Die vorliegende Dissertation befasst sich mit Entstehungsmechanismen kardialer Arrhythmien auf der Grundlage pathologisch veränderten Myokards. Es wurde eine systematische Analyse der elektrophysiologischen Veränderungen, die als Folge von Gap-Junction- Lateralisierung und zellulärer Hypertrophie auftreten, durchgeführt. Die Analyse beruht auf einem mathematischen Computermodell, das zur Simulation der Aktionspotentialausbreitung innerhalb einer Einzelzellschicht humaner ventrikulärer Kardiomyozyten entwickelt wurde. Ausgehend von bestehenden Einzelzellmodellen wurde ein räumlich und zeitlich hoch aufgelöstes Multizellmodell generiert und in der Programmiersprache Object Pascal implementiert. Nach Validierung des Modells wurde es zur gezielten, an experimentellen Daten orientierten Manipulation geometrischer Eigenschaften der Zellen (Länge, Durchmesser) und des Zellverbandes (Anordnung der Zellen untereinander) sowie der Gap-Junction-Verteilung genutzt. Die Analyse der elektrophysiologischen Effekte im Vergleich zur Kontrolle fand sowohl unter Normalbedingungen als auch unter Bedingungen, die pathologischen Veränderungen entsprechen (Entkopplung der Gap-Junctions, verringerte Aktivität des schnellen Natriumkanals, erhöhte Inhomogenität), statt. Es zeigte sich, dass ein größerer Zelldurchmesser bzw. erhöhte laterale Gap-Junction-Leitfähigkeit (Simulation von kardialer Hypertrophie bzw. Connexin- Lateralisierung) die Entstehungswahrscheinlichkeit eines unidirektionalen Leitungsblocks erhöhte. Die Erregungsausbreitungsgeschwindigkeit in hypertrophierten Zellen war zudem weniger stabil als in normalen Zellen. Beide Effekte gehören zu den Hauptursachen der Entstehung und Aufrechterhaltung ventrikulärer Arrhythmien. Die Ergebnisse der Arbeit erklären somit Ursachen des erhöhten Arrhythmierisikos in pathologisch veränderten und hypertrophierten Herzen und liefern eine theoretische Grundlage für zukünftige Studien.

Roughly thirty percent of coronary artery bypass graft (CABG) patients develop atrial fibrillation (AF) in the five days following surgery, increasing the risk of stroke, prolonging hospital stay three to four days, and increasing the overall cost of the procedure. Current pharmacologic and nonpharmacologic means of AF prevention are suboptimal, and their side effects, expense, and inconvenience limit their widespread application. An accurate method for identifying patients at high risk for postoperative AF would allow these methods to be focused on the patients on which its utility would be highest. The main objective of this research was to develop a Bayesian network (BN) which could model/predict/assign risk of the occurrence of atrial fibrillation in CABG patients using retrospective data. A secondary objective was to develop an integrated framework for more advanced methods of feature selection and fusion for medical classification/prediction. We determined that the naïve Bayesian network classifier used with features selected by a genetic algorithm is a better classifier to use, given our cohort. The naïve BN allows for reasonable prediction despite being presented with patients with missing data points as might occur in the hospital. This classifier achieves a sensitivity of 0.63 and a specificity of 0.73 with an AUC of 0.74. Furthermore, this system is based on probabilities that are well understood and easily incorporated into a clinical environment. These probabilities can be altered based on the cardiologists prior knowledge through Bayesian statistics, allowing for online sensitivity analysis by doctors, to perceive the best treatment options. Contributions of this research include: - An accurate, physician-friendly, postoperative AF risk stratification system that performs even under missing data conditions, while outperforming the state of the art system, - A thorough analysis of previously examined and novel pre- and postoperative clinical and ECG features for postoperative AF risk stratification, - A new methodology for genetic algorithm-built traditional Bayesian network classifiers allowing dynamic structure through novel chromosome, operator, and fitness definitions, and - An integrated methodology for inclusion of doctor s expert knowledge into a probabilistic diagnosis support system.

