title: 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 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.
authors.affiliation: Department of Heart and Vessels, Careggi Hospital, Florence, Italy. Electronic address: giampaolo.cerisano@gmail.com.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Cerisano
authors.affiliation: Department of Heart and Vessels, Careggi Hospital, Florence, Italy.
authors.forename: Piergiovanni
authors.initials: P
authors.lastname: Buonamici
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Italy; Don Carlo Gnocchi Foundation IRCCS, Florence, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Gori
authors.affiliation: Department of Heart and Vessels, Careggi Hospital, Florence, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Valenti
authors.affiliation: Nuclear Medicine Unit, Department of Clinical Physiopathology - University of Florence, Careggi Hospital, Florence, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Sciagrà
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Italy.
authors.forename: Betti
authors.initials: B
authors.lastname: Giusti
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Sereni
authors.affiliation: Nuclear Medicine Unit, Department of Clinical Physiopathology - University of Florence, Careggi Hospital, Florence, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Raspanti
authors.affiliation: Division of Cardiology, Hospital Policlinico of Bari, Bari, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Colonna
authors.affiliation: Department of Heart and Vessels, Careggi Hospital, Florence, Italy; Department of Experimental and Clinical Medicine, University of Florence, Italy; Don Carlo Gnocchi Foundation IRCCS, Florence, Italy.
authors.forename: Gian Franco
authors.initials: GF
authors.lastname: Gensini
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Abbate
authors.affiliation: Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, Departments of Pediatrics and Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Richard
authors.initials: R
authors.lastname: Schulz
authors.affiliation: Department of Heart and Vessels, Careggi Hospital, Florence, Italy.
authors.forename: David
authors.initials: D
authors.lastname: Antoniucci
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D017023:Coronary Angiography; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000008:administration & dosage*; D004562:Electrocardiography; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000097:blood*; D009203:Myocardial Infarction / Q000201:enzymology / Q000503:physiopathology / Q000628:therapy*; D015425:Myocardial Reperfusion / Q000379:methods*; D011446:Prospective Studies; D011480:Protease Inhibitors / Q000627:therapeutic use; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000627:therapeutic use*; D015899:Tomography, Emission-Computed, Single-Photon; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D020257:Ventricular Remodeling
chemical_list: D000900:Anti-Bacterial Agents; D011480:Protease Inhibitors; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D020782:Matrix Metalloproteinases; D004318:Doxycycline
keywords: Acute myocardial infarction; Doxycycline; Infarct size; Left ventricular remodeling; Metalloproteinases; Tissue inhibitor of metalloproteinases