(Circulation. 2001;103:1875.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
From the Departments of Pediatric Cardiology (M.H., A.K., U.S., S.Z., S.L.B., R.O., J.H.) and Cardiac Surgery (R.L.), Deutsches Herzzentrum, and Nuklearmedizinische Klinik der TU (F.M.B., S.G.N.), Munich, Germany.
Correspondence to Michael Hauser, MD, Lazarettstraße 36, 80636 Munich, Germany. E-mail hauser{at}dhm.mhn.de
| Abstract |
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Methods and ResultsA total of 21 children with transposition of the great arteries at a mean interval of 11.2±2.9 years after ASO and 9 adolescents at a mean interval of 4.2±2.1 years after the Ross procedure were investigated. All patients were asymptomatic and had a normal exercise capacity. On stress echocardiography, 2 of the ASO patients had dyskinetic areas within the left ventricular myocardium, and 5 had adenosine-induced perfusion defects on positron emission tomography. No coronary obstruction was detected on coronary angiography in any patient, but a common finding was right coronary dominance and a small caliber of the distal part of the left anterior descending artery. Coronary flow reserve (CFR) was significantly reduced in all patients after ASO when compared with 10 normal healthy volunteers (age, 25.6±5.3 years). CFR was normal in the 9 patients who had the Ross operation (age, 19.2±7.6 years); exercise-induced perfusion defects were not detected in the Ross patients.
ConclusionsChildren after ASO are asymptomatic, without clinical signs of coronary dysfunction. In contrast to patients who had the Ross operation, stress-induced perfusion defects and an attenuated CFR were documented. The prognostic implications of these findings and the clinical consequences are unclear; nevertheless, close clinical follow-up of ASO patients is mandatory.
Key Words: transposition of great vessels arteries exercise perfusion imaging
| Introduction |
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Positron emission tomography (PET) is a noninvasive method that was used in a previous study2 to address the problem of adequacy of myocardial blood supply after ASO. In that study, myocardial blood flow (MBF) was impaired under vasodilatation with adenosine, and coronary flow reserve (CFR) was markedly attenuated. The aim of the present investigation, as part of the clinical follow-up, was to highlight the clinical relevance of the PET findings, to compare the results with patients after the Ross operation, and to stratify the influence of coronary reimplantation on myocardial perfusion.
| Methods |
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Group 1
A total of 21 children without limitations precluding
exercise testing (age, 12.3±2.2 years; range, 8 to 16 years)
participated in the study. Fourteen of them (age, 9.3±1.2 years) had
d-TGA with an intact ventricular septum and underwent ASO
within the first 20 days of life. In the remaining 7 children (age,
13.4±3.1 years), more complex anomalies were present. The ASO was
performed at an age of 134 to 2847 days. Four had TGA and a large
ventricular septal defect (VSD), one had associated
valvular pulmonary stenosis, one had associated
aortic coarctation, and one had double outlet right ventricle
(DORV) with a single coronary artery, with the left being a
branch of the transposed right coronary artery and an accessory
anterior descending artery from the left sinus. Four of these 7
children underwent 2-stage surgery with prior pulmonary artery
banding. The median time interval between banding and ASO was 12
months. In addition to ASO, all associated anomalies of these children
were corrected during the surgical procedures.
The mean time interval between ASO and inclusion into the study for all children was 11.2±2.9 years. Surgery was performed under hypothermic cardiopulmonary bypass. For myocardial protection, cold cardioplegic solution was used. Mean extracorporeal bypass time was 144±36 minutes; aortic cross-clamp time was 103±23 minutes.
Surgical techniques for the ASO, with or without VSD closure, have been previously reported.3 The postoperative course was unremarkable for all patients, with no clinical signs of ischemia. From the surgical point of view, coronary reimplantation was without complications; no patient had an intramural course of the coronary arteries. All patients were fully active and asymptomatic; no patient was on cardioactive medication.
