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 6months. A (99m)Tc-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 (-1ml/m(2) [from -7ml/m(2) to 9ml/m(2)] vs. 3ml/m(2) [from -2ml/m(2) to 19ml/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 6month infarct size and severity as well as LV dilation.
['Cerisano|Giampaolo|G|', 'Buonamici|Piergiovanni|P|', 'Gori|Anna Maria|AM|', 'Valenti|Renato|R|', 'Sciagrà|Roberto|R|', 'Giusti|Betti|B|', 'Sereni|Alice|A|', 'Raspanti|Silvia|S|', 'Colonna|Paolo|P|', 'Gensini|Gian Franco|GF|', 'Abbate|Rosanna|R|', 'Schulz|Richard|R|', 'Antoniucci|David|D|']
D000284:Administration, Oral D000368:Aged D000900:Anti-Bacterial Agents D017023:Coronary Angiography D004305:Dose-Response Relationship, Drug D004318:Doxycycline D004562:Electrocardiography D005260:Female D005500:Follow-Up Studies D006801:Humans D008297:Male D020782:Matrix Metalloproteinases D009203:Myocardial Infarction D015425:Myocardial Reperfusion D011446:Prospective Studies D011480:Protease Inhibitors D019715:Tissue Inhibitor of Metalloproteinase-1 D015899:Tomography, Emission-Computed, Single-Photon D016896:Treatment Outcome D018487:Ventricular Dysfunction, Left D020257:Ventricular Remodeling
Metalloproteinases Doxycycline Acute myocardial infarction Infarct size Left ventricular remodeling Tissue inhibitor of metalloproteinases