High-density Lipoprotein Cholesterol Deficiency Research Articles

The Unique Role of Self-Rated Health in Metabolic Syndrome and its Diagnostic Cardiometabolic Abnormalities: An Analysis of Population-Based Data

Background: Historically, previous research demonstrating associations between self-rated health (SRH) and metabolic anomalies have rarely controlled for metabolic covariates. Thus, there is currently poor understanding of the unique contribution of SRH to metabolic syndrome (MetS) over and beyond diagnostic cardiometabolic abnormalities. Objective: This study explored unique associations between SRH and multiple cardiometabolic factors, after controlling for metabolic covariates. Methods: This study was based on an analysis of archived population-based data from the 2019 Health Survey for England. A total of 352 MetS cases were extracted from 10299 participants in the survey. Bootstrapped adjusted regression methods were used to predict MetS status and cardiometabolic abnormalities (HDL (high-density lipoprotein) cholesterol, waist/hip ratio, body mass index (BMI), systolic and diastolic blood pressure, and glycated haemoglobin (HbA1c)) from SRH. Structural Equation Modelling (SEM) was used to explore direct and indirect associations between SRH and cardiometabolic factors, with SRH treated as a mediating factor. Results: SRH predicted MetS status but this was negated after cardiometabolic adjustments. Poor SRH independently predicted HDL cholesterol deficiency, and elevated waist/hip ratio, BMI, and HbA1c, even after cardiometabolic adjustments. SEM generated two models with equivalent fit indices, but different structural pathways. In one model SRH mediated relations between anthropometric risk factors (waist/hip ratio and BMI). Conclusions: SRH can help identify people at risk of developing MetS, irrespective of cardiometabolic abnormalities. Poor SRH may represent a non-intrusive easily measurable risk factor for adiposity in MetS, especially where direct measurement of body fat is impractical or socially challenging.

High-density lipoprotein cholesterol — friend or enemy?

The article provides a review of the literature on the effect of excess and deficiency of high-density lipoprotein cholesterol on the prevention and treatment of cardiovascular pathology. Information about high-density lipoproteins structure, function, antiatherogenic role and the prospect of using various high-density lipoproteins subclasses in the pharmacotherapy of dyslipidemic conditions are also described. It is proven that a lowered level of such cholesterol is a predictor of cardiovascular disease. At the same time, many observations confirm the correlation between elevated high-density lipoprotein levels and mortality from myocardial infarction and other acute cardiovascular conditions. In large studies, the use of cholesterol ester transfer protein inhibitors and other drugs increased the level of high-density lipoprotein, but the unreduced risk of cardiovascular disease confirms the lack of positive results from the use as a therapeutic target. In addition, it was found that the composition of high-density lipoprotein cholesterol protein differs in healthy and diseased people: it becomes dysfunctional, losing its antioxidant and anti-inflammatory properties in diseased individuals. The atheroprotective activity of properly functioning high-density lipoprotein cholesterol is often impaired in clinical situations associated with oxidative stress. In these cases, high-density lipoproteins can have some changes, and even if the quantity is within the normal range, the quality is no longer the same. Thus, it is necessary to identify a better therapeutic target than high-density lipoprotein cholesterol levels, as there is currently insufficient clinical trial data to recommend targeted high-density lipoprotein therapy.

Progressively decreasing plasma high-density lipoprotein cholesterol levels preceding diagnosis of smoldering myeloma

We report a case of disappearing high-density lipoprotein (HDL) syndrome caused by oxidative modification of HDL and by autoantibodies against modified HDL, with subsequent diagnosis of myeloma. An elderly Caucasian man had normal lipid levels with HDL cholesterol (HDL-C) levels in the upper 70 mg/dL range from 1999 to 2003. In 2003, his HDL-C levels began to progressively fall, and by 2011, they were undetectable (<5 mg/dL) when measured with a Beckman Synchron LX auto analyzer. Analyses of the plasma sample from 2011 using ultracentrifugation (Vertical Auto Profile), nuclear magnetic resonance, and Ace EXCEL auto analyzer have shown that HDL-C levels were easily detectable (47–54 mg/dL), although reduced compared with his pre-2003 values. Analyses of his plasma sample from 2011 also showed the presence of lipid-adducted apolipoprotein A1 (apoA1) and high titer of antibodies against the adducted apoA1. Interestingly, a negative correlation between HDL-C levels and the titer of antibodies against apoA1 adducts was found in the control cohort. Finally, we show that in the mouse system, an antibody against apoA1 increases the clearance of HDL from plasma. This case of smoldering myeloma preceded by acquired, severe HDL-C deficiency, likely because of oxidative modifications of the HDL protein leading to the formation of autoantibodies, interference with clinical measurement of HDL-C, and increased plasma clearance of HDL, adds to the list of diagnostic considerations for unexplained HDL-C decreases over time.

