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Background: The Framingham Study from 1991 showed a clear correlation between atrial fibrillation (AF) and ischemic stroke, where patients with AF had an almost fivefold increase in risk of stroke compared with patients without AF. Since then, several trials have evaluated different antithrombotic treatments to reduce the risk of stroke in patients with AF. Other trials have investigated factors that increase the risk of stroke in patients with AF and risk score systems have been developed to categorize patients into low or increased risk of stroke to help clinicians to decide which patients benefit from antithrombotic treatment and in whom it can be abstained, not to expose patients with low stroke risk to an increased risk of bleeding conferred by antithrombotic treatment. The aims of this thesis were: [1] to evaluate if a warfarin dosing algorithm can increase hit rate and decrease mean error compared with manually changed doses; [2] to assess the prevalence and net clinical benefit of aspirin as monotherapy for stroke prevention in AF; [3] to investigate the risk of thromboembolic and haemorrhagic complications within 30 days after electrical cardioversion (ECV) of AF in patients with and without oral anticoagulation (OAC) pre-treatment; and [4] to assess the proportion of patients discontinuing OAC after pulmonary vein isolation (PVI), identify factors predicting stroke after PVI and to investigate risk of complications after PVI with and without OAC. Materials and methods: All studies are retrospective and based on data from Swedish national quality registries. In paper I, data from Auricula was used to compare the resulting INR values after algorithmic warfarin dose suggestions and manually changed doses. In paper II data was extracted from the Swedish National Patient Register, the Dispensed Drugs Register and the Cause of Death Register. Patients with aspirin treatment were compared with patients without any antithrombotic treatment regarding risk of thromboembolic and haemorrhagic complications. In paper III data was collected from the Swedish National Patient Register and the Dispensed Drugs Register to examine risk of complications (thromboembolic and haemorrhagic events) within 30 days after cardioversion, comparing patients with and without oral anticoagulation pre-treatment. In paper IV data from six different Swedish national quality registries were used (Swedish Catheter Ablation Register, Auricula, Swedish National Patient Register, Dispensed Drugs Register, Cause of Death Register and Riksstroke). Patients undergoing pulmonary vein isolation (PVI) were investigated for adherence to guidelines regarding oral anticoagulation, predictors for stroke after PVI, as well as risk of ischemic stroke or intracranial haemorrhage after PVI in patients with and without treatment. Results: Paper I showed that a computerized dosing algorithm for warfarin in most cases perform as well or better compared with doses that have been changed manually, with a better hit-rate (0.72 vs. 0.67) and a lower mean error (0.44 vs. 0.48). Paper II showed that 32% of 182.678 patients with a diagnosis of AF were on monotherapy with aspirin for stroke prevention. A total of 115.185 patients were included, 58.671 with aspirin treatment and 56.514 without antithrombotic treatment at baseline. After stratification after CHA2DS2-VASc score and after multivariable adjustment, aspirin treatment did not confer a decrease in thromboembolic events. After propensity score mathcing, rate of ischemic stroke was 7.4%/year (95% CI 7.1-7.6) in aspirin treated patients and 6.6%/year (95% CI 6.4-6.9) in patients without antithrombotic treatment. In paper III 22.874 patients undergoing electrical cardioversion were included, 10.722 with and 12.152 without OAC pre-treatment. In patients with low stroke risk (CHA2DS2-VASc 0-1), no thromboembolic complication was seen within 30 days after cardioversion. In patients with CHA2DS2-VASc ≥2, the risk of thromboembolic complications was increased when no oral anticoagulation pre-treatment was used, results that remained after propensity score matching. No difference regarding haemorrhagic complications was seen. Paper IV included a total of 1585 patients undergoing PVI with a mean follow up of 2.6 years. Adherence to current guidelines regarding oral anticoagulation was good in patients with CHA2DS2-VASc ≥2. Previous ischemic stroke was a predictor for a new stroke after PVI. In patients with CHA2DS2-VASc ≥2 stroke risk was increased in patients discontinuing OAC compared to those continuing OAC (1,60%/year vs. 0.34%/year). Conclusion: Oral anticoagulation is still underutilized for prevention of stroke and systemic embolism in patients with atrial fibrillation. Patients with risk factors for stroke (CHA2DS2-VASc ≥2p) benefit from continuous oral anticoagulation treatment to prevent stroke, also in conjunction with electrical cardioversion and after pulmonary vein isolation. If warfarin is chosen, a computerised dosing algorithm can facilitate and standardize warfarin dosing and lead to better resulting INR values than manually changed doses. Aspirin should not be used for stroke prevention in patients with atrial fibrillation.

