Author + information
- aDivision of Cardiology, Department of Pediatrics, University of Pittsburgh, School of Medicine, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania
- bCardiac Surgery Department, Austral University Hospital, Pilar, Provincia de Buenos Aires, Argentina
- ↵∗Address for correspondence:
Dr. Jacqueline Kreutzer, University of Pittsburgh School of Medicine, Cardiac Catheterization Laboratory, Children’s Hospital of Pittsburgh of UPMC, One Children’s Hospital Drive, 4401 Penn Avenue, Pittsburgh, Pennsylvania 15224.
In this issue of the Journal, the paper by Savla et al. (1) opens a new door into a relatively poorly understood subject in our field: lymphatic dynamic disorders after congenital heart surgery. Using dynamic contrast-enhanced magnetic resonance lymphangiography and intranodal lymphangiography in 25 patients, these investigators undertake a unique approach and provide further insight into the understanding of lymphatic disorders after cardiac surgery.
Although the morbidity and mortality related to these conditions is well-known (2), the lymphatic circulation continues to be a relatively undiscovered territory for the pediatric cardiologist and cardiothoracic surgeon. Still, the scientific background to this work is quite extensive and not new.
In the last decade of the 19th century, Ernest Starling at University College of London described the retention of plasma in the interstitial space as a “safety valve” to the circulation defending the failing heart from volume load (3,4). Thereafter, research in lymphatic circulation in heart failure flourished (4–7). Over the past decades, a series of discoveries have revealed new knowledge in the vascular and molecular aspects of the lymphatic system (8). However, these concepts are not commonly considered when evaluating cardiac physiology in patients with congenital heart disease. It is common knowledge that the majority of vascularized tissues contain a lymphatic capillary network. The lymphatic system has numerous crucial physiological functions in mammals, including fluid balance between the plasma and interstitial compartments of the extracellular space by returning protein and fluid filtered out of the capillaries to the vascular system and absorption of fat from the small intestines. It also maintains important immune functions; various antigens and activated antigen-presenting cells are transported into the lymph nodes and export immune effector cells and humoral response factors into the blood circulation.
The lymphatic vascular system consists of 2 types of vessels, the noncontractile initial lymphatic network and the collecting vessels. Lymphatic endothelial cells are strongly attached at the anchoring filaments to the surrounding collagen and elastin fibers. These cells show tight, single contact, and interdigitated junctions. During expansion of the initial lymphatic vessels, these junctions can be opened, allowing fluid to flow from the interstitium into the lymphatic vessels, whereas during compression, overlapping junctions can be closed, thereby attenuating the return of lymph flow into the interstitium, and acting as “flap valves” (8). If the lymphatic pressure increases, the safety function is activated and the system responds by increasing the amount of lymph contained within and transported by the system. In this way, the system functions as a reservoir, “protecting the failing heart” from volume overload (the Starling resistor effect).
The lymphatic capillaries drain into precollecting vessels, followed by larger collecting lymphatic vessels. The lymphatic drainage shows an extremely efficient centripetal flow of lymph augmented by rhythmic contractions (8). In humans, the thoracic duct (TD) originates in the cisterna chyle (Figure 1) and ascends anterior to the vertebrae, with the aorta on its left and the azygous vein to its right (9). Below the fifth thoracic vertebra, the duct is usually double or plexiform; above fifth thoracic vertebra, it is usually singular. At the level of the fifth thoracic vertebra, the TD inclines toward the left side to enter the superior mediastinum and ascends behind the aortic arch and the thoracic part of the left subclavian artery, between the left side of the esophagus and the left pleura, to the thoracic inlet (Figure 2). It ends by opening into the angle of junction of the left subclavian vein with the left internal jugular vein. Here, the drainage can be single (in nearly 50% of the cases) or multiple (10). At the most proximal end of the TD, a valve prevents blood from entering the duct, because contact with blood produces thrombosis or occlusion of the lymphatic vessels.
Given the proximity of lymphatic vessels to cardiac structures manipulated during surgical repair of congenital heart defects trauma of TD can occur. In addition, after congenital heart surgery, abnormally increased venous pressure is common. The effects of the abnormal physiological states prevalent in congenital heart disease on the lymphatic circulation are now being discovered (11). The long oblivion for the lymphatic circulation in pediatric cardiology is coming to an end. Several contributions have demonstrated its relevance and effect on devastating complications after surgery, such as effusions, chylothorax, plastic bronchitis, and protein-losing enteropathy (12,13). Lymphatic imaging and selective catheterization as reported by Dori et al. (1,12,13) now allow understanding lymphodynamics and identification of 3 modes of lymphatic failure: leak from a TD branch (traumatic leak); pulmonary lymphatic perfusion syndrome, when retrograde flow from the TD to the lung or mediastinum; and central lymphatic flow disorder, a newly characterized condition with abnormally low or absent central lymphatic flow, effusions in more than 1 compartment, and dermal backflow through abdominal lymphatic collaterals.
