Malgré de très nombreuses études expérimentales et cliniques dans le domaine de l'arrêt circulatoire, seulement 2% à 12% des patients quittent l'hôpital avec une bonne récupération neurologique. Il est donc nécessaire de proposer de nouvelles thérapeutiques pour tenter d'augmenter la survie après un arrêt circulatoire. Pour atteindre ce but il semble indispensable d'améliorer la qualité du massage cardiaque durant la réanimation et de protéger le myocarde et le cerveau contre les phénomènes d'ischémie-reperfusion. Dans la première partie de ce travail, nous avons évalués dans une étude pré hospitalière l'utilisation d'un dispositif innovant de massage cardiaque interne par minithoracotomie et montré une amélioration de l'hémodynamique en comparaison avec le massage cardiaque standard. Dans la deuxième partie, nous avons testés les possibles effets protecteurs de l'EPO (érythropoïétine) dans deux types d'arrêt circulatoire. Dans un modèle d'arrêt cardiaque expérimental chez le rat nous avons démontré que lorsque l'EPO était injectée avant l'arrêt cardiaque, la réanimation initiale était améliorée et la survie des animaux augmentée ce qui pouvaient suggérer un effet cardio et/ou neuroprotecteur de l'EPO contre les effets délétères de l'ischémie reperfusion. Dans une étude clinique en chirurgie cardiaque sous circulation extra corporelle, nous n'avons pas pu démontré d'effet bénéfique de l'EPO ni sur l'ischémie myocardique, ni sur l'ischémie cérébrale ni sur les paramètres de l'inflammation. Sur la base de ces deux études, il est donc difficile de conclure sur le potentiel rôle bénéfique de l'EPO dans l'arrêt circulatoire. Néanmoins, sur la seule base des résultats expérimentaux, l'EPO pourrait faire partie de l'arsenal thérapeutique pour mieux protéger le myocarde et le cerveau contre les effets délétères de l'ischémie reperfusion après un arrêt cardiaque. / Despite extensive experimental and clinical research on cardiac arrest, only 2-12% of resuscitated patients are discharged from hospital in good neurological conditions. There is, therefore, a dear need for new therapies that improve survival after cardiac arrest. It ‘s necessary to improve the quality of cardiac massage and to protect against cardiac and cerebral ischemia occurring during cardiac arrest. In a first part, we evaluated the prehospital feasibility of performing a new method of minimally invasive direct cardiac massage (MID-CM®) and we suggested that better haemodynamic results can be obtained than with standard cardiopulmonary resuscitation. In a second part, we tested erythropoietin (EPO) against placebo in two model of cardiac arrest. In an experimental model of cardiac arrest, we demonstrated that EPO, when administrated before cardiac arrest, improved initial resuscitation and increased the duration of post-resuscitation survival. In a second model of circulatory arrest during cardiac surgery with cardiopulmonary bypass, EPO administration did not protect against cerebral ischemia and inflammatory response occurring during cardiac surgery with CPB. It is difficult to make definitive conclusion on the potential role of EPO in myocardial and cerebral protection after circulatory arrest. We can hope that EPO administration will represent pharmacological approach in upcoming years to additional myocardial salvage of the reperfused myocardium after cardiac arrest.

The mortality of cardiovascular diseases remains high and it likely tends to increase in the future. Although many ways how to increase the resistance against myocardial ischemia- reperfusion damage have been described, few of them were transferred into clinical practice. Cardioprotective effect of chronic hypoxia has been described during 60s of the last century. Its detailed mechanism has not been elucidated, but a number of components has been identified. One of these components presents protein kinase C (PKC). The role of PKC was described in detail in the mechanism of ischemic preconditioning, but its involvement in the mechanism of cardioprotection induced by chronic hypoxia remains unclear. One reason is the amount of PKC isoforms, which have often contradictory effects, and the diversity of hypoxic models used. The most frequently mentioned isoforms in connection with cardioprotection are PKCδ and PKCε. The aim of my thesis was to analyze changes in these PKC isoforms at two different cardioprotective models of hypoxia - intermittent hypobaric (IHH) and continuous normobaric hypoxia (CNH). We also examined the target proteins of PKCδ and PKCε after the adaptation to IHH, which could be involved in the mechanism of cardioprotection. These included proteins associated with apoptosis and...

