The report of male gender and retinopathy status improves the current consensus guidelines for the screening of myocardial ischemia in asymptomatic type 2 diabetic patients.

BACKGROUND AND AIMS: American Diabetes Association (ADA), French-speaking Societies for diabetes & cardiology (ALFEDIAM-SFC) and Cardiac Radionuclide Imaging (CRI) have proposed guidelines for the screening of silent myocardial ischemia (SMI). The aim of the study was to evaluate their diagnostic values and how to improve them. METHODS AND RESULTS: 731 consecutive type 2 diabetic patients with ≥1 additional risk factor were screened between 1992 and 2006 for SMI by stress myocardial scintigraphy and for silent coronary artery disease (CAD) by coronary angiography. A total of 215 (29.4%) patients had SMI, and 79 of them had CAD. ADA (Odds Ratio 1.7 [95% Confidence Interval: 1.2-2.5]; p < 0.05), ALFEDIAM-SFC (OR 1.5 [1.0-2.5], p < 0.05) and CRI criteria (OR 2.0 [1.4-2.8], p < 0.01) predicted SMI. Considering the presence of male gender and retinopathy added to the prediction of SMI allowed by ADA criteria (c statistic: area under the curve AROC 0.651 [0.605-0.697] versus 0.582 [0.534-0.630]), p < 0.01 and ALFEDIAM-SFC criteria (AROC 0.672 [0.620-0.719] versus 0.620 [0.571-0.670], p < 0.05). CRI prediction of SMI was improved by considering the presence of macroproteinuria and retinopathy (AROC 0.621 [0.575-0.667] versus 0.594 [0.548-0.641], p < 0.01). Severe retinopathy (OR 3.4 [1.2-9.4], p < 0.05), smoking habits (OR 2.1 [1.1-4.2], p < 0.05) and triglyceride levels (OR 1.3 [1.0-1.6], p < 0.05) were independent predictors of CAD in the patients with SMI. CONCLUSION: Current guidelines criteria are able to predict SMI but prediction may be improved by considering male gender and the presence of retinopathy. CAD is more frequent in the patients with SMI who are current smokers, have severe retinopathy and higher triglyceride levels.

Nutritional AMD treatment phase I (NAT-1): feasibility of oral DHA supplementation in age-related macular degeneration.

PURPOSE: To create a pilot study in order to evaluate the feasibility of a prospective case-control study of oral supplementation with fish oil (docosahexaenoic acid [DHA]; eicosapentaenoic acid [EPA]) in a population with age-related macular degeneration (AMD). METHODS: A homogeneous group of 38 patients with drusenoid pigment epithelial detachment in one eye (PED) without choroidal new vessels (CNV) was selected. A complete ophthalmologic examination, and a complete profile of fatty acids in serum (S) and in red blood cell membranes (RBCM), were recorded at day 0 and month 6. In group 1, 22 patients were orally supplemented with EPA (720 mg/day) and DHA (480 mg/day) during 6 months. In group 2, 16 patients were followed as controls. Nutritional recommendations on fish consumption were given to both groups. RESULTS: In group 1, after 6 months supplementation we observed a significant blood enrichment in EPA (EPA-S: 2.20 vs 0.79, p<0.0001 and EPA-RBCM: 2.24 vs 0.85, p<0.0001) and in DHA (DHA-S: 2.47 vs 1.56, p<0.0001 and DHA-RBCM: 6.47 vs 4.67, p<0.0001). No change was observed in group 2 despite nutritional recommendations. In this short followup, no evolution to CNV was noted in either of the two groups. Neither side effects nor dropouts were observed in either of the groups. DISCUSSION: This study supports the feasibility of a long-term double-masked prospective case-control study in an AMD population in order to evaluate a potential benefit from oral supplementation with DHA.

[Lipid disorders in patients with HIV-induced diseases]. / Les désordres lipidiques des patients atteints d'affections causées par le VIH.

