Characterization of coronary flow reserve and left ventricular remodeling in a mouse model of chronic aortic regurgitation with carvedilol intervention

Xiangfei Wang; Jian Wu; Dan Zhu; Jieyun You; Yunzeng Zou; Juying Qian; Junbo Ge

doi:10.7863/ultra.34.3.483

Characterization of coronary flow reserve and left ventricular remodeling in a mouse model of chronic aortic regurgitation with carvedilol intervention

J Ultrasound Med. 2015 Mar;34(3):483-93. doi: 10.7863/ultra.34.3.483.

Authors

Xiangfei Wang¹, Jian Wu¹, Dan Zhu¹, Jieyun You¹, Yunzeng Zou¹, Juying Qian¹, Junbo Ge²

Affiliations

¹ Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China (X.W., J.W., J.Y., Y.Z., J.Q., J.G.); Department of Physiology, University of Toronto, Toronto, Ontario, Canada (J.W.); and Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China (D.Z.).
² Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China (X.W., J.W., J.Y., Y.Z., J.Q., J.G.); Department of Physiology, University of Toronto, Toronto, Ontario, Canada (J.W.); and Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China (D.Z.). jbge@zs-hospital.sh.cn.

PMID: 25715369
DOI: 10.7863/ultra.34.3.483

Abstract

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.

Keywords: aortic regurgitation; carvedilol; coronary flow reserve; echocardiography; left ventricular remodeling.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Aortic Valve Insufficiency / complications
Aortic Valve Insufficiency / diagnostic imaging*
Aortic Valve Insufficiency / drug therapy*
Carbazoles / therapeutic use*
Carvedilol
Chronic Disease
Echocardiography / methods
Fractional Flow Reserve, Myocardial / drug effects*
Male
Mice
Mice, Inbred C57BL
Propanolamines / therapeutic use*
Reproducibility of Results
Sensitivity and Specificity
Stroke Volume / drug effects
Treatment Outcome
Vasodilator Agents / therapeutic use
Ventricular Dysfunction, Left / complications
Ventricular Dysfunction, Left / diagnostic imaging*
Ventricular Dysfunction, Left / prevention & control
Ventricular Remodeling / drug effects*

Substances

Carbazoles
Propanolamines
Vasodilator Agents
Carvedilol