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Coronary heart disease (CHD) is one of the leading causes of death every year with nearly three-fourths of all deaths caused by the disease. The challenge scientists are facing today is discovering new drugs to protect the heart against cellular damage caused by ischemia-reperfusion injury (I-R injury). Rapamycin is one such drug that has been shown to protect the heart against ischemia-induced cellular injury. Rapamycin(sirolimus) inhibits protein synthesis through inhibition of the mammalian target ofrapamycin (mTOR). This property of rapamycin has led to its current clinical applications in drug-eluting stents and in immunosuppresive treatment to organ transplant patients. The mechanism by which this drug protects against I-R injury is currently unknown. The goal of this study is to elucidate rapamycin's cardioprotective signaling pathway. We hypothesized that upregulation of Akt occurs possibly as part of a positive feedback mechanism following the inhibition of mTOR by rapamycin. Adult male ICRmice were treated with rapamycin (0.25 mg/kg, i.p.), or volume-matched DMSO (solvent for rapamycin), or rapamycin (0.25mg/kg, i.p.) plus wortmannin (WTN, 15µg/kg, i.p.),an inhibitor of phosphatidylinositol 3-kinase, or wortmannin alone (15µg/kg, i.p.). After 30 min of stabilization, the hearts were subjected to 20 minutes of global ischemia and 30 minutes of reperfusion in Langendorff model. In a separate series of experiments mice were either injected with DMSO or rapamycin for 30 minutes, 1 hour, and 2 hours before harvesting the hearts for Western blot analysis of levels of total or phosphorylated Akt at Ser473. Our results showed that rapamycin protected the heart as observed by a reductionin infarct size from 33.8 ± 2.0% in DMSO-treated hearts to 19.3 ± 4.1% in rapamycin-treated hearts; a 43% reduction. This infarct-limiting effect was completely blocked by wortmannin (29.3 ± 4.8%). However, Western blot analysis showed no change in the level of Akt phosphorylation after administration of rapamycin. Our current resultsfurther confirmed rapamycin as a potential cardio-therapeutic drug to limit infarct size,potentially through the PI3K signaling pathway. However, the exact signaling pathway of this protection still remains elusive.

Avaliamos a função cardíaca frente a Isquemia e reperfusão, em corações isolados de ratas intactas, com hipotireoidismo (Hipo), hipotireoidismo subclínico (HTS), redução dos níveis de hormônios ovarianos (OO) e a ambas condições (HTS+OO). Na estabilização, a Pressão Desenvolvida pelo Ventrículo Esquerdo (LVDP), Pressão Diastólica Final (EDP) e Pressão de Perfusão não diferiram. Porém, a Primeira Derivada Positiva das Pressões (+dP/dt), Primeira Derivada Negativa das Pressões (-dP/dt) e frequência cardíaca foram menores no grupo Hipo. Na reperfusão, os corações Hipo tiveram EDP, +dP/dt e -dP/dt semelhantes a estabilização. Assim, sugere-se que o HTS, a OO e o HTS + OO não alteraram a recuperação cardíaca após a isquemia. E que o Hipo é resistente à lesão por isquemia, apesar da função cardíaca deprimida. / We evaluate the cardiac function in relation to an ischemia and reperfusion event in hearts isolated from intact rats, With hypothyroidism (Hypo), subclinical hypothyroidism (HTS), decreased levels of ovarian hormones (OO) and both conditions (HTS + OO). At etabilization the Left Ventricle Developed Pressure (LVDP), Final Diastolic Pressure (EDP) and Perfusion Pressure did not differ. However, the First Positive Pressure Derivative (+ dP / dt), First Negative Pressure Derivative (-dP / dt) and heart rate were lower in the Hypo group. On reperfusion the hypothyroid hearts presented EDP, + dP / dt and -dP / dt Similar to stabilization. Thus, it is suggested that HTS, a OO e o HTS + OO Did not change cardiac recovery after ischemia.Is that hipo is resistant to ischemia injury, despite depressed cardiac function.

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No description available.

