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  • 1. ISSN: 1524-4539 Copyright © 2007 American Heart Association. All rights reserved. Print ISSN: 0009-7322. Online 72514 Circulation is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX DOI: 10.1161/CIRCULATIONAHA.105.592378 2007;115;800-812Circulation Paul Khairy, Nancy Poirier and Lise-Andrée Mercier Univentricular Heart http://circ.ahajournals.org/cgi/content/full/115/6/800 located on the World Wide Web at: The online version of this article, along with updated information and services, is http://www.lww.com/reprints Reprints: Information about reprints can be found online at journalpermissions@lww.com 410-528-8550. E-mail: Fax:Kluwer Health, 351 West Camden Street, Baltimore, MD 21202-2436. Phone: 410-528-4050. Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, a division of Wolters http://circ.ahajournals.org/subscriptions/ Subscriptions: Information about subscribing to Circulation is online at by on June 3, 2008circ.ahajournals.orgDownloaded from
  • 2. Univentricular Heart Paul Khairy, MD, PhD; Nancy Poirier, MD; Lise-Andrée Mercier, MD Abstract—As early as 1699, Chemineau described a heart composed of 2 auricles but only 1 ventricle.1 The univentricular heart has since fascinated the medical community. Unique in its complexity and scope, the univentricular heart has sparked intense debates about embryology and nomenclature, challenged our understanding of cardiovascular physiology and hemodynamics, and inspired some of the most creative surgical and interventional approaches in human history. The present report provides an overview of the nomenclature and classification of the univentricular heart, epidemiology and pathological subtypes, genetic factors, physiology, clinical features, diagnostic assessment, therapy, and postoperative sequelae. Although the present report touches on issues applicable to neonates and children with univentricular hearts, the focus is on information of interest and relevance to the adult cardiologist. (Circulation. 2007; 115:800-812.) Key Words: heart diseases Ⅲ ventricles Ⅲ cyanosis Ⅲ Fontan operation Nomenclature and Classification Nomenclature and classification of the univentricular heart remains a subject of heated debate. Additional proposed terminology has included “single ventricle,” “cor triloculare biatrium (well-formed atrial septum),” “cor bilocu- lare (rudimentary or absent atrial septum),” “common ventri- cle,” and “functionally single ventricle.”2–4 The controversy stems, in part, from the morphological heterogeneity encoun- tered and the recognition that truly solitary ventricles are exceedingly rare. More commonly, a second rudimentary or hypoplastic accessory ventricle is present, which justifies the term “functional” single ventricle. It is generally agreed that the atrioventricular (AV) connection is central in defining the univentricular heart. Van Praagh used the terms “single,” “common,” and “univentricular” interchangeably to describe hearts with 1 ventricular chamber that receives both AV valves or a common AV valve, excluding mitral and tricuspid atresia.2 Anderson’s unifying criterion is that the entire AV junction be connected to 1 ventricular chamber, which includes hearts with 1 absent AV connection.3 Despite unresolved nomenclature issues, a classification scheme relevant to surgery was proposed.5 A “single ventri- cle” was characterized as lacking 2 well-developed ventricles, which thereby excluded hearts with nonseptable but well- formed ventricles. Hypoplastic left heart syndrome was recognized as a common form of univentricular heart but was classified independently.6 The proposed definition of univen- tricular heart encompassed double inlet AV connections [double inlet left (DILV) or right ventricle], absence of 1 AV connection (mitral or tricuspid atresia), common AV valve and only 1 well-developed ventricle (unbalanced common AV canal defect), and only 1 well-developed ventricle and heterotaxy syndrome (single ventricle heterotaxy syndrome). Heterotaxy syndromes refer to disorders of lateralization whereby the arrangement of abdominal and thoracic viscera differ from normal and mirror-image of normal. By these criteria, the univentricular heart includes a broad category of congenital cardiac malformations characterized by both atria related entirely or almost entirely to 1 functionally single ventricular chamber. A comprehensive nomenclature system should consider atriovisceral situs, relationship between systemic and pulmo- nary veins, AV valves, great arteries, and ventricular mor- phology. More specifically, the well-developed ventricle may be designated left, right, or indeterminate. Left ventricles have relatively smooth walls, fine trabeculations, and lack septal chordal attachments of the AV valve. In contrast, right ventricles are more coarsely trabeculated and commonly have chordal attachments of the AV valve to the septal surface. With regard to the AV connection, a single, double, or common inlet may exist.7 Convention dictates that if Ͼ75% of a common AV valve annulus empties into 1 ventricular chamber, a common inlet connection is present. Single inlet connections may be characterized as mitral or tricuspid valves. With double inlet connections, morphological AV valve features may not be sufficiently distinct to distinguish mitral from tricuspid configurations. Such valves may best be described as right- or left-sided. Epidemiology and Pathological Subtypes Notwithstanding the lack of a uniformly applied nomencla- ture and classification system and inaccuracies from method- ological limitations inherent to population estimates of con- genital heart disease, a New England registry reported the incidence of univentricular heart to be 54 cases per million From the Adult Congenital Heart Center, Montreal Heart Institute, Montreal, Canada. Correspondence to Dr Paul Khairy, Canada Research Chair, Electrophysiology and Adult Congenital Heart Disease, Adult Congenital Heart Center, Montreal Heart Institute, 5000 Bélanger St, Montreal, Quebec, H1T 1C8, Canada. E-mail paul.khairy@umontreal.ca © 2007 American Heart Association, Inc. Circulation is available at http://www.circulationaha.org DOI: 10.1161/CIRCULATIONAHA.105.592378 800 Congenital Heart Disease for the Adult Cardiologist by on June 3, 2008circ.ahajournals.orgDownloaded from
