Pilar Lopez Santi, MD, is a research fellow in the department of cardiology at Leiden University Medical Center.

Pilar Lopez Santi, MD

Females With AR Exhibit Lower Mortality LVESVi Thresholds, With Nina Marsan, MD, and Pilar Santi, MD

 exhibit worse survival during medical management due to lower mortality thresholds for left ventricular end-systolic volume index (LVESVi) in women than in men, according to a recent study.

Because LV dilatation is a strong indicator of adverse outcomes in patients with AR, current guidelines recommend using LV end-systolic diameter index (LVESDi) as a criterion for aortic valve surgery (AVS). However, other studies have indicated that LVESVi may depict adverse LV remodeling better than LVESDi, serving as a more effective predictor of heart failure, mortality, and survival. The 2025 European guidelines recognize LVESVi as an alternative criterion for AVS; however, the recommendation includes the same threshold for men and women.

“Existing literature is really predominantly focused on the male population, and there is not so much attention on sex-specific cutoffs, which have been proposed by the guidelines,” Nina Ajmone Marsan, MD, a research fellow in the department of cardiology at Leiden University Medical Center and co-author of the study, told 

 in an exclusive interview. “So, although the recent guidelines from the European Society of Cardiologists make mention of different cutoffs, we still don’t have enough data to support fully sex-specific cutoffs.”

Investigators collected data on asymptomatic patients with moderate-to-severe AR and left ventricular ejection fraction (LVEF) of ≥50% on transthoracic echocardiography, sourced from an ongoing multicenter registry. Patients with relevant symptoms, acute AR, aortic or mitral stenosis, mitral regurgitation more than mild, or previous aortic or mitral valve surgery were excluded from the study, as were patients with incomplete data for the assessment of AR severity or LV dimensions.

A total of 808 asymptomatic patients were included in the trial; among these, the mean age was 56 years (standard deviation [SD] 19 years). 371 patients (47%) had arterial hypertension, and 113 (15%) had coronary artery disease. The mean LVEF was 60% (SD, 6%), mean LVESVi was 35 mL/m2 (SD, 16), and mean LVESDi was 20 mm/m2 (SD, 4).

All patients were followed up with for the occurrence of a primary endpoint of all-cause mortality under medical management, censored at time of AVS, and all-cause mortality following AVS. Of the 808 included patients, 323 underwent AVS; of these, preoperative LV measurements performed within 3 months before surgery were available in 285 patients.

Based on echocardiographic data, women had a smaller mean LV mass index (111 g/m2 [SD, 54] vs 137 g/m2 [SD, 45]; 

 <.001) and lower prevalence of bicuspid aortic valve compared to men (36% vs 49%; 

 <.001). However, mean LVESDi values were similar between the sexes (20 mm/m2 [SD, 20] in women vs 20 mm/m2 [SD, 4] in men; 

 = .77), while mean volumetric LV end-systolic dimensions were larger in men than women (39 mL/m2 [SD, 16] vs 31 mL/m2 [SD, 31]; 

Over a median follow-up period of 7 years (interquartile range [IQR], 4-11), 125 patients died, of whom 61 were female and 64 were male. AVS was conducted more frequently in men than women (223 vs 100; 

 <.001). Of the 125 deaths, 74 occurred under medical management and 51 after AVS. Among those patients receiving medical treatment, 41 deaths occurred in women versus 33 in men. Adjusted survival at 1, 4, and 6 years’ follow-up was also substantially lower among women than men (96% vs 98%; 84% vs 91%; 80% vs 89%; 

After conducting receiver operating characteristic curve analysis, investigators identified an association between LVESDi ≥20 mm/m2 for both sexes, LVESVi ≥40 mL/m2 for women, and LVESVi ≥45 mL/m2 for men and mortality. The team then validated these cutoffs with age-adjusted cubic splines; the cutoffs remained associated with outcomes after multivariable adjustment, with a differential effect by sex for LVESVi but not for LVESDi. Coupled with the fact that survival did not differ by sex after AVS, this determined that only preoperative LVESVi was associated with mortality with a substantial sex interaction (HR, 1.03; 95% CI, 1-1.06; 

“We need to evolve from simple, linear measurements to volumetric measurements, and our research shows that we cannot rely as much on the diameters that we have,” Pilar Lopez Santi, MD, a research fellow in the department of cardiology at Leiden University Medical Center and lead author of the study, told 

 in an exclusive interview. “We must start looking at the volumes in these patients; otherwise, the mortality penalty that women will suffer will be high.”

Editor’s Note: Marsan reports disclosures with Abbott Vascular, Philips Ultrasound, Pfizer, and GE Healthcare. Santi reports no relevant disclosures.

Lopez Santi P, Fortuni F, Bernard J, et al. Sex Differences in Left Ventricular Remodeling for Risk Stratification of Patients With Aortic Regurgitation. 

Praz F, Borger MA, Lanz J, et al. 2025 ESC/EACTS Guidelines for the management of valvular heart disease. 

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Marsan and Santi discuss their recent study highlighting the need for lower LVESVi thresholds in aortic valve surgery in women to reduce mortality outcomes.

Pilar Lopez Santi, MD

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