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Experimental and clinical studies have clearly demonstrated significant sex differences in myocardial structure and function, both under physiological and pathological conditions. The best example are significant sex differences in the cardiac tolerance to ischemia/reperfusion injury: pre-menopausal adult female hearts are more resistant as compared to the male myocardium. The importance of these findings is supported by the fact that the number of studies dealing with this issue increased significantly in recent years. Detailed molecular and cellular mechanisms responsible for sex differences are yet to be elucidated; however, it has been stressed that the differences cannot be explained only by the effect of estrogens. In recent years, a promising new hypothesis has been developed, suggesting that mitochondria may play a significant role in the sex differences in cardiac tolerance to oxygen deprivation. However, one is clear already today: sex differences are so important that they should be taken into consideration in the clinical practice for the selection of the optimal diagnostic and therapeutic strategy in the treatment of ischemic heart disease. The present review attempts to summarize the progress in cardiovascular research on sex-related differences in cardiac tolerance to oxygen deprivation during the last 40 years, i.e. from the first experimental observation. Particular attention was paid to the sex-related differences of the normal heart, sex-dependent tolerance to ischemia-reperfusion injury, the role of hormones and, finally, to the possible role of cardiac mitochondria in the mechanism of sex-dependent differences in cardiac tolerance to ischemia/reperfusion injury. [ABSTRACT FROM AUTHOR]

The aim of the study was to examine the potential role of mitochondrial permeability transition pore (mPTP) in the cardioprotective effect of chronic continuous hypoxia (CH) against acute myocardial ischemia/reperfusion (I/R) injury. Adult male Wistar rats were adapted to CH for 3 weeks, while their controls were kept under normoxic conditions. Subsequently, they were subjected to I/R insult while being administered with mPTP inhibitor, cyclosporin A (CsA). Infarct size and incidence of ischemic and reperfusion arrhythmias were determined. Our results showed that adaptation to CH as well as CsA administration reduced myocardial infarct size in comparison to the corresponding control groups. However, administration of CsA did not amplify the beneficial effect of CH, suggesting that inhibition of mPTP opening contributes to the protective character of CH. [ABSTRACT FROM AUTHOR]

Aim: The transcriptional factor HIF‐1α is recognized for its contribution to cardioprotection against acute ischemia/reperfusion injury. Adaptation to chronic hypoxia (CH) is known to stabilize HIF‐1α and increase myocardial ischemic tolerance. However, the precise role of HIF‐1α in mediating the protective effect remains incompletely understood. Methods: Male wild‐type (WT) mice and mice with partial Hif1a deficiency (hif1a+/−) were exposed to CH for 4 weeks, while their respective controls were kept under normoxic conditions. Subsequently, their isolated perfused hearts were subjected to ischemia/reperfusion to determine infarct size, while RNA‐sequencing of isolated cardiomyocytes was performed. Mitochondrial respiration was measured to evaluate mitochondrial function, and western blots were performed to assess mitophagy. Results: We demonstrated enhanced ischemic tolerance in WT mice induced by adaptation to CH compared with their normoxic controls and chronically hypoxic hif1a+/− mice. Through cardiomyocyte bulk mRNA sequencing analysis, we unveiled significant reprogramming of cardiomyocytes induced by CH emphasizing mitochondrial processes. CH reduced mitochondrial content and respiration and altered mitochondrial ultrastructure. Notably, the reduced mitochondrial content correlated with enhanced autophagosome formation exclusively in chronically hypoxic WT mice, supported by an increase in the LC3‐II/LC3‐I ratio, expression of PINK1, and degradation of SQSTM1/p62. Furthermore, pretreatment with the mitochondrial division inhibitor (mdivi‐1) abolished the infarct size‐limiting effect of CH in WT mice, highlighting the key role of mitophagy in CH‐induced cardioprotection. Conclusion: These findings provide new insights into the contribution of HIF‐1α to cardiomyocyte survival during acute ischemia/reperfusion injury by activating the selective autophagy pathway. [ABSTRACT FROM AUTHOR]

