Hintergründe und Ziele: Vorhofflimmern (VHF) ist ein häufiger Auslöser zerebraler Ischämien. Asymptomatisches paroxysmales Vorhofflimmern wird durch die Standard-Diagnostik häufig übersehen. Die Detektion des Vorhofflimmerns führt zu einer Änderung der sekundärprophylaktischen Therapie. Diese Dissertationsarbeit basiert auf drei Originalpublikationen zur Verbesserung der Detektion und Prädiktion von paroxysmalem Vorhofflimmern bei Patienten mit akuter zerebraler Ischämie. In „Enhanced Detection of Paroxysmal Atrial Fibrillation by Early and Prolonged Continuous Holter Monitoring in Patients with Cerebral Ischemia Presenting in Sinus Rhythm” ermittelten wir die diagnostische Wertigkeit eines frühzeitig applizierten 7-Tage-Langzeit-EKGs. In “Age-dependent yield of screening for undetected atrial fibrillation in stroke patients: the Find-AF study” untersuchten wir die Altersverteilung des paroxysmalen Vorhofflimmerns um herauszufinden, welche Altersgruppe vornehmlich von dem eingesetzten Monitoring-Verfahren profitiert. In “Excessive Supraventricular Ectopic Activity Is Indicative of Paroxysmal Atrial Fibrillation in Patients with Cerebral Ischemia“ evaluierten wir die prädiktive Wertigkeit von gehäuften supraventrikulären Extrasystolen (SVES) und prolongierten supraventrikulären (SV-) Salven. Methoden: In die prospektive monozentrische Observationsstudie „Find-AF“ (ISRCTN 46104198) wurden Patienten mit akuter zerebraler Ischämie eingeschlossen. Diejenigen ohne Vorhofflimmern bei Aufnahme erhielten ein frühzeitiges, prolongiertes Langzeit-EKG. Um die Altersverteilung des paroxysmalen Vorhofflimmerns zu untersuchen, wurde die Detektionsrate in 5-Jahres-Gruppen von 60 bis 85 Jahren ermittelt. Die Marker einer exzessiven supraventrikulären ektopen Aktivität wurden in einem 24-Stunden-Langzeit-EKG-Intervall ohne Vorhofflimmern bestimmt. Als Cut-Off-Wert wurde der Median gewählt. Ergebnisse: 281 Patienten wurden eingeschlossen. 44 (15,7 %) hatten bei Aufnahme Vorhofflimmern. Die verbliebenen Patienten erhielten ein frühzeitiges (Median 5,5 Stunden nach Aufnahme) und prolongiertes (Median 6,7 Tage Laufzeit) Langzeit-EKG. Bei 28 (12,5 %) von 224 Patienten wurde erstmals ein paroxysmales VHF diagnostiziert, signifikant mehr als in jedem 48-Stunden-Intervall (6,4%, p = 0,023) oder 24-Stunden-Intervall (4,8 %, p = 0,015). Zwischen den einzelnen sieben 24-Stunden-Intervallen gab es hinsichtlich der Detektionsrate keine signifikanten Unterschiede. Die Detektionsrate stieg mit dem Alter an (p = 0,004), während die number needed to screen um einen Patienten mit paroxysmalem Vorhofflimmern zu identifizieren von 18 (< 60 Jahre) auf 3 (≥ 85 Jahre) abnahm. Patienten mit gehäuften SVES (> 4/Stunde) und solche mit prolongierten SV-Salven (> 5 Schläge) hatten signifikant häufiger paroxysmales VHF: 19,6 % vs. 2,8 % für gehäufte SVES (p = 0,001) und 17,0 % vs. 4,9 % für prolongierte SV-Salven (p = 0,003). Multivariate Analysen mit verschiedenen klinischen Vorhofflimmer-Prädiktoren bestätigten die unabhängige prädiktive Wertigkeit beider Marker. Schlussfolgerungen: 1.) Bei Patienten mit akuter zerebraler Ischämie führt die Prolongation des Langzeit-EKG-Intervalls zu einer signifikant höheren Detektionsrate von paroxysmalem Vorhofflimmern. Der frühzeitige Beginn erscheint weniger relevant. 2.) Die Detektionsrate paroxysmalen Vorhofflimmerns nimmt mit dem Alter zu, daher ist das prolongierte Langzeit-EKG bei älteren Patienten am effektivsten. 3.) Gehäufte SVES und prolongierte SV-Salven sind valide Prädiktoren für das Vorliegen eines paroxysmalen Vorhofflimmerns bei Patienten mit akuter zerebraler Ischämie.

