- Chief of Neurosurgical Spine and Education, Winthrop University Hospital, Mineola, NY, USA
Correspondence Address:
Nancy E. Epstein
Chief of Neurosurgical Spine and Education, Winthrop University Hospital, Mineola, NY, USA
DOI:10.4103/2152-7806.148050
Copyright: © 2014 Epstein NE. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.How to cite this article: Epstein NE. Commentary: Bone morphogenetic protein's contribution to pulmonary artery hypertension: Should this raise concern for patients undergoing spinal fusions with bone morphogenetic protein?. Surg Neurol Int 30-Dec-2014;5:
How to cite this URL: Epstein NE. Commentary: Bone morphogenetic protein's contribution to pulmonary artery hypertension: Should this raise concern for patients undergoing spinal fusions with bone morphogenetic protein?. Surg Neurol Int 30-Dec-2014;5:. Available from: http://sni.wpengine.com/surgicalint_articles/commentary-bone-morphogenetic-proteins-contribution-pulmonary-artery-hypertension-raise-concern-patients-undergoing-spinal-fusions-bone-morphogenetic-protein/
Abstract
Background:Congenital pulmonary artery hypertension (PAH) has been clinically correlated in 70–80% of cases with mutations at the bone morphogenetic protein receptor 2 (BMPR2) genetic site. However, there is also clinical and basic science/laboratory literature indicating a dose–response relationship between BMP signaling and the evolution of PAH (e.g., increased endothelial, smooth muscle, and progenitor cell production, with calcifications).
Methods:Clinical PAH, characterized by pulmonary artery remodeling, elevated right ventricular pressures, increased vascular constriction, and inflammation, is largely due to congenital mutations at the BMPR2 site. Both clinical and laboratory studies have confirmed the correlation between dysfunction at the BMPR2 genetic site and PAH. However, additional basic science and clinical studies suggest a dose–response relationship between BMP signaling and the evolution of PAH.
Results:Laboratory studies found that pulmonary artery smooth muscle cells (PASMCs) under hypoxic conditions proliferated in response to BMP-2 in a dose-dependent fashion. Others noted that PASMCs extracted from patients with Primary Pulmonary Hypertension (PPH) demonstrated abnormal growth responses to transforming growth factor-beta (TGF-β) in a dose-related manner.
Conclusions:The clinical/basic science literature appears to document a dose-dependent relationship between BMP and PAH (independent of the congenital lesions). Does this mean patients undergoing lumbar fusions with BMP are at risk for PAH?
Keywords: Bone morphogenetic protein, pulmonary hypertension, spinal surgery
INTRODUCTION
It is well documented that anomalies at the bone morphogenic protein receptor 2 genetic site (BMPR2) have been clinically linked to the congenital form of pulmonary hypertension (PAH) (e.g., accounting for 70–80% of cases). However, for BMP that is typically used “off-label” in spinal fusions, reported complications (e.g. heterotopic bone formation, osteolysis, infection, and seroma/hematoma with attendant neurological deficits, and others) have not yet included PAH. Nevertheless, there is cause for concern, since laboratory studies like that performed by Pi et al. found that pulmonary artery smooth muscle cells (PASMCs) under hypoxic conditions proliferated in response to BMP-2 in a dose-dependent fashion.[
Complications of BMP/INFUSE (Medtronic, Memphis, TN, USA) in spinal surgery do not cite Pulmonary Artery Hypertension
The list of clinical complications resulting from spinal fusions utilizing BMP have, thus far, not included PAH[
Clinical/Genetic-based studies of BMPR2-related PAH
Multiple clinical- and genetic-based studies attribute congenital PAH (e.g., defined as pulmonary artery remodeling prompting increased right ventricular systolic pressure [RVSP], vasoconstriction, and inflammation) to the bone morphogenetic protein receptor 2 (BMPR2) site[
Changes in the integration of TGF-β may contribute to the pathogenesis of PAH [ Table 1 ]
In an initial study, Morrell et al. found that PASMCs extracted from patients with PAH demonstrated abnormal growth responses to TGF-β, and that changes in the integration of TGF-β appeared to contribute to the pathogenesis of PAH.[
Dose-dependent impact of BMP-2 on pulmonary artery smooth muscle cells and vascular calcification
BMP-2 may promote dose-dependent changes in pulmonary SMCs and vascular calcification leading to PAH[
CONCLUSIONS
Clinical studies cited mutations at the BMPR2 genetic site as responsible for congenital PAH (70–80% of cases). However, both clinical and laboratory studies showed that BMPs may promote dose-dependent changes in pulmonary SMCs and vascular calcifications within vessel walls, which may lead to PAH.
For the purposes of a spine surgeon, this review raises the concern whether patients undergoing BMP-supplemented spinal fusions may be potentially exposed to developing PAH? As yet, this question remains unanswered, and it could take decades to know the answer. However, just being aware of the potential risk for developing PAH in patients undergoing spinal fusions (most “off-label”) utilizing BMP may curtail or eliminate its use.
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