Congenital heart
defects and heterotaxy
syndrome
Heterotaxy Hope Organization
Terence Prendiville, pediatric cardiology fellow, Boston Children’s Hospital
June 20th-23rd 2013
No conflicts of interest to
declare
Talk outline:
▪ Overview: spectrum of congenital heart defects seen in
patients with heterotaxy syndrome
▪ Outcome data after repair of congenital heart disease
▪ Highlighting some of the differences between patients with
and without heterotaxy syndrome passing through a
cardiac intensive care unit: (next slide)
Specific issues relating to congenital
heart disease in heterotaxy syndrome
▪ Single ventricle physiology in those with heterotaxy syndrome –
what’s known
▪ Fontan V’s biventricular repair (decision-waying)
▪ Pregnancy considerations in patients with congenital heart disease
(including single ventricle)
▪ Risk of liver cirrhosis in patients with Fontan repair (and whether
Heterotaxy syndrome affects this)
▪ Malrotation of the GI tract
Heterotaxy syndrome: definition
▪ Heterotaxy is defined as any arrangement of organs across the
body’s left-right axis that differs from complete situs solitus and
complete situs inversus.
Martina Brueckner, MD Associate Professor of Pediatrics (Cardiology)
and of Genetics; Yale University School of Medicine
Editorial, Circulation 2012
Origin of the term ‘heterotaxy’
Heteros: ‘other’
Taxis: ‘order or arrangement’
Stella Van Praagh, MD; Nadas Pediatric Cardiology, 2nd
edition
Incidence: 1 in 7,000 live births (1.7% of congenital heart
disease)
Normal and mirror image anatomy /
position of internal organs
Images: Laboratory Heymut Omran, MD; University Children’s Hospital Muenster, Germany
Organ malposition (and / or maldevelopment) in
heterotaxy syndrome
Asplenia or polysplenia in heterotaxy
syndrome
▪ Spleen frequently affected in heterotaxy syndrome:
 ABSENT (asplenia)
 MULTIPLE, small ‘splenules’ (polysplenia)
Theory for link with heart disease in heterotaxy syndrome: Splenic
development occurs at approximately the same time as the outflow
tracts of the heart and the valves inside the heart (atrioventricular
canal)
Heart defects in patients with
heterotaxy syndrome
1. Considerable variability
2. Definite clustering of cardiac malformations corresponding to
either asplenia or polysplenia
3. Recent data that genes implicated in heterotaxy syndrome may be
involved in congenital heart defects in patients without a formal
diagnosis of heterotaxy syndrome
Reference for heart disease in
Heterotaxy syndrome:
Nadas’ Pediatric Cardiology
2nd edition (2006)
Ch.39: Cardiac Malpositions and the Heterotaxy Syndromes
Stella Van Praagh
Normally connected inferior vena cava
Interrupted inferior vena cava
Abnormal hepatic vein connections
Absence of coronary sinus
Bilateral superior vena cavae
All pulmonary venous drainage to systemic vein
All pulmonary venous drainage to RA or ipsilateral atria
Atrial situs inversus
Complete atrioventricular canal (common AVV)
Intact atrioventricular canal septum
L-looped ventricles
Dextrocardia
Normal biventricular size
Left ventricular hypoplasia (or absence)
Right ventricular hypoplasia (or absence)
Sub-pulmonary stenosis
Sub-aortic stenosis
Double-outlet right ventricle
Transposition of the Great Vessels
Normally-related Great Vessels
Asplenia (n=58)
100%
0%
28%
95%
71%
64%
2%
31%
69%
7%
38%
36%
45%
28% (14%)
10% (3%)
96%
2%
82%
9%
9%
Adapted from Nadas Pediatric Cardiology, 2nd Ed 2007
Polysplenia (n=46)
20%
80%
80%
26%
50%
2%
37%
22%
33%
35%
30%
33%
63%
24% (0%)
11% (2%)
43%
22%
37%
2%
61%
Heterotaxy syndrome: congenital heart
disease associated with asplenia
• Normally connected inferior vena cava
• Pulmonary veins draining to other large vein
(instead of to the left atrium)
• Common (single) atrioventricular canal
• Double-outlet right ventricle with pulmonary
stenosis
Heterotaxy syndrome: congenital heart
disease associated with polysplenia
• Interrupted inferior vena cava
• Pulmonary veins draining to right atrium
(instead of to the left atrium)