Atrial fibrillation (AF), the most common arrhythmia encountered in clinical practice, is a major source of morbidity and mortality, and is highly associated with inflammation and oxidative stress. In the present study, we show that acute exposure of mice atrial tissue to tumor necrosis factor-α (TNF-α) increases susceptibility to AF. We further show that acute exposure to TNF-α led to increased spontaneous sarcoplasmic reticulum (SR) calcium release and generated triggered activities in isolated mice atrial myocytes. This increase in spontaneous SR calcium activity was found to be due to elevated reactive oxygen species production from mitochondria and NADPH oxidase sources triggered by TNF-α. Hence we concluded that acute exposure to TNF-α leads to elevated oxidative stress that increases spontaneous SR Ca2+ release and triggered activity through which it can lead to AF induction and maintenance

Atrial fibrillation (AF), the most common arrhythmia encountered in clinical practice, is a major source of morbidity and mortality, and is highly associated with inflammation and oxidative stress. In the present study, we show that acute exposure of mice atrial tissue to tumor necrosis factor-α (TNF-α) increases susceptibility to AF. We further show that acute exposure to TNF-α led to increased spontaneous sarcoplasmic reticulum (SR) calcium release and generated triggered activities in isolated mice atrial myocytes. This increase in spontaneous SR calcium activity was found to be due to elevated reactive oxygen species production from mitochondria and NADPH oxidase sources triggered by TNF-α. Hence we concluded that acute exposure to TNF-α leads to elevated oxidative stress that increases spontaneous SR Ca2+ release and triggered activity through which it can lead to AF induction and maintenance

La fibrillation auriculaire (FA) est le trouble du rythme le plus fréquemment observé en pratique clinique. Elle constitue un risque important de morbi-mortalité. Le traitement de la FA reste un défi majeur en lien avec les nombreux effets secondaires associés aux approches thérapeutiques actuelles. Dans ce contexte, une meilleure compréhension des mécanismes sous-jacents à la FA est essentielle pour le développement de nouvelles thérapies offrant un meilleur rapport bénéfice/risque pour les patients. La FA est caractérisée par i) un remodelage électrique délétère associé le plus souvent ii) à un remodelage structurel du myocarde favorisant la récurrence et le maintien de l’arythmie. La diminution de la période réfractaire effective au sein du tissu auriculaire est un élément clef du remodelage électrique. Le remodelage structurel, quant à lui, se manifeste principalement par une fibrose tissulaire qui altère la propagation de l’influx électrique dans les oreillettes. Les mécanismes moléculaires impliqués dans la mise en place de ces deux substrats restent mal connus. Récemment, le rôle des microARNs (miARNs) a été pointé du doigt dans de nombreuses pathologies notamment cardiaques. Dans ce contexte les objectifs principaux de ce travail ont été i) d'acquérir une compréhension approfondie du rôle des miARNs dans la régulation de l’expression des canaux ioniques et ii) de mieux comprendre le rôle de ces molécules dans l’installation d’un substrat favorable a la FA. Nous avons, dans un premier temps, effectué une analyse bio-informatique combinée à des approches expérimentales spécifiques afin d’identifier clairement les miARNs démontrant un fort potentiel de régulation des gènes codant pour l’expression des canaux ioniques cardiaques humains. Nous avons identifié un nombre limité de miARNs cardiaques qui possédaient ces propriétés. Sur la base de ces résultats, nous avons démontré que l’altération de l'expression des canaux ioniques, observée dans diverse maladies cardiaques (par exemple, les cardiomyopathies, l’ischémie myocardique, et la fibrillation auriculaire), peut être soumise à ces miARNs suggérant leur implication dans l’arythmogénèse. La régulation du courant potassique IK1 est un facteur déterminant du remodelage électrique auriculaire associée à la FA. Les mécanismes moléculaires sous-jacents sont peu connus. Nous avons émis l’hypothèse que l'altération de l’expression des miARNs soit corrélée à l’augmentation de l’expression d’IK1 dans la FA. Nous avons constaté que l’expression de miR-26 est réduite dans la FA et qu’elle régule IK1 en modulant l’expression de sa sous-unité Kir2.1. Nous avons démontré que miR-26 est sous la répression transcriptionnelle du facteur nucléaire des lymphocytes T activés (NFAT) et que l’activité accrue de