Evolving Therapies in Fontan Failure

What is Fontan Failure?
Fontan failure is a nebulous concept. Heterogeneity of intra-cardiac anatomy, varying Fontan subtypes and overlapping modes of clinical decline make a single, comprehensive definition difficult. In any of its iterations, the Fontan physiology induces maladaptive changes in the heart and in many other organs and bodily systems, with clinical implications that limit health and life expectancy. Fontan failure in childhood has become unusual1 and the burden has shifted into adulthood. The Australian and New Zealand Fontan Registry (ANZFR) defines Fontan failure as the occurrence of death, heart transplant, protein-losing enteropathy (PLE), plastic bronchitis or New York Heart Association (NYHA) Functional class III or IV at follow-up. In 683 adults >16 years, freedom from Fontan failure was 93%, 77%, 62% and 30% at ages 20, 30, 40 and 50 years respectively.2

Management of Atrioventricular Valve Regurgitation
Long recognized as a risk factor for mortality at Fontan completion, atrioventricular valve (AVV) regurgitation is also a critical influence on late outcome. A 2019 ANZFR study of 1,199 Fontan patients who experienced AVV failure had double the risk of subsequent Fontan failure compared to those with competent valves. By age 25, 56% of patients with a common AVV and 46% of those with a single tricuspid valve manifested AVV failure.3 An accompanying editorial discussed important unknowns, especially the potential benefits and optimal timing of AVV repair or replacement.4 Its authors even questioned whether children with important AVV regurgitation, particularly those with a common or tricuspid valve morphology, might better be managed without proceeding to Fontan completion.4 In an era when transcatheter intervention is an accepted therapy for mitral regurgitation in acquired heart disease and is being developed for use on the tricuspid valve,5 non-surgical strategies to improve AVV regurgitation may be attempted in carefully selected Fontan patients in the future.

Pulmonary Vasodilator Therapy
The relationship between pulmonary vascular disease and Fontan failure is complex and overlapping. Non-pulsatile pulmonary blood flow (PBF), thrombosis, AVV regurgitation and diastolic ventricular dysfunction all affect pulmonary vasculature. Even small increases in pulmonary vascular resistance reduce PBF, limit ventricular preload and cardiac output, and elevate central venous pressures. In a 2017 study of 261 adult Fontan patients, those with elevated pulmonary vascular resistance (>2 WU.m2) and low cardiac index (<2.5L/min/m2) were at increased risk of Fontan failure (death, transplant listing or initiation of palliative care) within five years.6 A 2019 meta-analysis of nine, small randomized controlled trials of various pulmonary vasodilators in 381 Fontan patients determined that pulmonary vasodilators led to improvement in peak V02, NYHA class, six-minute walking distance performance and hemodynamics, without affecting mortality.7 At present, it appears that in the failing Fontan population, pulmonary vasodilators are more beneficial than other standard guideline directed medical heart failure therapies.

External Ventilation
In a Fontan circulation, systemic venous and PBF patterns are related to breathing, and respiration affects the ability to exercise.8 Inspiration increases systemic venous flow amplitudes and venous pulsatility, although net flow seems only minimally influenced.9,10 The adverse impact of positive pressure ventilation on Fontan hemodynamics has long been recognized, and negative pressure ventilation strategies increase PBF and cardiac output after Fontan completion surgery.11,12 Lately, external ventilation devices that might be worn outside of a hospital setting have sparked some interest. Our group recently conducted a prospective pilot study of external negative and biphasic pressure in 10 healthy adult Fontan patients and 10 controls.13 We found that PBF and cardiac output increased during both modes of external ventilation, with a greater change and better tolerance seen with the biphasic setting.13 It is tempting to speculate that external ventilation might help failing Fontan physiology, though caution is required, and further study is essential. Respiratory driven retrograde hepatic flow is substantial in Fontan patients.10 Further augmentation by deepening inspiration might potentially increase hepatic afterload and theoretically worsen Fontan associated liver disease.10