Stroke is a major cause of premature death and disability throughout the world and atrial fibrillation (AF) is one of the most common preventable causes of stroke. AF affects about 10% of individuals aged ≥80 years, but warfarin is substantially under-used in this age group despite being effective in preventing AF-related thromboembolic events. AF-related ischaemic strokes tend to be severe and incur high care costs, and non-cerebral systemic embolism secondary to AF is also a major clinical burden. Despite that, there are few population-based studies on AF-related ischaemic stroke, and no recent study of the burden of AF-related thromboembolism and the population impact of under-treatment. I have used data from the Oxford Vascular Study (OXVASC), a prospective, population-based incidence study of vascular disease in all territories, which was started in April 2002 and is on-going. The study population comprises of 92,728 individuals registered with 100 family physicians in nine general practices and uses multiple overlapping methods of “hot” and “cold” pursuit to achieve near-complete ascertainment of all patients with acute vascular events. There are several findings described by the research in this thesis which have important implications for public health and can be utilised to improve secondary prevention in stroke. First, I have shown that one-third of all incident embolic events were related to AF and 60% of AF-related embolic events occurred at ≥80 years. Second, I have shown that only 9% of patients aged ≥80 years with incident embolic event related to known prior AF were on premorbid warfarin, and consequently three quarters of those previously independent were dead or disabled six months post event. Third, I have shown that there has been no reduction in age-specific incidence of AF-related ischaemic stroke in Oxfordshire over the last 25 years. Fourth, I have shown that assuming age-specific incidence does not continue to rise, if prevention is not improved, the number of embolic events at age ≥80 years would be expected to treble by 2050 (72,975 AF-related embolic events), with 84% of events at all ages occurring at age ≥80. Fifth, I have shown through a meta-analysis that one in five incident strokes had a history of prior AF of which only 19% were on premorbid warfarin, and AF was related to one in three incident ischaemic strokes. Sixth, I have shown that 1 in 5 stroke patients with known prior AF subsequently became institutionalised and incurred high acute and long-term care costs. Seventh, I have shown that one in five patients with undetermined cerebral ischaemic event subsequently had AF-related late recurrent stroke. Eighth, I have shown that even though TIA or ischaemic stroke patients who subsequently turned out to have new AF at follow-up had significantly higher baseline NT-proBNP compared to non-AF group, its utility is limited by low sensitivity and specificity. Ninth, I have shown in another meta-analysis that the duration of cardiac monitoring after cerebral ischaemic events was the main determinant of the observed rate of pAF, and that 5-7 days of monitoring may be adequate in unselected patient populations. Finally, I have shown that using 5-day event loop recording in clinic patients with TIA and minor ischaemic stroke could detect 12% new AF and the delay in monitoring did not reduce the sensitivity of pAF detection.

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the United States today. However, treatment options remain limited despite the enormous magnitude of both AF prevalence and the associated economic cost. Of those treatment options that are available, ablation-based interventional methods have demonstrated the highest rates of long-term cure. Unfortunately, these methods have substantially lower efficacy in patients with heavier burdens of disease, thus leaving the most affected individuals with the least hope for successful treatment. The focus of this research is to develop a mechanistically guided approach towards the treatment of multi-wavelet reentry (MWR), one of the primary drivers of AF. For this purpose, we use a computational model of electrical propagation in cardiac tissue to simulate both episodes of fibrillatory activity and the ablative treatment thereof. We demonstrate that the probability of forming the reentrant circuits necessary for continuous electrical activity is a function of the shape and size of a tissue as well as its underlying cellular properties. Ablation at tissue sites with high probability of circuit formation more efficiently reduces the overall duration of fibrillatory episodes than ablation at sites with low probability. We then propose and validate in silico a parameter-based metric for predicting the propensity of an individual tissue to support fibrillation, which we term the fibrillogenicity index. Using this metric, we develop an algorithm for prospectively determining optimized, tissue-specific ablation patterns. Finally, we examine the relationship between multi-wavelet reentry and focal drivers, and demonstrate that MWR and fibrillatory conduction exist along a continuum. We examine the complex interplay between functional and structural substrates within fibrillating tissue and define the mechanisms by which they promote the perpetuation of AF. These findings present a novel theoretical framework for understanding treatment of multi-wavelet reentry driven AF and provide a set of testable predictions that can serve to guide the design of future experimental studies aimed at advancing the rational design of patient-specific ablation sets for treating AF.