Endogenous cardiac protection against acute ischemia/reperfusion injury can by increased by cardiac adaptation to various forms of chronic hypoxia. Chronic hypoxia induces a large variety of adaptive changes in the myocardium that could be considered as protective, but the exact mechanism of increased ischemic tolerance is unknown. Different studies suggest that catecholamine release and their effect on -adrenergic signaling after adaptation to chronic hypoxia contributes to cardioprotection. In this study we focused on characterization of -adrenergic receptors ( -ARs) in the myocardium of rats after adaptation to three different hypoxic conditions: 1. intermittent normobaric hypoxia - INH/R (23 h hypoxia, 1 h reoxygenation), 2. intermittent normobaric hypoxia - INH (8 h hypoxia, 16 h normoxia), 3. continuous normobaric hypoxia - CNH (24 h hypoxia). We compared how each hypoxic model affects the total number of -adrenergic receptors and proportion of individual subtypes ( 1-and 2-ARs) in the left and right ventricles compared control normoxic rats. The INH model had apparently no effect on -ARs in either ventricles. On the other hand, adaptation to INH/R and CNH was accompanied by a significant decrease (by about 25%) in the total number of -adrenergic receptors in the right ventricles. Our present...

Ischemic heart disease and resulting heart failure (HF) belong to the leading causes of death in developed countries. In order to prevent HF and improve clinical outcome in patients with myocardial infarction, novel therapies are required to protect the heart against the detrimental effect of ischemic injury. Due to the failure to translate numerous available experimental cardioprotective strategies into clinical practice, the need for novel protective treatments persists. We have, therefore, tried to apply a novel approach to cardiac protection against the postischemic HF induced in rats by ligation of the coronary artery. For this purpose, we have studied (i) the preventive and therapeutic effects of adaptation to continuous normobaric hypoxia (CNH; 12% O2) and exercise training (ExT; treadmill running), and (ii) the possible cardioprotective potential of epoxyeicosatrienoic acid (EET)-based therapy in order to attenuate the postischemic HF in rats. Adaptation to CNH and ExT is known for their cardioprotection in acute ischemia/reperfusion (I/R) injury manifested as reduction of infarct size. EETs exert antihypertensive effects and thus seem to be perspective for the research in clinically relevant models of cardioprotection in hypertensive animals. Our results have revealed that: - CNH prior to...

O exercício é hoje reconhecidamente um fator de proteção para morbidade e mortalidade cardiovascular. Apesar de extensos dados de estudos epidemiológicos e de intervenção, os mecanismos subjacentes cardioprotetores do exercício ainda não estão bem elucidados. Alguns autores acreditam que o treinamento físico induz o desenvolvimento de células miocárdicas mais resistentes a agressões externas e maior vascularização. Além disso, o exercício parece exercer grande influência sobre o sistema imunológico. O entendimento dos mecanismos através dos quais o exercício influencia o desfecho clínico do infarto agudo do miocárdio (IM) pode trazer uma melhor compreensão das diferentes evoluções clínicas de indivíduos aparentemente semelhantes. O estudo de quais moléculas e sistemas estão envolvidas nessa cardioproteção e de como medeiam e integram a resposta miocárdica ao estresse pode influenciar futuras terapias. O objetivo do presente trabalho é testar a hipótese de que a ocorrência de IM em animais previamente treinados é acompanhada de melhor função ventricular pós-IM, maior vascularização, em associação com menor expressão de marcadores inflamatórios e moduladores do metabolismo, e menos apoptose. Materiais e Métodos: Sessões de 60 min/dia, 05 dias/semana, por 08 semanas foram aplicadas no grupo exercício. Após este período os animais exercitados e sedentários foram randomizados para cirurgia de IM através da ligadura da artéria coronária esquerda (EI e SI, respectivamente), ou cirurgia controle (ES e SS, respectivamente), seguido de um período de sedentarismo de 04 semanas. A função ventricular esquerda foi obtida através da ecocardiografia, bem como o tamanho do infarto. A técnica de imunohistoquímica foi utilizada para detecção de PPAR-&#945;, PPAR-&#947;, TNF-&#945;, NF-kB, e &#945;-actina, e os resultados foram quantificados através de um sistema de análise de imagens automática por detecção de cores. A técnica de TUNEL foi utilizada para marcação de apoptose. Foram estudadas três regiões do coração: infarto (I), peri-infarto (P), e miocárdio sem infarto (M). Resultados: a mortalidade relacionada ao infarto foi maior no grupo sedentário em relação ao exercitado (25% vs 12%; P<0,05), sem diferença em relação a tamanho de IM. Comparado ao grupo