Long Term Consequences of the Fontan Procedure PDF

YPCAD-00930; No of Pages 12 Progress in Cardiovascular Diseases xxx (xxxx) xxx–xxx Contents lists available at ScienceDirect...

YPCAD-00930; No of Pages 12 Progress Long Term Consequences of the Fontan Procedure and How to Manage Them☆ W. Aaron Kay a,⁎, Tabitha Moe b, Blair Suter c, Andrea Tennancour Richard A. Krasuski e, Ali N. Zaidi d a Indiana University School of Medicine, Krannert Institute of b University of Arizona School of Medicine, Phoenix, AZ c Indiana University School of Medicine, Departments of Medicine d Children's Hospital at Monteﬁore, Monteﬁore Medical e Duke University Health System, Durham, NC a r t i c l e i n f o a Available online xxxx In sia. Keywords: come Adult congenital heart disease disease. Fontan agement rhythm is term Contents Introduction.................................................................. Staged palliative surgery and Fontan variations................... Long term survival following Fontan repair........................ Long term complications following Fontan repair................... Heart failure................................................ Thrombosis............................................................... Arrhythmias............................................................... Residual cyanosis............................................ Protein losing enteropathy................................... Fontan-associated liver disease.............................. Chronic venous insufﬁciency................................ Renal disease................................................ Abbreviations and acronyms: A1AT, alpha-1-antitrypsin; ACHD, Registry; ARNIs, Combined angiotensin-receptor and neprilysin brain natriuretic peptide; CO, cardiac output; CT, computed tomography; GI, gastrointestinal; HF, heart failure; HLHS, hypoplastic left tricular septal defect; LT, lateral tunnel Fontan; MCS, mechanical orthotopic heart transplantation; PA, pulmonary artery; PDE5, tricle; SVR, systemic vascular resistance; TA, Tricuspid atresia; ☆ Disclosures:W. Aaron Kay: Nothing to discloseTabitha Moe: to discloseAli N. Zaidi, MD: Nothing to discloseRichard A. Krasuski, investigator for Edwards Lifesciences and is an unpaid member ⁎ Address reprint requests to: W. Aaron Kay, MD, 1801 N. E-mail addresses: [email protected] (W.A. Kay), [email protected] (T. Moe), [email protected] (B. Suter), [email protected] (A. Tennancour), [email protected] data-cfemail="75071c161d1407115b1e07140600061e1c3511001e105b101100">[email protected] (R.A. Krasuski), azaidi@monteﬁore.org (A.N. Zaidi). of the Fontan Procedure and How to Manage Them. Prog Cardiovasc Dis (2018), W.A. Kay et al. / Progress in Cardiovascular Diseases xxx (xxxx) xxx–xxx .................. 0 .............. 0 ........................ 0 0 0 homograft valve, at both the inﬂow and outﬂow of the right atrium (RA). In 1973, Kreutzer et al described the use of the pulmonary valve of a patient with TA to connect the RA to the pulmonary artery (PA).12 Since then, several different types of Fontan modiﬁcations have been devised (Fig. 1). Management strategies in the neonatal period are di- rected toward providing an adequate source of pulmonary blood ﬂow either by creating an aorticopulmonary shunt (such as a Blalock- Taussig shunt) to augment pulmonary blood ﬂow or by restricting ex- cessive pulmonary blood ﬂow to ensure adequate systemic blood ﬂow. An atrial septectomy or septostomy is done in most cases to ensure adequate pulmonary venous return to the systemic ventricle. The ﬁrst cavopulmonary connection is created in the ﬁrst year of life via a bidi- rectional Glenn shunt. The Fontan circulation is completed by connec- tion of the inferior vena cava (IVC) to the PA once growth of the pulmonary vasculature is appropriate, usually between 1 and 5 years of age. This staged surgical process serves to slowly acclimate the pul- monary vessels to the increased blood ﬂow and the SV to decreased vol- ume load in a stepwise fashion.3,13 Years ago, the Fontan connection was made by anastomosing the RA to the PA, hoping to maintain some pump function in the pulmonary cir- cuit using intrinsic contractility of the RA. This atriopulmonary (AP) Fontan has since been replaced by the total cavopulmonary connections (TCPC), which have less kinetic energy loss and more streamlined blood ﬂow. TCPC include lateral tunnel (LT) and the extracardiac (EC) conduits, which have improved survival and hemodynamic superiority over the AP technique.3,14 The LT operation was introduced in the 1980s and creates a path from the IVC to the PA using a prosthetic bafﬂe sutured to a portion of the lateral wall of the RA.3,15 The EC conduit was introduced in the early 1990s and uses a tube of synthetic graft material to