98th Annual Meeting of the United States & Canadian Academy of PathologyJohn B. Hynes Convention Center, Boston-MA, March 7-13, 2009

Course

CONGENITAL HEART DISEASE: CONGENITAL HEART DISEASE: CHALLENGES AND OPPORTUNITIES CHALLENGES AND OPPORTUNITIES

FOR PATHOLOGISTSFOR PATHOLOGISTS

Chairpersons:Frederick J. Schoen, Boston-MA, US

John P. Veinot, Ottawa, Canada

Hampton Room, Sheraton Boston HotelSaturday March 7, 2009

h.16:00 – 19:00

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Course ContentCourse Content

Congenital Heart Disease: Congenital Heart Disease: Challenges and Opportunities for PathologistsChallenges and Opportunities for Pathologists

Frederick Schoen, Boston-MA, USIntroduction

Gaetano Thiene, Padua, ItalyAnatomy and pathophysiology of CHD

David Brown, Boston-MA, USThe Pediatric Cardiologists’ view of CHD: diagnosis and surgical repairs

William D. Edwards, Rochester-MN, US Postoperative pathology of CHD

Bruce McManus, Vancouver-BC, Canada CHD in adults

Amy Juraszek, Robert Padera, Boston-MA, USDemonstration and hands-on specimens examination

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Anatomy and Pathophysiology of CHDAnatomy and Pathophysiology of CHD

Gaetano Thiene

Cardiovascular PathologyUniversity of Padua Medical SchoolVia A. Gabelli, 61 35121 Padova, Italy Phone:+39-049-827.2283Fax: +39-049-827.2284E-mail: gaetano.thiene@unipd.it

Congenital heart disease (CHD) are structural defects present at birth, with an incidence of nearly 1% of all neonates. They are malformations of cardiac septa and inflow-outflows, as well as wrong sequence of heart segments (veins, atria, ventricles and great arteries).They may result into increased pulmonary blood flow, mixed venous and arterial blood, systolic and/or diastolic overload of the ventricles. Aim of diagnosis is the identification of the anomalies to plan therapeutical procedures, either surgical or interventional, in order to restore correct blood flow, regular heart segments sequence, and to relieve blood obstruction and reflux, with complete separation of the right and left cardiac chambers.

When approaching a baby to make the diagnosis of congenital heart disease, whether in vivo or at autopsy, the sequential chamber localization should be used with the purpose to establish:

1. The visceral situs (solitus, inversus or ambiguous), namely the position of the atria and venous drainages.

2. The atrioventricular connection, whether concordant, discordant or univentricular (double inlet ventricles, mitral or tricuspid atresia).

3. The ventriculo-arterial connection, whether concordant, discordant, double outlet or single outlet (pulmonary atresia, aortic atresia, truncus arteriosus).

Position of the heart is uninfluent on pathophysiology.Anomalies in the sequence of heart segments are known as complex CHD and accounts for nearly 10%. Despite the challenging surgical anatomy, techniques are nowadays available for total repair even in these complex malformations (Fontan and Norwood procedures, atrial and arterial switch operations), with excellent results.

The remaining 90% are CHD with septal defects [atrial (ASD), atrioventricular (AVSD) and ventricular septal defects (VSD), persistent ductus arteriosus (PDA)], septal defects with outflow obstructions [tetralogy of Fallot (TOF), pulmonary stenosis with ASD, subaortic stenosis with VSD] or isolated outlow obstructions [isthmal coarctation, aortic or pulmonary valve stenosis].

In terms of physiopathology, CHD may be classified as follow:1. CHD with increased pulmonary blood flow due to left-to-right shunt. This is the case of

partial anomalous pulmonary venous drainage, isolated septal defects like ASD, AVSD and VSD, truncus arteriosus, PDA. Because of the gradient between pulmonary and systemic

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circulation resistances, a left to right shunt occurs, with the risk of onset of pulmonary vascular disease and reverse shunt (Eisenmenger syndrome with acquired cyanosis). To prevent this complication, repair should be accomplished early in infancy.

2. CHD with decreased pulmonary blood flow due to right to left shunt . This is the case for instance of TOF which combines pulmonary stenosis with VSD, pulmonary valve stenosis with ASD and Ebstein malformation of the tricuspid valve with ASD. The classical type of tricuspid atresia and double inlet ventricles with pulmonary stenosis can also be put in this group.

3. CHD with obstruction in the blood progression without shunt. This is the case of isolated pulmonary valve stenosis, aortic valve stenosis, isthmal coarctation. The major threat consists in systolic ventricular overload with concentric hypertrophy and myocardial impairment.

4. CHD incompatible with the post-foetal life. Foetal circulation, during which the lungs do not function and are almost excluded from circulation, depends on the patency of the foramen ovale, for draining the inferior vena cava blood flow to the left heart, and on the patency of ductus arteriosus, for transferring the blood from the right ventricle to the descending aorta, by-passing the lungs. The pulmonary artery and ductus arteriosus act like a second aorta: whether the aorta or pulmonary artery arise from right or left ventricles (or one of them be atretic) is uninfluential. With starting of lung function and pulmonary circulation at birth and with the closure of ductus arteriosus, the circulatory situation may precipitate as to become incompatible with the extrauterine life. The anomalies of this group include:a) Ductus dependent CHD.

Aortic atresia: with the ductal closure the heart becomes devoid of systemic outlet. Pulmonary atresia: with the ductal closure the lungs are deprived of blood flow. Severe coarctation-interruption of the aortic arch: with the ductal closure the

descending aorta and subdiaphragmatic organs are not perfused.b) Parallel systemic and pulmonary circulation. Complete transposition of the great

arteries in which the small pulmonary circulation is in parallel and not in sequence with the systemic circulation, so that respiratory function is useless.

c) Anomalous connections/obstructions of the pulmonary veins. Total anomalous pulmonary venous drainage. All the pulmonary venous blood flow

does not reach directly on left atrium and the systemic circulation becomes foramen ovale or Arantius ductus dependent, according to the site of the pulmonary venous drainage.