• Common (single) atrioventricular canal
• Normally-related great vessels exiting the
heart
Normally connected inferior vena cava
Interrupted inferior vena cava
Abnormal hepatic vein connections
Absence of coronary sinus
Bilateral superior vena cavae
All pulmonary venous drainage to systemic vein
All pulmonary venous drainage to RA or ipsilateral atria
Atrial situs inversus
Complete atrioventricular canal (common AVV)
Intact atrioventricular canal septum
L-looped ventricles
Dextrocardia
Normal biventricular size
Left ventricular hypoplasia (or absence)
Right ventricular hypoplasia (or absence)
Sub-pulmonary stenosis
Sub-aortic stenosis
Double-outlet right ventricle
Transposition of the Great Vessels
Normally-related Great Vessels
Asplenia (n=58)
100%
0%
28%
95%
71%
64%
2%
31%
69%
7%
38%
36%
45%
28% (14%)
10% (3%)
96%
2%
82%
9%
9%
Adapted from Nadas Pediatric Cardiology, 2nd Ed 2007
Polysplenia (n=46)
20%
80%
80%
26%
50%
2%
37%
22%
33%
35%
30%
33%
63%
24% (0%)
11% (2%)
43%
22%
37%
2%
61%
Single ventricle palliation
in patients with heterotaxy
syndrome
Historic data on outcome after Fontan
operation in patients with heterotaxy syndrome
▪ Pediatric Heart Network study: 546 survivors of the Fontan operation
(aged 6-18 years old)
▪ 42 (8%) had heterotaxy syndrome
▪ Families and patients completed functional health status
questionnaires
▪ Investigators performed echocardiography, EKG, exercise testing,
cardiac MRI
Functional state of patients with heterotaxy syndrome following the Fontan operation. Atz AM et
al. Cardiol Young 2007
Results:
▪ Heterotaxy syndrome patients had different anatomical
considerations (pulmonary veins, systemic ventricle and
atrioventricular valves)
▪ No difference in:
1. Length of hospital stay
2. Number of post-operative complications
3. Exercise performance
4. Levels of BNP (marker of heart failure)
5. Health status questionnaire scores
Pulmonary arteriovenous malformations…
Blood that drains from the liver needs to pass through the lungs
to prevent the growth of accessory vessels that drain blue blood
back to the heart (bypassing the lungs)
Heterotaxy syndrome patients can have an interrupted inferior
vena cava (drains blood from liver to heart)
Some heterotaxy syndrome pateints may require Fontan pathway
modifications to re-direct liver blood flow through both lungs.
Cavopulmonary pathway modification in patients with heterotaxy and newly diagnosed or
persistent pulmonary arteriovenous malformations after a modified Fontan operation.
McElhinney et al. J Thorac Cardiovasc Surg. 2011
Reporting the Boston Children’s Hospital experience on
managing patients with borderline small left ventricles
34 patients with
borderline left ventricle
(2001-2010)
• Careful selection of patients with borderline left ventricle (initial
single ventricle palliation)
 LV end-diastolic volume z-score of -5 to -0.5
 Failed any initial attempt at biventricular repair (balloon dil Ao V /
coarct repair) or PGE1 dept.
 EXCLUDED: aortic atresia; mitral atresia; ventricular septal defect;
l-transposed ventricles; transposed great vessels; heterotaxy
syndrome (for purposes of analysis)
Staged left ventricular recruitment after single-ventricle palliation in patients with borderline left heart hypoplasia.
Emani et al. JACC. 2012
Reporting the Boston Children’s Hospital experience on
managing patients with borderline small left ventricles
34 patients with
borderline left ventricle
(2001-2010)
• Careful selection of patients with borderline left ventricle (initial
single ventricle palliation)
• Staged left ventricular recruitment and left ventricular
rehabilitation
 Relief of inflow and outflow tract obstruction
 Resection of endocardial fibroelastosis
 Promotion of flow through the left ventricle
I. (4mm restrictive atrial septal defect with resultant >5mmHg
gradient across defect)
II. Providing additional source of pulmonary blood flow
Staged left ventricular recruitment after single-ventricle palliation in patients with borderline left heart hypoplasia.
