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Objectives: We evaluated end-tidal CO2 (etCO2), which has been proposed to assess acute hemodynamic changes, to guide percutaneous edge-to-edge mitral valve repair (PMVR) with the MitraClip system. Methods: Thirty-nine patients (aged 78 ± 14 years) undergoing PMVR for moderate-to-severe mitral regurgitation (MR) of primary and secondary etiology were included. General anesthesia was maintained with sevoflurane and constant ventilation parameters to ensure stable etCO2 tension. MR grade was determined semiquantitatively by transesophageal echocardiography by 2 experienced operators blinded to etCO2 measurements. etCO2 levels were measured 3, 5, 10, and 15 min after final MitraClip placement. Results: Overall, etCO2 increased from 32.2 ± 1.7 before to 35.4 ± 3.0, 34.6 ± 2.6, and 34.2 ± 2.4 mm Hg 3, 5, and 10 min after implantation. A significant correlation was noted between the echocardiographic reduction in MR grade and the increase in etCO2. ANOVA for repeated measures confirmed a significant increase in etCO2 after clip implantation (corrected F = 20.0; p < 0.001) and revealed a significantly greater increase in etCO2 in patients with MR reduction ≥2 grades as compared to lesser MR reductions (F = 6.47; p = 0.015). Blood pressure changes did not correlate with the degree of MR reduction. Conclusions: We observed a close correlation between the reduction in MR grade during PMVR and etCO2, which might evolve as a useful parameter to complement treatment guidance during PMVR.