457-P: Quantification of Vascular Density by 3D Light Sheet Imaging in a Surgical Ligation of the Left Anterior Descending Artery (LAD) Model in Mouse

Abstract

Introduction: Patients with diabetes have an increased risk of cardiovascular disease including myocardial infarction (MI). A major consequence of MI is left ventricular (LV) remodeling including compensatory hypertrophy without concomitant adaptation of the capillary vasculature. Targeting capillary density is thus a promising therapeutic strategy but methods for unbiased and direct quantification are lacking. In a surgical MI model, we used 3D light sheet imaging to visualize and quantify LV remodeling including capillary density. Methods: Surgical ligation of the left anterior descending artery (LAD) was performed in male C57BL/6 mice. Infarct localization and LV function were evaluated by echocardiography, and LV remodeling and capillary density quantified by 3D light sheet imaging. Results: Ejection fraction (EF) as measured by echocardiography was reduced in LAD-ligated mice with anterior wall MI compared to mice without MI (29.1±1.5 vs. 55.2±1.1 %, p<0.001), while internal LV volume (as assessed by 3D imaging) was increased (16.6±0.7 vs. 22.7±1.3 mm3, p<0.01) 10 days after LAD ligation. Furthermore, EF and LV volume correlated (R2: 0.59, p<0.001, slope -0.32). The capillary density in the infarct zone was reduced in MI versus no MI mice (10.5±1.00 vs. 23.5±2.5 % of total tissue volume, p<0.001). In a subsequent treatment study, EF was reduced by 43.2% in MI compared to no MI mice (p<0.001) 7 days after LAD ligation. The effects of 4 weeks of treatment with captopril on LV function, remodeling and capillary density was investigated by echocardiography and 3D light sheet imaging. Conclusions: The combination of echocardiography and 3D light sheet imaging offers a novel approach to visualize and quantify LV function, remodeling and capillary density in a mouse model of MI. This high-resolution 3D imaging technology thus allows for preclinical efficacy testing of novel therapeutics for heart disease including MI. Disclosure N.E. Zois: Employee; Self; Gubra. U. Roostalu: Employee; Self; Gubra. L. Thisted: Employee; Self; Gubra. P.J. Pedersen: Employee; Self; Gubra. K. Fosgerau: None. J. Jelsing: Board Member; Self; Gubra. Stock/Shareholder; Self; Gubra. N. Vrang: Board Member; Self; Gubra. Employee; Self; Gubra. Stock/Shareholder; Self; Gubra.