Real time spectrum analysis of signals obtained through lasso catheter during radiofrequency ablation of pulmonary vein was performed to determine the channel with dominant frequency. Threshold algorithm was used for signals which could be classified as type I and type II AF. Type III AF Signals which were highly fractionated or differentiated were evaluated for frequency content by performing Fast Fourier Transform. Data from Seven patients was collected and an episode of 180 ± 40 seconds was recorded and analyzed for each pulmonary vein that showed electrical activation. Frequency spectra for one second segment of signal for each channel were determined. The frequencies of channels were then compared to determine the channel with highest or dominant frequency. In most cases the frequency of a single channel varied erratically between 1 to 10 Hz for every subsequent one second segment which made DF detection among the channels unreliable and a single channel with dominant frequency could not be determined. A five second averaging for each channel did not produce a stable DF output and improvement was minimal. The erratic frequency behavior could be attributed to the spatial shift of micro- reentrant circuits or temporal variation in waveform over lap at the point of detection. To determine the DF more precisely either an increase in number of electrode or increase in time segment block for DF calculation is warranted. Increasing the time segment block will defeat the purpose of real time analysis thus an increase in number of electrode mapping the area of interest would be appropriate to resolve the issue.

L'adénosine est un nucléoside ubiquitaire issu de la déphosphorylation de l'ATP qui est libéré par les cellules endothéliales et les myocytes lors de l'hypoxie, de l'ischémie ou du stress oxydatif. Elle exerce un contrôle puissant sur les systèmes nerveux, immunitaire et cardiovasculaire par l'intermédiaire de quatre récepteurs membranaires : A1R, A2AR, A2BR et A3R. La compréhension de l'implication du système adénosinergique dans le système cardiovasculaire implique la possibilité technique d'un dosage de l'adénosine endogène et la quantification de l'expression de ses récepteurs. L'adénosine ayant globalement une action hypotensive (via les récepteurs A2AR) et chronotrope négative (via les récepteurs A1R), nous nous sommes intéressés à son implication chez les patients présentant des syncopes neurocardiogéniques, la bradycardie et l'hypotension étant 2 signes cardinaux dans ce syndrome. Les manifestations cliniques de cette affection peuvent être reproduites par le test d'inclinaison (HUT) et/ou le test à l'ATP. Dans un premier temps nous avons réalisé des dosages d'adénosine plasmatiques chez ces patients au moment d'un test d'inclinaison. Les concentrations en adénosine étaient élevées chez les patients présentant un test positif. Par la suite, nous avons comparé les concentrations en adénosine plasmatiques et l'expression des récepteurs A2A en fonction du résultat du test d'inclinaison et du test à l'ATP. / Adenosine is a ubiquitous nucleoside that comes from the dephosphorylation of ATP and which is released during hypoxia or oxidative stress, by endothelial cells and myocytes. Adenosine interacts on its cell surface receptors, namely A1R, A2AR, A2BR and A3R, to exert physiological effects on target tissues. Our knowledge about the adenosinergic system was improved because of our ability to measure adenosine plasma levels and to quantify its receptors expression. Because adenosine, via A1 or A2A receptor activation leads to bradycardia and hypotension, we first tried to understand the implication of the adenosinergic system in patients with neurocardiogenic syncope (NMS for neutrally mediated syncope). Indeed, this syndrome is characterized by relative or absolute bradycardia associated with a drop in blood pressure and a loss of consciousness. The symptomatology can be reproduced by the tilt test (HUT) or by the intravenous administration of ATP (ATP test). First, we measured adenosine plasma levels in patients with NMS just before and during HUT. We found that adenosine plasma levels were higher in patients with a positive HUT. Then, we compared adenosine plasma levels and the expression of A2A receptors in patients with NMS depending on the result of HUT and ATP-test. We found that elevated adenosine plasma levels and A2A receptors overexpression were associated with positive HUT. On the opposite, low adenosine plasma levels and normal expression of A2A receptor were associated with positive ATP test.