Control subjects for spiroergometry were 30 healthy children matched for age (11.6±4.9 years) and body surface area. Ten healthy adults (25.6±5.4 years) were used as a control group for PET.4
Group 2
Nine male patients who underwent the Ross operation
had PET to assess myocardial perfusion after reimplantation of the
coronary arteries into the sinus of the neoaorta; their mean
age at the time of the investigation was 19.2±7.6 years, with an
average time interval of 4.2±2.1 years after the Ross procedure. Four
patients had prior cardiovascular surgical procedures,
such as subaortic myectomy, commissurotomy of the aortic valve, and
aortic coarctation resection; 2 patients initially had
valvuloplasty of the aortic valve. Surgery was performed under
hypothermic cardiopulmonary bypass and cardioplegic solutions.
Mean extracorporal bypass time was 164.8±37.7 minutes; aortic
cross-clamp time was 117.1±26.1 minutes. Coronary artery ostia
buttons were reimplanted into the sinus of the autograft valve, and the
right ventricular outflow tract reconstruction was
accomplished with an allograft valve. Detailed surgical techniques were
previously reported.5 All
patients were fully active and clinically asymptomatic,
with a normal ECG at rest and exercise; none of the patients was on
cardioactive medication. On cross-sectional
echocardiography, 4 patients had moderate left
ventricular hypertrophy with normal dimensions
of the left ventricle, 7 patients had trivial insufficiency of the
neoaortic valve, and no patient had residual aortic stenosis.
Right and left ventricular function were within the normal
range in all patients (ejection fraction,
0.68±0.04).
Study Protocol and Testing
On arrival in the outpatient clinic, an
intravenous line was placed to administer the myocardial
imaging agent. A blood sample was taken at rest and after exercise for
measuring creatine kinase, troponin T, and glycogen
phosphorylase isoenzyme BB (GPBB) as markers for myocardial
ischemia. Symptoms, exercise tolerance (by spiroergometry for
ASO patients; Ross patients had only a treadmill test without
measurement of gas exchange parameters), left
ventricular function, wall motion analysis (by
echocardiography), rhythm disturbances or
ischemic changes on ECG, and myocardial perfusion (by PET) were
assessed. A 24-hour ECG monitor was fitted before
leaving.
Spiroergometry (Group 1)
The patients exercised on a treadmill using the Bruce
protocol. To examine their cardiopulmonary exercise capacity,
noninvasive determination of gas exchange parameters was
used. Oxygen uptake
(
O2)
and CO2 output
(
CO2)
were measured by an automated O2 and
CO2 analyzer system, the minute
ventilation and the respiratory rate were measured by a
pneumotachometer. The V-slope method according to Beaver et
al6 allowed for the
determination of the anaerobic threshold and the maximal
O2
during treadmill exercise.
Echocardiographic
Studies
Standard cross-sectional, Doppler, and M-mode
echocardiography were performed in all children.
Left ventricular shortening fraction and
contractility were measured at rest and after exercise
by previously described
methods.7 Left
ventricular wall motion was analyzed by
cross-sectional echocardiography using the
16-segment model advocated by the American Society of
Echocardiography.8
PET
MBF was quantified noninvasively at rest and during
adenosine-induced
vasodilatation9 by dynamic
PET with N-13 ammonia. A transmission scan was acquired to correct
photon attenuation. Subsequently, N-13 ammonia (
0.3 mCi/kg) was
injected intravenously at rest, and a dynamic imaging
sequence of 21 frames was acquired over 20 minutes. After 50 minutes to
allow for decay of N-13 ammonia, adenosine (0.14 mg ·
kg1 · min1)
was infused over 5 minutes. Two minutes after the onset of
adenosine infusion, a second dose of N-13 ammonia was
administered, and a dynamic imaging sequence was started. Heart rate,
blood pressure, and ECG were monitored throughout the procedure. MBF at
rest and during hyperemia were quantified using a volumetric
sampling approach and a validated 3-compartment
model.10 Because of the
relation of MBF at rest with the rate-pressure product as an index
of cardiac work,11 resting
flow was normalized to the corresponding rate-pressure
product.
