahydrofolate reductase (MTHFR) is the most common genetic cause of mild hyperhomocysteinemia. To examine mechanisms by which an elevation in plasma homocysteine leads to vascular disease, we first performed microarray analyses in livers of Mthfr-deficient mice and identified differentially expressed genes that are involved in lipid and cholesterol metabolism.