O Tempo de Condução Total Atrial (TACT) reflete a condução dos estímulos elétricos no território atrial. Tal parâmetro pode ser mensurado por meio do estudo eletrofisiológico ou por métodos não invasivos, como a ecocardiografia tecidual. Em medicina sabe-se que a mensuração do tempo decorrido entre o início da onda P do eletrocardiograma ao pico da onda A do gráfico do Doppler tecidual (intervalo PATDI) é um preditor independente da ocorrência de fibrilação atrial secundária a diversas causas. Em medicina veterinária não existem estudos publicados sobre o assunto até o momento. Objetivou-se estabelecer valores normais de TACT para cães e investigar quais variáveis podem influenciar os resultados obtidos. Além disso, propôs-se a investigação do TACT como um preditor da ocorrência de fibrilação atrial em cães com valvopatia mitral mixomatosa. Realizou-se estudo retrospectivo utilizando um banco de imagens ecocardiográficas de cães que participaram de projetos de pesquisa no Serviço de Cardiologia do VCM/HOVETUSP. O TACT foi mensurado empregando o Doppler tecidual guiado por cores, sendo o intervalo PA-TDI medido com o cursor do Doppler tecidual posicionado na parede lateral do átrio esquerdo, logo acima do ânulo da valva mitral. Para análise estatística as variáveis foram submetidas ao teste de Shapiro-Wilk e estimou-se o coeficiente de correlação de Pearson ou de Spearman com o TACT. Para verificar as diferenças do TACT quanto às variáveis utilizaram-se o teste t de Student, a ANOVA para medidas não repetidas, o procedimento de Bon Ferroni quando necessário e a ANOVA 2-fatores. Todos os testes estatísticos foram considerados significativos quando p<0,05. No que concerne à investigação das variáveis associadas à fibrilação atrial, foi realizada uma regressão múltipla de Cox considerando o tempo para a ocorrência da fibrilação atrial. De 264 estudos ecocardiográficos disponíveis, 144 foram selecionados. O intervalo PA-TDI médio dos cães livres de doenças cardiovasculares foi de 47 ± 9,09 ms. Observou-se que dentre os fatores estudados, o valor encontrado foi diferente entre animais de porte mini ou pequeno comparados aos animais de porte grande ou gigante (p=0,01) e que sexo, castração e obesidade não influenciaram nos valores de p, respectivamente, 0,50, 0,24 e 0,98. A duração do TACT apresentou correlação com a duração do intervalo PR, frequência cardíaca, peso e concentração de eosinófilos/mm3 de sangue nos animais sem doenças cardiovasculares. Quanto aos animais doentes, o intervalo PA-TDI foi significativamente mais longo nos indivíduos com valvopatia mitral mixomatosa estágios B2 e C (respectivamente, 55,4 ± 7,7 e 55,7 ± 9,2 ms). Além disso, observou-se aumento de 13% de chance de desenvolver fibrilação atrial a cada unidade aumentada do intervalo PA-TDI (p<0,01). Com base nos resultados encontrados, aventa-se a hipótese de que tanto o aumento atrial isolado quanto o advento da ICC possam já acarretar atrasos de condução interatrial e que o TACT mensurado pelo intervalo PA-TDI pode prever a ocorrência de fibrilação atrial secundária à valvopatia mitral mixomatosa em cães, embora a baixa frequência dessa arritmia na população estudada possa ter mascarado resultados mais expressivos neste sentido. / Total Atrial Conduction Time (TACT) reflects the conduction of the electrical stimuli in the atrial territory. It can be measured by electrophysiological study or by noninvasive methods, such as tissue Doppler echocardiography. In human medicine it is known that the time measured between the beginning of the electrocardiogram Pwave to the peak of A-wave tissue Doppler graph (PA-TDI interval) represents and independent predictor of the occurrence of atrial fibrillation secondary to several causes. In veterinary medicine there are no published studies on the subject so far. The objective was to establish normal TACT values for dogs and investigate which variables may influence the results obtained. In addition, TACT was proposed as a predictor of the occurrence of atrial fibrillation in dogs with myxomatous mitral valvopathy. A retrospective study was carried out using a bank of echocardiographic images of dogs that were enroled in research projects at the Cardiology Service of HOVET/FMVZ-USP. TACT was measured using color-coded tissue Doppler, and PATDI interval was measured with tissue Doppler sample positioned on the lateral wall of the left atrium, just above the mitral valve annulus. For statistical analysis, variables were submitted to Shapiro-Wilk test and Pearson or Spearman correlation coefficient with TACT was estimated. Student\'s t-test, ANOVA for non-repeated measurements, Bon Ferroni procedure when necessary, and the 2-factor ANOVA were used to verify the TACT