In addition to quantifying global MBF, regional myocardial perfusion was analyzed visually. Summed images of tracer distribution in the last 3 frames of the dynamic sequence were interpreted by 2 experienced observers for the presence of reversible or persistent defects in 9 myocardial segments.
Coronary Angiography
Cardiac catheterization was
undertaken in patients with pathological PET perfusion scans. Aortic
root and selective coronary artery angiography were performed
under local anesthesia in one patient and under general
anesthesia in 4 patients using the femoral artery approach;
selective coronary artery angiography was performed with
coronary catheters between 4F and 5F. Coronary artery
angiograms were performed by manual injection of contrast
medium.
Creatine Kinase, Troponin T, and GPBB
(Group 1)
Creatine kinase, troponin T, and GPBB (ELISA, Pace
Corp) were measured at rest and 2 hours after maximal exercise as
indicators of myocardial ischemia.
Statistical Analysis
Mean and SDs were calculated for all continuous
variables. Differences between the individual groups were tested
for significance by 1-way ANOVA and the post hoc test. Changes from
baseline to adenosine stress were compared by the paired
Students t test.
Univariate analysis of the effects of each
continuous variable was performed with linear regression. All tests
of significance were 2-tailed, and a value of
P<0.05 was considered
statistically significant.
| Results |
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Echocardiographic
Studies
Echocardiographic measurements of
fractional shortening and ejection fraction were normal in all patients
at rest and after maximal exercise. Satisfactory images for regional
wall motion analysis were available in 28 patients. Wall motion
abnormalities were absent under resting conditions, despite a
dyskinetic area in the septal region of one patient, which was
attributed to a large, patch-closed VSD. Dyskinetic areas could be
detected after exercise in 2 patients in the ASO group; they were
located in the anterolateral segments of the myocardium.
One patient had isolated d-TGA with both coronary arteries
transposed and was operated on as a newborn, and the other had DORV
with a single coronary artery and the left coronary
artery being a branch of the transposed right coronary artery
and had 2-stage surgery, with initial pulmonary artery
banding.
None of the children had evidence of neoaortic stenosis or significant aortic regurgitation; 1 child had mild supravalvular pulmonary stenosis with a maximal Doppler gradient of 40 mm Hg. None of the Ross patients had obstruction of the left or right ventricular outflow tract.
MBF
MBF at rest, when normalized to the corresponding
rate-pressure product, was significantly higher in the group of
children after ASO than it was in patients after the Ross procedure and
in healthy young adults (ASO: 112.2±27.7 mL · 100
g1 · min1
versus Ross: 61.0±17.2 mL · 100 g1 ·
min1,
P<0.001; versus controls:
77.4±16.49 mL · 100 g1 ·
min1,
P<0.005). The MBF of Ross
patients and normal adolescents did not differ
significantly.
Adenosine-induced vasodilatation resulted in a significantly increased MBF for all 3 groups, but it was significantly reduced in those groups after reimplantation of the coronary arteries (ASO: 263.2±44.1 mL · 100 g1 · min1 and Ross: 239.0±96.0 mL · 100 g1 · min1 versus controls: 310.3±75.4 mL · 100 g1 · min1; P<0.02).
As a result of the increased MBF at rest and the lower MBF
during adenosine infusion, CFR was markedly attenuated in the
group of patients after ASO than in either those who had the Ross
operation or in healthy adolescents (ASO: 2.54±0.61 mL · 100
g1 · min1
versus Ross: 3.99±1.49 mL · 100 g1 ·
min1,
P<0.005; versus controls:
4.09±0.95 mL · 100 g1 ·
min1,
P<0.001;
Table
).
|
In ASO patients, no significant correlation could be calculated between MBF or CFR and gas exchange parameters, ejection fraction, fractional shortening, and levels of GPBB, creatine kinase, and troponin T. MBF and CFR in ASO and Ross patients were not correlated to total bypass or aortic cross-clamp times.