pós-infarto agudo do miocárdio (IAM) têm mostrado baixo valor preditivo positivo quando estudados isoladamente. A possibilidade da Eletrocardiografia Dinâmica de 24 horas (ECGD) fornecer dados referentes a isquemia silenciosa (IS), arritmias ventriculares e modulação autonômica do coração pelo estudo da variabilidade da freqüência cardíaca (VFC), levou o autor a empregar este método em pacientes acometidos de IAM com o objetivo de avaliar se estas três variáveis estariam relacionadas a presença de eventos desfavoráveis em evolução a médio prazo. Material e Métodos – Foram selecionados 91 pacientes acometidos de um primeiro IAM não-complicado e realizados exames de ECGD de 24 h por dois dias consecutivos, antes da alta hospitalar. Os parâmetros pesquisados nos exames foram: isquemia silenciosa, identificação e quantificação de arritmias ventriculares e determinação dos índices de VFC pelos métodos do domínio do tempo e do mapa de retorno tridimensional. Foram considerados como desfechos: re-infarto, angina instável, taquicardia ventricular sustentada e morte. Resultados – No seguimento médio de 27,7 meses (DP=15,45), 23 (25%) dos pacientes apresentaram eventos, sendo nove fatais. Os eventos foram mais freqüentes entre os pacientes que apresentaram extra-sístoles ventriculares ≥10/hora (p=0,01) e também naqueles com IS (p=0,02). Em modelo de análise multifatorial, a presença de dislipidemia elevou o valor preditivo positivo dessas variáveis. Nenhum dos índices de VFC esteve significativamente relacionado ao surgimento de eventos. Conclusões – Em pacientes pós-IAM de baixo risco, a presença de arritmias ventriculares freqüentes ou de isquemia silenciosa está relacionada a um prognóstico desfavorável. O estudo da VFC não mostrou utilidade na estratificação de risco destes pacientes. / Introduction and objective – The noninvasive methods used in post-acute myocardial infarction (AMI) risk stratification have been shown to have a low predictive value when studied in isolation. The possibility that ambulatory electrocardiographic monitoring (AEM) may provide data on silent ischemia (SI), ventricular arrhythmias (VA) and autonomic modulation of the heart through the study of heart rate variability (HRV) led the present author to use this method in AMI patients with the aim of assessing whether these three variables could be related to the presence of unfavorable events in the medium term follow-up. Methods – Ninety-one patients with a first, uncomplicated AMI were selected and submitted to AEM for two consecutive days prior to discharge from the hospital. The parameters studied in the examination were as follows: presence of SI, identification and quantification of VA and determination of the HRV indices by the time domain and three-dimensional return map methods. The following were regarded as outcomes: new AMI, unstable angina, sustained ventricular tachycardia and death. Results – In the mean follow-up of 27.7 months (SD=15.45), 23 (25%) of the patients presented events, nine of which were fatal. Events occurred most frequently in the patients who presented ventricular premature contractions >= (p=0.01) and also in those with SI (p=0.04). In the multifactorial analysis the presence of dislipidemia raised the positive predictive value of these variables. None of the HRV indices was significantly correlated with the occurrence of events. Conclusions – In low-risk post-AMI patients the presence of frequent ventricular arrhythmias or silent ischemia is associated with an unfavorable prognosis. The study of HRV was not shown to be useful in the risk stratification of these patients.

pós-infarto agudo do miocárdio (IAM) têm mostrado baixo valor preditivo positivo quando estudados isoladamente. A possibilidade da Eletrocardiografia Dinâmica de 24 horas (ECGD) fornecer dados referentes a isquemia silenciosa (IS), arritmias ventriculares e modulação autonômica do coração pelo estudo da variabilidade da freqüência cardíaca (VFC), levou o autor a empregar este método em pacientes acometidos de IAM com o objetivo de avaliar se estas três variáveis estariam relacionadas a presença de eventos desfavoráveis em evolução a médio prazo. Material e Métodos – Foram selecionados 91 pacientes acometidos de um primeiro IAM não-complicado e realizados exames de ECGD de 24 h por dois dias consecutivos, antes da alta hospitalar. Os parâmetros pesquisados nos exames foram: isquemia silenciosa, identificação e quantificação de arritmias ventriculares e determinação dos índices de VFC pelos métodos do domínio do tempo e do mapa de retorno tridimensional. Foram considerados como desfechos: re-infarto, angina instável, taquicardia ventricular sustentada e morte. Resultados – No seguimento médio de 27,7 meses (DP=15,45), 23 (25%) dos pacientes apresentaram eventos, sendo nove fatais. Os eventos foram mais freqüentes entre os pacientes que apresentaram extra-sístoles ventriculares ≥10/hora (p=0,01) e também naqueles com IS (p=0,02). Em modelo de análise multifatorial, a presença de dislipidemia elevou o valor preditivo positivo dessas variáveis. Nenhum dos índices de VFC esteve significativamente relacionado ao surgimento de eventos. Conclusões – Em pacientes pós-IAM de baixo risco, a presença de arritmias ventriculares freqüentes ou de isquemia silenciosa está relacionada a um prognóstico desfavorável. O estudo da VFC não mostrou utilidade na estratificação de risco destes pacientes. / Introduction