Sex Differences in Left Ventricular Remodeling for Risk Stratification of Patients With Aortic Regurgitation

Importance Left ventricular (LV) dilatation is an established prognosticator in aortic regurgitation (AR). Current guidelines recommend aortic valve surgery (AVS) using LV end-systolic diameter index (LVESDi) with a uniform threshold, irrespective of sex. While LV end-systolic volume index (LVESVi) may better characterize LV remodeling, it was only recently included in European guideline recommendations, with a threshold of 45 mL/m 2 for both men and women. Objective To assess sex differences in LV remodeling using linear and volumetric dimensions and their association with outcomes in AR. Design, Setting, and Participants This was a multicenter cohort study of patients with moderate-severe AR and preserved LV ejection fraction (LVEF) between December 2003 and December 2022, with a median (IQR) follow-up of 7 (4-11) years. The study took place at 5 centers in the Netherlands, Singapore, Hong Kong, Canada, and Romania. Patients with at least moderate-severe AR and preserved LVEF (≥50%) were included. Those with symptoms, acute AR, significant other valvular disease, or prior valve surgery were excluded. Data were analyzed from January to November 2024. Exposure LV dilatation assessed by LVESDi and LVESVi. Main Outcomes and Measures All-cause mortality during medical management and following AVS. Results A total of 808 patients (mean [SD] age, 56 [19] years; 488 men and 320 women) were included, 323 of whom underwent AVS. Mean (SD) baseline LVESDi did not differ between sexes (women: 20 [5] mm/m 2 vs men: 20 [4] mm/m 2 ; P = .77), whereas men had larger mean (SD) LVESVi (39 [16] mL/m 2 vs 31 [15] mL/m 2 ; P < .001). During follow-up under medical management, 74 patients died. Adjusted 6-year survival was lower in women (80% vs 89%; P = .001). Receiver operating characteristic curve analysis identified LVESDi 20 mm/m 2 or greater for both sexes, LVESVi 40 mL/m 2 or greater for women, and LVESVi 45 mL/m 2 or greater for men as thresholds associated with mortality. These cutoffs were validated using age-adjusted cubic splines and remained associated with outcomes after multivariable adjustment, with a differential effect by sex for LVESVi but not for LVESDi. After AVS, survival did not differ by sex (85% women vs 89% men; P = .31). Only preoperative LVESVi was associated with mortality, with a significant sex interaction (HR, 1.03; 95% CI, 1.00-1.06; P = .04). Conclusions and Relevance In this study among individuals with moderate-severe AR, similar LVESDi thresholds (20 mm/m 2 ) for both sexes, but lower than currently recommended by guidelines, were independently associated with mortality. In turn, LVESVi thresholds were 40 mL/m 2 for women and 45 mL/m 2 for men, suggesting the need for sex-specific cutoffs to improve risk stratification.