Objetivo: Avaliar o uso de antitrombóticos em pacientes com fibrilação atrial (FA) em hospital cardiológico no Brasil (InCor).Métodos e resultados: Um estudo observacional transversal analisou os prontuários de todos os pacientes atendidos no InCor em cada um de 5 dias separados no ano de 2002 (Fase 1), sendo prospectivamente reanalisados após 1 ano (Fase 2). A prevalência da FA nos 3764 prontuários analisados foi de 8%. Antiplaquetários foram prescritos para 21,26% e 19,93%, anticoagulantes para 46,51% e 57,81%, e 32,23% e 22,26% não usavam nenhum antitrombótico nas Fases 1 e 2, respectivamente. Somente 15,60% e 23,25% apresentavam níveis de RNI terapêuticos.Conclusão: A anticoagulação é subutilizada nos pacientes com FA apesar do fato de serem tratados por cardiologistas em um hospital universitário / Objective: To assess antithrombotic therapy among atrial fibrillation (AF) patients in a Brazilian University Heart Hospital (InCor).Methods and results: A cross sectional study analyzed the charts of all patients treated at InCor in 5 separate days of 2002 (Phase 1), and prospectively reviewed them after one year (Phase 2). The prevalence of AF in the 3,764 assessed charts was of 8.0%. Antiplatelets were prescribed to 21.26% and 19.93%, anticoagulants to 46.51% and 57.81%, and 32.23% and 22.26% were not receiving any antithrombotic in Phases 1 and 2, respectively. Only 15.60% and 23.25% were within INR therapeutic range.Conclusion: Anticoagulation is underused in AF patients besides the fact of being treated by cardiologists in a University Hospital

O nó sinoatrial (NSA) é responsável pela geração dos impulsos nervosos determinantes da contração cardíaca, sendo seu suprimento sangüíneo feito pela artéria do nó sinoatrial - ANSA. Neste trabalho, objetivou-se estudar a vascularização arterial da região do NSA, em corações humanos normais, por meio de técnicas macroscópicas, procurando enfocar a terminação da ANSA, sua origem e trajeto, atentando para a presença ou não da chamada "rede arterial perisinusal". Vinte e cinco (25) corações, de indivíduos adultos, de ambos os sexos, sem doenças cardíacas, obtidos no "Serviço de Verificação de Óbitos da Capital (SVOC) da Universidade de São Paulo", tiveram os óstios coronários canulados para injeção de resina vinílica corada. As peças foram fixadas em solução aquosa de formol 10% (48 horas), seguindo-se a dissecação da circulação atrial. As metades direita e esquerda dos átrios apresentaram número equivalente de artérias (62 e 63, respectivamente), o que não ocorreu para as metades anterior e posterior (77 e 48, respectivamente). A ANSA originou-se da artéria coronária direita, em 15 casos (60%): em onze (11) da artéria atrial direita anterior medial (AADAM), dois (2) da direita intermédia (AADAI) e dois (2) da direita lateral (AADAL). Em oito casos (32%), originava-se da artéria coronária esquerda: três (3) da artéria atrial esquerda posterior lateral (AASPL), dois (2) da esquerda anterior intermédia (AASAI) e três (3) da anterior medial (AASAM). Em 8% dos casos (2) a distribuição era peculiar - em um AASAM e artéria atrial esquerda anterior lateral (AASAL) estavam em continuidade, até alcançarem e penetrarem a região do nó, e, no segundo caso, a AASAM unia-se com a artéria atrial direita posterior lateral (AADPL), com trajeto em forma "U", circundando a base da veia cava superior. Em oito corações, identificou-se intensa ramificação na região perinodal, indicativo da ocorrência da "rede arterial perisinusal". A diversidade do trajeto da ANSA ora observada e a indicada pela literatura reitera a necessidade de maiores estudos sobre este trajeto, de modo a contribuir para a higidez do NSA nas cirurgias envolvendo manipulação atrial. / The sinoatrial node (NSA) is responsible for the production of the nervous impulses, which determine the cardiac contraction and its blood supply is provided by the sinoatrial node artery - ANSA. In this research we aimed to study the arterial vascularization of the NSA area in normal human hearts, with macroscopic techniques intending to identify the origin of the sinoatrial node artery, its termination, attempting to the presence or not of the so called "arterial perisinusal network". Twenty five (25) hearts, without diseases, obtained from the "Serviço de Verificação de Óbitos da Capital (SVOC) da Universidade de São Paulo" were canulated by the coronary ostium following injected with colored resin. They were fixed in 10% watery formaldehyde solution (48 hours) an afterwards the atrial circulation was dissected. The left and right atrial halves