and objective – The noninvasive methods used in post-acute myocardial infarction (AMI) risk stratification have been shown to have a low predictive value when studied in isolation. The possibility that ambulatory electrocardiographic monitoring (AEM) may provide data on silent ischemia (SI), ventricular arrhythmias (VA) and autonomic modulation of the heart through the study of heart rate variability (HRV) led the present author to use this method in AMI patients with the aim of assessing whether these three variables could be related to the presence of unfavorable events in the medium term follow-up. Methods – Ninety-one patients with a first, uncomplicated AMI were selected and submitted to AEM for two consecutive days prior to discharge from the hospital. The parameters studied in the examination were as follows: presence of SI, identification and quantification of VA and determination of the HRV indices by the time domain and three-dimensional return map methods. The following were regarded as outcomes: new AMI, unstable angina, sustained ventricular tachycardia and death. Results – In the mean follow-up of 27.7 months (SD=15.45), 23 (25%) of the patients presented events, nine of which were fatal. Events occurred most frequently in the patients who presented ventricular premature contractions >= (p=0.01) and also in those with SI (p=0.04). In the multifactorial analysis the presence of dislipidemia raised the positive predictive value of these variables. None of the HRV indices was significantly correlated with the occurrence of events. Conclusions – In low-risk post-AMI patients the presence of frequent ventricular arrhythmias or silent ischemia is associated with an unfavorable prognosis. The study of HRV was not shown to be useful in the risk stratification of these patients.

pós-infarto agudo do miocárdio (IAM) têm mostrado baixo valor preditivo positivo quando estudados isoladamente. A possibilidade da Eletrocardiografia Dinâmica de 24 horas (ECGD) fornecer dados referentes a isquemia silenciosa (IS), arritmias ventriculares e modulação autonômica do coração pelo estudo da variabilidade da freqüência cardíaca (VFC), levou o autor a empregar este método em pacientes acometidos de IAM com o objetivo de avaliar se estas três variáveis estariam relacionadas a presença de eventos desfavoráveis em evolução a médio prazo. Material e Métodos – Foram selecionados 91 pacientes acometidos de um primeiro IAM não-complicado e realizados exames de ECGD de 24 h por dois dias consecutivos, antes da alta hospitalar. Os parâmetros pesquisados nos exames foram: isquemia silenciosa, identificação e quantificação de arritmias ventriculares e determinação dos índices de VFC pelos métodos do domínio do tempo e do mapa de retorno tridimensional. Foram considerados como desfechos: re-infarto, angina instável, taquicardia ventricular sustentada e morte. Resultados – No seguimento médio de 27,7 meses (DP=15,45), 23 (25%) dos pacientes apresentaram eventos, sendo nove fatais. Os eventos foram mais freqüentes entre os pacientes que apresentaram extra-sístoles ventriculares ≥10/hora (p=0,01) e também naqueles com IS (p=0,02). Em modelo de análise multifatorial, a presença de dislipidemia elevou o valor preditivo positivo dessas variáveis. Nenhum dos índices de VFC esteve significativamente relacionado ao surgimento de eventos. Conclusões – Em pacientes pós-IAM de baixo risco, a presença de arritmias ventriculares freqüentes ou de isquemia silenciosa está relacionada a um prognóstico desfavorável. O estudo da VFC não mostrou utilidade na estratificação de risco destes pacientes. / Introduction and objective – The noninvasive methods used in post-acute myocardial infarction (AMI) risk stratification have been shown to have a low predictive value when studied in isolation. The possibility that ambulatory electrocardiographic monitoring (AEM) may provide data on silent ischemia (SI), ventricular arrhythmias (VA) and autonomic modulation of the heart through the study of heart rate variability (HRV) led the present author to use this method in AMI patients with the aim of assessing whether these three variables could be related to the presence of unfavorable events in the medium term follow-up. Methods – Ninety-one patients with a first, uncomplicated AMI were selected and submitted to AEM for two consecutive days prior to discharge from the hospital. The parameters studied in the examination were as follows: presence of SI, identification and quantification of VA and determination of the HRV indices by the time domain and three-dimensional return map methods. The following were regarded as outcomes: new AMI, unstable angina, sustained ventricular tachycardia and death. Results – In the mean follow-up of 27.7 months (SD=15.45), 23 (25%) of the patients presented events, nine of which were fatal. Events occurred most frequently in the patients who presented ventricular premature contractions >= (p=0.01) and also in those with SI (p=0.04). In the multifactorial analysis the presence of dislipidemia raised the positive predictive value of these variables. None of the HRV indices was significantly correlated with the occurrence of events. Conclusions – In low-risk post-AMI patients the presence of frequent ventricular arrhythmias or silent ischemia is associated with an unfavorable prognosis. The study of HRV was not shown to be useful in the risk stratification of these patients.