Cor triatriatum. The pulmonary venous blood is obstructed by a fibrous shelf in the left atrium, just underneath the pulmonary veins.

Finally, there are CHD which are asymptomatic or silent until juvenile or adult age. This is the case of bicuspid aortic valve, congenitally corrected transposition, congenital anomalies of coronary arteries, accessory pathways in Wolff-Parkinson-White syndrome. Overall, they are quite frequent, doubling the incidence of CHD, and maybe not innocent, being at risk of sudden cardiac death.

REFERENCES: Thiene G, Frescura C. Codificazione diagnostica e Atlante delle cardiopatie congenite.

Trieste: Ed. Lint, 1984 Marino B, Thiene G. Atlante di anatomia ecocardiografica delle cardiopatie congenite.

Firenze: USES Ed. 1990

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Frescura C, Ho SY, Thiene G. La collezione anatomica di cardiopatie congenite dell’Università di Padova. Padova: CLEUP Ed. 1996

Basso C, Frescura C, Corrado D, Muriago M, Angelini A, Daliento L, Thiene G. Congenital heart disease and sudden death in the young. Hum Pathol 1995;26:1065-1072

Frescura C, Basso C, Thiene G, Corrado D, Pennelli T, Angelini A, Daliento L. Anomalous origin of coronary arteries and risk of sudden death: a study based on an autopsy population of congenital heart disease. Hum Pathol 1998;29:689-695

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The Pediatric Cardiologists’ view of CHD: The Pediatric Cardiologists’ view of CHD: Diagnosis and Surgical RepairsDiagnosis and Surgical Repairs

David W. Brown

Department of CardiologyChildrens Hospital Boston300 Longwood AvenueBoston, MA 02115Phone: 617-355-6429Fax: 617-739-6282Email: david.brown@cardio.chboston.org

Introduction: This lecture will consist of a general overview of the typical imaging modalities available to the pediatric cardiologist in clinical practice, primarily cardiac catheterization, echocardiography, and cardiac magnetic resonance imaging. We will then focus on a few congenital heart malformations in particular, including complete atrioventricular canal defect, tetralogy of Fallot, transposition of the great arteries, and hypoplastic left heart syndrome among other functional single ventricle lesions. We will review the malformations and view examples of imaging of each of these lesions pre-operatively, discuss the typical type and timing of surgical repairs, and briefly show examples of post-operative results. Cardiac Catheterization: Prior to the advent of cardiac ultrasound (echocardiography) in the 1980’s, the diagnosis of congenital heart disease was made by physical examination, electrocardiogram, chest xray, and cardiac catheterization. For decades, diagnostic or hemodynamic catheterization with angiography was the mainstay of diagnosis. Over the past 20 years, diagnostic catheterization has been largely replaced by other non-invasive techniques (generally less expensive, and with no ionizing radiation), and catheterizations have become primarily interventional in nature (such as for balloon dilation of valvular stenoses). Diagnostic catheterization is still the mainstay of diagnosis for certain forms of congenital heart disease such as complex tetralogy of Fallot with aorto-pulmonary collateral vessels, in which selective injection of collateral arteries allows for accurate depiction of the segments of lung supplied by those arteries. Measurement of pulmonary artery pressure and pulmonary vascular resistance can be important in some patients being considered for conversion to a Fontan-type circulation. Echocardiography: The first echocardiographic technique applied to congenital heart disease was M-mode imaging in the late 1970s; however, the information provided proved to be quite limited. During the first half of the 1980s 2-dimensional (2D) echocardiography (echo) became the primary diagnostic modality in pediatric cardiology. The technologic advances in transducer design, image processing, and display, together with development and refinement of new imaging planes and examination technique, allowed high-quality tomographic visualization of most cardiac defects. The application of Doppler ultrasound to investigate blood flow allowed assessment of cardiac output, estimation of pressure gradients, diagnosis of valve regurgitation, direction of flow across shunts, and estimation of intracardiac pressures. The introduction of color-coded Doppler flow mapping over the 2D images greatly improved the ability to obtain hemodynamic and anatomical information in patients with suspected heart disease. Analysis of ventricular function and

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myocardial mechanics has become more precise. The ability to image the heart from the esophagus has rapidly gained an important role in pediatric echo, particularly in the operating room, intensive care unit, in the catheterization laboratory during interventional procedures, and in adolescents and adults with congenital heart disease. New technologies of recent years include intravascular and intracardiac echo, 3D echo, fetal echo, stress echo, Doppler tissue imaging, teleconferencing, and digital archiving of echo data.Cardiac Magnetic Resonance: Although echocardiography is widely used in patients with congenital heart disease, its ability to comprehensively image all the relevant anatomy, particularly the thoracic vasculature, may be limited in some patients. Cardiac magnetic resonance (CMR) has emerged over the past decade as powerful, accurate diagnostic tool in infants, children, and adults with a wide range of congenital heart disease, including functional single ventricle. In addition to excellent spatial and temporal resolution, applications of various techniques such as velocity-encoded cine phase contrast sequences has allowed for estimates of the magnitude of intracardiac shunts and for quantification of atrioventricular or semi-lunar valve regurgitation. Other techniques such as myocardial delayed enhancement have allowed for the detection of scar tissue in the ventricular myocardium.

