Heart rate is modulated by the opposing activities of sympathetic and parasympathetic inputs to pacemaker cardiomyocytes in the sinoatrial (SA) node. Parasympathetic activity on nodal myocytes is mediated by acetylcholine-dependent stimulation of M2 muscarinic receptors and activation of Gαi/o signalling. Although, regulators of G-protein signalling (RGS) proteins are potent inhibitors of Gαi/o signalling in many tissues, the RGS protein(s) that regulate parasympathetic tone in the SA node are unknown. Our results demonstrate that RGS4 mRNA levels are higher in the SA node compared to right atrium. Conscious freely moving RGS4-null mice showed a greater extent of bradycardia in response to parasympathetic agonists compared to wild-type animals. Moreover, anaesthetized rgs4-null mice had lower baseline heart rates and greater heart rate increases following atropine administration. Retrograde-perfused hearts from rgs4-null mice also showed enhanced negative chronotropic responses to carbachol, while isolated SA node myocytes showed greater sensitivity to carbachol-mediated reduction in the action potential firing rate. Finally, rgs4-null SA node cells showed decreased levels of G-protein-coupled inward rectifying potassium (GIRK) channel desensitization, and altered modulation of acetylcholine-sensitive potassium current (IKACh) kinetics following carbachol stimulation. Taken together, our studies establish that RGS4 plays an important role in regulating sinus rhythm by inhibiting parasympathetic signalling and IKACh activity. Following these results, we predicted that loss of RGS4 expression and function will result in increased levels of parasympathetic effector activity leading to increased susceptibility to atrial fibrillation. Susceptibility to atrial fibrillation (AF) depends strongly on parasympathetic activity. Since RGS4 inhibits parasympathetic / M2-dependent Gαi/o signalling in the SA node, we explored whether changes in RGS4 levels altered the susceptibility of atrial fibrillation. We found that, RGS4 levels were decreased in atria of tachypaced dogs prior to their development of chronic AF. Moreover, in vivo ECG recordings of anaesthetized mice showed greater susceptibility to AF while optical mapping of isolated atrial preparations using a voltage-sensitive dye revealed greatly increased susceptibility to rotor formation when RGS4 was ablated. Consistent with altered parasympathetic signalling in the myocardium of rgs4-null mice, IKACh evoked by carbachol application were greater in isolated atrial myocytes from rgs4-null mice. These IKACh changes were, as expected, associated with marked action potential duration shortening in response to parasympathetic activation, but not to slower conduction velocities. Together, our findings establish that RGS4 protects atrial tissues from excess parasympathetic signalling that predispose to atrial fibrillation.

Thesis (Ph. D.)--University of Pennsylvania, 1916. / "From the John Herr Musser Department of Research Medicine, University of Pennsylvania, Philadelphia."

Thesis (Ph. D.)--University of Pennsylvania, 1916. / "From the John Herr Musser Department of Research Medicine, University of Pennsylvania, Philadelphia."

Thesis (M. Med. Sc.)--University of Hong Kong, 2005.

Made available in DSpace on 2015-07-22T20:49:51Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-04-29. Added 1 bitstream(s) on 2015-08-11T03:26:00Z : No. of bitstreams: 1 Publico-12179a.pdf: 1552964 bytes, checksum: a4661120e176f2799f91c1a2483bc2e3 (MD5). Added 1 bitstream(s) on 2015-08-11T03:26:00Z : No. of bitstreams: 2 Publico-12179a.pdf: 1552964 bytes, checksum: a4661120e176f2799f91c1a2483bc2e3 (MD5) Publico-12179b.pdf: 1447396 bytes, checksum: a67e6d0ce0751e8358db16d04ae025f7 (MD5) / O autor só colocou Abstract -Background: Atrial fibrillation (AF) is the most common sustained arrhythmia in clinical practice, and has major impact on health-relatedquality of life, thus, there is a need for a specific instrument to assess AF symptoms and quality of life. Methods: We developed and validated a specific questionnaire for quality of life inAF patients (QLAF) based on clinicalmanifestations (palpitation,breathlessness, dizziness and chest pain), and the usual treatments (medication, cardioversion and ablation). For validation, the new questionnaire was compared with the generic SF-36 questionnaire. Reproducibility was tested using 40 questionnaires administered by two different observers at distinct times and places. Responsiveness was evaluated based on variation of the QLAF score over time. Results: There were a total of 462 questionnaires (231 SF-36 and 231 QLAF) administered at baseline, 3, 6, 9 and 12 months. Construct validity was demonstrated by the negative correlation between QLAF and SF-36 scores that was observed over the follow-up period. Analysis of internal consistency for reproducibility showed excellent Cronbach's alpha coefficients (inter- and intraobserver coefficients of 0.98 and 0.96, respectively). QLAF was responsive as indicated by significant differences in mean domain scores from the beginning to the end of follow-up. It took much less time to administer the QLAF than the SF-36 (3:08±0:33 min vs. 9:25±1:14 min, pb0.001). Conclusion: The QLAF questionnaire is easy to understand and can be administered rapidly in the outpatient setting. Furthermore, the QLAF score is valid and reproducible and responsive to a change in clinical status.. / TEDE / BV UNIFESP: Teses e dissertações

