Drug transport across cells and cell membranes in the human body is crucial for the pharmacological effect of drugs. Active transport governed by transport proteins plays an important role in this process. A vast number of transport proteins with a wide tissue distribution have been identified during the last 15 years. Several important examples of their role in drug disposition and drug-drug interactions have been described to date. Investigation of drug-drug interactions at the transport protein level are therefore of increasing interest to the academic, industrial and regulatory research communities. The gene expression of transport proteins involved in drug transport was investigated in the jejunum, liver, kidney and colon to better understand their influence on the ADMET properties of drugs. In addition, the gene and protein expression of transport proteins in cell lines, widely used for predictions of drug transport and metabolism, was examined. The substrate and inhibitor heterogeneity of many transport proteins makes it difficult to foresee whether the transport proteins will cause drug-drug interactions. Therefore, in vitro assays for OCT1 and OATP1B1, among the highest expressed transport proteins in human liver, were developed to allow investigation of the inhibitory patterns of these proteins. These assays were used to investigate two data sets, consisting of 191 and 135 registered drugs and drug-like molecules for the inhibition of OCT1 and OATP1B1, respectively. Numerous new inhibitors of the transport proteins were identified in the data sets and the properties governing inhibition were determined. Further, antidepressant drugs and statins displayed strong inhibition of OCT1 and OATP1B1, respectively. The inhibition data was used to develop predictive in silico models for each of the two transport proteins. The highly polymorphic nature of some transport proteins has been shown to affect drug response and may lead to an increased risk of drug-drug interactions, and therefore, the OCT1 in vitro assay was used to study the effect of common genetic variants of OCT1 on drug inhibition and drug-drug interactions. The results indicated that OCT1 variants with reduced function were more susceptible to inhibition. Further, a drug-drug interaction of potential clinical significance in the genetic OCT1 variant M420del was proposed. In summary, gene expression of transport proteins was investigated in human tissues and cell lines. In vitro assays for two of the highest expressed liver transport proteins were used to identify previously unknown SLC transport protein inhibitors and to develop predictive in silico models, which may detect previously known drug-drug interactions and enable new ones to be identified at the transport protein level. In addition, the effect of genetic variation on inhibition of the OCT1 was investigated.

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No description available.

Les champignons mycorhiziens à arbuscules (CMA) ont une structure génétique très particulière et certains aspects de leur génétique sont encore incompris et peu documentés. Les CMA se reproduisent par voie asexuée à l’aide de spores multinucléées. Dans cette étude, j’ai cherché à comprendre les mécanismes de l’hérédité génétique des noyaux par la voie de la reproduction asexuée chez les CMA. La première étape était de déterminer le contenu en noyaux des spores matures, ainsi que celui des spores en formation. Des analyses statistiques ont été utilisées pour vérifier le type de relation entre le nombre de noyaux et le diamètre des spores. Quatre espèces du genre Glomus ont été observées au microscope confocal. Les résultats démontrent une hétérogénéité entre les spores dans leur contenu en noyau pour un même diamètre en plus d’une relation positive entre le nombre de noyau et le diamètre de la spore. Afin de vérifier le contenu en noyaux dans les phases extraracinaires, trois différentes structures du mycélium ont été observées au microscope confocal. Aucune structure n’a été retrouvée avec un seul noyau, ce qui permet de conclure que les CMA ne possèdent vraisemblablement pas de stade uninucléé dans leurs phases extraracinaires. Pour étudier l’hérédité des noyaux, deux différentes approches ont été utilisées: (i) Glomus irregulare a été mis sur milieu complémenté avec de l’aphidicoline pour inhiber la mitose. Des observations au microscope confocal ont permis de dénombrer les noyaux qui sont issus des hyphes et non des mitoses. Les résultats indiquent que la population de noyaux présents dans les spores matures provient d’une migration massive de noyaux à l’intérieur des spores en formation suivie d’un nombre faible de mitoses. (ii) La deuxième approche est l’observation microscopique en temps-réel de spores en formation de G. diaphanum qui a permis de confirmer cette affirmation, car il a été possible de voir plusieurs noyaux entrer dans la spore. Dans la dernière partie de cette étude, je me suis intéressée aux échanges génétiques horizontaux chez les CMA qui sont possibles grâce aux anastomoses. Quatre isolats de l’espèce G. irregulare ont été croisés en co-culture par couple de deux isolats (six croisements) pour permettre une proximité propice aux anastomoses et aux échanges génétiques. Ces croisements ont été maintenus pendant deux ans en culture par le repicage des racines colonisées. Des spores des deux différents isolats ont été confrontées sur eau gélifiée, afin d’observer la formation d’anastomose. Un pourcentage de 13% de formation de fusions d’hyphes pour une des confrontations suggère que l’échange des marqueurs parentaux a pu avoir lieu