title: Characterization of coronary flow reserve and left ventricular remodeling in a mouse model of chronic aortic regurgitation with carvedilol intervention.
abstract: OBJECTIVE
  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.
authors.affiliation: 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.).
authors.forename: Xiangfei
authors.initials: X
authors.lastname: Wang
authors.affiliation: 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.).
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.affiliation: 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.).
authors.forename: Dan
authors.initials: D
authors.lastname: Zhu
authors.affiliation: 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.).
authors.forename: Jieyun
authors.initials: J
authors.lastname: You
authors.affiliation: 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.).
authors.forename: Yunzeng
authors.initials: Y
authors.lastname: Zou
authors.affiliation: 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.).
authors.forename: Juying
authors.initials: J
authors.lastname: Qian
authors.affiliation: 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.
authors.forename: Junbo
authors.initials: J
authors.lastname: Ge
mesh_terms: D000818:Animals; D001022:Aortic Valve Insufficiency / Q000150:complications / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D002227:Carbazoles / Q000627:therapeutic use*; D000077261:Carvedilol; D002908:Chronic Disease; D004452:Echocardiography / Q000379:methods; D053805:Fractional Flow Reserve, Myocardial / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011412:Propanolamines / Q000627:therapeutic use*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013318:Stroke Volume / Q000187:drug effects; D016896:Treatment Outcome; D014665:Vasodilator Agents / Q000627:therapeutic use; D018487:Ventricular Dysfunction, Left / Q000150:complications / Q000000981:diagnostic imaging* / Q000517:prevention & control; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D002227:Carbazoles; D011412:Propanolamines; D014665:Vasodilator Agents; D000077261:Carvedilol
keywords: aortic regurgitation; carvedilol; coronary flow reserve; echocardiography; left ventricular remodeling