Abstract 21122: Contribution of ABCA1 Genetic Variation to Plasma Lipid Levels in Non-Hispanic White Americans

Introduction: Dyslipidemia [i.e., elevated levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG); decreased level of high-density lipoprotein cholesterol (HDL-C)] is one of the risk factors for cardiovascular disease (CVD). Genetics play an important role in inter-individual variation of lipid levels. ATP-binding cassette A1 (ABCA1), a membrane transporter, mediates cellular phospholipid and cholesterol efflux. Mutations in ABCA1 gene cause Tangier’s disease (OMIM #205400) presented with HDL-C deficiency, as well as, increased risk for developing CVD. In this study, we aimed to identify both common [minor allele frequency (MAF)≥5%] and uncommon (MAF&lt;5%) variants of ABCA1 associated with inter-individual variation in major lipid traits. Methods: We resequenced 50 exons and exon-intron boundaries of ABCA1 in a selected set of 95 individuals with extreme HDL-C levels (≤10 th and ≥90 th %tile), and subsequently genotyped selected variants in the entire sample of 623 US Non-Hispanic Whites. With resequencing, we identified 404 variants, and for genotyping we selected 250 variants (216 from sequencing data, 34 from HapMap-CEU data). A total of 182 successfully genotyped and QC-passed bi-allelic variants were tested for association with plasma lipid levels. Results: Gene-based test showed evidence of association between ABCA1 and TG ( p =0.0108). Single-site association analyses demonstrated 26 common variants nominally associated ( p &lt;0.05) with at least one lipid trait. After multiple testing correction, two variants [rs4743763 with TC levels, p =0.0005; rs2066716 (Thr1427Thr) with TG levels, p =0.0016] remained significant. Furthermore, rs2066716 (Thr1427Thr) was among 11 out of 26 lipid-associated ABCA1 variants for which the replication data were available in an independent sample ( n =744) and it remained significantly associated with TG levels in the meta-analysis (meta- p =0.0088). Rare variant analyses revealed association of multiple sets of rare variants with lipid traits. Conclusions: Our findings support the genetic contribution of ABCA1 , both common and rare variants, to lipid levels in humans.

Genetic association of single nucleotide polymorphisms of ABCA1, APOA1 and LCAT genes in subjects with low concentration of high density lipoprotein-cholesterol

Aim: Coronary artery disease (CAD) is the major cause of death in the developing world, including Malaysia. It has been well established that high density lipoprotein cholesterol (HDL-c) concentration is inversely correlated with risk of CAD. Molecular defects that lead to HDL-c deficiency have been identified in several candidate genes including ATP–binding cassette transporter A1 (ABCA1), Apolipoprotein A1 (APOA1) and Lecithin cholesterol acyltransferase (LCAT). Using a “power extreme” approach, this study attempts to investigate the genetic association of three candidate genes namely ABCA1, APOA1 and LCAT among 70 Malaysian subjects with low concentration of HDL-c.

Elevated Interleukin-10 and “Disappearing HDL Syndrome” in Lymphoproliferative Disorders