NFATc3/c4, aboutit à une expression réduite de miR-26. En conséquence IK1 augmente lors de la FA. Nous avons enfin démontré que l’interférence in vivo de miR-26 influence la susceptibilité à la FA en régulant IK1, confirmant le rôle prépondérant de miR-26 dans le remodelage auriculaire électrique. La fibrose auriculaire est un constituant majeur du remodelage structurel associé à la FA, impliquant l'activation des fibroblastes et l’influx cellulaire du Ca2 +. Nous avons cherché à déterminer i) si le canal perméable au Ca2+, TRPC3, jouait un rôle dans la fibrose auriculaire en favorisant l'activation des fibroblastes et ii) étudié le rôle potentiel des miARNs dans ce contexte. Nous avons démontré que les canaux TRPC3 favorisent l’influx du Ca2 +, activant la signalisation Ca2 +-dépendante ERK et en conséquence activent la prolifération des fibroblastes. Nous avons également démontré que l’expression du TRPC3 est augmentée dans la FA et que le blocage in vivo de TRPC3 empêche le développement de substrats reliés à la FA. Nous avons par ailleurs validé que miR-26 régule les canaux TRPC3 en diminuant leur expression dans les fibroblastes. Enfin, nous avons montré que l'expression réduite du miR-26 est également due à l’activité augmentée de NFATc3/c4 dans les fibroblastes, expliquant ainsi l’augmentation de TRPC3 lors de la FA, confirmant la contribution de miR-26 dans le processus de remodelage structurel lié à la FA. En conclusion, nos résultats mettent en évidence l'importance des miARNs dans la régulation des canaux ioniques cardiaques. Notamment, miR-26 joue un rôle important dans le remodelage électrique et structurel associé à la FA et ce, en régulant IK1 et l’expression du canal TRPC3. Notre étude démasque ainsi un mécanisme moléculaire de contrôle de la FA innovateur associant des miARNs. miR-26 en particulier représente apres ces travaux une nouvelle cible thérapeutique prometteuse pour traiter la FA. / Atrial fibrillation (AF) is the most frequently-encountered arrhythmia in clinical practice and constitutes a major cause of cardiac morbidity and mortality. The management of AF remains a major challenge as current therapeutic approaches are limited by potential adverse effects and high rate of AF recurrence/persistence. A better understanding of the mechanisms underlying AF is of great importance to improve AF therapy. AF is characterized by impaired electrical and structural remodeling, both of which favors the recurrence and maintenance of the arrhythmia. A key feature in electrical remodeling is the reduced atrial effective refractory period, due to ion channel alteration. Structural remodeling, on the other hand, mainly results from atrial fibrosis. However, the precise molecular mechanisms underlying these remodeling processes are still incompletely understood. The importance of microRNAs (miRNAs) in various pathophysiological conditions of the heart has been well established, but little is known with regard to cardiac arrhythmias. Emerging evidence suggests that dysregulation of miRNAs may underlie heart rhythm disturbances. The aim of the present work was to acquire a comprehensive understanding of miRNA-mediated regulation of ion channels in cardiac arrhythmias. Notably, we will focus on the mechanistic insights of miRNAs related to the control of AF. Currently available experimental approaches do not permit thorough characterization of miRNA targeting. For this purpose, we performed bioinformatic analyses in conjunction with experimental approaches to identify miRNAs from the database that potentially regulate human cardiac ion channel genes. We found that only a subset of miRNAs target cardiac ion channel genes. Based on these results, we further demonstrated that the dysregulation of ion channel gene expression observed in various cardiac disorders (e.g. cardiomyopathy, myocardial ischemia, and atrial fibrillation) can be explained by the dysregulation of miRNAs. These findings further support the potential implication of miRNAs in arrhythmogenesis under these cardiac conditions. The upregulation of the cardiac inward rectifying potassium current, IK1, is a key determinant of adverse atrial electrical remodeling associated with AF. The molecular mechanisms underlying this ionic remodeling are poorly understood. We hypothesized that altered miRNA expression is responsible for IK1 upregulation in AF. We found that miR-26 is significantly downregulated in AF and regulates IK1 by controlling the expression of its underlying subunit Kir2.1. Moreover, we demonstrated that miR-26 is under the transcriptional repression of the