Qualitative PET Analysis
Visual analysis of the PET images revealed
adenosine-induced reversible perfusion defects in 5 of 21
children (24%) after ASO (1 anterior, 2 anterolateral, and 2 lateral
defects), but no reversible, stress-induced perfusion defects were
detected in the group of Ross patients.
Persistent defects were found in 2 additional ASO patients; one was septal and the other was lateral. The septal persistent defect in one child was attributed to a large VSD, which was closed by patch during corrective surgery. The incidence of perfusion abnormalities was similar in children with ASO in the newborn period and children with complex TGA and 2-stage repair.
Creatine Kinase, Troponin T, and GPBB
(Group 1)
On average, all laboratory parameters
measured in the group of switch patients (group 1) were normal at rest
and were not elevated 2 hours after exercise. Patients with
stress-induced perfusion defects on PET scanning, when compared with
those without defects, had high resting levels of GPBB and a
significant rise in these levels after exercise (from 23.4±7.6 to
28.9±9.3 µg/L in those with defects and from 14.0±5.3 to 13.5±4.8
µg/L in those without defects;
P<0.002).
Coronary Angiography
Aortic root and selective coronary artery
angiography were performed in 5 patients with reversible perfusion
defects after vasodilatation with adenosine in PET. Three
children had isolated d-TGA, one had an associated perimembranous VSD
that was closed during the ASO, and one patient had DORV with
subpulmonary VSD. Four children had previous balloon
atrioseptostomy. The ASO was performed in 4 children within the first 2
weeks of life, and the one with DORV was operated on at the age of 234
days. No coronary obstruction was detected in any of the 5
patients with postoperative cardiac catheterization and
coronary angiography; the coronary ostia tended to
appear elliptical 7 to 10 mm cranial of the aortic sinus
(Figure 1
). The region of the sinotubular junction was
generally not detectable anymore. All patients had right dominance of
the coronary circulation, with a large right coronary
artery that gave rise not only to the posterior descending artery, but
also to the posterolateral branches, thereby perfusing the right
ventricular free wall and the inferoseptal and
posterolateral wall of the left ventricle. A remarkably small caliber
of the left anterior descending artery in the distal part was a common
finding in all patients. There was no circumscript stenosis,
disruption, or obstruction of the left anterior descending or other
coronary artery branches
(Figure 2
).
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| Discussion |
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Global left ventricular function was normal in all patients (groups 1 and 2), with a physiological increase of the ejection fraction and fractional shortening after exercise. However, on 2D echocardiography, 2 patients in the ASO group had stress-induced dyskinetic areas within the anterolateral region of the myocardium; this observation could be confirmed by PET imaging, which showed reversible stress-induced perfusion defects in the same area of the left ventricle.
Three patients in group 1 had reversible, stress-induced perfusion defects on PET scanning but had normal echograms at rest and after exercise. Most of the defects involved only a small area of a segment; these perfusion scan abnormalities reflect arteriolar or capillary processes, and the high sensitivity of PET myocardial perfusion imaging may result in the detection of defects that are too small to cause detectable alterations in ventricular function or regional wall motion on echograms. In contrast to the findings of Weindling et al,12 who could not detect any perfusion abnormalities assessed by technetium-99 sestamibi in the subgroup of primary ASO, the incidence of perfusion abnormalities in our study was comparable between patients with primary and 2-stage ASO. Perfusion defects may be related to inadequate coronary perfusion due to fibrosis of the suture line around the implanted coronary artery ostia, kinking, stenosis, or abnormal vasomotion of the coronaries in response to increased myocardial oxygen demand. In addition, one can hypothesize that the translocation of the coronary arteries initiates an intimal proliferation that progresses gradually postoperatively and may lead to impaired myocardial perfusion.13
In general, reimplantation of the coronary arteries may have some adverse effect on myocardial perfusion because in Ross and ASO patients, the MBF after vasodilatation was significantly reduced, with significantly impaired CFR in ASO patients but normal CFR in Ross patients. In all of our switch patients, the orifice of the reimplanted coronary arteries was located high in the ascending aorta, at least 7 mm above the aortic sinuses. Bellhouse and Bellhouse14 observed that the sinus ridge is an invariable and well-marked anatomical feature and that the coronary ostia always lie within the sinuses; if the ostia lay outside the sinuses on the aortic wall, the normal function of the sinus would be lost, and a serious reduction in coronary flow will occur.14 This might explain the difference in coronary flow in the Ross group, where the reimplantation usually happened at the level of the sinuses. The consequence for the surgical procedure would be a reimplantation of the coronaries within the neoaortic sinus.