  • 3. live births.8 More recent estimates are substantially higher. In hypoplastic left heart syndrome alone, the most common form of univentricular heart, a crude median incidence of 2.3 cases per 10 000 live births was derived when data was pooled from 36 studies that included a wide spectrum of disease severity, which ranged from mild left ventricular hypoplasia (amenable to biventricular repair) to aortic and mitral valve atresia with an absent left ventricle.9 Tricuspid atresia, the second most common subtype of univentricular heart, is thought to occur less than once for every 10 000 live births10 and was present in 2.9% and 1.4% of congenital heart disease autopsy and clinical series, respectively.10 DILV comprises 1% of all congenital heart malforma- tions.11 In an autopsy series of 60 univentricular hearts that excluded mitral and tricuspid atresia, DILV was present in 78%, double inlet right ventricle in 5%, and single ventricle heterotaxy syndrome in 13%.2,12 Unbalanced common AV canal defects, which coexist with other malformations, were identified in 12%. Typically, a DILV contains a rudimentary right ventricular chamber at its base. Great arteries may be normally related (type I or “Holmes heart”13), the aorta may be anterior and rightward (type II) or leftward (type III), or “inverted” in a posterior and leftward orientation (type IV).2 Most commonly, the hypoplastic right ventricle is anterior and to the left of the left ventricle, with L-transposition of the great arteries. In univentricular hearts of right ventricular morphology, both great arteries usually arise from the right ventricle. The aorta is characteristically “malposed,” as it is anterior to or side-by-side with the pulmonary artery.14 Genetic Factors Cardiovascular malformations have been observed in 19% to 33% of siblings with hypoplastic left heart syndrome.15,16 Although genetic determinants of other forms of univentric- ular heart have not been extensively elaborated, several subtypes that include DILV, single inlet, common inlet, and complex single ventricle heterotaxy syndromes are thought to be polygenic in nature, with recurrence and transmission risks far below that expected from Mendelian inheritance.17 In the polygenic model, the phenotype is presumed to result from additive effects of multiple genes, interactions with other genes and environmental factors, and stochastic effects.18 The risk to siblings and offspring of affected individuals is similar and generally in the order of 2% to 5%.16,17,19 Concordance rates may be higher in specific subtypes.20 Physiology Physiology of the univentricular heart depends on such key determinants as obstruction to outflow, inflow, and/or flow across the atrial septum; systemic and pulmonary venous return; pulmonary vascular resistance; and AV valve regur- gitation. With severe systemic outflow obstruction, the neo- nate is dependent on right-to-left shunting through a patent ductus arteriosus to maintain systemic output. Blood mixes within atrial and ventricular chambers and is predominantly ejected through the pulmonary valve to pulmonary and systemic vascular beds via the pulmonary artery and patent ductus arteriosus, in a ratio dependent on vascular resistanc- es.21 In contrast, with critical pulmonary outflow obstruction, pulmonary blood flow is dependent on left-to-right shunting across a patent ductus arteriosus. Once again, systemic and pulmonary blood flows are interdependent and determined by resistances of the 2 circulations. With obstruction to pulmonary venous return, severe pul- monary hypertension may ensue. In the presence of an atretic or critically stenotic AV valve, unobstructed communication between both venous inflows and the single ventricle requires an unrestrictive atrial septal defect (ASD). With an atretic mitral valve, a restrictive ASD is physiologically similar to pulmonary venous obstruction. In tricuspid atresia, the phys- iological effect of a restrictive ASD is akin to systemic venous obstruction. In short, optimal physiology of the univentricular heart requires good ventricular function with- out AV valve regurgitation, an unrestrictive ASD, and well- balanced systemic and pulmonary blood flow. Clinical Features Clinical manifestations hinge on the presence or absence of pulmonary outflow obstruction. Without pulmonary stenosis, infants with low pulmonary resistance present with signs and symptoms typical of large left-to-right shunting, ie, conges- tive heart failure and failure-to-thrive.4,14 Because of in- creased pulmonary blood flow, cyanosis may not be apparent. Aortic outflow obstruction may compound already excessive pulmonary blood flow and worsen congestive heart failure. Some patients (eg, type IV DILV) may have a preferential favorable stream of systemic venous return to the pulmonary artery and pulmonary venous return to the aorta.22 In contrast, an unfavorable stream with a transposition-like blood flow pattern may occur in patients with a right-sided subaortic right ventricle and straddling right AV valve. Cyanosis and