Abstract 15421: Mice Deficient in Endothelial Cell-Selective Adhesion Molecule Display Coronary Microvascular Rarefaction and Left Ventricle Diastolic Dysfunction

Abstract

Coronary microvascular dysfunction and chronic inflammation play a role in the development of left ventricular diastolic dysfunction (LVDD) in heart failure with preserved ejection fraction (HFpEF). Endothelial cell-selective adhesion molecule (ESAM) is part of the endothelial cell junction complex, which plays a role in the maintenance of cell barrier function, inflammatory cell transmigration and angiogenesis. Here, we examined the role of ESAM in affecting coronary microvascular density and left ventricle diastolic function by employing mice with genetic deletion of ESAM (ESAM -/- ). Using echocardiography, we found that ESAM -/- mice display LVDD, as indicated by a significantly (p<0.05) reduced E/A ratio (E=early, A=late mitral inflow peak velocities), increased E/e’ ratio, isovolumic relaxation time and E wave deceleration time, with no change in the ejection fraction. Using an unbiased, automated tracing and 3D reconstruction of microvascular network revealed that ESAM -/- mice have a reduced coronary microvascular density, which was accompanied by myocardial accumulation of myeloperoxidase-positive neutrophils and elevated myocardial levels of inflammatory cytokines and chemokines. ESAM -/- mice exhibited a reduced endothelial sprout formation in the carotid artery, whereas in cultured endothelial cells siRNA-mediated ESAM knockdown impaired tube formation. Thus, ESAM deficiency in mice leads to coronary microvascular rarefaction, which likely via a myocardial hypoperfusion-related neutrophil accumulation and inflammatory mediator production impairs LV diastolic function.