SPECIFIC LESIONS: Complete Atrioventricular Canal Defect (or Atrioventricular Septal Defect): Endocardial cushion defects involve the septal portions of the tricuspid and mitral valves and the adjacent atrial and ventricular septa. Several classification systems have been used to describe the wide spectrum of resulting malformations, from isolated primum atrial septal defects, isolated cleft mitral valve, to the “complete” form with a primum atrial septal defect, common atrioventricular valve, and atrioventricular canal-type ventricular septal defect. The typical repair is performed at 3-6 months of age, occasionally earlier for those with significant pulmonary vascular congestive symptoms, and most often includes patch closure of the atrial and ventricular septal defect components, septation of the common atrioventricular valve, and closure of the cleft of the left-sided atrioventricular valve. Mortality rates for uncomplicated defects is well less than 4%, and Down Syndrome is no longer a risk factor for survival. Reoperation is required in up to 13%, with most reoperations for left atrioventricular valve regurgitation. Tetralogy of Fallot: Tetralogy of Fallot is the most common cyanotic congenital heart defect (3.2/10,000 live births) and is comprised of the tetrad of infundibular pulmonary stenosis, conoventricular septal defect, overriding aorta, and right ventricular hypertrophy. One common variant (approximately 30%) includes those with pulmonary atresia. Timing of surgical repair for those with pulmonary stenosis is determined to some extent by the degree of right ventricular outflow obstruction, the resting saturation, and any history of hypercynanotic episodes; however, repair in infancy is now considered the norm. The typical repair includes patch closure of the ventricular septal defect and relief of muscular sub-pulmonary and valvar obstruction. Survival for uncomplicated tetralogy repair is quite good, with mortality well under 3%. More recent efforts have included methods to preserve the pulmonary valve, as many patients repaired more than a decade ago have required pulmonary valve replacement for the sequelae of severe pulmonary regurgitation. Transposition of the Great Arteries: D-loop transposition of the great arteries is the second most common cyanotic congenital heart defect (2.4/10,000 live births). With “simple” transposition, the aorta arises from a well-developed conus from the right ventricle, and the pulmonary artery from the left ventricle. From the mid-1960’s until the late1980’s, the surgical procedure of choice were the Mustard or Senning operations, which were “atrial switch” procedures designed to route pulmonary venous blood to the right ventricle, and systemic venous blood to the left ventricle. Surgical mortality was less than 5%, although now well-understood long term complications

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include systemic venous pathway obstruction, a high incidence of atrial dysrhythmias and sinus node dysfunction, and right ventricular dysfunction and failure. These procedures are now rarely performed, as the arterial switch procedure has replaced the atrial switch as the operation of choice for such infants, with mortality rates approaching 1-2% at most centers. Hypoplastic Left Heart Syndrome: Hypoplastic left heart syndrome encompasses a heterogeneous group with varying degrees of mitral and aortic pathology, but which have in common hypoplasia of the left ventricle. Infants with a left heart too small to function as the systemic ventricle typically undergo a series of operations that are designed to allow the right ventricle to function as the systemic ventricle, to create an unobstructed aortic arch, and to have systemic venous blood flow passively through the pulmonary vascular bed (a “Fontan” circulation). The first operation “Stage I” includes atrial septectomy, aortic reconstruction, connection of the native ascending aorta to the pulmonary artery (Stansel anastomosis), and some form of shunt to carry blood from the aorta or right ventricle to the distal main pulmonary artery. The second stage operation (Glenn Operation, typically 4-8 months of age) involves anastomosis of the superior vena cava to the pulmonary artery; the completion Fontan operation (typically age 2-3 years) involves baffling of the inferior vena cava in some fashion to the pulmonary artery. Current survival for the 3 operations together is ~80%, with most mortality occurring in early infancy. Long term outcomes are still an active area of study for these patients.

REFERENCES:

Bogers AJ, Akkesdijk GP, De Jong PL, et al. Results of primary two-patch repair of complete atrioventricular septal defect. J Thor Cardiovasc Surg 1999;18(4):473-9.

Huhta JC, Glasow P, Murphy DJ, Jr., Gutgesell HP, Ott DA, McNamara DG, Smith EO.Surgery without catheterization for congenital heart defects: management of 100 patients. J Am Coll Cardiol 1987; 9:823-9.

Keane JF, Lock JE, Fyler DC. Nadas’ Pediatric Cardiology. Saunders Elsevier, Philadephia PA, 2006.

Norwood WI, Lang P, Hansen DD. Physiologic repair of aortic atresia-hypoplastic left heart syndrome. N Engl J Med 1983;308:23.

Pfammatter JP, Berdat P, Hammerli M, Carrel T. Pediatric cardiac surgery after exclusively echocardiography-based diagnostic work-up. Int J Cardiol 2000; 74:185-90.

Pigula FA, Khalil PN, Mayer JE et al. Repair of tetralogy of Fallot in neonates and young infants. Circulation 1999; 100(19Suppl):II157-61.

Sano S. Ishino K, Kado H et al. Outcome of right ventricle-to-pulmonary artery shunt in first-stage palliation of hypoplastic left heart syndrome: a multi-institutional study. Ann Thorac Surg 2004;78:1951-8.

Tsai-Goodman B, Geva T, Odegard KC, Sena LM, Powell AJ. Clinical role, accuracy, and technical aspects of cardiovascular magnetic resonance imaging in infants. Am J Cardiol 2004; 94:69-74.

Tworetzky W, McElhinney DB, Brook MM, Reddy VM, Hanley FL, Silverman NH. Echocardiographic diagnosis alone for the complete repair of major congenital heart defects. J Am Coll Cardiol 1999; 33:228-33.

Vitiello R, McCrindle BW, Nykanen D, Freedom RM, Benson LN. Complications associated with pediatric cardiac catheterization. J Am Coll Cardiol 1998; 32:1433-40.

Williams WG, McCrindle BW, Ashburn DA et al. Outcomes of 829 neonates with complete transposition of the great arteries 12-17 years after repair. Eur J Cardiothorac Surg 2003; 24(1):1-10.

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Postoperative Pathology of CHDPostoperative Pathology of CHD

William D. Edwards

Department of Laboratory Medicine and PathologyMayo Clinic200 First Street SWRochester, MN 55905, USAPhone: +1-507-284-9342Fax: +1-507-284-1875E-mail: edwards.william@mayo.edu

IntroductionFrom a surgeon’s perspective, congenital heart disease (CHD) includes shunts, obstructions, valvular regurgitation, or combinations of these. And from a pathologist’s perspective, tissue received from such patients can be derived from autopsy or from surgical or biopsy procedures. Operations include partial or complete repairs, palliative procedures, and cardiac transplantation. Over the past 20 years, non-surgical catheter-based interventions have also become available to treat some forms of CHD.

