Background - One of the key targets in treating mitral regurgitation (MR) is reducing the otherwise progressive left ventricular (LV) remodeling that exacerbates MR and conveys adverse prognosis. We have previously demonstrated that severing 2 second-order chordae to the anterior mitral leaflet relieves tethering and ischemic MR acutely. The purpose of this study was to test whether this technique reduces the progression of LV remodeling in the chronic ischemic MR setting. Methods and Results-A posterolateral MI was created in 18 sheep by obtuse marginal branch ligation. After chronic remodeling and MR development at 3 months, 6 sheep were randomized to sham surgery (control group) and 12 to second-order chordal cutting (6 each to anterior leaflet [AntL] and bileaflet [BiL] chordal cutting, techniques that are in clinical application). At baseline, chronic infarction (3 months), and follow-up at a mean of 6.6 months post-myocardial infarction (MI) (euthanasia), we measured LV end-diastolic (EDV) and end-systolic volume (ESV), ejection fraction, wall motion score index, and posterior leaflet (PL) restriction angle relative to the annulus by 2D and 3D echocardiography. All measurements were comparable among groups at baseline and chronic MI. At euthanasia, AntL and BiL chordal cutting limited the progressive remodeling seen in controls. LVESV increased relative to chronic MI by 109±8.7% in controls versus 30.5±6.1% with chordal cutting (P<;0.01) (LVESV in controls, 82.5±2.6 mL; in AntL, 60.6±5.1 mL; in BiL, 61.8±4.1 mL). LVEDV increased by 63±2.0% in controls versus 26±5.5% and 22±3.4% with chordal cutting (P<;0.01). LV ejection fraction and wall motion score index were not significantly different at follow-up among the chordal cutting and control groups. MR progressively increased to moderate in controls but decreased to trace-mild with AntL and BiL chordal cutting (MR vena contracta in controls, 5.9,1.1 mm; in AntL, 2.6±0.1 mm; in BiL, 1.7±0.1 mm; P<;0.01). BiL chordal cutting provided greater PL mobility (decreased PL restriction angle to 54.2±5.0° versus 83±3.2° with AntL chordal cutting; P<;0.01). Conclusions-Reduced leaflet tethering by chordal cutting in the chronic post-MI setting substantially decreases the progression of LV remodeling with sustained reduction of MR over a chronic follow-up. These benefits have the potential to improve clinical outcomes. © 2010 American Heart Association, Inc.