Sex-based Differences in Mitral Annular Disjunction Severity and Arrhythmic Risk in Mitral Valve Prolapse.

Background: Arrhythmic mitral valve prolapse (AMVP), a condition with known female predominance, has been linked to mitral annular disjunction (MAD), yet the relationship between MAD, sex, body size and arrhythmic events remains unclear.

Objectives: To determine whether MAD exhibits sex-based differential effects on arrhythmic risk and explore the implications of indexing MAD measurements.

Methods: We examined 682 consecutive MVPs at the University of California San Francisco (2013-2023) with detailed clinical, rhythmic and echocardiographic data. MAD was indexed to body surface area, resulting in the identification of 3 distinct groups: no MAD, indexed MAD (iMAD) below and iMAD above the median. AMVP was defined as MVP with frequent and/or complex ventricular ectopy, including severe arrhythmic events such as sustained ventricular tachycardia, ventricular fibrillation/sudden cardiac arrest or death.

Results: Among 682 MVPs (48% females, mean age 58±17 years), 35% had AMVP and 41% had MAD, with a median iMAD of 4 mm. Compared to females, males had greater absolute MAD length (9.0 ± 3.2 mm vs 7.3 ± 2.6, p<0.001). Sex-based differences in MAD length were no longer appreciated after indexing for BSA (p = 0.33). In multivariable analyses, iMAD >4 mm was significantly associated with arrhythmic events in males but not in females (p=0.02 vs p=0.63). Bileaflet MVP had a direct effect on severe arrhythmic events in females (p=0.04 for MVP, p= 0.39 in mediation analysis), but in males this association was mediated by iMAD length (p=0.03).

Conclusion: In a large MVP cohort, males exhibit greater MAD length and a stronger association between iMAD length and arrhythmic events. In contrast, iMAD length in females may be less important for arrhythmic risk stratification compared to other imaging parameters such as bileaflet involvement. Further studies are needed to confirm alternative mechanisms beyond localized MAD-related myocardial traction in females with MVP.