Mice deficient in endothelial cell-selective adhesion molecule develop left ventricle diastolic dysfunction

Abstract

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): American Heart Association Background Dysfunction of vascular endothelium plays a key role in the development of left ventricular diastolic dysfunction (LVDD) in patients with heart failure with preserved left ventricular ejection fraction (HFpEF). Recently, Endothelial Cell-Selective Adhesion Molecule (ESAM) was proposed as a novel biomarker in HFpEF. Hypothesis. ESAM plays a mechanistic role in the development of both microvascular dysfunction and LVDD. Methods Animals: The study was performed utilizing ESAM knockout and wild type (WT) mice. Echocardiography: Left ventricular (LV) systolic and diastolic function and LV wall thickness were assessed by small animal ultrasound imaging (Vevo3100). Blood pressure measurement: Performed with tail-cuff plethysmography method. Vascular reactivity: Pulmonary arteries (2nd and 3rd order) were isolated from ESAM KO and WT mice, vascular reactivity was assessed with wire myography method. Evaluation of myocardial vascular density: Paraformaldehyde fixed paraffin embedded heart section (40 µm thick) from WT and ESAM KO mice stained with Tomato Lectin (Lycopersicon esculentum) DyLight594 to label vasculature were used. Unbiased automated tracing of the microvasculature was performed using the VesseLucida360 software (MBF), followed by a morphometric analysis (VesseLucida Explorer). Results Transthoracic echocardiography analysis showed that ESAM knockout mice displayed LV diastolic dysfunction, as indicated by a significantly reduced E/A ratio (E=early, A=late mitral inflow peak velocities), increased E/e’ ratio, isovolumic relaxation time (IVRT) and increased E wave deceleration time, with no change in the ejection fraction. The systolic blood pressure was not different between ESAM knockout and WT mice. Heart weight, related to body weight is increased in ESAM-deficient mice, pointing towards cardiac hypertrophy in these animals. Meanwhile, the analysis of the cardiac tissue vascularization with unbiased automated tracing of the microvasculature, reveals the decreased total vascular length per volume of the tissue in ESAM knockout mice. Using wire myography of the pulmonary artery vasodilator function we found that the endothelium-dependent, acetylcholine-induced relaxation of these arteries was significantly reduced in ESAM knockout mice, whereas endothelium-independent, nitric oxide donor, sodium nitroprusside-induced relaxation was similar in the two groups. Conclusion ESAM deficiency in mice resembles a HFpEF phenotype, in that ESAM knockout mice develop endothelial dysfunction and LVDD.