Etude des effets et des mécanismes cardioprotecteurs de l'éthanol chez le rat

Chronic and moderate ethanol drinking (CMED) is associated with low cardiac mortality andresults in increased plasma and cell levels of omega 3 fatty acids (ω3). Dietary ω3 are knownto reduce cardiac mortality in humans, induce cardioprotection in animals and incorporate inmembranes notably in mitochondria, an important target for cardioprotection. As ethanol andω3 seem to induce similar cardioprotective effects, our goal was to investigate whether aCMED might mimic dietary ω3-induced mitochondrial lipid remodeling. These structuralmodifications might modulate mitochondrial function and explain ethanol cardioprotection.We showed that dietary supplementation with ω3 and CCME protect both myocardiumagainst ischemic/reperfusion in reducing infarct size on isolated perfused rat heart. Afterchecking dietary ω3-induced ω3 increase in mitochondrial membranes, we demonstrated thatCCME results in increased mitochondrial phosphatidylcholine and cardiolipin levels of ω3but without disturbance on mitochondrial function. In plasma and cell membranes, CMEDresulted in higher ω3 and lower pro-apoptotic palmitate levels. In conclusion, CMED protectsmyocardium against cell necrosis, increases cardioprotective fatty acids levels (ω3) anddecreases concentration of pro-apoptotic fatty acid (palmitate). CMED cardioprotectionlikely results from the interaction between ethanol, ω3 and death cell pathways.La consommation chronique et modérée d'éthanol (CCME) est associée à une réduction de lamortalité cardiaque et à une élévation des acides gras oméga 3 (ω3) dans le sang et lescellules. Les ω3 d'origine alimentaire sont connus pour réduire la mortalité cardiaque chezl'homme, induire une cardioprotection chez l'animal et s'incorporer dans les membranesnotamment de la mitochondrie, siège important de la cardioprotection. Comme l'éthanol et lesω3 semblent induire des effets cardioprotecteurs similaires, nous avons déterminé si uneCCME pouvait mimer le remodelage lipidique mitochondrial induit par une supplémentationen ω3. Ces modifications structurales pourraient modifier la fonction mitochondriale etexpliquer la cardioprotection par l'éthanol. A partir d'un modèle de coeur isolé perfusé de rat,nous avons montré que l'éthanol et les ω3 protègent de manière similaire le myocarde enlimitant la taille de l'infarctus après une ischémie/reperfusion. Après avoir vérifié qu'unesupplémentation en ω3 induit un enrichissement en ω3 des membranes mitochondrialescardiaques, nous avons démontré qu'une CCME induit une augmention des ω3 dans lacardiolipine et la phosphatidylcholine mitochondriales mais sans conséquence sur la fonctionmitochondriale. Dans le plasma et les membranes cellulaires, une CCME augmente lesteneurs en ω3 et réduit la concentration en palmitate, un acide gras pro-apoptotique. Enconclusion, une CCME protège le myocarde contre la nécrose cellulaire, augmente la teneuren acides gras cardioprotecteurs (ω3) et diminue la concentration en acide gras proapoptotique(palmitate). La cardioprotection induite par une CCME pourrait donc résulterd'une interaction entre l'éthanol, la voie des ω3 et celle de l'apoptose

Etude des effets et des mécanismes cardioprotecteurs de l'éthanol chez le rat

La consommation chronique et modérée d'éthanol (CCME) est associée à une réduction de la mortalité cardiaque et à une élévation des acides gras oméga 3 ( 3) dans le sang et les cellules. Les 3 d'origine alimentaire sont connus pour réduire la mortalité cardiaque chez l'homme, induire une cardioprotection chez l'animal et s'incorporer dans les membranes notamment de la mitochondrie, siège important de la cardioprotection. Comme l'éthanol et les 3 semblent induire des effets cardioprotecteurs similaires, nous avons déterminé si une CCME pouvait mimer le remodelage lipidique mitochondrial induit par une supplémentation en 3. Ces modifications structurales pourraient modifier la fonction mitochondriale et expliquer la cardioprotection par l'éthanol. A partir d'un modèle de coeur isolé perfusé de rat, nous avons montré que l'éthanol et les 3 protègent de manière similaire le myocarde en limitant la taille de l'infarctus après une ischémie/reperfusion. Après avoir vérifié qu'une supplémentation en 3 induit un enrichissement en 3 des membranes mitochondriales cardiaques, nous avons démontré qu'une CCME induit une augmention des 3 dans la cardiolipine et la phosphatidylcholine mitochondriales mais sans conséquence sur la fonction mitochondriale. Dans le plasma et les membranes cellulaires, une CCME augmente les teneurs en 3 et réduit la concentration en palmitate, un acide gras pro-apoptotique. En conclusion, une CCME protège le myocarde contre la nécrose cellulaire, augmente la teneur en acides gras cardioprotecteurs ( 3) et diminue la concentration en acide gras proapoptotique (palmitate). La cardioprotection induite par une CCME pourrait donc résulter d'une interaction entre l'éthanol, la voie des 3 et celle de l'apoptose.GRENOBLE1-BU Sciences (384212103) / SudocSudocFranceF