Closure of ShuntsAn ASD may be closed with an operative patch or interventional device; mortality is <1% and in older adults is related to coexistent acquired cardiac disease (such as ischemic, valvular, or hypertensive). Patch closure of an isolated VSD also has <1% mortality. PDA closure has a mortality rate of <1% in premature infants, almost 0% in those <2 years old, and <2% in adults; death in adults is usually related to cardiomegaly or pulmonary hypertension. Atrioventricular septal defect (AV canal) includes partial and complete forms. Operative repair entails closure of the large AV septal defect and reconstruction of the mitral component of the AV valve. Mortality is <4% overall and is often related to mitral valve dysfunction, fixed subaortic stenosis, or arrhythmias.

Relief of ObstructionsRepair of non-critical aortic stenosis by surgical or balloon valvuloplasty is associated with a mortality of 15%, generally due to acute heart failure or acute aortic regurgitation. For non-critical pulmonary stenosis, mortality rates approach 0% for either surgical or balloon valvuloplasty. Coarctation repair has an operative mortality of 5% in infants and 1% for older groups; early deaths are generally attributable to acute heart failure, and late deaths are related to ascending aortic dissection or rupture, ruptured cerebral artery aneurysm, or complications related to a coexistent bicuspid aortic valve.

Ventriculopulmonary ConduitsConotruncal anomalies of the non-transposition type include tetralogy of Fallot, pulmonary atresia with VSD, double outlet RV, and persistent truncus arteriosus. These are usually repaired by closure of the VSD and insertion of a valved conduit (synthetic or homograft) between the RV and the pulmonary arteries. Operative mortality rates are <5% for tetralogy, 10% for PA-VSD and DORV, and 15% for truncus, and death is usually due to acute heart failure. Conduit stenosis is the most common late postoperative complication and is due to bioprosthetic valve calcification. In these anomalies, the ascending aorta is larger than normal and may be

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associated with the late development of appreciable aortic regurgitation, leading to valve replacement.

Arterial Switch ProceduresThe Jatene arterial switch procedure with Lecompte maneuver is applicable for patients with transposition of the great arteries (TGA) and those with DORV and a subpulmonary VSD (Taussig-Bing anomaly). For TGA, the procedure is usually performed during the first week of life. Early and late postoperative mortality rates are <5% each and are most often related to coronary artery injury, RV outflow tract obstruction, or LV failure.

Atriopulmonary ShuntsFor patients with only one functional ventricle (and one hypoplastic ventricle), a modified Fontan procedure can be performed to provide blood flow to the lungs without an intervening ventricle. This entails various types of anastomoses between the atrium receiving caval blood and the pulmonary arteries. Examples of single functional ventricles include tricuspid or mitral atresia, double inlet LV, common inlet RV, aortic valve atresia (hypoplastic left heart syndrome), and pulmonary atresia with an intact ventricular septum. Early and late mortality rates are 10-25% (depending on the anomaly) and 15%, respectively. Death may be due to chronic heart failure, infection, reoperation, arrhythmias, persistent fluid accumulation, or protein-losing enteropathy.

Repair of Regurgitant ValvesThe most common cause of congenital valvular regurgitation is Ebstein’s anomaly of the tricuspid valve. Surgical interventions include valve replacement or valve repair with annuloplasty, with or without reduction right atrioplasty or plication of the atrialized portion of the RV. The most common causes of postoperative death are heart failure and arrhythmias, often in the setting of substantial cardiomegaly. Kinking of the right coronary artery may occur as a complication of the tricuspid annuloplasty procedure.

Overview of Specimen DissectionPathologists who evaluate autopsy specimens from patients with operated congenital heart disease must function as “medical archeologists”, identifying changes that have occurred over time. This involves a detailed evaluation of:(1) the underlying cardiovascular malformations,(2) the state of all interventional procedures, both old and recent,(3) the post-operative enlargement of hypoplastic vessels or chambers, (4) the post-operative regression ventricular hypertrophy & chamber dilatation,(5) the post-operative regression of hypertensive pulmonary vascular disease,(6) the complications of old or recent procedures, including fibrosis or ischemia,(7) evidence of acute or chronic heart failure, (8) evidence of cardiac or extracardiac infections.

Microscopic evaluation of the ventricular myocardium and intra-pulmonary vasculature should be considered routine in patients with operated congenital heart disease. For sections of vessels and valves, an elastic-van Gieson stains should always be obtained.

REFERENCES:Textbooks

Edwards WD. Cardiac anatomy and examination of cardiac specimens. In: Moss and Adams’ Heart Disease in Infants, Children, and Adolescents, Including the Fetus and Young Adult, 7th

ed. HD Allen, DJ Driscoll, RE Shaddy, TF Feltes (ed). Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, 2008:2-34.

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Edwards WD. Classification and terminology of cardiovascular anomalies. In: Moss and Adams’ Heart Disease in Infants, Children, and Adolescents, Including the Fetus and Young Adult, 7th ed. HD Allen, DJ Driscoll, RE Shaddy, TF Feltes (ed). Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, 2008:34-56.

Edwards WD. Congenital heart disease. In Anderson’s Pathology, 10/e, I Damjanov, J Linder (ed). Mosby, St Louis, 1996:1339-1396.

Edwards WD. Pulmonary hypertension & related vascular diseases. In: Vascular Pathology. WE Stehbens, JT Lie (ed). Chapman and Hall, London, 1995:585-621.

Kouchoukos NT, Blackstone EH, Doty DB, Hanley FL, Karp RB. Kirklin/Barratt-Boyes Cardiac Surgery: Morphology, Diagnostic Criteria, Natural History, Techniques, Results, and Indications, 3/e. Churchill Living-stone, Philadelphia, 2003:715-1625.

