Indiana University-Purdue University Indianapolis (IUPUI) / The  cardiac  voltage-­gated  sodium  channels  (Nav1.5)  play  a  specific  and   critical  role  in  regulating  cardiac  electrical  activity  by  initiating  and  propagating   action  potentials  in  the  heart.  The  association  between  Nav1.5  dysfunctions  and   generation  of  various  types  of  cardiac  arrhythmia  disease,  including  long-­QT3   and  Brugada  syndrome,  is  well  established.  Many  types  of  post-­translational   modifications  have  been  shown  to  regulate  Nav1.5  biophysical  properties,   including  phosphorylation,  glycosylation  and  ubiquitination.  However,  our   understanding  about  how  post-­translational  lipid  modification  affects  sodium   channel  function  and  cellular  excitability,  is  still  lacking.  The  goal  of  this   dissertation  is  to  characterize  Nav1.5  palmitoylation,  one  of  the  most  common   post-­translational  lipid  modification  and  its  role  in  regulating  Nav1.5  function  and   cardiac  excitability.     In  our  studies,  three  lines  of  biochemistry  evidence  were  shown  to  confirm   Nav1.5  palmitoylation  in  both  native  expression  background  and  heterologous   expression  system.  Moreover,  palmitoylation  of  Nav1.5  can  be  bidirectionally   regulated  using  2-­Br-­palmitate  and  palmitic  acid.  Our  results  also  demonstrated   that  enhanced  palmitoylation  in  both  cardiomyocytes  and  HEK293  cells   increases  sodium  channel  availability  and  late  sodium  current  activity,  leading  to   enhanced  cardiac  excitability  and  prolonged  action  potential  duration.  In  contrast,   blocking  palmitoylation  by  2-­Br-­palmitiate  increases  closed-­state  channel inactivation  and  reduces  myocyte  excitability.  Our  computer  simulation  results   confirmed  that  the  observed  modification  in  Nav1.5  gating  properties  by  protein   palmitoylation  are  adequate  for  the  alterations  in  cardiac  excitability.  Mutations  of   potential  palmitoylation  sites  predicted  by  CSS-­Palm  bioinformatics  tool  were   introduced  into  wild-­type  Nav1.5  constructs  using  site-­directed  mutagenesis.   Further  studies  revealed  four  cysteines  (C981,  C1176,  C1178,  C1179)  as   possible  Nav1.5  palmitoylation  sites.  In  particular,  a  mutation  of  one  of  these   sites(C981)  is  associated  with  cardiac  arrhythmia  disease.  Cysteine  to   phenylalanine  mutation  at  this  site  largely  enhances  of  channel  closed-­state   inactivation  and  ablates  sensitivity  to  depalmitoylation.  Therefore,  C981  might  be   the  most  important  site  that  regulates  Nav1.5  palmitoylation.  In  summary,  this   dissertation  research  identified  novel  post-­translational  modification  on  Nav1.5   and  revealed  important  details  behind  this  process.  Our  data  provides  new   insights  on  how  post-­translational  lipid  modification  alters  cardiomyocyte   excitability  and  its  potential  role  in  arrhythmogenesis.