Emani et al. JACC. 2012
Endocardial fibroelastosis
Reporting the Boston Children’s Hospital experience on
managing patients with borderline small left ventricles
Conversion to
biventricular repair: 12
(40%) patients
Surgically restricted
atrial septum: 19 patients
Single ventricle repair: 15
patients with Fontan; 3
patients with BDG
31 survivors (88%)
34 patients with
borderline left ventricle
(1 transplanted)
Did not restrict atrial
septum: 11 patients
(2001-2010)
3 deaths (9%)
Staged left ventricular recruitment after single-ventricle palliation in patients with borderline left heart hypoplasia.
Emani et al. JACC. 2012
Reporting the Boston Children’s Hospital experience on
managing patients with borderline small left ventricles
Conversion to
biventricular repair: 12
(40%) patients
(1 transplanted)
*Median length of hospitalization: 94 days
Left ventricle volumes prior to biventricular conversion:
Echo: LV EDV z-score: 0.21 (mean)
MRI: LV EDV: 67mls/m2 (average)
Median follow-up 2.9 years: no mortality (one heart
transplant)
Staged left ventricular recruitment after single-ventricle palliation in patients with borderline left heart hypoplasia.
Emani et al. JACC. 2012
“In these patients (heterotaxy syndrome)
aggressive pursuit of biventricular
circulation may provide the best chance
of long term survival”
Sitiram Emani, Pedro del Nido
Strategies to maintain biventricular circulation in patients with high-risk
anatomy. Semin Thorac Cardiovasc Surg Pediatr Card Surg Ann. 2013
Non-cardiac anomalies in
heterotaxy syndrome:
160 autopsy cases
Extracardiac anomalies in the heterotaxy syndromes with focus on
anomalies of midline-associated structures.
Ticho, Goldstein and Van Praagh. Am J Cardiol 2000
Non-cardiac anomalies in heterotaxy
syndrome
▪ Abnormal lung morphology: 92%
▪ Central nervous system anomaly: 7% (brain and spinal cord)
▪ Genitourinary anomalies: 14% (kidneys)
▪ Craniofacial involvement: 9% (incl. cleft lip / palate)
▪ Musculoskeletal involvement: 13% (e.g. scoliosis of spine)
Non-cardiac anomalies in heterotaxy
syndrome
▪ Gastrointestinal involvement: ALL PATIENTS
– Malrotation of intestines (33%)
– Stomach positioned on the right of the body (~42%)
– Biliary atresia
– Tracheo-esophageal fistula
– Anal stenosis
Intestinal malrotation and prophylactic
Ladd’s procedure
malrotation
▪ Intestinal malrotation (abnormally
narrow base attachment of small
bowel) places the patient at risk of
volvulus (twisted bowel that is at
risk of necrosis)
volvulus
Intestinal malrotation in heterotaxy
syndrome and Ladd’s procedure: controversy
• Screen all patients with upper
gastro-intestinal fluoroscopy
• Upper gastro-intestinal fluoroscopy
may be challenging to interpret correctly
• Intervene with preventative
surgical procedure (Ladd’s)
with evidence of malrotation
• Preventative surgery is not without its
own risks (by recent report) for complications
including re-operation
Intestinal malrotation in heterotaxy
syndrome and Ladd’s procedure: controversy
• Volvulus (twisted bowel) is a surgical
• Don’t screen patients for malrotation
emergency and can be a life-threatening
event
• Educate families fully about early signs
of SYMPTOMATIC malrotation
• Waiting until a patient presents with volvulus
can put their life at risk
• Appropriately investigate those that
have any gastro-intestinal symptoms • ? Difficult medico-legally to NOT intervene
of concern
once there is radiology report of
(asymptomatic) malrotation
Symptoms of symptomatic malrotation /
volvulus
▪ Vomiting (especially green or bilious) – acute or chronic
▪ Abdominal pain, constipation or diarrhea, blood stools
▪ Lethargy or irritability, loss of appetite
60% present with symptoms in the first month of life, 20% in the
remaining first year, 20% thereafter
Diagnosis: Upper gastrointestinal fluoroscopy
Note: x-rays of the abdomen, CT scans, ultrasound and barium enemas
may NOT diagnose malrotation.
