Low Molecular Weight Heparin and Unfractionated Heparin Are Both Effective at Accelerating Pulmonary Vascular Maturation in Neonatal Rabbits

Abstract

Background-Creation of a bi-directional cavopulmonary shunt after the Norwood procedure for hypoplastic left heart syndrome is delayed to allow pulmonary vascular resistance to fall with maturation of the pulmonary vascular bed. We hypothesized that unfractionated heparin (UFH) and low molecular weight heparin (LMWH), which promote angiogenesis and inhibit smooth muscle cell growth, could accelerate this process. Methods and Results-Fifty-six newborn rabbits were randomly selected to receive UFH 225U/kg (nϭ12), LMWH 1 mg/kg (nϭ14), LMWH 10 mg/kg (nϭ16), or saline (nϭ14) Reduced PA medial wall thickness and muscularization, two additional features of pulmonary vascular maturation, were also more evident in heparin treated animals. Mean PA pressures in 14-day-old rabbits treated with heparin were lower than those measured in control rabbits less than 7 weeks of age suggesting that heparin shortens the pulmonary vascular maturation process by over 60%. Conclusions-These results indicate that both UFH and LMWH are effective at accelerating pulmonary vascular maturation in newborn rabbits. This raises the possibility that administration of heparin to children after the Norwood procedure might allow for earlier conversion to a bi-directional cavopulmonary shunt.

Mice deficient in galectin-1 exhibit attenuated physiological responses to chronic hypoxia-induced pulmonary hypertension

“…vascular remodeling; right ventricular failure; immune response; extracellular matrix CHRONIC PULMONARY ARTERIAL hypertension (PH) can lead to progressive right ventricular (RV) failure and death. The basis for the pulmonary vascular remodeling is smooth muscle cell (SMC) contraction, increased pressure, and hypoxia-induced injury (26,45,54,57). Endothelial cell injury is followed by the migration of medial SMC into the intimal vessel layer, subsequent SMC proliferation, and matrix deposition (1,2,15,19,26,33,34,39,43,45,54,57).…”

“…The basis for the pulmonary vascular remodeling is smooth muscle cell (SMC) contraction, increased pressure, and hypoxia-induced injury (26,45,54,57). Endothelial cell injury is followed by the migration of medial SMC into the intimal vessel layer, subsequent SMC proliferation, and matrix deposition (1,2,15,19,26,33,34,39,43,45,54,57). Additional evidence suggests that changes in composition of the extracellular matrix (ECM) contribute to changes in SMC phenotype, contractility, and promotion of pulmonary arterial (PA) SMC remodeling (2,33,34,39,41,43).…”

The Effects of Antenatal Anticoagulants (Low-Molecular-Weight Heparin and Aspirin) on Neonatal Pulmonary Vasculature in Rabbits

“…In an animal study, it was shown that UFH and LMWH are both effective at accelerating pulmonary vascular maturation [14]. The most prominent structural change in the pulmonary vascular bed of newborn rabbits was found to be reduction in the alveolar:arteriolar ratio associated with new vessel growth, but the mechanism could not be understood.…”

“…Group 1 control rabbits (14 newborn rabbits) received the same amount of saline instead of LMWH (10 mg/kg [100 IU/ kg]) subcutaneously daily until delivery of newborn rabbits. Dosages of heparin and aspirin were determined from previously published animal studies [13,14]. After delivery, all newborn rabbits were anesthetized and killed within 1 hour.…”

Primary In-Series Palliation of Hypoplastic Left Heart Syndrome With Mechanical Lung Assist in Neonatal Pigs

“…We have previously demonstrated, in a neonatal rabbit model, that heparin administration results in a 250% reduction in PA pressure after 2 weeks of treatment. 27 The decrease in PA pressure and resistance was related to enhanced PA angiogenesis. A combined approach of medical lung maturation and mechanical support might lead to a younger age of tolerance for unsupported primary in-series palliation.…”