systemic hypoxemia may result.23 In the setting of a univentricular heart, a certain degree of pulmonary stenosis is physiologically desirable to prevent pulmonary overcirculation. Severe pulmonary stenosis or atresia may result in profound hypoxemia and cyanosis, however. Diagnostic Evaluation Electrocardiograms Given the heterogeneity of the univentricular heart, the ECG appearance is highly variable. Patients with right atrial isomerism often have 2 separate sinus nodes, with a P-wave axis that fluctuates with the prevailing pacemaker.24 In contrast, most hearts with left atrial isomerism do not have a histologically recognizable sinus node, with consonant slow atrial or junctional escape rates.25 The AV conduction system may be displaced, particularly in hearts with AV discordance and AV canal defects. In L-looped single ventricles, the elongated course of the common bundle renders it susceptible to complete AV block.26 With a ventricular D-loop and a well-formed right ventricle, the AV node is normally positioned.27 In patients with tricuspid atresia, the PR interval is usually normal with tall and broad P-waves. Left axis deviation is characteristic.28 In the absence of a functional right ventricle, left Khairy et al Univentricular Heart 801 by on June 3, 2008circ.ahajournals.orgDownloaded from
  • 4. ventricular forces are unopposed, as manifested by small r waves and deep S waves over right precordial leads and tall r waves over left precordial leads. In the most common subtype of DILV, AV conduction is often abnormal, with PR prolongation or a higher degree AV block.29 Q-waves are absent over left prec- ordial leads and may be present over right precordial leads. Q-waves may also be seen in leads II, III, and aVF.30 In a series of 18 patients with univentricular hearts of right ventricular morphology, the ECG revealed right ventricular hypertrophy in all and 11 had a superior frontal QRS axis.14 Radiological Features The chest x-ray is particularly helpful in assessment of pulmo- nary arterial vascularization and configuration of the great arteries.31 Because pulmonary stenosis is less common in single left ventricles, increased pulmonary arterial vascularization evokes this diagnosis.4 An increased cardiac silhouette reflects volume overload. Dilation of the main and right pulmonary artery may produce a prominent right upper heart border, described as a “waterfall” appearance.32 In DILV, the ascending aorta silhouette is altered by the position of the rudimentary right ventricular chamber. When located anterior and leftward, a prominent left heart border is seen.31 In contrast, when the rudimentary right ventricle is right-sided, the aortic silhouette is generally convex to the right.31 In patients with moderate to severe pulmonary stenosis, common in univentricular hearts of right ventricular morphology, pulmonary arterial vascularization may be normal or oligemic.14 The cardiac silhouette may be mildly enlarged if at all. With pulmonary atresia, systemic-to- pulmonary shunting may result in asymmetric pulmonary vas- cularization patterns.14,31 Figure 1. Aortopulmonary shunts. A, The classic Blalock-Taussig shunt consists of an end-to-side anastomosis of the subclavian and pulmonary artery. B, The modified Blalock-Taussig shunt consists of an interposition tube graft that connects the subclavian artery to the ipsilateral pulmonary artery. C, A Waterston shunt consists of a connection between the ascending aorta and pulmonary artery. D, A Potts shunt involves a small communication between the descending aorta and ipsilateral pulmonary artery. 802 Circulation February 13, 2007 by on June 3, 2008circ.ahajournals.orgDownloaded from
  • 5. Noninvasive Imaging The diagnosis and morphological subtype may be fully characterized by a systematic and thorough echocardiograph- ic appraisal, with particular attention to apical position, atrial situs, AV relationship, and ventricular-arterial alignment. In DILV, there are usually 2 separate patent AV valves, but either may be imperforate, stenotic, or regurgitant.7,33 Either valve may straddle the bulboventricular foramen.34 A com- mon AV valve with a 5-leaflet configuration is commonly found in univentricular hearts with atrial isomerism and is best viewed from parasternal short axis and apical 4-chamber views.2,7,33 In DILV, the rudimentary right ventricular cham- ber may be readily identified and localized, often in the parasternal short-axis view. In the most common subtype (type III), the rudimentary right ventricle gives rise to the aorta and well-formed left ventricle to the pulmonary artery. Left ventricular morphology may be inferred when the aorta emanates from an anterosuperior rudimentary chamber.7,33 A univentricular heart with a well-formed right ventricle can often be surmised to exist on the basis of typical right ventricular morphological characteristics. Comprehensive hemodynamic assessment should include color-flow imaging and Doppler interrogation. An estimate of AV valve stenosis or regurgitation severity should supple- ment status of the AV connection (single, double, or com- mon) and appraisal of straddling and overriding features. Restriction of the bulboventricular foramen may likewise be assessed by continuous wave Doppler imaging. Of note, cardiac magnetic resonance imaging overcomes many of the limitations of echocardiography and is of great value in the demonstration of systemic and pulmonary venous anomalies, aortic arch malformations, and proximal pulmo- nary artery lesions.35 It may provide important insights in the pre- and postoperative assessment of patients with univen- tricular hearts. Cardiac Catheterization Cardiac catheterization may provide a detailed