Class III antiarrhythmic drugs share the common mechanism of widening the cardiac action potential without affecting conduction velocity. This thesis reports on the actions of newly developed putative Class III antiarrhythmic drugs, tedisamil, KC 8851, RP 62719, UK 68798, and risotilide, as well as an ATP-sensitive K⁺ channel blocker, glibenclamide. Studies were performed to examine the actions of these drugs in acute myocardial ischaemia and possible mechanisms responsible for these actions. The hypothesis tested was that drug treatment prevented arrhythmias induced by acute myocardial ischaemia. Species dependent actions of these drugs on ECG and blood pressure were examined in rats, guinea pigs, pigs and primates. The five putative class III drugs listed above were assessed for antiarrhythmic activity in a conscious rat model of myocardial ischaemia. It was found that only tedisamil and KC 8851, which widened the Q-T[formula omitted] interval of the ECG (by up to 65%) , were effective at suppressing fibrillation in this species. None of the drug treatments decreased the incidence of ventricular premature beats. Tedisamil, but not glibenclamide, prevented tachycardias in a rat model of myocardial ischaemia- and reperfusion-induced arrhythmias. In an anaesthetized pig model of acute myocardial ischaemia, tedisamil and UK 68,798 were shown to mildly prolong the Q-T[formula omitted] interval by less than 20%, but protection against arrhythmias was equivocal. In further studies, tedisamil and UK 68,798 were compared to each other for effects on ventricular epicardial action potential morphology using intracellular recording in vivo, and effects on ventricular effective refractory period using electrical stimulation in vivo in both rats and guinea pigs. Tedisamil (4 mg/kg, i.v.) prolonged rat ventricular epicardial action potential duration fourfold in vivo, while UK68,798 (up to 1 mg/kg, i.v.) was ineffective in this species. Tedisamil (4 mg/kg, i.v.) widened guinea pig ventricular epicardial potentials by 80%, while UK 68,798 (25 μg/kg, i.v.) increased these by 30%. Action potential widening paralleled increases in ventricular refractoriness to electrical induction of premature beats. It was found that the species selective actions of these drugs was most likely related to differences in selectivity for K⁺ channels which contribute to repolarization in myocardium. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

Background: The right ventricular outflow tract (RVOT) is known to be the origin of potentially dangerous ventricular tachycardias (VT). Arrhythmias can occur in what are otherwise assume to be structurally normal hearts as well as in arrhythmia syndromes like Brugada syndrome, catecholaminergic polymorphic VT and arrhythmogenic right ventricular dysplasia. In adults with surgically corrected tetralogy of Fallot (ToF), VT often originates in the RVOT. Methods: To investigate potential arrhythmia substrates in the structurally normal heart, the RVOT of adult rats was investigated and compared to the right ventricle (RV). In the human, the right atrium (RA), RV and the RVOT were examined in patients free of electrical and structural disease at the time of clinically indicated surgery on the left heart. The same tissue samples were collected from adults with surgically corrected ToF at the time of pulmonary valve replacement. Real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to explore changes on the mRNA level. Antibody based techniques (immunohistochemistry and Western blot) and mass spectrometry were used to identify changes on the protein level. In the rat RVOT, fine microelectrodes were employed to investigate electrophysiological characteristics. Results: A reduction in the Na+ channel Nav1.5 was found in the structurally normal RVOT in the rat and human. In the rat, RVOT-nodal like myocytes were identified. Unlike ventricular myocytes, the myocytes did not express the gap junction channel Cx43 and the K+ channel Kir2.1, but they did express the pacemaker Ca2+ channel Cav3.2 and the transcription factor Tbx3. Ectopic pacemaker and nodal-like action potentials with phase 4 depolarization were recorded from the region of the pulmonary valve. In the RA of ToF patients, SERCA2A was found to be downregulated (mRNA and protein) as seen in heart failure and atrial fibrillation. Further widespread remodelling was found in the RA, the RV and RVOT identifying multiple changes as seen in heart failure with downregulation of K+ channels and β-receptors and an increase in inflammatory markers and extracellular matrix molecules. Multiple molecules involved in the mitochondrial respiration chain were found to be downregulated in the RVOT of ToF patients. Conclusion: This is the first study that demonstrates reduction in Nav1.5 in the RVOT of structurally normal human hearts. The changes found in the rat RVOT could explain why arrhythmias originate in the RVOT. The widespread remodelling in ToF, especially in the ECM, could form a substrate for reentry arrhythmias. Mitochondrial dysfunction could point towards potential treatment targets for heart failure in this patient group.

