Short Term Doxycycline Treatment Induces Sustained Improvement In Myocardial Infarction Border Zone Contractility

Decreased contractility in the non-ischemic border zone surrounding a MI is in part due to degradation of cardiomyocyte sarcomeric components by intracellular matrix metalloproteinase-2 (MMP-2). We recently reported that MMP-2 levels were increased in the border zone after a MI and that treatment with doxycycline for two weeks after MI was associated with normalization of MMP-2 levels and improvement in ex-vivo contractile protein developed force in the myocardial border zone. The purpose of the current study was to determine if there is a sustained effect of short term treatment with doxycycline (Dox) on border zone function in a large animal model of antero-apical myocardial infarction (MI). Antero-apical MI was created in 14 sheep. Seven sheep received doxycycline 0.8 mg/kg/hr IV for two weeks. Cardiac MRI was performed two weeks before, and then two and six weeks after MI. Two sheep died prior to MRI at six weeks from surgical/anesthesia-related causes. The remaining 12 sheep completed the protocol. Doxycycline induced a sustained reduction in intracellular MMP-2 by Western blot (3649 +/- 643 MI+Dox vs 9236 +/- 114 MI relative intensity; p = 0.0009), an improvement in ex-vivo contractility (65.3 +/- 2.0 MI+Dox vs 39.7 +/- 0.8 MI mN/mm(2); p<0.0001) and an increase in ventricular wall thickness at end-systole 1.0 cm from the infarct edge (12.4 +/- 0.6 MI+Dox vs 10.0 +/- 0.5 MI mm; p = 0.0095). Administration of doxycycline for a limited two week period is associated with a sustained improvement in ex-vivo contractility and an increase in wall thickness at end-systole in the border zone six weeks after MI. These findings were associated with a reduction in intracellular MMP-2 activity.