assessment of anatomic and functional features.36,37 Objectives include assessment of hemodynamics, systemic and pulmonary ve- nous anatomy, AV and ventricular-arterial connections, ven- tricular morphology and function, pulmonary vascular resis- tance, aortic arch integrity, and systemic-pulmonary collaterals. Patients with univentricular hearts characteristi- cally have a complete mix of systemic and pulmonary venous circulations at the ventricular level. If one assumes a pulmo- nary venous oxygen saturation of 96% and normal systemic blood flow, the arterial oxygen saturation reflects total pulmonary blood flow. As a rule of thumb, values Ն85% and Ͻ75% signify increased and decreased pulmonary blood flow, respectively.36 The presence or absence of hemodynamic and anatomic abnormalities such as poor ventricular function, aortic coarc- tation, pulmonary artery distortion, increased pulmonary vascular resistance, and abnormal collateral vessels are rele- vant to therapeutic management plans.37 Proponents of rou- tine preoperative cardiac catheterization assert that noninva- sive imaging may fail to visualize pulmonary artery distortion, that cardiac catheterization is the only valid method to measure pulmonary vascular resistance, and that abnormal aortopulmonary collateral vessels may be identified and coil embolization performed if necessary.37 After initial palliation, patients not suited for Fontan completion may benefit from repeated catheterizations to reassess pulmonary pressures and magnitude of created shunts, and address complications such as shunt stenosis, pulmonary artery ste- nosis, and pulmonary arteriovenous fistulae. Surgical Management General objectives of initial surgical palliation are to provide unobstructed systemic outflow, unobstructed systemic and pulmonary venous return, and controlled pulmonary blood flow. In patients with severe pulmonary obstruction or atresia, this is currently accomplished by an aortopulmonary shunt, such as a modified Blalock-Taussig shunt (Figure 1), or bidirectional cavopulmonary anastomosis (Glenn shunt). It is worthwhile to note that adult patients today benefit from surgical techniques performed decades ago, which include end-to-side anastomosis of the subclavian artery to pulmo- nary artery (Figure 1A) and termino-terminal cavopulmonary anastomoses. Pulmonary circulations solely dependent on aortopulmonary collaterals pose particular challenges and may require unifocalization of collaterals as a component of a staged surgical approach.38 Initial palliation in patients with unrestrictive pulmonary blood flow may consist of pulmo- nary artery banding or division with creation of an aortopul- monary shunt to limit pulmonary blood flow.39 Pulmonary banding has been associated with adverse outcomes after the Fontan procedure, however, and may result in subaortic obstruction.40 A bidirectional Glenn shunt or superior cavopulmonary shunt is now performed at about 6 months of age (Figure 2). Obstructions or distortions to the pulmonary arterial tree are corrected during this intervention. A Fontan procedure is completed sometime between 18 months and 4 years of age, which thereby separates pulmonary from systemic circula- Figure 2. The bidirectional Glenn shunt consists of an end-to- side anastomosis of the divided superior vena cava to the undi- vided pulmonary artery. The modified Blalock-Taussig shunt, shown in white, was taken down and oversewn. Khairy et al Univentricular Heart 803 by on June 3, 2008circ.ahajournals.orgDownloaded from
  • 6. tions (Figure 3). Table 1 lists the initial proposed criteria for Fontan completion.41 Although criteria such as normal sinus rhythm have been discounted,42 and others that include age limits have been modified,43 several have withstood the scrutiny of large retrospective analyses.44 Developed in 1971 for tricuspid atresia,45 the Fontan proce- dure has undergone multiple modifications to encompass several forms of palliative surgery that divert systemic venous return to the pulmonary artery, usually without interposition of a subpul- monary ventricle. The classic Fontan involved a valved conduit between the right atrium and pulmonary artery.45 Currently, most adults will have had a modified Fontan, which consists of direct anastomosis of the right atrium to pulmonary artery (Figure 3A). In 1987, de Leval et al proposed a major variation that consisted of an end-to-side anastomosis of the superior vena cava to the undivided right pulmonary artery, a composite intraatrial tunnel with the right atrial posterior wall, and a prosthetic patch to channel the inferior vena cava to the transected superior vena cava (Figure 3B).46 Total cavopulmo- nary connections may also be performed as extracardiac tunnels, with inferior vena caval flow directed to the pulmonary artery via an external conduit (Figure 3C). As in the intracardiac lateral tunnel, the superior vena cava is anastomosed to the pulmonary artery.47 In addition, Fontan pathways may be “fenestrated” by creation of an ASD in the baffle or patch to provide an escape valve that allows right-to-left shunting, which may be beneficial Figure 3. Variations of Fontan surgery. A, The modified classic Fontan; B, the intracardiac lateral tunnel Fontan; C, the extracardiac Fontan. In (A), the modified Blalock-Taussig shunt, shown in white, was taken down and oversewn. In (C), permanent atrial epicardial pacemaker leads are illustrated in gray. 804 Circulation February 13, 2007 by on June 3, 2008circ.ahajournals.orgDownloaded from