demonstrating equivalence of arteries (62 and 63 respectively), which was not observed in the anterior and posterior halves of the heart (77 and 48 arteries respectively). The ANSA was originated from de right coronary artery in fifteen cases (60%): eleven by the right anterior medial atrial artery (AADAM), two by the right anterior intermedial atrial artery (AADAI) and two by the right anterior lateral atrial artery (AADAL). In eight cases (32%) was originated from the left coronary artery: three by the left posterior lateral atrial artery (AASPL), two by the left anterior intermedial atrial artery (AASAI) and three by left anterior medial atrial artery (AASAM). In 8% of the cases, the vascular distribution was peculiar - in one of them, the AASAM and left anterior lateral atrial artery (AASAL) were in continuous, reaching and penetrating the node area. In the second case, the AASAM artery joined to the right posterior lateral atrial artery (AADPL) forming a continuous "U" shape surrounding the base of the VCS. In eight hearts, the arterial distribution showed intense ramification in the perinodal area, which could indicate the occurrence of the "perisinusal arterial network". The diversity of the ANSA´s traject, indicated by the literature, shows the necessarily others studies about it to contribute to the integrity of the NSA in surgical procedures that involves the atrial walls.

Atrial fibrillation (AF) is the most common cardiac arrhythmia causing morbidity and mortality. Despite recent advances, developing effective and safe anti-AF pharmaceutical therapies remains challenging and is prone to adverse effects in the ventricles. Atrial-selective therapies are promising in managing AF. A better understanding of the role of the atrial-specific ion channels in the atrial arrhythmogenesis and contractility, as well as the anti-AF effects of blocking these channels is of interests. Also, a 3D ventricle-torso model capable of modelling ventricular electrical activities and the resulting electrocardiogram (ECG) is a valuable tool in evaluating the selectiveness and safety of an anti-AF pharmaceutical therapy. In part I, the role of an atrial-specific ion channel, IKur, in atrial electrical and mechanical activities and the potential of the current as a pharmaceutical target for anti-AF therapies were investigated in silico. The role of IKur in atrial arrhythmogenesis and mechanical contraction was revealed by elucidating the functional impacts of the KCNA5 mutations exerting either gain- or loss-in-function, on the atria. First, novel IKur models were developed and incorporated into multiscale biophysical models of human atrial electrophysiology to assess the effects of mutated IKur on atrial electrical dynamics. Then, a family of single cell human atrial electromechanical models was developed and incorporated into an updated 3D anatomical electromechanical model of human atria to clarify the effects of mutated IKur on the atrial contractile function. Finally, the antiarrhythmic effect of IKur block was assessed together with INa and other K+-current block. It was shown that the gain-of-function in IKur impaired atrial contractility and promoted atrial arrhythmogenesis by shortening the APD, whereas the down-regulated IKur exerted positive inotropic effects and increased the susceptibility of the atria to the genesis of early-afterdepolarisations. Both simulated IKur and INa block in human-AF demonstrated antiarrhythmic effects; the multi-channel block exerted synergistic anti-AF effects and enhanced the AF-selectivity of INa inhibitions. In Part II, a human ventricle-torso model was developed through proposing a new family of single cell ventricular models accounting for transmural, apicobasal and interventricular electrical heterogeneities and integrating an updated 3D biophysical and anatomical model of human ventricles with a heterogeneous anatomical model of a human torso. First, using the model, the role of heterogeneities in the genesis of T-wave was revealed. Then, ECG manifestations of bundle branch block and ventricular ischaemia were simulated. Finally, the platform was applied to investigate the impact of a long-QT-linked mutation (KCNQ1-G269S) on the ventricles and ECG. Good agreement between simulated and experimental/clinical ECG was reached under both normal and diseased conditions. It was shown that the apicobasal heterogeneity had a more pronounced effect on the T-wave than other heterogeneities. Simulations of the KCNQ1-G269S elucidated the causal link between the mutation and ECG manifestations of the patients.