A amiodarona é um dos fármacos mais usados para o tratamento de arritmias cardíacas, tanto ventriculares como supraventriculares. Apesar de sua eficácia, o uso da amiodarona está associado a vários efeitos adversos, incluindo a toxicidade pulmonar. O mecanismo pelo qual a amiodarona causa lesão nas células pulmonares humanas não é inteiramente conhecido, mas estudos em cultura de células hepáticas humanas e pulmonares de ratos têm sugerido que a disfunção mitocondrial e o estresse oxidativo têm um papel importante na citotoxicidade da amiodarona. Os compostos fenólicos, incluindo catequina e epicatequina são amplamente distribuídos na natureza e conhecidos por sua capacidade de reduzir o estresse oxidativo. Além disso, alguns compostos fenólicos são capazes de modular a atividade mitocondrial. Em vista disso, o objetivo deste trabalho foi avaliar a capacidade dos compostos fenólicos catequina e epicatequina em a disfunção mitocondrial e os danos oxidativos causados pela amiodarona em células de fibroblasto de pulmão humano (MRC-5). Para atingir os objetivos as células MRC-5 foram tratadas com diferentes concentrações de catequina e epicatequina e após foram expostas a amiodarona 100 μM. A disfunção mitocondrial foi determinada através da atividade do complexo I da cadeia de transporte de elétrons e a biossíntese de ATP usando kits específicos. A viabilidade celular foi avaliada através do ensaio de 3-[4,5- dimetiltiazol 2-il]-2,5 difenil brometo de tetrazolina. A atividade das enzimas superóxido dismutase e catalase foram determinadas espectrofotometricamente. Os danos oxidativos a lipídeos e proteínas foram verificados através dos ensaios de substâncias reativas ao acido tiobarbitúrico e a proteínas carboniladas, respectivamente, e os níveis de óxido nítrico foram avaliados usando o método de Griess. Os resultados mostraram que a amiodarona inibiu a atividade do complexo I da cadeia de transporte de elétrons em 53% e a biossíntese de ATP em 9,5% e tanto a catequina como a epicatequina foram capazes de evitar estes efeitos em todas as concentrações (5, 10, 20 μM) testadas. Verificou-se que a amiodarona reduziu a atividade das enzimas superóxido dismutase e catalase (indicando produção de superóxido e peróxido de hidrogênio) e aumentou os danos oxidativos a lipídeos e proteínas. Os compostos fenólicos catequina e epicatequina foram capazes de minimizar as alterações no metabolismo redox induzidos pela amiodarona e aumentar a viabilidade nas células MRC-5. Catequina e epicatequina reduziram a depleção de óxido nítrico causada pela amiodarona. Este trabalho mostrou, pela primeira vez, que o mecanismo de toxicidade da amiodarona em células MRC-5 está associado à disfunção mitocondrial, principal causa de geração de dano oxidativo celular e que estes efeitos tóxicos são em parte reduzidos pela catequina e epicatequina. Embora outros estudos sejam necessários, estes dados abrem novas perspectivas para estudos visando o desenvolvimento de medicamentos que minimizem os efeitos tóxicos da amiodarona. / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, CAPES. / Amiodarone is among the most widely used drugs for the treatment of ventricular and supraventricular cardiac arrhythmias. However, the use of amiodarone is associated with several side effects including pulmonary toxicity. The mechanism of amiodarone toxicity is not well known, but studies in human liver cells and rats lung cells have been suggested that mitochondrial dysfunction and oxidative stress play important role in the amiodarone cytotoxicity. Phenolic compounds, including catechin and epicatechin are widespread in nature and known for their ability to reduce oxidative stress. In addition, some phenolic compounds are able to modulate mitochondrial activity. Therefore, the objective of this study was to evaluate the ability of phenolic compounds catechin and epicatechin to minimize the mitochondrial dysfunction and oxidative damage induced by amiodarone in human lung fibroblast cells (MRC-5). To achieve the objectives, MRC-5 cells were treated with different concentrations of catechin and epicatechin and then amiodarone 100 μM. Mitochondrial dysfunction was determined by the activity of complex I of the electron transport chain and ATP biosynthesis using specific kits. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The activity of the enzymes superoxide dismutase and catalase were determined spectrophotometrically. The oxidative damage to lipids and proteins have been verified through the test substances reactive to the thiobarbituric acid and carbonyl protein, respectively, and nitric oxide levels were evaluated using the Griess method. The results showed that amiodarone inhibit 53% of the activity of complex I of the electron transport chain and 9.5% of ATP biosynthesis and both catechin and epicatechin were able to avoid these effects in all concentrations (5 10, 20 mM) tested. It was found that amiodarone reduced the superoxide dismutase and catalase activities (indicating the production of radicals superoxide and hydrogen peroxide) and increased oxidative damage to lipids and proteins. Phenolic compounds catechin and epicatechin were able to minimize alterations in the redox metabolism and increase in viability of MRC-5 cells. Furthermore, catechin and epicatechin reduced nitric oxide depletion caused by amiodarone. This study showed, for the first time, that toxicity of amiodarone in human lung cultured cells is associated, at least, in part, with mitochondrial dysfunction which was avoided by catechin and epicatechin. Although further studies are needed, these data open new perspectives for studies aiming the development of drugs that minimize the toxic effects of amiodarone.

Protein stability is critical for the proper function of all proteins in the cell. Ubiquitin is a key post-translational modification that serves as a universal regulator of protein turnover and has emerged as a highly sought-after signal for biological inquiry and drug development. Yet the pervasive role of ubiquitin signaling has given rise to the fundamental challenge of selectively manipulating a widespread signal: current pharmacological and genetic tools that target the ubiquitin-proteasome system (UPS) broadly alter cellular proteostasis with confounding side effects. Ion channels are essential proteins that regulate fundamental cellular properties including; electrical activity, fluid homeostasis, muscle contraction, neuronal firing, gastric acidification, and gene expression. Enhanced or reduced ion channel expression represents a pathological signature for a myriad of disease states, from chronic pain to cardiac arrhythmias, epilepsy, and cystic fibrosis. Although ubiquitin represents a critical mediator of ion channel expression, the inability to precisely manipulate ubiquitin modifications in situ has limited mechanistic insight and opportunities for therapeutic intervention. To address this barrier, I developed a novel nanobody-based toolset to selectively – and bidirectionally – manipulate the ubiquitin status and functional expression of target ion channels for basic study and therapeutic rescue.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23423号 / 医博第4768号 / 新制||医||1053(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 渡邊 直樹, 教授 湊谷 謙司, 教授 山下 潤 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

In the heart, sodium (Na+) influx via NaV1.5 channels initiates the action potential, and calcium (Ca2+) influx via CaV1.2 channels has a key role in excitation-contraction coupling and determining the plateau phase of the action potential. Mutations in the genes that encode these ion channels or in proteins that modulate them are linked to arrhythmias and cardiomyopathy, underscoring the need for characterizing mechanisms of regulation. The work presented in this thesis is subdivided into three different chapters, each with a distinct focus on ion channel modulation. The first chapter details our investigation of the functional PKA phosphorylation target for β-adrenergic regulation of CaV1.2. Physiologic β-adrenergic activation of PKA during the sympathetic “fight or flight” response increases Ca2+ influx through CaV1.2 in cardiomyocytes, leading to increased cardiac contractility. The molecular mechanisms of β-adrenergic regulation of CaV1.2 in cardiomyocytes are incompletely known, but