  • 7. early after the surgical procedure.48 If hemodynamics are favor- able, these fenestrations can later be closed by a transcatheter approach.49 In patients with univentricular hearts and systemic outflow obstruction, the most severe form of which is hypoplastic left heart syndrome, a variation of Norwood stages that culminate in a Fontan-type circulation is often indicated.50 Less than 3 decades ago, patients with hypoplastic left heart syndrome had no viable surgical options and died as neonates. Objec- tives of the Norwood stage 1 procedure, performed within the first 2 weeks of life, are to provide unobstructed pulmonary venous return, permanent systemic outflow from the right ventricle, and temporary pulmonary blood supply to allow the pulmonary vasculature to develop and mature. The main pulmonary artery is divided, the proximal portion is anasto- mosed to the ascending aorta, the aortic arch is repaired and augmented, and pulmonary blood flow is maintained via a modified Blalock-Taussig shunt50,51 (Figure 4A) or Gore-Tex shunt from the right ventricle (Figure 4B).52 “Hybrid” vari- ants have been described.53 The Norwood stage II procedure, performed before 6 months of age, consists of a bidirectional Glenn shunt or hemi-Fontan and closure of the Blalock- Taussig shunt.50,54 Between 18 months and 3 years of age, the stage III procedure completes the total cavopulmonary Fon- tan by connection of the inferior vena cava to the pulmonary artery. Overall mortality was recently reported to be 39% after stage I, 9.5% after stage II, and 10% after stage III.55 A lower-risk subgroup with an 86% hospital survival rate after a Norwood stage I procedure was retrospectively identified.56 When this staged approach cannot be performed, cardiac transplantation is considered. Natural History As a group, patients with unrepaired univentricular hearts have a poor prognosis. In the largest series of unoperated patients (nϭ83), Moodie et al reported that 70% with well- formed single left ventricles died before age 16, with an annual attrition rate of 4.8%.57 The natural history is even bleaker for patients with univentricular hearts of right ven- tricular morphology, with 50% survival 4 years after diagno- sis.57 The most common causes of mortality were arrhyth- mias, congestive heart failure, and sudden unexplained death. Ammash and Warnes reviewed their experience with 13 unoperated adults with univentricular hearts to determine which characteristics permitted long-term survival and to assess associated complications.58 Eleven patients had DILV with transposed great arteries, 1 patient had DILV with normally related great arteries, and 1 patient had tricuspid atresia. The oldest patient was 66 years old. All had either moderate-to-severe pulmonary stenosis or pulmonary hyper- tension. The left ventricular ejection fraction was normal (nϭ11) or mildly depressed (nϭ2), and no patient had more than mild AV valve regurgitation. Twelve patients reported good functional capacity and worked full- or part-time. Thus, despite the overall grim prognosis in unoperated patients, some adults with DILV, transposition of the great arteries, and well-balanced circulations may survive into their seventh decade with acceptable functional capacity and preserved ventricular function.58 As exemplified in Figure 5, it is worthwhile to note that a subgroup of adults with univentricular hearts who were considered high-risk Fontan candidates have had cavopulmo- nary or aortopulmonary shunts for sustained palliation. The Figure 4. A, Norwood stage I procedure; B, Sano modification. Original Criteria Proposed for Fontan Completion Age Ն4 years to Ͻ15 years Normal sinus rhythm Normal systemic venous return Normal right atrial volume Mean pulmonary artery pressure Յ15 mm Hg Pulmonary arteriolar resistance Ͻ4 Wood units/m2 body surface area Pulmonary artery to aortic diameter ratio Ն0.75 Left ventricular ejection fraction Ն0.60 Competent mitral valve Absence of pulmonary artery distortion Khairy et al Univentricular Heart 805 by on June 3, 2008circ.ahajournals.orgDownloaded from
  • 8. clinical course of this “intermediate” group of patients is less well characterized. Arrhythmias are a major cause of late morbidity and are associated with ventricular dysfunction and death.59,60 Long-term ventricular function appears better pre- served with cavopulmonary shunts that unload the single ventricle when compared with aortopulmonary shunts.60 Management of Cyanotic Patients With Univentricular Heart Because unoperated and partially palliated patients suffer from chronic cyanosis, early detection and treatment of multisystemic repercussions is essential. Hematologic de- rangements include erythrocytosis, iron deficiency, thrombo- emboli, and bleeding diathesis.61 Hyperviscosity symptoms consist of fatigue, headache, dizziness, visual disturbances, paresthesias, myalgias, and altered mentation. Although iso- volumic phlebotomy is no longer routinely performed, it may be indicated in iron-replete patients with moderate to severe symptoms or prophylactically in the preoperative setting when hematocrit levels exceed 65%. In the presence of iron-deficiency anemia, cautious iron repletion is recom- mended.62 Bleeding diatheses range from mild to life- threatening and are associated with altered coagulation fac- tors, thrombocytopenia, and platelet dysfunction.61 When indicated, antiplatelet and anticoagulant therapy should be judiciously monitored. Citrate should be adjusted for plasma volume when prothrombin and partial thromboplastin times are measured, especially if hematocrit levels exceed 55%.61 Neurological complications include cerebral hemorrhage, thromboemboli from right-to-left shunting, and cerebral abscess- es.63,64 Air filters are recommended for central and peripheral intravenous lines to prevent paradoxical air embolization. Renal complications include