Before the availability of protease inhibitors, elevated triglyceride levels were frequently observed in patients with advanced-stage HIV infection. Since the addition of protease inhibitors to combination treatments, metabolic side effects (alterations in distribution of adipose tissue and metabolic disorders combining dyslipidemia, insulin-resistance and glucose intolerance) have been observed in HIV-positive patients receiving these treatments. Reverse transcriptase nucleoside inhibitors also provoke metabolic disorders. Dyslipidemia is defined by an increase in triglyceride levels of varying and sometimes major intensity, either isolated or combined with a more moderate increase in LDL-cholesterol, while HDL-cholesterol levels may decrease or remain unchanged. These metabolic alterations are potentially atherogenic and may explain these patients' increased risk of cardiovascular disorders. Their mechanism is complex and not yet clearly elucidated. The infection, the improvement in patients' general health and immune status, and individual predisposing factors are probably involved. Treatment probably plays a major role, since the different drugs in these two classes show effects of clearly different intensity. In vitro and ex vivo studies suggest that protease inhibitors alter adipocyte differentiation and induce insulin resistance. Reverse transcriptase nucleoside inhibitors modify adipocyte metabolism too, promoting tissue atrophy. Endocrine factors (cortisol and growth hormones) are also likely to have a role in this hypertrophy of adipose, especially visceral, tissue. These metabolic abnormalities result mainly from the effects of the antiretroviral drugs, notably protease inhibitors, on the hepatic lipid metabolism and on tissue sensitivity to insulin. Lipodystrophy contributes to these abnormalities, as does the reduction in cytokine secretion by adipose tissue. Management of these metabolic disorders is based primarily on a change in the drug regimen (administration of the least deleterious combinations), followed by standard dietary measures and, when necessary, lipid-lowering agents.

[Dietary primary prevention of cardiac ischemic diseases]. / Prévention primaire diététique des maladies ischémiques cardiaques.

Population studies have shown that ischaemic cardiopathy is more frequent in countries where the inhabitants have diets rich in saturated fats and in cholesterol, and where cholesterolaemia is raised. The epidemiological data from large prospective studies have shown that total cholesterolaemia is positively correlated with coronary risk. Therapeutic trials performed with the statins in particular have demonstrated that a reduction in LDL cholesterol allows a reduction in coronary morbidity, suggesting a causal role for cholesterol. Primary prevention dietetic trials have often been disappointing, probably due to a drop in cholesterol which is too modest, insufficient study size and duration, and perhaps also because they concerned low risk subjects. A meta-analysis of 27 primary and secondary prevention dietetic studies produced evidence of a reduction in morbidity, principally when the studies lasting less than 2 years were not taken into account. In this meta-analysis the drop in cholesterol was correlated with a reduction in clinical events. The benefit of a modified fat diet in primary prevention is therefore potentially significant if it is maintained for a sufficient length of time. The very positive results of the American national programme of nutritional intervention, which has had an undeniable impact on the prevalence of lipid disorders in the general population and secondarily on coronary mortality, favours the continuation of this mode of prevention.

Autosomal dominant type IIa hypercholesterolemia: evaluation of the respective contributions of LDLR and APOB gene defects as well as a third major group of defects.

Autosomal dominant type IIa hypercholesterolaemia (ADH) is characterised by an elevation of total plasma cholesterol associated with increased LDL particles. Numerous different molecular defects have been identified in the LDL receptor (LDLR) and few specific mutations in the apolipoprotein B (APOB) gene resulting in familial hypercholesterolaemia and familial defective apoB-100 respectively. To estimate the respective contribution of LDLR, APOB and other gene defects in this disease, we studied 33 well characterised French families diagnosed over at least three generations with ADH through the candidate gene approach. An estimation of the proportions performed with the HOMOG3R program showed that an LDLR gene defect was involved in approximately 50% of the families (P = 0.001). On the other hand, the estimated contribution of an APOB gene defect was only 15%. This low estimation of ADH due to an APOB gene defect is further strengthened by the existence of only two probands carrying the APOB (R3500Q) mutation in the sample. More importantly and surprisingly, 35% of the families in the sample were estimated to be linked to neither LDLR nor APOB genes. These data were confirmed by the exclusion of both genes through direct haplotyping in three families. Our results demonstrate that the relative contributions of LDLR and APOB gene defects to the disease are very different. Furthermore, our results also show that genetic heterogeneity is, generally, underestimated in ADH, and that at least three major groups of defects are involved. At this point, the contribution of the recently mapped FH3 gene to ADH cannot be assessed nor its importance in the group of 'non LDLR/non APOB' families.

[Hypertriglyceridemia: danger for the arteries]. / Hypertriglycéridémie: danger pour les artères.