activation of PKA is required for this process. Recent data suggest that β-adrenergic regulation of CaV1.2 does not require any combination of PKA phosphorylation sites conserved in human, guinea pig, rabbit, rat, and mouse α1C subunits. To test if any non-conserved sites are required for regulation, we generated mice with inducible cardiac-specific expression of α1C with mutations at both conserved and non- conserved predicted PKA phosphorylation sites (35-mutant α1C). Additionally, we createdanother mouse with inducible cardiac-specific expression of β2 with mutations at predicted PKA phosphorylation sites (28-mutant β2B). In each of these mice, β-adrenergic stimulation of Ca²⁺ current was unperturbed. Finally, to test the hypothesis that redundant functional PKA phosphorylation sites exist on the α1C subunit and β2 subunit or that several sites confer incremental regulation, we crossed the 35-mutant α1C mice with the 28-mutant β2B mice to generate offspring expressing both mutant subunits. In these offspring, intact regulation was observed. These results provide the definitive answer that phosphorylation of the α1C subunit or β2 subunit is not required for β-adrenergic regulation of CaV1.2 in the heart. In the second chapter, we study the influence of calmodulin and fibroblast growth homologous factor (FHF) FGF13 on late Na+ current. Studies in heterologous expression systems show that the Ca²⁺-binding protein calmodulin plays a key role in decreasing late Na⁺ current. The effect of loss of calmodulin binding to NaV1.5 on late Na+ current has yet to be resolved in native cardiomyocytes. We created transgenic mice with cardiac-specific expression of human NaV1.5 channels with alanine substitutions for the IQ motif (IQ/AA), disrupting calmodulin binding to the C-terminus. Surprisingly, we found that the IQ/AA mutation did not cause an increase late Na⁺ current in cardiomyocytes. These findings suggest the existence of endogenous protective mechanisms that counteract the increase in late Na+ current that occurs with loss of calmodulin binding. We reasoned that FGF13, a known modulator of late Na+ current that is endogenously expressed in cardiomyocytes but not HEK cells, might play a protective role in limiting late Na+ current. Finally, we coexpressed the IQ/AA mutant NaV1.5 channel in HEK293 cells with FGF13 and found that FGF13 diminished the late Na⁺ currentcompared to cells without FGF13, suggesting that endogenous FHFs may serve to prevent late Na⁺ current in mouse cardiomyocytes. The third chapter of this thesis focuses on the use of proximity labeling and multiplexed quantitative proteomics to define changes in the NaV1.5 macromolecular complex in Duchenne muscular dystrophy (DMD), in which the absence of dystrophin predisposes affected individuals to arrhythmias and cardiac dysfunction.. Standard methods to characterize macromolecular complexes have relied on candidate immunoprecipitation or immunocytochemistry techniques that fall short of providing a comprehensive view of the numbers and types of interactors, as well as the potential dynamic nature of the interactions that may be perturbed by disease states. To provide an inclusive understanding of NaV1.5 macromolecular complexes, we utilize live-cell APEX2 proximity labeling in cardiomyocytes. We identify several proximal changes that align with the electrophysiological NaV1.5 phenotype of young dystrophin-deficient mice, including a decrease in Ptpn3 and Gdp1l and an increase in proteasomal machinery. Whole-cell protein expression fold-change results were used to reveal the altered global expression profile and to place context behind NaV1.5-proximal changes. Finally, we leveraged the neighborhood- specificity of proteins at the lateral membrane, intercalated disc, and transverse tubules of cardiomyocytes to demonstrate that NaV1.5 channels can traffic to all three membrane compartments even in the absence of dystrophin. Thus, the approach of proximity labeling in cardiomyocytes from an animal model of human disease offers new insights into molecular mechanisms of NaV1.5 dysfunction in DMD and provides a template for similar investigations in other cardiac diseases.