progressive glomerulosclerosis from rel- ative hypoperfusion, which justifies hydration prior to proce- dures that involve contrast agents. Hyperuricemia is attributed to decreased resorption of uric acid.65 Consequently, nephrolithia- sis, urate nephropathy, and gout may ensue. Additional rheuma- tological complications include hypertrophic osteoarthropathy in 30% of patients.66 Symptomatic hyperuricemia and gout should be treated as per usual, although nonsteroidal antiinflammatory agents are best avoided. Cholelithiasis is also common in patients with cyanotic heart disease; acute cholecystitis may require surgery. In general, noncardiac surgery should be undertaken only if essential, particularly in the presence of Eisenmenger physi- ology.67 Given the susceptibility of such patients to minor variations in systemic or pulmonary vascular resistance, caregivers experienced in cardiac anesthesia and postopera- tive intensive care management are central to multidisci- plinary management. In the absence of Eisenmenger physi- ology, pregnancy in the context of cyanotic heart disease has been associated with Ͼ30% incidence of maternal cardiovas- cular complications and prematurity.68 An oxygen saturation Ͻ85% was predictive of increased risk. In general, follow-up should include a thorough history with particular attention to hyperviscosity symptoms, bleed- ing diatheses, gallstones, and neurological, rheumatological, and renal complications. In addition to comprehensive car- diac work-up with ascertainment of functional capacity and oxygen saturation levels at rest and during exercise, standard blood tests should encompass complete blood count, ferritin, clotting profile, renal function, and uric acid.69 History and Long-Term Sequelae in Operated Patients Benefits of Fontan palliation are well defined, with an actuarial survival of 91% at 10 years with lateral tunnels70 and 78% at 12 years in patients with DILV, 83% of whom Figure 5. Cardiac magnetic resonance angiography in a patient with situs inversus, congenitally corrected transposition of the great arteries, mitral and pulmonary atresia, and left-sided Glenn shunt (GS). The arrow indicates 50% narrowing of the Glenn shunt at the site of anastomosis with the left pulmonary artery (LPA). Note the multiple left lower lobe pulmonary arteriovenous malformations. Figure 6. Subcostal echocardiographic view of the right atrium (RA) in a patient with a modified classic Fontan for D-transposition of the great arteries, multiple muscular ventricu- lar septal defects, a functional single ventricle, and atrial tachyarrhythmias. The arrow indicates a well-delineated throm- bus in the dilated right atrium. 806 Circulation February 13, 2007 by on June 3, 2008circ.ahajournals.orgDownloaded from
  • 9. had atriopulmonary connections.71 Nevertheless, the Fontan circulation constitutes a hemodynamic compromise. With biventricular optimal fluid dynamics, caval pressures are typically Ͻ10 mm Hg and mean pulmonary pressures exceed 15 mm Hg. Fontan physiology is paradoxical in that it imposes systemic venous hypertension with concomitant pulmonary arterial hypotension.72 Consequently, potential complications are numerous and include arrhythmias, throm- boemboli (Figure 6), hepatic dysfunction, protein-losing en- teropathy, and worsening cyanosis from pulmonary venous compression, systemic venous collateralization, or pulmonary arteriovenous malformations. All patients with Fontan physiology should be followed up by specialized teams with regular and comprehensive surveil- lance to prevent, detect, and manage complications.69,73 In addition to a thorough clinical history and physical examina- tion, minimum tests includes resting oximetry, 12-lead ECG, chest x-ray, echocardiography with Doppler interrogation, complete blood count, biochemical analyses for liver function tests, serum protein, albumin levels, and occasional Holter monitoring.69 Additional work-up may require transesopha- geal echocardiography, exercise spiroergometry, cardiac magnetic resonance imaging, isotopic ventriculography, com- plete heart catheterization, and electrophysiological study. Arrhythmias At mid-term follow-up, sinus node dysfunction occurs in 13% to 16% of patients with modified classic Fontans and contin- ues to increase with time.74 Atrial tachyarrhythmias are prevalent, challenging, and associated with substantial mor- bidity. These arrhythmias are notoriously resistant to antiar- rhythmic pharmacological therapy and, in some patients, may result in rapid hemodynamic deterioration and heart failure.75 Although the occurrence of atrial tachycardias increase with follow-up duration and depend on the particular type of repair, they have been reported in up to 57% of patients.60 The most common form is a macro-reentrant circuit, termed intraatrial reentrant tachycardia. These circuits may be com- plex or multiple.76 With the use of such tools as 3-dimensional mapping systems and irrigated-tip ablation catheters, transcatheter procedures are immediately success- ful in Ͼ80% of cases in dedicated centers (Figure 7).77 Although recurrences and development of new arrhythmias remain problematic, to the order of 30% to 45% 6 to 12 months after ablation,78,79 quality-of-life measures are improved.78 When atrial tachyarrhythmias are detected, underlying hemodynamic causes, such as obstruction of the right atrium to pulmonary artery anastomosis, should be sought and anticoagulation pursued.69 Patients with failing Fontans and atrial arrhythmias should be considered for surgical conver- sion to a lateral tunnel or extracardiac conduit with concom- itant arrhythmia surgery.80,81 In the patient with refractory atrial tachyarrhythmias