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Objectives: This study sought to investigate how regional left ventricular (LV) function modifies septal motion in left bundle branch block (LBBB)., Background: In LBBB, the interventricular septum often has marked pre-ejection shortening, followed by immediate relengthening (rebound stretch). This motion, often referred to as septal flash, is associated with positive response to cardiac resynchronization therapy (CRT)., Methods: In 10 anesthetized dogs, we induced LBBB by radiofrequency ablation and occluded the circumflex (CX) (n = 10) and left anterior descending (LAD) (n = 6) coronary arteries, respectively. Myocardial dimensions were measured by sonomicrometry and myocardial work by pressure-segment length analysis. In 40 heart failure patients with LBBB, including 20 with post-infarct scar and 20 with nonischemic cardiomyopathy, myocardial strain was measured by speckle-tracking echocardiography and myocardial work by pressure-strain analysis. Scar was assessed by cardiac magnetic resonance imaging with late gadolinium enhancement., Results: During LBBB, each animal showed typical septal flash with pre-ejection shortening and rebound stretch, followed by reduced septal systolic shortening (p < 0.01). CX occlusion caused LV lateral wall dysfunction and abolished septal flash due to loss of rebound stretch (p < 0.0001). Furthermore, CX occlusion restored septal systolic shortening to a similar level as before induction of LBBB and substantially improved septal work (p < 0.001). LAD occlusion, however, accentuated septal flash by increasing rebound stretch (p < 0.05). Consistent with the experimental findings, septal flash was absent in patients with LV lateral wall scar due to lack of rebound stretch (p < 0.001), and septal systolic shortening and septal work far exceeded values in nonischemic cardiomyopathy (p < 0.0001). Septal flash was present in most patients with anteroseptal scar., Conclusions: LV lateral wall dysfunction and scar abolished septal flash and markedly improved septal function in LBBB. Therefore, function and scar in the LV lateral wall should be taken into account when septal motion is used to evaluate dyssynchrony., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)