Characterization of Coronary Flow Reserve and Left Ventricular Remodeling in a Mouse Model of Chronic Aortic Regurgitation With Carvedilol Intervention

OBJECTIVES: We hypothesized that left ventricular (LV) remodeling might be exaggerated by an impaired coronary flow reserve in mice with chronic severe aortic regurgitation, and carvedilol, a β-adrenoceptor blocker, could regress the course. METHODS: Severe aortic regurgitation was induced by retrograde puncture of the aortic valve leaflets under sonographic guidance in 12-week-old male C57BL/6J mice. Four weeks after regurgitation, the mice were treated with carvedilol (30 mg/kg/d) or not treated (control). Before and 4 weeks after carvedilol treatment, the coronary flow reserve and LV structure and function were evaluated by echocardiography. Cardiomyocytes and fibrosis were validated by histologic analysis. RESULTS: Four-week aortic regurgitation caused a decreased LV ejection fraction and an increased LV end-systolic volume index. Regurgitation also impaired the coronary flow reserve due to an increase in the basal coronary peak diastolic velocity and velocity-time integral combined with the absence of substantial changes in the hyperemic coronary peak diastolic velocity and velocity-time integral. Four more weeks of regurgitation further deteriorated LV remodeling and coronary perfusion in the control group. In contrast, the carvedilol-treated group showed attenuated LV remodeling and a higher coronary flow reserve by decreasing the basal peak diastolic velocity and velocity-time integral without substantial changes in the hyperemic peak diastolic velocity and velocity-time integral. The coronary flow reserve and its pretreatment versus posttreatment difference were positively correlated with the pretreatment versus posttreatment LV ejection fraction and end-systolic volume index differences. In the carvedilol-treated group, subendocardial fibrosis was significantly reduced (P < .05), and the cardiomyocyte cross-sectional area tended to be smaller. CONCLUSIONS: In mice with chronic severe aortic regurgitation, carvedilol therapy significantly improves the impaired coronary flow reserve and sufficiently attenuates adverse LV remodeling. Sustained coronary flow reserve impairment indicates progressive LV remodeling.