entre les deux isolats grâce aux anastomoses. Un marqueur moléculaire mitochondrial nommé Indel 5 a été développé et utilisé pour l’analyse des spores filles. Ce marqueur possède entre les isolats une délétion de 39 pb et la différence entre les isolats est facilement détectable sur gel d’électrophorèse après amplification PCR. Le génotypage par PCR des spores individuelles a montré que certaines des spores filles issues du croisement possèdent un des deux marqueurs parentaux alors que d’autres spores ont un génotype qui semble posséder les deux marqueurs. Même si la fusion d’hyphes entre spores en germination est possible, d’autres recherches devront être réalisées pour confirmer qu’un échange génétique est possible entre deux isolats très éloignés géographiquement. Le fait qu’il n’existe aucun stade uninucléé au cycle de vie des CMA et qu’il y ait une migration massive de noyaux lors de la formation des spores permet de limiter la dérive génique lors de la reproduction asexuée. Les anastomoses, quant à elles, permettent de rétablir la diversité génétique. Ces deux particularités de la génétique des CMA ont été fort importantes au cours de leur évolution pour permettre de maintenir une variabilité génétique élevée et permettre ainsi une grande adaptation à différents type d’habitats. / Arbuscular Mycorrhizal Fungi (AMF) have a particular and complex genetic structure. Yet, many aspects of their genetics are still misunderstood and poorly documented. These organisms reproduce by asexual multinucleate spores. In this study, I investigated the mechanisms of genetic inheritance of nuclei through asexual reproduction in AMF. First, I determined the number of nuclei in mature and juveniles spores; I used statistical analysis to determine the relationship between the number of nuclei and the spore diameter. Four species from the genus Glomus were observed with a confocal microscope. The results showed that the number of nuclei has a significant positive relationship with spore diameter and more importantly, surprising heterogeneity in the number of nuclei among sister spores was found. To determine the number of nuclei in extraradical phases, three different structures from the mycelia were carefully examined with a confocal microscope. All the structures possessed more than one nucleus and showed that AMF probably lack a single-nucleus stage during their extraradical phases. To study the nuclei’s heritance, two different approaches were used: (i) Glomus irregulare was grown on medium complemented with aphidicolin to inhibit the mitosis. Observations with a confocal microscope permit to count the nuclei that come from the hyphae and not from the mitosis. The results showed that massive nuclear migration and mitosis are the mechanisms by which AMF spores are formed. (ii) The second approach confirm these results because with time-laps live cellular imaging of young spores of Glomus diaphanum it was possible to see many nuclei to get in the spores. In a second part of this thesis, I studied horizontal gene exchanges among AMF isolates through anastomoses. Thus, four isolates of the species G. irregulare were used in in vitro crossing experiments, in total six combinations using two isolates per crossing experiment. These crossing co-cultures were maintained over two years by subculturing. Spores of two different isolates were confronted in vitro prior to observation of anastomoses. 13% of spores formed anastomoses suggesting the occurrence of genetic exchange between two isolates. A mitochondrial molecular marker referred as Indel 5, was used to genotype individual spores of crossing progenies. A 39 bp deletion occurs in the marker among different isolates and is clearly discriminated by PCR. PCR patterns showed that some spores seem to have both parental markers demonstrating that genetic exchange could occur between the two isolates used in crossing experiment. Even though hyphal fusions occur between germinating spores, subsequent research needs to be done to confirm genetic exchange among different isolates from different geographic areas. The finding that AMF lack a single nuclear stage in their extraradical phases and that mitosis and nuclear migration are the mechanisms by which AMF spores are formed reduce genetic drift that acts on these organisms during asexual reproduction. Anastomoses are likely a mechanism that maintains the genetic diversity in AMF. These genetic characteristics of AMF were very important during their evolution to maintain a high genetic variability that allows their adaptation to many different ecosystems. / 3 vidéos sont dans des fichiers complémentaires à ce mémoire

Le système cardiovasculaire est composé d'un cœur qui pompe régulièrement le sang à travers des artères afin d'alimenter tous les tissus corporels en oxygène et nutriments qui leur sont nécessaires. Une caractéristique particulière de ce système est son aspect fermé, où le sang fait un cycle constant commençant par le ventricule gauche, allant vers tous les tissus corporels, revenant vers le cœur et le ventricule droit, étant propulsé vers la circulation pulmonaire en retournant au ventricule gauche. L'insuffisance cardiaque est alors une incapacité du cœur à effectuer sa tâche de pomper le sang efficacement. Une série d'ajustements sont alors enclenchés pour rétablir un débit sanguin adéquat; cette réponse systémique est principalement menée par le système rénine-angiotensine-aldostérone ainsi que par le système adrénergique. À court terme, le flot sanguin est rétabli et le métabolisme corporel continue comme si rien n'était, de telle sorte que, souvent ce stade passe