Atrioventricular septal defect: longterm follow-up after correction

Congenital heart defects are the most frequent congenital defects with an
incidence of 0.8% per year. Patients with an atrioventricular septal defect
(AVSD) constitute 5% of all congenital heart defects. The key features of AVSD
are the absence of a common atrioventricular valvular orifice with 2 bridging
leaflets, classically believed the result of nonfusion of the endocardial
cushions, thus preventing proper formation of the AV septum and closure of the
ostium primum. AVSD can present as an isolated defect or in the setting of
complex cardiac malformations. After birth, humans with an AVSD become
symptomatic within the first year of life and repair is nowadays undertaken
within the first 6 months of life1 with excellent long-term survival.1, 2
However, reoperation rate after AVSD correction is up to 15%, with
predominantly reintervention because of hemodynamically significant left
atrio-ventricular valve (AVV) regurgitation.3 In pregnant woman with corrected
AVSDs, the presence of left AVV regurgitation was related to more interventions
during delivery and after pregnancy AVV regurgitation showed deterioration in
over 10% of the woman.4 Furthermore, moderate to severe left AVV regurgitation
at latest follow-up in patients after AVSD correction is a risk factor for
mortality, stressing the need of careful follow-up of AVV function after AVSD
correction.
Left AVV regurgitation leads to a volume-overloaded atrium and ventricle, which
can lead to left ventricular myocardial failure.3 Numerous studies on long-term
follow-up in patients after AVSD correction have been published mainly
evaluating re-intervention rate. Few studies have evaluated clinical status,
exercise capacity and myocardial function after AVSD correction. Reduced
exercise capacity has been described in patients after correction of congenital
heart disease, including patients after AVSD correction.
Novel echocardiographic techniques have been introduced to assess global as
well as regional myocardial function. Tissue Doppler imaging and speckle
tracking strain imaging are echocardiographic techniques allowing detailed
evaluation of myocardial function.5-7
As stated above, evaluation of AVV regurgitation is important after AVSD
correction. Interestingly, evaluation of regurgitation of the AVVs in all
follow-up studies of patients after AVSD correction is performed with
echocardiography. Using echocardiography, AVV regurgitation can only be
assessed semi-quantitatively, using a grading system based on the width of the
vena contracta of the regurgitant jet.3 Direct quantification of AVV
regurgitation using 3D velocity encoded magnetic resonance imaging (3D-VE-MRI)
has been recently developed by Westenberg et al. from the department of
Radiology of the LUMC.8 Using this technique AVV regurgitation was directly
quantified in adult patients with ischemic heart disease.9 Recently, we
reported the use of 3D-VE MRI to assess AVV function in healthy children and in
children with corrected tetralogy of Fallot.10 No reports on the application of
3D-VE-MRI to assess AVV regurgitation after AVSD correction are available.
Indications for AVV surgery are well defined in adults. However, in the
pediatric patient population indications are less clear. Because of the
unpredictable need for AVV replacement and its concomitant problems of size
limitations and anticoagulation requirements.3 The use of recently introduced
imaging techniques such as TDI, speckle tracking strain imaging and 3D-VE-MRI
be aid in the decision making and timing of AVV surgery.
Reference List

1. Vohra,H.A. et al. Primary biventricular repair of
atrioventricular septal defects: an analysis of reoperations. Ann. Thorac.
Surg. 90, 830-837 (2010).
2. Bakhtiary,F. et al. Long-term results after repair of complete
atrioventricular septal defect with two-patch technique. Ann. Thorac. Surg. 89,
1239-1243 (2010).
3. Moran,A.M., Daebritz,S., Keane,J.F., & Mayer,J.E. Surgical
management of mitral regurgitation after repair of endocardial cushion defects:
early and midterm results. Circulation 102, III160-III165 (2000).
4. Drenthen,W. et al. Cardiac complications relating to pregnancy
and recurrence of disease in the offspring of women with atrioventricular
septal defects. Eur. Heart J. 26, 2581-2587 (2005).
5. van der Hulst,A.E. et al. Relation of left ventricular twist
and global strain with right ventricular dysfunction in patients after
operative "correction" of tetralogy of fallot. Am. J. Cardiol. 106, 723-729
(2010).
6. van der Hulst,A.E. et al. Tissue Doppler imaging in the left
ventricle and right ventricle in healthy children: normal age-related peak
systolic velocities, timings, and time differences. Eur. J. Echocardiogr.(2011).
7. van der Hulst,A.E. et al. Relationship between temporal
sequence of right ventricular deformation and right ventricular performance in
patients with corrected tetralogy of Fallot. Heart 97, 231-236 (2011).
8. Westenberg,J.J. et al. Mitral valve and tricuspid valve blood
flow: accurate quantification with 3D velocity-encoded MR imaging with
retrospective valve tracking. Radiology 249, 792-800 (2008).
9. Roes,S.D. et al. Flow assessment through four heart valves
simultaneously using 3-dimensional 3-directional velocity-encoded magnetic
resonance imaging with retrospective valve tracking in healthy volunteers and
patients with valvular regurgitation. Invest Radiol. 44, 669-675 (2009).
10. van der Hulst,A.E. et al. Tetralogy of fallot: 3D
velocity-encoded MR imaging for evaluation of right ventricular valve flow and
diastolic function in patients after correction. Radiology 256, 724-734 (2010).
11. Hoohenkerk,G.J. et al. More than 30 years' experience with
surgical correction of atrioventricular septal defects. Ann. Thorac. Surg. 90,
1554-1561 (2010).

In patients long-term after AVSD correction the objectives are:
1) To evaluate myocardial function using novel echocardiographic techniques.
2) To study atrial en ventricular size and function in relation to
quantification of AVV function with the use 3D VE MRI.
3) To study clinical status and exercise capacity after AVSD correction in
relation to cardiac dysfunction.
4) To assess the use of comprehensive evaluation of cardiac function, including
AVV function, using echocardiography and MRI in the decision-making and timing
of AVV surgery.

