The use of variability of repolarization for monitoring of arrhythmic risk : "the rocking of the boat"

Abstract

The majority of deaths in the western world are of cardiovascular origin. Approximately 60% of these cardiovascular deaths are sudden. Implantation of an implantable cardioverter defibrillator (ICD) has been proven effective in preventing sudden cardiac death in patients at increased risk. An ICD can monitor the heart for rhythms that are excessively fast (tachycardia) or chaotic (fibrillation) and apply a high-energy shock to restore normal sinus rhythm. Beat-to-beat variation in cardiac repolarization may hold information on the electrical stability of the heart and its susceptibility to arrhythmias. Monitoring this instability in an ICD may help guide therapy and prevent ICD shocks. In this thesis we investigated the use of short-term variability of repolarization duration (STV) for monitoring of arrhythmic risk in ICDs. For pre-clinical studies we used the dog with chronic atrio-ventricular block, as previous studies have shown that in this model STV is related to proarrhythmic remodeling of the heart, and predictive of drug-induced ventricular arrhythmia. We explored the steps to be taken to translate these results in animal experiments to a clinical application In a clinical setting, temporarily increasing heart rate through electrical stimulation is used to suppress torsade de pointes arrhythmias, but prolonged increase of heart rate can promote heart failure. Results are presented from a proof-of-concept study into STV guided heart rate modulation to prevent dofetilide-induced arrhythmia, in anesthetized dogs with chronic atrio-ventricular block. An increase in heart rate suppressed the arrhythmia, and this decrease in arrhythmic risk was reflected in lower values of STV. Furthermore, it was shown that STV can be derived from a chronic electrogram, as is used in an ICD to interpret cardiac rhythm. For evaluation of an algorithm that would modulate heart rate guided by STV-based risk estimation, prolonged testing would be required, limiting the use of anesthetics. However, anesthesia was found to be a critical factor in our current method of arrhythmia induction by dofetilide in our animal model. STV was determined in patients with structural heart disease using ICD electrograms. The long-term predictive value of baseline STV for sudden arrhythmic death was determined. Patients in the highest quartile of STV showed an almost twofold higher risk for sudden arrhythmic death. To further improve the predictive value of STV for ventricular arrhythmia, the mechanistic link between STV and proarrhythmia was investigated in the dog with atrio-ventricular block. Electrical remodeling and dofetilide only increased STV in a context of beat-to-beat changes in preload. This preload variability is a direct result of the dissociation between atrial and ventricular rhythms in this animal model. However, its importance for generation of STV had not been acknowledged previously. The response of repolarization (i.e. STV) to an external stimulus (i.e. variation in ventricular preload) unmasks the electrical lability of the heart. Changes in preload or other known variation in the environment of the heart may be used to improve sensitivity of STV for arrhythmic risk. A description and validation of the developed analysis methods for electrograms and monophasic action potentials are included in this thesis.