Usefulness in predicting coronary artery disease by ultrasonic evaluation of the carotid arteries in asymptomatic hypercholesterolemic patients with positive exercise stress tests.

A positive exercise electrocardiogram (ECG) is not infrequent occurrence in asymptomatic hypercholesterolemic patients, but the number of false-positive tests may be relatively high (50%). Therefore, the ability of a positive stress ECG to predict coronary artery lesions is low even in populations with > or =1 cardiovascular risk factors. To increase the diagnostic value of exercise tests for screening asymptomatic individuals, we analyzed whether combined clinical parameters with carotid echography would accurately predict coronary atherosclerotic lesions by coronary angiography in asymptomatic hypercholesterolemic patients with a positive exercise ECG. Seventy-six asymptomatic patients (between 35 and 65 years of age) with hypercholesterolemia (total plasma cholesterol >6.5 mmol/L or 250 mg/dl) and a positive stress ECG were referred for carotid B-mode echography and coronary angiography. Carotid echography data were divided into 2 categories: (1) absence of any atherosclerotic plaque, or (2) presence of > or =1 arterial plaques. Coronary stenosis assessed by coronary angiography was considered to correspond to a > or =50% reduction of coronary lumen diameter. Forty-three patients (57%) displayed coronary lesions; most (38; 88%) had carotid plaque. Multivariate analysis showed that the presence of carotid plaque was significantly associated with coronary stenosis (odds ratio 15.2; confidence interval 5.0 to 54.5). In subgroups characterized by high frequency of false-positive exercise electrocardiographic tests (women and patients with a 10-year predicted risk of coronary artery disease [CAD] <15%), none of the patients without carotid plaque exhibited coronary lesions. Echographic evaluation of carotid plaque (plaque vs no plaque) significantly improved the diagnostic specificity of exercise electrocardiography. We conclude that the combination of clinical, electrical, and echographic data facilitates cost-effective noninvasive detection of CAD in asymptomatic hypercholesterolemic patients.

[LDL-apheresis therapy, methods and indications]. / Traitement par LDL-aphérèse, techniques et indications.

A SEVERE DISEASE: Homozygote hyper cholestrolemia is a very severe disease with an extremely high atherogenic potential. The risk of sudden death starts at about the age of 10 years and mortality reaches nearly 100% at 20 years. In this homozygote autosomal dominant disorder, serum cholesterol rises above 6 g/l due to a total deficiency of LDL-receptors. LDL-APHERESIS: The treatment of choice, LDL-apheresis, is an aggressive treatment. Drug regimens and palliative surgery have little or no effect. Liver transplantation is highly effective but compromises long term prognosis. LDL-apheresis, indicated in case of drug resistance, can be used to clear atherogenic LDL particles extracorporally. Currently it is the most effective means of lowering serum cholesterol in these patients and avoid potential cardiovascular complications. SEVERAL TECHNIQUES: The most specific techniques are also the most costly. These techniques allow treating whole blood or previously separated plasma. Such specific techniques are indicated in children. Compared with other European countries such as Germany, the development of these techniques has been retarded in France due to the lack of financing by the national health insurance system.

[Effects of rilmenidine (hyperium) on lipid balance in hyperlipidemic hypertensive patients. Randomized, controlled, double-blind 8-week study vs. captopril in parallel groups]. / Effets de la rilmenidine (hyperium) sur l'équilibre lipidique des patients hypertendus hyperlipidémiques. Etude randomisée à double insu et en groupes parallèles, contrôlée contre captopril, pendant 8 semaines.

