Bozkurt B, Kribbs S B, Clubb F J, Michael L H, Didenko V V, Hornsby P J, Seta Y, Oral H, Spinale F G, Mann D L
Department of Medicine, Veterans Administration Medical Center, Baylor College of Medicine, Houston, Tex 77030, USA.
Circulation. 1998 Apr 14;97(14):1382-91. doi: 10.1161/01.cir.97.14.1382.
Although patients with heart failure express elevated circulating levels of tumor necrosis factor-alpha (TNF-alpha) in their peripheral circulation, the structural and functional effects of circulating levels of pathophysiologically relevant concentrations of TNF-alpha on the heart are not known.
Osmotic infusion pumps containing either diluent or TNF-alpha were implanted into the peritoneal cavity of rats. The rate of TNF-alpha infusion was titrated to obtain systemic levels of biologically active TNF-alpha comparable to those reported in patients with heart failure (approximately 80 to 100 U/mL), and the animals were examined serially for 15 days. Two-dimensional echocardiography was used to assess changes in left ventricular (LV) structure (remodeling) and LV function. Video edge detection was used to assess isolated cell mechanics, and standard histological techniques were used to assess changes in the volume composition of LV cardiac myocytes and the extracellular matrix. The reversibility of cytokine-induced effects was determined either by removal of the osmotic infusion pumps on day 15 or by treatment of the animals with a soluble TNF-alpha antagonist (TNFR:Fc). The results of this study show that a continuous infusion of TNF-alpha led to a time-dependent depression in LV function, cardiac myocyte shortening, and LV dilation that were at least partially reversible by removal of the osmotic infusion pumps or treatment of the animals with TNFR:Fc.
These studies suggest that pathophysiologically relevant concentrations of TNF-alpha are sufficient to mimic certain aspects of the phenotype observed in experimental and clinical models of heart failure.
尽管心力衰竭患者外周循环中肿瘤坏死因子-α（TNF-α）的循环水平升高，但生理病理相关浓度的TNF-α循环水平对心脏的结构和功能影响尚不清楚。
将含有稀释剂或TNF-α的渗透式输液泵植入大鼠腹腔。滴定TNF-α输注速率以获得与心力衰竭患者报告的生物活性TNF-α全身水平相当的水平（约80至100 U/mL），并对动物连续检查15天。使用二维超声心动图评估左心室（LV）结构（重塑）和LV功能的变化。使用视频边缘检测评估单个细胞力学，使用标准组织学技术评估LV心肌细胞和细胞外基质体积组成的变化。通过在第15天移除渗透式输液泵或用可溶性TNF-α拮抗剂（TNFR:Fc）治疗动物来确定细胞因子诱导效应的可逆性。本研究结果表明，持续输注TNF-α导致LV功能、心肌细胞缩短和LV扩张呈时间依赖性降低，通过移除渗透式输液泵或用TNFR:Fc治疗动物，这些降低至少部分可逆。
这些研究表明，生理病理相关浓度的TNF-α足以模拟在心力衰竭实验和临床模型中观察到的某些表型特征。
