High density mapping of ventricular scar: insights into mechanisms of ventricular tachycardia.

Ventricular tachyarrhythmias related to structural heart disease are the most common cause of sudden cardiac death. Many of these occur in patients with ventricular scarring, related predominantly to coronary artery disease or dilated cardiomyopathies. These regions of scarring remodel over time with ongoing collagen turnover and do not stay stable, such that patients are often subject to repeated episodes of the arrhythmia. Ventricular scars are composed of variable regions of dense interstitial fibrosis that create conduction block, interspersed with viable myocyte channels with diminished coupling which produce substrate for circuitous slow conduction pathways that promote reentry. During sinus rhythm, these channels can be identified by the presence of late potentials and long stimulus to QRS intervals during pacing in the channel. A high density of sampling in the left ventricle allows recording of small amplitude electrograms that are of fundamental emphasis in ventricular substrate mapping. Several studies have characterized channels in patients with ventricular scar and ventricular tachycardia (VT). However, there has been no assessment on the functional characteristics of these channels and whether channels that are critical to the VT circuit differ from non-VT channels. Chapter 1 reviews literature on arrhythmic burden and epidemiology of scar related VT, its cellular mechanisms, substrate characterization, techniques of VT mapping and gaps in the current knowledge. Chapter 2 presents the high density characterization of substrate in ischemic cardiomyopathy (lCM) patients with W and compares the features of VT supporting channels with channels that do not support VT. This study showed that compared to non-VT channels, VT channels are more often located in the dense scar, longer in length, have long stimulus to QRS latencies and slower conduction velocity. Chapter 3 describes the electrogram properties in regions of VT channels, and development of a stepwise model from multiple electrogram properties to ensemble regions supporting VT(s) during sinus rhythm. It also discusses the application of Shannon entropy, a fundamental measure of information content in signals, to map VT channels in sinus rhythm. This system of ablation along with high density mapping will significantly advance VT mapping and help individualize substrate based ablation. Chapter 4 presents data on high density characterization of substrate in ICM patients with W and compares with those who do not have spontaneous VT. It showed that patients without spontaneous VT have fewer channels with shorter lengths and faster conduction, compared to VT patients. These observations partly explain the relative higher predilection of few selected surviving myocyte channels in the post infarct ventricles to sustain VT. Structural heterogeneity in the scar produces spatial and temporal disturbances in ventricular repolarization over multiple time scales. Chapter 5 evaluates the role of acute autonomic modulation on beat-to-beat QT variability in patients with heart failure with and without VT and contrasts it with patients without structural heart disease. It showed that acute pacing and humoral modulation including beta-blockade fail to bring down high repolarization instability in heart failure patients and VT. Catheter ablation is the mainstay for treatment of recurrent ventricular arrhythmias in patients with structural heart disease. Chapter 6 analyses published literature on ventricular arrhythmia storm ablation in a systematic review and meta-analysis. It showed that the interventions are safe and patients often need multiple procedures including non-radiofrequency ablation measures. Although patients who had successful ablation had good long-term outcomes, a failed procedure portended an early and high rate of mortality compared with medically managed historic controls. It raised a pertinent concern of possible harmful effects of catheter ablation in a high risk patient population. In summary, this thesis has developed innovative insights into the surviving myocyte channels in patients with ischemic cardiomyopathy. It describes a novel tool for ventricular substrate mapping that is readily applicable in the clinical laboratory. The repolarization instability is elevated in these patients and is resistant to modulation by acute beta-blocker treatment. Finally, catheter ablation is safe and should be advised in most patients with ventricular arrhythmia storm.Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 201