Surgical Considerations for Patients with Heterotaxy Syndrome PCICS December 10, 2014 Surgical Considerations for Patients with Heterotaxy Syndrome Jeffrey P. Jacobs, M.D., FACS, FACC, FCCP Professor of Surgery, Johns Hopkins University Director, Andrews/Daicoff Cardiovascular Program, Surgical Director of Heart Transplantation and Extracorporeal Life Support Programs, Johns Hopkins All Children’s Heart Institute

Disclosure Chair of the STS Database Access and Publications Taskforce Chair of the STS Database Task Force on Longitudinal Follow-up and Linked Registries Chair of the STS Database Public Reporting Task Force

Objectives Define Heterotaxy Syndrome Understand the “outcomes” of surgical procedures commonly performed patients with Heterotaxy Syndrome

Two Manuscripts Jacobs JP, Anderson RH, Weinberg P, Walters III HL, Tchervenkov CI, Del Duca D, Franklin RCG, Aiello VD, Béland MJ, Colan SD, Gaynor JW, Krogmann ON, Kurosawa H, Maruszewski B, Stellin G, Elliott MJ. The nomenclature, definition and classification of cardiac structures in the setting of heterotaxy. In 2007 Supplement to Cardiology in the Young: Controversies and Challenges Facing Paediatric Cardiovascular Practitioners and their Patients, Anderson RH, Jacobs JP, and Wernovsky G, editors. Cardiology in the Young. 2007 Sept; 17(Suppl 2):1–28, doi: 10.1017/S1047951107001138.. Jacobs JP, Pasquali SK, Morales DLS, Jacobs ML, Mavroudis C, Chai PJ, Tchervenkov CI, Lacour-Gayet FG, Walters III H, Quintessenza JA. Heterotaxy: Lessons Learned About Patterns of Practice and Outcomes From the Congenital Heart Surgery Database of the Society of Thoracic Surgeons. The World Journal for Pediatric and Congenital Heart Surgery (WJPCHS). 2011 April; 2(2):278-286. DOI: 10.1177/2150135110397670.

Cardiac Connections – Sequential Segmental Approach (Anderson) Atrial arrangement, Atrioventricular connections, and Ventriculoarterial connections

Atrial Arrangement Robert Anderson

Atrioventricular Connections Robert Anderson

Atrioventricular Connections Normal atrioventricular connections (Concordant atrioventricular connections in biventricular heart) Discordant AV connections Absent left sided AV connection Absent right sided AV connection Double inlet AV connection Double inlet AV connection, Double inlet LV Double inlet AV connection, Double inlet RV Mixed ("Ambiguous") AV connections (biventricular)

Ventriculoarterial Connections Normal ventriculoarterial connections (Concordant ventriculoarterial connections in biventricular heart) Discordant VA connections (TGA) Single outlet VA connection, Common arterial trunk Single outlet VA connection, Single outlet VA connection via aorta (pulmonary atresia) Single outlet VA connection, Single outlet VA connection via pulmonary trunk (aortic atresia) Double outlet VA connections, Double outlet LV Double outlet VA connections, Double outlet RV Concordant VA connections with parallel great arteries (anatomically corrected malposition)

Concordant Atrioventricular Connections with Discordant Ventriculoarterial Connections (TGA) Robert H. Anderson, Paul M. Weinberg. The clinical anatomy of transposition. In: Jacobs JP, Wernovsky G, Gaynor JW, and Anderson RH (editors). 2005 Supplement to Cardiology in the Young: Controversies of the Ventriculo-Arterial Junctions and Other Topics, Cardiology in the Young, Volume 15, Supplement 1: 1 - 198, February 2005.

These variables are separately specified. Jacobs JP, Anderson RH, Weinberg P, Walters III HL, Tchervenkov CI, Del Duca D, Franklin RCG, Aiello VD, Béland MJ, Colan SD, Gaynor JW, Krogmann ON, Kurosawa H, Maruszewski B, Stellin G, Elliott MJ. The nomenclature, definition and classification of cardiac structures in the setting of heterotaxy. In 2007 Supplement to Cardiology in the Young: Controversies and Challenges Facing Paediatric Cardiovascular Practitioners and their Patients, Anderson RH, Jacobs JP, and Wernovsky G, editors. Cardiology in the Young. 2007 Sept; 17(Suppl 2):1–28, doi: 10.1017/S1047951107001138.. Specification of the atrial arrangement, the atrioventricular connections, and the ventriculoarterial connections, does not specify nor imply the ventricular topology, or the relationships of the cardiac chambers and great arteries in space. These variables are separately specified.

