Prevention of Cardiac9 Remodeling and Diastolic Dysfunction by inhibiting Fibrotic Process.

高血压心脏过度心肌纤维化损害心功能。本实验观察了转化生长因子（transforminggrowthfactor，TGF）-B在压力负荷大鼠心肌重构和心功能不全中的作用。在第3天后观察到成纤维细胞活化（增殖和向肌成纤维细胞的表型转变），并在第3-7天达到峰值。此后，到第28天出现肌细胞肥大和肌纤维化。在第28天，超声心动图显示正常的左心室短轴缩短率，但二尖瓣多普勒速度的早期至晚期充盈比率降低，血流动力学测量显示左心室舒张末期压升高，表明收缩功能正常，但舒张功能异常。心肌TGF-B mRNA的表达在术后第3天开始诱导，第7天达到高峰，第28天仍有一定程度的增加。从术前1天开始每天腹腔注射抗TGF-B中和抗体（NA B b），可抑制成纤维细胞的活化，随后可防止胶原mRNA的诱导和心肌纤维化，但对心肌细胞肥大无影响。NAb逆转舒张功能不全，而不影响血压和收缩功能。

Excessive myocardial fibrosis impairs cardiac function in hypertensive hearts. Roles of transforming growth factor (TGF)-B in myocardial remodeling and cardiac dysfunction were examined (in press)ure-overloaded rats.Pressure overload was induced by a suprarenal aortic constriction in Wistar rats. Fibroblast activation (proliferation and phenotype transition to myofibroblasts) was observed after day 3 and peaked at days 3-7. Thereafter, myocyte hypertrophy and myocWdial fibrosis developed by day 28. At day 28, echocardiography showed normal LV fractional shortening but the decreased early to late filling ratio of the transmitral Doppler velocity, and hemodynamic measurement revealed LV end-diastolic pressure elevation, indicating normal systolic but abnormal diastolic function. Myocardial TGF-B mRNA expression was induced after day 3, peaked at day 7, and remained modestly increased at day 28.An anti-TGF-B neutralizing antibody (NAb), which was intraperitoneally administered daily from 1 day before operation, inhibited fibroblast activation and subsequently prevented collagen mRNA induction and myocardial fibrosis, but not myocyte hypertrophy. NAb reversed diastolic dysfunction without affecting blood pressure and systolic function.TGF-B plays a causal role in myocardial fibrosis and diastolic dysfunction through fibroblast activation in