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Bakgrund: Hjärt- och kärlsystemet kan drabbas av ett stort antal sjukdomar som tar miljoner människors liv i hela världen varje år. Patientens dagliga liv påverkas negativt av dessa sjukdomar och symtom som uppkommer i samband med dessa sjukdomar. Pacemakeroperation är en av behandlingsalternativ med syfte till att förbättra hjärtats funktion och rytm. Syfte: Syftet var att belysa patienters erfarenheter av att leva med pacemaker. Metod: En litteraturbaserad metod baserat på fem kvalitativa vetenskapliga artiklar med inriktning på patientperspektivet. Resultat: Patienter upplever oro och rädsla direkt efter pacemakerimplantation, efter en viss tid dessa problem försvinner. Första året efter implantationen patienter får stöd av sina familjemedlemmar. Pacemakerimplantation var ett sätt att behålla patientens krafter och skydda deras liv. Pacemaker var en trygghets apparat för ett bra liv utan yrsel och svimningsanfall . Patienter upplever förändringar i deras kropps utseende, och har obekväma känsla. Begränsningar och förändringar i patientens roll i familjen efter pacemakerimplantation. Patienter upplever oro över sina familjemedlemmar. Ingen förtroende för pacemakers och dess teknik en del patienter upplevde. Vissa patienter accepterar pacemaker och upplever den som en del av deras kropp. Konklusion: Erfarenheter som patienter med pacemaker har är individuell, därför är det viktigt att sjuksköterskan bemöter dessa erfarenheter och utformar omvårdnaden utifrån patientens individuella behov. / Background: The cardiovascular system can be affected by a large number of diseases that take the lives of millions yearly. Patients' lives are affected by symptoms that occur in connection with these diseases. Pacemaker surgery is one of the treatment options that aims to improve the heart's function and rhythm. Aim: Patients' experiences of living with pacemakers. Method: A literature based method on five qualitative scientific articles focusing on the patient perspective. Findings: Patients experience anxiety and fear immediately after pacemaker implantation, which after a certain time disappear. Pacemaker implantation was a way to retain the patient's strength and protect their lives. It was a safety device for a good life without dizziness and fainting spells. Patients experience changes in their body appearance, and feel uncomfortable. Limitations and changes in the patient's role in the family after pacemaker implantation were seen as well as anxiety about their family members. Little confidence in pacemakers and its technology was experienced by a few patients, while others accept the pacemaker and experience it as part of their body. Conclusion: Experience that patients with pacemakers have is individual, therefore it is important that the nurse responds to these experiences and designs the care based on the patient's individual needs.

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第22074号 / 農博第2366号 / 新制||農||1072(附属図書館) / 学位論文||R1||N5228(農学部図書室) / 京都大学大学院農学研究科地域環境科学専攻 / (主査)教授 近藤 直, 准教授 小川 雄一, 教授 飯田 訓久 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

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No description available.

A fibrilação atrial (FA) é a arritmia cardíaca sustentada mais comum, de origem supraventricular, em que ocorre uma completa desorganização na atividade elétrica atrial, fazendo com que os átrios percam sua capacidade de contração, não gerando sístole atrial. É uma arritmia que acomete 1-2% da população mundial, sendo mais frequente em indivíduos idosos. Geralmente, está associada a algum tipo de doença cardíaca estrutural, podendo acarretar em complicações como o acidente vascular cerebral, internações e gastos com saúde. Algumas vezes a fibrilação atrial surge de forma precoce, em indivíduos jovens, saudáveis, e sem qualquer evidência de doença cardíaca estrutural ou de fatores desencadeantes, o que leva a hipótese da doença ter um componente genético. Trata-se de um estudo observacional, transversal, para identificação de possíveis variantes genéticas em pacientes portadores de fibrilação atrial isolada, a partir do sequenciamento de nova geração de um painel genético customizado para cardiomiopatias e canalopatias hereditárias. Foram incluídos 101 pacientes encaminhados pelo ambulatório de arritmias cardíacas do Instituto do Coração, que foram avaliados quanto às características clínicas principais antes de serem submetidos ao teste genético. A classificação das variantes em genes causais foi baseada nos critérios do American College of Medical Genetics and Genomics (ACMG). Foram sequenciadas e analisadas amostras de 101 pacientes, onde foram