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Dyssynchrony assessment in cardiac resynchronization therapy (CRT) is controversial, and there are no standard protocols for optimizing treatment. We studied the feasibility and reproducibility of several echocardiographic measures to optimize CRT pacemaker settings. We also assessed the utility of ‘stroke distance’ [left ventricular outflow tract velocity–time integral (LVOT VTI)] in performing this function.Thirty patients underwent the following functional assessments; 6 min walk test distance, peak VO2 consumption on cardiopulmonary exercise testing (VO2 peak), quality-of-life scoring, and echocardiography; before and at 3 and 6 months after implantation of the CRT device. At 3 months, patients received LVOT VTI-guided optimization of interventricular (VV) and atrioventricular (AV) delays. The feasibility and reproducibility of each optimization measurement was statistically analysed, and the functional benefits of optimization examined. Left ventricular outflow tract VTI, interventricular mechanical delay (IVMD), and tissue Doppler lateral-septal delay showed good feasibility (>90%), whereas LVOT VTI, IVMD, and the 12-segment tissue Doppler dyssynchrony index showed good reproducibility (coefficient of variation <20%). The most feasible and reproducible measure was LVOT VTI. Our optimization protocol necessitated alteration of AV and/or VV delays in 60% of patients at 3 months and was associated with a 50% improvement in functional responder status between 3 and 6 months.Left ventricular outflow tract VTI provides us with a single, direct measure of global LV function which is robust, and easily applicable in routine clinical practice, and which is effective at improving response to CRT.