50 years of Fontan operation - "not only good news

In functionally univentricular hearts, a Fontan circulation is a palliative surgical therapy with significant long-term complications-a challenge.

In 1968, Francis Fontan and Eugene Baudet successfully performed the first Fontan operation, offering a life-saving therapy for children with a univentricular heart defect. Within the spectrum of congenital heart defects, functionally univentricular vitiation occurs at 7-8%, with a great deal of morphologic heterogeneity within this group. The most commonly diagnosed malformations are hypoplastic left heart syndrome (25-67% of functionally univentricular hearts), tricuspid atresia (15-24%), double inlet left ventricle (14-18%), unbalanced atrioventricular canal, and severe Ebstein anomaly (Fig. 1).

Despite this heterogeneity, the common therapy using Fontan surgery is to achieve a reduction in the volume burden of the unicameral heart, as well as separation of the pulmonary and systemic circulation with normal oxygenation, through stepwise corrective surgery. Currently, the number of patients with unicameral vitium is estimated to be approximately 22,000 patients in Europe and approximately 50,000 patients in the United States [1].

The first Fontan operation consisted of the creation of an anastomosis between the superior vena cava and the right pulmonary artery and an anastomosis between the inferior vena cava and the left pulmonary artery using a homograft valve conduit.

The path to the currently favored total cavo-pulmonary anastomosis using an extracardiac conduit took several decades and various modifications. In the 1980s, the “multistage” concept consisting of an intermediate step by means of partial cavo-pulmonary anastomosis (“Glenn or Hemifontan operation”) was introduced. In the 1990s, replacement of the direct atrio-pulmonary anastomosis occurred with the creation of a lateral tunnel and later the use of an extracardiac conduit with or without fenestration (Fig. 2).

For patient selection, the so-called “ten commandments” were already formulated in the 1970s by Choussat and Fontan. Along with the modification and improvement of the Fontan operation, these were adjusted in the course. However, they still constitute a basic guideline of criteria that must be met with regard to the successful performance of a Fontan operation:

Deep pulmonary arterial pressures
(MAP <15 mmHg)
Deep pulmonary resistances (<3 ^WU/m2).
normally developed pulmonary arteries and
Vessel bed
Normal venous return
Good systolic function of the systemic ventricle
No significant AV valve regurgitation

In parallel, the age of patients undergoing surgery has been successively reduced, so that partial cavo-pulmonary anastomosis is currently performed at the age of 4-6 months, and total cavo-pulmonary anastomosis is performed at the age of 2-3 years. These modifications resulted in a significant reduction in mortality and morbidity. Recent studies show a decrease in mortality from 8% (1975-1990) to 1% (2001-2010) [2].

Problems and long-term course after Fontanpalliation

After palliation to the Fontan circulation, there is remarkably nonphysiologic hemodynamics. Passive systemic venous return to the pulmonary circulation has been implicated as a major causative factor in a number of long-term complications. Patient morbidity and mortality are significantly increased. In contrast to the massive decrease in early mortality over the last decades, the 15-year survival rate is 80-85% [3]. After 25 years, only 30% of Fontan patients live without complications. Central venous pressure is in the range of 12 mmHg after Fontan surgery. This chronic venous congestion, with concomitant decreased cardiac preload and progressive diastolic dysfunction and hypertrophy of the unicardium, causes an increase in postcapillary pressure and increased formation of interstitial fluid (Fig.3). This must be removed via the lymphatic system and ultimately the thoracic duct into the central venous system, where unphysiologically high pressure again prevails. Increased filled and more fragile lymphatics and lymphangiectasia with the potential for lymph leakage into third spaces result [4]. While chylothorax is an early postoperative complication that can usually be managed conservatively or may require prolonged placement of chest tubes, protein-loosing enteropathy (PLE) is seen in approximately 5% of patients during the long-term course. This results in sometimes considerable lymph leakage into the intestine, with large losses of lymphocytes, chylomicrons and protein, and thus antibodies. On the one hand, this amount of protein in the intestine leads to diarrhea and flatulence, and the subsequent hypoproteinemia in turn leads to edema, increased susceptibility to infection, and electrolyte imbalance with muscle cramps. The prognosis when PLE occurs is poor. 5 years after initial diagnosis 60% of Fontan patients are still alive, after 10 years 20%.

Spillover of protein-rich lymph into the bronchial system can cause plastic bronchitis with respiratory distress, bronchial obstruction, and atelectasis and occurs in 5-15% of Fontan patients, some fulminant with high acute lethality but also chronic recurrent.

The basis of treatment of these lymphatic loss syndromes is optimization of pulmonary circulation and elimination of any stenoses in the Fontan circulation. Therapy is usually catheter interventional by balloon dilatation and stent implantation in stenoses. The possibility of direct catheter interventional closure of lymphatic leakage also exists in individual cases, and these procedures are currently being established [5].