Journals Becker AE, Essed CE. The heart after surgery for congenital heart disease. Am J Cardiovasc

Pathol 1988;1:301-17. Berdat PA, Immer F, Pfammatter J-P, Carrel T. Reoperations in adults with congenital heart

disease: analysis of early outcome. Int J Cardiol 2004;93: 239-45. Daliento L, Rebellato L, Angelini A, Frescura C, Mazzotti E, Rotundo M, Thiene G. Fatal

outcome in Eisenmenger syndrome. Cardiovasc Pathol 2002;11:221-8. Nieminen HP, Jokinen EV, Sairanen HI. Causes of late deaths after pediatric surgery: a

population-based study. J Am Coll Cardiol 2007:50: 1263-71 Sun C-CJ, Alonsonzana G, Love JC, Li L, Straumanis JP. The value of autopsy in pediatric

cardiology and cardiovascular surgery. Hum Pathol 2003;34:491-6.

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Adult CHDAdult CHD

Bruce McManus

The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research University of British Columbia - St. Paul’s HospitalRoom 166 - Burrard Building, 1081 Burrard StreetVancouver, British Columbia, V6Z 1Y6 CANADAVoice: 1 604 806 8586 or 1 604 806 9853Fax: 1 604 806 9274Email: bmcmanus@mrl.ubc.ca

IntroductionDramatic changes have occurred over the past 70 years in the management of patients with congenital heart disease (CHD). From the time of the first successful ligation of a patent ductus arteriosus in 1938, here in Boston, to the development of successful of shunt operations for patients with pulmonary oligemia, to elaborate staged procedures to salvage those with hypoplastic left heart syndrome, to the capacity to close various septal defects, and to provide a range of hemodynamical, biomaterials and electrophysiological innovations, the patients with congenital heart and circulatory lesions have been greatly benefited. In many ways, it has been a miraculous era of progress. The consequences of this progress are mirrored in amazing statistics…whereas 50 years ago it was uncommon for children with CHD to live past their first birthdays, it is now the rule of thumb that nearly all such children (>85%) will live until adulthood. While approximately 800,000 adults were living with CHD in the USA alone in 2001 (Warnes CA et al. Task force 1: the changing profile of congenital heart disease in adult life. J Am Coll Cardiol 2001;37:1170-1175), there are now more than a million such patients, out-numbering their pediatric counterparts. Such numbers are reflected in a prevalence of those living with adult CHD that has reached >4 per 1000 population in the USA and Canada, a prevalence similar to that for congenital heart disease overall.

Training and Education In light of the large and continuously expanding population of adult patients with CHD, there has evolved a significant professional educational and training effort focused on these patients. Pioneering efforts in 1959 at the Toronto General Hospital led to the creation of a clinic focused on patients with adult congenital heart disease. In 1991, 14 regional centres across Canada joined together to form the Canadian Adult Congenital Heart (CACH) Network www.cachnet.org. Creation of such a network in the USA was recommended at an NHLBI workshop on research into adult CHD held in 2004. In a survey study of USA adult and pediatric cardiology training programs, Gurvitz MZ et al. (Variations in adult congenital heart disease training in adult and pediatric cardiology fellowship programs. J Am Coll Cardiol, 2005; 46:893-898) found nine adult and 2 pediatric programs that offered adult CHD fellowships, and only 31 adult and 11 pediatric fellows pursued advanced CHD training in the last 10 years. In the most recent ACC task force report (Childs JS et al. Task Force 9: Training in the care of adult patients with congenital heart disease. J Am Coll Cardiol, 2008; 51:389-393), the authors outlined levels of training required for those cardiologists involved in care of adults with CHD. The core curriculum for the basic level (Level 1) is reproduced here (Table 1). It emphasizes topics that are also relevant to cardiac pathologists in

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terms of modified anatomical lesions, as well as background knowledge and arenas in which caregivers may need our support. Indeed, the Canadian Adult Congenital Heart Disease Network, in its 2001 guidelines for adult CHD care includes in its description of the “Ideal National Adult Congenital Heart Disease Centre” a cardiac pathologist with substantial experience in congenital heart malformations.

Table 1 Level 1 Training in Congenital Heart Disease in Adults

Core Curriculum Knowledge Areas

Basic science Basic embryology, anatomy, pathology, physiology, geneticsNatural history/management

Clinical recognition and management of patients with common defects presenting in adulthood to include genetic counseling, care of pregnancy, and management during noncardiac surgery

Post-operative residua/sequelae

Includes but is not limited to specific diagnoses such as tetralogy of Fallot, atrial septal defects, ventricular septal defects, transposition of the great arteries (e.g., atrial baffle and arterial switch operations), single ventricle (e.g., Fontan operation), and ventricular outflow tract lesions (all levels of aortic and pulmonic stenosis and coarctation of the aorta)

Other Indications for and access to local or regional expert consultation

There are several illustrative programs where attempts are being made to prepared clinicians for the challenges of caring for the diverse adult patients with CHD. One such program is the Boston Adult Congenital Heart Disease (BACH) and Pulmonary Hypertension service, www.childrenshospital.org/clinicalservices, an internationally recognized multi-departmental, multi-institutional clinical service which functions for the benefit of both adult CHD patients and for those with pulmonary hypertensive disorders. The Toronto Congenital Cardiac Centre for Adults and Pacific Adult Congenital Heart (PACH) Program based at St. Paul’s Hospital in Vancouver are corresponding programs where similar training can be accessed. Enrollment of additional talented young clinicians in such training centres is rather urgently needed based on observations of sub-standard care for adults with CHD in North America and Europe. By example, the Euro Heart Survey on Adult Congenital Heart Disease obtained data from 71 voluntarily participating European centres that detailed their care practices for such patients. Forty-eight of the centres were specialist centres and 23 were non-specialist centres; only 19% of the specialist centres complied with defined current standards for optimal care structure (Moons P et al. Eur Heart J 2006 27:1324-1330. Fortunately, there are resources such as Laks H et al. Adult congenital heart disease. In Cohn LH, 3rd Ed. Cardiac Surgery in the Adult. New York: McGraw-Hill, 2008:1431-1464. For the pathologist, this latter chapter is very relevant and helpful in thinking about what anatomical features are most challenging or important to clinicians in these patients. As well, the two editions of the volume edited by WC Roberts, Adult Congenital Heart Disease, provide a strongly anatomical resource for pathologists and clinicians alike. Important topics related to cardiac pathologies involving the adult heart and accrued post-natally are covered thoroughly by Schoen FJ and Padera RF Jr. in Chapter 5, Cardiac surgical pathology in an earlier volume in the same series (Cohn LH, Edmunds LH Jr, eds. Cardiac Surgery in the Adult. New York: McGraw-Hill, 2003:119-185). It is on this background of “the chronic diseases with normal anatomy” that an understanding of CHD in the adult must be built.

