Objective: Cardiac injury is common in asphyxiated neonates and is associated with matrix metalloproteinase-2 activation. Although studies have demonstrated the cardioprotective effects of matrix metalloproteinase inhibition, this has not been tested in clinically translatable models of hypoxia-reoxygenation injury. We aimed to elucidate the effect of doxycycline, a matrix metalloproteinase inhibitor, on cardiac injury and functional recovery in a swine model of neonatal hypoxia-reoxygenation.
Design: Thirty-three newborn piglets were acutely instrumented for continuous monitoring of cardiac output and systemic arterial pressure. After stabilization, normocapnic alveolar hypoxia (10–15% oxygen) was instituted for 2 hours followed by 4 hours of normoxic reoxygenation. Piglets were blindly, block randomized to receive IV boluses of normal saline (control) and doxycycline at 5 minutes of reoxygenation (n = 7/group). Sham-operated piglets (n = 5) received no hypoxia-reoxygenation. Markers of myocardial injury (plasma and myocardial tissue troponin I; myocardial lactate) and oxidative stress (lipid hydroperoxides) were measured by enzyme-linked immunosorbent assay and Western blot. Myocardial matrix metalloproteinase-2 activity was quantified by gelatin zymography and immunoprecipitation.
Setting: University animal laboratory.
Subjects: Piglets (1–4 d old, weighing 1.4–2.5 kg).
Interventions: IV doxycycline (3, 10, or 30 mg/kg) given during resuscitation.
Measurements and Main Results: Hypoxic piglets had cardiogenic shock (cardiac output 58% ± 1% of baseline), hypotension (systemic arterial pressure 31 ± 1 mm Hg), and acidosis (pH 7.02 ± 0.02). Doxycycline improved cardiac and stroke volume index with no chronotropic effect in doxycycline-treated piglets compared with controls. Systemic arterial pressure was higher and the pulmonary artery pressure/systemic arterial pressure ratio was lower in doxycycline groups, with reduced levels of markers of myocardial injury and oxidative stress in doxycycline-treated piglets compared with controls. Negative correlations were found between markers of myocardial injury (plasma troponin I, myocardial lactate) and functional recovery and between myocardial tissue and plasma troponin I. Doxycycline-treated piglets had lower myocardial matrix metalloproteinase-2 activity compared with controls.
Conclusions: Postresuscitation administration of doxycycline attenuates cardiac injury and improves functional recovery in newborn piglets with hypoxia-reoxygenation.
1Department of Surgery, University of Alberta, Edmonton, AB, Canada.
2Department of Pharmacology, University of Alberta, Edmonton, AB, Canada.
3Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada.
4Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.
* See also p. 1007.
Dr. Labossiere’s institution received grant support from the Women and Children’s Health Research Institute (Grant-in-Aid). Dr. Ali received support for article research from Canadian Institutes of Health Research. Dr. Thiesen is employed by Alberta Health Services. Dr. Schulz consulted for Fresenius, Kabi, and GmbH and received support for article research from the Canadian Institutes of Health Research (MOP 77526). His institution received grant support from the Canadian Institutes for Health Research (research grant) and National Sciences and the Engineering Research Council of Canada (research grant). Dr. Cheung received support for article research form the Canadian Institutes of Health Research (MOP 53116). His institution received grant support from the Canadian Institutes of Health Research (MOP 53116) and Women and Children’s Health Research Institute (Grants-in-Aid). The remaining authors have disclosed that they do not have any potential conflicts of interest.
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