Studies on the Mechanisms of Cardiac Arrhythmias

: Role of stress, mapping atrial fibrillation and prediction of ventricular tachycardia origin

Abstract

Background Despite rapid advances in the treatment of complex cardiac arrhythmias major flaws remain in our understanding of the mechanisms underlying common arrhythmias. The incidence of life-threatening cardiac arrhythmias, primarily ventricular tachycardia, is significantly greater during times of psychological stress, but the underlying mechanism for this association is unclear. Sudden cardiac death remains a common cause of death in the developed world and our methods of risk stratification methods are sub-optimal. The underlying mechanism in persistent atrial fibrillation, the most common cardiac rhythm disorder, is very complex and remains controversial. Methods and Results 1. In subjects with structurally normal hearts undergoing invasive electrophysiology studies (n=19) unipolar electrograms were recorded from the right and left ventricle whilst watching an emotionally charged film, and repeated during a respiration control period. Activation recovery interval (ARI) decreased during the stress component (RV 193.8±14ms vs 198.0±13ms, LV 199.8±16ms vs 201.6±15ms, p=0.004). 2. In subjects with diseased hearts ARI was measured non-invasively from permanent epicardial left ventricular pacing leads during photographic and film-stimuli stress (n=16). ARI decreased during the stress periods (by 2.3 to 3.6ms for different sequences, p=0.02, 0.05).In addition ARI was observed to oscillate at the respiration frequency in 52% of recordings, and at the sympathetic 0.1Hz frequency in 55% of recordings. 3. An algorithm was developed that tested recent experimental work that identified the time interval between repolarization proximal to a line of functional block and the activation at the adjacent distal side, as a critical determinant of re-entry, termed the re-entry vulnerability index (RVI). This algorithm sampled all points on a multielectrode grid and calculated RVI between all pairs of electrodes within a given radius. Using data from an established Langendorff pig heart model the algorithm successfully identified the spatial region with increased susceptibility to re-entry. The feasibility of RVI mapping was evaluated during a clinical procedure by co-registering with the anatomy and physiology in a patient undergoing a VT ablation. 4. In patients undergoing ablation for persistent atrial fibrillation high density contact mapping was performed using bi-atrial 64 electrode mapping catheters (n=14). Phase singularities (PS) were located in both atria but we observed more PS in the left atrium (LA 779 ± 302, RA 552 ± 235, p=0.015). There was no significant difference in the mean dominant frequency (DF) in the LA compared to the right atrium. However, although some PS of duration sufficient to complete >1 rotation were detected, the maximum PS duration was only 1150ms, and the vast majority (97%) of PS persisted for too short a period to complete a full rotation. Whilst in selected patients there was evidence of PS local clustering, overall we found that PS were distributed globally throughout both chambers with no clear anatomical predisposition. Conclusions Our results document for the first time direct recordings of the effect of a mental challenge protocol on ventricular action potential duration in conscious humans. The effect of mental challenge on ARI was not secondary to emotionally-induced altered respiration or heart rate. The RVI algorithm accurately identified the region of re-entry in animal models of functional re-entry. The possibility of clinical application was demonstrated in a patient with VT. In the AF study no sustained rotors or localized drivers were detected, and instead the mechanism of arrhythmia maintenance was consistent with the multiple wavelet hypothesis, with passive activation of short-lived rotational activity.

Date of Award	2018
Original language	English
Awarding Institution	King's College London
Supervisor	Reza Razavi (Supervisor)