connect the IVC to the PA, bypassing the RA entirely and minimizing risk of inducing atrial arrhythmias.3,16 Other less common types of Fontan such as Bjork- Kreutzer modiﬁcation and intracardiac Fontan have also been performed less often but are beyond the scope of this paper. with anastomosis of right atrial appendage directly to pulmonary artery; B) lateral caval Fontan, with a patch separating the and anastomosis of superior vena cava to pulmonary artery; C) extracardiac Fontan, with a prosthetic tube conveying blood anastomosis. of the Fontan Procedure and How to Manage Them. Prog Cardiovasc Dis (2018), Kay et al. / Progress in Cardiovascular Diseases xxx (xxxx) xxx–xxx 3 type Fontans as well as poor survival due to the learning curve of the pioneering surgical era. Downing et al presented long-term follow up of 773 consecutive patients who underwent a ﬁrst Fontan operation at a single institution during an 18-year period. The 20-year estimate for survival with intact Fontan circulation was 74%. Independent risk fac- tors for death or loss of Fontan circulation were identiﬁed, but several of these characteristics conferred risk only in the early post-Fontan pe- riod. Late outcome was predicted only by presence of AV valve regurgi- tation pre-Fontan and length of post-Fontan ICU stay. Ventricular morphology and type of Fontan operation were not associated with early or late outcome.21 More recently, Zannino and colleagues de- scribed long term outcomes for 683 adult survivors of the Fontan proce- dure in ANZFR. Fontan type was AP connection in 201 and TCPC in 482 patients (249 LT and 233 EC). Survival for the entire cohort was 90% at 30 years and 80% at 40 years of age, with survival at 30 years of age sig- niﬁcantly worse for AP patients.22 The authors concluded that the long- term survival is improving, but signiﬁcant morbidity and mortality re- main for these patients. Of note, most patients (65%) had systemic left ventricular morphology. Additional risk factors for poor prognosis in- cluded male gender and moderate or severe AV valve regurgitation.22 It should be highlighted that the management of hypoplastic left heart syndrome (HLHS) has changed substantially over the past four de- cades. In the 1970s, children with HLHS could only be provided with supportive care and died within the neonatal period. The advent of the Norwood procedure in the early 1980s has greatly improved prog- nosis, and the majority of patients now undergo a series of three surgical stages that support survival into early adulthood.23 Despite these ad- vancements, patients with HLHS have considerable long-term morbid- ity following Fontan operation, and early mortality remains common.4,23 Pundi et al reported that only 40% of children with HLHS survived all three surgical stages and remained alive 10 years after Fontan completion.2 High systemic venous pressures, abnormal ventric- ular morphology, TE events, and recurrent arrhythmias create a tremen- dous burden of disease for these children as they reach adulthood. Exercise intolerance, HF, hepatic dysfunction, and disease processes more speciﬁc to patients with Fontan physiology such as PLE and plastic bronchitis are additional complications that can occur and further neg- atively impact the quality of life of patients with HLHS.24 Survival for patients with HLHS who undergo Fontan completion ranges from 72% to 85% at 10 years.4,25 However, when accounting for all the surgeries required from infancy, the overall survival drops to only 50% to 70% at 10 years.25,26 Despite this, there are now a small number of HLHS survivors reaching adulthood.27 In a recent multicenter study of 543 patients committed to Norwood surgery who could have reached 18 years of age by 2014, transplant-free survival to adulthood was only 14%, with most mortality driven by the perioperative period of the Norwood procedure (41%). As post-Norwood and interstage mor- tality continues to decrease, it is expected that the number of adult HLHS patients will continue to grow.28 Long term complications following Fontan repair Heart failure HF after Fontan is very different from and much more complex than HF in acquired heart disease. Fontan failure is a clinical syndrome in which circulation can no longer meet the metabolic demands of the body. Patients with Fontan failure predominately suffer from systemic venous congestion. Four phenotypes of Fontan failure have been established with renal hypoperfusion as the common terminal pathway for all phenotypes.29 (I) Fontan failure with reduced ejection fraction (EF), which most closely resembles acquired systolic HF, is characterized by signs Fontan connection Fontan. RA = and symptoms of low EF and is the most common type of HF seen in the pediatric Fontan population. of the Fontan