Pathophysiologically relevant concentrations of tumor necrosis factor-α promote progressive left ventricular dysfunction and remodeling in rats
Pathophysiologically relevant concentrations of tumor necrosis factor-α promote progressive left ventricular dysfunction and remodeling in rats
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DOI：
10.1161/01.cir.97.14.1382
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发表时间：
1998-04-14
期刊：
影响因子：
37.8
通讯作者：
Mann, DL
中科院分区：
文献类型：
--
作者：
Bozkurt, B;Kribbs, SB;Mann, DL
背景-尽管心力衰竭患者外周循环中肿瘤坏死因子-α(TNF-α)水平升高，但循环中病理生理相关浓度的肿瘤坏死因子-α对心脏的结构和功能影响尚不清楚。方法和结果-将含有稀释剂或肿瘤坏死因子-α的渗透泵植入大鼠腹膜腔内。滴定肿瘤坏死因子-α的输注速度，以获得与心力衰竭患者报告的水平相当的生物活性肿瘤坏死因子-α的系统水平(约为80~100U/mL)，并对动物进行连续15天的检查。应用二维超声心动图评价左心室结构(重塑)和左心室功能的变化。视频边缘检测用于评估分离的细胞力学，标准组织学技术用于评估左室心肌细胞和细胞外基质体积组成的变化，细胞因子诱导效应的可逆性通过在第15天移除渗透压泵或通过用可溶性肿瘤坏死因子-α拮抗剂(TNFR：Fc)处理来确定。这项研究的结果表明，持续输注肿瘤坏死因子-α导致时间依赖性的左心功能抑制、心肌细胞缩短和左室扩张，这些至少可以通过移除渗透输注泵或用TNFR：Fc治疗而部分逆转。结论--这些研究表明，病理生理学上相关浓度的肿瘤坏死因子-α足以模拟实验和临床心力衰竭模型中观察到的某些表型。
Background-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.Methods and Results-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 (approximate to 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.Conclusions-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.