Cardiac Relations - Segmental Approach (Van Praagh & Vlad) the sidedness of the atrial chambers, or, in other words, the atrial “situs”, the ventricular topology, in other words, the ventricular “loop”, and the relationships of the arterial trunks in space

Cardiac Relations - Segmental Approach (Van Praagh & Vlad) The viscera and atria: The types of visceroatrial situs S solitus I inversus A ambiguus The ventricular topology D D-loop ventricles, L L-loop ventricles Great vessels: The great arterial position S solitus I inversus D dextro L levo

Visceral Situs Associate Professor of Pediatrics William T. Mahle, MD Associate Professor of Pediatrics Emory University School of Medicine

Norman H Silverman Stanford University Lucile Packard Children’s Hospital

Morphologically Right Ventricle Robert Anderson Morphologically Right Ventricle

Morphologically Left Ventricle Robert Anderson Morphologically Left Ventricle

VENTRICULAR TOPOLOGY – Robert Anderson Right hand Left hand

The anatomic subtypes that are included in this nomenclature include: Jaggers JJ, Cameron DE, Herlong JR, et al: The Society of Thoracic Surgeons Congenital Heart Surgery Nomenclature and Database Project: transposition of the great arteries, Ann Thorac Surg 69(suppl):S205, 2000. In: Mavroudis C, Jacobs JP. Congenital Heart Surgery Nomenclature and Database Project: Ann Thorac Surg. 2000 Apr;69(4 Suppl):S1-372. Anatomic types of transposition of the great arteries (TGA) as described by Van Praagh and colleagues The anatomic subtypes that are included in this nomenclature include: TGA {S,D,D}; TGA {S,D,A}; TGA {S,D,L}; TGA {I,L,L}; TGA {I,L,D}; {A,L,L} {A,D,D} (Those with situs ambiguous technically cannot be TGA as described by Van Praagh, but may be physiologically uncorrected and appropriately treated by existing standard therapies for TGA)

These variables are separately specified. Jacobs JP, Anderson RH, Weinberg P, Walters III HL, Tchervenkov CI, Del Duca D, Franklin RCG, Aiello VD, Béland MJ, Colan SD, Gaynor JW, Krogmann ON, Kurosawa H, Maruszewski B, Stellin G, Elliott MJ. The nomenclature, definition and classification of cardiac structures in the setting of heterotaxy. In 2007 Supplement to Cardiology in the Young: Controversies and Challenges Facing Paediatric Cardiovascular Practitioners and their Patients, Anderson RH, Jacobs JP, and Wernovsky G, editors. Cardiology in the Young. 2007 Sept; 17(Suppl 2):1–28, doi: 10.1017/S1047951107001138.. Specification of the atrial “situs”, the ventricular “loop”, and the relationships of the arterial trunks in space does not specify the atrioventricular and ventriculoarterial connections. These variables are separately specified.

Cardiac Position

Cardiac Position Can be surgically important – for example – Pathway for extracardiac Fontan Dextrocardia (right sided ventricular mass) Levocardia (left sided ventricular mass) Mesocardia (central/midline ventricular mass) Dextroversion (ventricular apex points to the right) Levoversion (ventricular apex points to the left)

Jacobs JP, Anderson RH, Weinberg P, Walters III HL, Tchervenkov CI, Del Duca D, Franklin RCG, Aiello VD, Béland MJ, Colan SD, Gaynor JW, Krogmann ON, Kurosawa H, Maruszewski B, Stellin G, Elliott MJ. The nomenclature, definition and classification of cardiac structures in the setting of heterotaxy. In 2007 Supplement to Cardiology in the Young: Controversies and Challenges Facing Paediatric Cardiovascular Practitioners and their Patients, Anderson RH, Jacobs JP, and Wernovsky G, editors. Cardiology in the Young. 2007 Sept; 17(Suppl 2):1–28, doi: 10.1017/S1047951107001138.. “Heterotaxy is synonymous with “visceral heterotaxy” and “heterotaxy syndrome”. Heterotaxy is defined as an abnormality where the internal thoraco-abdominal organs demonstrate abnormal arrangement across the left-right axis of the body. By convention, heterotaxy does not include patients with either the expected usual or normal arrangement of the internal organs along the left-right axis, also known as “situs solitus”, nor patients with complete mirror-imaged arrangement of the internal organs along the left-right axis also known as “situs inversus”.”