nuclear factor of activated T cells (NFAT) and enhanced activities of members of the NFAT family, NFATc3/c4, results in miR-26 downregulation, which accounts for IK1 enhancement in AF. Furthermore, we observed that in vivo interference of miR-26 affects AF susceptibility via the regulation of IK1, suggesting an important role of miR-26 in atrial electrical remodeling. Atrial fibrosis is a major constituent in AF-associated adverse atrial structural remodeling, involving the activation of fibroblasts and cellular Ca2+ entry. Here, we sought to determine whether the Ca2+ permeable channel, TRPC3, plays a role in AF-induced fibrosis by promoting fibroblast activation. Furthermore, we investigated the potential role of miRNAs in this context. We found that TRPC3 channels promote Ca2+-entry, which results in activation of Ca2+-dependent ERK-signaling and consequently fibroblast activation. We also demonstrated that TRPC3 is upregulated in AF and in vivo TRPC3 blockade suppresses the development of AF-promoting substrate. Furthermore, we observed that miR-26 regulates TRPC3 channels via controlling the expression of the underlying channel subunit and is downregulated in AF-fibroblasts. Finally, we showed that the reduced expression of miR-26 is also due to the enhanced NFATc3/c4 activities in AF-fibroblasts and accounts for AF-induced upregulation of TRPC3, suggesting the potential contribution of miR-26 in AF-related adverse structural remodeling process. In conclusion, our findings emphasize the importance of miRNAs in the regulation of cardiac ion channels. Notably, miR-26 plays a crucial role in AF-associated electrical and structural remodeling via the regulation of IK1 and TRPC3 channel genes. Thus, our study unravels a novel molecular control mechanism of AF at the miRNA level, suggesting miR-26 as a new and promising therapeutic target for AF.

The current period is characterized by profound scientific and technological progress not only in the medicine but also in the field of nursing, which is now based more on scientific knowledge than ever before. Nursing as a science requires professionally trained nurses providing high quality nursing care. Therefore, the development of modern medicine, particularly in the field of cardiology, justifies the need to change the perception and status of nurses with respect to patient care together with strengthening the prestige and status of nurses in society. The main research intention of the dissertation was to determine how the nursing behaviour in connection with the procedure of radiofrequency catheter ablation (RFA) due to atrial fibrillation (AF) is perceived by nurses and patients, what is the impact of the RFA on the life quality of patients with AF, and what is the level of education in patients with AF. To meet these goals the research, the empirical part was divided into two phases. In the first phase, a non-standardized questionnaire was used, role of which was to assess the needs of patients with AF before and after RFA comparing baseline and 1 year follow-up data. In the second phase, which only examined the conditions 1 year after the RFA, a standardized questionnaire CBI - 24 (Caring Behaviour Inventory) was additionally used together with another form with questions investigating education of patients. Further data were obtained from nurses taking care for patients during the medical intervention. The research results show that quality of life of patients with AF before ablation was reduced. Patients´ most common problem areas included pain, physical and mental problems. Our research also showed that if we compared meeting patients´ physical and mental needs, meeting physical needs was evaluated better. Another area under consideration was the education of patients. Evaluated results showed the fact that education was focused on its content rather than its form. Evaluation of the perception of nursing care from the perspective of patients and nurses was the last part of the research. The results of the survey showed that nurses evaluated technical competence better than the humanistic approach to patients. It was also discovered that patients evaluated areas focused on performance of nurses better than creating a relationship of security and safety for patients. Finally, the results indicated that communication is also problematic area. We managed to meet the set goals and gain both theoretical and practical recommendations. Analyzing the results, we found out that there is a need to support humanistic approach in nursing care for cardiac patients, communication and education.

