Diastolic dysfunction in small and large animal models of moderate calcific aortic stenosis with preserved ejection fraction is heart rate dependent
G Geist, Y Ueyama, S Falero, C Zambataro, B Teng, S Roof, J Miller, C Abbas, C Del RioAbstract
Background
In patients with calcific aortic valve stenosis (CAVS), progressive calcium deposition in the aortic leaflets results in increased LV afterload, diastolic dysfunction, and cardiac remodeling. Notably, elevated resting heart rate (HR) is independently associated with major cardiovascular events in CAVS. Given that HR is a determinant of LV relaxation/filling, this study evaluated the relationship between indices of diastolic function and HR in two translationally relevant models of moderate CAVS.
Methods
CAVS was induced in Yucatan minipigs (8.0 ± 0.1M, 27.4 ± 1.4, n = 6) via acute (endothelial) aortic valve abrasion and 12-weeks of western diet; pigs were studied via echocardiography/invasive hemodynamics. Mutant mice with CAVS (ldlr-/-, ApoB100/100; n = 13, 9.7±0.2M, 28.3±1.7g - western diet fed for >6M) were studied via echocardiography. Systolic and diastolic function, including mitral-annulus tissue Doppler, were studied before/after a negative chronotropic challenge (ivabradine; +IVA), as well under right-atrial pacing (100-150ppm in pigs) in both CAVS animals and healthy/age-matched controls; relationships between indices of diastolic function and HR were tested via multiple linear regression. *: P < 0.05.
Results
CAVS pigs had elevated end-diastolic pressures (19 ±1 mmHg) and wall-thickness (RWT: 0.45 ± 0.02), with preserved EF (68.8 ± 1.2%); as HR increased, the normalized time-constant of relaxation prolonged (tau: 3.9 ± 0.4 vs. 2.1 ± 0.2%/RR*) and stroke volume decreased (32 ± 2 vs. 42 ± 2 mL*) despite increased inotropy. Similarly, CAVS mice had preserved EF (66 ± 3%) and impaired early filling velocities (e’: -16 ± 1 vs. -22 ± 2 mm/s*), slower relaxation times, and thicker LV walls; as HR decreased (472 ± 21 to 355 ± 32 bpm*), e' improved (to -21.6 ± 3.0 mm/s*), increasing stroke volume (VTI: 71 ± 5 vs. 56 ± 4 mm*). Overall, e’ values (in mice, R2 = 0.45*) and tau (in pigs, R2 = 0.55*) were linearly dependent on HR.
Conclusions
Diastolic dysfunction and LV hypertrophy were found to be hallmarks of both small and large animal models of CAVS with preserved EF. The CAVS-associated diastolic impairments were heart rate dependent, likely due to the imposed calcific afterload. These observations underscore the value of novel therapies targeting both valvular load and ventricular function in patients with CAVS.