LATERALIZED BODILY ARRANGEMENT 1 2 3 1 2 3 RAA LAA RAA LAA Liver Stomach Spleen Liver Stomach Spleen Mirror-imagery Usual Robert Anderson Supported by:

Isomerism In chemistry, isomers are defined as different compounds that have the same molecular formula. Isomers are classified as enantiomers when their molecules are mirror reflections of each other .

Jacobs JP, Anderson RH, Weinberg P, Walters III HL, Tchervenkov CI, Del Duca D, Franklin RCG, Aiello VD, Béland MJ, Colan SD, Gaynor JW, Krogmann ON, Kurosawa H, Maruszewski B, Stellin G, Elliott MJ. The nomenclature, definition and classification of cardiac structures in the setting of heterotaxy. In 2007 Supplement to Cardiology in the Young: Controversies and Challenges Facing Paediatric Cardiovascular Practitioners and their Patients, Anderson RH, Jacobs JP, and Wernovsky G, editors. Cardiology in the Young. 2007 Sept; 17(Suppl 2):1–28, doi: 10.1017/S1047951107001138.. “Isomerism in the context of the congenitally malformed heart is defined as a situation where some paired structures on opposite sides of the left-right axis of the body are, in morphologic terms, symmetrical mirror images of each other”

? ? ? ? VISCERAL HETEROTAXY 1 1 2 3 2 “Polysplenia” “Asplenia” Mid-line Liver Mid-line Liver Malrotated gut Malrotated gut “Polysplenia” “Asplenia” Robert Anderson Supported by:

Isomeric Lungs

Isomeric Bronchial Arrangements

Jacobs JP, Anderson RH, Weinberg P, Walters III HL, Tchervenkov CI, Del Duca D, Franklin RCG, Aiello VD, Béland MJ, Colan SD, Gaynor JW, Krogmann ON, Kurosawa H, Maruszewski B, Stellin G, Elliott MJ. The nomenclature, definition and classification of cardiac structures in the setting of heterotaxy. In 2007 Supplement to Cardiology in the Young: Controversies and Challenges Facing Paediatric Cardiovascular Practitioners and their Patients, Anderson RH, Jacobs JP, and Wernovsky G, editors. Cardiology in the Young. 2007 Sept; 17(Suppl 2):1–28, doi: 10.1017/S1047951107001138.. “Isomerism of the right atrial appendages is a subset of heterotaxy where the atrial appendages on both sides of the body have the appearance of the morphologically right atrial appendage.”

Jacobs JP, Anderson RH, Weinberg P, Walters III HL, Tchervenkov CI, Del Duca D, Franklin RCG, Aiello VD, Béland MJ, Colan SD, Gaynor JW, Krogmann ON, Kurosawa H, Maruszewski B, Stellin G, Elliott MJ. The nomenclature, definition and classification of cardiac structures in the setting of heterotaxy. In 2007 Supplement to Cardiology in the Young: Controversies and Challenges Facing Paediatric Cardiovascular Practitioners and their Patients, Anderson RH, Jacobs JP, and Wernovsky G, editors. Cardiology in the Young. 2007 Sept; 17(Suppl 2):1–28, doi: 10.1017/S1047951107001138.. “Isomerism of the left atrial appendages is a subset of heterotaxy where the atrial appendages on both sides of the body have the appearance of the morphologically left atrial appendage.”

Jacobs JP, Anderson RH, Weinberg P, Walters III HL, Tchervenkov CI, Del Duca D, Franklin RCG, Aiello VD, Béland MJ, Colan SD, Gaynor JW, Krogmann ON, Kurosawa H, Maruszewski B, Stellin G, Elliott MJ. The nomenclature, definition and classification of cardiac structures in the setting of heterotaxy. In 2007 Supplement to Cardiology in the Young: Controversies and Challenges Facing Paediatric Cardiovascular Practitioners and their Patients, Anderson RH, Jacobs JP, and Wernovsky G, editors. Cardiology in the Young. 2007 Sept; 17(Suppl 2):1–28, doi: 10.1017/S1047951107001138.. “Situs ambiguus is defined as an abnormality in which there are components of situs solitus and situs inversus in the same person. Situs ambiguus, therefore, can be considered to be present when the thoracic and abdominal organs are positioned in such a way with respect to each other as to be not clearly lateralised and thus have neither the usual, or normal, nor the mirror-imaged arrangements.”