The New Focus on Lymphatics
Blood is not the only substance that circulates. The past decade has revealed that the lymphatic system is intrinsically abnormal or specifically maladapted in many Fontan patients. Increased venous pressures not only enhance lymphatic production, but also obstruct emptying of the thoracic duct,14 mechanisms which may contribute to complications such as PLE, chylothorax, plastic bronchitis and ascites. Of tiny caliber and without a pumping ventricle, it may be a surprise that lymphatic vessels are highly active, with contractile walls propelling lymph back towards the central veins.15,16 Recent innovative studies from a Danish group demonstrated structural lymphatic changes and diminished lymphangion pumping in apparently healthy Fontan patients.17 Therapeutic options targeting lymphatics have been successful in small numbers of children and include surgical decompression of the thoracic duct18 and occlusive embolization of dilated lymphatic channels.19 Further characterization of lymphatic abnormalities may lead to preventative measures and new management options for what are currently the most challenging Fontan complications.

Transplant and Mechanical Support
Heart transplant for the failing Fontan circulation is effective therapy, but is challenging and in the current era, may be underutilized.20,21 Previously, survival after heart transplantation in Fontan patients was worse than that of other non-Fontan congenital heart disease recipients.22,23 More recent data shows an improvement and some groups now achieve Fontan heart transplant outcomes at par with those for other forms of congenital heart disease.24-26 Optimization of Fontan transplant outcomes requires concerted, multidisciplinary effort and the development of specific expertise,21 but is a worthy endeavor given the potential for excellent long-term survival.27 Some groups have demonstrated low mortality by opting for combined heart-liver transplant in the majority of Fontan recipients.28 The merits and disadvantages of such an approach warrant further evaluation. Experience suggests that in Fontan patients, even advanced liver fibrosis can regress after heart transplant,29 and there is data supporting equivalent 1-year post heart transplant outcomes for cirrhotic and non-cirrhotic Fontan patients.30 Heart transplant is also an effective treatment for PLE and in children, the severity and duration of PLE are not associated with worse post-transplant outcomes.31 Durable mechanical support options for Fontan circulations exist and are under further development. However, due to current technical and other challenges, their use is not widespread.32 Most Fontan failure now occurs in adult life.1 Traditional training pathways for advanced heart failure care, pediatric cardiology and/or adult congenital heart disease are quite different, and none is ideally suited to encompass all aspects of care these patients need. The failing Fontan patient is unique (Figure 1). A team approach, involving pediatric and adult congenital heart disease and advanced heart failure services, is essential (Figure 1).

Figure 1: Similarities and differences between Fontan Failure in children and adults and Heart Failure in adults without congenital heart disease

Figure 1
CHD – congenital heart disease, PLE - protein losing enteropathy, IART – interatrial reentry tachycardia, ACEi – angiotensin converting enzyme inhibitor, ARB – angiotensin receptor blocker, ANRi – angiotensin receptor-neprilysin inhibitor, b-blocker – beta-adrenergic blocking agent, MRA – mineralocorticoid receptor antagonist, NYHA – New York Heart Association, Peak VO2 – peak oxygen uptake, VAD – ventricular assist device

Evolution of care
In the current era, the transition of pediatric Fontan patients to effective adult congenital heart disease care, which maintains lifelong access to multidisciplinary expertise, specialist imaging, and advanced and emerging management options, is essential.33 Conversely, our growing experience with adult Fontan survivors should prompt ongoing critical evaluation of pediatric practices and inform our medical and surgical strategies for the next generation.


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Clinical Topics: Cardiac Surgery, Congenital Heart Disease and Pediatric Cardiology, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Valvular Heart Disease, Cardiac Surgery and CHD and Pediatrics, Cardiac Surgery and Heart Failure, Cardiac Surgery and VHD, Congenital Heart Disease, CHD and Pediatrics and Interventions, CHD and Pediatrics and Prevention, CHD and Pediatrics and Quality Improvement, Interventions and Structural Heart Disease, Mitral Regurgitation

Keywords: Heart Defects, Congenital, Fontan Procedure, Protein-Losing Enteropathies, Thoracic Duct, Central Venous Pressure, Liver Transplantation, Tricuspid Valve, Risk Factors, Chylothorax, Ascites, Mitral Valve Insufficiency, Prospective Studies, Vasodilator Agents, Palliative Care, Life Expectancy, Pilot Projects

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