Surgical myocardial revascularization remains the standard of care for patients with multi-vessel coronary artery disease. A growing body of evidence indicates that systemic inflammation and myocardial oxidative stress are associated with the development of postoperative atrial fibrillation (POAF) and low cardiac output syndrome in patients undergoing cardiac surgery. Statins have been shown to exert rapid anti-inflammatory and antioxidant effects by inhibiting myocardial NOX2 oxidases and by increasing the bioavailability of nitric oxide (NO). However, whether these so-called pleiotropic effects of statins result in improved patient outcomes remains to be established. To provide further insights into the mechanisms of action and impact on clinical outcomes of peri-operative statin treatment in patients undergoing cardiac surgery, I studied the molecular mechanisms underlying the myocardial nitroso-redox balance in samples of the right atrial appendages (RAA) obtained before (PRE) and after cardiopulmonary bypass (CPB) and reperfusion (POST) and setup two double-blind randomised placebo-controlled trials: 1) STARR (Statin Treatment on Atrial Refractoriness and Reperfusion injury), which tested the effect of Atorvastatin (80 mg once daily for up to 6 days before surgery and 5 days after) on the atrial effective refractory period (AERP, over 4 post-operative days) and superoxide production in paired PRE- and POST- RAA samples from 60 patients 2) STICS (Statin Treatment In Cardiac Surgery), which assessed the effects of peri-operative treatment with Rosuvastatin (20mg od) on POAF (assessed by continuous holter ECG monitoring for 5 days postoperatively) and myocardial injury (assessed by serial troponin I measurements) in 1922 patients undergoing elective cardiac surgery. I observed that atrial superoxide production increased significantly after reperfusion due to increased mitochondrial and NOX2 oxidase activity and to uncoupling of NOS activity. NOS activity in RAA samples decreased significantly after reperfusion (by 60&percnt;), but this reduction was not prevented by BH4 supplementation (10 &mu;M) or NOX2 inhibition. Instead, I identified increased endothelial NOS S-glutathionylation as the main mechanism responsible for NOS uncoupling after reperfusion. In STARR, atorvastatin prevented increase in RAA superoxide production, maintained the functionally coupled status of NOS and NO bioavailability after reperfusion but had no measurable effect on postoperative AERP. In STICS, treatment with rosuvastatin significantly reduced LDL-C concentration by 48 hours after surgery but had no effect on the incidence of POAF (203 (21&percnt;) of the Rosuvastatinallocated patients vs. 197 (20&percnt;) of the placebo-allocated patients) or on perioperative myocardial damage (P = 0.80). Pre-defined subgroup analyses (age, sex, prior statin use, baseline troponin concentration, duration of randomized treatment before surgery, type of cardiac surgery, and postoperative use of anti-inflammatory drugs) did not identify any category of patient who benefited from perioperative rosuvastatin treatment. Nor were there beneficial effects on any of the other in-hospital clinical outcomes that were assessed. In conclusion, cardiac surgery on CPB is associated with myocardial nitroso redox imbalance that is reversed by perioperative intensive therapy with statins. However, these effects have no beneficial effects on common in-hospital complications after elective cardiac surgery. Although the benefits of long-term statin therapy in patients requiring myocardial revascularization are well established, the work presented in this thesis does not support routine use of perioperative intensive therapy with statins for the prevention of postoperative complications in patients undergoing elective cardiac surgery.