Study design: prospective cohort-study
A surgical database including all AVSD patients corrected at the LUMC/AMC is
available.11 This database includes 312 patients, 162 patients with AVSD and
Down syndrome and 150 patients with AVSD without Down syndrome. Patient over 8
years of age and without any contrinidcatiosn for exercise testing or MRI
examination will be invited to undergo a symptom-limited exercise test
including peak oxygen uptake (VO2-max), echocardiographic examination and MRI
examination. Echocardiographic examination includes semi-quantitative
assessment of AVV regurgitation and tissue Doppler imaging and speckle tracking
strain imaging of myocardial function. MRI examination includes 3D VE-MRI of
the AVV for the quantification of AVV regurgitation.

The patients will be asked to visit the LUMC two times. During 1 visit a short
physical examination will be performed and a ECG will be made. Length and
weight will be measured. An echocardiographic examination will be performed
with a duration of 30 minutes, during which the patients will be asked to turn
to their left side and with the use of echogel and a transducer a
echocardiographic examination will be carried out, which poses a minimal burden
to the patient.
During the same visit a MRI examination will take place with a duration of
approx. 75 minutes. Prior to the MRI examination a intravenous canula will be
placed, which is needed for the administration of a contrast agent to allow
detection of scar tissue in the atria and/or ventricles of the patients. From
this IV canula, blood will be taken to assess proBNP, a blood marker for
cardiac stress, and therefore no additional puncture is needed. During the MRI
examination the subjects will be placed within the MRI scanner. A dummy
MRI-scanner is available to test if the subjects are feeling comfortable within
the MRI scanner. During the MRI examination, subjects own music can be played
and the parents are allowed to be close to the subject. The subjects are
monitored by ECG, microphone and camera monitoring.
During a second visit a symptom limited peak exercise test will be carried out
on a bicycle ergometer. The patient will be asked to sit a bicycle ergometer
and to exercise until exhaustion with a mask through which in and expired gas
will be analysed to assess peak oxygen uptake, a marker for exercise validity.

After collection of the data, the data will be analyzed. The obtained data on
myocardial performance obtained with echocardiography will be compared to
normal data from healthy subjects. Furthermore the atrial and ventricular size
obtained with MRI, will be compared to normal subjects and the relation between
size and function and the amount of AVV regurgitation will be analyzed.
Subsequently the parameters of myocardial and AVV-function will be related to
clinical status and exercise capacity in the patients. Finally, the obtained
parameters will be related to the indication for reintervention based on
standard examination and to the surgical records on correction and
reinterventions available in the AVSD-database, available through the research
of Dr Hoohenkerk, from the department of thoracic surgery of the LUMC.

The patients will be asked to visit the LUMC two times. During 1 visit a short
physical examination will be performed and a ECG will be made. Length and
weight will be measured. An echocardiographic examination will be performed
with a duration of 30 minutes, during which the patients will be asked to turn
to their left side and with the use of echogel and a transducer a
echocardiographic examination will be carried out, which poses a minimal burden
to the patient.
During the same visit a MRI examination will take place with a duration of
approx. 75 minutes. Prior to the MRI examination a intravenous canula will be
placed, which is needed for the administration of a contrast agent to allow
detection of scar tissue in the atria and/or ventricles of the patients. From
this IV canula, blood will be taken to assess proBNP, a blood marker for
cardiac stress, and therefore no additional puncture is needed. During the MRI
examination the subjects will be placed within the MRI scanner. A dummy
MRI-scanner is available to test if the subjects are feeling comfortable within
the MRI scanner. During the MRI examination, subjects own music can be played
and the parents are allowed to be close to the subject. The subjects are
monitored by ECG, microphone and camera monitoring.
During a second visit a symptom limited peak exercise test will be carried out
on a bicycle ergometer. The patient will be asked to sit a bicycle ergometer
and to exercise until exhaustion with a mask through which in and expired gas
will be analysed to assess peak oxygen uptake, a marker for exercise validity.
Subjects over 8 years of age will be asked to participate and therefore also
minors will be included in this study. As a consequence parents of children
from 8 to 12 years old will be asked to participate and sign the informed
consent document. For participants from 12 years to 16 years of age both the
participant him/herself and the parents are asked to sign the informed consent
document. Subjects over 16 years of age will sign their own informed consent
document.
Within the information letter the information provided to children will be
described in an age-specific way, to optimise the discussion making whether or
not to participate.
Minors over the age of 8 years will be included and if any verbal, physical
sign of resistance is observed by the researchers or the parents of the subject
the examinations will be terminated. During the echocardiographic examinations
the echocardiographist is in close contact with the subject and parents to
detect any resistance. During the MRI examination, microphones and camera*s are
used to detect any sign of resistance.

Benefits and risks assessment, group relatedness
The influence of possible sequella, due to correction of an AVSD, most-commonly
within the first year of life, start immediately after the operation. In case
of a regurgitant valve causing volume overload to the atrium and ventricle, the
period during which this volume overload occurs is essential to assess the
effects and meaning of the regurgitation. Therefore it is essential that
patients with different timeframes after correction are included in this study.
Better understanding of the influence of atrioventricular valve regurgitation
will lead to better patients managemnet. Furthermore, the need for
reintervention because of valve regurgitation sometimes is present already at
young age. If only adults were included in this study, the younger patients
will probably not benefit from the findings of this study. Finally, healthy
minors are included in this study because the findings in pediatric patients
can only be interpreted correctly if compared to subject with similar age and
body composition. Therefore a matched control group, also including minors, is
essential.