PATHOLOGICAL CONDITIONS

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Atrial Septal DefectAtrial septal defect (ASD) occurs as an error in the developmental process when there is an incomplete separation between the left and the right atrium. The ostium primum ASD is the result of the deficiency or absence of the most apical portion of the atrial septum. The ostium secundum ASD results from a deficiency of fossa tissue and/or effacement of the limbic bands in the fossa ovale region. The sinus venosus ASD may exist in the upper atrial septum with connection of the right pulmonary vein to the right atrium and may be associated with anomalous right upper pulmonary veins.In ASDs, shunt flow can occur in both systole and diastole and can flow from left to right or right to left. Blood in each atrium can either flow through the AV valve to the ventricle or across the defect and fill the opposite ventricle. Ventricular chamber compliance is the determinant factor of the direction of flow across the ASD during diastole. Being physiologically hypertrophied, the left ventricle is less compliant than the right ventricle, so blood in the left atrium is more likely to fill the more compliant right ventricle. When the right ventricle loses its compliance due to other pathological processes, such as congenital obstructions in the pulmonary arteries or veins, the shunt flows from right to left. During systole, the differential compliances of the atria and other defects, such as valve regurgitation, determine the flow of shunt. The size of the ASD determines the volume of shunt.Atrial arrhythmias may be the first presenting sign of an ASD due to the stretching of or damage to the conduction system. The most common complaint of a patient with an ASD is progressive shortness of breath because the pulmonary circulation often experiences volume overload. Other symptoms may relate to paradoxical embolism, which may occur when thrombi enter the right heart and pass across the atrial septum into the systemic circulation.

Ventricular Septal DefectImproper embryological development of the ventricular septum results in ventricular septal defect (VSD). The most common VSD is the perimembranous VSD, which occurs in the location where all septal components fuse. Excessive fetal muscular resorption results in the next most frequent type of VSD, the muscular septum VSD. The less common VSDs include endocardial-cushion VSDs which are often associated with AV valve insufficiency.The direction and the volume of systolic flow across the VSD depend on the comparative resistance between the usual ventricular and the VSD outflow tracts as well as the size of the defect. A left-to-right shunt may result from a large VSD along with a low pulmonary vascular resistance as compared to the systemic circulation, and vice versa. In addition, left ventricular output is reduced in a left-to-right shunt. To compensate for this reduction and to maintain a normal cardiac output, high left ventricular volumes and subsequent elevated left atrial filling pressures result. These consequences may cause pulmonary venous congestion. Diastolic flow direction across the VSD depends on the relative chamber volumes and compliance, and differences in ventricular contractile and relaxation properties. In patients with small VSDs, infective endocarditis may occur at the rim of the VSD and relate to injury of the endocardium from ejection of blood under pressure. Also, progressive aortic insufficiency may result from aortic cusp prolapse. With large VSDs, patients often experience a spectrum of symptoms from congestive heart failure. They are also susceptible to developing pulmonary vascular disease which can progress to Eisenmenger’s syndrome. Cyanosis is often present when there is a significant shunt from the right ventricle through the VSD to the aorta.

Patent Ductus ArteriosusThe ductus arteriosus is a tubular arterial structure connecting the aorta and the main pulmonary artery in the fetal circulation. Patent ductus arteriosus (PDA) occurs when the lumen of the ductus

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fails to obliterate after birth, leaving an arterial connection between the systemic and pulmonary circulations.The shunt direction and volume depend on the relative resistances between the normal and the PDA pathway as well as the size of the PDA. In most PDA patients, the shunt flows from left-to-right (aorta to main pulmonary artery) due to the significantly higher systemic resistance as compared to the pulmonary resistance. Similar to patients with VSDs, to supply a normal cardiac in a left-to-right-shunt, pulmonary venous congestion may result from elevated left ventricular volume and left atrial filling pressures. In patients with large PDAs, symptoms of congestive heart failure are commonly seen with progression to Eisenmenger’s syndrome. Differential cyanosis, wherein hypoxemia is only seen in the lower body, can also be observed when the pulmonary vascular resistance rises and a right-to-left shunt develops. There are essentially no clinical symptoms or signs in patients with small PDAs, except for those related to the occurrence of endarteritis.

Coarctation of the AortaCoarctation of the aorta is a congenital tubular narrowing of the aorta that occurs just distal to the origin of the left subclavian artery at the site of the fetal ductus arteriosus insertion. Some associated lesions include bicuspid aortic valve, patent ductus arteriosus, and atrial and ventricular septal defects.The most common form of coarctation of the aorta seen in adults creates an increased afterload for the left ventricle and a maldistribution of blood flow that leads to upper body hypertension and lower body hypotension. The renal system is triggered to restore perfusion pressure experienced caudally, and the result is elevated blood pressure proximal to the coarct. The development of collateral arterial circulation to supply the under-arterialized lower body also occurs.Because the coarctation of the aorta may be characterized by systemic hypertension in the upper body and lower body cyanosis (depending on the location of the coarctation), patients with such a condition are predisposed to premature coronary artery disease and also to cerebral berry aneurysm. Depending on the direction of the shunt, congestive heart failure and pulmonary vascular obstructive disease may occur.