differences. All statistical tests were considered significant when p <0.05. Regarding the investigation of the variables associated with atrial fibrillation, a multiple Cox regression was performed considering the time for the occurrence of atrial fibrillation. From 264 available echocardiographic studies, 144 were selected. The mean PA-TDI interval of dogs free from cardiovascular diseases was 47 ± 9.09 ms. It was observed that among the factors studied, the value found was different between small dogs compared to large or giant animals (p = 0.01) and that gender, castration and obesity had no influence (p values were, respectively, 0.50, 0.24 and 0.98). TACT duration correlated with the duration of the PR interval, heart rate, weight, and blood eosinophil concentration/mm3 in animals without cardiovascular disease. PA-TDI interval was significantly longer in patients with myxomatous mitral valvopathy stage B2 and C (55.4 ± 7.7 and 55.7 ± 9.2 ms, respectively). In addition, there was a 13% increase in the chance of developing atrial fibrillation at each increased unit of PA-TDI interval (p <0.01). On the basis of the results found, it is hypothesized that both isolated atrial strech and the advent of CHF may already lead to atrial conduction delays and that the TACT measured by the PATDI interval may predict the occurrence of atrial fibrillation secondary to myxomatous mitral valve disease in dogs. The low frequency of atrial fibrillation in the studied population may have masked more expressive results.

Afin de subvenir aux besoins et au bon développement du fœtus, la femme enceinte subit de nombreux changements cardiovasculaires. Notamment, la grossesse cause une accélération significative de la fréquence cardiaque au repos, créant ainsi un environnement arythmogène. Les arythmies supraventriculaires sont les arythmies cardiaques les plus fréquentes pendant la grossesse. Les femmes peuvent développer des arythmies de novo, tandis que d’autres peuvent voir leurs arythmies préexistantes exacerbées pendant leur grossesse. Bien que les arythmies supraventriculaires puissent compromettre la santé de la mère et du fœtus, les mécanismes qui en sont responsables restent à être explorés. Puisque les arythmies supraventriculaires peuvent être d’origine sinusale et auriculaire, l’objectif principal de cette thèse était de déterminer la contribution du remodelage du nœud sinusal et des oreillettes dans la survenue de ces arythmies. Depuis près de 20 ans, le laboratoire s’est intéressé aux mécanismes sous-jacents à l’accélération de la fréquence cardiaque associée à la grossesse. Plus précisément, le rôle des courants ioniques responsables de la dépolarisation diastolique et de la dépolarisation principale du potentiel d’action spontané du nœud sinusal ont été étudiés. Toutefois, bien que les courants ioniques responsables de la phase de repolarisation sont tout aussi importants dans l’automaticité cardiaque, le remodelage des courants K+ par la grossesse n’a pas encore été étudié. Ainsi, la première étude de cette thèse avait pour but d’examiner la contribution du courant potassique activé par l’acétylcholine (IKACh) dans l’accélération de l’automaticité cardiaque pendant la grossesse. Sachant que le remodelage des oreillettes peut également contribuer au développement d’arythmies supraventriculaires, le but de la deuxième étude était d’explorer le remodelage électrique, structurel et contractile des oreillettes pendant la grossesse. Afin de répondre aux objectifs de cette thèse, une analyse détaillée a été réalisée in vivo, sur les tissus et/ou les cellules isolées du nœud sinusal et des oreillettes de souris femelles non-gestantes et gestantes. Dans la première étude, nous avons montré que la fonction de IKACh, l’expression d’une des sous-unités formant le canal ionique (Kir3.1/Kcnj3) et l’expression du récepteur muscarinique de type 2 (M2R) sont diminuées dans le nœud sinusal de souris gestantes. En accord avec ces changements, des études cellulaires et in vivo ont montré que la réponse du nœud sinusal aux agents muscariniques est réduite pendant la grossesse. Les résultats de cette étude suggèrent que la réduction de IKACh contribue à l’accélération de la fréquence cardiaque pendant la grossesse. Dans la seconde étude, nous avons démontré que les oreillettes de souris gestantes subissent une hypertrophie physiologique, en plus d’une augmentation de leur fonction contractile. Cette augmentation de contraction est expliquée par 1) un remodelage des unités contractiles cellulaires, soit les sarcomères, et 2) un prolongement de la durée du potentiel d’action auriculaire expliqué par la réduction du courant potassique transitoire sortant indépendant du Ca2+ (Ito) et de l’expression de son