but no other indication for surgical revision, we favor a transcatheter ablation approach in light of its efficacy and low risk, with repeat procedures as required. Thromboemboli and Hepatic Dysfunction In addition to such thrombotic risk factors as atrial arrhyth- mias, distended and sluggish Fontan pathways, and intravas- cular prosthetic material, hepatic impairment with multiple clotting factor abnormalities have been described. These include decreased levels of protein C, protein S, and anti- thrombin III.82 Increased platelet reactivity has also been recognized.83 Hepatic congestion and cirrhosis are common, whereas hepatic adenoma and hepatocellular carcinoma occur less frequently.84 Hemodynamic assessment is required in any patient with ongoing liver dysfunction. In the absence of Figure 7. A 32-year-old man with intractable atrial tachyarrhythmias and a modified classic Fontan underwent electrophysiological study and trans- catheter ablation. A, Contrast angiography of the Fontan pathway in a posteroanterior view. Note the massive right atrial dilation, patent atriopulmo- nary connection, and divided main pulmonary artery (MPA). A permanent pacemaker lead is positioned at the atriopulmonary junction (Lead). The arrows indicate position of a reference catheter (Ref) inserted via the right internal jugular vein and screwed into the medial right atrial wall. B, A left lateral view of a 3-dimensional electroanatomic map. Local activation times in tachycardia are color-coded with earliest to latest signals in white, red, yellow, green, light blue, dark blue, and purple, respectively. A focal atrial tachycardia is noted, with concentric spread of activation from the white center indicated by the arrow. Khairy et al Univentricular Heart 807 by on June 3, 2008circ.ahajournals.orgDownloaded from
  • 10. atrial arrhythmias, the role of long-term antiplatelet or anti- coagulation therapy remains poorly defined. Asymptomatic pulmonary emboli are frequently identified.85 Some retro- spective reviews support antiplatelet therapy,86 whereas oth- ers suggest that anticoagulants are more effective,87,88 and still others discourage routine anticoagulation.89 Protein-Losing Enteropathy Loss of protein via the gastrointestinal tract occurs in 3.7% of patients with Fontan-type surgery and is clinically character- ized by fatigue, peripheral edema, pleural and pericardial effusions, ascites, and chronic diarrhea.90 The diagnosis is confirmed by low serum albumin and increased fecal ␣1- antitrypsin levels. Protein-losing enteropathy is thought to be mediated in part by chronically elevated central venous pressures. Other risk factors include longer cardiopulmonary bypass time and morphologic right ventricular anatomy.91 In patients with generalized edema, the 5-year survival rate is Ϸ50%.90 Multiple therapeutic approaches have been de- scribed with anecdotal successes. These include dietary modifications with high-protein and high–medium-chain tri- glycerides, afterload reduction agents, inotropic agents, hep- arin, albumin infusions, octreotide, prednisone, creation of an atrial fenestration, Fontan revision, and cardiac transplanta- tion.90 As the mean time between Fontan palliation and diagnosis of protein-losing enteropathy is 6.9 years,71 most adult survivors will have undergone some form of surgical intervention. Worsening Cyanosis In the absence of an atrial fenestration, the transcutaneous oxygen saturation in patients with Fontan procedures usually exceeds 94%.92 Common causes of worsening hypoxemia include progressive deterioration of ventricular function with or without AV valve regurgitation, shunting through a baffle leak or residual interatrial communication,93 pulmonary vein compression by a giant right atrium (Figure 8) or aorta,94 systemic venous collateralization, pulmonary arteriovenous malformations (Figure 9), pulmonary pathology that includes a restrictive respiratory function pattern, hepatic venous connection to the coronary sinus or left atrium, right-to-left interatrial shunting via small thebesian veins, and diaphrag- matic paresis. Exercise Tolerance and Quality of Life Impaired exercise capacity in patients with Fontan physiol- ogy is characteristically associated with reduced vital capac- ity, high residual volume-to–total lung capacity ratio, low arterial saturation with hypocapnia, and skeletal muscle dysfunction.95 Exercise capacity is not improved by a 10- week course of enalapril.96 Left ventricular morphology independently predicts higher peak oxygen uptake consump- tion.97 Despite reductions in exercise tolerance, repeated hospital admissions, and comorbidities, many patients with univentricular hearts report a satisfactory quality of life as assessed by the Duke questionnaire.98 Younger age is asso- ciated with better quality of life. In adults with Fontan physiology, quality-of-life assessment showed physical func- tion, mental health, and general health perception to be Figure 8. Transverse magnetic resonance image of a patient with a modified classic Fontan for tricuspid atresia and severe rotoscoliosis. The arrow designates the site where the massively enlarged right atrium (RA) compresses the right upper pulmo- nary vein (RUPV). Figure 9. Selective pulmonary angiography of the right lower lobe in a patient with tricuspid atresia and unidirectional Glenn shunt. A, Multiple pulmo- nary arteriovenous malformations. B, One residual pulmonary arteriovenous malformation after trans- catheter coil occlusion. 808 Circulation February 13, 2007 by on June 3, 2008circ.ahajournals.orgDownloaded from