EI, SI exibiu menor fração de encurtamento, maior taxa de apoptose, e aumento dos marcadores inflamatórios NF-kB e TNF-&#945; em I. O grupo SI mostrou correlações negativas entre quantidades de: a) PPAR-&#945; em M vs TNF-&#945; em I (R:-0,826, P=0,005); b) PPAR-&#945; vs NF-kB em I (R: -0,576, P=0,02) e em P (R:-0,505, P=0,03); c) TNF-&#945; em I e PPAR-alpha e PPAR-&#947; em M (R:-0,826, P=0,005 e R:-0,786, P=0,02); d) NF-kB em I e PPAR-&#945; em M (R:- 0,576, P=0,01) e e) NF-kB em P e PPAR-&#945; em M (R:-0,505, P=0,03). Houve correlação positiva entre NF-kB e PPAR-&#947; em P (R: 0,596, P=0,02). A densidade arteriolar não diferiu entre os dois grupos infartados, porém no grupo EI houve correlação negativa entre a densidade arteriolar em I e PPAR-&#947; em P (R: - 0,76, P=0,02). O número de células apoptóticas por campo (mediana) em SI e EI foi, respectivamente, 3,97 e 1,90 em I; 3,67 e 1,57 em P; e 1,41 e 1,13 em M. Houve menor número de células em apoptose em M em relação a I e P (P < 0,001) no grupo SI. Em EI, o número de células em apoptose/campo não diferiu entre as regiões estudadas. O número de células em apoptose por campo foi maior em SI comparado a EI em I (3,97 ± 0,61 vs 1,90 ± 1,82; P < 0,05) e em P (3,67 ± 0,73 vs 1,57 ± 1,07; P < 0,01). Conclusão: Os achados do presente trabalho suportam a hipótese de que a ocorrência de IM em animais previamente treinados é acompanhada de menor inflamação, menores taxas de apoptose, melhor função ventricular e possivelmente melhor interrelação entre moduladores do metabolismo energético e do sistema imunológico. / Exercise is a well recognized protective factor for cardiovascular morbidity and mortality. In spite of extensive data from epidemiologic studies and intervention, the subjacent cardioprotective mechanisms of exercise are still non clear. Some authors believe that the physical training induces development of more resistant myocardial fibers against external injuries and increased vascularization. Also, exercise seems to influence the modulation of the immune system. The understanding of mechanisms by which the exercise acts in the acute myocardial infarction (MI) progression may bring a better comprehension of different clinical outcome in apparently similar individuals. The knowledge of which molecules and systems are involved in this cardioprotection and how they mediate and integrate the stress myocardial response may help future therapies. The objective of the present work is to test the hypothesis that the occurrence of MI in previously trained animals is associated with a better post MI ventricular function, major vascularization, in association with lower expression of inflammatory markers and of metabolic modulators, and less apoptosis. Material and Methods: Sessions of 60 min/day, 05 days/week, for 08 weeks were applied in the exercised group. After this period, the exercised and sedentary animals were randomized to surgery for myocardial infarction, through the ligature of left coronary artery (EI and SI, respectively), or control surgery (ES and SS, respectively), followed by a 04 week sedentary period. The left ventricular function was obtained by the echocardiography as also the infarct size. Immunohistochemistry was used for detection of PPAR-&#945;, PPAR-&#947;, TNF-&#945;, NF-kB, ad &#945;-actin, and the results were quantified in an image analysis system by automatic collor detection. TUNEL technique was used for detection of apoptosis. Three regions of the heart were studied: infarcted (I), peri-infarcted (P), and non infarcted myocardium (M). Results: Infarction-related mortality was higher in SI comparing to EI group (25% vs 12%; P < 0.05), without differences in MI size. Compared to EI, SI group exhibited lower shortening fraction, higher apoptosis rate and higher local levels of inflammatory markers, such as NF-kB and TNF-&#945; at I. SI group showed negative correlations between the quantities of PPARs and inflammatory cytokines: a) PPAR-&#945; at M vs TNF-&#945; at I (R:-0.826, P=0.005); b) PPAR-&#945; vs NF-kB at I (R: -0.576, P=0.02) and P (R:-0.505, P=0.03); c) TNF-&#945; at I vs PPAR-&#945; and PPAR-&#947; at M (R:-0.826, P=0.005 e R:-0.786, P=0.02); d) NF-kB at I vs PPAR-&#945; at M (R:-0.576, P=0.01); and e) NF-kB at P vs PPAR-&#945; at M (R:-0.505, P=0.03). There was a positive correlation between NF-kB vs PPAR-&#947; at P (R: 0.596, P=0.02). The arteriolar density did not differ between the two infarcted groups. However, the exercised infarcted group showed a negative correlation between the arteriolar density at I and PPAR-&#947; at P (R:-0.76, P=0.02). Conclusion: These findings support the hypothesis that the occurrence of MI in previously trained animals is followed by lower local inflammatory markers, better ventricular function, and possibly a better interrelationship between modulators of the energetic metabolism and of the immune system.