Jacobs JP, Anderson RH, Weinberg P, Walters III HL, Tchervenkov CI, Del Duca D, Franklin RCG, Aiello VD, Béland MJ, Colan SD, Gaynor JW, Krogmann ON, Kurosawa H, Maruszewski B, Stellin G, Elliott MJ. The nomenclature, definition and classification of cardiac structures in the setting of heterotaxy. In 2007 Supplement to Cardiology in the Young: Controversies and Challenges Facing Paediatric Cardiovascular Practitioners and their Patients, Anderson RH, Jacobs JP, and Wernovsky G, editors. Cardiology in the Young. 2007 Sept; 17(Suppl 2):1–28, doi: 10.1017/S1047951107001138.. “Asplenia syndrome” can be defined as a subset of heterotaxy with components of bilateral right-sidedness, usually associated with absence of the spleen.

Jacobs JP, Anderson RH, Weinberg P, Walters III HL, Tchervenkov CI, Del Duca D, Franklin RCG, Aiello VD, Béland MJ, Colan SD, Gaynor JW, Krogmann ON, Kurosawa H, Maruszewski B, Stellin G, Elliott MJ. The nomenclature, definition and classification of cardiac structures in the setting of heterotaxy. In 2007 Supplement to Cardiology in the Young: Controversies and Challenges Facing Paediatric Cardiovascular Practitioners and their Patients, Anderson RH, Jacobs JP, and Wernovsky G, editors. Cardiology in the Young. 2007 Sept; 17(Suppl 2):1–28, doi: 10.1017/S1047951107001138.. “Polysplenia syndrome” can be defined as a subset of heterotaxy with components of bilateral left-sidedness, usually associated with multiple spleens.

Complete description of both the cardiac relations and connections: the arrangement of the atrial appendages the ventricular topology the atrioventricular connections the ventriculoarterial connections the infundibular morphologies the relationships of the arterial trunks in space the position of the heart in the chest the orientation of the cardiac apex In heterotaxy, particular attention is required for the venoatrial connections, since these are so often abnormal.

Heterotaxy Nomenclature is important Less than perfect association between the state of the spleen and the form of heart disease . Splenic morphology should be investigated in all forms of heterotaxy, regardless of the type of cardiac disease. The splenic morphology should not be used to stratify the form of disease within the heart The form of cardiac disease should not be used to stratify the state of the spleen.

8 centers in Canada perform pediatric and congenital heart surgery The Report of the 2010 STS Congenital Heart Surgery Practice and Manpower Survey undertaken by the Society of Thoracic Surgeons Workforce on Congenital Heart Surgery 125 centers in the United States of America perform pediatric and congenital heart surgery 8 centers in Canada perform pediatric and congenital heart surgery Jacobs ML, Daniel M, Mavroudis C, Morales DLS, Jacobs JP, Fraser CD, Turek JW, Mayer JE, Tchervenkov C, Conte JV. Report of the 2010 Society of Thoracic Surgeons Congenital Heart Surgery Practice and Manpower Survey. The Annals of Thoracic Surgery, 2011;92:762–9, August 2011.

Jacobs JP, Jacobs ML, Mavroudis C, Lacour-Gayet FG, Tchervenkov CI, Pasquali SK. Executive Summary: The Society of Thoracic Surgeons Congenital Heart Surgery Database - Twentieth Harvest – (January 1, 2009 – December 31, 2013). The Society of Thoracic Surgeons (STS) and Duke Clinical Research Institute (DCRI), Duke University Medical Center, Durham, North Carolina, United States, Spring 2014 Harvest.

Jacobs JP, Jacobs ML, Mavroudis C, Lacour-Gayet FG, Tchervenkov CI, Pasquali SK. Executive Summary: The Society of Thoracic Surgeons Congenital Heart Surgery Database - Twentieth Harvest – (January 1, 2009 – December 31, 2013). The Society of Thoracic Surgeons (STS) and Duke Clinical Research Institute (DCRI), Duke University Medical Center, Durham, North Carolina, United States, Spring 2014 Harvest.

Jacobs JP, Jacobs ML, Mavroudis C, Lacour-Gayet FG, Tchervenkov CI, Pasquali SK. Executive Summary: The Society of Thoracic Surgeons Congenital Heart Surgery Database - Twentieth Harvest – (January 1, 2009 – December 31, 2013). The Society of Thoracic Surgeons (STS) and Duke Clinical Research Institute (DCRI), Duke University Medical Center, Durham, North Carolina, United States, Spring 2014 Harvest.

