Background: Although edge-to-edge repair is an established adjunctive procedure, there is still debate on its long-term durability and efficacy. Methods: Fifteen porcine mitral valves were studied in a physiologic left heart simulator with a variable size annulus (dilated = 8.22 cm2, normal = 6.86 cm2, contracted = 5.5 cm2). Mitral valves were tested under steady and physiologic pulsatile flow conditions (cardiac outputs: 4 to 6 L/min), at peak transmitral pressures between 100 mm Hg and 140 mm Hg. A miniature force transducer was used to measure the Alfieri stitch force (FA). Mitral flow rate (MFR), transmitral pressure, effective orifice area, mitral regurgitation, and FA were monitored. Results: The edge-to-edge repair led to a decrease in effective orifice area of 16.55% ± 8.22%; further reduction in effective orifice area was attained with annular contraction. Mitral regurgitation after the edge-to-edge repair was significantly higher (p <0.05) with annular dilation. In the pulsatile experiments, two peaks in FA were observed: one during systole (FA = 0.059 ± 0.024 N) and a second during diastole (FA = 0.072 ± 0.021 N). Multivariate analysis of variance analysis showed that during systole, transmitral pressure and mitral annular area (MAA) had significant effects on FA [FA = (4.40 × 10-4) transmitral pressure (mm Hg) + (5.0 × 10-3) MAA (cm2) - 0.05 (R2= 0.80)], whereas during diastole MFR and MAA had significant effects on FA [FA = (1.03 × 10-4) MFR2 (L/min) - (1.60 × 10-3) MAA (cm2) + 0.02 (R2 = 0.90)]. Conclusions: With annular dilation, mitral regurgitation persisted even after the edge-to-edge repair. The edge-to-edge repair does not cause clinically relevant mitral valve stenosis in a normal size mitral valve. Mitral flow rate and transmitral pressure are the main determinants of FA during the cardiac cycle. Increasing annular area increases FA during systole but decreases FA during diastole. Systolic FA may become dominant with increases in MAA or peak transmitral pressure, or both.