Homocysteine and fibrinolysis in acute occlusive coronary events.
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Anticholesteremic Agents↗
Biomedical subjects
M de Lorgeril
Publications and source records attributed to M de Lorgeril.
Wine ethanol, platelets, and Mediterranean diet.
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Coronary Disease↗
Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study.
BACKGROUND: The Lyon Diet Heart Study is a randomized secondary prevention trial aimed at testing whether a Mediterranean-type diet may reduce the rate of recurrence after a first myocardial infarction. An intermediate analysis showed a striking protective effect after 27 months of follow-up. This report presents results of an extended follow-up (with a mean of 46 months per patient) and deals with the relationships of dietary patterns and traditional risk factors with recurrence. METHODS AND RESULTS: Three composite outcomes (COs) combining either cardiac death and nonfatal myocardial infarction (CO 1), or the preceding plus major secondary end points (unstable angina, stroke, heart failure, pulmonary or peripheral embolism) (CO 2), or the preceding plus minor events requiring hospital admission (CO 3) were studied. In the Mediterranean diet group, CO 1 was reduced (14 events versus 44 in the prudent Western-type diet group, P=0.0001), as were CO 2 (27 events versus 90, P=0.0001) and CO 3 (95 events versus 180, P=0. 0002). Adjusted risk ratios ranged from 0.28 to 0.53. Among the traditional risk factors, total cholesterol (1 mmol/L being associated with an increased risk of 18% to 28%), systolic blood pressure (1 mm Hg being associated with an increased risk of 1% to 2%), leukocyte count (adjusted risk ratios ranging from 1.64 to 2.86 with count >9x10(9)/L), female sex (adjusted risk ratios, 0.27 to 0. 46), and aspirin use (adjusted risk ratios, 0.59 to 0.82) were each significantly and independently associated with recurrence. CONCLUSIONS: The protective effect of the Mediterranean dietary pattern was maintained up to 4 years after the first infarction, confirming previous intermediate analyses. Major traditional risk factors, such as high blood cholesterol and blood pressure, were shown to be independent and joint predictors of recurrence, indicating that the Mediterranean dietary pattern did not alter, at least qualitatively, the usual relationships between major risk factors and recurrence. Thus, a comprehensive strategy to decrease cardiovascular morbidity and mortality should include primarily a cardioprotective diet. It should be associated with other (pharmacological?) means aimed at reducing modifiable risk factors. Further trials combining the 2 approaches are warranted.
Aged↗
Lipid-lowering drugs and homocysteine.
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Amino Acids↗
Effects of lipid-lowering drugs on left ventricular function and exercise tolerance in dyslipidemic coronary patients.
Previous studies suggested that certain lipid-lowering drugs such as statins suppress ubiquinone, affect mitochondrial function, and may have deleterious effect on skeletal or cardiac muscles with potentially serious clinical consequences, especially in patients with established coronary heart disease and left ventricular dysfunction. In this double-blind study, we assessed the effects of 20 mg simvastatin (S, n = 32) or 200 mg micronized fenofibrate (F, n = 32, control group) on rest and exercise left ventricular function in hypercholesterolemic survivors of a previous Q-wave acute myocardial infarction. Left ventricular radionuclide imaging was performed at rest and during submaximal exercise and global and segmental (nine segment regional wall-motion score) ejection fractions were measured before treatment and 12 weeks later. Serum ubiquinone was reduced after treatment (p = 0.03) in the S but not the F group, whereas total and low-density lipoprotein (LDL) cholesterol were significantly reduced in both groups. Before treatment, mean global ejection fraction was 52.1+/-12.2% and 49.3+/-11.8% at rest in F and S patients, respectively, and increased (56.0+/-13.7% in F and 52.1+/-12.9% in S) at peak exercise (no difference between groups). After treatment, the increase in ejection fraction tended to be lower in S (0) than in F (+3.8%) but not significantly. However, ejection fraction at rest increased after treatment in S (p = 0.009) but not in F. Subgroup analyses indicated that the improvement in rest ejection fraction in S was essentially observed in patients with ejection fraction <40% (n = 8, +6%), whereas it was stable in patients with ejection fraction >40% (+1.8%). Finally, the numbers of akinetic or hypokinetic segments at rest and during exercise were not different in the two groups before and after treatment. Mean maximal exercise load (113+/-23 watts in F vs. 104+/-27 W in S before treatment) was not modified by the treatment (111+/-21 and 104+/-27 W). Thus a 12-week lipid-lowering treatment with either S or F did not negatively alter left ventricular function during exercise in dyslipidemic patients with established coronary heart disease and did not affect their ability to exercise. The improvement in left ventricular function at rest after simvastatin in patients with left ventricular dysfunction warrants confirmation in further studies with large sample size.