BACKGROUND: Acquired severe HDL deficiency is relatively uncommon. It may occur with use of high doses of anabolic steroids or in severe liver diseases, which can lead to low LCAT activity and decreased apoA-I production. “Disappearing HDL Syndrome”*, a term first used by Goldberg and Mendez, refers to cases of severe HDL deficiency in patients that are not critically ill, sometimes long before the clinical or biochemical features of the underlying primary disease become evident. Disappearing HDL Syndrome can also result from an idiosyncratic reaction to medications, such as peroxisome proliferation-activated receptor (PPAR) agonists. Additionally, autoantibodies against LCAT in non-Hodgkin lymphoma have been described as a possible cause. Low high-density lipoprotein-cholesterol (HDL-C) is a risk factor for coronary artery disease.OBJECTIVE: To determine the cause of low HDL-C in patients with severe acquired HDL deficiency noted as an incidental finding associated with lymphoma and autoimmune lymphoproliferative syndrome (ALPS)** as well as following recombinant human IL10 therapy in psoriatric arthritis patients. Investigating mechanisms underlying acquired severe HDL deficiency in non-critically ill patients (“Disappearing HDL Syndrome”) could provide new insights into HDL metabolism and its role in lymphomagenesis.PATIENTS AND RESULTS: Patients with intravascular large B-cell lymphoma (IVLBCL, n=2), diffuse large B-cell lymphoma (DLBCL, n=1), and ALPS-FAS (n=1) presenting with markedly decreased HDL-C, low LDL-C and elevated triglycerides were identified. The abnormal lipoprotein profile returned to normal following therapy in all four cases (Figure). All of them were found to have markedly elevated serum interleukin-10 (IL-10) levels at presentation that also normalized following therapy. Besides accumulation of abnormal lymphocytes in lymph nodes and spleen, ALPS patients have elevated serum IL-10. In a cohort of ALPS patients with genetic mutations in FAS (n=93), IL-10 showed a strong inverse correlation with HDL-C (R2=0á3720, P<0á0001). A direct causal role for increased serum IL-10 in inducing the observed changes in lipoproteins was established in a randomized, placebo-controlled clinical trial of recombinant human IL-10 (rhIL-10) in psoriatic arthritis patients (n=18). Within a week of initiating subcutaneous rhIL-10 injections, HDL-C precipitously decreased to near-undetectable levels. LDL-C also decreased by over 50% (P<0.0001) and triglycerides increased by approximately 2-fold (P<0.005). All values returned to baseline after stopping IL-10 therapy.CONCLUSION: Increased IL-10 causes severe HDL-C deficiency, low LDL-C and elevated triglycerides. IL-10 is thus a potent modulator of lipoprotein levels, a potential new biomarker for B-cell disorders, and a novel cause of Disappearing HDL Syndrome. Elevated IL-10 plays a key role in linking inflammation and lipoprotein metabolism. As evidence for its causality, rhIL-10 treatment in a clinical trial of psoriasitic arthritis patients precipitously lowered HDL-C. Finding elevated IL-10 as a cause of “Disappearing HDL Syndrome” in patients with 3 different types of B-cell disorders suggests that IL-10 and low HDL-C could be useful biomarkers of disease activity in these conditions. Finally, future research focusing on strategies to alter lipoprotein levels by modulating circulating IL-10 levels or its signaling pathways may be useful for developing novel targeted therapies.*Ref: Severe acquired (secondary) high-density lipoprotein deficiency. Goldberg RB, Mendez AJ. J Clin Lipidol. 2007;1:41-56**Ref: Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. Price S, Shaw PA, Seitz A et al. Blood. 2014 Mar 27;123(13):1989-99. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Plasma Amyloid-β in Patients with Tangier Disease

Tangier disease (TD) is a rare genetic disorder caused by mutations in the ATP-binding cassette transporter A1 (ABCA1) gene, which results in impaired cellular cholesterol efflux and high-density lipoprotein cholesterol deficiency. Animal and in vitro studies indicate that ABCA1 is involved in the production of amyloid-β (Aβ), a pivotal protein in Alzheimer's disease. We here examined whether plasma Aβ levels are altered in TD patients. Plasma from 5 TD patients and 5 controls were analyzed for Aβ1-40, Aβ1-42, AβX-40, and AβX-42 but no differences were found. In conclusion, loss of ABCA1 function may not have any profound effect on Aβ metabolism in humans, at least not in the periphery, as reflected by plasma Aβ levels.