Rilmenidine (dose of 1 mg once or twice a day) is the first oxazoline compound with antihypertensive properties. Its effects on lipid parameters [total cholesterol, HDL and LDL fractions, triglycerides, apolipoprotein A1 and B, lipoprotein (a)] were compared under double-blind conditions and in parallel groups to those of captopril (50 to 100 mg per day, in 2 divided doses) over a period of 8 weeks, in 51 hyperlipidaemic hypertensive patients [age: 56.3 +/- 1.5 years, systolic and diastolic blood pressure (SBP/DBP): 165.1 +/- 2.0/99.1 +/- 0.6 mmHg, LDL cholesterol: 5.38 +/- 0.16 mmol/L]. No significant difference was demonstrated between the groups on inclusion for any of the clinical parameters (SBP, DBP, heart rate (HR)) and laboratory parameters, apart from apolipoprotein A1, for which the mean value was higher in the rilmenidine group than in the captopril group (p < 0.05). No difference between the groups was demonstrated during the 8 weeks of treatment for the course of blood pressure: SBP and DBP decreased by 20.5 and 13.9 mmHg, respectively, in the rilmenidine group and by 21.3 and 13.1 mmHg in the captopril group (no significant difference: NS). HR decreased by 0.3 beats per minute (bpm) in the rilmenidine group and by 4.1 bpm in the captopril group (NS). No statistically significant difference in lipid parameters was observed between the two groups. No clinically significant variation in any of the lipid parameters was observed after 8 weeks of treatment with rilmenidine or captopril. These results confirm the antihypertensive efficacy and neutrality of rilmenidine on lipid metabolism over a period of 8 weeks. Rilmenidine therefore represents a useful alternative in the first-line treatment of hypertension in hyperlipidaemic hypertensive patients.

Phenotypic expression in double heterozygotes for familial hypercholesterolemia and familial defective apolipoprotein B-100.

Variability in the expression of monogenic lipid disorders may be observed in patients carrying the same DNA mutation, suggesting possible genetic or environmental interactions. Our objective was to investigate the genotype-phenotype relationships in two unrelated French patients with an aggravated expression of a dominantly inherited hypercholesterolemia. In probands, segregation analysis complemented by DNA sequencing identified heterozygous defective alleles and mutations on two nonallelic loci for two monogenic lipid disorders: familial hypercholesterolemia at the low density lipoprotein (LDL) receptor locus and familial defective apolipoprotein B-100 at the locus encoding its ligand, apolipoprotein B-100. The LDL-receptor missense mutations had been reported in French Canadians. The apolipoprotein B mutation was the Arg3500Gln founder mutation in Northern Europe. Probands had an unusual phenotype of aggravated hypercholesterolemia that was complicated with premature coronary arterial disease, although remaining responsive to lipid-lowering drugs. This phenotype was distinct from that observed in their heterozygous relatives and distinct from those observed in FH or FDB homozygotes. These cases refer to a new class of patients with digenic lipid disorders, defined by specific clinical features that result from the combined effects of two independent loci. Moreover, the observed phenotype of aggravated hypercholesterolemia gives further evidence that receptor and ligand play distinct roles in regulating LDL metabolism. Although uncommon, these cases give insight into the molecular mechanisms that underly the clinical variability of inherited hypercholesterolemia.

[Metastatic pulmonary carcinoma, revealed by Cushing syndrome, initially considered to have a pituitary origin. Course over 25 years]. / Carcinome pulmonaire métastatique, révélé par un syndrome de Cushing, initialement considéré comme d'origine hypophysaire. Evolution sur 25 ans.

It is often difficult to differentiate between Cushing's syndrome and ectopic ACTH hypersecretion which, in rare cases, may result from a carcinoid tumour. Several years may be required before development of patent Cushing's syndrome. We report the 25-year clinical course in a patient with a pulmonary carcinoid tumour. Initially, the hormone results led to the diagnosis of Cushing's syndrome and the patient was treated accordingly. Bilateral adrenectomy was performed in 1969 followed by radiotherapy of the pituitary gland in 1975 for suspected Nelson's syndrome. Actually, the carcinoid tumour, located retrocardially, had gone unnoticed until 1989. Diagnosis was suspected during a hospitalization in our unit and the patient underwent tumour exeresis and left inferior lobectomy. Despite tumour removal and demonstration of tumoural ACTH secretion, the levels of ACTH and beta-lipotrope hormone remained high suggesting lymph node and/or pulmonary metastasis. This observation emphasizes the long clinical course of carcinoid tumours despite their malignancy and the unusual response to the dexamethasone test.