Les mutations du gène SCN5A, codant la sous-unité ? du canal Na+ cardiaque Nav1.5, sont responsables d'arythmies cardiaques héréditaires. La pénétrance incomplète observée dans ces maladies suggère l'existence d'autres facteurs modulant le phénotype associé à ces mutations. Dans ce travail de thèse, nous avons caractérisé deux mutations identifiées dans SCN5A. Le mutant R104W, identifié chez un patient atteint du syndrome de Brugada, est retenu dans le réticulum endoplasmique (RE), dégradé par le protéasome et abolit le courant Na+. Co-exprimé avec le canal sauvage, R104W conduit à la rétention de celui-ci dans le RE, résultant en un effet dominant négatif sur les canaux sauvages. Nous avons démontré que ce nouveau mécanisme mettait en jeu une interaction entre les sous-unités ? de Nav1.5. La mutation R1860Gfs*12 a été identifiée dans une famille présentant des arythmies auriculaires. Dans un système d'expression hétérologue, ce mutant induit à la fois une perte et un gain de fonction de Nav1.5. La modélisation informatique nous a permis de montrer que la perte de fonction était plus prononcée dans les cellules auriculaires que ventriculaires. De plus, nous avons montré que la présence de polymorphismes en amont du gène PITX2 dans cette famille pouvait expliquer la variabilité des phénotypes observés. En conclusion, l'interaction entre les sous-unités ? de Nav1.5, les propriétés électriques différentes entre oreillette et ventricule et la présence de polymorphismes chez les patients porteurs de mutations SCN5A sont des facteurs importants dans l'interprétation des effets fonctionnels de ces mutations, contribuant à la variabilité phénotypique des canalopathies Na+. / Mutations in the SCN5A gene, which encodes the α-subunit of the cardiac sodium channel Nav1.5, are implicated in different inherited cardiac arrhythmias. The incomplete penetrance observed in these diseases suggests the existence of other factors modulating the phenotype of these mutations. In this thesis work, we characterized two mutations identified in SCN5A. The R104W mutant identified in a patient with Brugada syndrome is retained in the endoplasmic reticulum (ER), degraded by the proteasome and abolishes the sodium current. Co-expressed with wild type (WT) channels, R104W leads to WT channels ER retention, causing a dominant-negative effect. We demonstrated that interaction between Nav1.5 α-subunits is responsible for the retention and the dominant-negative effect. The R1860Gfs*12 mutation was identified in a family with atrial arrhythmias. In a heterologous system, this mutant induces both loss- and gain-of-function effects on Nav1.5. Computer-model simulation showed that the loss-of-function was more pronounced in atrial than in ventricular cells. In addition, we showed that the presence of polymorphisms upstream of the PITX2 gene could explain the observed phenotypic variability in this family. In conclusion, the interaction between the α-subunits of Nav1.5, the different electrical properties between atria and ventricles and the presence of polymorphisms in patients with SCN5A mutations, are important factors in the interpretation of the functional effects of these mutations, which could explain the phenotypic variability of sodium channelopathies.

Introdução: Na última década, desde a descrição inicial da ablação das veias pulmonares, a ablação por cateter da fibrilação atrial (FA) tem evoluído consideravelmente em eficácia e segurança, consolidando-se como opção terapêutica em pacientes selecionados com FA. No entanto, a ablação da FA é um procedimento complexo e não isento de riscos. Ainda que seja uma complicação rara, o desenvolvimento de fístulas átrio-esofágicas (FAE) é a segunda complicação responsável por morte relacionada ao procedimento e responde por 16% dos casos de morte após ablação de FA. Consensos atuais não orientam recomendações definitivas para prevenção de lesões esofágicas, consideradas lesões precursoras de FAE. O objetivo deste trabalho foi comparar a incidência de lesões esofageanas e periesofageanas por ecoendoscopia após ablação de fibrilação atrial, utilizando diferentes estratégias de proteção esofágica durante as aplicações de radiofrequência na parede posterior do átrio esquerdo. Método: No período de outubro/2012 a julho/2014, foram estudados 45 pacientes submetidos à ablação percutânea de FA, portadores de FA paroxística ou persistente há menos de um ano. Todos os pacientes foram submetidos a ablação circunferencial com isolamento elétrico das veias pulmonares, com cateter de ablação 8 mm. Antes do procedimento, os