Identification and characterization of novel loss of function mutations in ATP-binding cassette transporter A1 in patients with low plasma high-density lipoprotein cholesterol

Objectives The current literature provides little information on the frequency of mutations in the ATP-binding cassette transporter A1 (ABCA1) in patients with low high-density lipoprotein cholesterol (HDL) levels that are referred to the clinic. In 78 patients with low plasma levels of HDL cholesterol that were referred to our clinic, we routinely screened for ABCA1 gene mutations and studied the functionality of newly identified ABCA1 missense mutations. Methods The coding regions and exon–intron boundaries of the ABCA1 gene were sequenced in 78 subjects with HDL cholesterol levels below the 10th percentile for age and gender. Novel mutations were studied by assessing cholesterol efflux capacity (using apolipoprotein A–I as acceptor) after transient expression of ABCA1 variants in BHK cells. Results Sixteen out of 78 patients (21%) were found to carry 19 different ABCA1 gene variants (1 frameshift, 2 splice-site, 4 nonsense and 12 missense variation) of which 14 variations were novel. Of three patients with homozygous mutations and three patients having compound heterozygous mutations only one patient presented with the clinical characteristics of Tangier Disease (TD) in the presence of nearly complete HDL deficiency. Seven out of eight newly identified ABCA1 missense mutations were found to exhibit a statistically significant loss of cholesterol efflux capacity. Conclusion This study shows that one out of five patients who are referred to our hospital because of low HDL cholesterol levels have a functional ABCA1 gene mutation. It is furthermore demonstrated that in vitro studies are needed to assess functionality of ABCA1 missense mutations.

Association of HDL Deficiency with a Novel Mutation in the ABCA1 Gene

The ATP-binding cassette transporter A1 (ABCA1) is a membrane-bound protein that is abundant in macrophages and is essential for the first step of reverse cholesterol transport and maintenance of homeostasis of high-density lipoprotein (HDL)-bound cholesterol. Low serum HDL levels are associated with increased risk for cardiovascular disease. Homozygous and heterozygous mutations in the ABCA1 gene may be associated with increased atherosclerosis. Here we report about two heterozygous mutations c.5398A>C and c.2369G>A in the ABCA1 gene associated with HDL cholesterol deficiency in serum.

High-density lipoproteins and cardiovascular disease: 2010 update

High-density lipoprotein-cholesterol (HDL-C) is a continuous inverse cardiovascular risk factor. The mechanisms by which HDLs protect against atherosclerosis are multiple. The major effect is thought to be reverse cholesterol transport, the mechanism by which excess cellular cholesterol is returned to the liver for excretion in the bile. HDLs also have pleiotropic roles: they decrease inflammation, prevent low-density lipoprotein oxidation, vascular endothelial cell apoptosis and thrombosis, and improve vascular endothelial function. Recent studies suggest that nascent HDL particles are metabolized rapidly and that their components (Apo AI, cholesterol and phospholipids) are rapidly exchanged within lipoprotein classes. There are many causes of HDL-C deficiency. Using Mendelian randomization, several groups have concluded that many genetic forms of HDL deficiency do not increase cardiovascular risk. This raises the controversial issue of the causality of low HDL-C as a cardiovascular risk factor, rather than a marker of cardiovascular health. This is reflected in the importance of lifestyle in determining HDL-C levels. The treatment of low HDL-C remains controversial, in part because the only currently available effective medication, niacin, is relatively poorly tolerated and outcomes studies on cardiovascular disease prevention are still pending.

Severe acquired (secondary) high-density lipoprotein deficiency

Decreased high-density lipoprotein cholesterol (HDL-C) levels have been designated a major risk factor for cardiovascular disease, and there is considerable interest in identifying individuals with these abnormalities for appropriate management. Although low HDL-C may result from genetic factors, it is estimated that approximately 50% of cases may be secondary to other abnormal or disease states or to their treatment. Very low HDL-C levels, arbitrarily defined as <20 mg/dL, are uncommon, and are best known to result from major genetic mutations of key steps in HDL metabolism. Less well-described are secondary forms of severe HDL-C deficiency, which need to be distinguished from the primary causes. In this review, causes of severe acquired HDL-C deficiency are identified from the literature and are reviewed extensively. These include moderate to severe hypertriglyceridemia, critical illness, androgenic anabolic steroids, and acquired lecithin cholesteryl acyl transferase deficiency and liver disease. A relatively new entity referred to as the “disappearing HDL syndrome” was coined to describe the fairly rapid development of severe HDL-C deficiency in ambulant subjects with previously normal HDL-C and triglyceride levels. This may occur with peroxisome proliferation-activated receptor agonist treatment or in patients with benign or malignant paraproteinemias. Case discussions from our clinical experience are provided to illustrate to the practitioner the clinical context in which these severe acquired deficiencies of HDL occur.