Blood Pressure↗
Mediterranean dietary pattern in a randomized trial: prolonged survival and possible reduced cancer rate.
BACKGROUND: The Mediterranean dietary pattern is thought to reduce the risk of cancer in addition to being cardioprotective. However, no trial has been conducted so far to prove this belief. METHODS: We compared overall survival and newly diagnosed cancer rate among 605 patients with coronary heart disease randomized in the Lyon Diet Heart Study and following either a cardioprotective Mediterranean-type diet or a control diet close to the step 1 American Heart Association prudent diet. RESULTS: During a follow-up of 4 years, there were a total of 38 deaths (24 in controls vs 14 in the experimental group), including 25 cardiac deaths (19 vs 6) and 7 cancer deaths (4 vs 3), and 24 cancers (17 vs 7). Exclusion of early cancer diagnoses (within the first 24 months after entry into the trial) left a total of 14 cancers (12 vs 2). After adjustment for age, sex, smoking, leukocyte count, cholesterol level, and aspirin use, the reduction of risk in experimental subjects compared with control subjects was 56% (P=.03) for total deaths, 61% (P=.05) for cancers, and 56% (P=.01) for the combination of deaths and cancers. The intakes of fruits, vegetables, and cereals were significantly higher in experimental subjects, providing larger amounts of fiber and vitamin C (P<.05). The intakes of cholesterol and saturated and polyunsaturated fats were lower and those of oleic acid and omega-3 fatty acids were higher (P<.001) in experimental subjects. Plasma levels of vitamins C and E (P<.05) and omega-3 fatty acids (P<.001), measured 2 months after randomization, were higher and those of omega-6 fatty acids were lower (P<.001) in experimental subjects. CONCLUSIONS: This randomized trial suggests that patients following a cardioprotective Mediterranean diet have a prolonged survival and may also be protected against cancer. Further studies are warranted to confirm the data and to explore the role of the different lipids and fatty acids in this protection.
Diet↗
Improved myocardial tolerance to ischaemia in the diabetic rabbit.
Because cardiac complications after myocardial infarction are more frequent in diabetics, we tested whether experimentally-induced diabetes may increase ischaemic myocardial injury in 23 rabbits. Diabetes was induced in randomized rabbits with the alloxan method. After 2 months, diabetic rabbits underwent a 30-min coronary occlusion followed by 3-h reperfusion and were compared with controls. Collateral flow was measured by the radioactive microsphere technique and infarct size by tetrazolium staining. Infarct size represented 28.6+/-4% of area-at-risk in controls and 16.5+/-3% in diabetics (P<0.05). Collateral flow (0.06+/-0.03 ml/min/g in controls and 0.014+/-0.004 ml/min/g in diabetics) and area-at-risk (50.2+/-4.2% of left ventricle in controls and 53.9+/-5. 4% in diabetics) were similar in both groups. There was a significant positive correlation between area-at-risk and infarct size in both groups (r=0.60 and 0.70, respectively) and for a given area-at-risk, diabetic rabbits developed smaller myocardial infarction than controls (covariance analysis, P<0.01). In additional experiments, hyperglycemia induced by intravenous glucose infusion in non-diabetic rabbits did not protect the ischaemic myocardium (infarct size: 37.9+/-12.5%). In conclusion, diabetes in the rabbit induces a chronic and metabolic form of preconditioning. Further studies are needed to explore the mechanism and time course of this protection.