Uma estreita relação entre a ação dos hormônios tireoidianos (HT) no sistema cardiovascular sendo mediada por componentes do sistema renina-angiotensina (SRA) tem sido descrita na literatura. Já foi demonstrado que o processo de isquemia/reperfusão (I/R) promove diminuição na expressão do receptor de angiotensina II do tipo 2 (AT2) no miocárdio, com consequente prejuízo funcional, enquanto o aumento de sua expressão melhorou a recuperação da função cardíaca. A hipótese do presente estudo é que o papel cardioprotetor exercido pelos HT ocorre com a participação do receptor AT2. Esta hipótese foi testada utilizando o modelo de I/R com a perfusão de coração isolado de camundongos selvagens e nocautes para o AT2, submetidos a tratamento por 14 dias com T3. Ainda foi avaliado o SRA mitocondrial, assim como o papel do óxido nítrico (NO) na recuperação pós-isquêmica. Os resultados apontam que a cardioproteção induzida pelo T3 é mediada pelo AT2, com consequente aumento na produção de NO e modulação de parâmetros do metabolismo mitocondrial. / Some authors have shown a close relationship between the action of thyroid hormone (TH) on cardiovascular system and renin angiotensin system (RAS) activation. Have been shown that ischemia/reperfusion (I/R) promotes decrease on angiotensin II type 2 receptor (AT2) expression in the myocardium, with functional worsening, on the other hand the AT2R increased improves the cardiac function after ischemia episodes. So, we have hypothesized that the cardioprotective effect of TH in I/R model may occur with the participation of AT2. This hypothesis was tested using I/R model in isolated hearts AT2 knockout and wild-type mice submitted to high levels of T3 by 14 days. The mitochondrial RAS was evaluated, as well as the nitric oxide (NO) role in post-ischemic recovery. The results show that TH induces cardioprotection through AT2 receptor, some mitochondrial metabolism parameters were modulated by TH and the NO production was increased.

In den ersten Versuchsreihen der hier vorliegenden Arbeit bestätigte sich, dass im in vitro Modell die klassische ischämische Präkonditionierung kardioprotektiv wirkt. Die Präkonditionierung bewirkte eine Infarktgrößenreduktion um 54 %; dies wird durch Literaturangaben bestätigt. Die Postkonditionierung dagegen, trotz drei verschiedener Postkonditionierungsprotokolle, ist am isoliert perfundierten Rattenherzen nicht protektiv. Im in vivo Rattenherz-Modell wurden die Präkonditionierung und die klinisch relevantere Postkonditionierung gegenüberstellend untersucht. Hier zeigte sich, dass die 3 Reperfusions-/Ischämiezyklen für jeweils 30 Sekunden der Postkonditionierung genauso protektiv wie die Präkonditionierung wirken. Infarktgrößen- und biochemische Untersuchungen belegen, dass hierbei die PI3-Kinase ein wichtiges Signaltransduktionselement ist, da einerseits durch die Inhibition der PI3-Kinase mittels Wortmannin die