Low molecular weight heparin and unfractionated heparin are both effective at accelerating pulmonary vascular maturation in neonatal rabbits.
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.


RESULTS
Fifty-six newborn rabbits were randomly selected to receive UFH 225U/kg (n=12), LMWH 1 mg/kg (n=14), LMWH 10 mg/kg (n=16), or saline (n=14) by subcutaneous injection every 12 hours for 14 days. Treatment with heparin reduced mean pulmonary artery (PA) pressure by 12% to 16% relative to controls [9.0+/-0.2 (UFH), 9.4+/-0.1 (LMWH 1 mg/kg), 9.2+/-0.2 (LMWH 10 mg/kg) versus 10.7+/-0.2 mm Hg (saline), P=0.0001]. Lower PA pressures were associated with reduced alveolar:arterial ratio consistent with enhanced pulmonary angiogenesis in heparin treated animals [8+/-1 (UFH), 13+/-2 (LMWH 1 mg/kg), 12+/-2 (LMWH 10 mg/kg) versus 23+/-5 (saline), P<0.03]. 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.
O'Blenes
Stacy B
SB
Division of Cardiovascular Surgery, The Hospital for Sick Children and The University of Toronto, Toronto, Ontario, Canada.
Merklinger
Sandra L
SL
Jegatheeswaran
Anusha
A
Campbell
Andrew
A
Rabinovitch
Marlene
M
Rebeyka
Ivan
I
Van Arsdell
Glen
G
D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006352:Heart Ventricles / Q000033:anatomy & histology / Q000187:drug effects; D006493:Heparin / Q000494:pharmacology*; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology*; D007700:Kinetics; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000033:anatomy & histology / Q000187:drug effects; D018919:Neovascularization, Physiologic; D011651:Pulmonary Artery / Q000033:anatomy & histology / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D011817:Rabbits
D006495:Heparin, Low-Molecular-Weight; D016222:Fibroblast Growth Factor 2; D006493:Heparin