[Management of dyslipidemia]. / Prise en charge des dyslipidémies.

There is now an enormous amount of literature on the relationship between blood lipids and coronary artery disease. It is clear that the treatment by modification of the diet and hypolipidaemic drugs is associated with a decrease of the coronary events. However there is no cure for any of the primary dyslipidemias and relative treatment involves a life-long commitment by the patient. In addition the efficiency of the treatment is dramatically different in patients at very high risk (secondary prevention, combination of several risk factors) and in those at moderate risk. Furthermore, patient's compliance is usually low. Therefore management of the hyperlipidaemic patients requires a rigorous approach to evaluate the global risk and consequently to adapt the treatment at an individual level. We describe here our outpatient clinic in which about 6000 hyperlipidaemic patients have been referred. We indicate the strategy that we used for taking care the patients including 1) the education of the subjects 2) the detection of secondary hyperlipidaemia 3) the evaluation of the global risk including non-invasive evaluation of the atherosclerosis and the results of such approach (for example, we found a much higher percentage of positive exercise ECG in patients with carotid atherosclerosis in our ultrasonographic examinations.

[Substitutive hormonal treatment of menopause. Effects on lipoprotein metabolism]. / Traitement hormonal substitutif de la ménopause. Effets sur le métabolisme des lipoprotéines.

A number of epidemiological studies have clearly shown that post-menopausal women on hormone therapy (which tends to simulate normal ovarian production) have a reduced risk of cardiovascular disease (coronary heart disease, stroke and thrombotic events). In fact most of the studies have involved equine oestrogen (Premarin) taken orally. The effects of oestrogens and the progestins depend on the type of administration (oral or percutaneous administration) and the variety of the drug chosen and finally is also dose dependent. The most favourable effect is obtained in normolipidaemic women with the combination of conjugated oestrogens given orally and a non-androgenic progestins. Such therapy is associated with an increase in HDL-cholesterol and a decrease in LDL-cholesterol. HDL subfraction analysis shows that HDL2 are the main species involved in this increase. The mechanism of action of oestrogens and progestins can be summarized as follows: oestrogens stimulate hepatic triglyceride secretion, inhibit the action of hepatic lipase, augment LDL breakdown via the cellular receptor apo B-E and may decrease LDL oxidability and Lp(a) levels. Although several points remain obscure, we may notice that most of studies show that the atherogenic profile of the women who are currently being treated tends to improve.

Blood antioxidants (vitamin E and beta-carotene) in long-term low density lipoprotein apheresis.

We measured vitamin E and beta-carotene in the serum and in circulating lipoproteins in a large population of 15 patients with familial hypercholesterolaemia who were undergoing long-term treatment by low density lipoprotein (LDL) apheresis. The technique used for apheresis was dextran sulphate cellulose adsorption. The results showed that before LDL apheresis, patients had high vitamin E and normal beta-carotene levels in the serum and in the VLDL+LDL fraction. There were no relationships between serum levels of vitamin E and beta-carotene and the duration of LDL-apheresis. Low vitamin E and beta-carotene levels in the HDL fraction could be related to the low HDL concentrations in these patients. Vitamin E/cholesterol ratios were similar to those of the normolipaemic controls whereas beta-carotene/cholesterol ratios were lower. After LDL-apheresis treatment, the ratios in the HDL fraction fell whereas the ratios in the serum and in the VLDL and LDL fraction did not change. This study shows that these patients exhibited no deficiency in either serum of VLDL-LDL of vitamin E or beta-carotene after long-term treatment by LDL-apheresis and that the status of these antioxidants in serum was independent of the duration of treatment.

Lipoprotein glomerulopathy: first case in a white European.

