BACKGROUND: Atrial Fibrillation (AF) is the most common cardiac arrhythmia, affecting over 3 million Americans. Many people who suffer from AF have pre-disposing factors such as hypertension, ischemia, and structural heart disease, but recent research has also demonstrated the importance of genetic factors that can contribute to AF. In the present study, we sought to determine the causative mutation in a family with AF, atrial septal, and ventricular septal defects. METHODS: We evaluated a pedigree with 16 family members, one of whom had an ASD, one a VSD, and three had AF. Exome sequencing was performed on three of the five affected family members followed by confirmation with Sanger sequencing in all family members. A separate cohort from the MGH AF Study with early-onset AF (age at onset 47.1 ± 10.9 years, 79.3% male) was also screened for mutations using a combination of Sanger sequencing and high resolution melting. Variants were then functionally characterized using reporter assays in a mammalian cell line using wild-type and mutant constructs driving NPPA, αMHC and NPPB promoter reporters. RESULTS: Exome sequencing of the three affected individuals in the family identified a highly conserved mutation, R585L, in the transcription factor gene, GATA6. We also identified three additional GATA6 variants (P91S, A177T, and A543G) in the cases with early-onset AF from the MGH AF Study. We found that three of the four variants had a marked upregulation of luciferase activity (R585L; 4.1 fold, p<0.0001; P91S; 2.5 fold, p=0.0002; A177T; 1.7 fold, p=0.03). Additionally, when co-overexpressed with GATA4 and MEF2C, all GATA6 variants exhibited upregulation of the αMHC and NPPA activity compared to control. CONCLUSION: Overall, we found gain-of-function mutations in GATA6 in both a family with early-onset AF and atrioventricular septal defects as well as in patients with sporadic, early-onset AF. This evidence suggests that specific gain of function mutations in GATA6 contribute to the development of AF. / 2017-06-16T00:00:00Z

Atrial Fibrillation (AF) is a debilitating heart rhythm disorder affecting over 2.7 million people in the US and over 30 million people worldwide annually. It has a high correlation with causing a stroke and several other risk factors, resulting in increased mortality and morbidity rate. Currently, the non-pharmocological therapy followed to control AF is catheter ablation, in which the tissue surrounding the pulmonary veins (PVs) is cauterized (called the PV isolation - PVI procedure) aims to block the ectopic triggers originating from the PVs from entering the atrium. However, the success rate of PVI with or without other anatomy-based lesions is only 50%-60%. A major reason for the suboptimal success rate is the failure to eliminate patientspecific non-PV sources present in the left atrium (LA), namely reentry source (a.k.a. rotor source) and focal source (a.k.a. point source). It has been shown from several animal and human studies that locating and ablating these sources significantly improves the long-term success rate of the ablation procedure. However, current technologies to locate these sources posses limitations with resolution, additional/special hardware requirements, etc. In this dissertation, the goal is to develop an efficient algorithm to locate AF reentry and focal sources using electrograms recorded from a conventionally used high-resolution multi-pole diagnostic catheter. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2019. / FAU Electronic Theses and Dissertations Collection