Nursing care continuing the treatment of cardiac arrhythmias is an inseparable part of the patient?s care. As there are various types of arrhythmias and different types of treatment, similarly, the subsequent nursing care has its specifics as well. It relates not only to the post-treatment care but also to pre-surgery preparation and subsequent education. The theoretical part of the thesis contains the information on arrhythmias, their development and treatment. Organizations associating nurses working in arrhythmologic centres are mentioned as well. The practical part consists of the survey research. The quantitative enquiry is conducted in arrhythmologic centres by means of questionnaires addressing the nurses. The qualitative part contains interviews with patients who underwent some of the types of cardiac arrhythmia treatment. The objective of the thesis was to find out whether the nurses are aware of the specifics of the nursing care that follows the treatment of cardiac arrhythmia, in which stage the treatment is the most demanding for nurses and whether they can apply standardized nursing procedures in their work. Another objective is focused on mapping of the educative activity within the nursing care. Interviews with the patients are aimed at the areas of admission, prior to surgery, after surgery and during education. They should outline the view from ?the other side?. All the defined hypotheses were confirmed. The cardinal hypothesis of the thesis was the assumption that nurses, when providing nursing care to patients undergoing treatment of cardiac arrhythmias, do not work according to standardized nursing procedures. Subsequently, a draft of standardized nursing procedure focused on nursing care of patients undergoing implantation of a permanent cardiostimulator was prepared ? it could be applied in the University Hospital in Plzeň where most of the enquiry was conducted.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-03-07T12:02:26Z No. of bitstreams: 1 danielepiresmagalhaesespiritosanto.pdf: 19885258 bytes, checksum: cc404305a80b23fea7d1a26415bf75bf (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-03-07T15:03:55Z (GMT) No. of bitstreams: 1 danielepiresmagalhaesespiritosanto.pdf: 19885258 bytes, checksum: cc404305a80b23fea7d1a26415bf75bf (MD5) / Made available in DSpace on 2017-03-07T15:03:55Z (GMT). No. of bitstreams: 1 danielepiresmagalhaesespiritosanto.pdf: 19885258 bytes, checksum: cc404305a80b23fea7d1a26415bf75bf (MD5) Previous issue date: 2014-08-29 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A arritmia ventricular maligna é uma das principais causas de morte no mundo. Muitas vezes o início de um episódio de arritmia está associado a uma excitação inoportuna no coração, também denominada extra-sístole, ou Potencial de Ação Espontâneo (PAE). O surgimento de PAEs pode estar relacionado a mudanças estruturais ou moleculares nos canais iônicos e a alterações no ciclo de cálcio intracelular. Anormalidades no ciclo de cálcio podem gerar transientes de cálcio espontâneos (TCEs) e estes podem desencadear Potenciais de Ação Espontâneos (PAEs). Estudos experimentais mostram que o surgimento de TCEs é mais frequente sob a estimulação β-Adrenérgica. Em experimentos recentes, notou-se que a presença de episódios de TCEs em cardiomiócitos saudáveis não desencadeia a geração de PAEs. Em contrapartida, em camundongos com a mutação de super expressão da bomba NCX (NaCa), PAEs foram observados em miócitos isolados e foram relacionados a episódios de TCEs. O principal objetivo deste trabalho foi a simulação da formação de PAEs utilizando modelos computacionais desenvolvidos para cardiomiócitos do ventrículo esquerdo de camundongos. Em particular os modelos computacionais foram capazes de reproduzir os cenários experimentais descritos acima, relacionando a geração de PAEs com a estimulação β-Adrenérgica e alterações de canais iônicos como a mutação NCX. Dessa forma, as simulações computacionais apresentadas neste trabalho permitem uma melhor compreensão dos complexos fenômenos associados a arritmias cardíacas. / Malignant ventricular arrhythmias are the major cause of death around the world. The beginning of an episode of arrhythmia is often associated