Animals↗
Effect of chronic severe diabetes on myocardial stunning in the dog.
In this study, we examined whether chronic severe diabetes may affect ischaemic and post-ischaemic regional myocardial dysfunction in vivo in the dog. Diabetes was chemically induced in randomized animals and major metabolic alterations were observed confirming the severity and chronicity of the diabetes. After 70 days, halothane-anaesthetized dogs underwent a 20-min coronary occlusion, followed by reperfusion. During ischaemia, global left ventricle function (dP/dtmax) was more altered (P<0.005) in diabetics ( n=10) than in controls (n=10), whereas area-at-risk (29+/-2.5% of the left ventricle in diabetics v 32.4+/-1.9% in controls) and ischaemic subendocardial myocardial blood flow (radioactive microsphere technique, 0.11+/-0.02 v 0.10+/-0.03 ml/min/g) were similar. During reperfusion, both groups developed significant (P<0.05) regional myocardial dysfunction (somomicrometry, 41+/-14% of baseline in controls and 66+/-8% in diabetics), whereas the difference between groups was not significant. No dog of either group developed myocardial cell necrosis on tissue histology. Multivariate analyses, including the severity of prior ischaemia and the occurrence of ventricular fibrillation as covariables, confirmed that myocardial stunning was not increased in diabetics, although ischaemia was clearly less-well-tolerated in diabetic dogs as global (dP/dtmax) as well as regional myocardial function were significantly (P<0.05) more altered in diabetics during ischaemia. Whilst alteration of arachidonate and cholesterol metabolism may partly explain this apparent paradox, further studies are required to resolve this issue.
Animals↗
Effect of dietary cholesterol on low density lipoprotein-receptor, 3-hydroxy-3-methylglutaryl-CoA reductase, and low density lipoprotein receptor-related protein mRNA expression in healthy humans.
We investigated the possibility that dietary cholesterol downregulates the expression of low density lipoprotein (LDL) receptor and 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase genes of circulating mononuclear cells in vivo in healthy humans. We also studied the variations of the LDL receptor-related protein (LRP) gene in the same conditions. Dieters (n = 5) were submitted to a 4-d fat restriction (mean cholesterol intake: 6+/-4 mg/d), followed by a 7-d cholesterol (a mean of 791+/-150 mg/d) supplementation. Controls (n = 3) did not change their diet. During fat restriction, serum total and LDL cholesterol decreased significantly (P < 0.05), and LDL receptor and HMG-CoA reductase mRNA copy numbers in mononuclear cells increased by 57 and 147%, respectively (P < 0.05). After reintroducing cholesterol, serum cholesterol was stable whereas LDL receptor and HMG-CoA reductase mRNA decreased by 46 and 72% (P < 0.05) and LRP mRNA increased by 59% (P < 0.005). The changes in LDL receptor and HMG-CoA reductase mRNA abundance were correlated (r = +0.79, P = 0.02) during cholesterol reintroduction as were LDL receptor and LRP mRNA levels, but negatively (r = -0.70, P = 0.05). Also, 70% of the variability in LRP mRNA (P < 0.005) was explained by dietary cholesterol. Thus, the basic mechanisms regulating cellular cholesterol content, the coordinate feedback repression of genes governing the synthesis and uptake of cholesterol, are operating in vivo in humans. However, serum cholesterol did not increase in response to dietary cholesterol, suggesting that these mechanisms may not play as predominant a role as previously believed in the short-term control of serum cholesterol in vivo in humans. A new finding is that LRP gene is also sensitive to dietary cholesterol, suggesting that it may participate in the control of serum cholesterol. Further in vivo studies in humans are warranted to explore the molecular mechanisms of the physiological response to dietary cholesterol in humans.
