Vasodilator Stress Echocardiography in the Assessment of Early Coronary Microvascular Function in Type II Diabetic Mice

Abstract

Background: The leptin receptor-deficient db/db mouse is a well-established type II diabetes animal model used to investigate diabetic cardiomyopathy. Diabetes mellitus induces functional and structural abnormalities of the coronary microvascular circulation, which can play a role in the development of diabetic cardiomyopathy. The objective of this study was to use vasodilator stress echocardiography to assess coronary microvascular function in vivo with diabetic db/db mice in order to study early changes of the coronary microvascular circulation in type II diabetes model. Materials and method: Male diabetic db/db mice and age-matched control mice from C57BL/6J strain at 8, 12 and 16 weeks of age were subjected to echocardiography. Mice were anesthetized with 2% isoflurane vaporized with 100% oxygen. At the mid-papillary level in the parasternal left ventricular short-axis view, end diastolic and systolic left ventricular diameter, interventricular septal thickness and posterior wall thicknesses, ejection fraction, fractional shortening were determined by M-mode echocardiography. Isoflurane was reduced to 1% to measure baseline left anterior descending coronary artery flow under a modified parasternal left ventricle long-axis view, and then increased to 3% to measure maximal coronary flow. Coronary flow velocity reserve (CFVR) was calculated as the ratio of peak diastolic velocity (PDV) at the highest flow attained during the high level of isoflurane (3%) to PDV at the minimum baseline flow obtained at the lowest level of isoflurane (1%): CFVR= Hyperemic coronary flow velocity (PDVh)/Basal coronary flow velocity (PDVb). Results: There was no significant difference in interventricular septal thickness, posterior wall thicknesses, end diastolic and systolic left ventricular diameter, ejection fraction and fractional shortening between db/db and age-matched control mice at 8, 12 or 16 weeks of age (P > 0.05). At 8 weeks of age, there was no significant difference in PDVb, PDVh and CFVR of the left anterior descending artery. At 12 weeks of age, CFVR in db/db mice was lower than in control mice (P < 0.01). At 16 weeks of age, PDVh and CFVR was significantly decreased in dbdb mice (P < 0.01), although PDVb remained unchanged. A significant negative correlation was noted between CFVR and the blood glucose level in db/db and C57BL/6 mice (r = –0.612, P < 0.01). Conclusion: The present study confirmed that db/db mice showed the decreased CFVR from the age of 12 weeks, suggesting the impairment of coronary microvascular function. The presence of hyperglycemia may be a significant contributor to the development of impaired coronary vasodilator response.