Thesis (Ph. D.)--University of Washington, 1994. / Vita. Includes bibliographical references (leaves [159]-165).

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.

The recently identified genetic short QT syndrome is characterised by abbreviated QT intervals on the electrocardiogram, an increased risk of atrial and ventricular arrhythmias, and an increased risk of sudden death. Although the short QT syndrome has been suggested to provide a paradigm for increasing understanding of the role of potassium channels in ventricular fibrillation, the basis for arrhythmogenesis in the short QT syndrome is incompletely understood. There are no animal models that accurately reproduce a short QT phenotype, and whilst in vitro electrophysiology of short QT mutant channels provides a route to greater understanding of the effects of short QT mutants on action potential repolarisation, on its own, this approach is insufficient to explain how arrhythmias arise and are maintained at the tissue level. Consequently, this thesis is concerned with the use of the viable alternative; in silico (computational) modelling to elucidate how the short QT syndrome facilitates the genesis and maintenance of ventricular arrhythmias and its effects on ventricular contraction. Using extant biophysical data on changes induced by the short QT mutations and data from BHF-funded in vitro electrophysiology, three novel mathematical models of the first three variants of the short QT syndrome were developed; a Markov chain model for short QT variant 1, a Markov chain model for short QT variant 2 and a Hodgkin-Huxley model for short QT variant 3. These models were incorporated into single cell and anatomically detailed tissue and organ computer models to elucidate how these variants lead to ventricular arrhythmias. The developed short QT models were then incorporated into electromechanically coupled single cell and tissue models to investigate the effects of the short QT mutants on ventricular contraction. It was found that each short QT variant uniquely increased the transmural dispersion of action potential duration across the ventricular wall, increased the temporal window of tissue vulnerability to premature excitation stimulus, leading to increased susceptibility to re-entrant arrhythmia.

No description available.

No description available.

A solution to distinguish ventricular fibrillation and ventricular flutter from other arrhythmias and from disturbances caused by body motion or muscle activity with the use of a neural network has been investigated. Ventricular fibrillation and ventricular flutter occurs when the cardiac muscle cells are not triggered by the cardiac conduction system, but rather by ectopic foci preventing a synchronized contraction of the cardiac muscle cells and therefore inhibiting the hearts capability to properly pump blood. Two different methods, gradient descent and quasi-Newton, used by the network for learning was tested and preprocessing methods used on the input data before introducing it to the network was evaluated. Gradient descent makes use of the gradient to the error function with regards to its weights and updates the network in the direction which the output error by the network decreases the most. Quasi-Newton update the network roughly in the Newton direction by iteratively build up an approximation to the Hessian of the error function with the use of information from the gradient. The preprocessing methods used were: Threshold Crossing Intervals (TCI) which looks at the time between baseline crossings of the ECG signal. Mean Absolute Value (MAV) which computes the mean absolute value of the normalized ECG signal. Spectral Analysis which takes into account different properties of the frequency spectrum of ventricular fibrillation and normal sinus rhythm. VF-filter which assumes VF to be sinusoidal and computes the leakage after the ECG signal has been bandstop filtered around the mean frequency. Period and Amplitude Information of the maximum amplitude of the input frequency spectrum and its period. It was found that the networks that used the preprocessed signal was a poor classifier for the arrhythmias partially because ventricular fibrillation was not easily separable from the arrhythmias by the implementaion of the preprocessed inputs given.

Indiana University-Purdue University Indianapolis (IUPUI) / Insulin is a hormone that plays a central role in the regulation of human metabolism, and as a drug, is used in the treatment of diabetes mellitus. Hyperglycemia characterizes this condition due to a range of reasons from impaired insulin production by pancreatic beta cells to abnormalities resulting in resistance to insulin action. Depending on time and mechanism of action, the main types of insulin analogs are basal and prandial. Basal insulin analogs are slow-acting insulins that maintain a continuous basal level of insulin in the bloodstream. Prandial insulin analogs are fast-acting and their therapeutic goal is to avoid immediate and late post-prandial hyperglycemia. Most analogs face the problem of chemical degradation and amyloid-like fibril formation (fibrillation) in delivery devices. Thus, many modifications have been made to insulin in the effort to make it more stable and faster-acting. This thesis aims to study the effects of modifications that could be used to design an insulin analog with improved chemical and physical properties, while maintaining biological activity. We studied six amino-acid substitutions to native human insulin in different combinations: desB1 , AB2 , EB3, EA8 , EA14, and EB29. Analogs of the protein were chemically synthesized. Then, fibrillation and circular dichroism assays were performed using purified proteins. The results suggested that EB3 and EA14 are stabilizing modifications that prevent fibril formation, whereas EA8 and EA14 increase the structural stability of an analog. Our findings also suggested that certain modifications in isolation may not impact overall stability, but when combined with others, may show detectable effects, which is why EA8 and EA14 became the focus of further experiments. Cell-based activity assays indicated that all the analogs had similar biological activities. Future work will assess chemical degradation, solubility, amide proton exchange (as monitored by NMR), and mitogenicity.