Sex-based differences in myocardial function and exercise physiology in moderate aortic stenosis

Abstract Background Moderate aortic stenosis may present differently in women and men. Sex -based differences in myocardial function and exercise capacity are still underexplored. Standard measures can miss subtle dysfunction, particularly in women with preserved ejection fraction. Combining strain imaging, myocardial work, coronary flow velocity reserve (CFVR) and cardiopulmonary exercise test (CPET) offers a comprehensive approach to reveal sex-specific functional phenotypes. Aim To investigate sex differences in myocardial workload, exercise capacity, and coronary microvascular function in patients with moderate AS using echocardiography, CPET, and CVFR. Methods We prospectively analyzed 74 (68% male) patients with moderate aortic stenosis and preserved ejection fraction. All underwent transthoracic echocardiography including global longitudinal strain (GLS) and myocardial work analysis, cardiopulmonary exercise testing (CPET), and transthoracic assessment of coronary flow velocity reserve (CFVR). For CVFR, peak diastolic coronary flow velocity was measured in basal conditions and during hyperemia, induced by adenosine infusion. CFVR was calculated as the hyperemic and basal peak diastolic flow velocities ratio. Myocardial work indices were derived using speckle-tracking echocardiography and non-invasive blood pressure, Pressure-strain loops were generated by synchronizing global longitudinal strain with estimated left ventricular pressure curves adjusted to brachial cuff systolic pressure. Systolic blood pressure measured at the brachial artery was corrected by adding the mean transvalvular aortic gradient, Patients were stratified by sex, and key imaging and functional parameters were compared. Results Women demonstrated significantly higher GWI and GCW than men, indicating greater myocardial workload despite smaller LV size and preserved EF. Men had larger LV volumes and higher transvalvular gradients. Women also showed significantly lower peak VO2, oxygen pulse, and OUES, suggesting limited stroke volume augmentation and reduced oxygen extraction during exertion. Systolic blood pressure was higher in women, which may partially explain the increased myocardial work. CFVR did not differ significantly between groups, although a trend toward lower values in women was observed. Conclusion Moderate AS is characterised by distinct adaptive profiles between men and women: women produce more myocardial work, potentially as a compensatory response to limited reserve, while men exhibit more advanced structural remodelling and pressure overload. These findings illustrate the importance of a sex-specific, multimodal evaluation to characterise disease burden fully and to guide management of moderate AS.