Thesis (M.D.)—Boston University

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Acute myocardial infarction (AMI) is one of the most common causes of death in our country. As population ages, such illness have its prevalence rates increased. In order to analyse drug effects over myocardial lesions as a result of AMI, the myocardial infarction induction model by means of the administration of isoproterenol in rats is one of the most used at all, given the capability of that substance of mimicking the myocardial injury observed in humans. In the present study, preconditioning with intra-peritoneal ternatin, at a dose of 1 mg/kg was used. Fourteen consecutive days were assessed in the isoproterenol-induced MI (120 mg/kg) in Wistar rats. Myocardial lesions induced by isoproterenol was indicated by the rise in biochemical markers levels, such as SGOT (serum glutamic oxaloacetic transaminase) and troponin I, reduction in the activity of catalase enzyme in the myocardial tissue, as well as by histopathological changes assessed in the apex of the left ventricle. It was also evaluated mortality rates, hemoglobin and SGPT (serum glutamic pyruvic transaminase) serum concentrations, leukocytes, neutrophils counts and renal function. Preconditioning with ternatin unveiled protective effects within the myocardial infarction induced by isoproterenol in rats, once it diminished mortality rates, attenuated SGOT and troponin I concentrations, preserved catalase levels in the myocardium and diminished histopathological changes in the apex of the left ventricle Possible pathways accountable for such good results, reducing the degree of myocardial injury in this experimental essay, might be related to the antioxidant properties attributable to ternatin. / O infarto agudo do miocÃrdio (IAM) à uma das principais causas de morte em nosso paÃs. Com o envelhecimento da populaÃÃo a tendÃncia à que se aumente a incidÃncia desta afecÃÃo. Para se estudar efeitos de drogas sobre a lesÃo miocÃrdica decorrente de IAM, um dos modelos experimentais mais utilizados à a induÃÃo de infarto do mocÃrdio (IM) com administraÃÃo de isoproterenol em ratos, uma vez que esta substÃncia causa uma lesÃo miocÃrdica semelhante à observada em IAM nos humanos. Nesse estudo o prÃ-condicionamento com ternatina administrada por via intraperitoneal, na dose de 1 mg/kg do animal, por catorze dias consecutivos, foi avaliado no IM induzido por isoproterenol (120 mg/kg do animal) em ratos Wistar. A lesÃo miocÃrdica induzida pelo isoproterenol foi indicada pela elevaÃÃo de marcadores bioquÃmicos, como transaminase glutÃmico-oxalacÃtica (TGO) e troponina I, reduÃÃo da atividade da enzima catalase no tecido miocÃrdico, bem como por alteraÃÃes histopatolÃgicas avaliadas na regiÃo do Ãpice do ventrÃculo esquerdo. Avaliou-se ainda a mortalidade, as concentraÃÃes sÃricas de transaminase glutÃmico-pirÃvica (TGP), hemoglobina, contagem de leucÃcitos e neutrÃfilos e marcadores da funÃÃo renal. O prÃ-tratamento com ternatina apresentou efeitos protetores no infarto do miocÃrdio induzido por isoproterenol em ratos, uma vez que dimunuiu a taxa de mortalidade, atenuou as elevaÃÃes de TGO e troponina I; preservou a atividade da enzima catalase e reduziu o grau de alteraÃÃes histopatolÃgicas. PossÃveis mecanismos de aÃÃo responsÃveis pelos efeitos benÃficos em reduzir o grau de lesÃo miocÃrdica neste modelo experimental podem estar relacionados a propriedades antioxidantes da ternatina.

