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Aims: Differentiation between physiologic and pathologic LV hypertrophy may be challenging in athlete with moderate LV septal hypertrophy (13mm to 15mm). We hypothesized that this issue may be overcome by myocardial deformation indexes derived from 2D and 3D strain by speckle tracking.Methods: Comprehensive 2D and 3D echocardiography was prospectively performed in 103 subjects: 49 with hypertrophic cardiomyopathies preserved LVEF>50% (HCM, 57±14 years, EF=61±6%); 34 professional athletes (27±5 years, EF=58±4%) and 20 control subjects (39±12 years, EF=62±4%). Peak global strain was computed from 2D (longitudinal) and 3D speckle tracking (longitudinal, radial, circumferential, and area) and LV dyssynchrony defined as the standard deviation of time to peak longitudinal strain (12SD) was derived from 2D speckle tracking.Results: Septal thickness averaged 19±5mm in HCM (>15mm [n=40], between 13 and 15mm [n=9] and), 12±2mm in athletes (between 13 and 15mm [n=15], <13mm [n=19]) and 10±1.5mm in controls (p<0.0001 for all). Overall, 2D and 3D peak strain was lower in HCM than in control and athlete subjects. In patients with moderate septal thickness (13-15mm), only 2D and 3D longitudinal global peak strain (-18±2% vs.-15±3%, p=0.03) and longitudinal myocardial dyssynchrony by 2D (70±31ms vs. 40±10ms, p=0.004) differed between HCM and athletes. However, LV dyssynchrony (AUC=0.87 for 12SD) appeared superior to peak strain (AUC=0.75 for 2D and AUC=0.79 for 3D) to identify moderate abnormal LV hypertrophy (13-15mm). Sensitivity and specificity to identify moderate abnormal LV hypertrophy was 89% and 73%, respectively when LV dyssynchrony >45ms.Conclusion: LV longitudinal dyssynchrony accurately differentiates physiologic LV hypertrophy (13-15mm) in athlete from abnormal LV hypertrophy in HCM.