with ectopic beats in the heart, also called extrasystole, or Spontaneous Action Potential (SAP). The development of SAP may be related to structural or molecular changes in ion channels and changes in intracellular calcium cycle. Abnormalities in calcium cycle can result in Spontaneous Calcium Transientes (SCT) and these can trigger SAP. Experimental studies show that the development of SCT is more common under β1-adrenergic stimulation. However, we found, in recent experiments, that the presence of episodes of SCT in healthy cardiomyocytes does not trigger the development of SAP. On the other hand, on mice presenting mutation of overexpression of NCX (NaCa) pump, SAP were observed in isolated cardiomyocytes and were related to episodes of SCT. Thus, we aimed, in this study, to simulate development of SAP using computational models developed for cardiomyocytes of left ventricle of mice. The computational models were able to reproduce the experimental scenarios described above, relating the development of SAP to the β-adrenergic stimulation and to the changes of ion channels as the NCX mutation. Therefore, the computational simulations showed in this work allow the best comprehension of the complex phenomena associated with cardiac arrhythmia.

Orientadores: Eduardo Tavares Costa, Rosana Almada Bassani / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Engenharia Elétrica e de Computação / Made available in DSpace on 2018-08-19T01:08:15Z (GMT). No. of bitstreams: 1 Buiochi_ElaineBelassiano_D.pdf: 9610613 bytes, checksum: 5fefa9e6cf5eaf8478c002d7ab57dc23 (MD5) Previous issue date: 2011 / Resumo: No ultrassom diagnóstico faz-se uso de ondas acústicas de baixa intensidade para investigar os tecidos biológicos, sendo uma técnica não invasiva. Ondas ultrassônicas de maior intensidade podem alterar as características do tecido, e isto é de interesse para aplicações terapêuticas, nas quais a ocorrência de efeitos biológicos é, até certo ponto, desejável. Com relação à cardiologia, o uso do ultrassom diagnóstico é bem estabelecido, enquanto há um potencial inexplorado para aplicações terapêuticas. Soma-se a isso o fato de que os tratamentos disponíveis para as arritmias com estimulação elétrica são limitados por sérias complicações, incluindo infecção sistêmica, choques desnecessários, potencial para pró-arritmia, falha em estimular e, até mesmo, morte. O ultrassom pode se mostrar uma alternativa atraente à estimulação elétrica, porém há poucos estudos sobre a possibilidade de aplicação do ultrassom para o tratamento de arritmias. O objetivo deste estudo foi desenvolver transdutores ultrassônicos de potência e usá-los para investigar conjuntos de parâmetros acústicos capazes de interferir na atividade cardíaca, sem provocar danos teciduais, buscando possíveis aplicações terapêuticas do ultrassom em cardiologia. Os parâmetros acústicos variados foram frequência de ressonância, modo de operação, frequência de repetição de pulso, e pressão de saída. Dois dos sete transdutores construídos se mostraram mais eficientes e, portanto, foram calibrados e usados nos experimentos biológicos. Em experimentos preliminares realizados em corações isolados de ratos Wistar, foi observada geração esporádica de arritmia usando-se o transdutor de 65 kHz, e aumento da frequência espontânea, acompanhada por redução da força de contração do miocárdio, usando-se o transdutor de 1MHz em exposição contínua prolongada. Em estudos in vivo, dez ratos Sprague-Dawley foram anestesiados com isoflurano e expostos a uma seqüência terapêutica de ultrassom, e outros cinco ratos foram usados como grupo controle. A estimulação ultrassônica consistiu de bursts de 1MHz, ciclo de trabalho de 1%, pico de pressão negativa de 3MPa (ISPTA=3W/cm2), e freqüência de repetição de pulso variável e decrescente. O ultrassom transtorácico exerceu efeito cronotrópico negativo, uma vez que foi capaz de reduzir a freqüência cardíaca em 19% logo ao final do período de estimulação. Os efeitos duraram, no mínimo, 15 minutos, sem aparente prejuízo hemodinâmico, que foi monitorado principalmente por meio da medição da fração de ejeção. Trata-se de um fenômeno promissor para o tratamento de taquiarritmias. O regime de exposição utilizado