Doxycycline Attenuates Cardiac Injury and Improves Cardiac Function with Inhibition of Myocardial Matrix Metalloproteinase (MMP)-2 in a Swine Model of Hypoxia- Reoxygenation (H-R)

Background Cardiac dysfunction is common in asphyxiated neonates. Although small animal studies support attenuation of cardiac injury with the known MMP inhibitor doxycycline in H‐R, this effect has not been tested in a clinically relevant large animal model of H‐R. We hypothesized that doxycycline would improve the recovery of cardiac function in newborn piglets with H‐R. Methods Piglets were instrumented for hemodynamic monitoring and subjected to 2 hr of hypoxia followed by 4 hr of normoxic reoxygenation. Piglets were blindly randomized to receive i.v. saline or doxycycline (3, 10, or 30 mg/kg) 5 min into reoxygenation (n=7/group). Sham piglets (n=5) received no H‐R. Markers of myocardial injury (serum and myocardial tissue troponin; myocardial lactate) and oxidative stress (lipid hydroperoxides) were measured by ELISA and Western blot. Myocardial MMP‐2 activity was quantified by gelatin zymography. Results Doxycycline dose‐dependently improved cardiac (CI) and stroke volume (SVI) index (30mg/kg: 84±3 (SEM)% and 78±5% of baseline vs. 65±3% and 50±5% in controls [p<0.05]). Markers of myocardial injury, oxidative stress and MMP‐2 activity were improved in doxycycline groups vs. control [all p<0.05]. Significant correlations were found between markers of myocardial injury and CI and SVI recovery (r =−0.5, p<0.01), with a negative correlation also observed between myocardial tissue and serum troponins (r =−0.4, p=0.02). Conclusions Doxycycline attenuates cardiac injury and improves functional recovery in newborn pigs with H‐R. Funded by: Canadian Institutes of Health Research and the Women and Children's Health Research Institute