Left Bundle Branch Area Pacing: Clinical and Mechanistic Evaluation

Abstract

Left bundle branch area pacing (LBBAP) has emerged as a promising physiological alternative for pacing, capable of restoring synchrony by engaging the native conduction system. This thesis systematically evaluates LBBAP across diverse clinical contexts through five complementary studies, providing mechanistic insights and clinical validation to support its adoption in routine practice. The first study compares LBBAP with biventricular pacing (BVP) cardiac resynchronization therapy (CRT) in patients with heart failure (HF) and broad QRS, demonstrating that LBBAP is at least as effective, with superior improvements in left ventricular ejection fraction (LVEF), reductions in left ventricular end-systolic volume (LVESV), better QRS narrowing, and enhanced quality of life (QoL). LBBAP was associated with significantly fewer HF hospitalizations and healthcare encounters, and with better long-term lead performance. The second study evaluates electrocardiographic (ECG) markers in patients with non-ischemic cardiomyopathy undergoing LBBAP. It shows that paced qR morphology and transition during threshold test predicted greater improvement in LVEF while R wave peak time (RWPT), measured from the pacing stimulus to the peak of the R wave in lead V6, lacked predictive value. Loss of terminal 'R' in lead V1 and prolongation of RWPT on follow up prognosticated non-response to LBBAP. The third study, PACE HF randomized trial, enrolled patients with preserved or mildly reduced LVEF and pacing indications requiring significant ventricular pacing. It demonstrated that LBBAP preserved or improved LVEF, significantly reduced HF hospitalizations and cardiovascular mortality, and lowered the incidence of new-onset atrial fibrillation compared to conventional right ventricular pacing (RVP). Structural reverse remodeling and improved NYHA class further reinforced its clinical superiority. The fourth study is the first randomized controlled trial comparing lumenless leads (LLL) and stylet-driven leads (SDL) for left bundle branch pacing (LBBP). Both lead systems demonstrated high success rates, comparable procedure times, and similar pacing thresholds with no significant differences in complications, suggesting that either system can be safely and effectively used for LBBAP based on operator preference and availability. Finally, the fifth study explores the mechanistic basis of response heterogeneity to LBBAP in HF population using electrocardiographic imaging (ECGi). Super-responders (20% or greater improvement in LVEF) had significantly greater reductions in left ventricular and biventricular activation times and improvement in ventricular electrical uncoupling compared to partial-responders (LVEF improvement of 10% or less). A reduction in LVtat 26.86% or greater was highly predictive of confirmed left bundle branch (LBB) capture (AUC 0.96), which in turn predicted 7.4-fold odds of super-response in Bayesian analysis. RWPT did not correlate with outcomes, emphasizing the need for physiologically grounded metrics to establish LBB capture during implantation. Together, these studies establish LBBAP as a physiologically superior pacing strategy capable of delivering meaningful clinical and electrophysiological benefits. The findings support its consideration as an alternative to BVP-CRT and a preferable option over RVP in pacing for bradyarrhythmia. This work provides robust evidence for refining implantation strategies, guiding future guideline updates, and fostering broader adoption of LBBAP in clinical practice. Show more