Procedure and How to Manage Them. Prog Cardiovasc Dis (2018), Kay et al. / Progress in Cardiovascular Diseases xxx (xxxx) xxx–xxx conversion from AP Fontan to extracardiac Fontan. (A) Prior to Fontan conversion showing massive dilated right atrium. tube connecting IVC directly to PA. RA = right atrium; IVC = inferior vena cava; EC = extracardiac conduit; PA = decrease in venous return, and are essentially dependent on heart rate to augment CO.36 Since the phenotype of Fontan failure with preserved systolic func- tion is distinct from that of the traditionally-accepted HF model, it brings into question whether treatment should resemble currently ac- cepted HF therapy or rather the treatment for portal hypertension. Med- ications traditionally used in HF such as systemic vasodilators may not be well tolerated, and an approach more speciﬁcally tailored to the unique hemodynamics of the Failing Fontan may be more beneﬁcial.30 It is also unclear how traditional diagnostics such as biomarkers and im- aging aid in diagnostics and evaluation of the Failing Fontan patient. Brain natriuretic peptide (BNP), N-terminal pro-B natriuretic pep- tide (NT-proBNP), and serum sodium (hyponatremia) are biochemical parameters often monitored for HF exacerbations and have been shown to predict outcome in traditional HF. Use of biomarkers in Fontan patients continues to be investigated. Baggen et al showed that elevated NT-proBNP levels were associated with increased risk of death or HF exacerbation.37 BNP elevation has been shown to be a predictor of Fontan failure, mortality, and morbidity in adult patients in multiple studies.38,39 Hyponatremia has also been shown to be very common in adults with congenital heart disease (ACHD) and carries a high risk of mortality.40 In the Failing Fontan patient, cardiac and non-cardiac ﬁbrosis are common and precede adverse outcomes in adulthood; therefore, bio- markers assessing ﬁbrosis may be useful in assessing risk. These include galectin-3, a carbohydrate-binding protein, which is associated with a variety of biological effects including inﬂammation and ﬁbrosis. Opotowsky et al showed that galactin-3 levels were elevated in Fontan patients compared with a control group, and correlated with worsened kidney function, advanced age, and higher risk of hospital admission or death. Galectin-3 levels did not correlate with speciﬁc underlying ven- tricular morphology nor type of Fontan procedure.41 The paradigm of traditional HF treatment has two distinct scopes: symptomatic relief and mortality beneﬁt. Symptomatic therapies focus both on traditional HF symptoms as well as unique Fontan-related prob- lems such as plastic bronchitis, protein losing enteropathy (PLE), and re- current ascites. Given the lack of randomized controlled trials of HF therapy in Fontan patients, use of traditional HF medications is still widespread, with only very small trials and expert opinion to guide decision-making. In 2016, a systematic review of drug therapy trials in Fontan patients revealed only nine small trials with a total of 267 Fontan patients studied. Sildenaﬁl was the drug most commonly examined.42 of the Fontan Procedure and How to Manage Them. Prog Cardiovasc Dis (2018), al. / Progress in Cardiovascular Diseases xxx (xxxx) xxx–xxx 5 help determine timing for transplant include a combination of declining functional status and changes on imaging, biomarkers, and cardiopul- monary exercise testing.59 In the United States, only a very small minor- ity (3.3%) of adult OHT occur in CHD patients.60 Indications for OHT after Fontan include systemic ventricular failure refractory to medical ther- apy, chronic passive congestion, intractable ascites, and progressive cy- anosis leading to functional decline. Currently, OHT wait-list mortality or delisting due to worsening clinical status is disproportionately com- mon for ACHD patients listed as status 1A in the United States.61 It is controversial if the current allocation system is appropriate for ACHD and whether it should be adapted given the unique aspects of this pa- tient population.62 Given the high incidence of FALD, some centers have started performing combined heart-liver transplants, although there overall is very limited experience with this technique; and very few centers have performed N10 combined OHT-liver transplants on Fontan patients.63 Thrombosis Despite changes in the surgical design of Fontan, and although the AP Fontan has largely been abandoned, thrombosis continues to be a major problem following the Fontan procedure.64 The reported preva- lence of thromboembolic (TE) events is as high as 33%, contributing to approximately 25% of mortalities via deep venous thrombosis, pulmo- nary embolism, or cerebrovascular accident.64–66 Thrombosis risk fac- tors include