Since 1988, 11 cases of a new entity, 'Lipoprotein glomerulopathy' (LG), were described in Japan. Some of these reports suggested that this glomerular lipid storage is due to excess apo E associated with heterozygous E2/3 apo E isoform. We report the first case of LG in a white European with no such lipid abnormalities. Proteinuria was discovered in 1967 when he was 42. Blood pressure and renal function were normal. Family history was negative. Renal biopsy disclosed lesions which were only understood at the time of the Japanese publications. They were composed of endocapillary glomerular deposits. Staining for lipids disclosed capillary loop obstruction with lipid droplets. Electron microscopy showed confluent droplets of various sizes obstructing capillary loops. Proteinuria progressively increased. In 1974 repeat renal biopsy showed the same lipid deposits, now associated with focal-segmental glomerulosclerosis (FSGS). Several serum lipoprotein and apolipoprotein studies ruled out any specific lipid derangement. This suggested a local glomerular disorder, presumably affecting the glomerular endocapillary disposal of lipids. A third biopsy showed progressive glomerular destruction by FSGS with persistence of the lipid droplets. Renal insufficiency progressed and haemodialysis was started in 1992. This observation suggests that LG is a local glomerular, not a general lipid disorder and indicates that this disease is not restricted to Asian patients.

Lipid profile and antihypertensive efficacy in hyperlipidemic hypertensive patients: comparison of rilmenidine and captopril.

In hypertensive patients with lipid abnormalities, an ideal antihypertensive agent would control blood pressure without interfering with lipid metabolism. The aim of the present study was to assess whether in addition to angiotensin-converting enzyme inhibitors, calcium antagonists, and alpha 1-antagonists, rilmenidine (RIL), the first antihypertensive drug that is selective to imidazoline receptors, fulfills these requirements. To assess the effects of RIL (daily doses of 1 mg o.d. or b.i.d.) in comparison to captopril (CAP) (doses of 25 or 50 mg b.i.d.), an 8-week, double-blind, randomized, parallel-group study was carried out. Fifty-one patients (mean age: 56.3 +/- 1.5 years) with mild-to-moderate hypertension (supine systolic/diastolic blood pressure, 165.1 +/- 2.0/99.1 +/- 0.6 mm Hg) and type 2a or 2b hyperlipidemia (low-density lipoprotein (LDL) cholesterol: 5.38 +/- 0.16 mmol/L) were included in the study, and they were followed by their general practitioner at 4-week intervals. Twenty-six patients received RIL, and 25 received CAP. The permanence of hypercholesterolemia was checked twice before inclusion into the study, at 3-week intervals, for patients who had already been on a hypocholesterolemic diet for 6 weeks. Plasma lipid evaluation included total, LDL and high-density lipoprotein (HDL) cholesterol, triglycerides, apolipoproteins A1 and B, lipoprotein (a), and, last, a uric acid assay. Assays were centralized at the Lipid Laboratory, CHU Pitié-Salpétrière, Paris. In each group, 1 patient withdrew from the study for personal reasons, and four patients required a dose adjustment (double dose) at the week 4 visit. After 8 weeks of therapy, systolic blood pressure decreased significantly in both groups, with no statistically significant difference between groups (RIL, 20.5 mm Hg; CAP, 21.3 mm Hg; NS). Diastolic blood pressure also decreased (RIL, 13.9 mm Hg; CAP, 15.1 mm Hg; NS). No difference between groups was observed on the changes of lipid parameters between week 0 and week 8 visits. No severe adverse event occurred other than an asymptomatic atrial fibrillation in a CAP group patient at week 8. This study provides evidence that over a follow-up period of 8 weeks, both RIL and CAP are efficient and well-tolerated drugs in the first-line treatment of hypertensive patients with lipid abnormalities.

[Hypocholesterolemic statins. Evaluation and prospects]. / Statines hypocholestérolémiantes. Bilan et perspectives.

