Invited Commentary

Abstract

Pulmonary hypertension, regardless of the cause, represents a significant challenge to cardiothoracic surgeons with regard to preoperative risk assessment, perioperative management, and postoperative outcomes. Despite multiple pharmacologic strategies, including prostanoids, endothelin-receptor antagonists, and phosphodiesterase inhibitors, pulmonary hypertension remains a source of significant morbidity and mortality. One of the most recognized regulators of pulmonary vascular vasomotor tone is nitric oxide (NO). Otherwise known as endothelial-derived relaxation factor, NO is biosynthesized from L-arginine in the vasculature by two forms of nitric oxide synthase: constitutive nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS). Upregulation of endogenous NO or exogenous delivery of NO has been well studied in a variety of cardiovascular models as well as humans. Indeed adenoviral gene transfer of eNOS has been previously reported to ameliorate monocrotaline and hypoxia-induced pulmonary hypertension. Zhang and colleagues [1Zhang F. Wu S. Lu X. Wang M. Liu M. Gene transfer of endothelial nitric oxide synthase attenuates flow-induced pulmonary hypertension in rabbits.Ann Thorac Surg. 2008; 85: 581-586Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar] report a therapeutically-aimed study on the effects of tracheal-delivered adenoviral eNOS gene transfer in a rabbit model of pulmonary overcirculation. They establish a background associated with congenital heart disease by performing pre-tricuspid shunts (carotid-jugular bypass). They demonstrate successful delivery of the gene and achieve a functional response by significantly decreasing pulmonary vascular resistance. The model seems challenging as only 18 of 40 animals survived or developed significant pulmonary hypertension. Although their biochemical data is firm, some of the kinetics associated with gene transfer remains nebulous. Quite frankly, the effects of only 10 minutes of adenoviral exposure are impressive. Notably missing are the data related to transfection efficiency and time course of activity. They surveyed tissues after 4 days for gene expression, but hemodynamic testing was done at 3 months. Adenoviral gene expression is usually lost by 3 to 4 weeks after transduction. It remains unknown if pulmonary hypertension returns when transfected eNOS gene expression ceases. Furthermore, the effects of endogenous NO compared with the transgene are unable to be deciphered, and thus, the effect of exogenous eNOS on their physiologic outcomes comes into question. Although they claim that eNOS was mostly expressed in the endothelial cells of resistance size vessels, it would have been nice to see immunohistochemical evidence of uptake of eNOS in other locations in the tracheobronchial tree or cell-type (ie, vascular smooth muscle). This is especially important as many other reports have demonstrated tracheal delivery of transgenes to be located in airway epithelial cells. Finally, others have shown that this model of flow-induced pulmonary hypertension causes an increased expression of native eNOS. Why would delivery of even more eNOS help? Because there is no true control group in their study, they are unable to comment on this paradox. They speculate that although eNOS is elevated, its biologic activity is decreased because the endothelial function is impaired. As such, it would have been nice to see some assessment of endothelial function in their model. Despite some of the specific limitations just outlined, their results offer additional evidence particularly related to NO for adopting translational motivated therapies for cardiopulmonary disease. The pulmonary vasculature is easily accessible and offers a clinically relevant avenue for using such innovative technology. Indeed, inhaled NO has proven effective for short-term treatment of adult and newborn acute pulmonary hypertension. Although L-arginine has gained popularity for treating patients with chronic pulmonary hypertension, no randomized study has documented its long-term effects, particularly in light of some of its pro-proliferative metabolites. As such, direct manipulation of the nitric oxide and nitric oxide synthase axis with locally delivered eNOS could offer an effective strategy for this difficult patient population. Gene Transfer of Endothelial Nitric Oxide Synthase Attenuates Flow-Induced Pulmonary Hypertension in RabbitsThe Annals of Thoracic SurgeryVol. 85Issue 2PreviewNitric oxide, a potent vasodilator with an important role in the regulation of pulmonary vascular tone, is synthesized by a family of nitric oxide synthases. To determine whether endothelial nitric oxide synthase (eNOS) gene transfer may prevent pulmonary hypertension, the effects of transfer of the eNOS gene to the lung were studied in rabbits with pulmonary hypertension induced by high pulmonary blood flow. Full-Text PDF