Cardioprotective effect of chronic low dose ethanol drinking: insights into the concept of ethanol preconditioning.

International audienceThe reason why low-to-moderate alcohol drinking is associated with reduced cardiovascular mortality is not elucidated. While data suggested that ethanol drinking may have a protective effect on global cardiac ischemia, the effect of chronic low dose ethanol drinking (CLEthD) on myocardial infarct size has not been evaluated in a model of regional ischemia. Using an isolated rat heart model to exclude the effect of various in vivo confounders, we have studied the effect of CLEthD on infarct size (IS) and left ventricular function after 30 min of regional ischemia and 120 min of reperfusion. The effect of CLEthD was compared with ischemic preconditioning (IPC) and protein kinase C (PKC) isoforms were analysed in the myocardium before the 30-min ischemia. Ethanol-fed rats received 9% (v/v) ethanol in their drinking water for 7 weeks. Four groups of rats were studied: (1) control, (2) ethanol, (3) control + IPC, (4) ethanol + IPC. Compared with controls (59 +/- 10), IS (as percent of risk zone) was smaller in the ethanol (39 +/- 6) and IPC (31 +/- 8) groups (both p < 0.05). Combination of ethanol and IPC in the same rats further decreased IS (-46% vs. ethanol, p < 0.05). PKC analyses did not show sustained isoform translocation in that model. These data indicate that chronic low dose ethanol drinking actually induces in the rat heart a chronic protective state that is independent from an effect on the traditional (lipid and coagulation) risk factors. Further studies are required to elucidate the mechanisms of that protection

Lipid-lowering drugs and essential omega-6 and omega-3 fatty acids in patients with coronary heart disease.

International audienceBACKGROUND AND AIM: There are only little data about the effects of lipid-lowering drugs (LLDs) on the metabolism of essential n-6 and n-3 fatty acids in patients with established coronary heart disease (CHD). METHODS AND RESULTS: Male patients with CHD and high cholesterol levels (>6.2 mmol/L) were randomized (double-blind protocol) to receive either simvastatin 20mg (S) or fenofibrate 200mg daily (F) for 3 months. Dietary habits and plasma fatty acids were not different in the two groups at baseline. After treatment, there were significant changes in both the groups for the main n-6 fatty acids, with an increase in arachidonate (from 6.5+/-1.7% of total fatty acids to 7.5+/-2.1, p<0.001 in S and from 6.2+/-1.4 to 6.8+/-1.4, p<0.005 in F) and a decrease in linoleate (from 26.9+/-3.9 to 24.2+/-3.6, p<0.001, and from 27.8+/-3.4 to 26.1+/-4.2, p<0.05, in S and F, respectively). In addition, there was a decrease in two major n-3 fatty acids (alpha-linolenate and docosahexanoate, both p<0.05), but only in F. CONCLUSIONS: For the first time in a double-blind randomized study in CHD patients, we report that LLDs significantly alter the metabolism of essential fatty acids that are critically important for the pathogenesis and prevention of CHD. Further studies are urgently needed to examine the effects of higher dosages of statins (as currently proposed to reduce more cholesterol) on these essential fatty acids in the clinical setting and the crucial questions of whether specific dietary intervention (combining low intake of n-6 fatty acids and high intake of n-3 fatty acids) may improve the effectiveness of these drugs

Ethanol, wine, and experimental cardioprotection in ischemia/reperfusion: role of the prooxidant/antioxidant balance.

