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Purpose The aim of the current study was to evaluate the relationship between the site of latest mechanical activation as assessed with gated myocardial perfusion SPECT (GMPS), left ventricular (LV) lead position and response to cardiac resynchronization therapy (CRT). Methods The patient population consisted of consecutive patients with advanced heart failure in whom CRT was currently indicated. Before implantation, 2-D echocardiography and GMPS were performed. The echocardiography was performed to assess LV end-systolic volume (LVESV), LVend-diastolic volume (LVEDV) and LV ejection fraction (LVEF). The site of latest mechanical activation was assessed by phase analysis of GMPS studies and related to LV lead position on fluoroscopy. Echocardiography was repeated after 6 months of CRT. CRT response was defined as a decrease of Q15% in LVESV. Results Enrolled in the study were 90 patients (72% men, 1667±10 years) with advanced heart failure. In 52 patients (58%), the LV lead was positioned at the site of latest mechanical activation (concordant), and in 38 patients (42%) the LV lead was positioned outside the site of latest mechanical activation (discordant). CRT response was significantly more often documented in patients with a concordant LV lead position than in patients with a discordant LV lead position (79% vs. 26 %, p<0.01). After 6 months, patients with a concordant LV lead position showed significant improvement in LVEF, LVESV and LVEDV (p≤ 0.05), whereas patients with a discordant LV lead position showed no significant improvement in these variables. Conclusion Patients with a concordant LV lead position showed significant improvement in LV volumes and LV systolic function, whereas patients with a discordant LV lead position showed no significant improvements. [ABSTRACT FROM AUTHOR]