A novel nonsense apolipoprotein A-I mutation (apoA-I E136X) causes low HDL cholesterol in French Canadians

The molecular causes of severe high-density lipoprotein cholesterol (HDL-C) deficiency was examined in a group of 54 unrelated French Canadian subjects. The lecithin:cholesterol acyl transferase (LCAT) and apolipoprotein (apo) A-I gene were analyzed in all probands by direct DNA sequencing. While no LCAT mutation was detected, a novel nonsense apoA-I mutation (E136X) was found in 3/54 probands. Genetic analysis of two kindreds showed a stong co-segregation of the apoA-I locus with the low HDL-C trait. The E136X mutation was detected in families by MaeI restriction digestion. E136X carriers ( n = 17) had marked HDL-C deficiency; among the nine carriers ≥35 years old, five men had developed premature coronary artery disease (CAD). A peptide of apparent molecular weight of 14 kDa was identified in fresh plasma, the HDL fractions and lipoprotein deficient plasma from the three probands but not in normal controls ( n = 3), suggesting that the mutant apoA-I peptide is secreted and binds lipids. The mutation was not observed in an additional 210 chromosomes from unrelated subjects of French Canadian descent, <60 years of age, with CAD and low HDL-C levels. We conclude that apoA-I (E136X) is a cause of HDL-C deficiency in the French Canadian population and is associated with premature CAD.

Genetic determinants of low high-density lipoprotein cholesterol.

High-density lipoprotein cholesterol (HDL-C) has been well established as an inverse predictor of coronary heart disease (CHD), and in recent years, investigations have focused on the genetic regulation of high-density lipoprotein. Although numerous candidate genes contribute to the low HDL-C phenotype, their impact on CHD is heterogeneous, reflecting diverse gene-gene interactions and gene-environmental relationships. This review summarizes recent data involving HDL regulatory genes and their role in atherothrombosis. The primary genetic determinants associated with relative HDL-C deficiency states are the ATP binding cassette protein, ABCA1; apolipoprotein (APO) A1; and lecithin cholesteryl acyl transferase. Other potentially important candidates invoked in low HDL-C syndromes in humans include APOC3, lipoprotein lipase, sphingomyelin phosphodiesterase 1, and glucocerebrosidase. Molecular variation in ABCAI and APOAI and, in selected cases, lecithin cholesteryl acyl transferase deficiency have been associated with increased CHD, whereas two notable variants, APOAIMilano and APOAIParis, are associated with reduced risk. Low HDL-C syndromes have generally been correlated with an increased risk of CHD. However, single-gene abnormalities responsible for HDL-C deficiency states may have variable effects on atherothrombotic risk.

Novel ABCA1 compound variant associated with HDL cholesterol deficiency

The recent discovery of an ATP-binding cassette transporter, ABCA1, as an important regulator of high density lipoprotein (HDL) metabolism and reverse cholesterol transport has facilitated the identification of novel variants associated with HDL cholesterol deficiency states. We identified a subject with HDL cholesterol deficiency (4 mg/dl) who developed and died of complications related to cerebral amyloid angiopathy (CAA). The proband had a compound heterozygous mutation. One mutation was a G3295T substitution with conversion of asparagine to tyrosine (D1099Y) in ABCA1. The single-base substitution at codon 1099 resulted in the abolition of an RsaI cleavage site. The proband and affected individuals having another mutation were heterozygotes for T5966C with phenylalanine converted to serine (F2009S). The presence of the T5966C mutation was detected by restriction digestion with HinfI. These variants were not identified in over 400 chromosomes of healthy subjects. In the kindred, family members heterozygous for the ABCA1 variant exhibited low levels of HDL cholesterol. Direct sequencing of all coding regions and splice site junctions of other HDL candidate genes revealed no additional mutations, indicating that combined defective ABCA1 alleles may result in familial HDL deficiency.

