Lymphatic failure occurs when the lymphatic circulation is unable to adequately transport excess fluid and other contents out of the interstitium and into the systemic venous circulation, which is directly responsible for many of the clinical manifestations and severe complications associated with congenital heart disease (i.e., peripheral edema, pleural effusions, ascites, chylothorax, protein-losing enteropathy, plastic bronchitis, among others)1, 2, 3, 4, 5, 6, 7, 8. Individuals with right-sided or single ventricle defects are especially prone to lymphatic failure because chronically elevated central venous pressures increase lymphatic fluid production and impede lymphatic fluid drainage into the systemic venous circulation, which can lead to progressive overload and congestion of the lymphatic circulation1,4,8,11.

As a result, there has been growing enthusiasm towards emerging and expanding the applications of novel percutaneous and surgical interventions that may be able to improve lymphatic flow12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24. However, the exact causes of lymphatic failure remain incompletely understood, and to date, there are no targeted therapeutics that reliably prevent or treat its development and progression11,25. Thus, there is consensus that focused investigations are needed to elucidate these underlying mechanisms, which could help identify novel therapeutic targets and develop other innovative procedures26, 27, 28.

Therefore, this review aims to provide an overview of the lymphatic circulation and its vasculature with respect to current understandings and existing knowledge gaps in the pathophysiology and pathogenesis of lymphatic failure. In doing so, strategies for evaluating and managing lymphatic failure are summarized alongside their existing limitations, and specific areas of interest for future translational and clinical investigations are highlighted that may help advance this new frontier in congenital heart disease.