Background: Since its introduction in the early 2000s, energy drinks have become increasingly popular among an extensive range of consumers, including adolescents and young adults. Currently, the United States Food and Drug Administration (FDA) does not regulate the formulation of energy drinks, which may vary widely in the amounts of caffeine and sugar, as well as various types of supplements. Recent reports of severe and fatal adverse effects related to energy drinks have led to growing concerns on the safety of energy drink consumption. Objective: This study aimed to investigate the effects of chronic daily consumption of energy drinks on cardiometabolic endpoints, including blood pressure, ECG parameters, blood glucose, lipid parameters, weight, body mass index, and body fat consumption in a healthy adult population. Methods: The study was an unblinded, non-randomized, proof-of-concept, prospective study that evaluated the effects of chronic consumption of energy drinks in a healthy, adult population. Each participant consumed two 16 oz. cans of a commercially available ED daily in two divided doses for 28 days. Investigators met with the participants on days 0, 7, 14, 21, and 28 of the study. Participants were required to complete a standardized log of consumption, which include date and time of consumption, as well an estimate of additional caffeine intake. The following measurements were taken for each participant over the 28 days: blood pressure (BP), electrocardiogram (ECG), fasting blood glucose (FBG), fasting lipid panel (FLP), weight, BMI, body fat composition, and serum creatinine. Adverse side effects related to energy drink consumption were also recorded. Wilcoxan signed-rank tests were used to compare and detect statistical difference between endpoints for baseline and maximum post-dose systolic BP, QTc, FBG, FLP, weight, BMI, body fat, and serum creatinine values. Results: Of the 14 total participants that were enrolled in the study, 12 participants completed the full study protocol for 28 days. Maximum measurements in peripheral systolic blood pressure (pSBP), peripheral diastolic blood pressure (pDBP), central systolic blood pressure (cSBP), central diastolic blood pressure (cDBP), and heart rate (HR) were found to be statistically significantly higher than baseline measurements (all P < 0.05). The maximum change from baseline to maximum pSBP, pDBP, cSBP, and cDBP were 9±7 mmHg, 5±4 mmHg, 7±6 mmHg, 5±4 mmHg, respectively. Maximum QTcB and QTcF intervals were also statistically higher than baseline (both P = 0.001). The maximum change from baseline in QTcB and QTcF interval were 19±13 ms and 15±10 ms, respectively. Both QTcB and QTcF intervals on days 7, 14, 21, and 28 were all found to be significantly higher than baseline (all P Results: Of the 14 total participants that were enrolled in the study, 12 participants completed the full study protocol for 28 days. Maximum measurements in peripheral systolic blood pressure (pSBP), peripheral diastolic blood pressure (pDBP), central systolic blood pressure (cSBP), central diastolic blood pressure (cDBP), and heart rate (HR) were found to be statistically significantly higher than baseline measurements (all P < 0.05). The maximum change from baseline to maximum pSBP, pDBP, cSBP, and cDBP were 9±7 mmHg, 5±4 mmHg, 7±6 mmHg, 5±4 mmHg, respectively. Maximum QTcB and QTcF intervals were also statistically higher than baseline (both P = 0.001). The maximum change from baseline in QTcB and QTcF interval were 19±13 ms and 15±10 ms, respectively. Both QTcB and QTcF intervals on days 7, 14, 21, and 28 were all found to be significantly higher than baseline (all P