Submitted by Suzana Dias (suzana.dias@famerp.br) on 2018-11-09T16:20:01Z No. of bitstreams: 1 SabrinaQueirozArdito_tese.pdf: 553115 bytes, checksum: 3a2e5134532370664d754e2648b56cf0 (MD5) / Made available in DSpace on 2018-11-09T16:20:01Z (GMT). No. of bitstreams: 1 SabrinaQueirozArdito_tese.pdf: 553115 bytes, checksum: 3a2e5134532370664d754e2648b56cf0 (MD5) Previous issue date: 2018-04-06 / Chagas disease is caused by the parasite Trypanosoma cruzi. It is a chronic, systemic disease, which affects about 6 million people in Latin America and 30-40% has cardiomyopathy secondary to this disease. In the vast majority of cases, the main cause of death is related to the final stages of chronic heart failure. Chagas disease has become a growing health problem in non-endemic areas due to migration. Objective: To evaluate the impact of atrial fibrillation on the prognosis of chronic systolic heart failure secondary to Chagas cardiomyopathy. Material and Methods: About 234 patients routinely followed at the Cardiomyopathy Outpatient Service of Hospital de Base of São José do Rio Preto Medical School in the SUS, from January 2000, to December 2010, with the diagnosis of chronic heart failure secondary to Chagas cardiomyopathy were included in the study. A Cox proportional hazard model was used to detect independent predictors of all-cause mortality in the studied population. A survival curve was built for patients with and without atrial fibrillation. In all the circumstances, p value <0.05 was considered statistically significant. Results: Atrial fibrillation was observed in 63 patients (26.9%). In a cox proportional hazard model analysis, beta-blocker therapy ( Hazard Ratio=0.381; 95% Confidence Interval 0.257 to 0.563, p value <0.001), use of metoprolol succinate (Hazard Ratio=0.382; 95% Confidence Interval 0.170 to 0.855, p value=0.019), use of Losartan (Hazard Ratio=0.611; 95% Confidence Interval 0.380 to 0.981, p value =0.041), and left systolic ventricular diameter (Hazard Ratio=1.042; 95% Confidence Interval 1.021 to 1.063, p value <0.001) were determined independent predictors of all-cause mortality. Survival probability at 12, 24, 36, 48 and 60 months was 80%, 65%, 56%, 44% and 37%, respectively, in patients without atrial fibrillation, and 76%, 58%, 48%, 41% and 32% in patients with atrial fibrillation, (p=0.393). Conclusion: Atrial fibrillation has no prognostic significance in patients with chronic systolic heart failure secondary to Chagas Cardiomyopathy. / A doença de Chagas é causada pelo parasita Trypanosoma cruzi. É uma doença crônica, sistêmica, que afeta cerca de seis milhões de pessoas na América Latina, e 30-40% têm cardiomiopatia secundária a essa patologia. Para a grande maioria, a principal causa de morte está relacionada a estágios finais de insuficiência cardíaca crônica. A Doença de Chagas tem se tornado um problema de saúde crescente em áreas não endêmicas devido ao deslocamento e crescimento populacional. Objetivo: Avaliar o impacto da fibrilação atrial no prognóstico da insuficiência cardíaca crônica sistólica secundária à cardiomiopatia da Doença de Chagas. Casuística e Método: Foram incluídos no estudo 234 pacientes seguidos no Ambulatório de Cardiomiopatia do Hospital de Base da Faculdade de Medicina de São José do Rio Preto, no Sistema Único de Saúde, no período de janeiro de 2000 a dezembro de 2010, que apresentavam o diagnóstico de insuficiência cardíaca crônica sistólica secundária à cardiomiopatia da Doença de Chagas. O modelo de risco proporcional de Cox foi utilizado para detectar variável de predição independente de mortalidade geral na população como um todo, bem como para revelar variáveis de predição independentes de mortalidade geral em pacientes com fibrilação atrial. Foi construída curva de sobrevida