Nevertheless, the angiographic findings in the ASO group did not reveal any concrete stenosis of the coronary arteries. A common finding was hypoplasia of the left anterior descending artery in the distal part; however, this finding does not explain the global decrease in CFR, because the right coronary artery was dominant in all of those patients.
The significantly elevated levels of GPBB in patients with stress-induced perfusion defects are interesting; these levels corroborate the presence of myocardial ischemia. The isoenzyme BB of glycogen phosphorylase is the predominant isotype in human myocardium; because it is the key enzyme of glycogenolysis, the release of GPBB from injured myocardium may reflect the burst of glycogenolysis initiated during acute myocardial ischemia.15
The specific mechanism of GPBB release adds some new aspects to the laboratory diagnosis of acute myocardial ischemia that are different from other blood serum markers of myocardial damage, such as creatine kinase and its isoenzymes MB and MM and cardiac troponin T; levels of these markers were normal in our patients.
The reason for the increased MBF at rest in the group of ASO children remains unclear and contributes to the attenuated CFR. The effects of hemodynamic alterations in the expression of genes coding for the contractile proteins are well established16 ; whether this leads to derangements in myocardial energy metabolism, elevated oxygen demand, and elevated MBF under resting conditions remains hypothetical and needs further investigation.
Cardiac efferent sympathetic signals modulate
MBF.17 Increased sympathetic
activity dilates the coronary resistance vessels and thus
increases MBF, which is modulated by endothelial
function; however, resting coronary flow is not substantially
affected by either humoral or neural adrenergic influences. The
increase in coronary flow response to sympathetic stimulation
correlates with the magnitude of regional stores of
norepinephrine in cardiac sympathetic nerve terminals,
which correlates with contractility, oxygen demand, and
reactive metabolic vasodilatation or direct activation of
ß-adrenergic receptors on smooth muscle and
endothelial cells in the vessel wall. Coronary
vasodilatation may also result from the direct stimulation of
2-adrenergic receptors in intact
endothelial cells and the release of nitric oxide,
presumably through the activation of local kinin
synthesis.18
Translocation of the coronary arteries may result in partial myocardial sympathetic denervation, with a potential influence on MBF, and impaired development of vasoreactive capacity or growth potential of the coronaries in Ross and (more so) ASO patients.
In addition, abnormalities of the coronary walls may occur as a primary abnormality or as part of a multisystem disorder, and they may mimic atherosclerotic disease, with impairment of MBF and CFR.19 Endothelial function and coronary vasoreactivity may be altered substantially in children with TGA, independent of surgical manipulations and coincident with congenital abnormalities of cardiac anatomy.
The limitations of the study are mainly derived from the ethical constraints concerning radiation exposure in children; no published blood flow data in normal children at any age are available. Young adult volunteers older than 18 years of age were used as a normal control group, and adolescents with a previous Ross operation were used as controls for coronary reimplantation; in both groups, age-related influences on the results cannot be ruled out completely. By splitting patients with TGA and Ross operations into different age groups, no trend in myocardial flow parameters, which may be influenced by age, was identified.
| Conclusions |
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Received October 3, 2000; revision received January 3, 2001; accepted January 18, 2001.