abstract: Atrial fibrillation (AF) is the most common abnormal heart rhythm, affecting nearly 2% of the world’s population at a cost of $26 Billion in the United States annually, and incalculable costs worldwide. AF causes no symptoms for some people. However, others with AF experience uncomfortable symptoms including palpitations, breathlessness, dizziness, and fatigue. AF can severely diminish quality of life for both AF sufferers and their loved ones. Beyond uncomfortable symptoms, AF is also linked to congestive heart failure and stroke, both of which can cause premature death. Medications often fail to control AF, leading patients and healthcare providers to seek other cures, including catheter ablation. To date, catheter ablation has yielded uneven results, but garners much attention in research and innovation in pursuit of a cure for AF. This dissertation examines the historical development and contemporary practices of AF ablation to identify opportunities to improve the innovation system for the disease. First, I trace the history of AF and AF ablation knowledge from the 2nd century B.C.E. through the present. This historical look identifies patterns of knowledge co-development between science, technology, and technique, as well as publication patterns impacting knowledge dissemination. Second, I examine the current practices of AF ablation knowledge translation from the perspective of clinical practitioners to characterize the demand-side of knowledge translation in real-world practice. Demand-side knowledge translation occurs in nested patterns, and requires data, experience, and trust in order to incorporate knowledge into a practice paradigm. Third, I use social network mapping and analysis to represent the full AF ablation knowledge-practice system and identify opportunities to modify research and innovation practice in AF ablation based on i measures of centrality and power. Finally, I outline six linked recommendations using raw data capture during ablation procedures and open big data analytics, coupled with multi-stakeholder social networking approaches, to maximize innovation potential in AF ablation research and practice. / Dissertation/Thesis / Doctoral Dissertation Human and Social Dimensions of Science and Technology 2016

Objetivo. Verificar se as características espectrais dos eletrogramas atriais (EgA) em ritmo sinusal (RS) se correlacionam com a presença de gânglios parassimpáticos cardíacos. Materiais e Resultados. Treze pacientes encaminhados para submeter-se a ablação de fibrilação atrial (FA) foram incluídos de forma prospectiva. Previamente ao início da ablação, realizou-se o registro de EgA em RS em uma série de regiões anatômicas pré-determinadas, seguindo-se uma ordem sequencial. Em seguida, aplicou-se estímulos elétricos de alta frequência (20 Hz de frequência, amplitude de 100 V e duração de pulso de 4 ms), nos mesmos locais. Uma resposta vagal evocada foi definida como um súbito aumento no intervalo RR ou a indução de bloqueio na condução átrio-ventricular imediatamente após a aplicação do estímulo de alta-frequência (EAF). Procedeu-se à análise espectral dos sinais atriais em RS registrados, com amostragem de 1000 Hz, janela Hanning. No total, 1488 EgA oriundos de 186 locais anatômicos foram registrados, sendo 129 de regiões com resposta vagal negativa e 57 correspondentes a regiões de resposta vagal positiva. A duração do eletrograma e o número de deflecções foram similares nos pontos com resposta vagal positiva e negativa. A densidade de potência espectral em locais de resposta vagal positiva, no entanto, foi menor entre 26 e 83 Hz, e maior entre 107 e 200 Hz, comparados com os locais de resposta negativa. A área sobre a curva entre 120 e 170 Hz normalizada para a área total do espectro foi testada como um novo parâmetro diagnóstico. A análise de curva ROC demonstrou que o valor area 120-170 / area total > 0,14 foi capaz de identificar locais de inervação vagal com sensibilidade de 70,9% e especificidade de 72,1%. Conclusão. A análise espectral de sinais atriais durante RS é um método factível e simples de mapear os locais de inervação parassimpática cardíaca, sem a necessidade de qualquer tipo de estimulação / Objective. To verify whether spectral components of atrial electrograms (AE) during sinus rhythm (SR) correlate with cardiac ganglionated plexus (GP) sites. Methods and Results. Thirteen patients undergoing atrial fibrillation (AF) ablation were prospectively enrolled. Prior to radio frequency application, endocardial AE were recorded with a sequential point-by-point approach. Electrical stimuli were delivered at 20 Hz, amplitude 100 V, and pulse width of 4 msec. A vagal response was defined as a high-frequency stimulation (HFS) evoked AV block or a prolongation of RR interval. Spectral analysis was performed on single AE during SR, sampling rate of 1000 Hz, Hanning window. Overall, 1488 SR electrograms were analyzed from 186 different left atrium sites, 129 of them corresponding to negative vagal response sites and 57 to positive response sites. The electrogram duration and the number of deflections were similar in positive and negative response sites. Spectral power density of sites with vagal response was lower between 26 and 83 Hz and higher between 107 and 200 Hz compared with negative response sites. The area between 120 and 170 Hz normalized to the total spectrum area was tested as a diagnostic parameter. ROC curve analysis demonstrated that an area 120-170 / area total value > 0,14 identified vagal sites with 70,9% sensitivity and 72,1% specificity. Conclusions. Spectral analysis of AE during SR is feasible and simple method of mapping the cardiac autonomic nervous system (ANS), with no stimulation required