STS Database Penetrance in USA The STS Congenital Heart Surgery Database (STS-CHSD) is the largest clinical database in the world for congenital and pediatric cardiac surgery. The Report of the 2010 STS Congenital Heart Surgery Practice and Manpower Survey, undertaken by the STS Workforce on Congenital Heart Surgery, documented that 125 hospitals in the United States of America and 8 hospitals in Canada perform pediatric and congenital heart surgery. The STS-CHSD contains data from 119 of the 125 hospitals (95.2% penetrance by hospital) in the United States of America and 3 of the 8 centers in Canada.

Heterotaxy in the EACTS-STS Congenital Heart Surgery Databases: 10 TERMS 3 Preoperative Factors 7 Diagnostic terms

Heterotaxy in the EACTS-STS Congenital Heart Surgery Databases: 10 TERMS 3 Preoperative Factors: Heterotaxy syndrome Heterotaxy syndrome, Asplenia syndrome Heterotaxy syndrome, Polysplenia syndrome

Heterotaxy in the EACTS-STS Congenital Heart Surgery Databases: 10 TERMS 7 Diagnostic terms Single ventricle, Heterotaxia syndrome Atrial Isomerism, Left {CAN NOT BE PRIMARY DIAGNOSIS} Atrial Isomerism, Right {CAN NOT BE PRIMARY DIAGNOSIS} Dextrocardia {CAN NOT BE PRIMARY DIAGNOSIS} Levocardia {CAN NOT BE PRIMARY DIAGNOSIS} Mesocardia {CAN NOT BE PRIMARY DIAGNOSIS} Situs inversus {CAN NOT BE PRIMARY DIAGNOSIS}

Heterotaxy syndrome Heterotaxy is synonymous with ‘visceral heterotaxy’ and ‘heterotaxy syndrome’. Heterotaxy is defined as an abnormality where the internal thoraco-abdominal organs demonstrate abnormal arrangement across the left-right axis of the body. By convention, heterotaxy does not include patients with either the expected usual or normal arrangement of the internal organs along the left-right axis, also known as ‘situs solitus’, nor patients with complete mirror-imaged arrangement of the internal organs along the left-right axis also known as ‘situs inversus’.

Heterotaxy syndrome, Asplenia syndrome “Asplenia syndrome” can be defined as a subset of heterotaxy with components of bilateral right-sidedness, usually associated with absence of the spleen.

Heterotaxy syndrome, Polysplenia syndrome “Polysplenia syndrome” can be defined as a subset of heterotaxy with components of bilateral left-sidedness, usually associated with multiple spleens.

Single Ventricle Single ventricle, DILV Single ventricle, DIRV Single ventricle, Mitral atresia Single ventricle, Tricuspid atresia Single ventricle, Unbalanced AV canal Single ventricle, Heterotaxia syndrome Single ventricle, Other Single Ventricle + Total anomalous pulmonary venous connection (TAPVC)

STS Congenital Heart Surgery Database All Index Operations in Database over 12 years January 1, 1998 - December 31, 2009 Excludes participants with > 15% missing for discharge mortality or non-cardiac abnormalities, and individual records missing discharge mortality or non-cardiac abnormalities Excludes patients weighing less than or equal to 2,500 g undergoing PDA ligation as their primary procedure

STS Congenital Heart Surgery Database 77,153 total operations 1,144 with asplenia 361 with polysplenia

Percentage Discharge Mortality All Index Operations in Database Asplenia Polysplenia No Asplenia or Polysplenia STS-EACTS Category 1 0.5% 5.5% 10.6% STS-EACTS Category 2 1.7% 4.6% 7.6% 1.6% STS-EACTS Category 3 2.7% 4.3% 2.6% STS-EACTS Category 4 8.2% 15.1% 14.1% 7.8% STS-EACTS Category 5 20.8% 30.8% 16.1% 20.4%

STS Congenital Heart Surgery Database All Index Operations in Database over 12 years January 1, 1998 - December 31, 2009 Include all patients with Single Ventricle who underwent Shunt, Glenn, or Fontan Excludes participants with > 15% missing for discharge mortality

STS Congenital Heart Surgery Database 804 Shunt (148 with heterotaxy) 1669 Glenn (201 with heterotaxy) 1936 Fontan (240 with heterotaxy)

Percentage Discharge Mortality Shunt Glenn Fontan All Single Ventricle 7.3% 1.4% 2.1% All Single Ventricle except Heterotaxy 6.6% 1.8% Single ventricle, Heterotaxia syndrome 10.8% 1.5% 4.2%

Heterotaxy: Lessons learned from the STS Database STS Database is largest Congenital Heart Surgery Database in North America Review of Data allows for unique picture of Patterns of Practice and Outcome Heterotaxy is a challenging problem with increased discharge mortality in most subgroups.

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