International audienceIt is now well established that oxidative stress resulting from reactive oxygen species (ROS) that are generated in cardiac myocytes subjected to ischemia/reperfusion plays a causative role in the development of heart failure and may contribute to promote cell death. During the last decade, several groups have reported that, in animal models of myocardial ischemia/reperfusion, certain nutrients, including ethanol and nonethanolic components of wine, may have a specific protective effect on the myocardium, independent of the classical risk factors implicated in vascular atherosclerosis and thrombosis. Mechanisms through which the consumption of alcoholic beverages protects against ischemia-induced cardiac injury are still unknown. One major open question is whether ethanol and nonethanolic components of wine are cardioprotective, at least in part, by interfering with the myocardial prooxidant/antioxidant balance. Important concepts, such as cardiac preconditioning, are now entering the field of nutrition, and recent experimental evidence suggests that ethanol and/or nonethanolic components of wine might exert preconditioning effects in animal models of myocardial ischemia/reperfusion. There is no doubt that such an observation, if confirmed in human subjects, might open new perspectives in the prevention and treatment of ischemic coronary heart disease

Interactions of ethanol drinking with n-3 fatty acids in rats: potential consequences for the cardiovascular system.

International audienceModerate ethanol drinking (ED) and n-3 fatty acids have both been associated with low cardiac mortality. However, there are few data evaluating the interactions of ED with n-3. We recently reported that moderate ED results in increased n-3 in cardiac patients. The main aim of the present study was, through a well-controlled experimental model, to confirm that chronic ED actually results in increased n-3. Secondary aims were to examine the effects of chronic ED on cardiac mitochondria, cardiac function and experimental myocardial infarction. We studied the fatty acid profiles of plasma, cell membranes and cardiac mitochondria phospholipids in a rat model of chronic ED. In plasma and cell membranes, ED actually resulted in higher n-3 (P = 0.005). In mitochondria phospholipids of ED rats, n-3 were also increased (P < 0.05) but quite modestly. Cardiac mitochondrial function and left ventricular function were not significantly different in ED and control rats, while infarct size after 30 min ischaemia and reperfusion was smaller (P < 0.0001) in ED rats. This is the first animal study confirming interaction of alcohol drinking with n-3. We found no harmful effect of chronic ED on the heart in that model but a significant cardioprotection. Further studies are warranted to investigate the mechanisms by which moderate ED alters the metabolism of n-3 and whether n-3 are the mediators of the ED-induced cardioprotection

Effect of general anaesthesia on functional outcome in patients with anterior circulation ischaemic stroke having endovascular thrombectomy versus standard care: a meta-analysis of individual patient data

Background: General anaesthesia (GA) during endovascular thrombectomy has been associated with worse patient outcomes in observational studies compared with patients treated without GA. We assessed functional outcome in ischaemic stroke patients with large vessel anterior circulation occlusion undergoing endovascular thrombectomy under GA, versus thrombectomy not under GA (with or without sedation) versus standard care (ie, no thrombectomy), stratified by the use of GA versus standard care. Methods: For this meta-analysis, patient-level data were pooled from all patients included in randomised trials in PuMed published between Jan 1, 2010, and May 31, 2017, that compared endovascular thrombectomy predominantly done with stent retrievers with standard care in anterior circulation ischaemic stroke patients (HERMES Collaboration). The primary outcome was functional outcome assessed by ordinal analysis of the modified Rankin scale (mRS) at 90 days in the GA and non-GA subgroups of patients treated with endovascular therapy versus those patients treated with standard care, adjusted for baseline prognostic variables. To account for between-trial variance we used mixed-effects modelling with a random effect for trials incorporated in all models. Bias was assessed using the Cochrane method. The meta-analysis was prospectively designed, but not registered. Findings: Seven trials were identified by our search; of 1764 patients included in these trials, 871 were allocated to endovascular thrombectomy and 893 were assigned standard care. After exclusion of 74 patients (72 did not undergo the procedure and two had missing data on anaesthetic strategy), 236 (30%) of 797 patients who had endovascular procedures were treated under GA. At baseline, patients receiving GA were younger and had a shorter delay between stroke onset and randomisation but they had similar pre-treatment clinical severity compared with patients who did not have GA. Endovascular thrombectomy improved functional outcome at 3 months both in patients who had GA (adjusted common odds ratio (cOR) 1·52, 95% CI 1·09–2·11, p=0·014) and in those who did not have GA (adjusted cOR 2·33, 95% CI 1·75–3·10, p&lt;0·0001) versus standard care. However, outcomes were significantly better for patients who did not receive GA versus those who received GA (covariate-adjusted cOR 1·53, 95% CI 1·14–2·04, p=0·0044). The risk of bias and variability between studies was assessed to be low. Interpretation: Worse outcomes after endovascular thrombectomy were associated with GA, after adjustment for baseline prognostic variables. These data support avoidance of GA whenever possible. The procedure did, however, remain effective versus standard care in patients treated under GA, indicating that treatment should not be withheld in those who require anaesthesia for medical reasons