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Background: There is little consensus on the optimal atrioventricular delay (AVD) and ventricular-to-ventricular interval (VVI) in cardiac resynchronization therapy (CRT). The aim of this study was to compare a novel combination of doppler echocardiography (DE) and three-dimensional echocardiography (3DE) for optimization (opt) of AVD and VVI with ECG opt.Methods: 65 consecutive patients (pts, male: n=47, age: 41-83 years) with severely reduced ejection fraction (EF), NYHA III/IV, QRS>120ms have been included. After biventricular pacemaker implantation pts were randomized to either the AV-and VV-opt using DE and 3DE (group 1) or ECG (group 2). In group 1, first aortic velocity time integral (AoVTI) was examined in eight AVDs, and the AVD with the highest AoVTI was programmed. Consecutively, full-volume datasets of the left ventricle (LV) were obtained and analyzed in six different VVIs. In each VVI, a systolic dyssynchrony index (SDI) was calculated from the dispersion of time to minimal regional volume for all 16 LV segments. Then, the VVI with the lowest SDI was programmed. In Group 2, a delay of 100 ms between the end of the p-wave and peak/nadir of the paced ventricular complex, a known physiological AV interval in healthy subjects, was programmed. Then, the VVI with most simultaneous peak/nadir of the QRS in V1-V6 was set. 3DE was performed in all pts, LV dimensions, EF and dyssynchrony index (SDI) evaluated, and NYHA class obtained before CRT and after three months. Pts with a change of ≥ 1 NYHA class were considered responders.Results: At 3 months, there were significantly more responders in group 1 (87%) than in group 2 (60%). Moreover, group 1 showed a higher increase in EF, reduction of SDI and LV dimensions (see table).Conclusions: Compared with ECG opt of CRT, the combination of DE-AVD and 3DE-VVI opt resulted in a higher response rate and improved LV systolic function and may be used to select the optimal AVD and VVI in CRT.