Clinical and Biochemical Results of the Metalloproteinase Inhibition with Subantimicrobial Doses of Doxycycline to Prevent Acute Coronary Syndromes (MIDAS) Pilot Trial

Abstract

Background-Vulnerable plaque demonstrates intense inflammation in which macrophages secrete matrix metalloproteinases (MMPs) that degrade the fibrous cap, ultimately leading to rupture, in situ thrombosis, and an associated clinical event. Thus, inhibition of MMP activity or more general suppression of vascular inflammation are attractive targets for interventions intended to reduce plaque rupture. We hypothesized that subantimicrobial doses of doxycycline (SDD) (20 mg twice daily) would benefit patients with coronary artery disease by reducing inflammation and MMP activity and thus possibly prevent coronary plaque rupture events. Methods and Results-We conducted a prospective, randomized, double-blind, placebo-controlled pilot study of 6 months of SDD or placebo treatment to reduce inflammation and prevent plaque rupture events. A total of 50 patients were enrolled, of whom 24 were randomized to placebo and 26 to SDD. At 6 months, there was no difference in the composite endpoint of sudden death, fatal myocardial infarction (MI), non-fatal MI, or troponin-positive unstable angina in SDD compared with placebo-treated patients (8.4% versus 0%, Pϭ0.491). Biochemical markers of inflammation were assessed in plasma at study entry and after 6 months of therapy in 30 patients. In SDD-treated patients, high-sensitivity C-reactive protein (CRP) was reduced by 46% from 4.8Ϯ0.6 g/mL to 2.6Ϯ0.4 g/mL (Pϭ0.007), whereas CRP was not significantly reduced in placebo patients. Interleukin (IL)-6 decreased from 22.1Ϯ3.7 pg/mL at baseline to 14.7Ϯ1.8 pg/mL at 6 months in SDD-treated patients (Pϭ0.025) but did not decrease significantly in placebo-treated patients. On zymography, pro-MMP-9 activity was reduced 50% by SDD therapy (Pϭ0.011), whereas it was unchanged by placebo treatment. Conclusion-SDD appears to exert potentially beneficial effects on inflammation that could promote plaque stability.These findings should be investigated in a larger study.

Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function

“…The longer term consequences from this initial clinical study are yet to be fully realized, but the near future for developing pharmacological strategies for MMP inhibition in the clinical context of cardiovascular disease is certainly in question. Nevertheless, since the MMP system clearly causes cardiovascular remodeling, then alternative pharmacological approaches such as using doxycycline as an MMP inhibitor remain in clinical evaluation (47). In addition, MMP inhibitors with a highly specific inhibitory profile continue to be developed and refined (83,93,99,172,357).…”

Matrix metalloproteinase-9 in the pathophysiology and diagnosis of dry eye syndrome

“…[86][87][88][89][90][91] Doxycycline has been found to decrease activation of the MAPK and NF k B pathways and improve corneal barrier function and the number of mucusproducing conjunctival goblet cells in dry eye. 48,62,65,[92][93][94][95] We and others have tested different preparations of doxycycline in our mouse desiccating stress dry eye model, and we have shown significant improvement in corneal barrier function (reduced uptake of a fluorescent dye) and decreased transcript levels of inflammatory cytokines such as IL-1β, IL-6, tumor necrosis factor-a and MMPs.…”

Matrix metalloproteinases and myocardial infarction

“…In a small, sample-sized clinical study, Brown et al (56) demonstrated that inflammatory markers, such as MMP-9 level, C-reactive protein and IL-6, were reduced after doxycycline administration for six months in patients with coronary artery disease. However, clinical benefits of doxycycline such as a composite end point of sudden death, fatal MI, nonfatal MI or troponin-positive unstable angina, could not be identified in their study.…”