pacientes foram randomizados para uma de três estratégias de proteção esofágica durante as aplicações de radiofrequência na parede posterior do átrio esquerdo para ablação da FA: Grupo I - aplicações limite fixo e de baixa energia, 30 W; Grupo II - aplicações com energia limitada pela temperatura esofágica; GIII - aplicações com limite fixo de energia durante resfriamento esofágico contínuo. A pesquisa de lesões esofágicas/periesofágicas foi feita por ecoendoscopia realizada em até 48 horas após a ablação. Resultados: As características basais foram similares nos três grupos, não sendo encontradas diferenças significativas entre as variáveis clínicas, laboratoriais, ecocardiográficas ou ecoendoscópicas prévias, com exceção da distância átrio-esofágica pré-ablação medida pela ecoendoscopia, que foi menor no Grupo III (GI = 3,9 mm +- 0,4; GII = 3,9 mm +- 0,5; GIII = 3,4 mm +- 0,4, p = 0.002). Nas ecoendoscopias pós-ablação de FA, foram encontradas 04 lesões esofágicas/periesofágicas: duas úlceras de parede esofágica e dois casos de edemas de mediastino periesofágico. Todos os casos de lesões esofágicas/periesofágicas ocorreram no grupo de resfriamento esofágico, G III (p= 0,008). A comparação das características clínicas dos pacientes que apresentaram lesões esofágicas/periesofágicas com os que não apresentaram essas alterações, pela análise bivariada, mostrou que foram similares nos dois grupos, exceto pelos valores médios de proteína C reativa (PCR) após a ablação de fibrilação atrial, que foram significativamente maiores no grupo com lesões (Grupo sem lesões: PCR = 0,82 mg/dl; Grupo com lesões: PCR = 2,12 mg/dl, p < 0,001). A comparação dos parâmetros das ablações por regiões das veias abordadas, quanto ao tempo das aplicações de radiofrequência, a potência e a temperatura do cateter de ablação, identificou que os pacientes que apresentaram lesões esofágicas/periesofágicas tiveram maiores valores de média de potência nas aplicações realizadas na parede posterior das veias pulmonares esquerdas, que os pacientes que não tiveram lesões (Grupo sem lesões esofágicas: potência média cateter = 37,7 w; Grupo com lesões esofágicas: potência média do cateter = 48,8 w, p = 0.013). A incidência de recorrência de arritmia após um único procedimento de ablação de Fibrilação Atrial, em seguimento clínico de 11 +- 5 meses, foi de 7 casos (15.6%), sem diferença significativa entre os grupos (GI = 26,7%, GII = 13,3% e GIII = 6,7%, p = 0,305). A incidência de complicações maiores relacionadas aos procedimentos de ablação realizados foi de 2,2% (um caso de congestão pulmonar no segundo dia após o procedimento, resolvido com uso de diuréticos). Conclusão: O uso da estratégia de resfriamento esofágico durante ablação de FA foi ineficaz como estratégia preventiva de lesões esofágicas/periesofágicas na população estudada, quando comparada às estratégias de aplicações de radiofrequência com baixa energia ou de energia limitada pela temperatura esofágica / Introduction: In the last decade, since the initial description of the ablation of pulmonary veins, the atrial fibrillation (AF) catheter ablation has evolved significantly in terms of efficacy and safety, consolidating itself as the therapeutic choice for AF selected patients. However, AF ablation is a complex procedure not without risks. Despite being a rare complication, the development of atrialesophageal fistulas (AEFs) ranks second in terms of procedure-related deaths, accounting for 16% of all post-AF ablation losses of life. Current consensus is not dispositive with regards to directives for the prevention of esophageal lesions, which come first and lead to AEFs. The objective of this work is to compare the incidence of esophageal and periesophageal lesions post-AF ablation, given use of different esophageal protection strategies during the radiofrequency applications on the left-atrium posterior wall. Method: From October 2012 through July 2014, 45 patients submitted to AF percutaneous ablation were studied. All of them were bearers of paroxistic or persistent AF for less than one year, and all of them were submitted to 8mm-catheter, pulmonary vein electric-shielding circumferential ablation. Before the procedure, patients were randomly assigned to one of three esophageal lesion protection strategies: Group I - 30w, low energy, fixed limited applications; Group II - energy applications limited by esophageal temperature; and Group III - fixed limit energy applications during continuous esophageal cooling. The survey for esophageal/periesophageal lesions was carried by means of esophageal