Resolving the Conundrum of Functional Mitral Regurgitation in Heart Failure with reduced Ejection Fraction.

Background: Appraisal of Functional-Mitral-Regurgitation (FMR) in Heart-failure with reduced Ejection-fraction (HFrEF) is challenging because risks of excessmortality remain uncertain and guidelines diverge . Objective: To define excess-mortality linked to FMR quantified in routine-practice. Methods: HFrEF (ejection-fraction (EF)<50%) stage B-C diagnosed 2003-2011, with routine-practice FMR quantitation (FMR-cohort, n=6381) was analyzed for excessmortality thresholds/rates within-cohort and vs. general-population and compared to degenerative-mitral-regurgitation simultaneous cohort (DMR-cohort, n=2416). Results: In FMR-cohort (age 70±11years, EF 36±10%, effective-regurgitant-orifice- EROA 0.09±0.13cm2), EROA distribution was skewed towards low-values (≥0.40cm2 in only 8% vs. 38% for 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-Ratio1.57 [1.19-2.97], p=0.001). Long-term, 3538 FMR-cohort patients died with excess-mortality threshold ~0.10cm2 (vs.~0.20cm2 in DMR-cohort), with 0.10cm2 EROA-increments independently associated with considerable mortalityincrement (adjusted-hazard-ratio 1.11[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 0.40cm2), much steeper vs. DMR-cohort (p<0.0001). In nested models, individualized EROA was strongest FMR survival-marker and a new expanded FMRgrading scale, based on 0.10 cm2 EROA increments, provided incremental power over current AHA-ACC/ESC guidelines (all P<0.03). Conclusion: In HFrEF, FMR is skewed towards smaller EROA. Nevertheless, 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, much steeper than in DMR, for any EROA increment. An expanded ERObased stratification, superior to existing grading-schemes in determining survival, should allow guidelines harmonization.