Le surpoids et l'obésité, en constante augmentation à l'échelle mondiale à un rythme exponentiel, conduit au développement du syndrome métabolique et du diabète de type 2. Plusieurs études ont mis en évidence l'association entre l'excès de masse grasse, en particulier dans la région abdominale, et le développement des maladies cardiovasculaires. Une telle augmentation de masse grasse corporelle caractérise le vieillissement normal, qui est considéré per se comme un facteur de risque majeur pour les maladies cardiovasculaires. De plus, dans le monde industrialisé, l'incidence des maladies cardiovasculaires est encore plus élevée et fortement liée aux habitudes occidentales (régimes obésogènes, sédentarité) qui contribuent à l'accumulation de la graisse abdominale. L'objectif général de ce travail consiste à suivre les changements corporels qui surviennent entre la jeunesse et l'âge moyen où commence à survenir les complications cardio-vasculaires et à savoir comment l'obésité induite par l'alimentation peut modifier ces aspects. Dans un premier temps, nous avons montré que les coeurs des rats Wistar d'âge moyen sont caractérisés par une moindre restauration de l'activité mécanique cardiaque au cours de la réperfusion post-ischémique en raison de perturbations de la perfusion coronaire et d'une insuffisance de l'apport en oxygène. La présence d'un stress oxydant systémique suite à l'augmentation de la masse grasse survenant entre la jeunesse et l'âge adulte est également en cause. Une diminution progressive de la dilatation endothélium-dépendante des microvaisseaux coronaires est également observé avec le vieillissement, ce qui résulte d'une évolution différentielle du comportement fonctionnel des cellules endothéliales et musculaires lisses apparemment liée au métabolisme énergétique et au stress oxydant. L'obésité induite par un régime riche en graisse provoque un certain nombre de modifications corporelles, métaboliques et cardiovasculaires au cours de cette période du vieillissement. L'excès de masse grasse abdominale induit une augmentation du stress oxydant aux niveaux systémique, cytosolique et mitochondrial accompagné par des altérations biochimiques concernant le métabolisme du glucose et les niveaux plasmatiques de cholestérol et de triglycérides. L'obésité induite par une hyperphagie et la présence d'un diabète de type 2 chez les rats Zucker obèses diabétiques provoque également une insulino-résistance sévère. Ces deux modèles d'obésité sont caractérisés par une diminution de la fonction cardiaque ex vivo liée au métabolisme énergétique mitochondrial et au stress oxydant. En outre, ils sont tous les deux caractérisés par une adaptation des microvaisseaux coronaires dont la réactivité est augmentée dans le cas de régime riche en graisse et maintenue dans le cas du diabète. Ces adaptations sont dues à des mécanismes différents dans les deux modèles d'obésité. Elles permettent de mieux répondre aux exigences métaboliques élevées liées à l'obésité. En conclusion, notre travail montre que les caractéristiques corporelles et métaboliques, le métabolisme énergétique mitochondrial, la fonction cardiaque et la réactivité coronaire sont modifiés lors du vieillissement dans les conditions normales ou obésogènes. Ces résultats encouragent la recherche ultérieure des mécanismes mis en jeu. Les interventions visant à réduire la masse grasse, qu'elle soit spontanément accrue par l'âge ou qu'elle résulte du régime alimentaire, seraient d'un grand intérêt pour retarder les complications cardiovasculaires. / The prevalence of overweight and obesity is increasing worldwide at an alarming rate leading to the development of metabolic syndrome and diabetes mellitus. Previous studies have highlightened the association between fat accumulation, especially in the abdominal area, and the development of cardiovascular diseases. An increase in body and fat mass characterizes normal aging, which is considered per se the major risk factor for cardiovascular diseases. In the industrialized societies, the incidence of cardiovascular diseases occurring with age is even more increased due to the Western-world lifestyle habits (e.g. obesogenic diets, sedentariness) that contribute to excess fat accumulation. Accordingly, the overall goal of this work was to understand how body changes occurring from youth to middle age were related to middle age cardiovascular complications and how diet-induced obesity altered these aspects. Initially, we demonstrated that in normal aging middle-aged hearts of Wistar rats were characterized by lower restoration of the cardiac mechanical activity during reperfusion ex vivo due to impaired recovery of the coronary flow and insufficient oxygen supply. This was also related to the presence of increased systemic oxidative stress following the increase in fat mass that occurred from youth to young adulthood. A progressive decline in the endothelium-dependent dilatation of the coronary microvasculature also occurred with aging, which was due to different functional behaviours of the endothelial and smooth muscular cells, which appeared to be related to the energy metabolism and oxidative stress. High-fat diet-induced obesity triggered a number of alterations in the body, metabolic and cardiovascular characteristics of the animals during this aging period. The excess abdominal fat accumulation provoked the increase of oxidative stress at the systemic, cytosolic and mitochondrial levels accompanied by biochemical alterations in the glucose and lipid metabolisms such as hypercholesterolemia and hypertriglyceridemia. The hyperphagia-induced obesity and the related type 2 diabetes in the Zucker diabetic fatty rats provoked also severe insulin resistance. Both models of diet-induced obesity were characterized by decreased ex vivo cardiac function related to mitochondrial energy metabolism and oxidative stress. Furthermore, they were both characterized by an adaptation of the coronary microvasculature whose reactivity was enhanced in the first case and maintained in the second, in order to meet the elevated metabolic demands of the hearts due to obesity. These adaptations were due to different mechanisms in these two models of obesity. In conclusion, our work revealed a temporal pattern of changes concerning the body and metabolic characteristics, mitochondrial energy metabolism, cardiac function and coronary microvascular reactivity that occur from youth to middle age either under normal or obesogenic-related conditions. These results encourage further research in order to explain the mechanisms related to these alterations. Interventions aiming at reducing the fat mass that increases with age or diet would be of great interest in an effort to delay the cardiovascular

