Low MMP-8/TIMP-1 reflects left ventricle impairment in takotsubo cardiomyopathy and high TIMP-1 may help to differentiate it from acute coronary syndrome

Background
Matrix metalloproteinase 8 (MMP-8) is the most potent type-I collagen protease. Such collagen mainly constitutes the transient fibrosis in takotsubo cardiomyopathy (TTC) endomyocardial biopsies. High MMP-8 and tissue-inhibitor of matrix metalloproteinase-1 (TIMP-1) levels are implicated in acute coronary syndrome (ACS). We compared MMP-8 and TIMP-1 levels in consecutive TTC and ACS patients, and their association to TTC severity.
Methods and results
In 45 acute serum samples of TTC, 2072 ACS and 1000 controls, TIMP-1 differed between ACS 146.7ng/mL (115.0–186.3) (median (interquartile range)), TTC 115.7 (94.3–137.7) and controls 80.9 (73.2–90.4), (p<0.0001). MMP-8 levels were similar between ACS and TTC. In receiver-operating characteristics analysis, TIMP-1 differentiated TTC from ACS with an area under the curve (AUC) of 0.679 (p<0.0001) surpassing troponin T (TnT) at 0.522 (p = 0.66). Compared to other differing factors (age, sex, smoking), TIMP-1 improved diagnostic specificity and sensitivity from AUC of 0.821 to 0.844 (p = 0.007). The MMP8/TIMP-1 molar ratio differentiated normal ejection fraction (EF) at 0.27 (0.13–0.51) from decreased EF<50% at 0.08 (0.05–0.20), (p = 0.04) in TTC, but not in ACS.
Conclusions
Even with other differing factors considered, TIMP-1 differentiated TTC from ACS better than TnT. In TTC, the low MMP-8/TIMP-1 molar ratio may reflect decreased proteolysis and increased transient fibrosis, perhaps in part explaining the left-ventricle impairment.

背景
基质金属蛋白酶8（Matrix metalloproteinase 8, MMP-8）是活性最强的I型胶原蛋白酶。该类胶原主要构成应激性心肌病（Takotsubo cardiomyopathy, TTC）心内膜活检标本中的一过性纤维化病变。基质金属蛋白酶组织抑制剂1（tissue-inhibitor of matrix metalloproteinase-1, TIMP-1）水平升高与急性冠状动脉综合征（acute coronary syndrome, ACS）密切相关。本研究对比了连续纳入的TTC与ACS患者的MMP-8及TIMP-1水平，并分析其与TTC病情严重程度的相关性。

方法与结果
本研究纳入45例TTC患者急性期血清样本、2072例ACS患者急性期血清样本及1000例健康对照样本。TIMP-1水平在三组间存在显著差异：ACS组为146.7ng/mL（四分位数间距115.0~186.3），TTC组为115.7（94.3~137.7），对照组为80.9（73.2~90.4），组间差异具有统计学意义（p<0.0001）。MMP-8水平在ACS组与TTC组间无显著差异。受试者工作特征曲线（Receiver-operating characteristics, ROC）分析显示，TIMP-1区分TTC与ACS的曲线下面积（Area under the curve, AUC）为0.679（p<0.0001），优于肌钙蛋白T（Troponin T, TnT）的0.522（p=0.66）。相较于年龄、性别、吸烟等其他混杂因素，加入TIMP-1后可将诊断模型的AUC从0.821提升至0.844（p=0.007），改善了诊断特异性与敏感性。在TTC患者中，MMP8/TIMP-1摩尔比值可区分射血分数正常（EF≥50%，摩尔比值为0.27[0.13~0.51]）与射血分数降低（EF<50%，摩尔比值为0.08[0.05~0.20]）的亚组（p=0.04），但该现象在ACS患者中未观察到。

结论
即便校正年龄、性别、吸烟等其他混杂因素后，TIMP-1区分TTC与ACS的效能仍优于TnT。在TTC患者中，较低的MMP-8/TIMP-1摩尔比值可能反映蛋白水解作用减弱及一过性纤维化程度升高，这或许可部分解释应激性心肌病患者的左心室功能受损机制。