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Objectives: This study sought to investigate if contractile asymmetry between septum and left ventricular (LV) lateral wall drives heart failure development in patients with left bundle branch block (LBBB) and whether the presence of lateral wall dysfunction affects potential for recovery of LV function with cardiac resynchronization therapy (CRT)., Background: LBBB may induce or aggravate heart failure. Understanding the underlying mechanisms is important to optimize timing of CRT., Methods: In 76 nonischemic patients with LBBB and 11 controls, we measured strain using speckle-tracking echocardiography and regional work using pressure-strain analysis. Patients with LBBB were stratified according to LV ejection fraction (EF) ≥50% (EF preserved ), 36% to 49% (EF mid ), and ≤35% (EF low ). Sixty-four patients underwent CRT and were re-examined after 6 months., Results: Septal work was successively reduced from controls, through EF preserved , EF mid , and EF low (all p < 0.005), and showed a strong correlation to left ventricular ejection fraction (LVEF; r = 0.84; p < 0.005). In contrast, LV lateral wall work was numerically increased in EF preserved and EF mid versus controls, and did not significantly correlate with LVEF in these groups. In EF low, however, LV lateral wall work was substantially reduced (p < 0.005). There was a moderate overall correlation between LV lateral wall work and LVEF (r = 0.58; p < 0.005). In CRT recipients, LVEF was normalized (≥50%) in 54% of patients with preserved LV lateral wall work, but only in 13% of patients with reduced LV lateral wall work (p < 0.005)., Conclusions: In early stages, LBBB-induced heart failure is associated with impaired septal function but preserved lateral wall function. The advent of LV lateral wall dysfunction may be an optimal time-point for CRT., Competing Interests: Funding Support and Author Disclosures Drs Sletten and Aalen were supported by grants from the Norwegian Health Association. Dr Larsen was a recipient of a clinical research fellowships form the South-Eastern Norway Regional Health Authority. Prof Voigt holds a personal research mandate of the Flemish Research Council. Prof Voigt and Dr Duchenne were further supported by a grant of the University of Leuven. Dr Smiseth is co-inventor, but since May 24, 2017 has had no financial relations to the patent “Method for myocardial segment work analysis,” which was used to calculate the myocardial work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose, (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)