Adult↗
Dietary arginine and the prevention of cardiovascular diseases.
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Animals↗
Mediterranean diet in the prevention of coronary heart disease.
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Coronary Disease↗
Ticlopidine increases nitric oxide generation in heart-transplant recipients: a possible novel property of ticlopidine.
The objective of this study was to evaluate the effects of ticlopidine on the generation of eicosanoids and nitric oxide in heart-transplant recipients. In a randomized double-blind study, we studied the urinary excretion of the stable metabolites of thromboxane, prostacyclin, and nitric oxide before and after ticlopidine (250 mg/day). Platelet aggregation was significantly reduced in ticlopidine-treated patients [from 40.2 +/- 24.2% of maximal aggregation to 14.7 +/- 8.2% in response to adenosine diphosphate (ADP); p < 0.001] but not in the placebo group, confirming the efficacy of the drug with that dosage in these specific patients. The 24-h urinary excretion of prostacyclin metabolites was not modified by ticlopidine (1,865 +/- 833 ng/24 h at day 14 and 1,664 +/- 425 ng/24 h at day 0), whereas the excretion of thromboxane B2 tended to increase in the ticlopidine group (from 3,854 +/- 1,163 ng/24 h at day 0 to 5,014 +/- 2,914 ng/24 h at day 14), although not significantly. The excretion of nitric oxide metabolites (although not different from that of healthy nonimmunosuppressed subjects) was significantly (p < 0.005) increased in the ticlopidine group (from 3,082 +/- 1,683 micromol/24 h at day 0 to 4,133 +/- 2,262 micromol/24 h at day 14), but not in controls. Thus ticlopidine does not reduce prostacyclin but increases the systemic generation of nitric oxide, both substances having major antiplatelet and vasodilator properties. Further studies are warranted to examine whether ticlopidine could reduce the incidence of thromboembolic complications in these patients and whether this possible novel property of ticlopidine is restricted to immunosuppressed heart-transplant recipients.
Analysis of Variance↗
A drug interaction study between ticlopidine and cyclosporin in heart transplant recipients.
OBJECTIVES: Previous uncontrolled studies have suggested an interaction between ticlopidine, a major antiplatelet agent, and cyclosporin in heart- and kidney-transplant recipients. The aims of this study were to examine in a randomised, double-blind fashion, the possible interaction between cyclosporin A and ticlopidine (250 mg per day) and the tolerability of this combination in heart-transplant recipients. METHODS: Twenty heart-transplant recipients were randomised into either a treated or a placebo group. Blood samples were drawn for time-course evaluation of cyclosporin blood levels over a period of 12 h, following the morning intake of cyclosporin and, for platelet aggregation studies, before and after 14 days of ticlopidine administration. Twenty four-hour urine samples were collected for 6-beta-hydroxycortisol measurements, before and after 14 days of ticlopidine. RESULTS: Although given at half the recommended daily dosage, ticlopidine significantly reduced platelet aggregation. Pharmacokinetic parameters indicate that the bioavailability of cyclosporin A was not significantly modified by ticlopidine. However, one patient in the ticlopidine group was withdrawn because of a major fall in cyclosporin blood level within 3 days of treatment. Urinary excretion of 6-beta-hydroxycortisol was augmented after treatment in the ticlopidine group compared with the placebo group, suggesting that induction of drug metabolism might have occurred. Data also show quite a large intra-individual variability in cyclosporin bioavailability in the placebo group, suggesting that poor absorption of the drug formulation and/or poor compliance might have contributed to the decreased cyclosporin blood levels in the patient withdrawn from this study and in previous uncontrolled studies. CONCLUSION: Cyclosporin bioavailability was not clearly modified by a half dosage of ticlopidine in this study. We, however, recommend closely monitoring cyclosporin blood levels when prescribing ticlopidine. Further studies will be needed with new formulations of cyclosporin or when using the full dosage of ticlopidine.
