Published Online
on September 2, 2003

A more recent version of this article appeared on September 23, 2003

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Submitted on June 26, 2002
Revised on June 30, 2003
Accepted on July 9, 2003

Early Short-Term Treatment With Doxycycline Modulates Postinfarction Left Ventricular Remodeling

Francisco J. Villarreal MD, PhD^*, Michael Griffin BS, Jeffrey Omens PhD, Wolfgang Dillmann MD, Judy Nguyen BS, and James Covell MD

From the Department of Medicine, University of California, San Diego, Calif.

^* To whom correspondence should be addressed. E-mail: fvillarr{at}ucsd.edu.

Background--Myocardial infarction (MI) is associated with early metalloproteinase (MMP) activation and extracellular matrix (ECM) degradation. We hypothesized that preserving the original ECM of the infarcted left ventricle (LV) by use of early short-term doxycycline (DOX) treatment preserves cardiac structure and function.

Methods and Results--LV morphometry and function were measured in 3 groups of rats (sham, MI, and MI+DOX). DOX (30 mg/kg per day) was given orally 48 hours before and 48 hours after MI. Rats were examined at 2 and 4 weeks after MI. By 4 weeks, DOX significantly decreased (P<0.05 versus MI) the heart weight to body weight ratio, myocyte cross-sectional area, and internal LV diameter, whereas it preserved anterior wall thickness within the infarct. Collagen/muscle area fraction did not change in the region of the infarct/scar. Parallel left shifts (versus MI) were observed in pressure-volume relationships of DOX MI rats at all pressures. DOX treatment also shifted passive epicardial strains within the scar area toward normal values. No differences were observed in LV end-diastolic or peak systolic pressures, peak positive or negative LV dP/dt, or isovolumic relaxation rates. Assessment of LV global MMP and MMP-2/9 activities 1 hour after MI using fluorescent probes yielded significant differences with DOX.

Conclusions--Brief, early MMP inhibition after MI yields preservation of LV structure and global as well as scar area passive function, supporting the concept that preserving the original ECM early after coronary occlusion lessens ventricular remodeling.

Key words: infarction • remodeling • collagen • metalloproteinases

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