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

^a Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
^b Department of Pharmacology, Osaka Medical College, Takatsuki City, Osaka, Japan

Received 26 March 2007; received in revised form 17 September 2007; accepted 21 September 2007.

^_* Corresponding author. Address: Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan. Tel.: +81 75 751 3780; fax: +81 75 751 4960. (Email: komelab{at}kuhp.kyoto-u.ac.jp).

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.

Key Words: Chymase • Angiotensin II • Transforming growth factor (TGF)-β • Left ventricular repair (LVR) • Myocardial fibrosis