Tetralogy of FallotTetralogy of Fallot (TF) is an embryological defect that involves the spiral septum being displaced rightward and anteriorly. It is the most common complex cyanotic congenital heart defect characterized by a large ventricular septal defect, an overriding aorta, obstruction of the right ventricular outflow tract, and right ventricular hypertrophy. Other common additional associations include right aortic arch, atrial septal defect, and coronary arterial anomalies.The direction and magnitude of blood flow in TF patients are determined by the systemic vascular resistance. In most patients, the systemic vascular resistance is low while the resistance in the right ventricular outflow tract is high due to the obstruction. This results in right-to-left shunting in majority of patients. Left-to-right shunt occurs when systemic resistance is increased. Cyanosis, dyspnea, and limited exercise tolerance are the most common symptoms of TF patients. The severity of these symptoms is determined by the degree of obstruction of the right ventricular outflow tract. Other complications include erythrocytosis, hyperviscosity, cerebral abscesses, and endocarditis. Patients with repaired TF are usually asymptomatic, but they are at risk for other chronic complications such as pulmonary regurgitation, aneurysm, and residual or recurrent obstruction of the right ventricular outflow tract, as well as late arrhythmias.

Transposition of the Great Arteries

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L-transposition of the great arteries (L-TGA) results in the development of the right ventricle on the left side of the fetal heart and the left ventricle on the right side of the heart. Hence, the morphological right ventricle receives blood from the left atrium and pumps it into the aorta, while the left ventricle receives flow from the right atrium and delivers oxygenated blood to the pulmonary circulation. The aortic root in this case arises from the right ventricle and is anterior and leftward (L-transposed) relative to the pulmonary artery root. L-TGA is often associated with ventricular septal defects and pulmonary outflow obstructions. Late failure of right ventricle and tricuspid regurgitation are often evident in L-TGA patients due to the high resistance in the systemic arterial circuit, similar to the physiological consequences observed with left ventricular failure and mitral regurgitation in the anatomically normal heart. D-transposition of the great arteries (D-TGA) is another embryological malformation in which the aorta arises from the right ventricle and the pulmonary artery arises from the left ventricle. Hence, deoxygenated blood from venous return is directly returned to the aorta and bypassing the oxygenation process in the lungs. Similarly, the oxygenated blood from the pulmonary system loops back to the lungs without delivering any oxygen to the body. In this case, the aortic root is anterior and to the right (D-transposed) of the pulmonary artery. It often occurs without other associated cardiac anomalies, but defects such as atrial septal defect and patent ductus arteriosus have been noted. Cyanosis, arterial acidosis, and hypoxemia are commonly seen in D-TGA patients. Pulmonary vascular obstructive disease can also occur from the elevated left ventricular pressure.

Single Ventricle and Fontan CirculationThe Fontan operation is the preferential palliative procedure to help patients with functional single ventricles. It helps patients live to adulthood by rerouting the systemic venous return in order to completely bypass the right heart. The Fontan circulation typically involves three stages of palliation. The first stage reroutes the systemic venous return to achieve a complete mixing of systemic and pulmonary venous return, an unobstructed flow to the ventricle and the systemic circulation, and a source of pulmonary blood flow. The second stage is known as the bidirectional Glenn shunt or hemi-Fontan procedure. It redirects superior vena caval flow directly to the pulmonary arteries. The final stage is the Fontan operation in which the inferior vena caval flow is redirected away from the atrium to the pulmonary arteries. After the initial palliation, many patients experience ongoing cyanosis and hypervolumic ventricles. Respectively, this is due to the complete mixing of systemic and pulmonary venous blood and the necessity of having enough volume of blood to pump to both the systemic and pulmonary circuits. The hemi-Fontan procedure increases the systemic oxygen saturations due to the more effective oxygenation of the venous return. Also, volume loading of the ventricle is eliminated because it only pumps blood to the systemic circulation. The Fontan operation allows for full saturation of oxygen in these patients. Low pulmonary resistance is critical in a Fontan circulation. Increase in resistance due to circulatory issues leads to higher systemic venous pressures. This in turn results in a spectrum of symptoms of right heart failure such as fluid retention, low cardiac output, and systemic venous congestion.

Ebstein AnomalyEbstein anomaly is a congenital abnormality of the tricuspid valve that results in an “atrialized” right ventricle. The leaflets are malformed and displaced into the right ventricle. Most patients with Ebstein anomaly also have an associated atrial septal defect or patent foramen ovale. The two significant hemodynamic outcomes of Ebstein anomaly are the reduced functional size of the right ventricle and the regurgitation of the tricuspid valve. They in turn lead to increased

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impedance to right ventricular filling, elevated right atrial filling pressures, and venous congestion in severe forms. In addition, right-to-left shunting may occur due to the interatrial communication. Clinical symptoms are highly variable ranging from asymptomatic to severe heart failure. Some patients may present with a murmur of tricuspid regurgitation, supraventricular tachycardia, cyanosis, or systemic venous congestion. The interarterial right-to-left shunt may lead to systemic arterial hypoxemia.

Current Issues in the Pathophysiology of Adult CHDThere is considerable evidence that replacement of pulmonary valves in corrected tetralogy of Fallot and related conditions improves prognosis. In this regard, the latest approach is to achieve percutaneous replacement with one of the prostheses on the market. As with all prostheses, they require evaluation for failures. The AmplatzerTM ASD closure device has significant utility, but there have been some late heart perforations resulting in death, a rare embolization, and occasional sizing challenge.Stent dilatation of native and residual coarcts is now common and may be associated with particular anatomic consequences.Fontan circulations are now commonly failing in adult patients with CHD. These failures are a significant challenge as they must be revised, or the patient may need to undergo heart transplantation or destination ventricular assist device implantation.

KEY MESSAGE:1) Adults living with congenital heart disease (CHD) are numerous, at a prevalence of about 4 per

1000 population; many of these patients are now > age 40 years.2) Typically, these adult CHD patients have had or require one or more invasive interventions,

and thus most of them have modified anatomy and physiology.3) Despite professional education programs aimed at cardiologists, surgeons, radiologists,

pathologists and others to improve awareness of “grown up kids” with CHD, there is still a paucity of caregivers who feel competent with these patients.

4) An appreciation by pathologists of the main types of clinically-modified congenital lesions seen in adult patients with CHD is of great importance in terms of helping clinicians understand why patients ultimately die (often prematurely), in explaining the dysfunction and deterioration of biomaterials and devices required for care.