AN INDEPENDENT RISK FACTOR: Although debate continues on the epidemiological impact, all surveys report that elevated serum triglyceride is an important risk factor in one-way analysis. More recent case-control studies in patients with premature coronary artery disease have shown that total triglyceride and VLDL levels discriminate better between subjects with and without coronary artery disease. Angiographic studies demonstrate that elevated serum triglyceride is found in coronary artery disease patients and that elevated VLDL or IDL is associated with severity. This relationship is persistently found when the serum cholesterol is taken into consideration but is no longer significant in most of the multivariate analyses. A recent meta-analysis is however in favor of an independent role for triglycerides, particularly in women. Two prospective studies published in 1998 confirmed that hypertriglyceridemia is an independent risk factor. VARIABLE IMPACT: Hypertriglyceridemia is a heterogeneous anomaly, not only due to different underlying pathophysiological mechanisms, but also in terms of cardiovascular risk. In familial hypertriglyceridemia, cardiovascular risk is apparently only moderately affected. Inversely, in combined familial hypertriglyceridemia and hyperapobetalipoproteinemia, the risk of premature cardiovascular disease is increased. ATHEROGENIC EFFECT: Unlike large VLDL rich in triglycerides, small VLDL rich in cholesterol ester have a strong atherogenic potential. Likewise, remnants are potentially atherogenic due to their relatively high cholesterol ester component and their accumulation on the arterial wall (Zilversmit postprandial atherogenesis theory). INCREASED RISK: The triglyceride-related risk is partly the consequence of frequently associated changes in lipoprotein distribution (lower HDL cholesterol, principal consequence of hypertriglyceridemia, elevation of small dense more readily oxidizable LDL) and hemostasis disorders (increased factor VIIc and PAI-1). In addition, hypertriglyceridemia is often found with other cardiovascular risk factors, particularly it readily occurs in insulin resistance syndromes.

[Inhibitors of GPIIb/IIIa platelet receptors]. / Inhibiteurs des récepteurs GP IIB/IIIA plaquettaires.

Acute myocardial ischaemia is nearly always the result of thrombosis of an unstable coronary lesion responsible for activation of platelet aggregation. The inhibition of platelet activation should lead to a decrease in the incidence of acute complications. However, the pathways of activation of platelet aggregation are multiple (nearly 100 pathways have been identified). The activation of the GPIIb/IIIa receptors which contribute to the formation of the fibrin bridge between two platelets represents the final phase of this activation. The anti-GPIIb/IIIa molecules have, therefore, a much more powerful and rapid anti-aggregant effect than classical anti-aggregant drugs which only act on one of the pathways of this activation. Clinical trials with these therapeutic agents in patients with acute coronary syndromes requiring angioplasty, have shown the superiority of these molecules compared with classical treatment. The main result of these clinical trials are presented.

[The hemochromatosis gene (HFE). Molecular analysis--diagnostic applications]. / Le gène de l'hémochromatose (HFE). Analyse moléculaire--applications diagnostiques.

Hemochromatosis is the most common single gene disorder in Caucasian populations. Regulation of iron balance by intestine is impaired, leading to a widespread deposition of iron, and the disease is associated with an increased risk of hepatocellular carcinoma. Typically the excess of iron treated by phlebotomies is performed in our Blood Center. In 1996 an original paper identifying HFE as a strong candidate gene for hemochromatosis was published and two mutations were described (C282Y and H63D). The former results in a cysteine to tyrosine substitution at amino acid 282 and was found in different patient populations up to 80-90% of patients homozygous for the C282Y mutation. The frequency of the second variant H63D is also increased in hemochromatosis patients but its penetrance is probably not complete. Assessing clinical implications is a new way of identifying patients at risk for this frequent and probably underdiagnosed disease, and important because treatment by venesections is safe with a proven benefit in preventing development of the disease. Four hundred and eighty patients were included in our study and we have shown in this work a correlation between the genotype and the phenotypic presentation of the disorder, with patients homozygous for the C282Y mutation having a greater excess of iron.

Determination of plasma protein-bound malondialdehyde by derivative spectrophotometry.

We describe a method for the measurement of protein-bound malondialdehyde with the thiobarbituric acid reaction in human plasma using second-derivative spectrophotometry. Calibration was done by spectrum height measurement from the baseline at 532 nm. The data were compared with those obtained by using conventional absorbance and fluorimetric measurements. The results were linear from 0.2 to 80 mumol/l and the detection limit was 0.19 mumol/l. Within-run and between-run precision, evaluated by analysing pooled normal plasma, were 8 and 14% respectively. The method was tested for the influence of bilirubin, haemoglobin, glucose, urea, uric acid, sucrose and N-acetyl-neuraminic acid which interfered in the colorimetric method but not in the technique proposed here. The mean (+/-SD) malondialdehyde concentration determined in 59 healthy blood donors with the new assay was 0.34 (+/-0.14) mumol/l. This assay procedure could represent an alternative to high-performance liquid chromatography for the measurement of malondialdehyde in biological media.

