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

Abstract 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 ^99mTc-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/m² [from - 7 ml/m² to 9 ml/m²] vs. 3 ml/m² [from - 2 ml/m² to 19 ml/m²], 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.