non-pulsatile pulmonary ﬂow, low cardiac output, arrhythmias, type of Fontan connection, residual shunts or intentional fenestration, dilated atrium, ventricular dysfunction, hypoxia, liver dis- ease, PLE, and underlying coagulation abnormalities.65–67 In some small studies, Fontan patients have been found to have decreased levels of anticoagulant proteins (proteins C and S) and an increase in prothrombotic factors (factor VIII and von Willebrand factor).65 Most clinicians treating Fontan patients agree with routine use of pharmacologic prophylaxis against TE events, but there is no consensus on what speciﬁc medication(s) should be used.65,67 Some authors favor- ing antiplatelet medications (usually aspirin), while others favor vita- min K antagonists (VKA) such as warfarin. In a large meta-analysis on thromboprophylaxis in Fontan patients, aspirin was statistically noninferior to VKA with regard to TE events, but patients in neither group had many TE events.65 A retrospective multicenter study (TAC- TIC) evaluating anticoagulation therapy for atrial arrhythmias (in a wide variety of CHD types, including Fontan patients) also showed no signiﬁcant difference between the use of antiplatelet or VKA therapy in the prevention of TE events, though bleeding events were higher in the VKA group (p = 0.039). Of note, patients with more complex con- genital heart lesions were more likely to have a TE event (p b 0.001), and risk scores used in general adult cardiology to predict TE events (CHADS2 and CHA2DS2-VASc scores) did not accurately predict TE events in Fontan patients.68 Events in VKA patients often are caused by failure to maintain a therapeutic International Normalized Ratio (INR); and some studies have suggested that well-managed pharmacist-assisted protocols can help reduce overall event rates of both bleeding and thrombosis.69 Given the intrinsic limitations of VKA therapy, novel oral anticoagu- lant (NOAC) therapy to prevent TE events is increasingly being consid- ered in Fontan patients, despite very limited data regarding safety or efﬁcacy.70 NOACs are often favored as they do not require blood draws for INR monitoring, have no dietary interactions, and may lead to better medication compliance and improved quality of life.71 The NOTE regis- try has been actively recruiting patients to determine effectiveness and safety of NOACs in ACHD patients. A recent publication from NOTE showed only 8 minor events in the ﬁrst 30 days after starting a NOAC for arrhythmia in 99 patients. Events included nonfatal bleeding and other minor side effects in patients who transitioned from VKA to NOAC therapy, and there were no reported adverse events in those who were started on a NOAC without prior anticoagulation.71 Another of the Fontan Procedure and How to Manage Them. Prog Cardiovasc Dis (2018), al. / Progress in Cardiovascular Diseases xxx (xxxx) xxx–xxx When traditional percutaneous access is difﬁcult or impossible, other routes can be considered. Nehgme et al descripted utilizing direct puncture of the chest wall (percutaneous transthoracic access) with ﬂuoroscopic guidance to obtain access to the pulmonary venous atrium in six LT Fontan patients.80 Mapping and ablation catheters were placed in the pulmonary venous atrium, and additional electrophysiologic catheters were placed within the Fontan bafﬂe and esophagus. Compli- cations included one pneumothorax and two hemothoraces requiring drainage. Another new procedure that was recently described involves CT-guided transconduit puncture in patients with EC Fontan, in which the dilator tip is grasped with a snare catheter.81 Subxiphoid and epicar- dial approaches may be used in patients without ACHD, however, they are generally not employed for patients with ACHD. Both these ap- proaches rely on the ability to access the pericardial sac, which in Fontan patients is likely to be immobile and scarred with thick, ﬁbrous adhesions.82 Surgical ablation is considered the gold standard for invasive rhythm control in SV patients. Early surgeries involved conversion of AP Fontan to TCPC Fontan in conjunction with surgical ablation for AF.83 Fontan conversion that did not include surgical ablation has been associated with a high incidence of postoperative atrial arrhythmias.84The surgical approach has since progressed from isthmus ablation, to a modiﬁed right-sided maze procedure, and eventually to the MAZE-Cox III (right and left-sided maze) procedure for AF.85,86 With three-dimensional mapping and pace-mapping techniques, the focus of ventricular arrhythmias can be marked by an ablation cath- eter. This allows for the localization and surgical excision of the arrhyth- mogenic tissue, thereby substantially reducing the possibility for future ventricular arrhythmias and resultant ICD discharges.87 