endoscopy combined with radial ultrasound performed within 48 hours post ablation. Results: Baseline characteristics were even across groups; no significant differences in clinical, laboratorial, ecocardiographic or endoscopic variables were found, except for pre-ablation distance between posterior left atrium wall and the esophagus as measured by radial ultrasound endoscopic, smaller in Group III (GI = 3,9 mm +- 0,4; GII = 3,9 mm +- 0,5; GIII = 3,4 mm +- 0,4, p = 0.002). Post FA-ablation endoscopies revealed the existence of 4 counts of esophageal/periesophageal lesions: 2 esophageal wall ulcer and 2 periesophageal mediastin edema. All cases of esophageal/periesophageal lesions occurred in the esophageal cooling group (GIII) (p=0.008). Bivariate analysis on the clinical characteristics of patients that presented esophageal/periesophageal lesions showed no significant difference from those in the lesion-free group, except for average values for post ablation reactive-C protein (RCP), significantly greater in the lesion group (2.12 mg/dl vs. 0.82 mg/dl for the lesion-free group, p < 0.001). Ablation parameter comparison by approached vein region revealed that patients with post ablation lesions had received higher-powered applications in their posterior wall left pulmonary veins (average catheter power = 48.8 w vs. 37.7 w for lesion-free group, p=0.013). After a 11 +- 5 month clinical following, arrhythmia recurrence post a single AF ablation procedure added to 7 cases (15.6%), and no significant difference among the three different groups was found (GI = 26.7%, GII = 13.3% e GIII = 6.7%, p = 0.305). Incidence of major complications related to the ablation procedures reached 2.2% (one case of pulmonary congestion occurring in the second day post procedure, and resolved with the use of diuretics). Conclusion: The use of esophageal cooling during AF ablation was an ineffective strategy to prevent esophageal/periesophageal lesions in the studied population when compared to low-energy radiofrequency or energy limited by esophageal temperature lesion prevention strategies

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&lt;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 &#177; 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 &#177; 7,7 e 55,7 &#177; 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&lt;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 &lt;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 &#177; 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 &#177; 7.7 and 55.7 &#177; 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 &lt;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.

Eventuais alterações no substrato anatômico miocárdico, no sistema nervoso autônomo (SNA) cardíaco intrínseco, envolvendo os plexos ganglionares (PG) comumente presentes em organizações de gordura epicárdicas denominadas fatpads (FP) ou a expressão dos receptores muscarínicos, poderiam ser responsáveis pela gênese e manutenção da fibrilação atrial (FA). Com o objetivo de analisar a relação entre fibrilação atrial permanente (FAP) e possíveis alterações anatômicas e micromorfológicas do coração, do SNA cardíaco intrínseco e da expressão dos receptores muscarínicos miocárdicos, foram estudados 13 corações de autópsias de portadores de FAP e cardiopatia crônica definida (grupo I) e 13 casos pareados pela mesma doença cardíaca, porém sem esta arritmia (grupo II). Foram analisados a anatomia da drenagem venosa do átrio esquerdo (AE), peso do coração, espessura do septo ventricular e diâmetro dos FP epicárdicos. Foram ressecadas duas amostras no átrio direito (AD1 e AD2), três no átrio esquerdo - no trajeto médio da VoAe (AE1), na junção da veia pulmonar superior esquerda (AE2) e na aurícula (AE3), três em FPs, atrial esquerdo superior (FP1), atrial direito posterior (FP 2) e no atrial esquerdo póstero-medial (FP 3) e uma amostra do septo ventricular (SIV), como controle. As alterações estruturais das fibras miocárdicas, as espessuras do epicárdio, endocárdio e miocárdio e o percentual de colágeno intersticial no miocárdio foram analisados através de histomorfometria computadorizada sob coloração de tricrômio de Masson. O SNA cardíaco intrínseco foi analisado através imuno-histoquímica para S-100 e tirosina-hidroxilase quanto a: quantidade e área das fibras nervosas, quantidade e área média de fibras simpáticas, quantidade e área média de fibras parassimpáticas e proporção de fibras simpáticas/parassimpáticas. A expressão miocárdica dos receptores muscarínicos 1 a 5 (M1 a M5) foi avaliada pela proporção