inaperçu et les individus qui en sont affectés sont asymptomatiques. Cependant, le cœur doit alors fournir un effort constant supérieur et si la cause n'est pas résolue, la condition cardiaque se dégradera encore plus. Si tel est le cas, pour s'ajuster à cette nouvelle réalité, le cœur, comme tout muscle, deviendra plus massif et changera de conformation afin de répondre à sa nouvelle charge de travail. Cette transformation cardiaque est communément connue sous le terme de remodelage. Par contre, le remodelage cardiaque est délétère à long terme et entrave encore plus le cœur à bien effectuer sa tâche. Au fur et à mesure que la fonction cardiaque décline, les systèmes compensatoires persistent et s'intensifient; il y a alors établissement d'un cercle vicieux destructeur qui ne peut être renversé que par une transplantation cardiaque. Entre temps, des thérapies inhibant le système rénine-angiotensine-aldostérone et le système adrénergique se sont avérés très efficaces pour prolonger la survie, diminuer la mortalité, réduire les hospitalisations ainsi que soulager la symptomatologie associée à l'insuffisance cardiaque. Par contre, ces régimes thérapeutiques ne semblent pas induire une réponse positive chez tous les patients, de sorte que certains n'en retirent pas de bénéfices tangibles, tandis que d'autres éprouvent plusieurs difficultés à les tolérer. Suite à des analyses rétrospectives, surtout en comparant la réponse thérapeutique entre des populations de diverses ethnies, les variations génétiques, particulièrement les polymorphismes ayant le potentiel de moduler le mécanisme d'action de la pharmacothérapie, furent proposés comme responsables de cette variabilité dans la réponse aux médicaments. Certains ont aussi proposé que certains polymorphismes pourraient être considérés comme des facteurs de risque prédisposant à l'insuffisance cardiaque ou coupables de moduler sa progression en tant que facteurs aggravants ou atténuants. Avec de telles hypothèses proposées, plusieurs associations génétiques furent étudiées en commençant par des gènes directement impliqués dans la pathogénèse de cette maladie. Dans le cadre de cette thèse, nous allons revoir les diverses données disponibles dans la littérature au sujet de l'influence que peuvent avoir les divers polymorphismes impliqués dans la prédisposition, la progression et la pharmacogénétique de l'insuffisance cardiaque. / The cardiovascular system is composed of a heart that regularly pumps blood through the arteries in order to meet the peripheral tissues' demand for oxygen and nutrients. One particularity of this system is its closed aspect where the blood constantly travels in a circular fashion: starting from the left ventricle it is thrusted towards the body tissues, returns to the right side of the heart, is propelled through the pulmonary circulation by the right ventricle and returns again to its starting point, the left ventricle. Heart failure is then the incapacity of the heart to perform its task of appropriately pumping blood. A series of adjustments are then put in place in order to restore an adequate blood flow; this systemic response is mainly lead by the renin-angiotensin-aldosterone and the adrenergic systems. In the short term, the proper blood flow is re-established and the body's metabolism is mainly not affected. This initial stage goes frequently unnoticed and the affected individuals are essentially asymptomatic. However, the heart now needs to deliver a constantly elevated effort and if the precipitating cause is not resolved, the cardiac condition will degrade even further. If this is the case, to adjust itself to this new state, as would any muscle, the heart will become more massive and change its conformation in order to respond to this new workload. This transformation of the heart is commonly referred to as remodelling. However, in the long run, this cardiac remodelling is detrimental and hinders even further the ability of the heart to effectively perform its task. As the cardiac function declines, the compensatory systems persist and intensify; a destructive vicious cycle is then established which will ultimately lead to a heart transplantation or death. In the meantime, therapies inhibiting the renin-angiotensin-aldosterone and the adrenergic systems were found to be very effective in prolonging lifespan, diminishing mortality, reducing hospitalisations and relieving some of the symptomatology associated with heart failure. However, these therapeutic strategies do not seem to induce a positive response in all, thus some patients do not derive any tangible benefits, whereas others experience many difficulties in tolerating them. Following retrospective analysis, especially when comparing the therapeutic response between different ethnic populations, the genetic variations, particularly polymorphisms having the potential to modulate the mechanism of action of pharmacotherapy, were put forward as culprits of this variability in response to medications. Furthermore, some researchers have also suggested that certain polymorphisms might be considered as risk factors predisposing towards heart failure or capable of modulating its progression, whether they act as aggravating or attenuation factors. With such hypothesis, many genetic associations were studied, many starting with genes directly implicated in the pathogenesis of this disease. Within the framework of this thesis, we will review the current data available in the literature as it pertains to the influence that various polymorphisms can have on the predisposition, the progression and the pharmacogenetics of heart failure.