This work focuses on the regression analysis of morphological parameters calculated from the ECG for estimating the position of the heart to the measuring electrodes. It consists of a theoretical analysis of the problems of ECG recording and description of the data obtained from experiments on isolated animal hearts. On the theoretical part is followed by a description of the calculation parameters suitable for regression analysis and their application in the training and testing of the following regression models to estimate the position of the heart to the measuring electrode.

Bien qu’il ait prouvé son efficacité dans différentes espèces (lapin, porc, souris,…) ainsi que dans différents organes (rein, foie coeur, poumon,…), le Postconditionnement (PostC) peut être limité par plusieurs facteurs. Parmi les limites du Post C, on note la nécessité de son application à l’initiation de la reperfusion. L’objectif de notre travail était d’évaluer la protection induite par la Basse pression de reperfusion (BP) après un décalage temporel de son application et d’étudier les principales fonctions mitochondriales connues pour être impliquées dans la cardioprotection. Nos résultats nous ont permis de démontrer que, contrairement au PostC, la BP pouvait s’appliquer avec succès même après un décalage temporel de 10 minutes après le début de la reperfusion. Cette protection décalée est en lien avec les fonctions mitochondriales, en particulier, l’inhibition du pore de transition de perméabilité mitochondriale (PTPm). L’utilisation de la cyclosporine A (CsA), puissant inhibiteur de l’ouverture du PTPm, permet également de décaler de 10 minutes la manœuvre de protection à la reperfusion dans le modèle de coeur isolé perfusé de rat. Le PostC, comme la BP, utilise deux sources de production de NO (NOS et Xanthine oxydase reductase) pour induire la cardioprotection. Ces résultats nous semblent importants dans le sens où ils proposent une nouvelle fenêtre thérapeutique pour combattre les dégâts liés à l’ischémie/reperfusion, la BP / Although its efficacy in various species (rabbit, pig, mouse,…) and various organs (kidney, liver heart, lung), Postconditioning (PostC) can be limited by many factors such as the necessity of its application in the initiation of the reperfusion. The objective of our work was to evaluate the protection by low pressure reperfusion (LPR) with delayed intervention at reperfusion and to study the mitochondrial functions which are known to be involved in the cardioprotection. Our results showed that, contrary to PostC, LPR can protect until 10 minutes of its delayed intervention at reperfusion. This delayed protection is in correlation with mitochondrial functions, particularly, inhibition of mitochondrial transition pore (PTPm). Cyclosporine, inhibitor of PTPm, has also shown protection until 10 minutes of delayed intervention, on isolated heart rat model. PostC, like LPR, use tow sources of prodution of NO (NOS and Xanthine oxydase reductase). These results seem, to us, very important because they propose LPR as a new therapeutic window to reduce ischemia/reperfusion injury

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No description available.