Objectives: This study assessed myocardial damage in patients with chronic isolated mitral regurgitation (MR) and left ventricular ejection fraction (LVEF) >60%. Background: Typically, MR patients have decreased LVEF after mitral valve (MV) repair despite normal pre-operative LVEF. Methods: Twenty-seven patients with isolated MR had left ventricular (LV) biopsies taken at time of MV repair. Magnetic resonance imaging with tissue tagging was performed in 40 normal subjects and in MR patients before and 6 months after MV repair. Results: LVEF (66 ± 5% to 54 ± 9%, p < 0.0001) and LV end-diastolic volume index (108 ± 28 ml/m2 to 78 ± 24 ml/m2, p < 0.0001) decreased, whereas left ventricular end-systolic (LVES) volume index was 60% above normal pre- and post-MV repair (p < 0.05). The LV circumferential and longitudinal strain rates decreased below normal following MV repair (6.38 ± 1.38 vs. 5.11 ± 1.28, p = 0.0009, and 7.51 ± 2.58 vs. 5.31 ± 1.61, percentage of R to R interval, p < 0.0001), as LVES stress/LVES volume index ratio was depressed at baseline and following MV repair versus normal subjects (0.25 ± 0.10 and 0.28 ± 0.05 vs. 0.33 ± 0.12, p < 0.01). LV biopsies demonstrated cardiomyocyte myofibrillar degeneration versus normal subjects (p = 0.035). Immunostaining and immunoblotting demonstrated increased xanthine oxidase in MR versus normal subjects (p < 0.05). Lipofuscin deposition was increased in cardiomyocytes of MR versus normal subjects (0.62 ± 0.20 vs. 0.33 ± 0.11, percentage of area: p < 0.01). Conclusions: Decreased LV strain rates and LVES wall stress/LVES volume index following MV repair indicate contractile dysfunction, despite pre-surgical LVEF >60%. Increased oxidative stress could cause myofibrillar degeneration and lipofuscin accumulation resulting in LV contractile dysfunction in MR. © 2010 American College of Cardiology Foundation.