Wilson Eric M, Gunasinghe Himali R, Coker Mytsi L, Sprunger Philip, Lee-Jackson Dorellyn, Bozkurt Biykem, Deswal Anita, Mann Douglas L, Spinale Francis G
Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
J Card Fail. 2002 Dec;8(6):390-8. doi: 10.1054/jcaf.2002.129659.
Changes in myocardial matrix metalloproteinases (MMPs) and the inhibitors of MMPs (TIMPs) have been demonstrated in congestive heart failure (CHF). The first objective of this study was to measure plasma profiles of MMPs and TIMPs in CHF patients (n = 24; 62 +/- 3 years; left ventricular ejection fraction [LVEF] = 24 +/- 2%) and age-matched nonfailing patients (n = 48; 63 +/- 2 years; LVEF >/= 55%). Cytokines such as tumor necrosis factor (TNF)-alpha can induce MMP expression in vitro. The second objective of this study was to determine the relationship between soluble TNF-alpha receptors (TNFR1; TNFR2) and MMP plasma profiles.
Plasma levels of MMP-2, MMP-9, MMP-8, TIMP-1, TIMP-2, TNF-alpha, TNFR1, and TNFR2 were measured by enzyme-linked immunosorbent assay kits. Plasma MMP-9 levels were increased in CHF patients (25 +/- 6 versus 72 +/- 15 ng/mL, P <.05). Interestingly, plasma levels of MMP-8 were decreased in CHF patients (16 +/- 2 versus 9 +/- 2 ng/mL, P <.05). The MMP-9/TIMP-1 ratio was increased by 3-fold, whereas the MMP-9/TIMP-2 ratio was increased by 16-fold in CHF patients (both P <.05). With a 48-week follow-up in CHF patients, an absolute reduction in plasma TNFR1 from baseline was accompanied by reduced MMP-9 levels (-30 +/- 16 ng/mL; P =.058), whereas stable or increased plasma TNFR1 resulted in persistently elevated MMP-9 levels.
The unique findings of this study were 2-fold. First, a discordant change in plasma MMP and TIMP levels occurred in CHF patients. Second, changes in cytokine activity were related to changes in plasma MMP levels. These changes in MMP/TIMP levels likely reflect the progression and/or acceleration of the LV remodeling process in CHF. Thus serial measurements of plasma MMP/TIMP levels may hold diagnostic/prognostic significance in CHF patients.
在充血性心力衰竭（CHF）中已证实心肌基质金属蛋白酶（MMPs）及其抑制剂（TIMPs）发生了变化。本研究的首要目的是测定CHF患者（n = 24；62±3岁；左心室射血分数[LVEF]=24±2%）和年龄匹配的非心力衰竭患者（n = 48；63±2岁；LVEF≥55%）血浆中MMPs和TIMPs的水平。细胞因子如肿瘤坏死因子（TNF）-α可在体外诱导MMP表达。本研究的第二个目的是确定可溶性TNF-α受体（TNFR1；TNFR2）与MMP血浆水平之间的关系。
采用酶联免疫吸附测定试剂盒测定血浆中MMP-2、MMP-9、MMP-8、TIMP-1、TIMP-2、TNF-α、TNFR1和TNFR2的水平。CHF患者血浆MMP-9水平升高（25±6对72±15 ng/mL，P<.05）。有趣的是，CHF患者血浆MMP-8水平降低（分别为16±2对9±2 ng/mL，P<.05）。CHF患者的MMP-9/TIMP-1比值增加了3倍，而MMP-9/TIMP-2比值增加了16倍（均P<.05）。对CHF患者进行48周随访，血浆TNFR1较基线水平绝对降低伴随着MMP-9水平降低（-30±16 ng/mL；P =.058），而血浆TNFR1稳定或升高则导致MMP-9水平持续升高。
本研究的独特发现有两点。第一，CHF患者血浆MMP和TIMP水平出现不一致的变化。第二，细胞因子活性的变化与血浆MMP水平的变化有关。MMP/TIMP水平的这些变化可能反映了CHF患者左心室重构过程的进展和/或加速。因此，连续测定血浆MMP/TIMP水平可能对CHF患者具有诊断/预后意义。