excluiu efeitos térmicos, de forma que o efeito observado foi provavelmente resultante de mecanismos não-térmicos, possivelmente da força da radiação. A variação na frequência de repetição de pulso parece ter sido a chave para a indução do efeito em questão, uma vez que experimentos realizados com frequências de repetição constantes não resultaram em tal efeito / Abstract: Diagnostic ultrasound consists of application of low intensity acoustic waves to noninvasively investigate biological tissues. Higher ultrasound intensities may alter tissue characteristics, and this is of interest for therapeutic applications, when the occurrence of bioeffects is - to a certain extent - desirable. The use of diagnostic ultrasound in Cardiology is well established, although there is an unexplored potential for therapeutic applications. The currently available treatments of arrhythmias by electrical stimulation are limited by serious complications, including systemic infection, inappropriate shock delivery, proarrhythmia, failure to pace and to defibrillate, and even death. Ultrasound can be an interesting alternative for electrical stimulation, but there are only a few studies that investigate the possibility of applying ultrasound for treating arrhythmias. The objective of this study was to develop power ultrasonic transducers to be applied to the investigation of sets of acoustical parameters able to interfere with the cardiac activity without causing tissue damage, thus aiming at potential therapeutic applications of ultrasound in cardiology. The acoustical parameters investigated were resonance frequency, operation mode, pulse repetition frequency, and output pressure. The two most efficient out of the seven transducers built were calibrated and used in biological experiments. In preliminary experiments conducted on isolated hearts from Wistar rats, arrhythmia was esporadically observed at the onset of ultrasound application using the 65kHz transducer, whereas an increase in spontanous beating rate accompanied by a reduction in the force developed by the myocardium occurred during continuous, prolonged exposure using the 1MHz transducer. In in vivo studies, ten Sprague-Dawley rats were anesthetized with isoflurane and exposed to a sequence of therapeutic ultrasound, and other five rats were used as a control group. The ultrasonic stimulation consisted of 1-MHz bursts of 1% duty cycle, 3 MPa peak negative pressure (ISPTA=3W/cm2), and decreasingly variable pulse repetition frequencies. Transthoracic ultrasound application was able to promote a negative chronotropic effect, decreasing the heart rate by 19% just after stimulation ceased. The effect lasted at least 15 minutes, without apparent alteration of pumping function, which was monitored mainly by evaluation of the ejection fraction. This phenomenon is promising for treating tachyarrhythmias. The insonification scheme used in this study excluded thermal effects, so the observed effect seems to have resulted from nonthermal mechanisms, possibly from radiation force. The variation in the pulse repetition frequency seems to be the key element for induction of the described effect, because the latter was not observed for constant repetition rates / Doutorado / Engenharia Biomedica / Doutor em Engenharia Elétrica

INTRODUÇÃO: O Lúpus Eritematoso Sistêmico (LES) é uma doença inflamatória crônica que pode acometer qualquer órgão ou sistema. O acometimento do coração pode ocorrer em até 50% dos casos e não existem estudos de prevalência de eventos arrítmicos (EA) em pacientes com LES, nem de correlações laboratoriais preditoras de sua ocorrência. OBJETIVOS: Estabelecer a taxa de ocorrência de EA e identificar variáveis laboratoriais preditoras de sua ocorrência em pacientes com LES em seguimento em ambulatório de hospital terciário; estabelecer a associação entre o uso de cloroquina com a ocorrência de EA e óbitos (tipo, número e tempo de seguimento). MÉTODOS: Foi realizado um estudo clínico descritivo, observacional e aberto com pacientes em seguimento ambulatorial no Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo que foram submetidos a avaliação clínica, exames laboratoriais, ECG de repouso e Holter de 24h. A associação entre