SV patients scheduled for Fontan revision may be appropriate candidates for similar hybrid approaches that include surgical resection of arrhythmogenic atrial tissue. With advanced planning, patients undergoing open-thoracotomy procedures can have epicardial leads placed intraoperatively, poten- tially avoiding another open sternotomy or thoracotomy if they develop a future pacing indication. Therefore, surgical ablation should always be discussed whenever an open heart surgical procedure is planned in these patients. Finally, elective surgical excision of thrombogenic struc- tures such as the left atrial appendage and residual, ligated, blind-ended pulmonary artery stump should be performed if feasible and with low enough risk at the time of concomitant open heart cardiac surgical repairs. Residual cyanosis Cyanosis late after Fontan is common. Fontan patients may remain mildly hypoxemic, even after full repair and closure of atrial level shunts. Cyanosis can signiﬁcantly worsen over time. Desaturation is sec- ondary to multiple causes including an intentionally placed surgical fen- estration, persistent coronary sinus drainage into the right atrium, pulmonary arteriovenous malformations, aorticopulmonary collaterals, or venovenous collaterals.3 The degree of cyanosis may not be readily apparent at rest and can be unmasked by exercise. Persistently cyanotic Fontan patients without a known fenestration may beneﬁt from inter- ventional catheterization by an appropriately trained operator who can evaluate and treat these various causes of right-to-left shunts by deploying a variety of coils and devices (Fig. 4).70,88 Unfortunately, clin- ically signiﬁcant venous collateral channels and other right-to-left shunts tend to recur after coiling or device closure.89 Closure of venovenous collaterals in some series has been found to be associated with a higher overall mortality rate.90 If cyanosis cannot be corrected (or is accepted in a patient with intentional fenestration), appropriate preventative measures to avoid air embolism should be instituted such as the use of air ﬁlters with intravenous lines. Anticoagulation ther- apy is recommended for all patients with cyanosis or fenestration post- Fontan due to the risk of paradoxical systemic TE.70 of the Fontan Procedure and How to Manage Them. Prog Cardiovasc Dis (2018), Kay et al. / Progress in Cardiovascular Diseases xxx (xxxx) xxx–xxx 7 in chronic inﬂammation, and an increase in interferon-y, tumor necrosis factor-α, and serum albumin transmission across the intestinal mucosa. Elevated BNP levels can contribute to PLE by impeding lymph transport. Since not all patients with the Fontan circulation develop PLE, it has been hypothesized that individuals who develop PLE may have a con- genitally abnormal lymphatic system.94 Treatment for PLE is targeted toward decreasing protein loss and re- ducing symptoms by decreasing CVP, improving cardiac function, re- ducing inﬂammation, and improving nutrition.96,98 Identifying reversible hemodynamic abnormalities is an important step in treat- ment. Obstruction to systemic venous ﬂow, which elevates venous pres- sures, should be corrected with balloon angioplasty and stenting.99 Creating a Fontan fenestration (generally by catheterization) results in a Fontan pressure “pop-off,” which can lower Fontan pressure and im- prove systemic cardiac output, although at the expense of reducing ox- ygen saturation. Fontan fenestration is rarely a long-term solution, however, given the high incidence of spontaneous fenestration closure, and thus it is generally considered to be a bridge to cardiac transplant or Fontan revision.100 Atrial or ventricular pacing to increase heart rate may in some cases help improve symptoms via increasing CO.91 Pharmacological treatments include loop diuretics and aldosterone antagonists to decrease edema. Afterload reducing medications such as ACE inhibitors and angiotensin receptor blockers may improve car- diac output by reducing SVR. Pulmonary vasodilators such as phospho- diesterase‑5 (PDE5) inhibitors may help reduce PVR and subsequently CVP. PDE5 inhibitors have also been shown to improve mesenteric arte- rial blood ﬂow. Corticosteroids can reduce inﬂammation; however long-term use leads to other well-known complications of long term steroid use. Oral budesonide is more enteric-speciﬁc with less systemic absorption, which limits systemic side effects; and therefore is often used for long term management of PLE.101 Heparin has been shown to decrease inﬂammation (by inhibiting mast cell activity in the intestine), and also provides a barrier to larger molecules such as albumin.96 Hep- arin can also reduce the occurrence of pulmonary and mesenteric micro-thrombi. Octreotide mimics natural somatostatin and can de- crease