dos pacientes pelo método de Kaplan-Meier de acordo com as variáveis de predição identificadas. Da mesma forma, construiu-se curva de sobrevida para pacientes com e sem fibrilação atrial. Em todas as circunstâncias, considerou-se valor de p <0,05 como estatisticamente significante. Resultados: A fibrilação atrial foi observada em 63 pacientes (26,9%). Terapia com betabloqueador (Razão de Risco=0,381; Intervalo de Confiança 95% de 0,257 a 0,563, p<0,001), uso de succinato de metoprolol ( Razão de Risco=0,382; Intervalo de Confiança 95% de 0,170 a 0,855, p=0,019), uso de Losartan (Razão de Risco=0,611; Intervalo de Confiança 95% de 0,380 a 0,981, p=0,041), e o diâmetro sistólico do ventrículo esquerdo (Razão de Risco=1,042; Intervalo de Confiança 95% de 1,021 a 1,063, p<0,001) as variáveis de predição independentes de mortalidade geral. A probabilidade de sobrevida em 12, 24, 36, 48 e 60 meses foi de 80%, 65%, 56%, 44% e 37%, respectivamente em pacientes sem fibrilação atrial, e 76%, 58%, 48%, 41% e 32% em pacientes com fibrilação atrial, (p=0,393). Conclusão: A fibrilação atrial não tem significado prognóstico em pacientes com insuficiência cardíaca crônica sistólica secundária à cardiomiopatia da Doença de Chagas.

Introdução: O tromboembolismo é uma grave complicação da fibrilação atrial (FA), particularmente em pacientes que vão se submeter à cardioversão, química ou elétrica. Para reduzir esse risco, os pacientes submetem-se à anticoagulação clássica, que vem sendo praticada há várias décadas. Apesar desta abordagem, em pacientes plenamente anticoagulados, não se conhece a prevalência de trombo ou contraste espontâneo no átrio esquerdo (AE). Por essa razão, alguns autores sugerem a realização do ecotransesofágico (ECOTEE) para confirmar o sucesso do tratamento e reduzir o risco de complicações tromboembólicas após a reversão. Os objetivos deste estudo foram: a) avaliar a prevalência de trombos e contraste espontâneo ao ECOTEE em pacientes que vão ser submetidos à cardioversão sob regime de anticoagulação plena; b) avaliar a incidência de tromboembolismo até 30 dias após o procedimento; c) avaliar a influência das variáveis clínicas (doenças associadas) e do ECOTEE (tamanho e volume indexado do AE, fração de ejeção ventricular; velocidade de fluxo no apêndice atrial esquerdo), além do escore CHA2DS2VASc e níveis de pró-BNP plasmático sobre a formação de trombo/contraste espontâneo. Métodos: Foram incluídos 85 pacientes (62 homens; média de idade 61±12 anos) com FA não valvar com indicação para cardioversão. Todos receberam varfarina com controle da taxa de INR. Quando se considerava o paciente plenamente anticoagulado (INR ente 2 e 3 por três semanas consecutivas), era prescrito um fármaco antiarrítmico (propafenona, sotalol ou amiodarona) cuja escolha se baseou em critérios clínicos. Na ausência de normalização do ritmo, eram encaminhados para cardioversão elétrica (CVE). No dia da CVE, os pacientes submetiam-se ao ECOTEE cujo resultado só era conhecido no dia seguinte após a cardioversão. Os pacientes recebiam alta com anticoagulante e retornavam ao ambulatório após 30 dias quando realizavam outro ECOTEE. Resultados: Todos os pacientes foram cardiovertidos com INR na faixa terapêutica (2,9±0,7). A reversão com fármacos ocorreu em 9/85 pacientes (10,6%); 67/76 pacientes submeteram-se à CVE e, destes, 58/67 (86%) reverteram ao ritmo sinusal. O ECOTEE antes da CVE evidenciou trombo no AE em 8/85 pacientes (9,4%) e contraste espontâneo em 36/85 pacientes (42,3%). Nenhuma variável clínica, escore CHA2DS2VASc, níveis plasmáticos de pró-BNP ou variáveis ecocardiográficas identificou pacientes com maior probabilidade de apresentar trombo/contraste espontâneo no AE. Após 30 dias, houve normalização das variáveis do ECOTEE. Em 5/8 (62,5%) pacientes, os trombos desapareceram e surgiu em outros dois pacientes (2,3%). O contraste espontâneo desapareceu em 24/38 (63%) pacientes. Não houve registro de nenhum caso de tromboembolismo sistêmico em 30 dias. A taxa de recorrência de FA foi de 21%. Conclusões: a) trombo atrial/contraste espontâneo foi detectado em 9,4% da população e nenhuma variável clínica ou ecocardiográfica identificou pacientes de risco; b) houve melhora das variáveis do ECOTEE após a reversão ao ritmo sinusal; d) o sucesso global da cardioversão foi de 88% e a taxa de recorrência de FA de 21% em 30 dias; c) não houve registro de tromboembolismo sistêmico em 30 dias, em ritmo sinusal ou em FA. / Introduction: Thromboembolism is a serious complication of atrial fibrillation (AF), particularly in patients who will undergo chemical or electrical cardioversion. To reduce this risk patients receive classic anticoagulant therapy, which has been practiced for several decades. Despite this approach, it is not known the prevalence of thrombus or spontaneous contrast in the left atrium (LA) in patients fully anticoagulated. For this reason, some authors have recommended the transesophageal echocardiogram (TEECHO) to reduce the risk of thromboembolic complications after cardioversion. The objectives of this study were: a) to evaluate the prevalence of thrombus and spontaneous contrast by TEECHO in patients about to undergo cardioversion under full anticoagulation regime; b) evaluate the incidence of thromboembolism within 30 days after the procedure; c) evaluate the influence of clinical variables (associated diseases) and TEECHO parameters (LA size and LA indexed volume, ventricular ejection fraction, flow velocity in the left atrial appendage), CHA2DS2VASc score and plasma pro-BNP levels on thrombus/spontaneous contrast formation. Methods: We included 85 patients (62 men; mean age 61 ± 12 years) with non-valvular AF referred for cardioversion. All received warfarin with INR control. When considering the patient fully anticoagulated (INR in the range of 2 to 3 for three weeks) it was prescribed an anti-arrhythmic drug (propafenone, sotalol or amiodarone) whose choice was based on clinical criteria. In the absence of normal rhythm, patients were referred for electrical cardioversion (ECV). On the day of ECV, all patients were submitted to the ECOTEE whose result was known only the next day after cardioversion. The patients were discharged with anticoagulant and returned to the clinic after 30 days when another ECOTEE was performed. Results: All patients were cardioverted with INR in the therapeutic range (2.9±0.7). Sinus rhythm was restored with drugs in 9/85 patients (10.6%); 67/76 patients underwent ECV and 58/67 (86%) reverted to sinus rhythm. The TEECHO before cardioversion showed a thrombus in LA in 8/85 patients (9.4%) and spontaneous contrast in 36/85 patients (42.3%). No clinical variable, CHA2DS2VASc score, pro-BNP plasma levels or echocardiography variables identified patients with an increased likelihood of thrombus/spontaneous contrast in LA. After 30 days, there was normalization of TEECHO variables. In 5/8 (62.5%) patients thrombi disappeared and appeared in two patients (2.3%). Spontaneous contrast disappeared in 24/38 (63%) patients. There were no reports of any case of systemic thromboembolism in 30 days. The AF recurrence rate was 21%. Conclusions: a) LA thrombus/ spontaneous contrast were detected in 9.4% of the population and no clinical or echocardiography variable identified patients at risk; b) there was an improvement of TEECHO variables after reversion to sinus rhythm; d) the overall success of cardioversion was 88% and the AF recurrence rate was 21% in 30 days; c) there was no systemic thromboembolism in 30 days, in patients in sinus rhythm or AF.