Adolescent↗
Control of bias in dietary trial to prevent coronary recurrences: The Lyon Diet Heart Study.
BACKGROUND AND OBJECTIVES: A major limitation of dietary trials is that double blind design is not feasible. These trials are therefore prone to biases. The Lyon diet heart study is a single-blind secondary prevention trial to test the hypothesis that a Mediterranean-type of diet may prevent recurrences after a first myocardial infarction. A surprising 73% reduction of the risk of new major cardiac events was observed in the experimental group. For this reason, it is important to describe the methods used in the trial. We now report our techniques to randomize the patients, to change their diet and to control for possible bias, in particular any investigator or attending physician bias. DESIGN: In this dietary trial, a specific design was used to recruit and randomize the patients without informing them and their physicians that they were participating in a comparative trial. The attending physician bias was evaluated by studying drug usage and the investigator bias by constructing a questionnaire from which specific scores were used to evaluate (1) how the patients appreciated their participation in the study and (2) whether this participation resulted in significant changes in their way of living. SUBJECTS: 605 survivors of a first myocardial infarction were randomized into either a control or a Mediterranean group. RESULTS: The two randomized groups were similar for all the variables of prognosis. Drug usage was not significantly different between groups, suggesting that there was no major attending physician bias. Analyses of the appreciation scores and of the change score did not detect any significant investigator bias. CONCLUSIONS: Although the study cannot be completely shielded from minor biases, the data presented here provide evidence that the dietary modifications per se were protective, not other (including psychosocial) changes resulting from the participation to the trial.
Adrenergic beta-Antagonists↗
The 'diet heart' hypothesis in secondary prevention of coronary heart disease.
From this detailed analysis of the main dietary trials conducted over the last 30 years in the secondary prevention of coronary heart disease, it can be said that the older trials were conducted on low risk patients and used high fat diets (about 40% of energy as lipids), comprising low saturated fat and cholesterol intake but very high (15 to 20% of energy) polyunsaturated fat intake, particularly from the omega-6 fatty acid family. These experimental diets were designed to reduce blood cholesterol and failed to improve prognosis. By contrast, recent trials were not primarily designed to reduce cholesterol, were conducted in medium- and high-risk patients and used low fat diets supplemented by omega-3 fatty acids from various sources. In two of these trials, the consumption of natural antioxidants, oligoelements and vegetable proteins was increased. Recurrence rate was reduced in the range of 30 to 70%. One conclusion from these well-conducted recent experiments on more than 3000 patients is that new and more specific dietary recommendations are clearly warranted in secondary prevention of coronary heart disease. They should be more specific and more clearly defined and therefore different from those generally provided in the U.S.A. and Europe at present. In a recent Consensus Panel statement, authors wrote less than one line to describe a cardioprotective diet in patients with coronary heart disease, summarized as < or = 30% fat, < 7% saturated fat, < 200 mg.day-1 cholesterol. This is both too much (too restrictive to hope that white European and American patients will adhere in the long-term) and insufficient because dietary counselling cannot be restricted to three factors. Ulbricht and Southgate recently emphasized that the relationship between diet and coronary heart disease is more complex than the current cholesterol hypothesis. They identified at least seven major dietary factors, including fibres, although the evidence of an effect on coronary heart disease is weak. However, they did not mention vegetable and fish proteins which are rich in arginine and L-glutamine, major regulators of cardiovascular function. Thus, new dietary advice should include: reduce intake of total (not more than 30% of energy) and saturated (less than 10%) fats maintain intake at least minimally, of the essential omega-6 fatty acids augment consumption of oleic acid and moderately increase consumption of omega-3 fatty acids augment intake of natural antioxidants and oligo-elements maintain sufficient intake of vegetable proteins As conceptualized in the 'Mediterranean' and 'Asian-vegetarian' types of diet, it is very important that a healthy diet should be thought of as a whole rather than as a recitation of good and bad components. Although these protective dietary modifications should probably all be used in each patient to obtain maximal efficacy, these scientifically quantitated principles should be adapted to the culture, ethnic origin and 'image of the world' of each patient in order to create an environment favourable to the perception of positive associations between various foods and healthy habits.