encontradas 144 variantes raras; 14/144 foram classificadas como patogênicas em relação à fibrilação atrial, 130/144 foram classificadas como de significado incerto, e em 28 dos 101 pacientes não foram encontradas variantes raras. Dos 101 pacientes 77,2% eram do sexo masculino, 87,1 % de raça branca, 75,2 % tinham fibrilação atrial paroxística, 52,4 % eram sintomáticos, 65,3% realizaram procedimento de ablação por cateter e 62,4% tinham história familiar de FA precoce, morte súbita, marcapasso e/ou insuficiência cardíaca. A presença dos achados genéticos esteve associada nos pacientes com FA que tinham história familiar de marcapasso e/ou morte súbita. A análise genética desta população permitiu um diagnóstico precoce de miocardiopatias hereditárias que se apresentaram inicialmente como FA isolada / Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia of supraventricular origin, with a complete disorganization in the electrical activity of the atria, losing their capacity of contraction, not generating atrial systole. It is an arrhythmia that affects up to 2% of the world population, appearing more often in elderly individuals. It is usually associated with some types of structural heart disease, which can lead to complications such as stroke, hospitalizations and health costs. In some times atrial fibrillation emerges early, in younger healthy people, with no apparent evidence of structural heart disease or triggering factors, leading to the hypothesis that the disease has a genetic component. This is a cross-sectional, observational study to identify possible genetic variants in patients with isolated atrial fibrillation from new generation sequencing and a customized genetic panel for inherited cardiomyopathies and channelopathies. A total of 101 patients were referred and evaluated by the Cardiac Arrhythmias Outpatient Unit of the Heart Institute for the main clinical characteristics before being submitted to the genetic test. The classification of variants into causal genes was based on the American College of Medical Genetics and Genomics (ACMG) criteria. Samples were sequenced and analyzed from 101 patients, were found 144 rare variants; 14/144 were classified as pathogenic in relation to atrial fibrillation and 130/144 were classified as uncertain significance, and in 28 of 101 patients no rare variants were found. Of the 101 patients, 77.2% were males, 87.1% were white, 75.2% had paroxysmal atrial fibrillation, 52.4% were symptomatic, 65.3% had a catheter ablation procedure, and 62.4% had a family history of early AF, sudden death, pacemaker and/or heart failure. The presence of genetic findings was associated in patients with AF who had a family history of pacemaker and / or sudden death. The genetic analysis of this population allowed an early diagnosis of hereditary cardiomyopathies that initially presented as isolated AF

Heart rhythm disorders alias arrhythmias rank among the most frequent heart diseases. They result from a disorder of generation or conduction of electric impulses at the heart. There are often arrhythmias of which one is not conscious and which may be detected in long-term ECG monitoring. Patients{\crq} problems mostly arise from rhythm disorders that are paroxysmal or permanent. These may endanger the patient{\crq}s life. Subjective troubles reported by patients include uncomfortable heart palpitation, fatigue, breathlessness, distress, shorter breath, dizziness or even unconsciousness; sometimes patients may feel unpleasant chest pain. These subjective feelings are very uncomfortable for a person suffering from heart arrhythmia and can make it impossible for him/her to manage routine daily activities. The task of a nurse is to help a patient overcome this difficult period and instruct him/her of a healthy lifestyle as a prevention of heart diseases. In this respect, cooperation between the nurses in hospitals and the nurses in cardiologic out-patient departments is important. Four hypotheses were raised. The first hypothesis was to confirm that the care of patients with heart arrhythmia after their discharge to home-care is sufficient in respect of their needs. This hypothesis was confirmed. The second hypothesis was to confirm that the patients are sufficiently instructed on prevention of recurrence of heart arrhythmias. This hypothesis was not confirmed. The third hypothesis was to confirm that patients know the impacts of heart arrhythmias on their overall health state, and was not confirmed. The fourth hypothesis was to confirm that patients are aware of other options of the care after discharge from hospital. This hypothesis was not confirmed. In the practical part of the thesis I used a quantitative research. The research was conducted in hospitals in České Budějovice, Jihlava, Plzeň and Prague, in the form of anonymous questionnaires distributed to patients in cardiologic out-patient departments. The results have been processed in charts and tables in the SPSS programme. The objectives were fulfilled. The appendix to the thesis contains a brief proposal suggesting on what the nursing care should be focused after a patient{\crq}s discharge from hospital. The results will be offered to deputy managers for the nursing care and to nurses in cardiologic out-patient departments.