Bakgrund: Arytmi innebär en avvikande rytm hos hjärtat, alltså att det uppstått en avvikelse i impulsbildning och/eller impulsfortledning. Det kan inverka negativt på livskvalitén, orsaka följdsjukdomar eller leda till livshotande tillstånd. Utöver den konventionella behandlingen finns det behov av ytterligare alternativ. Magnesium är ett essentiellt mineralämne som är viktigt för hjärtats elektrofysiologi. Det har i tidigare studier visat sig att magnesium har haft effekt på postoperativt uppkomna arytmier och att låga nivåer av magnesium hos en frisk population har ökat risken för utvecklandet av olika arytmier. Magnesiums föreslagna antiarytmiska egenskaper är därför av intresse att studera vidare.  Syfte: Syftet med studien är att studera om magnesium har någon antiarytmisk effekt hos individer med arytmi.  Metod: En litteraturstudie genomfördes avseende relevanta artiklar publicerade i databasen PubMed från år 2000 och framåt. En relevansbedömning och kvalitetsgranskning genomfördes med utgångspunkt från Statens beredning för medicinsk och social utvärderings (SBU) metodbok.  Resultat: Tolv artiklar inkluderades i litteraturstudien varav sju uppvisade en antiarytmisk effekt av magnesium. En antiarytmisk effekt vid förmaksflimmer uppvisades i samtliga studier där det administrerades mer än 4 gram intravenöst magnesium. Eftersom magnesium i olika former har olika biotillgänglighet skulle formen eventuellt också kunna vara en bidragande faktor till effekten men studiematerialet var för litet gällande olika magnesiumformer. Vidare går det inte att särskilja om magnesium har olika effekt på olika arytmier då representationen av respektive arytmi var för liten. Slutsats: Magnesium har en antiarytmisk effekt vid administrering över 4 gram intravenöst. Huruvida detta gäller för fler arytmier än förmaksflimmer framkommer inte av denna litteraturstudie. Det finns ett behov av fler studier för att dels undersöka vilken som är den eventuella optimala formen och dosen av magnesium, dels för att utreda vilka typer av arytmier som verkar mottagliga för magnesium som behandlingsalternativ. / Background: Arrhythmia means a deviating rhythm in the heart, either in impulse formation and/or impulse conduction. It can adversely affect the quality of life, cause sequelae or lead to life-threatening conditions. In addition to the conventional treatment, there is a need for alternatives. Magnesium is an essential mineral that is important for the electrophysiology of the heart. Previous studies have shown that magnesium has had an effect on postoperative arrhythmias and that low levels of magnesium in a healthy population have increased the risk of developing various arrhythmias. The proposed antiarrhythmic properties of magnesium are therefore of interest for further study.  Aim: The aim of the study is to investigate whether magnesium has any antiarrhythmic effect in individuals with arrhythmias.  Methods: A literature study was conducted regarding relevant articles published in the PubMed database from the year 2000 and until today. Relevance assessment and quality review were carried out on the basis of  Swedish Agency for Health Technology Assessment and Assessment of Social Services (SBU) method book.  Results: Twelve articles were included in the literature study, seven of which showed an antiarrhythmic effect. An antiarrhythmic effect in atrial fibrillation was shown in all studies where more than 4 grams of intravenous magnesium was administered. Since magnesium in different forms has different bioavailability, the form could possibly also be a contributing factor to the effect, but the study material was too small for different forms of magnesium. Furthermore, it is not possible to distinguish whether magnesium has different effects on different arrhythmias as the representation of each arrhythmia was too small.  Conclusions: Magnesium has antiarrhythmic effect when administrated in excess of 4 gram intravenously. Whether this applies to more arrhythmias than atrial fibrillation does not emerge from this literature study. There is a need for more studies to investigate the possible optimal form and dose of magnesium, and to investigate which types of arrhythmias seem susceptible to magnesium as a treatment alternative.

