<b><i>Background:</i></b> Paradoxical associations exist between serum lipid levels and mortality in patients on maintenance hemodialysis (MHD) including those of Hispanic origin. However, there are significant racial and ethnic variations in patients of ‘Hispanic' background. We hypothesized that clinically meaningful differences existed in the association between lipids and survival in Hispanic MHD patients on the West versus East Coast. <b><i>Methods:</i></b> We examined the survival impact of serum lipids in a 2-year cohort of 15,109 MHD patients of Hispanic origin being treated in California, Texas, representing the West versus New York, New Jersey and Florida representing the East Coast, using Cox models with various degrees of adjustments. <b><i>Results:</i></b> The association of serum total and HDL cholesterol with mortality follows a U-shaped pattern in Hispanic patients residing in the West. This is in contrast to Hispanic patients in the East Coast whose survival seems to improve with increasing total and HDL cholesterol levels. Elevated serum LDL levels in Hispanic patients on the West Coast are associated with a significant increase in mortality, while this association is not observed in patients residing on the East Coast. <b><i>Conclusions:</i></b> Substantial differences exist in the association of serum lipids with mortality in MHD patients of Hispanic background depending on whether they reside on the West or East Coast of the United States. These geographical variances most likely reflect ethnic, racial and genetic distinctions, which are usually ignored. Future studies should take into account these critical variations in a population of patients who make up a significant portion of our society.
Epidemiological and interventional studies clearly indicate that dyslipidemia (with elevated cholesterol, triglycerides [TGs], low-density lipoproteins [LDLs], lipoprotein(a) [Lp(a)] and decreased high-density lipoproteins [HDLs]) is a major risk factor involved in atherosclerotic cardiovascular disease (CVD). Among various lipid-regulating agents (e.g., fibrates and niacin), statins (3-hydroxy-3-methyl-glutaryl coenzyme-A [HMG-CoA] reductase inhibitors) have bypassed other lipid-lowering medications in their efficacy at lowering LDL and decreasing the rate of primary and secondary cardiovascular events by approximately a third [1–10]. They are the most widely used medications for dyspidemia in the world. Even with their broad use, their effects leave a large number of individuals still having cardiovascular events that could be prevented. This remaining risk of a cardiovascular event is referred to as residual risk. The residual risk that remains after improvement of LDL with statins is not solely due to the effects of dyslipidemia. The metabolic syndrome, diabetes mellitus, hypertension, cigarette smoking, age, family history, and other emerging or unknown markers are all major risk factors for heart disease that need to also be improved, if possible, to lower a person's risk of CVD. In this chapter, the authors assess the approaches that can further improve a patient's dyslipidemia and the treatment strategies currently available, as well as emerging therapies. The authors will also review clinical trials aimed at reducing residual risk.
The new combination of niacin extended-release (ER) and lovastatin (Advicor™, Kos pharmaceuticals), is a powerful lipid modifying agent and takes advantage of the different mechanisms of action of its two components. Niacin decreases hepatic atherogenic apolipoprotein (apo) B production whereas lovastatin increases apoB removal. Whereas niacin potently increases high density lipoprotein (HDL) levels by decreasing hepatic removal of antiatherogenic apoA-I particles, 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors (‘statins’) appear to increase production of apoA-I. Although there is no outcome data with this combination product, each component has been independently associated with a reduction of cardiovascular event risk by ∼ 25 – 35%. The results of a long-term trial in 814 patients, where > 600 had been treated for 6 months and > 200 for 1 year, found reductions of 45 and 42% in low density lipoprotein cholesterol and triglycerides, respectively, at the maximum dose (niacin ER 2000 mg/ lovastatin 40 mg). HDL cholesterol increased by 41%. In addition, the combination decreased lipoprotein (a) by 25% and C-reactive protein by 24%. The niacin ER/lovastatin combination was generally well-tolerated. Flushing was the most common side effect, with ∼ 10% of patients intolerant to niacin ER/lovastatin. Hepatotoxicity in this study was 0.5% and myopathy did not occur. Recent studies indicate that niacin can be used safely in diabetic patients who have good glucose control (HbA 1c < 9%). Once-daily niacin ER/lovastatin exhibits potent synergistic actions on multiple lipid risk factors and represents an effective new agent in the clinical management of dyslipidaemia. Outcome studies are needed to evaluate if combination therapy would result in additive effects on morbidity and mortality.