5) Among the most common lesions observed in adults, atrial and ventricular septal defects, patent ductus arteriosus, coarctation of the aorta, tetralogy of Fallot, pulmonary atresia, transposition of the great arteries, single ventricle and Fontan circulation and Ebstein anomaly are worthy of mention.

6) General considerations needing attention for patients with adult CHD include tracking and followup, pregnancy guidance and counseling, non-cardiac surgery risks, thrombosis, pulmonary hypertension, endocarditis risk and arrhythmia management. Pathologists may contribute to supporting the families who are affected. As well, many of the adult patients with CHD now live long enough to develop atherosclerosis and all its attendant morbidities and pathologies.

REFERENCES: Anderson RH, Ho SY. The postoperative pathology of congenital heart disease. Cardiol

Young, 1993;3:147-157.

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Bedard E, Shore DF, Gatzoulis MA. Adult congenital heart disease: a 2008 overview. Brit Med Bull, 2008;85:151-180.

Brickner ME, Hillis, LD, Lange RA. Congenital heart disease in adults - first of two parts. N Engl J Med, 2000;342:256-263

Brickner ME, Hillis, LD, Lange RA. Congenital heart disease in adults - second of two parts. N Engl J Med, 2000;342:334-342

Canadian Adult Congenital Heart (CACH) Network www.cachnet.org. Childs JS et al. Task force 9: Training in the care of adult patients with congenital heart

disease. J Am Coll Cardiol, 2008; 51:389-393. Dearani J et al. Caring for adults with congenital heart disease: successes and challenges for

2007 and beyond. Cardiol Young, 2007;17(Suppl 2):87-96. D’Udekem Y et al. The Fontan procedure: contemporary techniques have improved long-

term outcomes. Circulation, 2007;116:I-157-I-164. Ghai A et al. Outcomes of late atrial tachyarrhythmias in adults after the Fontan operation J

Am Coll Cardiol. 2001; 37:585-592. Graham TP. The year in congenital heart disease. J Am Coll Cardiol, 2008;52:1492-1499. Gurvitz MZ et al. Variations in adult congenital heart disease training in adult and pediatric

cardiology fellowship programs. J Am Coll Cardiol, 2005;46:893-898. Hildick-Smith DJR, et al. Amplatzer device closure of atrial septal defects in mature adults:

analysis of 76 cases. Heart, 2004;90:334–335. Hockings BEF, Wilkinson JL, Blanton. AmplatzerTM atrial septal septal defect closure device

used in adult patients. Heart Views, 2000;1:248-250. Laks H et al. Chapter 61, Adult congenital heart disease. In Cohn LH, 3rd Ed. Cardiac Surgery

in the Adult. New York: McGraw-Hill, 2008:1431-1464. Meijboom FJ et al. Consequences of a selective approach toward pulmonary valve

replacement in adult patients with tetralogy of Fallot and pulmonary regurgitation. J Thorac Cardiovasc Surg, 2008;135:50-55

Mulder BJM, de Winter RJ, Wilde AAM. Percutaneous pulmonary valve replacement: a new development in the lifetime strategy for patients with congenital heart disease. Neth Heart J, 2007;15: 3–4.

Moons P et al. Delivery of care for adult patients with congenital heart disease in Europe: results from the Euro Heart Survey. Eur Heart J, 2006 27:1324-1330.

Piechaud J-C. Stent implantation for coarctation in adults. J Interven Cardiol, 2003;16:413–418.

Rhodes JF, Hijazi ZM, Sommer RJ. Pathophysiology of congenital heart disease in the adult: part II: Simple obstructive lesions. Circulation, 2008;117:1228-1237.

Roberts WC. Adult Congenital Heart Disease, Philadelphia: F.A. Davis Company, 1987: 1-752.

Schoen FJ and Padera RF Jr. Chapter 5, Cardiac surgical pathology. In Cohn LH, Edmunds LH Jr, eds. Cardiac Surgery in the Adult. New York: McGraw-Hill, 2003:119-185.

Sommer RJ, Hijazi ZM, Rhodes JF Jr. Pathophysiology of congenital heart disease in the adult: part I: Shunt lesions. Circulation, 2008;117:1090-1099.

Sommer RJ, Hijazi ZM, Rhodes JF. Pathophysiology of congenital heart disease in the adult: part III: Complex congenital heart disease. Circulation, 2008;117:1340-1350.

Veldtman GR et al. The Fontan procedure in adults. Heart, 2001;86:330-335. Warnes CA et al. Task force 1: the changing profile of congenital heart disease in adult life.

J Am Coll Cardiol 2001;37:1170-1175. Warnes CA et al. ACC/AHA 2008 guidelines for the management of adults with congenital

heart disease. J Am Coll Cardiol, 2008;52:e1-e121.

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20

Specimen demonstration and Hands-onSpecimen demonstration and Hands-on examinationexamination

Amy L. Juraszek

Children's Hospital BostonHarvard Medical School300 Longwood AvenueBoston, MA 02115617-355-5961 phone617-730-0207 faxAmy.Juraszek@cardio.chboston.org

Robert Padera

Department of Pathology Brigham and Women's Hospital 75 Francis Street Boston, MA 02115 Phone: (617) 732-7510 Email: rpadera@partners.org

We will briefly review the pertinent anatomical features of congenital heart malformations discussed in this symposium, then allow time for session attendees to individually examine heart specimens from the collections of the Cardiac Registry at Children's Hospital Boston and Brigham and Women’s Hospital.

Fetal heart specimens will be used to illustrate preoperative anatomy of several common malformations including hypoplastic left heart syndrome, tetralogy of Fallot, truncus arteriosus, common atrioventricular canal defects and ventricular septal defects. Heterotaxy syndrome includes a large spectrum of disease and common malformations encountered with heterotaxy will be demonstrated. Typical surgical repairs will be illustrated including the single ventricle palliation procedures of Norwood, Sano, Bidirectional Glenn and lateral tunnel Fontan. D-Transposition operations including Mustard, Senning and arterial switch will be demonstrated.

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