Matrix metalloproteinases and their tissue inhibitor after reperfused ST-elevation myocardial infarction treated with doxycycline. Insights from the TIPTOP trial

Background: The TIPTOP (Early Short-term Doxycycline Therapy In Patients with Acute Myocardial Infarction and Left Ventricular Dysfunction to Prevent The Ominous Progression to Adverse Remodelling) trial demonstrated that a timely, short-term therapy with doxycycline is able to reduce LV dilation, and both infarct size and severity in patients treated with primary percutaneous intervention (pPCI) for a first ST-elevation myocardial infarction (STEMI) and left ventricular (LV) dysfunction. In this secondary, pre-defined analysis of the TIPTOP trial we evaluated the relationship between doxycycline and plasma levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Methods: In 106 of the 110 (96%) patients enrolled in the TIPTOP trial, plasma MMPs and TIMPs were measured at baseline, and at post-STEMI days 1, 7, 30 and 180. To evaluate the remodeling process, 2D-Echo studies were performed at baseline and at 6 months. A Tc-99m-SPECT was performed to evaluate the 6-month infarct size and severity. Results: Doxycycline therapy was independently related to higher plasma TIMP-2 levels at day 7 (p < 0.05). Plasma TIMP-2 levels above the median value at day 7 were correlated with the 6-month smaller infarct size (3% [0%-16%] vs. 12% [0%-30%], p = 0.002) and severity (0.55 [0.44-0.64] vs. 0.45 [0.29-0.60], p = 0.002), and LV dilation (-1 ml/m(2) [from -7 ml/m(2) to 9 ml/m(2)] vs. 3 ml/m(2) [from -2 ml/m(2) to 19 ml/m(2)], p=0.04), compared to their counterpart. Conclusions: In this clinical setting, doxycycline therapy results in higher plasma levels of TIMP-2 which, in turn, inversely correlate with 6 month infarct size and severity as well as LV dilation. (C) 2015 Elsevier Ireland Ltd. All rights reserved.