Statins are a family of compounds which act on cells by inhibiting hydroxymethylglutaryl (HMG) CoA reductase, an enzyme that blocks the intracellular cholesterol synthesis and stimulates the formation and action of LDL receptors. Experience of 3 years after they were introduced in France and 10 years for studies of the first compound (lovastatin) has demonstrated that these drugs are potent hypercholesterolaemia-lowering agents, fairly well tolerated but possibly with some toxicity to muscles. In severe forms of pure hypercholesterolaemia they may be prescribed either alone or combined with biliary acid chelating resins. Their use in mild forms of hypercholesterolaemia will be justified when low-dose preparations are reimbursed by the French Social Security. In mixed hyperlipidaemia, statins are more effective than fibric acid derivatives on cholesterol but weaker on triglycerides. They provide an alternative to fibric acid derivatives when these fail, but they are not indicated in hypertriglyceridaemia. Studies are being carried out to demonstrate that statins have a preventive effect on cardiovascular diseases, in either clinical regression trials or atheromatous plaque regression studies.

[Molecular genetics in pure primary hypercholesterolemia]. / Apports de la génétique moléculaire dans les hypercholestérolémies pures primitives.

Pure primary hypercholesterolemia include a set of lipid disorders related to the metabolism of Low Density Lipoproteins (LDL), which are now recognised as causes of atherosclerosis. Although many genetic and environmental factors contribute to their pathogenesis, two major genes influence LDL metabolism: the LDL receptor and its natural ligand, apolipoprotein B. These genes have been characterised and localised on human chromosomes, and can be studied at the molecular level. The many gene defects observed on both these loci as causes of primary hypercholesterolemia, have demonstrated the genetic heterogeneity of these disorders (one phenotype related to different predisposing loci). The candidate gene approach, is a method that can overcome the difficulties of this genetic heterogeneity. Using simplified molecular techniques it can be used in predictive diagnosis, pointing the predisposing locus, leading to the identification of causative mutations and guiding therapeutic strategies. Hence, new inborn errors of metabolism for which the molecular basis is well defined are now recognised, delineating the remaining defects to be characterised that also underlie primary hypercholesterolemia. These disorders account for the most frequent monogenic disorders in the French population. A better knowledge of their influence among other predisposing causes of atherosclerosis, will help define new preventive strategies based on the genetic component to its predisposition.

[Biological efficacy of LDL apheresis in major hypercholesterolemia]. / Efficacité biologique des LDL aphérèses dans les hypercholestérolémies majeures.

Severe hypercholesterolaemia include familial homozygous hypercholesterolaemia and certain heterozygous hypercholesterolaemias which become severe, due to spontaneous non-response to treatment or to iatrogenic side effects. Other causes include an associated overload in Lp(a) or uncontrolled atheromatous disease. Surgical treatment has been replaced by iterative LDL apheresis in these severe forms. Mean cholesterol and LDL cholesterol levels can be reduced by 41 to 63% and 49 to 68% respectively with LDL apheresis. In general, HDL cholesterol is protected in selective LDL apheresis. We observed similar decrease for apo B and LDL cholesterol levels. Fifty percent of the Lp(a) was removed in the 3 groups of patients studied.

[Frequency of hypothyroidism in a population of hyperlipidemic subjects]. / Fréquence des hypothyroïdies dans une population de sujets hyperlipidémiques.

Hypothyroidism is a classical cause of hypercholesterolaemia. As we sometimes met patients with hyperlipidaemia whose thyroid state was unknown, we carried out a prospective study aimed at evaluating the frequency of hypothyroidism in a population of 1210 hyperlipidemic patients who were referred to our out-patient clinic at the La Pitié Hospital, Paris, for metabolic and cardiovascular assessment. The proportion of subjects with high thyroid-stimulating hormone (TSH) levels was 12, 56 percent, which is distinctly higher than the figures reported in previous studies in patients who were not selected for lipid abnormalities. Among those with high TSH levels, 16 had overt hypothyroidism with a low free T4 level. Analysis of lipid parameters showed that hypertriglycidaemia was frequent and did not confirm the hyperHDLaemia classically observed in hypothyroidic populations. We conclude that screening for hypothyroidism by measuring TSH values is of particular importance in patients with hyperlipidaemia, especially in the group of women over 50 years of age.

