Background-In asymptomatic patients with severe isolated mitral regurgitation (MR), identifying the onset of early left ventricular (LV) dysfunction can guide the timing of surgical intervention. We hypothesized that changes in LV transmural myocardial strain represent an early marker of LV dysfunction in an ovine chronic MR model. Methods and Results-Sheep were randomized to control (CTRL, n = 8) or experimental (EXP, n = 12) groups. In EXP, a 3.5-or 4.8-mm hole was created in the posterior mitral leaflet to generate "pure" MR. Transmural beadsets were inserted into the lateral and anterior LV wall to radiographically measure 3-dimensional transmural strains during systole and diastolic filling, at 1 and 12 weeks postoperatively. MR grade was higher in EXP than CTRL at 1 and 12 weeks (3.0 [2-4] versus 0.5 [0-2], 3.0 [1-4] versus 0.5 [0-1], respectively, both P < 0.001). At 12 weeks, LV mass index was greater in EXP than CTRL (201 +/- 18 versus 173 +/- 17 g/m(2), P < 0.01). LVEDVI increased in EXP from 1 to 12 weeks (P = 0.015). Between the 1 and 12 week values, the change in BNP (-4.5 +/- 4.4 versus-3.0 +/- 3.6 pmol/L), PRSW (9 +/- 13 versus 23 +/- 18 mm Hg), tau (-3 +/- 11 versus-4 +/- 7 ms), and systolic strains was similar between EXP and CTRL. The changes in longitudinal diastolic filling strains between 1 and 12 weeks, however, were greater in EXP versus CTRL in the subendocardium (lateral:-0.08 +/- 0.05 versus 0.02 +/- 0.14, anterior:-0.10 +/- 0.05 versus-0.02 +/- 0.07, both P < 0.01). Conclusions-Twelve weeks of ovine "pure" MR caused LV remodeling with early changes in LV function detected by alterations in transmural myocardial strain, but not by changes in BNP, PRSW, or tau.