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

Atrial fibrillation (AF) is a troublesome disease often overlooked by more serious myocardial infarctions. Up until now, there has been very little or no use of high order spectral techniques in order to evaluate the organization of the atrium during AF. Cross-bicoherence algorithm can be used alongside a surrogate data threshold in order to determine significant phase coupling interactions, giving rise to an organizational metric. This proposed algorithm is used to show rotigaptide, a gap junction coupling drug, significantly increases the organization of the atria during episodes of AF due to improvement of cell-to-cell coupling.

Cardiac disease is the most common cause of death among the adult population worldwide and atrial fibrillation (AF) is the most common cardiac arrhythmia. The state of the art in AF treatment involves creating lesions of heart tissue through radiofrequency ablation. In this thesis, mathematical modelling techniques are developed to design decision support tools that could help a cardiologist determine the best location to ablate in clinic. Firstly, parameter optimisation methods are explored to adapt a model designed for the ventricles to the atria, and a novel technique is introduced to characterise pathways through parameter space from a healthy state to a diseased state using a multi-objective genetic algorithm. Next, I reproduce clinical signals recorded during AF ablation through the use of a phenomenological model of the cardiac action potential on a cylinder and show how this model can enable us to recover information lost in clinic to improve clinical decision. This is followed by introducing a more simplistic approach to the same problem, by characterising the electrical activity on the recording by a sine wave. Finally, the effectiveness of these two approaches is compared in the clinical setting by testing both as decision support tools. The emphasis of the approaches throughout the thesis is on developing techniques with clinical applicability. We demonstrate that lost information in clinic can affect the decision made by an experienced clinician, and that the mathematical modelling approaches developed in the thesis can significantly reduce the impact that this information loss can have on clinical decision making.

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.

Ion channels are membrane proteins that facilitate electrical signaling in important physiological processes, such as the rhythmic contraction of the heart. KCNQ1 is the pore-forming subunit of a voltage-gated potassium channel that assembles with the β-subunit KCNE1 in the heart to generate the IKs current, which is critical to cardiac action potential repolarization and electrical conduction in the heart. Mutations in IKs subunits can cause potentially lethal arrhythmia, including long QT syndrome, short QT syndrome, and atrial fibrillation. Each channel consists of four voltage-sensing domains and a central pore through which ions permeate. Voltage-dependent gating occurs when movement of voltage sensors cause pore opening/closing through coupling mechanisms. Although KCNQ1 by itself is able to form a voltage-dependent potassium channel, its assembly with KCNE1 is essential to generating the physiologically critical cardiac IKs current, characterized by a delay in the onset of activation, an increase in current amplitude, and a depolarizing shift in the current-voltage relationship. KCNE1 is thought to have multiple points of contact with KCNQ1 that reside within both the voltage-sensing domain and the pore domain, allowing for extensive modulation of channel function. Atrial fibrillation is the most common cardiac arrhythmia and affects more than 3 million adults in the United States. Much rarer, genetic forms of atrial fibrillation have been associated with gain-of-function mutations in KCNQ1, such as two adjacent mutations, S140G and V141M. Both mutations drastically slow channel deactivation, which underlies their pathophysiology. Deactivation slowing causes accumulation of open channels in the context of repeated stimulation, which abnormally increases the repolarizing K+ current, excessively shortens the action potential duration, and predisposes to re-entry arrhythmia such as atrial fibrillation. Although both mutations are located in the voltage-sensing domain, their mechanisms of action remain unknown. Understanding the gating mechanisms underlying deactivation slowing may provide key insights for the development of mechanism-based pharmacologic therapies for arrhythmias associated with KCNQ1 mutations. In addition to gain-of-function mutations, molecular activators of KCNQ1 can slow deactivation and increase channel activity. An existing problem in the pharmacologic treatment of arrhythmia is that many antiarrhythmic drugs do not have specific targets and cause undesired side effects such as additional arrhythmia. Thus, developing mechanism-based therapies may optimize clinical treatment for patients with specific forms of channel dysfunction. Two KCNQ1 activators, ML277 and R-L3, have been previously shown to slow current deactivation, but the underlying gating mechanisms remain known. Although these modulators are unlikely to serve directly as antiarrhythmic therapy, investigating their mechanisms will likely provide fundamental insights on channel modulation and guide future efforts to develop personalized therapies for arrhythmia, such as congenital long QT syndrome. Given the central importance of deactivation slowing in both pathophysiology and pharmacology, we focused on investigating gating mechanisms that underlie deactivation slowing. To this end, we utilized voltage clamp fluorometry, a technique that simultaneously assays for voltage sensor movement and ionic current through the channel pore. In Chapter 1, we begin our study by examining the gating mechanisms of KCNQ1 atrial fibrillation mutations in the absence of KCNE1. We show that S140G slows voltage sensor deactivation, which indirectly slows current deactivation. On the other hand, V141M neither slows voltage sensor nor current deactivation. This is followed by Chapter 2, where we examine the gating mechanisms underlying deactivation slowing by atrial fibrillation mutations in the presence of KCNE1. We show that both S140G and V141M slow IKs deactivation by slowing pore closing and altering voltage sensor-pore coupling. Based on these findings, we proposed a molecular mechanism in which both mutations disrupt the orientation of KCNE1 relative to KCNQ1 and thus impede pore closing, implying that future efforts to modulate KCNQ1 function can benefit from targeting the β-subunit. Finally, in Chapter 3, we explore the gating mechanisms underlying deactivation slowing for two small-molecule activators of KCNQ1. We show that ML277 predominantly slows pore transitions, whereas R-L3 slows voltage sensor deactivation, which indirectly slows current deactivation. Taken together, these studies guide future efforts to develop mechanism-based therapies for arrhythmia.

