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Masiero et al. Mini-invasive Surg 2022;6:4 https://dx.doi.org/10.20517/2574-1225.2021.104 Page 5 of 19

has been suggested as a surrogate marker of prognostic importance in AS patients as strongly associated
with worse morbidity and mortality [26-30] . MDCT data of AS patients support sex-related differences in the
[8]
levels of AVC load required to reach hemodynamically severe AS . For the same degree of AS severity,
women have a lower AVC load compared with men, also after adjustment for BSA, resulting in sex-specific
calcium scores for the diagnosis of AS [4,31,32] . They have a more fibrotic remodeling of the aortic valve with
higher levels of valvular fibrosis and dense connective tissue at the same degree of hemodynamic stenosis
severity, while men have a more calcific remodeling, irrespective of patients’ age . These discordant
[33]
calcific/fibrotic patterns between men and women may be exacerbated by specific valve morphology.
Women with stenotic bicuspid aortic valve have less calcification than men for the same hemodynamic
[33]
severity of AS, as well as less calcification than women with stenosed tricuspid aortic valve . Interestingly,
despite lower AV calcium, women have more significant progression of AVC over three years of follow-
up . This imbalance in clinical presentation and pathophysiological process should be brought to the
[10]
attention of the cardiology community to ensure equivalent care for AS in men and women. Due to the
different onset of symptoms and the different pathophysiological mechanisms, AS classification in women
may further benefit from an integrated TTE and MDCT diagnostic approach in order to avoid late referral
and adverse outcomes.

Treatment choice
In patients with severe symptomatic AS, valve replacement has a beneficial impact on survival, symptoms,
and left ventricular function . The choice between surgical aortic valve replacement (SAVR) and
[34]
transcatheter intervention is based on patient’s age and clinical and anatomic features . International
[35]
guidelines do not include specific recommendations for AS treatment according to sex. However,
historically, women have been more often than men denied for SAVR [12,36] . Several reasons account for this
unequal referral pattern: compared with men, women with AS feature older age, atypical symptoms, and
more advanced cardiac disease despite preserved left ventricular ejection fraction . In addition, men have
[37]
higher prevalence of concomitant coronary artery disease requiring coronary artery bypass grafting, and
physicians usually overestimate the operative risk of female patients by perceiving a greater risk related to
their physical frailty . This sex gap has partially narrowed with the widespread adoption of TAVI, as
[38]
[39]
women represent more than 50% of the treated population . The heart team plays a pivotal role in the
selection of the optimal modality of intervention (surgical or transcatheter) based on several features and
[4]
avoiding futility, especially for TAVI . Female sex is a risk factor for perioperative mortality in both the
EuroSCORE and the Society of Thoracic Surgeons Risk Score. However, sex is not listed among factors that
could preferentially drive the choice between SAVR and TAVI. Historically, at the time of intervention,
women present with advanced age at presentation and greater prevalence of higher frailty that potentially
increases the risk of procedural complications and delays recovery after surgical intervention . Despite the
[38]
augmented incidence of adverse vascular events that are discussed below [Table 1], several further factors
make female patients preferential candidates for TAVI than SAVR, including the lower prevalence of
concomitant severe coronary artery disease and the lower occurrence of patient-prosthesis mismatch and
paravalvular regurgitation despite small aortic annulus . However, considering their longer life expectancy,
[4]
assessing TAVI durability is of paramount importance even in higher risk cohorts. Long-term clinical
results (> 10 years) on cardiovascular mortality, need of reintervention, and bioprosthetic valve failure
(BVF) according to type treatment (surgical vs. percutaneous) and bioprosthesis (balloon vs. self-
expandable) are needed. In particular, the impact of sex on structural and non-structural mechanisms of
valve deterioration still needs to be clarified. To date, only anecdotical observational experiences identified
female sex, small BSA, and smaller size of THV as possible predictors of BVF .
[40]