  • 11. significantly lower than normal controls, as determined by a Short Form 36 questionnaire.99 In particular, quality of life was substantially impaired by reoperations, arrhythmias, and thromboembolic events. Pregnancy In the patient with Fontan physiology who contemplates pregnancy, we favor a multidisciplinary approach that in- cludes availability of high-risk obstetric care, specialized cardiology assessment and follow-up, and genetic counseling. In carefully selected candidates with favorable hemodynam- ics, pregnancy may be successfully undertaken with relatively low risk to the mother and fetus.100,101 Careful surveillance is warranted with prompt recognition of symptoms related to systemic venous congestion, increased AV valve regurgita- tion, atrial and ventricular arrhythmias, thromboemboli, and paradoxical emboli if the Fontan is fenestrated.69,100 Noncardiac Perioperative Care Particular vigilance is mandated when noncardiac surgery is required in the patient with Fontan physiology. If present, worsening cyanosis should be addressed prior to surgery. Close monitoring of hemodynamic factors is crucial; pulmo- nary blood flow is dependent on systemic venous pressure and highly sensitive to minor variations in pulmonary vascu- lar resistance, which may be modulated by anesthetics, hypoxemia, atelectasis, thromboemboli, or pneumonia.102 Both excess volume loading and volume depletion with decreased venous return (eg, positive pressure ventilation) should be avoided, and oxygenation optimized. Early in- volvement of experienced anesthesiology and intensive care personnel is essential to prevent complications from changes in preload or pulmonary vascular resistance. Fontan Conversion Surgical revision should be considered in patients with failing Fontan circulations; experienced centers report combined perioperative cardiac transplantation and mortality rates of 2.4% to 6.7%.81,103,104 Perceived advantages of Fontan con- version to a lateral or extracardiac conduit include a lower incidence of atrial arrhythmias and thrombosis related to atrial distension and improved hemodynamics.72,81 Surgery typically involves debulking of the right atrium, removal of thrombus, excision of right atrial scar tissue, epicardial pacemaker implantation, a modified right atrial Maze proce- dure and, in patients with prior documented atrial fibrillation, a left-sided Maze procedure as well.81,105 Left-sided Maze procedures are not routinely recommended, given the longer ischemic time.81,105 Case series with short-term follow-up report promising results, with arrhythmia recurrence rates of 13% to 30%.80,81 Advantages of the extracardiac versus intracardiac lateral tunnel include a decreased incidence of sinus node dysfunc- tion,103 although not consistently so,104,106 and avoidance of potential thromboembolic risk associated with intracardiac prosthetic material.72 If atrial arrhythmias recur, however, access to the arrhythmia substrate via a transbaffle puncture may be considerably complicated by an extracardiac conduit. In our opinion, this constitutes a noteworthy drawback given the real potential for late arrhythmias and limited success with pharmacological therapy (Figure 10). Conclusion “Univentricular heart” denotes a wide variety of rare and complex congenital cardiac malformations whereby both atria predominantly egress into a functional single ventricle. Although most patients will be managed by a staged surgical approach in view of an ultimate Fontan procedure, a minority Figure 10. A 12-lead ECG in a 31-year-old woman with tricuspid atresia, atrial septal defect, ventricular septal defect, and classic mod- ified Fontan later converted to an extracardiac conduit with a right atrial Maze procedure. Recurrent persistent intraatrial reentrant tachycardia with a ventricular response rate of 167 beats per minute was electrically cardioverted. Khairy et al Univentricular Heart 809 by on June 3, 2008circ.ahajournals.orgDownloaded from
  • 12. will not undergo Fontan palliation either because they main- tain reasonably balanced systemic and pulmonary circula- tions or as a result of unfavorable hemodynamics. Manage- ment of the adult with a univentricular heart therefore encompasses a thorough appreciation of diverse anatomic variants, tenuous cardiovascular physiology, multisystemic repercussions of cyanotic heart disease, and postoperative sequelae in surgically palliated patients. Follow-up by dedi- cated multidisciplinary teams with expertise in all facets of adult congenital heart disease is essential to the optimal care of these patients. Although many questions about best med- ical, interventional, and surgical therapies remain, provision of educated care in the current era should ensure that the majority of patients born with univentricular hearts thrive well into their adult years. Acknowledgments The authors wish to thank Drs Patricia Ugolini and Éléonore Paquet, Department of Radiology, Montreal Heart Institute, for their expert assistance in preparing and interpreting cardiac magnetic resonance images. Source of Funding This work was supported in part by the Canada Research Chair in Adult Congenital Heart Disease and Electrophysiology (Dr Khairy). Disclosures None. References 1. Peacock TB. Malformations of the heart. In: Peacock TB, ed. On Malformations of the Human Heart: With Original Cases. London, UK: John Churchill; 1858:10–102. 2. Van Praagh R, Ongley PA, Swan HJ. Anatomic types of single or common ventricle in man: morphologic and geometric aspects of 60 necropsied cases. Am J Cardiol. 1964;13:367–386. 3. Anderson RH, Becker AE, Wilkinson JL. Proceedings: morphogenesis and nomenclature of univentricular hearts. Br Heart J. 1975;37:781–782. 4. Marin-Garcia J, Tandon R, Moller JH, Edwards JE. 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