Carotid stenosis is a powerful predictor of a positive exercise electrocardiogram in a large hyperlipidemic population.

Hypercholesterolemia is a major risk factor in coronary heart disease (CHD) and ischemic stroke. However, there is no general agreement on the usefulness of systematic screening of patients with hyperlipidemia by stress exercise electrocardiogram (ECG). The feasibility of this approach would depend on selecting patients with a high risk of CHD, since the sensitivity and specificity of the test depends on the prevalence of the disease. In view of the association of CHD and ischemic stroke, we undertook a study to determine whether the presence of atherosclerosis in the carotid arteries was predictive of a positive exercise ECG in a group of 778 asymptomatic patients referred to their hyperlipidemia. We a much higher percentage of positive exercise ECG in patients with carotid atherosclerosis in our ultrasonographic examinations. In a multiple regression analysis which included 13 parameters (age, sex, body mass index, arterial blood pressure, lipid parameters, serum level of glucose, smoking status and the severity of carotid lesions), the strongest predictors of a positive exercise ECG test were age (P = 0.014) and the degree of carotid atherosclerosis (P = 0.010). We therefore conclude that hyperlipidemic patients with atherosclerotic lesions on carotid arteries would benefit most from screening by the exercise ECG.

Screening for new mutations in the LDL receptor gene in seven French familial hypercholesterolemia families by the single strand conformation polymorphism method.

To investigate the molecular basis of familial hypercholesterolemia (FH) in France, we applied the single strand conformation polymorphism (SSCP) method to the promoter region and the 18 exons of the low density lipoprotein receptor (LDLR) gene. Seven probands, 4 heterozygotes, 2 compound heterozygotes, and 1 homozygote, belonging to FH families were tested. In all cases, previous genetic analysis and/or LDL receptor fibroblast assay had shown that the disease was due to defects in the LDLR gene. Out of the nine mutations expected, one nonsense mutation in exon 2 and six missense mutations were identified in exons 3, 6, 8, 11, and 15. Two of the latter were found in exon 6. In each family, cosegregation of the base substitution and the disease was observed. Ninety-five control subjects were screened for the presence of the six missense mutations. None was detected, implying that the mutations identified are deleterious. Our results indicate that the SSCP analysis of amplified genomic DNA fragments can be successfully used to rapidly screen mutation containing exons in large genes. Furthermore, all these mutations are newly described and demonstrate heterogeneity of LDLR gene mutations responsible for FH in the French population, as in other reported Caucasian populations.

[Which hypocholesteremic agents for which hypercholesterolemias?]. / Quels hypocholestérolémiants pour quelles hypercholestérolémies?

Three groups of drugs can be used in hypercholesterolemia: 1) Drugs chelating bile acids (resins) which stimulate LDL receptors. 2) HMG R inhibitors which competitively inhibit the enzyme and increase the synthesis of LDL receptors. 3) Fibrate derivatives which are second line drugs in pure hypercholesterolemia. They should be used in case of intolerance of resins and may be preferred to inhibitors in moderate forms for economic reasons of lower cost. However fibrates are the treatment of choice in hypertriglyceridemia and mixed hyperlipidemias. All fibrates increase HDL cholesterol. 4) Probucol, neomycin and nicotinic acid are adjuvant hypolipidemic agents. The following steps must precede the prescription of a hypolipidemic drug: 1) Classification of the disorder. 2) Elimination of secondary dyslipidemias. 3) Family assessment. 4) An absolutely essential dietary phase. 5) This is permanent treatment without gaps. 6) No other atherogenic risk factor should be allowed to persist. 7) Iatrogenic effects must be avoided.