A fibrilação atrial (FA) é a arritmia mais comum no pós-operatório de cirurgia cardíaca. Apesar de estar relacionada a alterações estruturais, alguns pacientes, mesmo que sem tais condições, ainda assim, cursam com fibrilação atrial no pós-operatório (FAPO) causando aumento no tempo de internação e custos. Estudos recentes vem ampliando o conhecimento sobre pequenos fragmentos de RNA, chamados de microRNAs (miRNAs) que podem interferir diretamente no aparecimento de algumas doenças na área cardiovascular. O objetivo do presente estudo é: 1) comparar a expressão dos miRNAs 1, 23 e 26 entre pacientes com e sem FAPO; 2) comparar nos grupos a expressão destes miRNAs entre os período pré e pós-cirúrgico; 3)comparar a expressão dos genes GJA1, KCNJ2, CACNB1, CACNA1C e KCNN3 entre os tempos pré e pós-cirúrgico no grupo FAPO; 4) comparar estes últimos genes no tecido atrial; 5) comparar os genes relacionados à produção de interleucinas (IL)-1, 6 e fator de necrose tumoral alfa (TNF?) entre os grupos e entre os tempos pré e pós-cirúrgico; 6)avaliar as características clínicas e evolutivas da população estudada. Pacientes submetidos à cirurgia de revascularização miocárdica foram submetidos à coleta de 20ml de sangue pré e pós-cirurgia bem como fragmento de tecido atrial. Um total de 143 pacientes compuseram os grupos: FAPO (24 pacientes), controle genético (24 pacientes) e controle total (97 pacientes + 24 grupo controle genético). Do ponto de vista clínico observou-se maior idade, tempo de anóxia, tempo de internação em terapia intensiva e hospitalar no grupo FAPO. A análise genética revelou menor expressão do miRNA-23 no grupo FAPO (p=0,02). A comparação entre os períodos pré e pós-cirúrgico revelou redução dos três miRNAs no tempo pós-cirúrgico (p<0,05) e dos genes relacionados às proteínas de canal (p<0,05). A comparação no tecido não evidenciou alterações entre os grupos. Os genes relacionados ás citocinas revelaram redução no período pós-cirúrgico (p<0,05) em ambos os grupos. Concluiu-se que o miRNA-23 pode ter implicação no surgimento da FAPO e outros miRNAs não estudados devem estar envolvidos neste processo uma vez que houve redução de outros genes de canais relacionados ao aparecimento de FAPO. / Atrial fibrillation (AF) is the most common arrhythmia after cardiac surgery. AF is related to cardiac structural changes although a group of patients still remains developing post-operative atrial fibrillation (FAPO) even without those changes, leading to more days in the hospital and costs. Recent studies showed that short fragments of RNA, called microRNA (miRNA) can contribute to the development of several diseases in the cardiovascular area. The aim of this study is to 1) compare the expression of miRNA-1, 23 and 26 between the group with and without FAPO; 2) compare, in the FAPO group, the expression of these miRNAs in the pre and post-surgery periods; 3) compare the expression of GJA1, KCNJ2, CACNB1, CACNA1C e KCNN3 genes between the pre and post-surgery periods; 4) compare this genes in atrial tissue; 5) compare the genes related to inflammation cytokines as interleukin(IL)-1, 6 and alpha tumoral necrosis factor between the groups in the pre and post-surgery periods; 6) evaluate clinical and evaluative patterns of the study population. Twenty milliliters of blood samples in the pre and post-operative periods and an atrial fragment were extracted from patients submitted to coronary artery bypass graft surgery. A total of 143 patients were divided in the FAPO group (24 patients), genetic control group (24 patients) and a total control (97 + 24 genetic control patients). The clinical analysis showed bigger age and clamp-time, more days in the intensive care unit and hospital in the FAPO group. The genetic analysis revealed less expression of miRNA-23 in the FAPO group (p=0.02). The comparison between the pre and post-surgery periods showed reduction in the three studied miRNAs (p<0.05) and reduction in the genes related to the production of the membrane protein channel sites. The comparisons in the atrial tissue didn´t show any difference in the study groups. The cytokines showed post-surgery reduction (p<0.05) in both groups. The conclusion is that miRNA-23 can be implicated in FAPO as others miRNAs not studied can also be, once there was a significative reduction in the genes related to FAPO development.

