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.

Abstract Short QT syndrome is an inherited arrhythmia disorder characterized by a short QT interval, typical T-wave and ST-segment morphology and an increased risk of sudden cardiac death. The purpose of this thesis was to study the epidemiology and prognosis of the subjects with short QT intervals. Special attention was paid to the ECG changes that could illustrate the prognosis of subjects with short QT interval. The first study comprised a group of patients with short QT syndrome. We report clinical presentation, ECG morphology, the prevalence of genetic mutations and the results of therapies in this group of patients. The second study population consisted of 10 822 randomly selected middle-aged subjects followed up for 29 ± 10 years. QT intervals were measured using three correction methods for the heart rate in order to assess the prevalence and prognosis of those subjects with short QT intervals. The third population consisted of three patients with short QT syndrome and nine controls. Holter recordings were analyzed to compare transmural dispersion of repolarization between patients and controls and also to study their capability to change repolarization indexes from baseline to maximal values. In the fourth study ECGs from 10 patients with short QT syndrome were compared with ECGs of 12 asymptomatic subjects with short QT intervals. The aim was to find ECG abnormalities that would predict the outcome of the patients. We found 62% of patients to be symptomatic, 34% had cardiac arrest. Atrial fibrillation was common. Most of the patients received an ICD or were placed on hydroquinidine. The prevalence of QTc < 320ms was 0.10% and QTc < 340ms was 0.4%, respectively. Mortality or other serious symptoms did not differ between subjects and controls. We also found that the TPE/QT ratio as an index for abnormal transmural dispersion of repolarization was high compared to controls. Short QT syndrome patients had also lesser capacity to change the QT interval, indicating blunted autonomic response in SQTS. Ten SQTS patients had significantly shorter Jpoint–Tpeak interval and higher TPE/QT ratio compared to controls. In conclusion, shorter than normal QT interval might represent a novel short QT syndrome. However, in the general community short QT interval can reflect only the extreme end of the normal Gaussian distribution of QT intervals and these subjects carry a good prognosis. TPE/QT ratio and Jpoint–Tend intervals can be used as risk stratifiers in subjects with short QT intervals.