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.

Tocainide carbamoyl ester glucuronlde (TOCG) (R-NHCO.O-GA) is a major metabolite of tocainide (TonocardR). The structure of TOCG was first proposed by Elvin (35) based on the structure of 3-(2,6-xylyl)-5-methylhydantoln, a base hydrolyzed product of TOCG in urine. Due to the presence of two carbonyl groups on the hydantoin ring, TOCG was proposed to arrive from a novel metabolic pathway involving the addition of carbon dioxide to the terminal nitrogen of tocainlde followed by glucuronic acid conjugation. With the initial intention of carrying out a bioavailability study of tocainide using a deuterated pseudoracemic sample, the stereospecific synthesis of R(-)- and S(+)-trideuterated tocainide was attempted through two synthetic approaches. This thesis describes a chemical reaction between tocainide and urea, a second pathway which leads to the formation of 3-(2,6-xylyl)-5-methylhydantoin through a tocainide ureide intermediate. With this observation, a tocainide N-ureide glucuronide structure (R-NHCO.NH-GA) was proposed for TOCG in support of the theory that an in vivo reaction between tocainide and urea may have resulted a tocainide N-ureide which can be further conjugated with glucuronic acid. Attempts were made to assign the correct structure of TOCG by identification of the theoretical tocainide carbamic acid (based on Elvln's proposed structure) or the tocainide N-ureide intermediate in urine. This thesis also describes the preparative HPLC isolation and the structural characterization of this novel glucuronic acid conjugate. Evidence obtained as proof for the identity of TOCG as a conjugate was obtained from acid hydrolysis, basic hydrolysis, beta-glucuronidase hydrolysis, with or without the presence of sacchro-1,4-lactone, and a naphthoresorcinol color test. Structural evidence for the carbamoyl ester linkage of TOCG was obtained from proton-NMR and FAB analysis. The 400-MHz proton NMR data of the isolated glucuronide provided partial evidence for the intact structure of TOCG. In FAB analysis, the [M+1] ion adduct at m/z 413, [M+Na] at m/z 435, and [M-H+2Na] at m/z 457 have provided positive evidence for the molecular ion of TOCG at m/z 412 in favor of the carbamoyl ester structure. In addition to the hydrolysis of TOCG at pH > 12 to the hydantoin, this hydantoin was found to also undergo spontaneous first-order hydrolysis at pH > 12. To assay the levels of TOCG in urine as the hydantoin, a set of accurately timed calibration samples were employed in an assay protocol to take Into account the spontaneous hydrolysis of the hydantoin. Based on this analytical approach, the levels of TOCG were determined in three subjects both after an IV and oral dose of 200 mg tocainide HC1. The urinary excretion half-lives of TOCG of 13.86 hours and 13.33 hours, after an IV and oral dose respectively, were found to agree with literature values. / Pharmaceutical Sciences, Faculty of / Graduate

Cardiac conduction abnormalities can often lead to heart failure, stroke and sudden cardiac death. Heart disease stands as the leading cause of mortality and morbidity in the United States, accounting for 30% of all deaths. Early detection of malfunctions such as arrhythmias and systolic heart failure, the two heart conditions studied in this dissertation, would definitely help reduce the burden cardiovascular diseases have on public health and overcome the current clinical challenges. The imaging techniques currently available to doctors for cardiac activation sequence mapping are invasive, ionizing, time-consuming and costly. Thus, there is an undeniable urgent need for a non-invasive and reliable imaging tool, which could play a crucial role in the early diagnosis of conduction diseases and allow physicians to choose the best course of action. The 12-lead electrocardiogram (ECG) is the current non-invasive clinical tool routinely used to diagnose and localize cardiac arrhythmias prior to intracardiac catheter ablation. However, it has limited accuracy and can be subject to operator bias. Besides, QRS complex narrowing on the clinical ECG after pacing device implantation is also used for response assessment in patients undergoing Cardiac Resynchronization Therapy (CRT). The latter is an established treatment for systolic heart failure patients who have Left Bundle Branch Block as well as a reduced ejection fraction and prolonged QRS duration. Yet, it is still not well understood why 30 to 40 % of CRT recipients do not respond. Echocardiography, due to its portability and ease-of-use, is the most frequently used imaging modality in clinical cardiology. In this dissertation, we assess the clinical performance of Electromechanical Wave Imaging (EWI) as a high frame rate ultrasound-based functional modality that can non-invasively map the electromechanical activation of the heart, i.e., the transient deformations immediately following the electrical activation. The objective of this dissertation is to demonstrate the potential clinical value of EWI for both arrhythmia detection and CRT characterization applications. The first step in translating EWI to the clinic was ensuring that the technique could reli- ably and reproducibly measure the electromechanical activation sequence independently of the probe angle and imaging view in healthy human volunteers (n=7). This dissertation then demonstrated the accuracy of EWI for localizing a variety of ventricular and atrial arrhythmias (accessory pathways in Wolff-Parkinson-White (WPW) syndrome, premature ventricular contractions, focal atrial tachycardia and macro-reentrant atrial flutter) in pediatric (n=14) and adult (n=55) patients prior to catheter ablation more accurately than 12-lead ECG predictions, as validated against electroanatomical mapping. Additionally, 3D-rendered EWI isochrones were illustrated to be capable of significantly distinguishing different biventricular pacing conditions (p≤0.05) with the RWAT and LWAT metrics, assessing the ventricular dyssynchrony change in heart failure patients (n=16) undergoing CRT, and visualizing it in 3D. EWI also provided quantification of %𝘙𝘔𝘓𝘝 in CRT patients (n=38): the amount of left-ventricular resynchronized myocardium, which was found to be a reliable response predictor at 3-, 6-, or 9-month clinical follow-up through its post-CRT values by significantly identifying super-responders from non-responders within 24 hours of implantation (p≤0.05). Furthermore, 3D-rendered isochrones successfully characterized the ventricular activation resulting from His Bundle pacing for the first time (n=4), which was undistinguishable from true physiological activation in sinus rhythm healthy volunteers with the EWI-based activation time distribution dispersion metric. The dispersion was, however, reported to significantly discriminate novel His pacing from other more conventional biventricular pacing schemes (p≤0.01). Finally, we developed and optimized a fully automated zero-crossing algorithm towards a faster, more robust and less observer dependent EWI isochrone generation process. The support vector machine (SVM) and Random Forest machine learning models were both shown capable of successfully identifying the accessory pathway in WPW patients and the pacing electrode location in paced canines. Nevertheless, the best performing algorithm was hereby proven to be the Random Forest classifier with n=200 trees with a precision rising to 97%, and a predictivity that was not impacted by the type of testing dataset it was applied to (human or canine). Overall, in this dissertation, we established the clinical potential of EWI as a viable assisting visual feedback tool, that could not only be used for diagnosis and treatment planning prior to surgical procedures, but also for monitoring during, and assessing long-term resolution of arrhythmia after catheter ablation or heart failure after a CRT implant.

