Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Background: Glucagon-like Peptide 1 (GLP-1) is a human incretin hormone that has been demonstrated to protect against non-lethal ischaemia reperfusion injury in the left ventricle in humans. It has been suggested from some animal research that this protection may be mediated through the pathway of ischaemic conditioning, of which the opening of the mKATP channel is a key step. Furthermore, it is uncertain whether the protection applies to the right ventricle. Finally, there is limited human evidence of a protective effect against lethal ischaemia reperfusion injury. Methods: Two studies use non-lethal ischaemia to test whether GLP-1 protection is maintained despite blockade of the mKATP channel with the sulfonylurea, glibenclamide. A demand ischaemia study uses dobutamine stress echo to compare LV function. The other uses transient coronary balloon occlusion to generate supply ischaemia during GLP-1 infusion, assessed by conductance catheter. A further transient balloon occlusion is also used to assess the effect of supply ischaemia on RV function. Finally, the GOLD PCI study assesses whether GLP-1 protects against periprocedural myocardial infarction when administered during elective PCI in a randomised, placebo controlled double blind trial. Results: Glibenclamide did not affect GLP-1 cardioprotection in either supply of demand ischaemia suggesting that GLP-1 protection is not mediated through the mKATP channel. The RV experienced stunning with RCA balloon occlusion but there was little evidence of cumulative ischaemic dysfunction with further occlusions. GOLD PCI is continuing to recruit patients. The nature of the study means results cannot be assessed until recruitment is complete. Conclusions: GLP-1 is an agent with potential for clinical use as a cardioprotective therapy. It’s mechanism of action in the heart remains uncertain.

Submitted by FERNANDO AZADINHO ROSA null (rosa.fa@gmail.com) on 2016-03-17T15:23:11Z No. of bitstreams: 1 Fernando Azadinho Rosa_TESE Doutorado.pdf: 4178073 bytes, checksum: fd6bb2a00ca16ebfbbaccdcb82ec48c7 (MD5) / Approved for entry into archive by Sandra Manzano de Almeida (smanzano@marilia.unesp.br) on 2016-03-17T19:31:15Z (GMT) No. of bitstreams: 1 rosa_fa_dr_jabo.pdf: 4178073 bytes, checksum: fd6bb2a00ca16ebfbbaccdcb82ec48c7 (MD5) / Made available in DSpace on 2016-03-17T19:31:15Z (GMT). No. of bitstreams: 1 rosa_fa_dr_jabo.pdf: 4178073 bytes, checksum: fd6bb2a00ca16ebfbbaccdcb82ec48c7 (MD5) Previous issue date: 2016-02-24 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A doxorrubicina é um dos mais eficazes agentes quimioterápicos atualmente disponíveis. No entanto, seu emprego tem sido limitado por sua ação cardiotóxica principalmente quando de seu uso por período prolongado, podendo induzir cardiomiopatia iatrogênica relacionada à dose cumulativa administrada. No presente estudo, avaliou-se a ação de três fármacos (carvedilol, ciclosporina-A e sildenafil) sobre os efeitos cardiotóxicos exercidos pela doxorrubicina. Foram utilizados 45 coelhos, alocados em cinco grupos: controle, doxorrubicina (DOX), DOX + carvedilol, DOX + ciclosporina-A, DOX + sildenafil. A antraciclina foi administrada por seis semanas, e exames seriados de hematologia, bioquímica sérica, eletrocardiografia e ecocardiografia foram realizados. Ao término de oito semanas, os animais foram submetidos a eutanásia e fragmentos de miocárdio foram utilizados para realização de exames de histopatologia, imunoistoquímica e microscopia eletrônica de transmissão. Os tratamentos testados não evitaram a ocorrência de disfunção sistólica, cardiomegalia e insuficiência cardíaca congestiva nem reduziram a mortalidade ocasionada pelo tratamento com doxorrubicina. No entanto, o tratamento concomitante com carvedilol reduziu o número de animais com disfunção diastólica do ventrículo esquerdo, reduziu o número de fibras apoptóticas e a ocorrência de fibrose intersticial nos ventrículos direito e esquerdo. Os dados obtidos permitem inferir que o tratamento com carvedilol resultou em melhora em alguns dos parâmetros avaliados, sugerindo um efeito de proteção miocárdica conferido por esse agente sobre a cardiomiopatia induzida pela doxorrubicina em modelo experimental com coelhos. / Doxorubicin is one of the most effective chemotherapeutic agents currently available. However, its use has been limited by its cardiotoxic effect, especially when used for a long time, leading to iatrogenic cardiomyopathy, related to the cumulative dose administered. In the present study, the effects of three drugs (carvedilol, cyclosporin-A and sildenafil) on doxorubicin-induced cardiomyopathy were analyzed. Fourty five rabbits were allocated in four groups: control, doxorubicin (DOX), DOX + carvedilol, DOX + cyclosporin-A, DOX + sildenafil. Animals received doxorubicin for six weeks and were monitored for eight weeks by hematological and biochemical evaluations, electrocardiography and echocardiography. At week eight, animals were killed and myocardium was analyzed by histopathology, immunohistochemistry and transmission electron microscopy. Any treatment prevented the development of systolic dysfunction, cardiomegaly and heart failure or reduced mortality induced by doxorubicin. However, treatment with carvedilol reduced the number of rabbits with left ventricle diastolic dysfunction, reduced the number of apoptotic cells and the occurrence of interstitial fibrosis in both ventricles. The results showed that treatment with carvedilol improved some of the evaluated parameters, suggesting that this drug has some cardioprotective effect on doxorubicin-induced cardiomyopathy in rabbits.