Functional Loss of ABCA1 in Mice Causes Severe Placental Malformation, Aberrant Lipid Distribution, and Kidney Glomerulonephritis As Well As High-Density Lipoprotein Cholesterol Deficiency

Tangier disease (TD) and familial HDL deficiency (FHA) have recently been linked to mutations in the human ATP-binding cassette transporter 1 (hABCA1), a member of the ABC superfamily. Both diseases are characterized by the lowering or lack of high-density lipoprotein cholesterol (HDL-C) and low serum cholesterol. The murine ABCA1-/- phenotype corroborates the human TD linkage to ABCA1. Similar to TD in humans, HDL-C is virtually absent in ABCA1-/- mice accompanied by a reduction in serum cholesterol and lipid deposition in various tissues. In addition, the placenta of ABCA1-/- mice is malformed, resulting in severe embryo growth retardation, fetal loss, and neonatal death. The basis for these defects appears to be altered steroidogenesis, a direct result of the lack of HDL-C. By 6 months of age, ABCA1-/- animals develop membranoproliferative glomerulonephritis due to deposition of immunocomplexes followed by cardiomegaly with ventricular dilation and hypertrophy, ultimately succumbing to congestive heart failure. This murine model of TD will be very useful in the study of lipid metabolism, renal inflammation, and cardiovascular disease and may reveal previously unsuspected relationships between them.

Lipid-free apolipoprotein (apo) A-I is converted into alpha-migrating high density lipoproteins by lipoprotein-depleted plasma of normolipidemic donors and apo A-I-deficient patients but not of Tangier disease patients

Plasma of patients with Tangier disease (TD) is devoid of α-LpA-I (apolipoprotein A-I-containing lipoprotein), which in normolipidemic plasma constitutes the majority of high density lipoprotein (HDL). The residual amounts of apolipoprotein A-I (apo A-I) in TD plasma have electrophoretic pre β 1-LpA-I mobility. We have previously demonstrated that TD plasma does not convert pre β 1-LpA-I into α-LpA-I. In this study we found that plasmas of normolipidemic controls, apo A-I-deficient patients and patients with fish-eye disease, but not plasmas of six TD patients, convert biotinylated lipid-free apo A-I into α-LpA-I. Supplementation of plasma with free oleic acid or fatty acid free albumin neither inhibited conversion activity in normal plasmas nor reconstituted it in TD plasma. In normal plasma the conversion activity was assessed in HDL and in the lipoprotein-free fraction. The latter fraction, however, generated larger particles only in the presence of exogenous phospholipid vesicles. To obtain particles with α-mobility, these vesicles had to contain phosphatidylinositol and/or cholesterol. Lipoprotein-depleted TD plasma did not convert lipid-free apo A-I into α-LpA-I even in the presence of exogenous vesicles with phospholipids or cholesterol. Taken together we conclude that disturbed transfer of glycerophospholipds onto apo A-I or pre β 1-LpA-I prevents maturation of HDL and thereby possibly causes deficiency of HDL cholesterol in patients with TD. Moreover, the lack of α-LpA-I in TD plasma together with its failure to convert exogenous apo A-I into an α-migrating particle provide specific tests for the diagnosis of TD.

Bezafibrate. An update of its pharmacology and use in the management of dyslipidaemia.

The lipid-modifying profile of bezafibrate is characterised by marked decreases in elevated triglyceride levels, increases in high density lipoprotein (HDL) cholesterol levels and decreases in total and low density lipoprotein (LDL) cholesterol levels. Bezafibrate also reduces elevated levels of lipoprotein(a) [Lp(a)] and fibrinogen, which are independent cardiovascular risk factors. Bezafibrate is effective in most types of primary and secondary dyslipidaemia. It is of greatest benefit in conditions featuring hypertriglyceridaemia and/or HDL cholesterol deficiency. This is particularly true for patients with diabetes mellitus, notably those with non-insulin-dependent diabetes mellitus (NIDDM) who are also likely to have increased fibrinogen levels. In the limited comparisons available, there appear to be few consistent differences in lipid-modifying effects between bezafibrate and other fibrates. Compared with HMG-CoA reductase inhibitors, bezafibrate causes larger changes in triglyceride and, in general, HDL cholesterol levels, and has a lesser influence on LDL and total cholesterol levels. These differences are advantageous when bezafibrate and HMG-CoA reductase inhibitors are used as combined therapy in patients with severe dyslipidaemia unresponsive to either modality alone. The combination of bezafibrate plus an HMG-CoA reductase inhibitor in clinical trials has not led to the predicted increase in myalgia. Indeed, bezafibrate is generally free of serious unwanted effects: rhabdomyolysis is rare and has occurred mainly in patients with renal dysfunction given excessive dosages. Other patient groups in whom bezafibrate has improved serum lipid profiles are those with isolated HDL cholesterol deficiency, dyslipidaemia secondary to renal insufficiency, and following cardiac surgery or other procedures. However, data for these indications are not extensive. Evidence is now available to show a beneficial effect of bezafibrate on retarding atherosclerotic processes and in reducing risk of coronary heart disease. The 5-year Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) in young male survivors of myocardial infarction demonstrated a smaller decrease in luminal diameter and a reduction in coronary events with bezafibrate compared with placebo. The Bezafibrate Infarction Prevention (BIP) study is expected to provide mortality data which is currently lacking for bezafibrate. In conclusion, bezafibrate is a useful and well-tolerated lipid-modifying agent in the management of primary and secondary dyslipidaemia. It has particularly beneficial effects in patients with hypertriglyceridaemia and/or low HDL cholesterol levels, and reduces fibrinogen levels. Together with its ability to sustain or improve glycaemic control, these properties make it a logical choice for treating patients with diabetes mellitus and dyslipidaemia. Additionally, the drug may be of value as combination therapy in patients with severe dyslipidaemia. Importantly, there is evidence that the drug can slow the atherosclerotic process and reduce cardiovascular morbidity. The ongoing BIP secondary intervention study and other investigations will help clarify the effects of bezafibrate on cardiovascular mortality and morbidity.