Objective: Synthetic class A amphipathic helical peptide analogs of apolipoprotein-AI (apoAI; with varied phenylalanine residues) are emerging therapeutic approaches under investigation for atherosclerosis. Utilizing retroinverso sequencing, we designed reverse-D4F (Rev-D4F) peptide with 18 d-amino acids containing 4 phenylalanine residues and reverse order that allows the side chain residues to be of exact alignment and superimposable to those of the parent l-amino acid peptide. This study examined the effect of Rev-D4F on atherosclerosis in apolipoprotein E (apoE)-null mice and the underlying mechanisms. Materials/Methods: ApoE-null mice were fed a chow diet and administered water (control), Rev-D4F, or L4F mimetic peptides (0.4 mg/mL, equivalent to 1.6 mg/d) orally in drinking water for 6 weeks. Aortic root atherosclerotic lesion area, lesion macrophage content, and the ability of plasma high-density lipoprotein (HDL) to influence monocyte chemotaxis were measured. Results: Rev-D4F significantly decreased aortic sinus atherosclerotic lesion area and lesion macrophage content without affecting plasma total and HDL-cholesterol levels in apoE-null mice. The HDL from Rev-D4F-treated mice showed enhanced anti-inflammatory monocyte chemotactic activity, while low-density lipoprotein (LDL) exhibited reduced proinflammatory activity. In in vitro studies, Rev-D4F inhibited LDL oxidation, endothelial cell vascular cell adhesion molecule 1 (VCAM-1), and monocyte chemotactic factor 1 (MCP-1) expression, and monocyte adhesion to aortic endothelial cells. Conclusions: The Rev-D4F inhibits atherosclerosis by inhibiting endothelial inflammatory/oxidative events and improving HDL function. The data suggest that Rev-D4F may be an effective apoAI mimetic peptide for further development in preventing atherosclerosis.
Several! recently developed methods assessing triglyceride metabolism have resulted in clearer definitions of distinct disorders of triglyceride metabolism. Beyond the basic lipid profile (plasma inspection, chemical determinations of cholesterol, triglycerides and high-density lipoprotein cholesterol) a judicious use of simple to complex methods allows the clinician and researcher to arrive at the phenotypic, etiologic or genotypic diagnosis of most such disorders.
The biochemical, clinical, and genetic features were examined in the proband (homozygote) and heterozygotes (n = 17) affected with familial apolipoprotein A-I and C-I11 deficiency, variant I1 (previously described as apolipoprotein A-I absence).The proband was a 45-year-old white female with mild corneal opacification and significant three-vessel coronary artery disease (CAD), who died shortly after bypass surgery.Autopsy findings included significant atherosclerosis in the coronary and pulmonary arteries and the abdominal aorta as well as extracellular stromal lipid deposition in the cornea.No reticuloendothelial lipid deposits in the liver, bone marrow, or spleen were noted (unlike Tangier disease).Laboratory features included marked high density lipoprotein (HDL) deficiency and undetectable plasma apolipoproteins (apo) A-I and C-111.The percentage of plasma cholesterol in the unesterified form was normal at 30%.The activity and mass of 1ecithin:cholesterol acyltransferase (LCAT) were 42% and 36% of normal, respectively, and the cholesterol esterification rate was 43% of normal.Deficiencies of plasma vitamin E and essential fatty acid (linoleic, C18:2) were also noted.Evaluation of plasma lipoproteins and apolipoproteins in 37 kindred members revealed 17 heterozygotes with HDL cholesterol values below the 10th percentile of normal.Of these, all had apoA-I levels more than one standard deviation below the normal mean, and 37.5% had a similar decrease in apoC-I11 values.Mean ( * SD) plasma HDL cholesterol, apoA-I, and apoC-I11 values (mgldl) in heterozygotes were 54.0%, 62.4%, and 79.2% of normal, respectively.No evidence of CAD was observed in 10 heterozygotes 40 years of age or less; however, CAD was detected in 3 of 7 heterozygotes over 40 years of age, one of whom died at age 56 years of complications of myocardial infarction and stroke.The inheritance pattern in this kindred was autosomal codominant.ApoA-I isolated from a heterozygote had an isoelectric focusing pattern and amino acid composition similar to normal.Utilizing DNA isolated from two obligate heterozygotes, no abnormalities in the apoA-I or apoC-I11 genes were detected by Southern blot analysis utilizing specific probes following restriction enzyme digestion.The data indicate that familial apolipoprotein A-I and C-I11 deficiency, variant 11, is similar to variant I (described by Norum et al. 1982.N Engl.J. Med.306: 1513-1519), but differs at the clinical level (lack of xanthomas), the biochemical level (lack of detectable apoA-I, lower apoA-I1 level), and at the gene level.Our data are consistent with the view that apoA-I is essential for HDL formation but not for LCAT activation, and that apolipoproteins A-I and C-I11 may be important for vitamin E and essential fatty acid intestinal absorption.
