Abstract 1611: Sex-dependent Alterations in Myofilament Mechanical Properties in Patients with Aortic Stenosis
Background: Pressure overload due to aortic stenosis (AS) elicits complex myocardial responses. These usually result in preserved left ventricular (LV) ejection fraction (EF) but slowed relaxation. Sex differences in the LV adaptation to AS have been reported. At similar AS severity, females have higher EF, smaller chamber size, greater wall thickness and worse functional capacity than males. To assess whether fundamental changes in the contractile properties of the myofilaments underlie these sex-related differences, we carried out mechanical experiments in human myocardial tissue.
Methods and Results: Sub-epicardial biopsies were obtained from 22 patients during cardiac surgery, 10 patients with AS undergoing valve replacement [4 females (F) and 6 males (M), age 49 – 81] and 12 control patients [4 F and 8 M, age 44–72]. All patients had normal regional and global LV wall motion. Dissected strips were chemically skinned, attached to a length motor and force transducer, and stretched to sarcomere length 2.2 μm. Myofilaments were calcium activated and small-amplitude sinusoidal length perturbation analysis was performed at 37°C at varying frequencies to delineate cross-bridge kinetics and myofibrillar oscillatory work. Maximal isometric tension was higher in patients with AS than in controls in both females and males (29.6±6.0 vs 12.4±2.8 and 38.9±6.2 vs 23.0±2.7 mN/mm2 respectively, P<0.01). “Dip” frequency, the frequency of minimal dynamic stiffness that correlates with the rate of acto-myosin force production, was lower in AS females (F-AS) compared with F controls (3.63±0.36 vs 5.00±0.35 Hz, P<0.01). F-AS also had a reduced frequency of maximal myofibrillar oscillatory work (1.95±0.38 vs 2.88±0.14 Hz, P<0.05) with a shift of the range of positive oscillatory work toward lower frequencies (P<0.05). Differences in sinusoidal analysis variables between AS males and controls were much less prominent than those in females.
Conclusions: Alterations in myofilament mechanical properties in AS are highly sex-dependent. Slower cross-bridge kinetics in F-AS may underlie sex-dependent phenotypic features, including depressed frequency-dependent contractile responses. The latter could contribute to poorer functional capacity observed in F-AS.