Cardiac sensitivity to oxygen deprivation changes significantly during ontogenetic development. However, the mechanisms for the higher tolerance of the immature heart, possibilities of protection, and the potential impact of perinatal hypoxia on cardiac tolerance to oxygen deprivation in adults have not yet been satisfactorily clarified. The hypoxic tolerance of an isolated rat heart showed a triphasic pattern: significant decrease from postnatal day 1 to 7, followed by increase to the weaning period, and final decline to adulthood. We have observed significant ontogenetic changes in mitochondrial oxidative phosphorylation and mitochondrial membrane potential, as well as in the role of the mitochondrial permeability transition pores in myocardial injury. These results support the hypothesis that cardiac mitochondria are deeply involved in the regulation of cardiac tolerance to oxygen deprivation during ontogenetic development. Ischemic preconditioning failed to increase tolerance to oxygen deprivation in the highly tolerant hearts of newborn rats. Chronic hypoxic exposure during early development may cause in-utero or neonatal programming of several genes that can change the susceptibility of the adult heart to ischemia-reperfusion injury; this effect is sex dependent. These results would have important clinical implications, since cardiac sensitivity in adult patients may be significantly affected by perinatal hypoxia in a sex-dependent manner. Key words: immature heart, ontogeny, hypoxic tolerance, cardiac protection. La sensibilite cardiaque a la privation d'oxygene change significativement au cours de l'ontogenie. Cependant, les mecanismes responsables de la tolerance plus elevee du coeur immature, ainsi que les possibilites de protection et de l'impact potentiel d'une hypoxie perinatale sur la tolerance cardiaque a la privation d'oxygene chez les adultes n'ont pas encore ete clarifies de maniere satisfaisante. La tolerance hypoxique du coeur de rat isole a revele un patron triphasique : une diminution significative du jour post-natal 1 au jour 7, suivie d'une augmentation lors du sevrage et d'un declin final a l'age adulte. Les auteurs ont observe des changements ontogeniques significatifs sur le plan de la phosphorylation oxydative mitochondriale, du potentiel membranaire mitochondrial, ainsi que du role des pores de transition de permeabilite de la mitochondrie dans le dommage myocardique. Ces resultats appuient l'hypothese que les mitochondries cardiaques sont profondement impliquees dans la regulation de la tolerance cardiaque a la privation d'oxygene durant l'ontogenie. Le pre-conditionnement ischemique ne parvenait pas a augmenter la tolerance a la privation d'oxygene chez les coeurs de rats nouveau-nes, hautement tolerants. L'exposition chronique a l'hypoxie, tot dans le developpement, peut induire la programmation in utero ou neonatale de plusieurs genes qui peuvent modifier la susceptibilite du coeur adulte au dommage d'ischemie/reperfusion; cet effet est dependant du sexe. Ces resultats pourraient avoir des implications cliniques importantes, puisque la sensibilite des patients adultes peut etre significativement affectee par l'hypoxie perinatale de maniere dependante du sexe. [Traduit par la Redaction] Mots-cles : coeur immature, ontogenie, tolerance hypoxique, protection cardiaque., Introduction The most frequent (and hence the most widely studied) cardiovascular diseases of modern times undoubtedly include hypoxic states. They originate as a result of disproportion between the amount of [...]

Coronary heart disease (CHD) is the leading cause of morbidity and mortality in both men and women in the developed countries. Despite this fact, females are still under-represented in the majority of clinical trials. At the present time, only limited evidence is available with respect to the female-specific aspects of pathogenesis, management, and outcomes in acute coronary syndrome (ACS). Women less frequently undergo coronary intervention, and a lower proportion of women receive evidence-based pharmacotherapy, compared with men. It has been shown that women benefit from an invasive approach and coronary intervention in ACS as much as men, despite their advanced age and higher rate of bleeding complications. Also, administration of beta-blockers, ACE-inhibitors, and intensive statin therapy is associated with a comparable reduction of cardiovascular event rates in women and men. On the other hand, women may profit less than men from fibrinolytic or glycoprotein IIb/IIIa inhibitor therapy. Both sexes benefit equally from aspirin therapy, whereas contradictory data are available on the efficacy of clopidogrel in women. There is an urgent need for intensive research in the development of female-specific therapeutic strategy in ACS, even though the detailed mechanisms of sex differences are still unknown. Key words: sex differences, acute coronary syndrome, coronary revascularization, pharmacotherapy, women. La maladie coronarienne (MC) est la principale cause de morbidite et de mortalite tant chez l'homme que chez la femme dans les pays developpes. Malgre cela, les femmes sont encore sous-representees dans la plupart des essais cliniques. Aujourd'hui, il n'existe que peu de donnees sur les aspects specifiques aux femmes de la pathogenese, de la prise en charge et de l'issue de syndrome coronarien aigu (SCA). Les femmes subissent moins d'interventions coronariennes et recoivent dans une moindre proportion une pharmacotherapie basee sur des donnees probantes comparativement aux hommes. Il a toutefois ete demontre que les femmes beneficient d' une approche invasive et d' une intervention coronarienne lors d'un SCA autant que les hommes, malgre un age avance et un taux plus eleve de complications hemorragiques. Aussi, l'administration de beta-bloquants, d'inhibiteurs de l'enzyme de conversion de l'angiotensine et d'une therapie intensive aux statines est associee a une reduction comparable des risques d'evenements cardiovasculaires chez les femmes et chez les hommes. En revanche, les femmes profitent moins que les hommes d'une therapie fibrinolytique ou aux inhibiteurs de la glycoproteine IIb/IIIa. Les deux sexes beneficient de facon egale d'une therapie a l'aspirine, alors que les donnees disponibles sur l'efficacite du clopidogrel chez les femmes sont contradictoires. Il est urgent d'intensifier la recherche sur le developpement d' une strategie therapeutique du SCA chez la femme, meme si les mecanismes detailles des differences sexuelles sont encore inconnus. Mots-cles : differences sexuelles, syndrome coronarien aigu, revascularisation coronarienne, pharmacotherapie, femmes. [Traduit par la Redaction], Introduction Coronary heart disease (CHD) is the leading cause of morbidity and mortality in both men and women in the developed countries, and according to the World Health Organization, CHD [...]