Atrioventricular nodal reentrant tachycardia (AVNRT) is an abnormal heart rhythm caused by aberrant electrical conduction within the AV node. AVNRT is the most common type of paroxysmal supraventricular tachycardia (PSVT), with approximately 50,000 new cases per year in the United States. Catheter ablation of AV node tissue has become the first-line definitive treatment for AVNRT, owing to its high efficacy, tolerability, and safety. Two modalities of ablation, radiofrequency (RF) and cryoablation are commonly utilized in clinical practice with high levels of success in treating AVNRT. To date, studies on the two modalities have compared metrics such as acute success rate, procedure time, fluoroscopy time, and recurrence of AVNRT. Recurrence of AVNRT has been observed as far as 10 years after RF ablation. In patients with a history of RF ablation for AVNRT, rates of atrial fibrillation are higher than that of the general population. However, long-term studies directly comparing RF and cryoablation outcomes do not exist. This retrospective cohort study is designed to examine the rates of AVNRT recurrence and new arrythmias in patients 10 to 15 years after receiving either RF or cryoablation. To accomplish this, eligible participants will have their medical records reviewed for documentation of AVNRT recurrence, atrial fibrillation, atrial flutter, and complete AV block requiring pacemaker implantation. In doing so, we hope to give providers more insight into the risk profiles for each modality.

No description available.

Dravet syndrome (DS) is a severe form of pediatric epilepsy with characterizations of pharmacoresistant seizures and developmental delay. A rarer variant of the DS model is caused by heterozygous loss-of-function mutations in SCN1B, which is essential in regulating sodium channel gating, expression, localization, and the firing of action potentials. Mutations in SCN1B result in severe seizures as well as a higher risk of Sudden Unexpected Death in EPilepsy (SUDEP). Factors underlying SUDEP are poorly understood, although cardiac arrythmias have been implicated. Acebutolol (ACE) is a common beta-blocker used in the treatment of arrhythmias and hypertension. We hypothesized that treating mice with ACE will decrease cardiac arrhythmias and the incidence of SUDEP, prolonging lifespan of Scn1b null mice. Wild-type (WT) and null (KO) mice were given daily injections of 10 mg/kg ACE or saline starting at postnatal day 15 (after typical seizure onset) either during the day (09:00) or at night (21:00). ECG was recorded daily including a baseline and a 20-minute post injection measurement to analyze the long-term and acute effects of treatment. 20 minutes following ACE injection, KO mice displayed a significant reduction in heart rate compared to WT (38% vs. 11%). Interestingly, HR the day prior to death consistently dropped ~50% (average 414 bpm to 193 bpm) in our saline group; this was prevented in KO animals treated with ACE (421 bpm). A modest, but significant, increase in survival curves in our KO animals was observed compared to saline treated mice for those given injections during the day (a 2 day increase in median survival). In addition, in this group, the onset of animal death was delayed. Surprisingly, in the mice injected during the night hours, there was a trend towards a decrease in lifespan. From these findings there is a notable hypersensitivity to ACE in this DS model. Leading up to death, we believe it is possible ACE assisted in decreased cardiovascular deficits that could lead to SUDEP and contributed to the modest increased lifespan. While we are still seeing death in the ACE treated group because of unnoticed, prolonged seizures, or other mechanisms of SUDEP. In addition, our results demonstrate the importance of timing in delivery of drugs targeted at SUDEP. Further work includes testing this hypothesis by adding 24 hour drug delivery or an anti-epileptic drug to see if lifespan is further affected is warranted.

No description available.

No description available.

No description available.

No description available.