Background: Arrhythmias are a collection of heart conditions that affect almost half of the world’s population and accounted for roughly 32.1% of all deaths in 2015. More importantly, early detection of arrhythmia through electrocardiogram analysis can prevent up to 90% of deaths. Neural networks are a modern and increasingly popular tool of choice for classifying arrhythmias hidden within ECG-data. In the pursuit of achieving increased classification accuracy, some of these neural networks can become quite complex which can result in overfitting. To combat this phenomena, a technique called regularization is typically used. Thesis’ Problem Statement: Practically all of today’s research on utilizing neural networks for arrhythmia detection incorporates some form of regularization. However, most of this research has chosen not to focus on, and experiment with, regularization. In this thesis we measured and compared different regularization techniques in order to improve arrhythmia classification accuracy. Objectives: The main objective of this thesis is to expand upon a baseline neural network model by incorporating various regularization techniques and compare how these new models perform in relation to the baseline model. The regularization techniques used are L1, L2, L1 + L2, and Dropout. Methods: The study used quantitative experimentation in order to gather metrics from all of the models. Information regarding related works and relevant scientific articles were collected from Summon and Google Scholar. Results: The study shows that Dropout generally produces the best results, on average improving performance across all parameters and metrics. The Dropout model with a regularization parameter of 0.1 performed particularly well. Conclusions: The study concludes that there are multiple models which can be considered to have the greatest positive impact on the baseline model. Depending on how much one values the consequences of False Negatives vs. False Positives, there are multiple candidates which can be considered to be the best model. For example, is it worth choosing a model which misses 11 people suffering from arrhythmia but simultaneously catches 1651 mistakenly classified arrhythmia cases? / Bakgrund: Arytmier är en samling hjärt-kärlsjukdomar som drabbar nästan hälften av världens befolkning och stod för ungefär 32,1% av alla dödsfall 2015. 90% av dödsfallen som arytmi orsakar kan förhindras om arytmin identifieras tidigare. Neurala nätverk har blivit ett populärt verktyg för att detektera arytmi baserat på ECG-data. I strävan på att uppnå bättre klassificeringsnogrannhet kan dessa nätverk råka ut för problemet ’overfitting’. Overfitting kan dock förebyggas med regulariseringstekniker. Problemställning: Praktiskt taget all forskning som utnyttjar neurala nätverk för att klassifiera arytmi innehåller någon form av regularisering. Dock har majoriteten av denna forsknings inte valt att fokusera och experimentera med regularisering. I den här avhandlingen kommer vi att testa olika regulariseringstekniker för att jämföra hur de förbättrar grundmodellens arytmiklassificeringsförmåga. Mål: Huvudmålet med denna avhandling är att modifiera ett neuralt nätverk som utnyttjar transfer learning för att klassificera arytmi baserat på två-dimensionell ECG-data. Grundmodellen utökades med olika regulariseringstekniker i mån om att jämföra dessa och därmed komma fram till vilken teknik som har störst positiv påverkan. De tekniker som jämfördes är L1, L2, L1 + L2, och Dropout. Metod: Kvantitativa experiment användes för att samla in data kring teknikernas olika prestationer och denna data analyserades och presenterades sedan. En litteraturstudie genomfördes med hjälp av Summon och Google Scholar för att hitta information från relevanta artiklar. Resultat: Forskningen tyder på att generellt sett presterar Dropout bättre än de andra teknikerna. Dropout med parametern 0.1 förbättrade mätvärderna mest. Slutsatser: I specifikt denna kontext presterade Dropout(0.1) bäst. Dock anser vi att falska negativ och falska positiv inte är ekvivalenta. Vissa modeller presterar bättre än andra beroende på hur mycket dessa variabler värderas, och därmed är den bästa modellen subjektiv. Är det till exempel värt att låta 11 personer dö om det innebär att 1651 personer inte kommer att vidare testas i onödan?

Idiopathic ventricular tachycardias, which occur in patients without structural heart disease, are a common entity, representing up to 10% of all ventricular tachycardias evaluated by cardiac electrophysiology services. Pregnancy can increase the incidence of various cardiac arrhythmias. Factors that can potentially promote arrhythmias in pregnancy include the effects of hormones, changes in autonomic tone, hemodynamic perturbations, hypokalemia, and underlying heart disease. Ventricular arrhythmias in pregnancy are repetitive monomorphic ventricular premature complexes and couplets that frequently originate at the right ventricular outflow tract. New onset symptomatic repetitive right ventricular outflow tract ventricular tachycardia during pregnancy has been inadequately reported in the literature. We present a case of symptomatic repetitive right ventricular outflow tract tachycardia that started during pregnancy and continued in the postpartum period, requiring curative treatment with electrophysiology study and radiofrequency ablation.