The importance of physical exercise tends to be neglected in today’s modern lifestyle. This increased passive way of life conveys a notable increase in the prevalence of lifestyle disorders such as hypertension and vascular pathology which lead to cardiovascular strain. Taking this into account, the aim of this investigation was to explore the empirical association between the heart health status of an active and sedentary South African lifestyle, thus intending to provide insight into impact of the significant changes that are associated with the modernised society. With the aforementioned objective in mind, four separate studies were completed: Study 1 sought to investigate the cardiovascular status of 162 undergraduate university students in order to determine whether, despite their youth, students remained at risk of cardiovascular complications. Astonishingly, results indicate that a number of students between the ages of 18 and 25 in a university setting present with preeminent cardiovascular risk. This data highlights some serious concerns regarding the cardiovascular health among the youth. In sequel to study 1, study 2 permitted the comparison of a sedentary and active South African population, however some discrepancies originated due to the notable age difference between the groups. Nevertheless, results gained from this crosssectional comparison between the populations indicate significantly higher cardiac risk amongst the sedentary population. Study 3 was conducted on 202 infantry service recruits between the ages of 18 and 24 years. A pre- post intervention study design was incorporated in pursuit of determining the influence of an intense training programme on cardiovascular variables of a population over a 20 week time-frame. Results yielded from this study indicate a significant decrease in overall cardiovascular risk, as tested over three intervals (week 1, week 12, and week 20) during the 20 week training period. Study 4 was designed as a longitudinal study with self-controls for within group comparisons, as well as a comparative study between the two contrasting populations. Thus, affording the opportunity to determine the impact of physical activity on cardiovascular risk by comparing two divergent South African lifestyles over a 20-week time frame. The 202 infantry service recruits of study 3 served as the intervention group, while the control group comprised of 126 sedentary university students. Findings from this study conveyed strong association between the active population and decreased cardio-stress index and related heart health measurements in comparison to results of the sedentary population. This research validates the positive correlation between a physically active lifestyle and improved heart health, thereby implying reduced cardiovascular risk. In the combat against cardiovascular disease it is clear that focus should be shifted from pharmacological treatment to behavioural prevention. As a principle component of this preventative approach it is vital that individuals are equipped with screening technology that enables early detection and monitoring of probable cardiovascular complications. Several novel ideas were introduced in this research, including the endorsement of the cardio-stress index method as an efficient non-invasive technique to directly observe cardiovascular stress. / Dissertation (MSc)--University of Pretoria, 2014. / lk2014 / Physiology / MSc / Unrestricted

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Cardiovascular diseases, particularly acute myocardial infarction, are one of the leading causes of death in developed countries. It is well known that adaptation to chronic intermittent hypobaric hypoxia (IHH) confers long-lasting cardiac protection against acute ischemia/reperfusion injury. Protein kinase C (PKC) appears to play a role in its cardioprotective mechanism since the administration of general PKC inhibitor completely abolished the improvement of ischemic tolerance in IHH hearts. However, the involvement of individual PKC isoforms remains unclear. Therefore, the primary aim of this study was to investigate the potential involvement of PKCδ and PKCε, the most prevalent PKC isoforms in rat heart, in the mechanism of IHH-induced cardioprotection. We showed that IHH up- regulated PKCδ protein in left ventricle, enhanced its phosphorylation on Ser643 and increased its co-localization with markers of mitochondrial and sarcolemmal membranes. PKCδ subcellular redistribution induced by IHH as well as the infarct size-limiting effect of IHH was reversed by acute treatment with PKCδ inhibitor rottlerin. These data support the view that PKCδ plays a significant role in IHH-induced cardioprotection. On the other hand, adaptation to IHH decreased the PKCε total protein level without affecting its...

The aim of present project was to uncover the effect of pharmacological increase in acute and chronic nitric oxide (NO) production on cardioprotective effect of chronic hypoxia. We studied the effect of NO donor molsidomine on hemodynamic conditions and ischemia - induced myocardium injury. Male Wistar rats were exposed to continual hypoxia in a normobaric chamber (10 % O2, 4 weeks). Rats received molsidomine either chronically (15 mg/kg/day) in drinking water or acutely (10 mg/kg) in saline infused 30 min before ischemia. Control rats were kept under normoxia and treated in a corresponding manner. Adaptation to chronic hypoxia resulted in development of pulmonary hypertension. Chronic treatment with molsidomine slightly reduced these consequences of chronic hypoxia but it had no effect on increased cardiac ischemic tolerance in chronically hypoxic rats. On the other hand acute treatment with molsidomine significantly reduced infarct size and increased the number of arrhythmias in both normoxic and chronically hypoxic animals. In conclusion, our data suggests that acute increase in availability of NO is cardioprotective in both normoxic and chronically hypoxic rats contrary to its chronic increase which seems to have no protective contribution.

These studies have examined the effect of hypoxia inducible factor 1α (HIF-1α) on nucleotide metabolism in the ischemic heart using a genetic mouse model with heart-specific and regulated expression of a stable form of HIF-1α. We find that AMP deaminase (AMPD), the entry point of the purine nucleotide cycle (PNC), is induced by HIF-1α at the level of mRNA, protein, and activity. AMP that accumulates during ischemia can be metabolized to adenosine by 5'-nucleotidase or to IMP by AMPD. Consistent with the finding of AMPD induction, adenosine accumulation during ischemia was much attenuated in HIF-1α-expressing hearts. Further investigation of nucleotide salvage enzymes found that hypoxanthine phosphoribosyl transferase (HPRT) is also upregulated in HIF-1α-expressing hearts. Treatment of hearts with an inhibitor of the PNC, hadacidin, hastens the fall of the adenylate energy charge during ischemia and the accumulation of AMP. The results provide new insight into the role of the PNC in the heart, especially as it relates to ischemia, and indicate that HIF-1α regulates nucleotide metabolism as a compensatory response to hypoxia.

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