Infarktgrößenreduktion vollständig aufgehoben war und andererseits nach einer 1,5-minütigen Reperfusion eine vermehrte Phosphorylierung der Akt im Western-Blot auftrat. Des Weiteren konnte erstmals die Inaktivierung der GSK-3ß durch eine verstärkte Phosphorylierung über einen PI3-Kinase-vermittelten Signaltransduktionsweg nachgewiesen werden. Die Zugabe des spezifischen Inhibitors TDZD-8 der GSK-3ß verringert ebenfalls die Infarktgröße signifikant. Auch konnte zum ersten Mal gezeigt werden, dass das mammalian target of Rapamycin in der Postkonditionierung des in vivo Rattenherzens eine wichtige Rolle zu spielen scheint. Außerdem konnte neben dem PI3-Kinase/Akt-Signaltransduktionsweg auch die Beteiligung des MEK1/2-ERK1/2–Wegs als Signaltransduktionsweg der Postkonditionierung im in vivo Rattenherzen nachgewiesen werden. Erstmals wurde die Apoptose in einem in vivo Herzen nach regionaler Ischämie untersucht. Die Ergebnisse des TUNEL-Tests und der Western-Blot-Analysen zeigen eine unterdrückte Apoptose durch die Postkonditionierung. Ein weiterer Teil der vorliegenden Arbeit widmete sich der Untersuchung der Postkonditionierung in pathologischen Rattenherzen. Im Gegensatz zu gesunden Herzen schlug die Postkonditionierung in hypertrophiertem Myokardium von spontan-hypertensiven Ratten mit einer signifikant arteriellen Hypertension fehl. Diese Blockierung der Kardioprotektion zeigte sich durch die fehlende Reduzierung der Infarktgröße trotz unterschiedlicher Postkonditionierungsprotokolle (3x30’’ und 6x10’’ R/I) und unterschiedlich langer Ischämiedauern (20 und 30 Minuten). Gleichfalls war auch die Phosphorylierung der GSK-3ß aufgehoben. Als Modell des metabolischen Syndroms wurde die WOKW-Ratte untersucht. Diese Ratten entwickeln in sehr jungem Alter klassische Symptome wie Dyslipidämie, Hyperinsulinämie und Fettsucht. Wie bei der Herzhypertrophie war auch beim Modell des metabolischen Syndroms die Postkonditionierung - mit 3 Reperfusions-/ Ischämiezyklen für jeweils 30 Sekunden - blockiert. Dabei konnte weder eine Infarktgrößenreduktion noch eine vermehrte Phosphorylierung der GSK-3ß nachgewiesen werden. Die Ergebnisse der vorliegenden Arbeit erlauben die Schlußfolgerung, dass das Substrat der GSK-3ß, die mPTP des Mitochondriums, eine „Schlüsselrolle“ in der Apoptose innehat - die Postkonditionierung vermindert nicht nur die Nekrose, sondern reduziert auch die Apoptose. Bemerkenswert und potentiell von klinischer Bedeutung ist die Beobachtung, dass bei Vorliegen von Risikofaktoren, wie arterielle Hypertonie und metabolischem Syndrom, solche Schutzmechanismen des Herzens aufgehoben sind. Diese Erkenntnisse sind im Hinblick auf die Therapie am Menschen von großer Bedeutung. Ob langfristig einzelne Komponenten der Signaltransduktionswege, wie PI3-Kinase, Akt, mTOR, ERK1/2 oder GSK-3ß, Angriffspunkte einer pharmakologischen Therapie sein könnten, muß in weiteren Untersuchungen geklärt werden.