thoracic duct lymphatic ﬂow.93 Diet modiﬁcation is also an important component of treatment. Mal- nutrition and failure to thrive are common sequelae of PLE. As a result, attention to incorporating a high protein diet (≥2 g/kg/d), high medium chain triglycerides, low sodium, and low fat (b25% calories) diet may also beneﬁt patients.94 patient with exercise-induced cyanosis due to formation of a decompressing venovenous collateral. SVC = superior vena cava; collateral from innominate vein draining to pulmonary veins. (B) Arrow demonstrating site of successful coil to colour in this ﬁgure legend, the reader is referred to the web version of this article.) of the Fontan Procedure and How to Manage Them. Prog Cardiovasc Dis (2018), al. / Progress in Cardiovascular Diseases xxx (xxxx) xxx–xxx 16 years) undergoing liver biopsies, all biopsies had at least some de- gree of liver ﬁbrosis, with some demonstrating advanced cirrhosis.113 Wu et al performed a retrospective analysis of liver histopathology sam- ples available in 68 adult and pediatric Fontan patients, including both autopsy and biopsy specimens. Every specimen had centrilobular ﬁbro- sis, with 41.2% grading as severe. Portal ﬁbrosis was found in 82.3% of specimens (14.7% with cirrhosis) and centrilobular ﬁbrosis grade was worse in patients with a dominant single ventricle compared to a com- bined right and left systemic ventricle.114 Despite the high incidence of abnormal histopathology, neither centrilobular ﬁbrosis nor portal ﬁbro- sis grade correlated with transplant-free survival or overall survival. Although there is a high incidence of hepatic ﬁbrosis in Fontan pa- tients, liver biopsy ﬁndings have not correlated well with clinical out- comes. Liver biopsy results can be misleading, as ﬁbrosis is patchy, and it is easy to obtain a false negative or false positive sample.115 Stan- dard pathologic grading systems may mischaracterize hepatic ﬁbrosis patterns in Fontan patients, since the areas of ﬁbrosis are different in Fontan patients than in non-Fontan patients with portal hypertension.95 Prevention of FALD is an important but elusive clinical goal. This can be attempted by optimization of anatomy and physiology, as well as prevention of liver injury both prior to and after Fontan. Additional pre- ventive strategies include immunization against and treatment of viral hepatitis, as well as avoidance of hepatotoxins and obesity (steatohepatitis). Moderation of alcohol intake should be considered, al- though the effects of alcohol on FALD are unknown.8 Liver function biochemistries are often normal, even in the presence of signiﬁcant liver ﬁbrosis in Fontan patients. Given the concerns about potentially severe risks and uncertain beneﬁts of liver biopsy, other test- ing has been developed. The MELD score (Model of End Stage Liver Dis- ease) has commonly been used to risk-stratify patients in the general population to allocate organs for liver transplantation112 as well as to risk-stratify cirrhotic patients who need open-heart surgery.116 This score is a mathematical model including serum creatinine, sodium, bil- irubin and INR, as well as a correction variable if the patient is on dialy- sis. Scores range from 6 to 40, with higher scores being associated with a higher risk of death due to severe liver disease. Many Fontan patients are managed on chronic vitamin K antago- nists, as their INRs are elevated out of proportion of the degree of liver disease; thus the MELD-XI score (MELD excluding INR) may have better prognostic value. MELD-XI correlates with degree of hepatic ﬁbrosis,111 as well as mortality and need for heart transplant in adult Fontan patients.110,117 Laboratory data in these patients usually demonstrates only mild abnormalities, even when advanced cirrhosis is present,118 making assessment of liver dysfunction with tools such as the MELD score119 of limited clinical value. Consequently, the search for a more meaningful measure of liver function in this population is critical and re- mains ongoing.11 Elder et al evaluated a novel risk score to determine risk of portal hy- pertension after Fontan they termed the VAST score (varices, ascites, splenomegaly, and thrombocytopenia).109 The score includes one point for each of these features, and a score ≥ 2 points was considered to be consistent with portal hypertension. This score was then validated retrospectively against 73 adult and pediatric Fontan patients using lo- gistic regression. Features of portal hypertension, as identiﬁed as a VAST score ≥ 2 were found in 36% of the cohort; and VAST score ≥ 2 after adjusting for other variables resulted in a 9-fold increased risk of adverse events. Given the increasing morbidity associated with liver disease, identi- fying it early and with less invasive assessment