LDL oxidation: therapeutic perspectives.

The peroxidation step of lipid transormation is considered to be essential in the pathogenesis of atherosclerosis. Although data concerning the mechanisms by which lipid peroxidation occurs in vivo are scarce, several lines of evidence suggest that some endogenous and exogenous compounds with antioxidant activity could have some beneficial effects in the prevention of atherosclerosis. Ascorbic acid (vitamin C) and alpha-tocopherol (vitamin E) act as the most important hydrophilic and lipophilic antioxidants, respectively in vivo. Accordingly, animal and human studies suggest that these compounds may have some preventive effect against the development of clinical coronary heart disease. Many plant phenols and flavonoids may be important dietary antioxidants and it has been speculated that these compounds in red wine or in the Mediterranean diet could explain the 'French paradox'. Several studies show that antioxidants such as probucol and butylated hydroxytoluene can inhibit development of atherosclerotic lesions in Watanabe and cholesterol-fed rabbits. Some drugs such as beta-blockers, calcium antagonists, hypolipodemic drugs,...appear to have at least in vitro antioxidant effects but the clinical relevance of these properties remains unkonwn. Moreover, some interventions aimed to decrease the LDL-oxidative susceptibility have not been shown to attenuate atherogenesis when cholesterol levels remain markedly elevated.

High prevalence of a novel mutation in the exon 4 of the low-density lipoprotein receptor gene causing familial hypercholesterolemia in Belgium.

In a cohort of 70 unrelated patients living in Southern Belgium with autosomal dominantly inherited hypercholesterolemia, 11 had a hitherto undescribed mutation in exon 4. It consisted in a C-->A mutation at nucleotide 366, resulting in a stop codon at residue Cys122. This C122X mutation is expected to cause a class I receptor defect. The biochemical and clinical data collected from the patients carrying the mutation were consistent with a severe form of familial hypercholesterolemia (FH). Some differences between generations were noted. Amongst the C122X carriers, those born after 1926 had cardiovascular complications earlier than those born before 1926. This raises the possibility that changes in environmental factors during the course of the century have had an unfavorable impact on the prognosis of the disease. The mutation was found in 16% of the suspected FH patients and less frequently (less than 3% of suspected FH) in Northern Belgium. The haplotype of the chromosomes carrying the mutation was the same in all C122X families, but extensive genealogical studies failed to reveal a common ancestor. We conclude that C122X is an old and common cause of FH in Belgium. Screening for this mutation may be useful in the diagnosis of FH in Belgium.

An improved method for detection of low density lipoprotein receptor defects in human T lymphocytes.

Familial hypercholesterolemia (FH) results from an inherited functional defect of the low density lipoprotein (LDL) receptor and is complicated by premature atherosclerosis. FH diagnosis is obtained by sophisticated techniques or is suggested by clinical criteria. We have developed a technique based on flow cytometry for the measurement of DiI-labeled LDL uptake in human peripheral blood T lymphocytes left for 2 days in a lipoprotein-deficient culture medium. Flow cytometry allowed us to discriminate the uptake of DiI-LDL by T lymphocytes subpopulation from the uptake by the whole mononuclear population using a T cell-specific anti-CD3 antibody. The method appeared to be highly specific for the receptor-mediated pathway of LDL uptake as DiI-LDL uptake was inhibited in the presence of a 10-fold excess of unlabeled LDL and by EDTA. A good relationship was found between the uptake of DiI-LDL and 125I-labeled LDL degradation. The test was applied in three groups of patients: patients with normal cholesterol levels, patients with heterozygous FH, and patients with high cholesterol levels but without clinical criteria of FH. The mean fluorescence intensities were 23.1 +/- 8.9, 6.3 +/- 1.7, and 17.1 +/- 3.5 (mean +/- standard deviation), respectively. The ability to measure the fluorescence in T lymphocytes improved the discrimination between FH and non-FH subjects when compared with values obtained from the whole mononuclear cell population. These results suggest that our method could be useful for LDL receptor defects screening.

[Lipoprotein (a) in liver diseases. Correlation between low levels and liver function]. / La lipoprotéine(a) dans les hépatopathies. Corrélation entre sa diminution et l'état fonctionnel du foie.

OBJECTIVES: To analyze the role of the liver function on the serum levels of lipoprotein(a) (Lp(a)), a lipoprotein considered to be a risk factor for atherosclerosis. METHODS: To measure the Lp(a) levels in patients with liver disease (n = 68) due to various causes and in patients with no liver disease and of similar age and sex-ratio (n = 62) and to analyze the relationship between Lp(a) levels on one hand and liver function and lipid and apoprotein levels on the other hand. RESULTS: Patients with liver disease had significantly lower levels of Lp(a). Lp(a) levels were significantly lower in patients with more severe liver disease (Child Turcotte classification) and significantly correlated with liver function tests, in particular those related to the microsomal function and the synthetic capacity of the liver (albumin, coagulation tests, apoprotein A-II). In patients with liver disease, mean Lp(a) levels were not significantly different between those with and those without chronic alcohol intake. CONCLUSIONS: Patients with liver disease have low levels of Lp(a) that are related to reduced synthetic capacity of this organ and are not linked to a specific cause of liver disease, in particular excess alcohol intake.

Serum lipoprotein(a) in patients with diabetes mellitus.

OBJECTIVE: To investigate subjects with different types of diabetes mellitus regarding their serum levels of lipoprotein(a). High serum Lp(a) concentration is associated with a high risk of coronary heart disease. Diabetic patients are prone to developing coronary heart disease. RESEARCH DESIGN AND METHODS: The subjects were 66 type I diabetic patients, 100 type II diabetic patients treated with diet alone or diet combined with oral hypoglycemic agents, and 46 insulin-requiring type II diabetic patients. Subjects were compared with 142 nondiabetic outpatients. RESULTS: Subjects with insulin-requiring type II diabetes mellitus were found to have an increase both in serum Lp(a) concentration and in prevalence of serum Lp(a) concentration > 30 mg/dl compared with the other groups of diabetic patients and nondiabetic control subjects. A nonsignificant increase in the prevalence of coronary heart disease was also found in insulin-requiring type II diabetic patients. The levels of serum concentrations of Lp(a) were not significantly related to the degree of glycemic control, duration of diabetes, presence of macrovascular disease, or intake of female hormone therapy. High levels of Lp(a) in this group of diabetic patients could not be explained by the presence of albuminuria. CONCLUSIONS: Insulin-requiring type II diabetic patients have high levels of Lp(a). Chronic hyperinsulinemia might be an eventual causal factor.

The lipoprotein(a). Significance and relation to atherosclerosis.

Lipoprotein(a) has many similarities to low density lipoproteins but possesses a unique protein moiety called apolipoprotein(a). The plasma concentration of lipoprotein(a) is mainly under genetic control and most of diets and hypolipidemic drugs do not change its level. Only nicotinic acid and neomycin are able to reduce its concentration. Epidemiological studies suggest that high level (greater than 30 mg/dl) of lipoprotein(a) is an independent risk factor for atherosclerosis of the coronary and carotid arteries. The risk is highest in patients with hypercholesterolemia. The atherogenic role of lipoprotein(a) is attributed to the lack of its recognition by the cellular receptors and its consequent diversion to the atherogenic "non receptor" pathway. Due to its strong homology with plasminogen, lipoprotein(a) could also favour thrombosis. It is suggested that its determination is of importance when evaluating a patient with atherosclerosis. Reducing high plasma levels of cholesterolemia appears to be mandatory when plasma lipoprotein(a) concentration is higher than 30 mg/dl.