Homozygous Tangier disease and cardiovascular disease

Decreased levels of plasma high density lipoprotein (HDL) cholesterol have been associated with premature cardiovascular disease (CVD). Tangier disease is an autosomal co-dominant disorder in which homozygotes have a marked deficiency of HDL cholesterol and apolipoprotein (apo) A-I levels (both < 10 mg/dl), decreased low density lipoprotein (LDL) cholesterol levels (about 40% of normal), and mild hypertriglyceridemia. Homozygotes develop cholesterol ester deposition in tonsils (orange tonsils), liver, spleen, gastrointestinal tract, lymph nodes, bone marrow, and Schwann cells. Our purpose was to assess the prevalence of CVD in Tangier disease. We reviewed published clinical information on 51 cases of homozygous Tangier disease, report 3 new cases and provide autopsy information on 3 cases. Mean (±S.D.) lipid values of all cases were as follows: total cholesterol 68 ± 30 mg/dl (32% of normal), triglycerides 201 ± 118 mg/dl (162% of normal), HDL cholesterol 3 ± 3 mg/dl (6% of normal) and LDL cholesterol 50 ± 38 mg/dl (37% of normal). The most common clinical finding in these subjects ( n = 54) was peripheral neuropathy which was observed in 54% of cases versus < 1% of control subjects ( n = 3130). CVD was observed in 20% of Tangier patients versus 5% of controls ( P < 0.05), and in those that were between 35 and 65 years of age, 44% (11 of 25) had evidence of CVD (either angina, myocardial infarction or stroke) versus 6.5% in 1533 male controls and 3.2% in 1597 female controls in this age group ( P < 0.01). In 9 patients who died, 2 died prior to age 20 of probable infectious diseases, 3 of documented coronary heart disease at ages 48, 64, and 72, 2 of stroke at ages 56 and 69, one of valvular heart disease, and 1 of cancer. In three autopsy cases, significant diffuse atherosclerosis was observed in one at age 64, moderate atherosclerosis and cerebral infarction in another at age 56, but no atherosclerosis was noted in the third case who died of lymphoma at age 62. In one patient with established coronary heart disease, none of the lipid lowering agents used (niacin, gemfibrozil, estrogen or lovastatin) raised HDL cholesterol levels above 5 mg/dl. However, these agents did have significant effects on lowering triglyceride and LDL cholesterol levels. Our data indicate that there may be heterogeneity in these patients with regard to CVD risk, that peripheral neuropathy is a major problem in many patients, and that CVD is a significant clinical problem in middle aged and elderly Tangier homozygotes. These patients may be somewhat protected from strikingly premature CVD because of their low LDL cholesterol levels, but their CVD prevalence is at least six-fold higher than normal between the ages of 35 and 65 years. Both the apo A-I and apo MI genes have been noted to be normal in selected cases. The precise defect in Tangier disease remains unknown and clear guidelines for therapy have not been developed. However, it is prudent to treat CVD risk factors in these patients when present, especially hypertension, cigarette smoking, and diabetes.