Thesis (Ph. D.)--Ohio State University, 2006. / Available online via OhioLINK's ETD Center; full text release delayed at author's request until 2007 Sep 12

Atrial natriuretic factor (ANF) is a cardiac hormone that helps maintain cardiovascular homeostasis. ANF secretion is linked to the constitutive, regulated and constitutive-like pathways. Presence of a monensin-sensitive pool that may follow constitutive-like secretion has previously been identified in an isolated atrial perfusion study. The intracellular ANF storage pools linked to each secretory pathway have not been identified. In this study, ANF storage and secretion was characterized in HL-1 atrial cardiomyocytes through the use of pharmacological agents, density gradient and RP- HPLC analysis. Treatment of HL-1 cells with monensin followed by cell fractionation was unsuccessful in identifying the monensin-sensitive pool. RP-HPLC analysis identified presence of low molecular weight ANF in low density gradient fractions that were defined by the presence of organelle markers of Golgi, early endosome, clathrin and corin. Since the monensin-sensitive pool was thought to be of a constitutive-like nature, targeting this pathway with pharmacological inhibitors of clathrin coat vesicle (CCV) formation and endosomal trafficking failed to prevent stimuli-independent secretion. Based on an inability to prevent ANF secretion by targeting the constitutive-like pathway and the presence of low molecular weight ANF in low density gradient fractions, stimuli- independent ANF secretion seems to be through a constitutive pathway.

Atrial natriuretic factor (ANF) is a cardiac hormone that helps maintain cardiovascular homeostasis. ANF secretion is linked to the constitutive, regulated and constitutive-like pathways. Presence of a monensin-sensitive pool that may follow constitutive-like secretion has previously been identified in an isolated atrial perfusion study. The intracellular ANF storage pools linked to each secretory pathway have not been identified. In this study, ANF storage and secretion was characterized in HL-1 atrial cardiomyocytes through the use of pharmacological agents, density gradient and RP- HPLC analysis. Treatment of HL-1 cells with monensin followed by cell fractionation was unsuccessful in identifying the monensin-sensitive pool. RP-HPLC analysis identified presence of low molecular weight ANF in low density gradient fractions that were defined by the presence of organelle markers of Golgi, early endosome, clathrin and corin. Since the monensin-sensitive pool was thought to be of a constitutive-like nature, targeting this pathway with pharmacological inhibitors of clathrin coat vesicle (CCV) formation and endosomal trafficking failed to prevent stimuli-independent secretion. Based on an inability to prevent ANF secretion by targeting the constitutive-like pathway and the presence of low molecular weight ANF in low density gradient fractions, stimuli- independent ANF secretion seems to be through a constitutive pathway.