PALHETA JÚNIOR, Raimundo Campos. A distensão mecânica atrial direita diminui a complacência gástrica em ratos normovolêmicos anestesiados. 2006. 91 f. Dissertação (Mestrado em Farmacologia) - Universidade Federal do Ceará. Faculdade de Medicina, Fortaleza, 2006. / Submitted by denise santos (denise.santos@ufc.br) on 2012-05-09T16:01:43Z No. of bitstreams: 1 2006_dis_rcpjunior.pdf: 506057 bytes, checksum: ce2d477c8dac2509783864b5c0c7f538 (MD5) / Approved for entry into archive by Eliene Nascimento(elienegvn@hotmail.com) on 2012-05-14T16:02:01Z (GMT) No. of bitstreams: 1 2006_dis_rcpjunior.pdf: 506057 bytes, checksum: ce2d477c8dac2509783864b5c0c7f538 (MD5) / Made available in DSpace on 2012-05-14T16:02:01Z (GMT). No. of bitstreams: 1 2006_dis_rcpjunior.pdf: 506057 bytes, checksum: ce2d477c8dac2509783864b5c0c7f538 (MD5) Previous issue date: 2006 / Graça et al. (2002) observou em ratos que a hipervolemia aumenta o tônus gástrico, enquanto a hipovolemia o diminuía. Resolvemos estudar o efeito do estiramento cardíaco sobre o tônus gástrico e os mecanismos neurais envolvidos. Metodologia: Ratos albinos machos (n=82, ~320g), anestesiados, com vasos cervicais canulados para registros hemodinâmicos e distensão do átrio (DA). Um grupo separado de animais foi submetido à vagotomia subdiafragmática (DAIV) ou esplancnotomia (DAV). Para registro do volume gástrico (VG), foi introduzido per os um cateter com um balão de látex posicionado no estômago proximal e acoplado a um pletismômetro. Após período basal (15min), os ratos foram submetidos aos protocolos: falso distendido (FDA) ou animais submetidos durante 5 min à DA com 30, 50 ou 70µL, respectivamente (DAI), (DAII) e (DAIII), ou (DAIV) e (DAV) submetidos a DA com 50µL. Em seguida, houve monitoração nos 30min seguintes, divididos em intervalos de 10 min, designados de D10, D20 e D30. Os dados relativos ao VG estão representados em percentagem de seus respectivos valores basais. Sendo analisados por ANOVA seguida do teste de Bonferroni. Resultados: Não houve variações do VG e PVC no grupo FDA, porém no grupo DAI houve uma diminuição significativa do VG em D20 e D30 (9.9% e 14%, respectivamente), não houve aumento da PVC durante a DA. Nos grupos DAII e DAIII o VG diminuiu a partir de D10 (5% e 5.8%, respectivamente, p<0,05) com persistência em D20 (8,5 e 13%,respectivamente) e D30 (11,5 e 16,5%, respectivamente). Além disso, a PVC aumentou em ambos os grupos durante a DA (p< 0,05). No grupo IV, a vagotomia preveniu a diminuição do GV, permanecendo inalterado o VG durante o período experimental. No grupo V, a esplancnotomia aumentou tal efeito, o VG diminuiu a partir de D10 (10,5%, p<0,05) se intensificando em D20 e D30 (16 % e 23,4%, respectivamente). Conclusão: A distensão do balão atrial além de desencadear ajuste hemodinâmicos diminui o VG em ratos anestesiados, efeito abolido após vagotomia subdiafragmática, e permanecendo acentuado nos animais esplancnotomizados