Children’s Hospital Los Angeles experience: managing
patients with heterotaxy and ‘malrotation’ report
▪ Data from 2003-2011: 224 patients identified with heterotaxy
syndrome (ISNPCHD definition)
▪ 62 patients: upper GI fluoroscopy screening
▪ 30 screened patients had ‘malposition’ and underwent a prophylactic
Ladd’s procedure – 11 complications (8 re-operations)
▪ Incidence of volvulus: 0.2%
▪ 138 patients (asymptomatic) had no investigations: remained
asymptomatic after 4 years of follow-up.
Congenital heart disease and heterotaxy: upper gastrointestinal fluoroscopy can be misleading and surgery in an
Asymptomatic patient is not beneficial. Papillon et al. Journal of Pediatric Surgery. 2013
Liver disease in Fontan patients (with
heterotaxy syndrome)
▪ Boston Children’s Hospital / Brigham Women’s Hospital (unpublished
data):
▪ 68 liver biopsies in patients after Fontan repair (13 with heterotaxy
syndrome)
 Heterotaxy syndrome was not a risk factor for liver cirrhosis
 Heterotaxy syndrome diagnosis was not a risk factor for death or
transplantation in this cohort
Liver disease in Fontan patients (with
heterotaxy syndrome)
 Unclear what significance (if any) biopsy-only evidence of fibrosis has
in a patient after Fontan palliation
 Usually liver function tests are NORMAL in asymptomatic (biopsyproven fibrosis) patients
 Clinically apparent liver cirrhosis does complicate subsequent patient
outcome
 Practical advice: Hep A and B vaccination
Airway complications in patients with
heterotaxy syndrome
▪
▪
Circulation. 2012 May 8;125(18):2232-42. doi: 10.1161/CIRCULATIONAHA.111.079780. Epub 2012 Apr 12. High prevalence of respiratory
ciliary dysfunction in congenital heart disease patients with heterotaxy. Nakhleh et al. Circulation 2012.
Airway complications in patients with
heterotaxy syndrome
▪ 42% (18/43) of patients with heterotaxy syndrome and congenital
heart disease had documented ciliary dyskinesia (CD)
▪ CD risk higher in those heterotaxy syndrome patients with abnormal
position of other thoraco-abdominal organs (in addition to the heart
disease)
▪ This likely accounts for (at least some) of the post-operative
respiratory complications after cardiac surgery in patients with
heterotaxy syndrome
Fertility in patients with heterotaxy
syndrome
▪ Anecdotal experience from my adult congenital heart disease
colleagues at BCH:
▪ Our program – 2 women with heterotaxy syndrome (polysplenia)
who successfully carried pregnancies
I.
Fontan repair: 1 pregnancy (no complications)
II. Biventricular heart repair: 4 pregnancies (no complications)– one
child with heterotaxy syndrome and heart disease, another child
with heart disease alone (TGA).
▪ Any concerns for male fertility unknown
In summary
Heterotaxy syndrome research has made significant advances in the
last several years
Researchers are unravelling the specific reasons that patients with
heterotaxy syndrome and congenital heart disease may have a more
challenging post-operative course
Newer surgical techniques (left ventricular recruitment) will continue
to advance the outcomes for children with heterotaxy syndrome
The genetic underpinnings of heterotaxy syndrome is being actively
pursued and will further enlighten our understanding of this complex
disease
Acknowledgements
Research support from:
Heterotaxy Foundation
Keegan’s Spirit Foundation (Bruce Southers)
My contact details: terence.prendiville@cardio.chboston.org
‘Preservation’ of cardiac developmental
pathways: robust tolerance to perturbation
An example of
the variation
in heart
disease
associated
with one
(well-known)
cardiac gene…