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Made available in DSpace on 2015-07-22T20:49:22Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-10-29. Added 1 bitstream(s) on 2015-08-11T03:25:34Z : No. of bitstreams: 1 Publico-018.pdf: 1910669 bytes, checksum: a40b61267560276f1db47642341c6e56 (MD5) / Introdução: Polimorfismos genéticos estão associados com um aumento do risco de tromboembolismo venoso (TEV) e outras doenças cardiovasculares. Estudos prévios sugerem que a doença venooclusiva hepática (DVOH), que se desenvolve intra transplante de medula óssea pode ser atribuída à polimorfismos gênicos. Objetivos: Avaliar a correlação entre polimorfismos genéticos e o risco de doença venooclusiva hepática no transplante de medula óssea e a associação com a presença de variáveis como o uso de vancomicina, drogas citotóxicas usadas no regime de condicionamento, presença de disfução hepática anterior ao transplante, presença de infecção por citomegalovírus, e grupos de doenças avaliáveis. Pacientes e métodos: Este estudo caracteriza-se por um estudo clinico observacional multicêntrico. Foram avaliados 120 pacientes, submetidos a transplante alogênico de medula óssea. Cada paciente foi avaliado propectivamente para DVOH, confirmado pelo critério de Seattle modificado, idade variando de 2 a 65 anos. Fatores de risco para DVOH severo foram analisados usando modelos estatisticos de avaliação. Detectamos simultaneamente através de PCR seguido de digestão e detecção através de eletroforese em gel de agarose, mutação do HFE C282Y, H63D, S65C; MTHFR C677T; Fator V de Leiden, Protrombina 20210A e glutationa S-tranferase. Resultados: Neste estudo observacional de pessoas, submetidas a transplante de medula óssea alogênico, a presença de disfução hepática pré transplante foi um fator de risco significante para DVOH. Nós tambem observamos uma associação entre a presença de mutação HFE S65C e disfunção hepática. Conclusões: Em resumo, nossos dados sugerem que disfunção hepatica observada pré transplante de medula óssea é um fator de risco estatisticamente significante para DVOH e que a presença da mutação do HFE S65C apresenta uma tendência ao desenvolvimento de dano hepático. Contudo, não evidenciamos associação dos polimorfismos estudados com DVOH. / TEDE

O sistema renina-angiotensina e o estresse oxidativo têm participação importante na fisiopatologia das complicações crônicas do diabetes. No presente estudo, foram avaliados 103 pacientes com diabetes tipo 1 (DM1) com idade de 28,810,6 anos e duração de doença de 13,18,5 anos e 158 controles não diabéticos quanto à presença dos polimorfismos I/D da ECA e C242T do p22phox, componente essencial para a ativação da NADPH oxidase. Esta análise foi realizada por reação de polimerase em cadeia para ambos os polimorfismos, seguida de restrição enzimática para avaliação do polimorfismo C242T p22phox. Ambas as distribuições genotípicas obedeciam ao princípio do equilíbrio de Hardy-Weinberg. Os pacientes diabéticos foram submetidos a avaliação clínica e laboratorial quanto à presença de fatores associados ao risco de complicações (história de tabagismo e antecedentes familiares de diabetes tipo 2, dose diária de insulina, níveis pressóricos, índice de massa corporal, relação cintura-quadril, excreção urinária de albumina, taxa de filtração glomerular, perfil lipídico, controle glicêmico, níveis de proteína C-reativa) e rastreados quanto à presença de nefropatia diabética, considerada presença de micro ou macroalbuminúria; retinopatia diabética não proliferativa ou proliferativa e hipertensão arterial. Não houve diferença significativa entre a presença dos alelos D e I da ECA ou C e T do p22phox entre