Cardiac resynchronization therapy (CRT) has become a standard treatment in patients with symptomatic chronic systolic heart failure, reduced left ventricular (LV) function and wide electrocardiographic ventricular (QRS) complex, but approximately one third of patients do not respond to the treatment. Current ability to predict long-term response to CRT at implant is slight. Investigations have focused mostly on early prediction of the reversal of LV remodeling by means of LV pacing, which is delivered more frequently as biventricular pacing, combined with conventional right ventricular (RV) pacing. LV dyssynchrony areas have been identified as suitable targets for pacing, but no methods still can evaluate real-time, intra-operative acute effects of pacing on LV mechanics. This issue has become even more evident in the subset of CS implants of quadripolar leads, which offer relevant advantages but highlight the lack of methods for selecting the pacing configuration among the safe and effective ones.