Department of Cardiology, Angiology, and Pulmonology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
Clin Res Cardiol. 2017 Dec;106(12):974-985. doi: 10.1007/s00392-017-1147-5. Epub 2017 Aug 4.
Extracellular matrix (ECM) biomarkers such as matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are pathophysiological key, prognostic marker and therapeutic target in chronic heart failure (HF). Serial measurements of MMPs and TIMPs may be useful for guidance of these applications. However, interpretation of time-dependent changes requires knowledge about the biological variation of ECM biomarkers.
We performed measurements of MMP-2, MMP-9, TIMP-1, and TIMP-4 in 50 patients with chronic HF who met rigid criteria for clinical stability at 3-h, 6-h, 1-week and 2-week time intervals. In addition, clinical and haemodynamic assessment was performed at baseline, at 1- and 2-week intervals. Haemodynamic variables were measured using inert gas rebreathing and impedance cardiography. Heart rhythm was monitored with external ECG event recorders throughout the complete study. Reference change values (RCVs) and minimal important differences (MIDs) were determined for MMP-2, MMP-9, TIMP-1, and TIMP-4.
Clinical and haemodynamic variables were stable over time. Depending on the time-interval, RCVs ranged between 4.9 and 11.7% for MMP-2, 26.4 and 56.7% for MMP-9, 10.8 and 30.7% for TIMP-1, and 16.0 and 47.4% for TIMP-4, respectively. The MIDs varied between 43.38 and 65.22 ng/ml for MMP-2, 28.71 and 40.96 ng/ml for MMP-9, 52.32 and 156.07 ng/ml for TIMP-1, and 293.92 and 798.04 pg/ml for TIMP-4, respectively.
The biological variation of ECM biomarkers differs with respect to individual biomarkers and time intervals. MMP-2 may be most suitable for serial biomarker measurements, as the biological variation is low irrespective of the time interval between measurements.
细胞外基质 (ECM) 生物标志物，如基质金属蛋白酶 (MMPs) 及其抑制剂 (TIMPs)，是慢性心力衰竭 (HF) 病理生理学关键、预后标志物和治疗靶点。MMPs 和 TIMPs 的连续测量可能对这些应用的指导有用。然而，对时间依赖性变化的解释需要了解 ECM 生物标志物的生物学变异性。
我们对 50 名符合严格临床稳定标准的慢性 HF 患者进行了 MMP-2、MMP-9、TIMP-1 和 TIMP-4 的测量，时间间隔为 3 小时、6 小时、1 周和 2 周。此外，还在基线、1 周和 2 周时进行了临床和血液动力学评估。血液动力学变量使用惰性气体再呼吸和阻抗心图测量。整个研究过程中，使用外部 ECG 事件记录器监测心律。确定了 MMP-2、MMP-9、TIMP-1 和 TIMP-4 的参考变化值 (RCV) 和最小临床重要差异 (MID)。
临床和血液动力学变量随时间保持稳定。根据时间间隔，MMP-2 的 RCV 范围为 4.9%至 11.7%，MMP-9 的 RCV 范围为 26.4%至 56.7%，TIMP-1 的 RCV 范围为 10.8%至 30.7%，TIMP-4 的 RCV 范围为 16.0%至 47.4%。MMP-2 的 MID 范围为 43.38 至 65.22 ng/ml，MMP-9 的 MID 范围为 28.71 至 40.96 ng/ml，TIMP-1 的 MID 范围为 52.32 至 156.07 ng/ml，TIMP-4 的 MID 范围为 293.92 至 798.04 pg/ml。
ECM 生物标志物的生物学变异性因标志物和时间间隔而异。MMP-2 可能最适合连续的生物标志物测量，因为无论测量之间的时间间隔如何，其生物学变异性都较低。