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S. R.F.F. Pedra, C. A.C. Pedra, A. A. Abizaid, S. L.N. Braga, R. Staico, R. Arrieta, J. R. Costa Jr, V. D. Vaz, V. F. Fontes, and J. E. R. Sousa Intracoronary Ultrasound Assessment Late After the Arterial Switch Operation for Transposition of the Great Arteries J. Am. Coll. Cardiol., June 21, 2005; 45(12): 2061 - 2068. [Abstract] [Full Text] [PDF] |
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S. G Raja, A. Shauq, and M. Kaarne Outcomes after Arterial Switch Operation for Simple Transposition Asian Cardiovasc Thorac Ann, June 1, 2005; 13(2): 190 - 198. [Abstract] [Full Text] [PDF] |
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A. M. Taylor, S. Dymarkowski, P. Hamaekers, R. Razavi, M. Gewillig, L. Mertens, and J. Bogaert MR Coronary Angiography and Late-Enhancement Myocardial MR in Children Who Underwent Arterial Switch Surgery for Transposition of Great Arteries Radiology, February 1, 2005; 234(2): 542 - 547. [Abstract] [Full Text] [PDF] |
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L Hui, A K T Chau, M P Leung, C S W Chiu, and Y F Cheung Assessment of left ventricular function long term after arterial switch operation for transposition of the great arteries by dobutamine stress echocardiography Heart, January 1, 2005; 91(1): 68 - 72. [Abstract] [Full Text] [PDF] |
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R. Formigari, A. Toscano, A. Giardini, G. Gargiulo, R. Di Donato, F. M. Picchio, and L. Pasquini Prevalence and predictors of neoaortic regurgitation after arterial switch operation for transposition of the great arteries J. Thorac. Cardiovasc. Surg., December 1, 2003; 126(6): 1753 - 1759. [Abstract] [Full Text] [PDF] |
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M Hauser, F M Bengel, A Hager, A Kuehn, S G Nekolla, H Kaemmerer, M Schwaiger, and J Hess Impaired myocardial blood flow and coronary flow reserve of the anatomical right systemic ventricle in patients with congenitally corrected transposition of the great arteries Heart, October 1, 2003; 89(10): 1231 - 1235. [Abstract] [Full Text] [PDF] |
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The Task Force on the Management of Grown Up Conge, Task Force members, J. Deanfield, E. Thaulow, C. Warnes, G. Webb, F. Kolbel, A. Hoffman, K. Sorenson, H. Kaemmerer, et al. Management of Grown Up Congenital Heart Disease Eur. Heart J., June 1, 2003; 24(11): 1035 - 1084. [Full Text] [PDF] |
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M. Hauser, A. Kuehn, J. Hess, G. Oskarsson, E. Pesonen, P. Munkhammar, S. Sandstrom, and P. Jogi Myocardial Perfusion in Patients With Transposition of the Great Arteries After Arterial Switch Operation * Reply Circulation, May 13, 2003; 107 (18): e126 - e126. [Full Text] [PDF] |
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H. H. Hovels-Gurich, M.-C. Seghaye, Q. Ma, M. Miskova, R. Minkenberg, B. J. Messmer, and G. von Bernuth Long-term results of cardiac and general health status in children after neonatal arterial switch operation Ann. Thorac. Surg., March 1, 2003; 75(3): 935 - 943. [Abstract] [Full Text] [PDF] |
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E De Caro, G P Ussia, M Marasini, and G Pongiglione Transoesophageal atrial pacing combined with transthoracic two dimensional echocardiography: experience in patients operated on with arterial switch operation for transposition of the great arteries Heart, January 1, 2003; 89(1): 91 - 95. [Abstract] [Full Text] [PDF] |
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G. Oskarsson, E. Pesonen, P. Munkhammar, S. Sandstrom, and P. Jogi Normal Coronary Flow Reserve After Arterial Switch Operation for Transposition of the Great Arteries: An Intracoronary Doppler Guidewire Study Circulation, September 24, 2002; 106(13): 1696 - 1702. [Abstract] [Full Text] [PDF] |
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