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-02-24T12:24:27Z No. of bitstreams: 1 brunogouveadebarros.pdf: 4637517 bytes, checksum: 0db5f859f17bd37484772dd26a331ce5 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-02-24T15:33:28Z (GMT) No. of bitstreams: 1 brunogouveadebarros.pdf: 4637517 bytes, checksum: 0db5f859f17bd37484772dd26a331ce5 (MD5) / Made available in DSpace on 2017-02-24T15:33:28Z (GMT). No. of bitstreams: 1 brunogouveadebarros.pdf: 4637517 bytes, checksum: 0db5f859f17bd37484772dd26a331ce5 (MD5) Previous issue date: 2013-02-25 / FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais / Os modelos computacionais tornaram-se ferramentas valiosas para o estudo e compreensão dos fenômenos da eletrofisiologia cardíaca. No entanto, a elevada complexidade dos processos biofísicos e o nível microscópico de detalhes exigem complexos modelos computacionais. Aspectos-chave da eletrofisiologia cardíaca, tais como condução lenta e bloqueio de condução tem sido tema de pesquisa de muitos estudos, uma vez que estão fortemente relacionados à arritmia cardíaca. No entanto, ao reproduzir estes fenômenos os modelos necessitam de uma discretização sub-celular para a solução das equações diferenciais e uma condutividade eléctrica do tecido não uniforme e heterogênea. Devido aos elevados custos computacionais de simulações que reproduzem a microestrutura fina do tecido cardíaco, estudos prévios têm considerado experimentos de tecido de pequenas dimensões e têm utilizados modelos simples de células cardíacas. Neste trabalho, desenvolvemos um modelo (modelo microscópico) da eletrofisiologia cardíaca que capta a microestrutura do tecido cardíaco usando uma discretização espacial muito fina (8µm) e utilizamos um modelo celular moderno e complexo baseado em Cadeias de Markov para a caracterização da estrutura e dinâmica dos canais iônicos. Para lidar com os desafios computacionais, o modelo foi paralelizado usando uma abordagem híbrida: a computação em cluster e GPGPUs (General-purpose computing on Graphics Processing Units). Nossa implementação paralela deste modelo, utilizando uma plataforma multi-GPU, foi capaz de reduzir os tempos de execução das simulações de mais de 6 dias (em um único processador) para 21 minutos (em um pequeno cluster de 8 nós equipado com 16 GPUs). Além disso, para diminuir ainda mais o custo computacional, foi desenvolvido um modelo discreto equivalente ao modelo microscópico. Este novo modelo foi paralelizado usando a mesma abordagem do modelo microscópico e foi capaz de executar simulações que demoravam 21 minutos em apenas 65 segundos. Acreditamos que esta nova implementação paralela abre caminho para a investigação de muitas questões em aberto associadas à natureza complexa e discreta da propagação dos potenciais de ação no tecido cardíaco. / Computer models have become valuable tools for the study and comprehension of the complex phenomena of cardiac electrophysiology. However, the high complexity of the biophysical processes and the microscopic level of details demand complex mathematical and computational models. Key aspects of cardiac electrophysiology, such as slow conduction, conduction block and saltatory effects have been the research topic of many studies since they are strongly related to cardiac arrhythmia. However, to reproduce these phenomena the numerical models need to use sub-cellular discretization for the solution of the PDEs and nonuniform, heterogeneous tissue electric conductivity. Due to the high computational costs of simulations that reproduce the fine microstructure of cardiac tissue, previous studies have considered tissue experiments of small or moderate sizes and used simple cardiac cell models. In this work we develop a cardiac electrophysiology model (microscopic model) that captures the microstructure of cardiac tissue by using a very fine spatial discretization (8µm) and uses a very modern and complex cell model based on Markov Chains for the characterization of ion channel's structure and dynamics. To cope with the computational challenges, the model was parallelized using a hybrid approach: cluster computing