The ablative management of atrial fibrillation, despite a number of landmark discoveries, remains one of the most challenging fields in interventional electrophysiology. It is generally accepted that successful isolation of the pulmonary veins is a highly effective way of managing paroxysmal forms of AF. However, despite almost a decade of research into alternative lesion patterns, the solution to persistent AF remains beyond our grasp. A variety of strategies have been proposed to target key areas in the atria; these use various complex mapping systems, usually based on tailored lesion sets to try and improve outcomes. None have proven to be the golden bullet. We have investigated the role of a lesion set intended to alter the electrical properties of the posterior wall of the left atrium. Commonly known as the ‘box-set’, this pattern has shown promise in early studies and may provide some key insights into future developments. Surgical ablation using the Epicor system aims to deliver the box-set lesion, outcomes have previously been documented but each series has its limitations. In our series, very late outcomes are reported to show an 80% freedom from AF rate in patients with paroxysmal AF pre-operatively and only 20% in those with long-standing persistent forms. The reason behind this dramatic variation is explored through the invasive electrophysiologal assessment of both successful and unsuccessful cases. We report a clear correlation between the successful isolation of the posterior wall and long-term freedom from AF. Though surgical ablation may be an acceptable approach for some, the ultimate goal is a lesion set that can be delivered purely endocardially. We explore the outcome of one such empirical pattern based on the box-set concept delivered through linear catheter technology and report outcomes broadly similar to alternative patterns.

Dissertação (mestrado)—Universidade de Brasília, Faculdade de Medicina, Programa de Pós-Graduação em Ciências Médicas, 2015. / Submitted by Fernanda Percia França (fernandafranca@bce.unb.br) on 2016-03-15T19:49:57Z No. of bitstreams: 1 2015_GustavoGirGomes.pdf: 997787 bytes, checksum: debff5f0a1815f51bba1e3d256bae525 (MD5) / Approved for entry into archive by Raquel Viana(raquelviana@bce.unb.br) on 2016-03-21T20:40:23Z (GMT) No. of bitstreams: 1 2015_GustavoGirGomes.pdf: 997787 bytes, checksum: debff5f0a1815f51bba1e3d256bae525 (MD5) / Made available in DSpace on 2016-03-21T20:40:23Z (GMT). No. of bitstreams: 1 2015_GustavoGirGomes.pdf: 997787 bytes, checksum: debff5f0a1815f51bba1e3d256bae525 (MD5) / Fundamento: A operação de Cox-Maze III é útil no tratamento cirúrgico da fibrilação atrial (FA). Objetivos: Verificar os resultados tardios da cirurgia de Cox-Maze III na manutenção de ritmo sinusal e identificar preditores de recorrência tardia de FA. Métodos: Avaliamos os pacientes consecutivamente operados de Cox-Maze III associado a correção de cardiopatia estrutural, entre janeiro de 2006 e janeiro de 2013. Foram obtidos dados demográficos, clínicos e ecocardiográficos dos períodos pré e perioperatório. No seguimento pós-operatório, ritmo cardíaco foi verificado por eletrocardiograma e Holter. Índices de eficácia da operação foram estudados por métodos longitudinais e os preditores de recorrência por análise de regressão de Cox multivariada. Resultados: oitenta pacientes foram incluídos, com idade média de 49,9 anos, sendo 33 (41,2%) do sexo masculino. FA persistente de longa duração ocorreu em 47 pacientes (58,7%). Valvopatia reumática ocorreu em 63 pacientes (78,7%). A média do diâmetro atrial esquerdo foi 55 mm. Correção da valva mitral ocorreu em 67 pacientes (83,7%). Tempo médio de seguimento de 27,5 meses. Os índices de manutenção do ritmo sinusal foram 85,4%, 82%, 72% e 72%, aos 6, 12, 24 e 36 meses, respectivamente. Os preditores de recorrência tardia foram sexo feminino (RR 3,52 IC95% 1,21 – 10,25; p = 0,02), doença arterial coronária (RR 4,73 IC95% 1,37 – 16,36; p = 0,01) e maior diâmetro de átrio esquerdo (RR 1,05 IC95% 1,01 – 1,09; p = 0,02). Conclusões: em população heterogênea, a taxa de manutenção do ritmo sinusal pôde ser comparada a grandes centros. Identificados preditores de recidiva tardia de FA. / Introduction: The Cox-Maze III procedure is effective in the surgical treatment of atrial fibrillation (AF). Objectives: Verify the late results of the Cox-Maze III procedure in maintenance of sinus rhythm and identify predictors of late AF recurrence. Methods: we assessed consecutive patients who underwent Cox-Maze III procedure in association with structural heart disease treatment, between January 2006 and January 2013. Demographics, clinical and echocardiographic findings data were obtained from preoperative and perioperative periods. Recordings of heart rhythm in the postoperative follow-up were obtained with eletocardiogram and 24-hour Holter. Procedural success rates were determined by longitudinal methods and recurrence predictors by multivariate Cox regression models. Results: eighty patients were included. Mean age was 49.9 years. Thirty-three (41.2%) patients were men. Forty-seven patients (58.7%) had long-standing persistent AF. Mean left atrial diameter was 55mm. Mitral valve treatment occurred in 67 (83.7%) patients. Mean follow-up time was 27.5 months. Procedural rates of sinus rhythm maintenance were 85.4%, 82%, 72% and 72% at 6, 12, 24 and 36 months, respectively. Late AF recurrence predictors were female sex (RR 3.52 IC95% 1.21 – 10.25; p = 0.02), coronary artery disease (RR 4.73 IC95% 1.37 – 16.36; p = 0.01) and greater left atrium diameter (RR 1.05 IC95% 1.01 – 1.09; p = 0.02). Conclusions: in a heterogeneous population, the rates of maintenance of sinus rhythm could be compared to great reference centers. Predictors of late AF recurrence were identified.