Thesis (M.S.M.) PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / BACKGROUND: Atrial fibrillation (AF) that occurs during acute critical illnesses such as sepsis may have different risk factors than AF that occurs in the community setting. METHODS: We investigated associations between baseline electrocardiographic (ECG) parameters related to conduction, ischemia, and chamber size and new-onset AF that occurs in the setting of severe sepsis in a matched case-referent study. We matched 100 patients with new-onset AF during sepsis to 300 patients with similar age (plus or minus 5 years) who were hospitalized within Boston Medical Center intensive care units (ICU) between 2003-2009 with sepsis. Variables that were found to be significant (p<0.05) during conditional univariable logistic regression were entered into age, sex and race-adjusted conditional logistic regression in order to identify risk factors for new-onset AF during sepsis. RESULTS: Among 100 case and 300 referent patients with sepsis, the distribution of mean age was 69 +/-11 years vs. 71 +/- 11 years, sex was 42% female vs. 49% female, and race was 56% white and 33% black vs. 65% white and 21% black between cases and referents, respectively. Univariable analysis revealed that older age per year [OR 1.25 95% CI (1.07-1.46), p<0.01], longer PR interval per millisecond [168 +/- 43 ms vs. 157 +/- 30 ms; OR 1.01 95% CI (1.00-1.02), p=0.02], and presence of left bundle branch block (LBBB) [9 (9%) vs. 7 (2.3%); OR 4.42 95% CI (1.45-13.5), p<0.01] were significant risk factors among the new-AF cases. Our multivariable model found significant associations between new-onset AF during hospitalization and presence of prolonged PR interval per millisecond [OR 1.01 95% CI (1.00-1.02), p=0.04] and LBBB [OR 6.83 95% CI (1.68-27.8), p=0.01] on ICU admission ECG. CONCLUSION: Increased PR interval length and LBBB found on a 12-lead ECG upon ICU admission was associated with new-onset AF during hospitalization in the setting of sepsis. / 2031-01-01

Abstract Brugada syndrome is an inherited arrhythmia disorder that predisposes to sudden cardiac death. It is characterized by its distinct ECG pattern. The purpose of this thesis was to study the phenotype and genotype characteristics of subjects with Brugada syndrome type ECG. The first study population consisted of 2479 young male Air Force applicants and 542 healthy middle-aged subjects. The 12-lead ECG was analyzed to assess the prevalence and prognosis of Brugada pattern in Finnish population. The second population consisted of 168 patients with AF. The ECGs of the patients with family history of lone AF were analysed in order to characterize the ECG features of familial AF. The third population consisted of 200 patients with Brugada syndrome and their ECGs were analyzed for detection of distinct ECG characteristics. In a substudy, the H558R variant was genotyped and the clinical presentation of this variant was evaluated. The clinical characteristics were collected of 47 patients with induced Brugada ECG during fever or medication. The prevalence of type 2 or 3 Brugada ECG was 0.61% in the young population and 0.55% in the middle-aged Finnish population. In a retrospective analysis, none of the Brugada ECG carriers had died. In the AF study, the prevalence of type 2 or 3 Brugada ECG was significantly higher among the subjects with lone AF compared to the healthy controls (p &lt; 0.001). Many of the Brugada ECG carriers had a family history (> 30% of first-degree relatives) of AF. In patients with Brugada syndrome, the prolonged QRS duration was associated with previous symptoms. The R allele carriers in H558R variant had a trend towards less symptoms (p = 0.067) and had less conduction disturbances in 12-lead ECG than the HH genotype carriers (p &lt; 0.05 in all ECG analysis). Among the subjects with induced Brugada ECG, 51% exhibited arrhythmic symptoms during the medical condition that had provoked the ECG pattern. In conclusion, type 2 and 3 Brugada ECGs were found to be benign in the Finnish population since no mortality occurred during an extensive follow-up period. On the other hand, these ECG abnormalities seem to be a marker of familial AF. Among patients with the Brugada syndrome, a prolongation of QRS is associated with prior symptoms. The variant H558R R allele seems to be a protecting genetic modulator. Induced Brugada ECG is a medical emergency since the patients are at high risk of sudden cardiac death.