diabéticos e controles. Os polimorfismos avaliados não apresentaram associação com a presença de nefropatia, retinopatia ou hipertensão arterial. Pacientes portadores do alelo D apresentaram maiores níveis de pressão arterial diastólica (72,2 12,3 vs 65,4 11,6 mmHg , p=0,047) e proteína C-reativa comparados aos portadores do genótipo II [0,18 (0,04-0,38) vs 0,09 (0,04-0,16) mg/dl, p=0,05] , porém ambas as análises perderam significância estatística após correção para duração do diabetes. A combinação dos polimorfismos não esteve associada à presença de complicações microvasculares ou hipertensão arterial. Concluímos que, na população de diabéticos tipo 1 estudada, a frequência dos polimorfismos I/D da ECA e C242T do p22phox , isoladamente ou em combinação, não apresentou diferença em pacientes com ou sem complicações microvasculares precoces ou hipertensão arterial. Os níveis dos diferentes marcadores de risco cardiovascular também não apresentaram diferença nos pacientes com os polimorfismos acima descritos. Entretanto, estudos prospectivos poderão determinar a possível interação entre estes polimorfismos e a duração do diabetes na expressão clínica das complicações crônicas da doença. / The renin-angiotensin system and the oxidative stress play an important role in the pathogenesis of the diabetic complications.In the present study 103 patients with type 1 diabetes (T1DM) aged 28.8 10.6 years and with a disease duration of 13.1 8.5 years and 158 non-diabetic controls were evaluated for the presence of the I / D polymorphism of the angiotensin converting enzyme (ACE) and the C242T polymorphism of the p22phox, an essential component for NADPH oxidase activation. The analysis was performed using polymerase chain reaction for both polymorphisms, followed by enzymatic restriction for C242T p22phox polymorphism. Genotypic distributions of both polymorphisms were in Hardy-Weinberg equilibrium. Diabetic patients underwent clinical and laboratory evaluation for the presence of risk factors associated with complications of diabetes (smoking and family history of type 2 diabetes, daily insulin dose, blood pressure, body mass index, waist hip ratio, urinary albumin excretion, glomerular filtration rate, lipid profile, glycemic control, C-reactive protein levels) and screened for the presence of diabetic nephropathy, considered as the presence of micro or macroalbuminuria, diabetic retinopathy and hypertension. There was no significant difference between the presence of ACE D or I allele and p22phox C or T allele between diabetic patients and controls. The evaluated polymorphisms were not associated with the presence of nephropathy, retinopathy or hypertension. Patients with the D allele showed higher levels of diastolic blood pressure (72.2 12.3 vs 65.4 11.6 mmHg, p = 0.047) and C-reactive protein compared with those carrying the II genotype [0.18 (0.04-0.38) vs 0.09 (0.04-0.16) mg/dl, p = 0.05], but both analysis lost statistical significance after correction for duration of diabetes. The combination of both polymorphisms was not associated with microvascular complications or hypertension. We conclude that in the studied population of type 1 diabetic patients, the frequency of ACE I / D and C242T of p22phox polymorphisms, alone or in combination, was not different in patients with or without early microvascular complications or hypertension. Also, the levels of different markers of cardiovascular risk did not differ for patients with the polymorphisms described above. However, prospective studies may determine the possible interaction between these polymorphisms and duration of diabetes in the clinical expression of chronic complications of diabetes.

