Activation of matrix metalloproteinases (MMPs) in the heart is known to facilitate cardiac remodeling and progression to failure. We hypothesized that regional dyskinetic wall motion of the left ventricle would stimulate activation of MMPs. Abnormal wall motion at a target site on the anterior lateral wall of the left ventricle was induced by pacing atrial and ventricular sites of five open-chest anesthetized dogs. Changes in shortening at the left ventricular (LV) pacing site and at a remote site at the anterior base of the left ventricle were monitored with piezoelectric crystals. Simultaneous atrial and ventricular pacing resulted in abnormal motion at the LV pacing site yielding early shortening and late systolic lengthening, while the shortening pattern at the remote site remained unaffected. Assessment of global myocardial MMP activity showed a seven-fold increase in substrate cleavage (p<0.02) at the LV pacing site relative to the remote site. Gelatin zymography revealed increases in 92 kDa MMP-9 activity and 86 kDa MMP-9 activity at the LV pacing site relative to the remote site, whereas MMP-2 activity was unaffected. Abnormal wall motion was associated with increases in collagen degradation (~2 fold; p<0.03), plasmin activity (~1.5 fold; p<0.05), nitrotyrosine levels (~20 fold; p=0.05), and inflammatory infiltrate (~2 fold; p<0.02) relative to the remote site. Results indicate that regional dyskinesis induced by epicardial activation is sufficient to stimulate significant MMP activity in the heart, suggesting that abnormal wall motion is a stimulus for MMP activation.