The Fontan operation is the anticipated final stage of a now well-established and successful reconstructive strategy for children born with a single ventricle type of congenital heart disease. Direction of vena cava return directly to the branch pulmonary arteries absent ventricular thrust provides for sufficient pulmonary blood flow, which allows for survival and can be achieved today with excellent surgical results.^1,2 However, the circulation is far from normal, and important physiological deficiencies exist.

Sustained central venous hypertension is present in every patient with a Fontan circulation. Without a pump driving blood through the pulmonary circuit, filling of the systemic ventricle is impaired and stroke volume is diminished. Impaired chronotropy combined with low stroke volume leads to diminished cardiac output at rest, and an incapacity to properly increase cardiac output in response to stress and exercise.

While providing for survival, we now appreciate that the Fontan circulatory state comes at a price. With a growing number of survivors comes increased interest and focus on the end-organ consequences of this physiological state. A current focus is not just to create survival but also to allow the potential for a normal duration and quality of life.

How can one achieve this goal? The first step is to improve the current understanding of the consequences of the Fontan circulation on individual organ systems, characterizing individual functional state and identifying potentially modifiable variables that influence this state. The liver is one organ that is currently receiving much attention. Hepatic fibrosis is ubiquitous in patients with a Fontan circulation, likely secondary to the pathophysiology of a chronic congestive hepatopathy.³ Fontan-associated hepatopathy can manifest as mild liver enzyme abnormalities with mild liver enlargement in most cases for at least the first decade or so after surgery. However, there have been concerning reports of more severe cirrhosis and even malignant transformation in some cases.⁴ The effects of chronic venous hypertension on the hepatic parenchyma as our children with Fontan circulation enter adulthood are of serious concern. Characterization of the extent of liver fibrosis is a challenge since adequate noninvasive tools have not yet been developed and sufficiently validated. Large-scale studies will be necessary to identify factors that may influence degree of fibrosis. Candidate variables may include a possible genetic predisposition to the common stressor of chronic venous hypertension, perinatal or neonatal course, anatomical considerations, or type of Fontan operation. Cavopulmonary architecture and flow characteristics may variably affect egress of hepatic venous flow adding impedance to drainage.⁵ Increased impedance to drainage activates mechanoreceptors on hepatic stellate ganglion cells, transforming them into fibroblasts, which lay down collagen fiber. Anti-fibrotic therapies are being vigorously studied in other models of hepatic fibrosis such as hepatitis C, and may offer clues towards effective anti-fibrotic strategies in the Fontan population.

Protein losing enteropathy (PLE) and plastic bronchitis remain challenging complications after the Fontan operation. These conditions share a common theme of manifesting as "endoluminal protein loss syndromes." Recent developments in the capacity to image the lymphatic circulation has led to improved understanding of the role of this system in Fontan-related complications and a new paradigm. Chronic elevated central venous hypertension leads to both an increase in tissue and lymph fluid generation, as well as an impediment to drainage capacity as the lymphatic circulation must ultimately drain into the high-pressure central venous system. Lymphatic engorgement and a need to drain lymph leads to spillage of protein- and lymphocyte-rich fluid into pathways of least resistance, such as the gut lumen resulting in protein losing enteropathy, or into the airway, resulting in plastic bronchitis. Inflammation plays a key role in this process, as well. Strategies aimed towards aggressive reduction of central venous hypertension through diuretic regimens, pulmonary vasodilator therapy, and, specifically for PLE, intestinal targeted anti-inflammatory treatment have proven successful in some patients but not all.⁶ Detailed lymphatic characterization with selective lymphatic embolization utilizing catheter techniques has been demonstrated to be effective for patients with plastic bronchitis.⁷ Of note, low levels of sub-clinical enteric protein loss may exist in all of our patients with a Fontan circulation; witness the fact that most have subtle evidence for lymphopenia, perhaps related to chronic low levels of lymphatic gut leakage. It remains a mystery as to why and in whom low levels of enteric lymph loss transform into full-blown clinical PLE.

Bone health, somatic growth, pubertal development, immunological state and renal function (just to name a few) are additional areas worthy of focus after Fontan operation.^8,9 Perhaps it has been somewhat naïve to think that a circulatory system that manifests with chronically elevated central venous pressure and relatively low cardiac output would not potentially affect all organ systems in some manner or another. In order to best characterize these effects and ultimately optimize care for our Fontan patients, the team at the Children's Hospital of Philadelphia has developed a unique multidisciplinary clinic called the "Single Ventricle Survivorship Program." The program brings together interested pediatric sub-specialists in gastroenterology, hepatology, endocrinology, immunology, pulmonology, and nephrology into a clinical service, in which participants create a common understanding, narrative, and language focused on these unique patients. Standardized surveillance with assessment of end-organ functionality is provided above and beyond the routine visits to pediatric cardiology as an additional layer of consultative care.

