Sex-specific prognostic significance of right-sided cardiopulmonary remodelling among patients undergoing intervention for primary mitral regurgitation

Background Comprehensive evaluation of right heart function is increasingly performed using non-invasive right ventricle-pulmonary artery (RV-PA) coupling, which has gained clinical prominence in primary mitral regurgitation (PMR) as a robust, independent predictor of adverse long-term outcomes after intervention. However, females and males may face increased risk at different thresholds, as already demonstrated in tricuspid regurgitation. Purpose To investigate sex-specific RV-PA coupling thresholds associated with all-cause mortality in patients undergoing PMR intervention. Methods Consecutive patients undergoing surgical or transcatheter PMR intervention from June 2010 to November 2023 were identified. RV-PA coupling was quantified as the ratio of pre-intervention tricuspid annular plane systolic excursion (TAPSE) to pulmonary artery systolic pressure (PASP) on echocardiography. Sex-stratified receiver operating characteristic curve analysis was used to identify potential sex differences in risk calibration for TAPSE/PASP. Results Within the study population (n=817), females comprised the minority (38.6%) and were significantly older than males (72 [61-78] vs. 69 [59-76] years, p=0.012). During follow-up of 5.8 ± 4.2 years, 213 (26.1%) patients died, with no significant sex difference in mortality (HR [male vs. female]: 1.19 [0.90-1.58], p=0.222). TAPSE/PASP was an independent predictor of all-cause mortality (p=0.010). Sex-specific optimum cut-offs emerged (females: 0.50 mm/mmHg vs. males: 0.42 mm/mmHg) which corresponded to similar hazard ratios (HR) in males (HR: 2.27 [1.64-3.23], p<0.001) and females (HR: 2.13 [1.35 to 3.33]) (Fig 1). Thresholds remained similar when excluding 190 patients with ≥moderate TR (females: 0.52 mm/mmHg vs. males: 0.42 mm/mmHg). Prognostic performance according to sex, assessed by area under the curve, did not differ significantly by sex. On interaction analysis, compared to males, females with reduced TAPSE/PASP (representing RV-PA uncoupling) had relatively lower mortality up to a threshold of ~0.6 mm/mmHg, beyond which mortality was relatively higher in males (Fig 2). Sex-specific optimum cut-offs were also identified for PASP (females: 31mmHg vs. males: 49mmHg) and TAPSE (females: 22mm vs. males: 19mm). Conclusion We identified sex specific TAPSE/PASP thresholds that improved discrimination and conferred a similar relative risk of long-term mortality. At TAPSE/PASP values indicative of RV-PA uncoupling, males appeared to experience relatively higher mortality than females, suggesting that despite improved discrimination with sex-specific thresholds, RV-PA uncoupling may broadly confer a greater mortality burden in males than in females. These findings underscore the need for a nuanced approach to risk stratification using TAPSE/PASP, potentially including sex-specific thresholds.