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Introduction: The success rate of cardiac resynchronization therapy (CRT) in reducing mechanical dyssynchrony has progressively increased, but it is still hampered by different factors. A novel quadripolar coronary sinus lead (QuartetCS, St. Jude Medical) for biventricular pacing can offer up to ten pacing options. We sought to evaluate the different configurations by multiple echocardiographic parameters.Methods: Eleven consecutive patients (mean age 69.5±9.7yo;6 males) with severe LV systolic dysfunction and LBBB with wide QRS (QRS 160±7.8 ms; EF 26.7±4.5%; NYHA III/IV 9/2) underwent CRT with quadripolar lead implant. Before discharge, all patients underwent a complete bidimensional, Doppler and 2D strain echocardiogram in all 10 different configurations. Simpson's biplane ejection fraction (EF), myocardial performance index (MPI), interventricular mechanical delay (IVMD), mitral regurgitation (MR) and 2D-circumferential strain were analyzed.Results: A total of 110 echocardiograms were performed. The best option was defined by higher EF (26.7±4.5% vs29.8±5.6%, p=0.17), reduced IVMD (38.2±32.5ms vs 17.75±11.18, p=0.06), increased VTI (+3.12±1.9, p =0.001), decreased MPI (-0.36±0.3, p=0.03), a significant reduction in delayed contraction, with improved global synchronization by 2D strain, MR reduction was not statistically significant. Among the 10 possible configurations, there were different best pacing options, with a significant reduction in terms of QRS lenght (p=0.014).Conclusions: In case of multiple pacing configurations, the best-performing configuration should be the best compromise between electrocardiographic and echocardiographic parameters. Echocardiographic assessment of the acute haemodynamic response to CRT is a useful tool in the device optimization procedure.