Ventricular remodeling and intervention with losartan following rabbit chronic hibernating myocardium

Objectives To explore the changes of myocyte and the interstitial collagen in a model of chronic hibernating myocardium (CHM) in rabbits, and to determine whether these alterations affect the cardiac function, and to further observe the effects of losartan on ventricular remodeling. Methods A left anterior descending (LAD) coronary artery stenosis was created and maintained for 4 weeks to create a CHM model in rabbits. Thirty-six rabbits were assigned to the following three groups(12 rabbits per group): CHM for 4 weeks(CHM group), low-dose of losartan intervention group for 4 weeks(LTl group, 10 mg·kg-1·d-1), high-dose of losartan intervention group for 4 weeks (LT2 group, 30 mg·kg-1·d-1); and 12 sham-operated rabbits served as controls (SO group). A microscopic imaging system (Image-Pro Plus, Olympus) was used to assess the Interstitial collagen volume fraction (ICVF) in myocardial sections with picrosirius-red staining, and a polarized light microscopy to qualitatively analysis the changes in the type and the proportion of collagen fibers, to semi-quantitatively score the proportion of collagen I to collagen III(PI/III). The expression of MMP-2, 9 and TIMP-2 was assessed by immunohistochemistry and western bloting. The myocyte apoptosis rate (Rapo) was calculated with TUNEL-staining. And echocardiography was performed to measure left ventricular end-systolic and end-diastolic diameter (LVESD, LVEED), and left ventricular short-axis fraction shortening (LVFS) and ejection fraction (LVEF). Results The animal model of CHM was induced successfully in 36 out of 39-rabbits and maintained for 28 days. Compared with the sham group, ICVF) was significantly increased (P【0.01) in CHM group; compared with CHM group, ICVF was significantly decreased (P【0.01,each) in LTl group and LT2 group, and the change were more remarkable in LT2 group, compared to LTl group(P【0.05). Compared with sham group, PI/IH was significantly increased (P 【 0.01) in CHM group; compared with CHM group, PI/III was significantly decreasedin the losartan intervention groups (P【0.01,each), and the change was more remarkable in LT2 group compared to LTl group (P【0.05). Compared with sham group, the expression of MMP-2 and MMP-9 were greatly increased (P【0.01) in CHM group, while TIMP-2 were greatly decreased(P【 0.01); compared with CHM group, the expression of MMP-2 and MMP-9 were significantly decreased (P【0.01,each) .while TIMP-2 were significantly increased (P【0.01,each) in the losartan intervention groups, and the change was more remarkable in LT2 group than in LT1 group (.P【0.05). Compared with sham group, myocyte Rapo was markedly increased (P【0.01) in CHM group; compared with CHM group, myocyte Rapo was significantly decreased (P【0.01,each) in the losartan intervention groups, and the change was more remarkable in LT2 group than in LT1 group (P【0.05). Compared with sham group, LVEF and LVFS were significantly reduced in CHM group (P 【0.01), compared with CHM group, LVEF and LVFS were higher (P【0.01,each) in the losartan intervention groups ,and the changes were more remarkable in LT2 group than in LTl group (P【0.05). Conclusions CHM underwent interstitial collagen proliferation and myocyte apoptosis, leading to ventricular remodeling and ventricular functional impairment, Losartan intervention reduces myocyte apoptosis and interstitial collagen proliferation, and improve ventricular function.