Abstract P3022: Multiscale Characterization Of Left Ventricular Diastolic Dysfunction In Diabetic And Cardiac Myosin Binding Protein-C Phospho-Ablated Murine Models
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Introduction: Left ventricular (LV) diastolic dysfunction (LVDD) is often characterized by organ-level (global) metrics whose quantitative connections to mechanical remodeling events at the tissue and fiber levels remain poorly studied. Methods: We performed measurements in the LV at three length scales, namely, organ, tissue, and fiber, in two murine models of LVDD: (i) diabetic (db/db) (n=10) versus wild-type (WT; n=10) mice, and (ii) novel knock-in cardiac myosin binding protein-C (cMyBP-C) phospho-ablated (KI-3A; n=8) versus cMyBP-C phospho-mimetic (KI-3D, n=6) and WT (n=8) mice. Echocardiography was done in vivo. Left ventricular free wall (LVFW) specimens were harvested and passively stretched along with circumferential (C) and longitudinal (L) directions (schematically identified in Fig. 1c) in select mice. Passive tests were followed by activation-relaxation tests of the LVFW specimens at resting biaxial stretches. Active force-pCa measurements at resting stretch were carried out on the skinned papillary muscle fibers. Results: Both db/db and KI-3A mice demonstrated slow relaxation at the organ level indicated by increased E/e' (Figs. 1a-b). db/db LVFW specimens showed increased circumferential stiffness at the tissue level under biaxial passive stretching (p<0.05 for strains >0.25). Biaxial activation-relaxation tests of LVFW specimens in knock-in mice (Fig. 1c shows the results for KI-3A mice) revealed that KI-3A mice relax significantly slower than KI-3D mice along the longitudinal direction (Fig. 1d). Fiber-level tests demonstrated that active force development was significantly enhanced in db/db mice (Fig. 1e) while it was significantly suppressed in KI-3A mice relative to KI-3D and WT mice (Fig. 1f). Conclusions: Although both db/db and KI-3A mice showed LVDD at the organ level, they demonstrated different mechanical alterations at the fiber and tissue fiber levels, suggesting that global metrics should be complemented with metrics characterizing the LV properties at the fiber and tissue levels to fully characterize LVDD.
