Ventricular repolarization in the human heart : Effects of pharmacological and non-pharmacological interventions

University dissertation from Stockholm : Karolinska Institutet, Department of Medicine

Abstract: Ventricular arrhythmias is the main cause of sudden cardiac death. A prolonged repolarization might cause such arrhythmias, and an increased understanding about mechanisms is therefore important for their primary and secondary prevention.The present research program was set up to investigate ventricular repolarization in the human heart, and the effects of pharmacological and non-pharmacological interventions assessed by standard, signal-averaged, and vectorcardiographic methods. In study I, the time-dependent variation in QT interval and QT dispersion was investigated in 10 healthy individuals before and after administration of a repolarization-prolonging antiarrhythmic drug. In response to disopyramide the QT interval prolonged consistently, but there were no systematic changes in QT dispersion. In contrast to the QT interval, QT dispersion is not a reliable tool to assess changes in an individual patient due to considerable time-dependent intra-individual variation. Furthermore, the large variation of QT dispersion has to be taken into account when designing interventional studies in order to avoid type II-errors. In study II, coronary occlusion during percutaneous transluminal coronary angioplasty (PTCA) in 29 individuals was used as a human model of regional transient ischemia, and induced an increased QT dispersion, and a characteristic change in T vector loop morphology, a novel method, which has the potential for assessing repolarization changes online. In study III, 40 patients were included to investigate if atrioventricular (AV) junctional radiofrequency (RF) ablation was followed by a time-dependent, altered repolarization that could be related to the observed risk for early ventricular arrhythmia after the procedure. There was a time and rate dependent shortening of repolarization during the first week after the procedure, compatible with a transient pro-arrhythmic response. We suggest that the early phase after AV junctional RF ablation can be regarded as a variant of the acquired Long QT Syndrome. Based on a retrospective analysis of 259 patients, we suggest as a routine pacing at a rate of 80 bpm during the first week after ablation to decrease the risk for serious arrhythmic events, and monitoring in hospital for at least 48 hours after the procedure (study IV). In study V, the effect of 12 months combined hormone replacement therapy on electrocardiographic measures of depolarization and repolarization was assessed and compared to placebo in 46 postmenopausal women with cardiovascular disease. Hormone replacement therapy did not affect repolarization measures. The inverse relation between serum concentrations of sex hormones and repolarization measures suggests that androgens rather than estrogens might affect repolarization. In study VI, depolarization and repolarization measures were assessed by standard and signal-averaged ECG in patients with hypertrophic obstructive cardiomyopathy before and after DDD pacing under conditions presumed to induce cardiac memory. The presence of cardiac memory was associated with changes in the relation between depolarization and repolarization, and repolarization was shorter during DIDD pacing compared to sinus rhythm. In conclusion, administration of dispoyramide, PTCA and AV junctional RF ablation are all potentially pro-arrhythmic interventions, which induced systematic changes in repolarization. These changes were more accurately assessed by the QT interval, and the T vector loop morphology than by QT dispersion. Furthermore, sex hormones, androgens rather than estrogens, seem to affect repolarization. Ventricular (DDD) pacing in patients with hypertrophic obstructive cardiomyopathy was associated with changes in depolarization and repolarization, which might reflect an antiarrhythmic effect.

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