Chronic chymase inhibition preserves cardiac function after left ventricular repair in rats

• Published in: European journal of cardio-thoracic surgery 2008-01, Vol.33 (1), p.25-31
• Main Authors: Kanemitsu, Hideo, Takai, Shinji, Tsuneyoshi, Hiroshi, Yoshikawa, Eiji, Nishina, Takeshi, Miyazaki, Mizuo, Ikeda, Tadashi, Komeda, Masashi
• Format: Article
• Language: English
• Subjects: Angiotensin II; Animals; Biological and medical sciences; Blood Pressure - drug effects; Cardiology. Vascular system; Chymase; Chymases - antagonists & inhibitors; Echocardiography; Enzyme Inhibitors - therapeutic use; Heart Arrest, Induced - methods; Heart Ventricles - enzymology; Hemodynamics; Left ventricular repair (LVR); Male; Medical sciences; Myocardial fibrosis; Myocardium - enzymology; Pneumology; Random Allocation; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction - methods; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of the heart; Transforming growth factor (TGF)-β; Treatment Outcome; Ventricular Dysfunction, Left - drug therapy; Ventricular Dysfunction, Left - enzymology; Ventricular Remodeling - drug effects
• ISSN: 1010-7940; 1873-734X
• DOI: 10.1016/j.ejcts.2007.09.040

Objective: Although left ventricular repair (LVR) has been widely performed, the initial improvement of LV function does not last because of LV remodeling. Recent studies have demonstrated that chymase, a local enzyme in the heart, promotes angiotensin II formation as well as activation of transforming growth factor (TGF)-β, both of which facilitate myocardial fibrosis. Therefore, chymase blockade may play an important role in the prevention of cardiac remodeling after LVR. In this study, the effects of chronic chymase inhibition (Chy-I) after LVR were evaluated in a rat LV aneurysm model. Methods: Rats that developed LV aneurysms 4 weeks after coronary artery ligation underwent LVR by plicating the LV aneurysm, and were randomized into two groups, the LVR group and the LVR + Chy-I group that received an oral chymase inhibitor (10 mg/kg/day) for 4 weeks. Results: Echocardiography revealed better LV function in the LVR + Chy-I group than in the LVR group at 4 weeks. Four weeks after LVR, LV end-diastolic pressure and the time constant of LV isovolumic pressure decay, were significantly lower in the LVR + Chy-I group. The end-systolic pressure–volume relationship was higher in the LVR + Chy-I group. In the LVR + Chy-I group, mRNA expressions of TGF-β1 and BNP significantly decreased in the LV myocardium. Histology showed reduced interstitial fibrosis in the LVR + Chy-I group. Conclusions: Chronic chymase inhibition prevented myocardial fibrosis and preserved cardiac function after LVR. A chymase inhibition could be an important strategy for management after LV repair surgery.