It is not surprising that in this most recent contribution from Dori's group (1), the vast majority of patients who suffered either from TD leak or pulmonary lymphatic perfusion syndrome had conditions typically associated with increased central venous pressure and secondary impaired lymphatic drainage. In pure right heart failure, as seen in the Glenn and the Fontan circulations, the lung is exposed to a paradox in which lymph from the lung is required to drain at a higher pressure than it is created. In the normal lung, both the pulmonary arteriolar pressure and pulmonary capillary wedge pressures are higher than the central venous pressure, resulting in normal reabsorption of fluid. After the superior cavopulmonary anastomosis, the lung interstitium is subjected to a normal hydrostatic pressure, because more than 80% of the total lung arterial flow returns to the heart via pulmonary veins. However, there is a constant propensity toward fluid accumulation in the lung, because the lymphatic circulation drains to a higher pressure compared with normal. The increase in resistance to lymphatic drainage results in lymphatic endothelial cells adherence and lymph cannot be effectively removed from the interstitium. In contrast with pulmonary edema resulting from increased pulmonary capillary wedge pressure as a result left heart pump failure or left-sided obstruction, the congested lung commonly seen in the early Glenn/Fontan patient is often related to lymph formation and accumulation, with pleural effusions as a manifestation of this imbalance (11).
This represents another paradox of the Fontan circulation and a challenge to Starling’s forces: pulmonary lymph is required to drain at a higher or very similar pressure as it is produced (Figures 3A and 3B). As a consequence, it is not surprising that lymphatic disorders, such as chylous effusions, plastic bronchitis, and protein-losing enteropathy, are seen in this patient population, and that most of the patients reported in the study from Savla et al. (1) had a form of single ventricle variant.
The morbidity and mortality from post-operative chylothorax continues to be high (2). Historically, there have been limited diagnostic or therapeutic strategies available to treat these patients. Standard therapies are frequently ineffective (e.g., surgical TD ligation) and/or have significant unwanted side effects (e.g., eliminating fat from the diet during key growing stages of childhood, use of total parenteral nutrition, chemical pleuridesis often leading to massive formation of aortopulmonary chest wall collaterals, medical therapy with octreotide, pleuroperitoneal shunts) (1,2). Thus, the use of dynamic contrast-enhanced magnetic resonance lymphangiography to understand the pathophysiology of these lymphatic disorders after congenital heart surgery and allow directed effective therapy reported by Savla et al. (1) is a breakthrough in our field. In addition to the diagnostic value, the technique provides an opportunity for a therapeutic benefit based on the particular diagnosis; 23 of the 25 patients studied underwent directed lymphatic intervention. Among the 25 patients, there were 16 with either a traumatic leak from the TD or pulmonary lymphatic perfusion syndrome, and in this group lymphatic interventions performed had 100% success. The procedures were, however, mostly unsuccessful for the group with central lymphatic flow disorder (only 1 of 7 benefited), for whom there seem to be no reliably successful therapies known to date. All patients reported had previously failed standard therapies. Specific lymphatic interventions applied in this study included a variety of procedures with or without closure of the TD. These interventions aimed to close the leaking sites. Direct leak of contrast into the pleural space due to trauma was indeed rare (2 patients), and lymphatic intervention for these patients was highly successful.
Further studies to understand the physiopathology of lymphatic disorders after congenital heart surgery and testing of potential new modalities of directed therapy, such as lymphovenous anastomosis (14,15), may eventually reduce these patients’ morbidity. Indeed, promising surgical procedures are nowadays being reintroduced (14,15) with early success to divert the lymph flow to the lower pressure side of the Fontan circulation, primarily for treatment of both protein-losing enteropathy and plastic bronchitis, and secondarily to reduce the chronic end organ lymphedema.
This study enlightens a path to therapy of a poorly understood serious problem after congenital heart surgery, and one that has been largely mismanaged. As further pointed out in the discussion section by Savla et al. (1), many of the assumptions frequently used to base treatment plans in this patient population are proven to be wrong. The authors demonstrate how essential it is to understand the underlying physiopathology of the lymphatic system disorder to provide a directed therapy to the problem, as indeed simple surgical ligation of the TD may possibly worsen the leak in some cases.
Dori et al. (1) should be congratulated for reporting an innovative diagnostic and therapeutic tool with a defined relevant application in our field, which can bring a solution to a serious life-threatening postoperative condition. We recommend increased use of the proposed diagnostic approach to further discover ways to achieve a lasting positive impact on the outcome of lymphatic flow disorders after congenital heart surgery.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2017 American College of Cardiology Foundation
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