Le pore de transition de perméabilité mitochondriale (PTPm) joue un rôle majeur dans la mort cellulaire et dans la cardioprotection. Notre hypothèse est que le complexe I de la chaîne respiratoire est impliqué dans la régulation de l'ouverture du PTPm. Sur des mitochondries isolées de cœurs des rongeurs, nous avons pu démontrer que le PTPm est désensibilisé par la cyclosporine A, un inhibiteur de la cyclophiline D (CyP-D), et cet effet est largement amplifié en présence de la roténone, un inhibiteur du complexe I. Ces résultats ont été confirmés chez la souris CyP-D déficiente. L'étude de plusieurs types cellulaires a aussi confirmé l'effet de la roténone dans la régulation du PTPm. Ainsi, nous avons pu montrer que le flux d'électrons travers le complexe I est capable de réagir sur un site de régulation du PTPm cardiaque masqué par la CyP-D. De plus, les analogues de l'ubiquinone, élément de la chaîne respiratoire impliqué dans le transfert d'électrons entre les complexes I, II et III, modulent la susceptibilité du PTPm vis-à-vis du Ca2+. Par ailleurs, dans un modèle de cœur isolé du rat, le postconditionnement par le perindoprilate, un inhibiteur de l'enzyme de conversion, diminue la taille de l'infarctus après l'ischémie-reperfusion d'une façon NO-dépendant. L'ensemble de nos résultats ouvre de nouvelles perspectives thérapeutiques dans la cardioprotection et montre l'importance du complexe I et de la CyP-D comme cibles moléculaires incontournables dans la cardioprotection

O exercício é hoje reconhecidamente um fator de proteção para morbidade e mortalidade cardiovascular. Apesar de extensos dados de estudos epidemiológicos e de intervenção, os mecanismos subjacentes cardioprotetores do exercício ainda não estão bem elucidados. Alguns autores acreditam que o treinamento físico induz o desenvolvimento de células miocárdicas mais resistentes a agressões externas e maior vascularização. Além disso, o exercício parece exercer grande influência sobre o sistema imunológico. O entendimento dos mecanismos através dos quais o exercício influencia o desfecho clínico do infarto agudo do miocárdio (IM) pode trazer uma melhor compreensão das diferentes evoluções clínicas de indivíduos aparentemente semelhantes. O estudo de quais moléculas e sistemas estão envolvidas nessa cardioproteção e de como medeiam e integram a resposta miocárdica ao estresse pode influenciar futuras terapias. O objetivo do presente trabalho é testar a hipótese de que a ocorrência de IM em animais previamente treinados é acompanhada de melhor função ventricular pós-IM, maior vascularização, em associação com menor expressão de marcadores inflamatórios e moduladores do metabolismo, e menos apoptose. Materiais e Métodos: Sessões de 60 min/dia, 05 dias/semana, por 08 semanas foram aplicadas no grupo exercício. Após este período os animais exercitados e sedentários foram randomizados para cirurgia de IM através da ligadura da artéria coronária esquerda (EI e SI, respectivamente), ou cirurgia controle (ES e SS, respectivamente), seguido de um período de sedentarismo de 04 semanas. A função ventricular esquerda foi obtida através da ecocardiografia, bem como o tamanho do infarto. A técnica de imunohistoquímica foi utilizada para detecção de PPAR-&#945;, PPAR-&#947;, TNF-&#945;, NF-kB, e &#945;-actina, e os resultados foram quantificados através de um sistema de análise de imagens automática por detecção de cores. A técnica de TUNEL foi utilizada para marcação de apoptose. Foram estudadas três regiões do coração: infarto (I), peri-infarto (P), e miocárdio sem infarto (M). Resultados: a mortalidade relacionada ao infarto foi maior no grupo sedentário em relação ao exercitado (25% vs 12%; P<0,05), sem diferença em relação a tamanho de IM. Comparado ao grupo EI, SI exibiu menor fração de encurtamento, maior taxa de apoptose, e aumento dos marcadores inflamatórios NF-kB e TNF-&#945; em I. O grupo SI mostrou correlações negativas entre quantidades de: a) PPAR-&#945; em M vs TNF-&#945; em I (R:-0,826, P=0,005); b) PPAR-&#945; vs NF-kB em I (R: -0,576, P=0,02) e em P (R:-0,505, P=0,03); c) TNF-&#945; em I e PPAR-alpha e PPAR-&#947; em M (R:-0,826, P=0,005 e R:-0,786, P=0,02); d) NF-kB em I e PPAR-&#945; em M (R:- 0,576, P=0,01) e e) NF-kB em P e PPAR-&#945; em M (R:-0,505, P=0,03). Houve correlação positiva entre NF-kB e PPAR-&#947; em P (R: 0,596, P=0,02). A densidade arteriolar não diferiu entre os dois grupos infartados, porém no grupo EI houve correlação negativa entre a densidade arteriolar em I e PPAR-&#947; em P (R: - 0,76, P=0,02). O número de células apoptóticas por campo (mediana) em SI e EI foi, respectivamente, 3,97 e 1,90 em I; 3,67 e 1,57 em P; e 1,41 e 1,13 em M. Houve menor número de células em apoptose em M em relação a I e P (P < 0,001) no grupo SI. Em EI, o número de células em apoptose/campo não diferiu entre as regiões estudadas. O número de células em apoptose por campo foi maior em SI comparado a EI em I (3,97 ± 0,61 vs 1,90 ± 1,82; P < 0,05) e em P (3,67 ± 0,73 vs 1,57 ± 1,07; P < 0,01). Conclusão: Os achados do presente trabalho suportam a hipótese de que a ocorrência de IM em animais previamente treinados é acompanhada de menor inflamação, menores taxas de apoptose, melhor função ventricular e possivelmente melhor interrelação entre moduladores do metabolismo energético e do sistema imunológico. / Exercise is a well recognized protective factor for cardiovascular morbidity and mortality. In spite of extensive data from epidemiologic studies and intervention, the subjacent cardioprotective mechanisms of exercise are still non clear. Some authors believe that the physical training induces development of more resistant myocardial fibers against external injuries and increased vascularization. Also, exercise seems to influence the modulation of the immune system. The understanding of mechanisms by which the exercise acts in the acute myocardial infarction (MI) progression may bring a better comprehension of different clinical outcome in apparently similar individuals. The knowledge of which molecules and systems are involved in this cardioprotection and how they mediate and integrate the stress myocardial response may help future therapies. The objective of the present work is to test the hypothesis that the occurrence of MI in previously trained animals is associated with a better post MI ventricular function, major vascularization, in association with lower expression of inflammatory markers and of metabolic modulators, and less apoptosis. Material and Methods: Sessions of 60 min/day, 05 days/week, for 08 weeks were applied in the exercised group. After this period, the exercised and sedentary animals were randomized to surgery for myocardial infarction, through the ligature of left coronary artery (EI and SI, respectively), or control surgery (ES and SS, respectively), followed by a 04 week sedentary period. The left ventricular function was obtained by the echocardiography as also the infarct size. Immunohistochemistry was used for detection of PPAR-&#945;, PPAR-&#947;, TNF-&#945;, NF-kB, ad &#945;-actin, and the results were quantified in an image analysis system by automatic collor detection. TUNEL technique was used for detection of apoptosis. Three regions of the heart were studied: infarcted (I), peri-infarcted (P), and non infarcted myocardium (M). Results: Infarction-related mortality was higher in SI comparing to EI group (25% vs 12%; P < 0.05), without differences in MI size. Compared to EI, SI group exhibited lower shortening fraction, higher apoptosis rate and higher local levels of inflammatory markers, such as NF-kB and TNF-&#945; at I. SI group showed negative correlations between the quantities of PPARs and inflammatory cytokines: a) PPAR-&#945; at M vs TNF-&#945; at I (R:-0.826, P=0.005); b) PPAR-&#945; vs NF-kB at I (R: -0.576, P=0.02) and P (R:-0.505, P=0.03); c) TNF-&#945; at I vs PPAR-&#945; and PPAR-&#947; at M (R:-0.826, P=0.005 e R:-0.786, P=0.02); d) NF-kB at I vs PPAR-&#945; at M (R:-0.576, P=0.01); and e) NF-kB at P vs PPAR-&#945; at M (R:-0.505, P=0.03). There was a positive correlation between NF-kB vs PPAR-&#947; at P (R: 0.596, P=0.02). The arteriolar density did not differ between the two infarcted groups. However, the exercised infarcted group showed a negative correlation between the arteriolar density at I and PPAR-&#947; at P (R:-0.76, P=0.02). Conclusion: These findings support the hypothesis that the occurrence of MI in previously trained animals is followed by lower local inflammatory markers, better ventricular function, and possibly a better interrelationship between modulators of the energetic metabolism and of the immune system.

- 4 - Abstract Adaptation to hypoxia or exercise training has cardioprotective effects against acute ischemic injury, but can potentially negatively influence heart function. Possible negative changes depend on the degree of hypoxia and exercise training intensity. It is therefore necessary to evaluate the effects of the specific adaptation protocols used. The ideal technique is echocardiography, which enables non-invasive, repeated and long-term measurements of the same individual allowing to study the development of changes in the course of adaptation. The aim of this study was to determine the effects of selected protocols of adaptation to intermittent hypobaric hypoxia (corresponding to the altitude of 4,000 to 8,000 meters above sea level, for 15 weeks in total) and exercise training (running speed 30 m.min-1 for 60 min a day, 4 weeks in total) on the left ventricle geometry and systolic function in rats. We assessed basic echocardiographic parameters of the ventricle geometry and function such as fractional shortening, ejection fraction, stroke volume, cardiac output etc. The adaptation of rats to intermittent hypobaric hypoxia lead neither to the impairment of systolic function nor to the development of left ventricle hypertrophy compared to controls; signs of moderate hypertrophy were observed only...