Clinical care models for "best practices" are still waiting to be developed for this population. Although pathological conditions exist after the Fontan operation, the precise strategies to prevent disease progression in what appears to be an indolent situation are unclear. For example, we are just now at the initial stage of identifying liver fibrosis after Fontan in a cross-sectional manner.¹⁰ Is this a progressive process of linear time elapsed after the Fontan procedure, a process that advances in periodic stages, or not at all? Only standardized surveillance and longitudinal follow-up will answer this and many other questions. In a select group of individuals who manifest end-organ complications, within the context of cardiac catheter–derived, moderately elevated pulmonary artery pressures, health care providers have argued for what are believed to be common sense recommendations of pulmonary vasodilator therapy use. Data exists suggesting a role for the use of agents such as sildenafil and others after Fontan.^11,12 Whether prophylactic use of daily pulmonary vasodilator therapy will halt or stem the progression of complications is an important question, and one that will hopefully be addressed through upcoming multicenter randomized trial studies.

Health care providers have an obligation to these patients to be as aggressive with understanding and managing the long-term consequences after Fontan as in the development of the surgical intervention in the first place. In the current state of affairs, the work has begun, but there is a long way to go in providing the promise of a lifetime of health and wellbeing for these unique patients.

References

1. Rogers LS, Glatz AC, Ravishankar C, et al. 18 years of the Fontan operation at a single institution: results from 771 consecutive patients. J Am Coll Cardiol 2012;60:1018-25.
2. d'Udekem Y, Iyengar AJ, Galati JC, et al. Redefining expectations of long-term survival after the Fontan procedure: twenty-five years of follow-up from the entire population of Australia and New Zealand. Circulation 2014;130:S32-8.
3. Kendall TJ, Stedman B, Hacking N, et al. Hepatic fibrosis and cirrhosis in the Fontan circulation: a detailed morphological study. J Clin Pathol 2008;61:504-8.
4. Elder RW, Parekh S, Book WM. More on hepatocellular carcinoma after the Fontan procedure. N Engl J Med 2013;369:490.
5. Tang E, Restrepo M, Haggerty CM, et al. Geometric characterization of patient-specific total cavopulmonary connections and its relationship to hemodynamics. JACC Cardiovasc Imaging 2014;7:215-24.
6. Thacker D, Patel A, Dodds K, Goldberg DJ, Semeao E, Rychik J. Use of oral budesonide in the management of protein-losing enteropathy after the Fontan operation. Ann Thorac Surg 2010;89:837-42.
7. Dori Y, Keller MS, Rychik J, Itkin M. Successful treatment of plastic bronchitis by selective lymphatic embolization in a Fontan patient. Pediatrics 2014;134:e590-5.
8. Avitabile CM, Goldberg DJ, Zemel BS, et al. Deficits in bone density and structure in children and young adults following Fontan palliation. Bone 2015;77:12-6.
9. Avitabile CM, Leonard MB, Zemel BS, et al. Lean mass deficits, vitamin D status and exercise capacity in children and young adults after Fontan palliation. Heart 2014;100:1702-7.
10. Rychik J, Veldtman G, Rand E, et al. The precarious state of the liver after a Fontan operation: summary of a multidisciplinary symposium. Ped Cardiol 2012;33:1001-12.
11. Goldberg DJ, French B, McBride MG, et al. Impact of oral sildenafil on exercise performance in children and young adults after the fontan operation: a randomized, double-blind, placebo-controlled, crossover trial. Circulation 2011;123:1185-93.
12. Hebert A, Mikkelsen UR, Thilen U, et al. Bosentan improves exercise capacity in adolescents and adults after Fontan operation: the TEMPO (Treatment With Endothelin Receptor Antagonist in Fontan Patients, a Randomized, Placebo-Controlled, Double-Blind Study Measuring Peak Oxygen Consumption) study. Circulation 2014;130:2021-30.

Keywords: Bronchitis, Cardiac Catheters, Cardiac Output, Low, Central Venous Pressure, Collagen, Child, Cross-Sectional Studies, Disease Progression, Diuretics, Drainage, Electric Impedance, Fibroblasts, Follow-Up Studies, Fontan Procedure, Gastroenterology, Genetic Predisposition to Disease, Health Personnel, Hepatic Veins, Hepatitis C, Hypertension, Inflammation, Liver Cirrhosis, Lymphocytes, Lymphopenia, Mechanoreceptors, Nephrology, Piperazines, Protein-Losing Enteropathies, Pulmonary Artery, Pulmonary Medicine, Purines, Stellate Ganglion, Stroke Volume, Sulfones, Survival Rate, Survivors, Syndrome, Vasodilator Agents

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