Felkin Leanne E, Birks Emma J, George Robert, Wong Sissie, Khaghani Asghar, Yacoub Magdi H, Barton Paul J R
National Heart and Lung Institute, Imperial College London, Heart Science Centre, Harefield, Middlesex.
J Heart Lung Transplant. 2006 Dec;25(12):1413-9. doi: 10.1016/j.healun.2006.09.006.
Mechanisms underlying the rapid deterioration of heart failure patients who subsequently require left ventricular assist device (LVAD) support are poorly understood. Matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) play a key role in myocardial remodelling and heart failure. We hypothesized that MMP and TIMP expression would be altered in these patients.
Quantitative polymerase chain reaction was used to measure myocardial messenger RNA levels of MMP1 to MMP14, TIMP1 to TIMP4, collagen I and collagen III in 24 dilated cardiomyopathy (DCM) patients with deteriorating clinical status who required LVAD support (LVAD Group) and in 7 stable DCM patients undergoing transplantation without need for LVAD support (Tx Group).
Levels of MMP1, MMP8 and TIMP4 were higher in the LVAD Group compared with the Tx Group (188% +/- 141%, 646% +/- 432%, and 66% +/- 33% higher, respectively, p < 0.05) whereas MMP2, MMP9, MMP10, MMP11, and MMP14 levels were similar. MMP3, MMP7, MMP12, and MMP13 were undetectable. All TIMPs were generally higher in the LVAD group, but only TIMP4 reached significance. Collagen I and III were not altered. We tested for correlations between MMP and TIMP expression with myocardial cytokine levels. MMP8 correlated positively with interleukin-6 and interleukin-1beta, suggesting a link between cytokines and MMPs in these patients.
The data show that high myocardial collagenase (MMP1 and MMP8) expression without compensatory changes in collagen or TIMP expression is a feature of patients requiring LVAD support. This may be linked in part to elevated cytokine expression and suggests collagenase activity may be an important therapeutic target in deteriorating heart failure.
对于那些随后需要左心室辅助装置（LVAD）支持的心力衰竭患者病情迅速恶化的潜在机制，人们了解甚少。基质金属蛋白酶（MMPs）和金属蛋白酶组织抑制剂（TIMPs）在心肌重塑和心力衰竭中起关键作用。我们推测这些患者的MMP和TIMP表达会发生改变。
采用定量聚合酶链反应来测量24例临床状况恶化且需要LVAD支持的扩张型心肌病（DCM）患者（LVAD组）以及7例无需LVAD支持而接受移植的稳定DCM患者（Tx组）心肌中MMP1至MMP14、TIMP1至TIMP4、I型胶原和III型胶原的信使核糖核酸水平。
与Tx组相比，LVAD组的MMP1、MMP8和TIMP4水平更高（分别高出188%±141%、646%±432%和66%±33%，p<0.05），而MMP2、MMP9、MMP10、MMP11和MMP14水平相似。未检测到MMP3、MMP7、MMP12和MMP13。LVAD组中所有TIMP通常都更高，但只有TIMP4具有统计学意义。I型和III型胶原未发生改变。我们检测了MMP和TIMP表达与心肌细胞因子水平之间的相关性。MMP8与白细胞介素-6和白细胞介素-1β呈正相关，表明这些患者中细胞因子与MMPs之间存在联系。
数据表明，心肌胶原酶（MMP1和MMP8）高表达且胶原或TIMP表达无代偿性变化是需要LVAD支持患者的一个特征。这可能部分与细胞因子表达升高有关，并提示胶原酶活性可能是心力衰竭病情恶化时的一个重要治疗靶点。