Chronic hypoxia has been shown to stimulate myocardial microvascular growth and improve cardiac ischemic tolerance in young and adult rats. The aim of this study was to determine whether the ANG II type 1 receptor (A[T.sub.1]) pathway was involved in these processes. Newborn Wistar rats, exposed to chronic intermittent hypoxia (8 h/day) for 10 days, were simultaneously treated with A[T.sub.1] receptor blocker irbesartan and compared with untreated animals. The major finding is that chronic hypoxia increased the capillary supply of myocardial tissue, which was even more pronounced in hypertrophied right ventricle, whereas increased arteriolar supply was found only in the left ventricle. This angiogenic response was completely prevented by irbesartan. Moreover, chronic hypoxia improved the postischemic recovery of cardiac contractile function during reperfusion, and this protective effect was also completely abolished by irbesartan. Chronic hypoxia increased the myocardial density of A[T.sub.1] but not of ANG II type 2 receptor subtypes, whereas the effect of irbesartan was not significant. The expression of caveolin-1[alpha] markedly increased in response to chronic hypoxia, and irbesartan prevented this effect. Neither hypoxia nor irbesartan treatment altered the expression of nitric oxide synthase 3, heat shock protein 90, and VEGF. It is concluded that the A[T.sub.1] receptor pathway plays an important role in coronary angiogenesis and improved cardiac ischemic tolerance induced in neonatal rats by chronic hypoxia. angiotensin II receptors; ischemia-reperfusion; caveolin-1

Hypoxia from birth increases resistance to myocardial ischemia in infant rabbits. We hypothesized that increased cardioprotection in hearts chronically hypoxic from birth persists following development in a normoxic environment and involves increased activation of nitric oxide synthase (NOS) and ATP-dependent K ([K.sub.ATP]) channels. Resistance to myocardial ischemia was determined in rabbits raised from birth to 10 days of age in a normoxic ([MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII.]) or hypoxic ([MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII.]) environment and subsequently exposed to normoxia for up to 60 days of age. Isolated hearts (n = 8/group) were subjected to 30 min of global ischemia followed by 35 min of reperfusion. At 10 days of age, resistance to myocardial ischemia (percent recovery postischemic recovery left ventricular developed pressure) was higher in chronically hypoxic hearts (68 [+ or -] 4%) than normoxic controls (43 [+ or -] 4%). At 10 days of age, [N.sup.G]-nitro-L-arginine methyl ester (200 [micro]M) and glibenclamide (3 [micro]M) abolished the cardioprotective effects of chronic hypoxia (45 [+ or -] 4% and 46 [+ or -] 5%, respectively) but had no effect on normoxic hearts. At 30 days of age resistance to ischemia in normoxic hearts declined (36 [+ or -] 5%). However, in hearts subjected to chronic hypoxia from birth to 10 days and then exposed to normoxia until 30 days of age, resistance to ischemia persisted (63 [+ or -] 4%). L-NAME or glibenclamide abolished cardioprotection in previously hypoxic hearts (37 [+ or -] 4% and 39 [+ or -] 5%, respectively) but had no effect on normoxic hearts. Increased cardioprotection was lost by 60 days. We conclude that cardioprotection conferred by adaptation to hypoxia from birth persists on subsequent exposure to normoxia and is associated with enhanced NOS activity and activation of [K.sub.ATP] channels. ischemia-reperfusion: cardioplegia

I. INTRODUCTION Clinical-epidemiological studies have shown that the risk factors of serious cardiovascular diseases, such as atherosclerosis and ischemic heart disease, are present during the early phases of ontogenetic development [...]