as variáveis e os EA foi avaliada por meio dos testes qui-quadrado, razão de verossimilhança, teste exato de Fisher, teste t-Student, teste não-paramétrico de Mann-Whitney, regressão logística múltipla e curva ROC. RESULTADOS: Entre agosto/2005 e agosto/2006 foram estudados 325 pacientes consecutivos, sendo 8 excluídos. A idade média foi de 40,25 anos, 91% mulheres. O tempo médio do diagnóstico de LES foi de 11,36 anos e apenas 6 pacientes apresentaram critérios para atividade do LES (escore SLEDAI). Duzentos e vinte e um pacientes estavam em uso de cloroquina. Alterações ao ECG ocorreram em 66 pacientes (20,82%): 5 bloqueios atrioventriculares de 1º grau; 4 bradicardias sinusais; 4 taquicardias sinusais e 1 supraventricular; 6 bloqueios do ramo direito (BRD); 2 bloqueios do ramo esquerdo (BRE); 45 QT prolongados. Ao Holter foram identificados 4 pacientes com pausas > 2,0 segundos; 45 com FC mínima < 50bpm; 90 com extrassístoles supraventriculares (ESV); 26 com taquiarritmias supraventriculares (FA/TA); 65 com extrassístoles ventriculares (EV). Foram registrados 7 óbitos (2,47%). Idade acima de 40 anos foi preditora da ocorrência de EA (p=0,002; OR=2,523; IC 95%= 1,389-5,583). A presença do anticorpo anticardiolipina foi preditora da ocorrência de BRD/BRE (p = 0,005; OR 3,989; IC 95% = 1,615-9,852). Títulos de C3 abaixo de 105mg% foram preditores de menor probabilidade de ocorrência de FC mínima < 50bpm (p=0,016; OR=1,018; IC 95%=1,003-1,033). Os preditores para a ocorrência de EV foram a idade (p=0,002; OR=1,051; IC95%=1,018-1,085) e a duração do QRS (p=0,005; OR=1,061; IC95%=1,018-1,106); quanto mais avançada a idade e quanto mais largo o QRS, maior a probabilidade de ocorrência de EV. Para a ocorrência de TA/FA, os preditores foram a idade (p<0,001; OR=1,100; IC95%=1,050-1,154) e o tempo de uso cloroquina (p=0,035; OR=0,921; IC95%=0,853-0,994); quanto mais avançada a idade e quanto menor o tempo de uso de cloroquina, maior a probabilidade de ocorrência de TA/FA. Pacientes com mais de 50 anos e tempo de uso de cloroquina inferior a 8 anos tiveram mais TA/FA. CONCLUSÕES: Neste estudo, que avaliou pacientes com LES em seguimento ambulatorial em hospital terciário, a taxa de ocorrência de EA foi elevada; a sua correlação com variáveis laboratoriais identificou como preditores de maior ocorrência: idade acima de 40 anos, título de C3 abaixo de 105mg% e presença de anticorpo anticardiolipina. A cloroquina demonstrou efeito protetor cardíaco sobre a evolução da doença. / INTRODUCTION: Systemic Lupus Erythematosus (SLE) is a chronic inflammatory illness that can affect any organ and system. Up to 50% of patients have their heart affected and there are no prevalence studies of arrhythmic events (AE) in SLE patients and laboratory predictors are also unknown. OBJECTIVES: To establish the rate of occurrence of AE and to identify laboratory predictors in outpatients with SLE; to establish the association between chloroquine use and the occurrence of AE and death (type, number and time of follow-up). METHODS: A descriptive, observational and opened clinical study was carried out with SLE oupatients selected from the Rheumatology clinic of São Paulo University Medical School, Brazil. They were submitted to clinical evaluation, laboratory exams, resting-ECG and 24-hour Holter monitoring. Statistics: The association between the variables and the occurrence of AE was assessed by chi-square, likelihood ratio, Fishers test, t-Student, Mann-Whitney, ROC curve and logistic regressions. RESULTS: Between august/05-august/06, 325 consecutive patients were studied. Resting-ECG abnormalities were found in 66 patients, rate of 20.82%. The average age was 40.25yo, 91% female. The average time of SLE diagnosis was of 11.36y and only 6 presented criteria for diseases activity (SLEDAI score). There were 221 patients using chloroquine. ECG disturbances found: 5 1st degree AV-block; 4 sinus bradycardia; 4 sinus tachycardia and 1 supraventricular tachycardia; 6 RBBB; 2 LBBB; 45 long QT. At Holter monitoring: 4 pauses>2.0s; 45 HR<50bpm; 90 atrial ectopies; 26 atrial tachyarrhythmia; 65 ventricular ectopies. Seven death were registered (2.47%). Age above 40yo was predictor of AE (p=0.002; OR=2.5; 