Background: Autophagy is a conserved physiological process in the body that functions to maintain homeostasis via degradation and recycling of dysfunctional proteins and even entire organelles. It is typically triggered by nutritional stress and/or growth factor deprivation and ultimately results in the packaging of cellular components into autophagosomes. These autophagosomes then fuse with lysosomes to be degraded. Autophagy is suggested to play a significant role in cardiac remodeling, particularly following myocardial infarction (MI). Ataxia-telangiectasia mutated kinase (ATM) is a cell cycle checkpoint protein activated in response to DNA damage. Mutations in ATM cause a multi-systemic disease known as Ataxia-telangiectasia (AT). The present study aims to investigate the relationship between ATM and autophagy in the heart, particularly post-MI. Methods: Wild-type (WT) and ATM heterozygous (hKO; aged ~4 months) were injected with either bafilomycin (Baf; autophagy inhibitor) or rapamycin (Rap; autophagy activator) for 30 minutes. MI was then induced mice by ligation of the left anterior descending coronary artery. Heart function was measured using M-mode echocardiography 4 hours post-MI. For cellular analysis of autophagy, confluent cultures of cardiac fibroblasts were isolated from adult male rats and treated with KU-55933 (KU; specific ATM inhibitor) in serum-free media for 4 hours. Cardiac fibroblasts were also isolated from ATM WT, heterozygous (hKO), and knockout (KO) mice, grown to confluency, and serum-starved for 4 hours. Levels of microtubule-associated protein light chain 3-II (LC3-II), a marker for autophagy, was examined in the heart and cell lysates using western blots. Results: M-mode echocardiography revealed that MI decreases heart function in both genotypes as measured by decreased %FS and EF. No change in heart function was observed between WT-MI and hKO-MI groups following Baf treatment. Rap treatment resulted in the functional recovery of the heart in WT-MI, not in hKO-MI group. Levels of LC3-II protein were higher in hKO-sham versus WT-sham hearts. MI decreased LC3-II protein in hKO-MI, not in WT-MI group. Baf treatment further decreased LC3-II protein levels in hKO-MI group. LC3-II levels were lower in KU-treated rat cardiac fibroblasts when compared to control. Cardiac fibroblasts isolated from hKO and KO hearts exhibited decreased LC3-II levels versus those isolated from WT hearts. Conclusion: Although further investigations are needed to confirm our findings, these data provide evidence that ATM deficiency hinders improvement in heart function post-MI following activation of autophagy. ATM deficiency results in reduced autophagy post-MI, an effect that appears to be exaggerated following autophagy inhibition. ATM deficiency also reduces autophagy in rat and mouse cardiac fibroblasts.

The management of acute myocardial infarction (AMI) has been improved by the realisation that the size of infarction can influence mortality (Sobel et al, 1972) and that the infarct size can be altered by subsequent therapy (Maroko et al, 1972). The identification of any factor which may have adverse effects on the ischaemic myocardium and which is amenable to treatment would therefore have important prognostic implications. Elevation of circulating free fatty acid (FFA) concentrations is a consistent feature (Kurien and Oliver, 1966; Oliver et al, 1968) of the profound, non-specific metabolic reaction associated with the onset of AMI (Opie, 1975). The FFA rise has been correlated with the development of arrhythmias (Oliver et al, 1968) after AMI, and with the severity of ischaemic damage (Oliver et al, 1968; Gupta et al, 1969; Russell & Oliver, 1978) on clinical grounds. The method of quantifying infarct size developed by Shell et al (1972) has provided a means of correlating the degree of metabolic disturbance with extent of myocardial damage, and of assessing the benefits of metabolic interventions. The purpose of the studies reported in this thesis was to examine in detail the FFA rise in the early phase of AMI and to correlate this rise with the development of arrhythmias and other complications of AMI and with enzymatically estimated infarct size, thus leading to a more rational approach to therapeutic interventions.

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The accurate exclusion of myocardial ischemia as the cause of acute chest pain is a clinically demanding and resource intensive process. An estimated three to five million patients present to emergency departments in the United States each year with chest pain of uncertain etiology. Emergency departmente valuation of patients presenting with acute chest pain has traditionally involved patient history, physical examination, electrocariography, and cardiac enzyme evaluation. Unfortunately these methods suffer from suboptimal sensitivity and specificity. The majority of these patients will not have myocardial ischemia as the cause of their chest pain. Out of concern for the potential complications and legal consequences of a missed diagnosis of AMI, emergency physicians commonyl recommend hospital admission for all patients at risk of acute ischemia. Resulting in unnecessary admissions and tremendous cost. The goal of this project is to develop a research-based approach to the assessment and management of chest pain patients presenting to the Emergency Department. A chest pain observation unit will be designed for out-patient evaluation of those patients at moderate to low risk of acute coronary ischemia to rule out occult cardiovascular disease. The chest pain center model presented in this project will guide this unit structure. A community outreach educational program to and a continuous quality management program was also developed.

The purpose of this integrative research review is to summarize the research studies of the effect of music therapy on anxiety of cardiovascular patients with acute myocardial infarction in the intensive care unit. Studies from 1990-2000 were examined for inclusion in the review. The initial library search yielded 65 articles; however, only four studies met inclusion criteria. This review covers a description of music therapy including historical, physiological, and psychological aspects. It explores the effects of music therapy on the cardiovascular system and in reducing anxiety. It also analyzes the common and conflicting findings along with the implication for practice and research. Findings support improvement in psychological and physiological parameters with music intervention. Music therapy not only has no adverse effects on ill patients but also has therapeutic effects in relieving anxiety and creating familiarity in intensive care. Recommendations for future research includes evaluating the effectiveness of music therapy with various cultural groups to examine the impact of music on psychoneuroimmunological variables are needed.