With increasing patient age, the slow progression of singular ventricle insufficiency comes to the fore. On the one hand, diastolic and systolic dysfunction is explained by the increased volume load before the Fontan operation, and on the other hand, by the long-term function of a frequently morphologically right ventricle as a systemic ventricle. Often there is concomitant AV valve regurgitation, which further increases pulmonary venous pressure. TTE and, if necessary, MRI diagnostics can be used to determine systolic ventricular function and valve insufficiencies. Although no randomized trials have demonstrated a benefit of heart failure therapy in univentricular circulation, the use of ACE inhibitors or AT2 receptor anatogonists, as well as low-dose diuretics and beta-blockers, is recommended for declining systolic function.

Other relevant cardiac problems represent arrhythmias caused by atrial surgical scars or progressive atrial dilatation in the presence of a previous Fontan modification, e.g., RA-PA-Fontan. Supraventricular tachycardias (SVT) are often poorly tolerated hemodynamically, are usually resistant to drug therapy, and must be addressed with electroconversion followed by ablation. In this context, evaluation of the Fontan circulation is important to diagnose and adequately treat hemodynamic causes (Fig. 4) . Ablation therapy of SVT’s requires expertise of the electrophysiologist for the specific anatomy and is supported by mapping systems and combining cardiac MR or CT images. In patients with extra-cardiac Fontan tunnel, tunnel fenestration or retro-aortic catheter intervention becomes necessary to access the atria. Ventricular tachycardia may occur as a result of ventricular dysfunction or surgical or embolic scarring and require medical therapy and evaluation for secondary prophylactic ICD implantation (subcutaneous vs. epicardial ICD). Access routes for pacemaker electrodes in AV blocks or severe sinus node dysfunction are usually epicardial given the specific anatomy.

In the presence of previous Fontan modification with RA-PA anastomosis, significant right atrial dilatation leads to progressive deterioration of hemodynamics and arrhythmias, and the indication for surgical Fontan conversion is given. Here, the anastomosis of the right atrium with the pulmonary artery is replaced with an extracardiac conduit, reduction plasty of the dilated right atrium is performed, and open cryoablation therapy is performed.

Chronic central venous congestion and progressively decreased cardiac ejection fraction lead to centro-lobular hepatic fibrosis, with late laboratory chemical changes detectable. Diagnostics using fibroscan, MR liver elastography, and liver biopsies, if necessary, allow different degrees of severity of hepatic remodeling processes to be detected. The risk of developing hepatocellular carcinoma is significantly increased in Fontan patients [6]. Therapeutically, attempts are made to help by hemodynamic optimization of Fontan circulation (where possible), avoidance of noxious agents (alcohol, medications). The ultima ratio is a high-risk heart-liver transplant.

In this context, the increased risk of thrombosis and thromboembolic events should be seen, which is caused on the one hand by the successive liver damage and synthesis performance with subsequent coagulopathy, but also by progressive protein losses via lymph leakage. Thromboembolic events represent the most common sudden cause of death in Fontan patients. Whether prophylactic long-term anticoagulation versus aspirin therapy is more protective against thrombus formation in the Fontan circulation is not clear according to studies. Anticoagulation should be used for SVTs, significantly impaired ventricular function, RA-PA-Fontan, and secondary prophylaxis after thromboembolic events. Because of pulmonary veno-venous collaterals or fenestrations between an extracardiac conduit or lateral tunnel and the atrium, right-to-left shunts significantly increase the risk of cerebrosvascular events.

Optimization of hemodynamics in Fontan patients is of utmost importance. Catheter invasive pulmonary pressure and resistance determination and adequate evaluation of all possible causes by TTE, Holter ECG, and cardiac MR or CT is necessary. Mechanical obstruction due to anastomotic stenosis, thrombus formation, or stenosis of the pulmonary arteries must be treated by catheter intervention or surgery. In the presence of hemodynamically relevant aorto-pulmonary collateral vessels, MAPCAs, catheter-based coiling is recommended. Administration of pulmonary vasodilator drugs (sildenafil, bosentan) has been shown to have a beneficial effect on pulmonary vascular resistance and exercise capacity in several studies.

“Failing Fontan”

Despite great advances and improvements, the palliative nature of Fontan surgery as a life-saving therapy for univentricular hearts has not changed since its introduction 50 years ago. Currently, at 25 years, survival is 83%, event-free survival is 30%, and no failing Fontan (i.e., death, heart transplant, Fontan reoperation, NYHA class III/IV, or PLE/plastic bronchitis) is 56%. Ultimately, the Fontan operation is a successful postponement of heart transplantation by decades until the situation of a “failing Fontan”.

The definition of a failing Fontan includes severe cardiac (severely impaired ventricular dysfunction) and extra-cardiac complications (PLE that cannot be managed therapeutically, liver cirrhosis, increased PVR). Despite the aforementioned drug therapy options (heart failure therapy, anticoagulation, pulmonary vasodilator medications) and interventions/surgeries (arrhythmia ablations, fenestrations, MAPCA coiling, stenting and dilations, pacemaker/ICD implantations, Fontan conversion, valve interventions), generalized organ malperfusion ultimately occurs in the long-term course.

