Prognostic implications of sex-related disparities in severity assessment of primary mitral regurgitation following intervention

Background Current guidelines advocate intervention in primary mitral regurgitation (PMR) based upon detection of ‘severe’ mitral regurgitation (MR), using transthoracic echocardiography (TTE) thresholds applied equally to both sexes. Given that females demonstrate significantly lower MR severity compared to males, waiting for females to reach the same degree of MR severity as their male counterparts before offering intervention may lead to sub-optimal outcomes. Nevertheless, whether these disparities in MR severity have long-term prognostic significance remains unknown. Purpose To quantify sex-related differences in TTE-derived quantitative MR severity and subsequent long-term mortality after transcatheter and surgical intervention for PMR. Methods 420 patients (70.5±8.5 years, 40% women) undergoing intervention for significant PMR between June 2010 and November 2023 were identified from the APEX registry. MR severity was quantified using validated vena contract (VC) measurements on TTE. The primary endpoint of all-cause mortality was investigated using Cox models adjusted for established PMR risk-factors for mortality (age, atrial fibrillation [AF], LA volume index, left ventricular [LV] end-systolic diameter index, LV ejection fraction [LVEF], tricuspid regurgitation [TR] grade, pulmonary artery systolic pressure [PASP]). VC was modelled as a restricted cubic spline, with the reference value set at 0.7cm, the guideline threshold for severe MR. Results There were no significant differences in rates of concomitant tricuspid (p=0.103) or aortic (p=0.214) interventions, nor in the type of mitral intervention performed (surgical repair/ surgical replacement/ transcatheter repair: 106 (63%)/ 54 (32%)/ 8 (4.8%) vs. 162 (64%)/ 77 (31%)/ 13 (5.2%), p=0.934). Females underwent less coronary revascularisation with bypass grafting (34 [20%] vs 77 [31%], p=0.019). On TTE, females had significantly smaller VC (0.60 [0.55-0.80] vs. 0.70 [0.60-0.80] cm, p=0.003) and lower MR severity grades (II/III/IV: 103 (61%)/ 36 (14%)/ 32 (13%) vs. 103 (61%)/ 40 (24%)/ 25 (15%), p=0.024). There were no significant sex differences in LA volume index, LVEF and LV end-systolic diameter, or pulmonary pressures, although females had higher TR grades (p=0.043). Over 5.8±3.9 years of follow-up, 105 (25.0%) patients died, with no significant sex difference (p=0.814). After adjustment, VC showed a significant non-linear relationship with all-cause mortality and a significant interaction with sex (Pinteraction=0.013) was found. Above a VC of ~0.9cm, mortality associated with increasing VC was higher in males compared to females. Conclusions For the first time, we have demonstrated sex-related differences in TTE-measured VC and subsequent prognosis following intervention for PMR. This supports a nuanced sex-specific assessment to quantifying MR severity, which may warrant individualised thresholds.