and GPGPUs (General-purpose computing on graphics processing units). Our parallel implementation of this model using a Multi-GPU platform was able to reduce the execution times of the simulations from more than 6 days (on a single processor) to 21 minutes (on a small 8-node cluster equipped with 16 GPUs). Furthermore, in order to decrease further the computational cost we have developed a discrete model equivalent to the microscopic one. This new model was also parallelized using the same approach as the microscopic model and was able to perform simulations that took 21 minutes to be executed in just 65 seconds. We believe that this new parallel implementation paves the way for the investigation of many open questions associated

Nous avons développé des méthodes de traitement d’image et de fusion multimodalité et les avons appliqué à l’étude des relations structure-fonction dans la fibrillation auriculaire et la tachycardie ventriculaire. Dans la fibrillation auriculaire, nos résultats indiquent que le rehaussement tardif par IRM est fortement associé à présence et à la persistance d’une fibrillation auriculaire. Nous avons par ailleurs démontré que ce rehaussement tardif est associé à des caractéristiques électrophysiologiques propres : le signal fibrillatoire est plus lent et moins fragmenté au sein des zones rehaussées, alors qu’à l’inverse la complexité globale de la fibrillation augmente avec l’étendue des rehaussements. Nos résultats préliminaires sur la distribution des rotors vont dans le même sens, ces derniers étant plus volontiers observés à la périphérie des zones rehaussées, et le nombre de régions actives augmentant avec l’étendue des rehaussements. L’ensemble de ces résultats confirme que l’imagerie de rehaussement tardif par IRM permet une caractérisation du tissu atrial. Dans les arythmies ventriculaires, nous avons développé une stratégie permettant l’intégration systématique de données non-invasives multimodales au cours des procédures d’ablation de tachycardie ventriculaire. Nous avons démontré l’intérêt d’une fusion scanner et IRM, et décrit une méthode permettant l’intégration du substrat ischémique à partir de données scanner applicable chez les patient porteurs de défibrillateurs ne pouvant bénéficier de l’IRM. Dans la dysplasie arythmogène du ventricule droit, nous avons introduit une méthode automatique de quantification et de cartographie du substrat dysplasique applicable au diagnostic et au guidage thérapeutique. Enfin, nous avons introduit une méthode d’exploration multimodale des arythmies cardiaques intégrant la cartographie électrocardiographique 3D aux autres méthodes d’imagerie cardiaque, et permettant une exploration non invasive simultanée de l’anatomie, du substrat, et des mécanismes de l’arythmie / We have developed and applied image-processing methods to the study of structure-function relationships in atrial fibrillation and ventricular tachycardia. In Atrial Fibrillation, our results indicate that the late gadolinium enhancement observed with the use of MRI is strongly associated with the presence and persistence of the disease. In addition, we have demonstrated that these enhancements show distinctive electrophysiological characteristics: the fibrillatory signal is slower and less fractionated within enhanced areas, whereas the global complexity of atrial fibrillation is conversely increasing with the extent of enhancement. Our preliminary results on rotor distribution are consistent, rotors being more likely found at the border of enhanced areas, and the number of regions with high rotor activity being positively related to the extent of enhancement. These results confirm that late gadolinium enhancement MRI enables a non-invasive characterization of the atrial tissue. In Ventricular Arrhythmias, we have developed a strategy to integrate multimodal non-invasive data during ventricular tachycardia ablation procedures. We have demonstrated the value of fusing MDCT and MRI data and have introduced a method enabling the integration of ischemic substrate from MDCT data, feasible in patients with implantable defibrillator who cannot undergo MRI. In arrhythmogenic right ventricular cardiomyopathy, we have developed an automatic method for the mapping and quantification of fat in the right ventricular free wall based on MDCT data, and have successfully applied the method to the diagnosis and therapy guidance of the disease. Last, we have introduced a method for the multimodal assessment of cardiac arrhythmias combining electrocardiographic mapping with MDCT and MRI. The method enables a non-invasive and combined assessment of cardiac anatomy, myocardial structural substrate, and arrhythmia mechanisms.