Class of 2015 Abstract / Objectives: Warfarin has historically been the anticoagulant used for the primary prevention of stroke in atrial fibrillation (AF), however three target specific oral anticoagulants, dabigatran, rivaroxaban, and apixaban, have recently been approved for use in this setting. Current literature lacks a comparison of these four drugs in relation to post-stroke outcomes, and this study aims to compare their performance in a natural setting. Methods: This retrospective cohort study identified stroke patients admitted to an academic medical center between January 2013 and December 2014 using the Quintiles, Inc.-American Heart Association Get With The Guidelines-Stroke database; pertinent data was collected from the database and patient electronic medical records. Primary endpoints measured were length of stay, 30-day readmission, and discharge disposition; secondary endpoints included rates of admission to the intensive care unit (ICU) and complications. Results: Of 940 stroke admissions, 53 ischemic stroke patients were identified as receiving an oral anticoagulant for stroke prevention in AF. The warfarin (n=40) and non-warfarin (dabigatran, rivaroxaban, and apixaban; n=13) groups were well matched regarding admission demographics, however patients taking warfarin were more likely to have an elevated INR at hospital admission (P=0.0053) and receive tPA (P=0.047). Patients in the warfarin group were also statistically significantly more likely to receive warfarin on discharge (P=0.004). No endpoints achieved statistical significance. Conclusions: No differences in post-stroke outcomes between warfarin and non-warfarin oral anticoagulants used for stroke prevention in AF were found.

Cardiovascular disease remains the leading cause of death in the developed world. In this thesis computational modelling techniques were used to study the mechanisms and genesis of atrial arrhythmias. It is separated into 2 parts: (1) The mechanistic links between mutations of the fast Na+ channel (INa) and the ability of the sinoatrial node to pace the surrounding atrial muscle were investigated. The mutations were separated into two groups, one for the mutations affecting the steady-state activation, and the other for those affecting steady-state inactivation. On the single cell level it was found that all mutations slowed the pacing rate of the sinoatrial node in a similar way, but at the 2D level the two mutation groups modulated the excitation of the tissue differently. One caused a conduction block between the sinoatrial node and atrium, where the other abolished pacemaking all together. (2) A new set of mathematical models were then developed for the sheep atria. This was incorporated into an anatomically detailed 3D geometry of the whole sheep atria to form a platform suitable for the study of clinical atrial fibrillation, and other atrial arrhythmias. Due to the lack of single cell electrophysiology data available, a method of cross-species modelling was utilised. A biophysically detailed model of the 3D sheep atria was created, and used in a preliminary study into the susceptibility of tissue to atrial fibrillation from the rapid pacing of the pulmonary vein area. It was found that both electrical heterogeneity and the complex fibre structure of the atria need to be considered for sustained atrial fibrillation to be seen.

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La fibrillation atriale (FA) est le trouble du rythme cardiaque le plus fréquent et dont la prévalence est en constante augmentation. Les extrasystoles déclenchant cette arythmie naissent le plus souvent des veines pulmonaires. Ainsi l’ablation des veines pulmonaires est devenue un traitement important de cette arythmie, surtout quand elle est paroxystique. Cependant le maintien de la FA est assuré par du substrat atrial pathologique.Le traitement endocavitaire de ce substrat comprend essentiellement l’ablation de potentielsfragmentés enregistrés en FA.Nous avons démontré que ces potentiels fragmentés existent aussi en rythme sinusal etqu’une partie de ces potentiels pouvait être générée par une activation vagale myocardiquelocale.Par ailleurs cette ablation de FA présente de nombresuses complications dont certaines sont potentiellement graves comme par exemple la tamponnade.Nous avons montré que la ponction transseptale nécessaire pour réaliser cette intervention pouvait être effectuée de manière sure en utilisant un monitorage du septum interatrial parechocardiographie endovasculaire utilisée par voie oesophagienne, diminuant ainsi le risque de tamponnade.Nous avons aussi montré que la présence d’une récidive d’arythmie précoce (<1 mois) postablationétait hautement prédictive d’une récidive tardive et qu’une réablation précoce dansle mois suivant la première intervention était efficace mais nécessitait un nombre plusimportant de procédures pour obtenir une efficacité stable dans le tempsPar ailleurs, nous avons montré que l’ablation de FA générait une importante inflammation systémique et que cette inflammation était associée à un taux plus faible de récidives précoces mais non tardives.Enfin nous avons montré qu’un cycle fibrillatoire rapide< 142 ms, une ancienneté de la FA >21 mois et une amplitude de l’onde fibrillatoire < 0.07 mV étaient des facteurs importants d’échec d’ablation de FA persistante. / Pas de résumé anglais