Submitted by Daniely Januário (daniely.januario@gmail.com) on 2018-03-02T12:31:14Z No. of bitstreams: 1 joseresendedecastrojunior.pdf: 3078753 bytes, checksum: f22309c68ef54befb8ce6682fdfa7d3e (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2018-03-14T18:29:39Z (GMT) No. of bitstreams: 1 joseresendedecastrojunior.pdf: 3078753 bytes, checksum: f22309c68ef54befb8ce6682fdfa7d3e (MD5) / Made available in DSpace on 2018-03-14T18:29:39Z (GMT). No. of bitstreams: 1 joseresendedecastrojunior.pdf: 3078753 bytes, checksum: f22309c68ef54befb8ce6682fdfa7d3e (MD5) Previous issue date: 2016-09-30 / PROQUALI (UFJF) / A fibrilação atrial é a arritmia cardíaca sustentada mais comum, acometendo principalmente idosos e aumenta o risco de acidente vascular cerebral. É atualmente um problema de saúde pública pela sua elevada morbimortalidade e custos crescentes. A varfarina é o anticoagulante que se mostrou efetivo na prevenção deste evento, contudo apresenta limitações que contribuem para a sua baixa aderência e subutilização. O surgimento de novos anticoagulantes, como a rivaroxabana, evidenciou que esta medicação pode ser tão efetiva quanto à varfarina, mas, com menores taxas de complicações hemorrágicas graves, principalmente cerebrais, não havendo necessidade de exames de monitorização, porém com um custo maior. O objetivo deste estudo foi avaliar a custo-utilidade da rivaroxabana comparada à varfarina nesta arritmia, ou seja, comparar o custo da intervenção com sua efetividade medida como ganho em anos de vida ajustada pela qualidade. Inicialmente foi realizada uma revisão sistemática de estudos econômicos sugerindo que a rivaroxabana pode ser uma opção custo-efetiva, principalmente em países desenvolvidos. Houve apenas um estudo realizado em país em desenvolvimento que mostrou resultado divergente. Posteriormente, foi desenvolvido um modelo econômico de Markov, na perspectiva do Sistema Único de Saúde, que permitiu simular a evolução de uma coorte de idosos com fibrilação atrial, em ciclos trimestrais durante toda a vida. Os resultados evidenciaram que os custos incrementais da rivaroxabana foram superiores à varfarina (R$ 7.135,48), com um discreto aumento de utilidade, resultando numa razão de custo-utilidade incremental de R$ 206.816,45/anos de vida ajustada pela qualidade. Este valor encontra-se acima do limiar proposto pela Organização Mundial da Saúde, podendo não ser uma opção custo-efetiva. Apesar das limitações, este trabalho conseguiu reunir as evidências disponíveis e mostrou a necessidade de se ajustar os protocolos clínicos e diretrizes para uma prática clínica que possa conciliar os princípios de integralidade do cuidado à sustentabilidade do sistema de saúde. / Atrial fibrillation is the most common sustained cardiac arrhythmia, affecting mainly the elderly and increases the risk of stroke. It is currently a public health problem because of its high morbidity and mortality and increasing costs. Warfarin is an anticoagulant that was effective in preventing this type of stroke, but has limitations that contribute to its low adhesion and underutilization. The emergence of new anticoagulants such as rivaroxaban, suggest that this drug may be as effective as warfarin, but with lower rates of major bleeding complications, mainly brain. Also, with this drug, there is no need for monitoring tests, but is more expensive. The aim of this study was to evaluate the cost-utility of rivaroxabana compared to warfarin in this arrhythmia, or compare the cost of a health intervention with effectiveness measured as a gain in years of life adjusted for quality. Initially, a systematic review of economic studies was performed that suggest that rivaroxaban can be a cost-effective option compared to warfarin, especially in developed countries. There was only one study in a developing country which showed divergent results. Later, it was developed an economic model of Markov was developed with the Unified Health System perspective, which allowed simulation of the evolution of a cohort of elderly patients with Atrial fibrillation in quarterly cycles throughout life. The results showed that the incremental costs of rivaroxaban was superior to warfarin (R$ 7.135,48), with a slight increase of utility, resulting in incremental cost-utility ratio of R$ 206.816,45/years of life adjusted for quality. This value is above the threshold proposed by the Wolrd Health Organization, may not be a cost-effective option. Despite the limitations, this study brought together the available evidence and showed the need to adjust the clinical protocols and guidelines for clinical practice that can reconcile the principles of comprehensive care to the sustainability of the health system.