Evaluation of Treatment Effect of Sirolimus on Pediatric Pulmonary Vein Stenosis Using a Neonatal Rat Model Induced by Bilateral Pulmonary Vein Banding

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Pulmonary vein stenosis (PVS) is a rare and often devastating disease of infants and young children resulting in progressive luminal obstruction, pulmonary edema, pulmonary hypertension, and right heart failure. PVS commonly involves multiple vessels, and a hallmark feature is recurrence or progression after successful relief of anatomic obstruction by transcatheter dilation or surgery. The modern story of treatment for PVS began 25 years ago with the first description of neoproliferation causing luminal obstruction as caused by myofibroblasts, based on histochemical staining patterns and electron microscopy.¹ The first prospective clinical trial used agents targeted at pediatric myofibroblastic tumors based on this initial insight.² The second trial targeted PDGF and VEGF identified in the proliferating neointima.^3,4 Over the past 2 decades, much progress has been made using a multimodal approach including cardiac surgery, interventional cardiology and adjunct antiproliferative therapy. However, mortality remains high, especially in patients with aggressive disease or comorbid conditions; stabilization requires intensive treatment with frequent procedural intervention and prolonged high-risk medical treatment; and survivors have pulmonary vein scarring and atresia. From a clinical perspective, there is considerable room for improvement.

Current medical advances were informed by translational research aimed at further characterizing the underlying cellular activity and biologic mechanisms leading to the disease. Although PVS is heterogeneous, a current disease model explaining certain clinical features is increased wall shear stress inciting endothelial to mesenchymal transition of endocardial cells resulting in cellular expansion and matrix formation.^5,6 The critical pathways regulating this transition in PVS remain speculative and have been difficult to study, although clinically relevant information has come from histopathology, immunohistochemistry, and electron microscopy of human diseased tissue and neonatal pig animal models.^5,7

The study in this issue of JACC: Basic to Translational Science by Li et al⁸ presents a detailed description of a new neonatal rat model of pediatric pulmonary vein stenosis. The authors conclude that their rat model has advantages over a prior version that led to rapid vessel atresia with collateral formation. The description of the surgical approach placing bilateral bands on pulmonary veins at the junction with the left atrium in newborn rats is an important contribution to the literature and offers a promising new tool in the study of this difficult disease. The authors deserve recognition for development of a useful animal model that is less costly than the pig model, for providing a detailed description of the technique, and for successfully completing the operation requiring high technical skill by 4 surgeons in 120 rat pups.

Li et al⁸ demonstrate the usefulness of their rat PVS model using bulk RNA sequencing to compare gene expression patterns in PVS and control animals, with potential to identify new therapeutic targets. Bulk RNA sequencing has limitations because of lack of temporal or cellular specificity but is a useful starting point. Li et al⁸ also examine the effect of sirolimus, an mTOR target, on neoproliferation. Although the response was heterogeneous, administration of sirolimus significantly reduced the number of α-SMA–positive cells and intimal thickness, and treated animals had a larger lumen diameter.⁸ These findings are supportive of prior translational studies in neonatal pigs^5,7 and clinical studies showing a therapeutic benefit for sirolimus, especially for in-stent restenosis.^9,10

This new and less expensive animal model is an important development that should accelerate translational research. From a clinical perspective, the disease is heterogeneous, with common patterns but significant variation in the aggressiveness and response to treatments among patients and even among individual veins in the same patient. The disease also changes over time, and the optimal medical interventions and biologic triggers at various stages are not known. The increasing interest from basic and translational scientists is a fantastic development to assist those of us caring for infants and children with PVS and their families, as quality of life and survival should continue to improve. While PVS in infants is fortunately rare, the mechanisms leading to neoproliferation and recurrent luminal obstruction like endothelial to mesenchymal transition are fundamental and knowledge is increasing rapidly. Translational PVS research offers insight not only for a rare and devastating illness in infants, but also aspects of vascular biology, pulmonary development, pulmonary hypertension, and atrial fibrillation, with enormous potential for cure and prevention. Li et al⁸ have added an important contribution, and hopefully their work will garner interest from other basic and translational scientists.

Funding Support and Author Disclosures

The author has reported that they have no relationships relevant to the contents of this paper to disclose.