Made available in DSpace on 2016-06-02T20:18:17Z (GMT). No. of bitstreams: 1 4192.pdf: 6083601 bytes, checksum: a411c24424aa71f8ff5f0404ef48215b (MD5) Previous issue date: 2012-02-16 / Universidade Federal de Sao Carlos / The multifactorial nature of coronary artery disease (CAD) includes complications related to angina and acute myocardial infarction (AMI) and disorders involving sympathetic and parasympathetic cardiac autonomic modulation. The objective of this study was to evaluate the autonomic modulation of heart rate (HR) by linear and non-linear methods in healthy men and in patients with AMI and different percentages of coronary stenosis, as well as its relation with CAD risk factors. In order to evaluate heart rate variability (HRV), the HR and the RR intervals were recorded for 15 min in the supine position. Based on the results of this study, three manuscripts were written: The first manuscript presents the results of 10 men with AMI (57±9 years old) (2nd and 7th day after coronary event) and 11 healthy men (53±4 years old). The HRV analysis was carried out using linear methods in the time domain (TD=RMSSD and SDNN) and frequency domain (FD= low frequency (LF) and high frequency (HF) in normalized units (nu) and LF/HF) and using the non-linear methods approximate entropy (ApEn). A significant relationship between the linear and non-linear methods and the RMSSD, SDNN, LFun, HFun and LF/HF and ApEn indexes was observed. The linear and non-linear HRV indexes from the healthy group were higher than those of the AMI group on the 2nd and 7th days, which suggests that the analysis of HRV with linear methods in the TD and FD and the use of ApEn for linear analysis are in agreement, both for healthy subjects and patients after AMI. The second manuscript presents the results of 52 men (54±5 years old) divided into two groups with coronary obstruction CAD+ &#8805; 50% (n=18) and CAD- < 50% (n=17) and one control group (n=17). HRV analysis was carried out with Shannon entropy (SE) and symbolic analysis (0V and 2ULV). The patients with DAC+ presented lower SE (complexity), 2ULV (vagal predominance) and higher 0V (sympathetic predominance) than the DAC- and control groups, which indicates that cardiac autonomic disorder is related to the degree of coronary occlusion and to cardiac impairment. The third manuscript presents the results for risk factors, ACE I/D polymorphism and the indexes in the TD and FD of 151 patients with CAD (56±8 years old, DD=54, DI=70 and II=27). The results show that there was no relation between the ACE I/D polymorphism and HR, BP or HRV. However, the highest indexes of the HRV, which reflect vagal autonomic modulation, are related to a lower percentage of stenosis and the use of ACE inhibitors. / A doença arterial coronariana (DAC) é de natureza multifatorial sendo que as principais complicações estão relacionadas à angina e infarto agudo do miocárdio (IAM), apresentando disfunção da modulação autonômica cardíaca simpática e parassimpática. Assim, o objetivo foi avaliar a modulação autonômica da frequência cardíaca (FC), a partir de métodos lineares e não lineares, de homens saudáveis, de pacientes com IAM e com diferentes percentuais de estenose coronariana e sua relação com os fatores de risco para a DAC. Para a análise da variabilidade da FC (VFC) foi realizada a captação dos intervalos RR e da FC, durante 15 min na posição supina. A partir dos resultados do estudo foram elaborados três manuscritos. Primeiro manuscrito: Foram apresentados os resultados de 10 homens com IAM (57±9 anos) (avaliados no 2º e 7 º dia após evento coronariano) e 11 homens saudáveis (53±4 anos). A análise da VFC foi realizada utilizando-se dos métodos lineares no domínio do tempo (DT=RMSSD e RMSM) e da frequência (DF=baixa frequência (BF) e alta frequência (AF) em unidades normalizadas (un) e BF/AF) e pelo método não linear de entropia aproximada (EnAp). As análises da relação entre os métodos lineares e o não linear (índices RMSSD, RMSM, BFun, AFun e BF/AF com a EnAp) foi significativa. Os índices lineares e não linear da VFC do grupo saudável foram maiores em relação ao grupo IAM no 2º e no 7º dia. Os resultados mostram que os métodos lineares no DT e no DF e o não linear , são concordantes, para análise da VFC, tanto para voluntários saudáveis como para pacientes após o IAM. Segundo manuscrito: Foram apresentados os resultados de 52 homens (54±5 anos) divididos em três grupos, sendo dois grupos com obstrução coronariana DAC+ (&#8805; 50%; n=18) e DAC- (< 50%; n=17) e um grupo controle (n=17). A análise da VFC foi pela entropia de Shannon (ES) e análise simbólica (0V e 2ULV). Os pacientes com DAC+ apresentam menor ES (complexidade) e 2ULV (predominância vagal) e maior 0V (predominância simpática) quando comparado aos grupos DAC- e controle, o que indica que a disfunção autonômica cardíaca está relacionada ao grau de oclusão coronariana. Terceiro manuscrito: Foram apresentados os resultados da possível relação existente entre dos fatores de risco, do polimorfismo I/D do gene da ECA com os índices no DT e no DF de 151 pacientes com DAC (56±8 anos, DD=54, DI=70 e II=27). Os resultados mostram que não há relação entre o polimorfismo I/D do gene da ECA com a FC, PA e VFC. Já os maiores índices da VFC que refletem a modulação autonômica vagal estão relacionados ao menor percentual de estenose e ao uso de inibidores da ECA.