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To develop a novel myocardial deformation index that is highly sensitive to the effect of cardiac resynchronization therapy (CRT) and that can be used to predict response to CRT.Before and 6.5 ± 2.3 months after implantation of a CRT device, longitudinal shortening and stretch were timed and quantified by speckle tracking echocardiography in a cohort of 62 patients. Distinction was made between systolic total stretch (STS; all systolic stretch) and systolic rebound stretch (SRS; only systolic stretch following initial shortening). Systolic total stretch and SRS could be measured in all wall segments in 41 of 62 patients. Septal SRS quantification was possible in all 62 patients and was performed by a blinded observer. Cardiac resynchronization therapy reduced STS (−55 ± 30%) but reduced SRS (−77 ± 21%) significantly more (P < 0.01). The largest amount of baseline SRS and the largest reductions in SRS (−90 ± 22%) were found in the septum. Reductions in local SRS were paralleled by increases in local systolic shortening that were twice as large (r=0.79), thereby strongly improving septal function. Baseline values of septal SRS correlated with reductions in left ventricular end-systolic volume index (ΔLVESVi; r=0.62) and brain-type natriuretic peptide (BNP) (Δlog10BNP; r=0.57). Septal SRS was an independent predictor of CRT response in linear regression analysis and predicted ΔLVESVi of ≥15% with a sensitivity and specificity of 81% at ROC analysis (areas under the curve 0.89 ± 0.04).Septal rebound stretch appears to be a sensitive and practical diagnostic criterion to quantify the functional substrate amenable to CRT and to predict response.