In case of terminal insufficiency of the systemic ventricle or occurrence of severe extracardiac Fontan complications, the use of a ventricular assist device as a “bridge-to-transplant” should be discussed. Recent studies show a survival rate of 60% after 12 months of VAD therapy in Fontan patients, which, however, is significantly worse compared to patients with VAD therapy in biventricular circulation [7].

The only solution to achieve true correction of palliative Fontan circulation and its associated problems is cardiac transplantation. Compared to patients with dilated or ischemic cardiopathy, early mortality is increased after transplantation of Fontan patients [8]. This is due, among other things, to difficult surgical conditions (pronounced adhesions after repeated operations), increased bleeding tendency, and the altered complex anatomy. Over the long-term, transplant recipients after Fontan circulation have acceptable survival rates compared with other groups (1-year survival: 62-86%, 5-year survival: 59-77%, 10-year survival: 47-62%) [8,9]. In this context and with the background of the donor organ shortage, the selection of transplant candidates is of high importance. It should be kept in mind that Fontan patients are young patients in whom mechanical circulatory support is associated with higher mortality and morbidity compared with patients with biventricular circulation. Similarly, timely evaluation of Fontan patients is important to reduce the risk of transplantation due to advanced Fontan-associated comorbidities (liver fibrosis, PLE, etc.).

The care of Fontan patients is a long-standing challenge, and Fontan patients should be affiliated with a center with expertise in the treatment of complex congenital heart defects. This allows for the necessary interdisciplinary care and treatment of these complex patients. Thus, it may be necessary to involve the expertise of various specialists (congenital heart surgery, electrophysiology, interventional cardiology, imaging, transplant team, hepatology, gynecology, anesthesiology, social services, etc.). Follow-up ex aminations mostly include history and clinical examination at annual intervals, TTE, resting ECG, and at 2-4-year intervals, spiroergometry, long-term ECG, cardiac MR examinations (or CT for non-MR conditional pacemakers), laboratory control, liver sonography and fibroscan, liver MR or CT examinations as appropriate.

In the lifelong care of these patients, ensuring a good transition from pediatric cardiology to adult cardiology with expertise in “Grown-up congenital heart disease” is an important component. Likewise, a comprehensive Patient information It is important for the patient to be aware of the existing heart defect and to understand important life decisions such as choice of profession (no physically demanding occupations), ineligibility for military service, choice of contraception (IUD or progesterone-only contraceptives) and sporting activities (no weight training), avoidance of obesity, tobacco consumption, increased alcohol consumption and drugs. Topics such as family planning or the desire to become pregnant play a major role in young women and here it must be evaluated individually during the course whether the risk for the expectant mother (arrhythmias, thrombi, heart failure, spontaneous abortion) and the child (prematurity, small-for-gestational age) is acceptable and a pregnancy can be recommended under close monitoring.

Despite the successive reduction in surgical mortality and a 25-year survival of approximately 83%, it should be noted that Fontan surgery represents palliation with significant disadvantages compared with a normal circulatory situation (Fig. 6). The increasing number of Fontan patients represents a growing complex challenge.

Take-Home Messages

Fontan circulation is a palliative surgical therapy for functionally univentricular hearts, which is associated with significant long-term complications.
Fontan circulation is achieved through several intermediate surgical steps in infancy to toddlerhood.
The ability to increase cardiac output is limited in Fontan patients. Venous pressure is unphysiologically chronically elevated. Various complications of the Fontan circulation result from altered lymph flow with concomitant systemic venous congestion.
An obstruction-free Fontan circulation and low transpulmonary pressure gradients are a basic requirement for a “good Fontan”
Arrhythmias, especially supraventricular tachycardias are poorly tolerated hemodynamically by Fontan patients, are usually resistant to drug therapy, and must be addressed with electroconversion and subsequent ablation.
The care of Fontan patients is a long-standing challenge, and Fontan patients should be affiliated with a center with expertise in the treatment of complex congenital heart defects.

Literature:

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Iyengar AJ, et al: Trends in Fontan surgery and risk factors for early adverse outcomes after Fontan surgery: the Australia and New Zealand Fontan Registry experience. J Thorac Cardiovasc Surg 2014;148: 566-575.
Kverneland LS, et al: Five decades of the Fontan operation: A systematic review of international reports on outcomes after univentricular palliation. Congenit Heart Dis. 2018. 13(2): 181-193.
Menon S., et al: The Lymphatic Circulation in Adaptations to the Fontan Circulation. Pediatr Cardiol, 2017. 38(5): 886-892.
Dori Y, et al: Percutaneous Lymphatic Embolization of Abnormal Pulmonary Lymphatic Flow as Treatment of Plastic Bronchitis in Patients With Congenital Heart Disease. Circulation, 2016. 133(12): 1160-1170.
Gordon-Walker TT, et al: Fontan-associated liver disease: A review. J Cardiol, 2019 (in press, available online).
Blume ED, et al: Second annual Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) report: pre-implant characteristics and outcomes. J Heart Lung Transplant. 2018.37(1): 38-45.
Mauchley DC, et al: Transplantation in the Fontan Patient. Seminars in Thoracic and Cardiovascular Surgery: Pediatric Cardiac Surgery Annual. 2015;18: 7-16.
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