Functional Mitral Regurgitation Outcome and Grading in Heart Failure With Reduced Ejection Fraction

Objectives: This study aims to define excess-mortality linked to functional mitral regurgitation (FMR) quantified in routine-practice. Background: Appraisal of FMR in heart failure with reduced ejection fraction (HFrEF) is challenging because risks of excess mortality remain uncertain and guidelines diverge. Methods: Cases of HFrEF (ejection-fraction <50%) Stage B-C that were diagnosed between 2003 and 2011 and had routine-practice FMR quantitation (FMR cohort, n = 6,381) were analyzed for excess mortality thresholds/rates within the cohort and in comparison to the general population. These were also compared to those of a degenerative mitral regurgitation (DMR) simultaneous cohort (DMR cohort, n = 2,416). Results: In the FMR cohort (age: 70 ± 11 years, ejection fraction: 36 ± 10%, effective regurgitant orifice area [EROA]: 0.09 ± 0.13 cm²), EROA distribution was skewed towards low-values (≥0.40 cm² in only 8% vs 38% for the DMR cohort; P < 0.0001). One-year mortality was high (15.6%), increasing steeply from 13.3% without FMR to 28.5% with EROA ≥0.30 cm² (adjusted odds ratio: 1.57 [95% CI: 1.19-2.97]; P = 0.001). In the long term, 3,538 FMR cohort patients died with excess mortality threshold ∼0.10 cm² (vs ∼0.20 cm² in the DMR cohort), with 0.10 cm² EROA increments independently associated with considerable mortality increment (adjusted HR: 1.11 [95% CI: 1.08-1.15]; P < 0.0001) and with no detectable interaction. Compared to the general population, FMR excess mortality increased exponentially with higher EROA (risk ratio point estimates 2.8, 3.8, and 5.1 at EROA 0.20, 0.30, and 0.40 cm², respectively), and was much steeper than that of the DMR cohort (P < 0.0001). In nested models, individualized EROA was the strongest FMR survival marker, and a new expanded FMR grading scale based on 0.10 cm² EROA increments provided incremental power over current American Heart Association–American College of Cardiology/European Society of Cardiology guidelines (all P < 0.03). Conclusions: In HFrEF, FMR is skewed towards smaller EROA. Nevertheless, when measured in routine practice, EROA is the strongest independent FMR determinant of survival after diagnosis. Excess mortality increases exponentially above the threshold of 0.10 cm², with a much steeper slope than in DMR, for any EROA increment. An expanded EROA-based stratification, superior to existing grading schemes in determining survival, should allow guideline harmonization.