Cardiovascular disease is prevalent across the western world and is a major cause of morbidity and mortality, accounting for approximately a third of all fatalities. Investigating the heart by simulating its electrophysiology via the aid of mathematical models has advanced significantly over the past 60 years and is now a well established field. While much of the research focus is placed on the ventricles, the study of the atria is in comparison neglected. Therefore this Thesis is focused on the genesis and maintenance of atrial fibrillation (AF). A series of case studies are performed whereby established biophysically detailed mathematical models are implemented and modified to incorporate electrophysical alterations of atrial cells resulting from a variety of external conditions. The opening section of this Thesis is dedicated to developing a background to the field, including a discussion into the clinical aspect of the diagnosis and management of AF. The suitability of two atrial cell models is discussed and the development of single cell, 1D, 2D, and 3D multi-scale simulation protocols are described in detail. In addition measurements taken to quantify the arrhythmogenic properties of the cells susceptibility to AF are outlined. The second section is focused on the incorporation of conditions thought to enhance atrial tissues ability to initiate and maintain the genesis of AF. Included is a case study into the missence S140G gene mutation, and elevated physiological levels of the hormone Homocystein. The third section investigates the effectiveness of well established and widely used pharmacological treatments such as Beta-Blockers. In addition possible avenues of investigations for the development of atrial specific drugs are explored. These include blocking of the ultra rapid potassium channel and a more novel target for therapy via the targeting of 5HT4 receptors; which is transcribed solely in the atria and alters the electrophysical properties of the L-type Calcium current. The final part of this Thesis is dedicated to the development of a 2D atrial sheet model which includes electrical and spatial heterogeneities via the inclusion of multiple cell types and basic fiber orientation respectively. This allows for an investigation into the role that heterogeneities play in role genesis and maintenance of AF. The main finding of this Thesis is that alterations to the electrophysiology of atrial cells, due to external factors, can be successfully simulated via the implementation of mathematically detailed atrial cell models. It is concluded that simulations of the KENQ1 mutation and elevated levels of Homocystein successfully reproduce conditions which increase the onset of AF. Established treatments such as Beta-Blockers are found to have limited effectiveness. Possible theoretical treatments, such as the blocking of IKur, are found to provide a small amount of therapeutic benefit. In contrast, investigations into the effects of Serotonin were inconclusive. The study into the 2D atria indicated the importance that heterogeneities play in atria. The conclusions show that models provide a powerful tool when investigating how changes to electrophysiology of cells are manifested at a multi-scale level. The models also have their limitations and require further advancement to improve their accuracy.

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.