Thirty years arterial switch operation for transposition of the great arteries; a follow-up study.

The Wilhelmina children*s hospital (WKZ) was one of the first centres in the
world were the arterial switch operation (ASO) was used as first choice of
treatment for transposition of the great arteries (TGA). Therefore the WKZ has
one of the longest follow-up periods for this group of patients. As after
introduction of any new surgical technique, long-term follow-up studies are
mandatory to provide patients and physicians with data about morbidity and
mortality; what to expect when patients are adolescent and adult. Early and
intermediate follow-up studies, with a maximum of 15 years follow-up, have
shown a favourable survival compared with the atrial switch operation, with
less morbidity. Only a limited number of follow-up studies have been performed
that focused on myocardial blood flow and left ventricular function. These
showed decreased myocardial blood flow, decreased coronary flow reserve and
overall slightly depressed left ventricular (LV) function in a substantial
proportion of patients studied (long) before they reached adult age. Based on
these observations and the theoretical consideration that manipulation and
reimplantation (in the neo-aorta) of the coronary arteries at neonatal age,
without an anatomic sinus of Valsava, may lead to altered coronary blood flow
throughout life, it is of great interest to investigate alterations of LV
function and coronary capacity in patients long after ASO. If factors
associated with these outcomes are identified, the therapeutic regimen at
neonatal age might be adjusted, in order to improve outcome.
Little is known about the long term effects of use of cardiopulmonary bypass
(CPB) at a neonatal age. Short-term effects of increased oxidative stress and a
persisting pro-inflammatory state have been reported. Whether these
abnormalities persist is unknown, because no studies have been performed to
investigate this. Possible CPB- related immunological effects on endothelial
function, a major determinant of atherosclerosis in the normal population, will
be scrutinized in this study.

The main objectives are 1) is to evaluate the prevalence of cardiac
complications long-term after ASO by investigation of cardiac function as well
as clinical outcome and to determine which factors (associated with life style
or operative techniques) are associated with occurrence of late problems;
2) to investigate the coronary anatomy and presence of wall irregularities in
the coronary arteries and - if present - to determine the etiological
determinants for these wall irregularities (e.g. abnormal blood flow pattern or
endothelial dysfunction).
With all this information we hope to provide more evidence for future
guidelines for patients after ASO;
3) to investigate the immunological consequences of neonatal thymectomy on the
developing immune system and to evaluate the role of thymic regrowth.

Observational, cross-sectional cohort study

Most of the investigations that are part of the study protocol are also
implemented in the regular follow-up after ASO. Based on the new American Heart
Association (AHA) guidelines and Canadian guidelines, extensive
echocardiography, physical examination, electrocardiogram (ECG), saturation
measurement and ergometry should be routinely performed. Secondly these
guidelines recommend cardiac MR and/or CT imaging be performed if any doubt
remains on anatomy or hemodynamic status. The new European Society of
Cardiology (ESC) guidelines also recommend a new, more extensive work-up as
part of standard follow-up after ASO for TGA.
Additional to the normal 2D echocardiography protocol, the Ventripoint system
will be used. This is a 2-dimensional method that localizes different anatomic
landmarks in magnetic 3D space and reconstructs RV volumes and EF using a
database consisting of many MR datasets of patients with different pathologies.
It will add approximately 5 minutes to the echoprotocol.
If not already clinically indicated, patients will be asked to undergo FMD,
CIMT, CT imaging of the coronary arteries, cardiac MR imaging including the
administration of gadolinium contrast and blood withdrawal in addition to the
routine check-up.
There are some risks associated with these additional investigations. The risk
for insertion of an intravenous (i.v.) catheter (for gadolinium infusion and
blood withdrawal) is considered very low and the risk of FMD and CIMT, which
both use high resolution ultrasonography, is even nonexistent.
The administration of gadolinium contrast, as part of the MR imaging, can give
side effects in a small portion of patients (<0.1%), most of these are minor,
but seldom (<0.01%) an anaphylactic reaction will occur.16 In case of any doubt
about kidney function, serum creatinin and glomerular filtration rate (GFR)
will be determined before planning a patient for the cardiac MR imaging.
Patients with a GFR < 30 ml/min will not receive gadolinium contrast. CT scan
uses X-ray beams; this radiation can lead to the development of malignancies in
a small portion of patients. However different dose minimizing strategies, such
as prospective ECG gated scanning, can reduce the radiation to a maximum of 2-3
mSv, which is equivalent to the average background radiation a person annually
receives. As part of the coronary CT-scan, contrast will also be administered.
For the CT-scan low osmolar iodinated contrast will be used, Ultravist, Bayer
B.V., Mijdrecht. Patients will be screened for contra-indications (e.g.
previous reactions) for use of iodinated contrast and for elevated risk of
contrast nephropathy (page 22 of protocol). A severe reaction to iodinated
contrast occurs rarely (< 1/1000), but all general precautions will be taken. A
minor reaction occurs more often but is self limiting and subsides quickly.
Patients with a history of reactions to iodinated contrast or with renal
problems will not undergo CT-scan. In contrast to the standard coronary CT
protocol, neither nitrolglycerine nor beta-blockade will be given, since this
is not necessary for answering the research question.

The major burden for participants will be the extra time that the study related
investigations will take. MR imaging is a long investigation which can also be
burdensome. Furthermore insertion of an i.v. catheter can be painful. To reduce
the burden for the patients all investigations will be planned consecutively if
possible, in a maximum of two days.

The benefit for the participating patients is little. However, there is a
possible benefit for the entire group of patients undergoing ASO in the future:
with all the information gathered in this study, a more appropriate follow-up
regime might be developed. Also the information about complications later in
life and possible predictors thereof can provide better insight for patient and
their parent(s) on what to expect long term after ASO for TGA.