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.

acase@tulane.edu

Atrial fibrillation (AF) is a common cardiac arrhythmia that requires extensive medical and pharmaceutical management. The coagulation antagonist warfarin is commonly prescribed to reduce AF-associated stroke. Although warfarin effectively mediates thromboembolitic risk, its management is complex as many factors influence its therapeutic range including: genetics, diet, medication, and herbal and dietary supplement (HDS) interactions. Lack of patient knowledge regarding these factors contributes to poor patient outcomes. With the emerging epidemic of AF, readily available educational tools are necessary to improve patient outcomes while reducing clinician burden. The purpose of this study was to develop both a self-learning, DVD-based and one-on-one education program to educate patients with atrial fibrillation about the risks of HDS-warfarin interactions and to compare education method efficacy in AF disease management. This study found patients lack knowledge regarding HDS-warfarin management, and both DVD-based and one-on-one education models could increase patient knowledge regarding HDS-warfarin factors. It is hypothesized this education method may be employed to further educate chronic disease populations about essential disease-associated factors to improve outcomes while reducing clinical burdens.

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

The aim of this thesis was to explore variations in stroke prevention and the effect of prevention on outcome. The studies were based on patients registered in the Swedish Stroke Register between 2001 and 2009 and although used to different extents in each paper, additional information was retrieved through linkage to The National Patient Register, the Cause of Death Register, the Prescribed Drug Register and the Total Population Register. Cardiovascular risk factors were prevalent among ischemic stroke (IS) patients; however, they were not always prescribed the drugs recommended, and increasing age was an important negative predictor (Paper I). After IS, the rate of hemorrhage in patients prescribed antiplatelet agents (2.4 per 100 person-years) was double to results from randomized controlled trails, but was similar for patients prescribed warfarin (2.5 per 100 person-years).  Age ≥75 years and previous hemorrhage were associated with a moderately increased risk of future hemorrhage (Paper II). Among IS patients with atrial fibrillation, one-third was prescribed warfarin and two-thirds were prescribed antiplatelets. After adjustment for a propensity score (used to adjust for the non-randomized design), warfarin was associated with a reduced risk of death (0.67; 95% CI, 0.63-0.71) (Paper III). The rate of subsequent hemorrhagic stroke was 0.4 per 100 person-years and the risk did not change (HR 1.04; 95% CI, 0.73-1.48) when later years of the 2000s (inclusion period 2005-8: follow-up until 2009) was compared with earlier years (inclusion period 2001-4: follow-up until 2005) (Paper IV, cohort). Although the risk of first-ever hemorrhagic stroke more than doubled with warfarin than without, the risk did not change between 2006 and 2009 (Paper IV, case-control). In summary, the prescription of secondary preventive drugs varies with age, even though cardiovascular risk factors are prevalent in all ages. The risk of death and hemorrhage are affected by the type of antithrombotic prescribed. Therefore, it is important individual’s stroke and bleeding risks in stroke prevention are assessed.