Atrial natriuretic factor (ANF) is a cardiac hormone that helps maintain cardiovascular homeostasis. ANF secretion is linked to the constitutive, regulated and constitutive-like pathways. Presence of a monensin-sensitive pool that may follow constitutive-like secretion has previously been identified in an isolated atrial perfusion study. The intracellular ANF storage pools linked to each secretory pathway have not been identified. In this study, ANF storage and secretion was characterized in HL-1 atrial cardiomyocytes through the use of pharmacological agents, density gradient and RP- HPLC analysis. Treatment of HL-1 cells with monensin followed by cell fractionation was unsuccessful in identifying the monensin-sensitive pool. RP-HPLC analysis identified presence of low molecular weight ANF in low density gradient fractions that were defined by the presence of organelle markers of Golgi, early endosome, clathrin and corin. Since the monensin-sensitive pool was thought to be of a constitutive-like nature, targeting this pathway with pharmacological inhibitors of clathrin coat vesicle (CCV) formation and endosomal trafficking failed to prevent stimuli-independent secretion. Based on an inability to prevent ANF secretion by targeting the constitutive-like pathway and the presence of low molecular weight ANF in low density gradient fractions, stimuli- independent ANF secretion seems to be through a constitutive pathway.

Atrial fibrillation and atrial flutter are the most common sustained arrhythmias, however their underlying mechanisms are yet to be fully characterised. This thesis evaluates the electrophysiological and electroanatomical substrate of the atria in patients with these arrhythmias. Experimental studies of atrial fibrillation have demonstrated effective refractory period shortening and conduction slowing as a result of atrial fibrillation giving rise to the concept that "atrial fibrillation begets atrial fibrillation". However, cardioversion to prevent electrical remodelling does not prevent progression of disease, suggesting a "second factor" drives this process. Chapters 2 and 3 evaluate the atrial substrate in patients with "lone" atrial fibrillation. These studies demonstrate such patients, remote from an arrhythmic event, have prolongation of atrial refractoriness, conduction slowing, impairment of sinus node function, site-specific conduction delay, lower voltage and a greater proportion of complex electrograms compared to reference patients. These abnormalities constitute the "second factor" critical to the development and progression of atrial fibrillation. Atrial flutter has a close inter-relationship with atrial fibrillation and these rhythms frequently co-exist. Atrial fibrillation often occurs in patients with heart disease known to demonstrate abnormal atrial substrate; whether similar substrate exists in patients with atrial flutter to account for the co-existence of both arrhythmias is unknown. Chapters 4 and 5 evaluate the atrial substrate in patients with atrial flutter, remote from arrhythmia, demonstrating structural abnormalities characterised by loss of myocardial voltage, conduction slowing and impaired sinus node function, without reduction in atrial refractoriness. These findings implicate a common substrate as the cause of the close inter-relationship between these arrhythmias. There is a frequent association between atrial arrhythmia and sinus node disease for which several mechanisms have been postulated. In addition, there is a size discrepancy between the anatomical sinus node and the much larger functional sinus node complex. little is known about normal sinus node function or the effects of remodelling due to arrhythmia. Chapter 6 characterises sinus node activation to determine the nature and extent of the functional sinus node complex in patients with and without chronic atrial flutter. The functional sinus node complex demonstrates dynamic shifts in activation with preferential pathways of conduction to atrial myocardium. Patients with atrial flutter demonstrate lesser voltage, longer conduction times along preferential pathways and a smaller functional sinus node complex. These findings provide insights into the function of the human sinus node in health and disease. Sites of complex fractionated atrial electrograms and highest dominant frequency are implicated in maintaining atrial fibrillation. Chapter 7 determines the minimum recording duration that accurately characterises electrogram complexity and activation frequency. An electrogram duration of 5 seconds is required to accurately identify these sites. Chapter 8 evaluates the relationship between sites of fractionation and high frequency activation during atrial fibrillation. Greater fractionation and higher dominant frequency are seen in persistent atrial fibrillation and left atria. Preferential areas of high dominant frequency are observed in paroxysmal but not persistent atrial fibrillation. Areas of complex fractionated atrial electrograms are found adjacent to sites of high dominant frequency. / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2009