has become paramount. Imaging has been shown to accurately identify structural liver disease, but unfortunately not the degree or severity.3,120 Abdominal ultrasound with Doppler evaluation should be performed at baseline with consid- eration for elastography. Transient elastography by ultrasound or MRI has been evaluated by several groups as a manner for assessing hepatic stiffness. Its role, however, remains limited by difﬁculty in distinguishing edema from ﬁbrosis.121 Cardiac MRI routinely includes of the Fontan Procedure and How to Manage Them. Prog Cardiovasc Dis (2018), al. / Progress in Cardiovascular Diseases xxx (xxxx) xxx–xxx 9 dysfunction.129 Opotowsky et al showed that traditional means of eval- uating GFR using creatinine overestimates true GFR and that either cystatin C or urinary biomarkers may be a better reﬂection of true GFR.130 right he- Plastic bronchitis Pro- Plastic bronchitis is a rare condition after Fontan palliation in which mucoﬁbrinous bronchial casts develop and result in marked airway ob- struction. Patients often expectorate large casts or require urgent re- moval by bronchoscopy, and life-threatening events may occur in up to 40% of affected patients.131 Plastic bronchitis occurs in 3–4% of Fontan patients132 and is associated with similar risk factors as PLE.133 Initial management of these patients is similar to that of PLE, including optimi- zation of Fontan hemodynamics and ensuring there is no alternate re- versible cause of elevated CVP. Proposed treatment options include inhaled or systemic steroids, aerosolized mucolytics, and aerosolized ﬁ- brinolytics such as tissue plasminogen activator. Bronchoscopy is often needed for acute airway rescue.134 Intervention on abnormal lym- phatics has resulted in clinical improvement in isolated patients with Fontan-related plastic bronchitis.135 OHT can be effective as a long- term option for treating plastic bronchitis,136 although plastic bronchitis has occurred after OHT,137 and plastic bronchitis is a risk-factor for short-term mortality following OHT.138 criteria Lung disease Patients with Fontan often have a restrictive pattern on pulmonary function testing associated with reduced exercise capacity,139 and this is likely related to multiple prior sternotomies and chest wall deformi- ties such as scoliosis that are very common, particularly following prior thoracotomy.140,141 Pulmonary function testing demonstrates re- duced forced vital capacity, breathing reserve, and diffusing capacity; and cardiopulmonary exercise testing shows reduced functional capacity.140 Pregnancy in the Fontan patient Patients with prior Fontan procedure who are contemplating preg- nancy should undergo preconception assessment and counseling by an ACHD specialist, including a comprehensive cardiovascular evalua- tion to identify residual issues following Fontan operation that may ad- versely affect pregnancy outcome.142 Women after Fontan are generally fertile, unless they are severely cyanotic. Pregnancy is often well- tolerated in patients with good hemodynamics, reasonably normal oxy- gen saturation, no atrial arrhythmias, and no history of TE events, but there is still an elevated risk of adverse outcomes compared to healthy controls.142 Women who have already had signiﬁcant post-Fontan events or who are likely to be at high risk for such events should be dis- couraged from attempting pregnancy and should be offered safe and ef- fective forms of contraception. Fontan physiology is a thrombogenic state, thus high-estrogen containing medications are not favored70; and instead other forms of contraception should be considered such as intrauterine devices or intramuscular depot progesterone injections. The largest study to date evaluating pregnancy outcomes after Fontan is now over 20 years old143 and thus included mostly AP Fontans. This data therefore needs to be interpreted with caution, given that AP Fontans have a much higher overall mortality rate than TCPC.2 This survey-based study evaluated 116 female patients at several United States centers and reported on 33 pregnancies in 14 women. There were 15 (45%) live births, 13 spontaneous abortions, and 5 elec- tive abortions. There were no maternal complications reported during labor, delivery, or immediate postpartum period.143 Sporadic cases of women with Fontan palliation having multiple pregnancies and healthy children have also been reported.144,145 of the Fontan Procedure and How to Manage Them. Prog Cardiovasc Dis (2018), W.A. Kay et al. / Progress in Cardiovascular Diseases xxx (xxxx) xxx–xxx 4. Khairy P, et al. Long-term survival, modes of death, and predictors of mortality in patients with Fontan surgery. Circulation 2008;117(1):85-92. 5. Cetta F, et al. 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