[Combined oral estrogen / progestin contraception: practical attitude. Vascular attacks and contraception]. / Contraception oestro-progestative: attitude pratique. Accidents vasculaires et contraceptifs.

PIP: Cardiovascular effects, especially thromboembolism, have been considered the leading complication of hormonal contraceptives. It appears that these effects are most often partially related to the estrogen dosage and to a lesser degree on the progestogen dosage of combined oral contraceptives (OCs). Further, certain preexisting or not yet revealed risk factors increase the likelihood of cardiovascular effects. OCs aggravate such risk factors. These contraindications include smoking, age (= or 35 years old), arterial hypertension, diabetes, and hyperlipemia. The frequency of cardiovascular complications among OC users began to fall after low-dose OCs were introduced. Thus, reducing the hormone dosage of OCs and better screening of patients are needed to further reduce the frequency of cardiovascular complications.^ieng

Efficacy and safety of simvastatin (alone or in association with cholestyramine). A 1-year study in 66 patients with type II hyperlipoproteinaemia.

The effects and safety of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, were investigated alone or in association with cholestyramine in 66 patients with hypercholesterolaemia, in a 1-year study. In type IIa hypercholesterolaemia (41 patients), the association was more effective than simvastatin used alone in lowering total cholesterol (37% vs 29%) and LDL-cholesterol (45% vs 37%). In type IIb hypercholesterolaemia (23 patients), the association simvastatin-cholestyramine did not appear more effective than simvastatin used alone. The decrease of apoprotein B was parallel to the LDL-cholesterol decrease. Apoprotein A1 did not change significantly. The long-term safety of simvastatin was good. No lens opacity was noted. The most serious side-effect in our study was myolysis which occurred in two patients with a marked increase in creatine phosphokinase.

[Effects of simvastatin on plasma lipids, lipoproteins and apoproteins (A1 and B). 24 cases of major primary hypercholesterolemia]. / Effets de la simvastatine sur les lipides, lipoprotéines et apoprotéines (A1 et B) plasmatiques. 24 cas d'hypercholestérolémie primaire majeure.

We studied the effects of simvastatin (MK 733), a new competitive inhibitor of HMG CoA reductase, alone and in combination with a bile acid sequestrant, cholestyramine, on serum levels of lipoproteins and apoproteins A1 and B, in 24 patients with familial hypercholesterolemia. After simvastatin treatment (40 mg/day) alone for 12 weeks, serum total and low density lipoprotein cholesterol decreased by 31 and 36 percent respectively. With the addition of cholestyramine, there was a 41 per cent total decrease in serum cholesterol from the control value and a 50 percent decrease in low density lipoprotein cholesterol. After cholestyramine treatment alone for 12 weeks, serum total and low density lipoprotein cholesterol decreased by 20 percent and 29 percent respectively. With the addition of simvastatin (20 mg per day), there was a 32 percent total decrease in serum cholesterol from the control value and a 43 percent decrease in low density lipoprotein cholesterol. High density lipoprotein cholesterol remained unchanged. No major adverse effect was observed. If long term safety can be confirmed, the simvastatin-cholestyramine regimen may prove useful in heterozygous familial hypercholesterolemia.

Changes in lipid and lipoprotein levels and Achilles tendon diameters and indices in familial hypercholesterolaemic patients with tendinous xanthomatosis treated by diet and bezafibrate for 2 years.

Thirteen young adult patients suffering from heterozygotic familial hypercholesterolaemia with tendinous xanthomatosis, previously treated with a suitable special diet, were studied to assess the effect of bezafibrate, given for 2 years at a dose of 800 mg/day, on plasma lipid and lipoprotein levels and on changes in size of the Achilles tendon xanthomas. Measurements were made before and at intervals during treatment, the tendinous xanthomas being measured by an echographic procedure to give data on antero-posterior and lateral diameters, thus enabling an Achilles tendon index to be defined. The results confirm the hypolipidaemic activity of bezafibrate, changes in the levels of total cholesterol, triglycerides, lipids and lipoproteins (LDL, VLDL and HDL) being similar in direction and magnitude to those reported previously. A significant regression in the size of the Achilles tendon xanthomas was observed in 11 of the 13 patients, and the regression in the Achilles tendon index correlated significantly with a favourable change in the ratio HDL/LDL + VLDL. It is suggested that, as a result of this objective observation, a favourable effect of bezafibrate treatment would possibly be seen on the anatomical atheromatous lesions which are usual in this type of hyperlipidaemia.