Clinical Trials as Topic↗
Effect of chronic oral supplementation with alpha-tocopherol on myocardial stunning in the dog.
Recent clinical and experimental studies have suggested that antioxidant supplements might actually have harmful as well as beneficial effects in the setting of cardiovascular disease. The mechanisms underlying the beneficial effects of the various antioxidants are poorly understood in humans. Reperfusion-associated myocardial injury, and particularly the phenomenon of stunning, is important because it occurs in clinical settings and may condition the prognosis after short ischemic insult. We studied the effects of chronic (3 months) alpha-tocopherol supplementation with a large oral dose (500 mg daily) on myocardial contractility (stunning) and ventricular arrhythmias in a dog model of short ischemia followed by reperfusion. Twenty dogs were randomized to either an alpha-tocopherol supplemented or a control group. After 3 months, dogs were anesthetized and underwent a 20-min coronary artery occlusion followed by reperfusion. Myocardial regional blood flow was measured by the radioactive microsphere technique and myocardial contractility by sonomicrometry. Plasma alpha-tocopherol was measured by high-performance liquid chromatography in all dogs. Twelve dogs (seven supplemented and five controls) developed ventricular fibrillation at reperfusion, showing no difference between groups. Hemodynamic parameters, blood flow in the ischemic area (collateral flow), and area at risk were similar in the two groups. Regional systolic segment shortening in the ischemic area was similar during ischemia and reperfusion in both groups, representing 41 +/- 15% (mean +/- SEM) of baseline contractility in controls and 51 +/- 8% in supplemented dogs after 150 min of reperfusion. Plasma alpha-tocopherol level was higher in supplemented than in controls (19.1 +/- 1.6 and 6.9 +/- 0.6 mg/L; p < 0.001). Thus a long-term large dose of alpha-tocopherol had no significant effect on postischaemic ventricular arrhythmias and dysfunction (myocardial stunning) in this canine model. These data suggest that if alpha-tocopherol supplementation might be useful to improve the prognosis of coronary patients, it is likely not by interfering with the stunning phenomenon.
Administration, Oral↗
Effect of colchicine on circulating and myocardial neutrophils and on infarct size in a canine model of ischemia and reperfusion.
Myocardial injury after ischemia/reperfusion has been attributed in part to the effects of neutrophils. We examined whether colchicine, a potent and rapid inhibitor of neutrophils, may reduce inflammatory leukocytosis, prevent postischemic myocardial neutrophil accumulation, and reduce infarct size (IS). Twenty-four dogs were randomized to either a control (saline administration) or a colchicine (1 mg/kg intravenously, i.v.) group. Anesthetized open-chest dogs underwent 120-min coronary artery occlusion followed by 6-h reperfusion. Determinants of IS [area-at-risk (AAR) and collateral flow] and IS were measured in 22 dogs (11 in each group). We evaluated neutrophil toxicity by measuring ex vivo production of reactive oxygen species by chemiluminescence. Myocardial localization and accumulation of neutrophils were histologically evaluated by independent observers. The number of circulating neutrophils (p < 0.01), neutrophil cytotoxicity (p < 0.05), and neutrophil myocardial accumulation after 6-h reperfusion (p = 0.006) were reduced in treated dogs. Left ventricular (LV) peak rate of pressure increase was similar in both groups during ischemia /reperfusion. However, whereas collateral blood flow and AAR, the main determinants of IS, were similar in control and treated dogs, there was no reduction in IS: 37.1 +/- 7% of AAR in controls and 37.4 +/- 8% in treated dogs. Despite marked reduction of neutrophil toxicity and postischemic myocardial neutrophil accumulation, no myocardial protection could be detected in this dog model.
Animals↗