positiva no miocárdio nos cortes AD1, AE1, AE2 e FP1. Não houve diferenças entre os grupos quanto às variáveis anatômicas e ao percentual de colágeno intersticial. A análise do SNA revelou fibras nervosas com menor área no grupo I, redução do número de fibras nervosas totais e parassimpáticas nos cortes AD1 e SIV, aumento de fibras totais e parassimpáticas AE2 e FP2 e aumento do número de fibras simpáticas nos cortes AD2, AE1, AE2 e AE3. Quanto à expressão dos receptores muscarínicos, houve aumento significante na porcentagem positiva para M1 em todas as regiões, exceto na AE1 (média de todos os cortes, grupo I 5,84 e grupo II 2,92, p=0,002); o M2 e M3 apenas junto ao FP1 (M2 grupo I 5,67 e grupo II 3,63, p=0,037; M3 grupo I 30,95 e grupo II 20,13, p=0,026) e o M4 foi aumentado no grupo I na região AE1 (grupo I 9,90 e grupo II 4,45, p=0,023); não houve alteração estatisticamente significante no M5. A anatomia e a disposição das fibras musculares atriais, bem como a fibrose intersticial não parecem estar relacionadas à FAP nos grupos estudados. Alterações no número de fibras nervosas bem como e alterações na expressão dos receptores muscarínicos atriais, especialmente o M1, particularmente em regiões próximas aos PG, parecem estar relacionadas à FAP, indicando a importância da modulação autonômica nesta arritmia / Possible changes in myocardial substrate, in the intrinsic cardiac autonomic nervous system (ANS), involving the ganglionated plexus (GP) present in fat-pads (FP) or the expression of muscarinic receptors could be responsible for the genesis and maintenance of atrial fibrillation (AF). Aiming to analyze the relationship between permanent atrial fibrillation (pAF) and possible anatomical and micromorphological heart changes, intrinsic cardiac ANS and expression of myocardial muscarinic receptors, 13 hearts from autopsies of patients with PAF and chronic heart disease (group I) were studied; and 13 cases matched by the same heart disease, but without this arrhythmia (group II). It was analyzed the anatomy of the venous drainage of the left atrium (LA), heart weight, ventricular septal thickness and diameter of epicardial FP. Two samples were taken in the right atrium (RA1 and RA2), three in the left atrium - in the middle portion of the left atrium oblique vein (LaOv LA1), at the junction of left superior pulmonary vein (LA2) and in the auricle (LA3), three FPs, left atrial superior (FP 1), right atrial posterior (FP 2) and the left atrial posteromedial (FP 3) and one sample of the ventricular septum (VS), as control. The structural changes of the myocardial fibers, thickness of the epicardium, endocardium and myocardium, and the percentage of interstitial collagen in the myocardium were analyzed by computerized histomorphometry on Masson trichrome staining. The intrinsic cardiac ANS was analyzed through immunohistochemistry for S-100 and tyrosine hydroxylase regarding the: amount and area of nerve fibers, amount and average area of sympathetic fibers, number and average area of parasympathetic fibers and sympathetic/parasympathetic fiber proportion. The myocardial expression of muscarinic receptors 1-5 (M1 to M5) was evaluated by positive ratio in the myocardium in sections RA1, LA1, LA2 and FP1. There were no differences between groups regarding the anatomical variant and the percentage of interstitial collagen. Analysis of the ANS revealed nerve fibers with the smallest area in group I, reduction in the number of total and parasympathetic nerve fibers of sections RA1 and VS, increase of total and parasympathetic fibers LA2 and FP2 and increased numbers of sympathetic fibers in sections RA2, LA1, LA2 and LA3. Regarding the expression of muscarinic receptors, there was a significantly increase in the positive percentage for M1 in all regions except for LA1 (average of all the sections, group I 5.84 and group II 2.92, p = 0.002), M2 and M3 just adjacent to the FP1 (M2 Group I 5.67 and Group II 3.63, p = 0.037; M3 Group I 30.95 and Group II 20.13, p = 0.026) and the M4 was increased in group I in the region LA1 (group I 9.90 and group II 4.45, p = 0.023) and there was no statistically significant change in the M5. The anatomy and arrangement of atrial muscle fibers, as well as the interstitial fibrosis did not appear to be related to PAF in both studied groups. Changes in the number of nerve fibers as well as changes in expression of atrial muscarinic receptors, specially the M1, particularly in regions close to the GP appear to be related to pAF, indicating the importance of autonomic modulation in this arrhythmia