canal potassique KV4.3 (Kcnd3). Par ailleurs, des contractions spontanées et des relâches spontanées de Ca2+ diastoliques sont plus fréquemment observés dans les oreillettes de souris gestantes. Ce remodelage structurel, contractile et électrique des oreillettes crée un environnement favorable au développement d’arythmies supraventriculaires pendant la grossesse. Ces études permettent une meilleure compréhension des mécanismes cellulaires et moléculaires responsables du remodelage du nœud sinusal et des oreillettes causés par la grossesse. Les nouvelles connaissances acquises dans ces études sont d’une grande importance pour la santé des femmes et, à terme, pourraient permettre d’améliorer la gestion des arythmies induites par la grossesse. De nos jours, ce sujet de recherche est encore plus essentiel, considérant l’âge maternel avancé et la présence de comorbidités chez les femmes enceintes, des facteurs de risque supplémentaires d’arythmies cardiaques. / Pregnant women undergo several cardiovascular changes to support the needs and the healthy development of their fetus. Notably, pregnancy causes a significant acceleration in resting heart rate, creating an arrhythmogenic environment. Supraventricular arrhythmias are the most frequent type of cardiac arrhythmias during pregnancy. Some women may develop arrhythmias de novo, while others may have their pre-existing arrhythmias exacerbated during pregnancy. Although supraventricular arrhythmias can compromise the health of both the mother and fetus, their underlying mechanisms remain to be explored. Considering that supraventricular arrhythmias can be of both nodal and atrial origin, the main objective of this thesis was to determine the contribution of sinoatrial node and atrial remodeling to the occurrence of these arrhythmias. For almost 20 years, the laboratory has been investigating the mechanisms underlying the accelerated heart rate associated with pregnancy. More specifically, the role of ionic currents responsible for the diastolic depolarization and the main depolarization of the spontaneous action potential of the sinoatrial node has been studied. However, although the ionic currents responsible for the repolarization are equally important in cardiac automaticity, the remodeling of K+ currents by pregnancy has yet to be investigated. Therefore, the aim of the first study presented in this thesis was to examine the acetylcholine-activated K+ current IKACh during pregnancy and its contribution to the increased cardiac automaticity. Since atrial remodeling may also contribute to the development of supraventricular arrhythmias, the aim of the second study was to explore the electrical, structural, and contractile remodeling of the atria during pregnancy. To meet the objectives of this thesis, a detailed analysis was carried out in vivo, on tissue and/or isolated cells from the sinoatrial node and atria of non-pregnant and pregnant female mice. In the first study, we showed that the function of IKACh as well as the expression of one of its ion channel-forming isoforms (Kir3.1/Kcnj3) and the type 2 muscarinic receptor (M2R) is decreased in the sinoatrial node of pregnant mice. In line with these changes, the responsiveness to muscarinic agents of sinoatrial node is reduced during pregnancy, at cellular level and in vivo. These results strongly suggest that reduced IKACh may contributes to pregnancy-induced increased heart rate. In the second study, we demonstrated that the atria of pregnant mice undergo physiological hypertrophy, in addition to an increase in their contractile function. This increase in contraction is explained by 1) the remodeling of cellular contractile units, i.e. the sarcomeres, and 2) a prolongation of atrial action potential duration explained by a reduction in the Ca2+-independent transient outward K+ current (Ito) and expression of its underlying K+ channel KV4.3 (Kcnd3). Moreover, spontaneous contractions and spontaneous diastolic Ca2+ releases are more frequently observed in atrial myocytes of pregnant mice. Collectively, this structural, contractile, and electrical remodeling of the atria may contribute to the development of supraventricular arrhythmias during pregnancy. These studies provide a better understanding of the cellular and molecular mechanisms responsible for the pregnancy-induced remodeling of the sinoatrial node and atria. The new knowledge gained from these studies is of great importance to women's health and may ultimately help to improve the management of pregnancy-induced arrhythmias. Nowadays, this area of research is even more essential considering the advanced maternal age and the presence of comorbidities in pregnant women, additional risk factors for cardiac arrhythmias.