Ventricular Repolarization and the Long QT Syndrome

In 1895 Willem Einthoven first described the electrocardiogram. The electrical activation of the heart and its translation into the body surface ECG was revealed by Durrer in 1970. Yet, 100 years after the first ECG, we still don't understand the repolarization of the heart, and most 'knowledge' on the T-wave and ECG interpretation therefore is empirical. Most experiments have been performed in animal models, in isolated cells, or wedge preparations. In such wedge preparations a group of midmural cells have been described in the dog, that have intrinsically longer action potentials. However, such a midmural zenith in action potential duration has not been observed in in vivo studies, not in the dog and not in the human (this thesis). Strong coupling between cells and cell layers probably abolishes intrinsic differences between the cells, if even they exist. The long QT syndrome is a hereditary disease in which repolarization is prolonged. It is characterized by a long QT interval on the ECG and the occurrence of life-threatening cardiac arrhythmias. The two most common forms of this syndrome are type 1 and 2, which are based on mutations in potassium channels. Clinical differences exist between these 2 subtypes, e.g. with regards to triggering stimuli for arrhythmic events. However, in this thesis it is shown that typical triggers for patients with the long QT syndrome type 2, startling or a loud acoustic stimulus, are only typical for a subgroup of mutation types and locations and not for the whole long QT 2 population. We show that similar differences exist within subtypes of long QT 2 for ECG parameters, response to ß-blockers, and the occurrence of arrhythmias. The long QT syndrome bore the promise, because of its monogenetic nature, to be simple disease model to increase our understanding of repolarization and related disorders. Yet the uncovering of large variations in clinical presentation not only between, but also within subtypes, complicates the picture