95%IC=1.4-5.6). Presence of anticardiolipine antibody was predictor of QRS>120ms occurrence (p = 0.005; OR 3.989; IC 95% = 1.615-9.852). C3 level bellow 105mg% was predictor of non-occurrence of HR<50bpm (p=0.02; OR=1.02;95% IC=1.003-1.03). The predictor for ventricular ectopies (VE) occurrence were age (p=0,002; OR=1,051; IC95%=1,018-1,085) and QRS duration (p=0,005; OR=1,061; IC95%=1,018-1,106); advanced age and longer QRS predicted greater probability of VE. For supraventricular tachyarrhythmia (AT/AF) the predictors were age (p<0,001; OR=1,100; IC95%=1,050-1,154) and time of Chloroquine use (p=0,035; OR=0,921; IC95%=0,853-0,994); advanced age and short time of Chloroquine use are related to greater probability of AT/AF. Patients older than 50y and using chloroquine for less than 8y had more AT/AF. CONCLUSIONS: The rate of AE occurrence was high (20%) and the correlation with laboratory variables identified predictors of occurrence of AE: age above 40 years, C3 level below 105mg% and anticardiolipin antibody. Chloroquine demonstrated cardiac protection effect.

Les canaux activés par l’hyperpolarisation et sensibles aux nucléotides cycliques (hy- perpolarization cyclic nucleotide-gated channel; HCN) ont un rôle dans la régulation du rythme cardiaque ainsi que dans la transmission des influx nerveux. De nombreuses pathologies sont causées par un disfonctionnement de ces canaux. A ce jour, Ivabradine représente la seule molécule utilisée comme médicament, mais malgré sa spécificité en- vers les canaux HCNs, elle n’est pas sélective entre les isoformes de la famille HCN. Dans le but d’identifier une molécule plus adéquate pour le traitement qu’Ivabradine, nous avons analysé l’interaction entre les canaux HCNs et 9 bloqueurs connus garce à l’arrimage moléculaire. Cette analyse nous a permis d’identifier les résidus nécessaires pour la liaison des ligands. On observe aussi qu’Ivabradine ne forme aucune liaison so- lide avec les canaux HCNs mais ne fait que bloquer le passage par sa présence tout comme ses dérivées Zatebradine et Cilobradine. Les ligands de plus petites tailles quant à eux, se logent dans une cavité hydrophobe et forme des liaisons stable avec les pro- téines. Nos résultats semblent suggérer que le blocage par Ivabradine est plus efficace, mais que les liaisons stables des petits ligands possèdent un potentiel plus grand vers une meilleure affinité. Par contre, les interactions observées suggèrent que la spécificité envers les isoformes proviendrait des cinétiques des canaux et des dépendances d’états des ligands plutôt que des interactions identifiées. Pour finir, l’arrimage des ligands sur la conformation fermé du canal HCN1 suggère qu’il existerait une conformation fermée- liée non connue puisqu’aucun ligand n’a pu accéder au pore. / HCN channels have a role in regulating heart rate as well as in the transmission of nerve impulses. Many pathologies are caused by a malfunction of these channels. To date, Ivabradine is the only molecule used as a drug, but despite its specificity for HCN chan- nels, it is not selective between the isoforms of the HCN family. In order to identify a molecule more suitable for the treatment than ivabradine, we analyzed the interaction between HCN family and 9 known blockers using docking. This analysis allowed us to identify the necessary residuals for ligand binding. It is also observed that ivabradine forms no solid bond with the HCN channels but only blocks the passage by its pres- ence, the same was observed for its derivatives Zatebradine and Cilobradine. Ligands of smaller size, for their part, are lodged in a hydrophobic cavity and form stable bonds with the proteins. Our results seem to suggest that blocking with Ivabradine is more effi- cient but that the stable bonds of small ligands have a greater potential for better affinity. However, the observed interactions suggest that the specificity towards isoforms would come from the kinetics of the channels and state dependencies of ligands rather than identified interactions. Finally, the binding of the ligands to the closed conformation of the HCN1 channel suggests that there would be a closed-bound conformation that is not known since no ligand has been able to access the pore.