| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2002;106:1696.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
From the Departments of Pediatric Cardiology (G.O., E.P., P.M.), Radiology (S.S.), and Cardiothoracic Surgery (P.J.), University Hospital of Lund, Sweden.
Correspondence to Gylfi Oskarsson, MD, Department of Pediatric Cardiology, Lund University Hospital, S-221 85 Lund, Sweden. E-mail oggylfi{at}hn.is
| Abstract |
|---|
|
|
|---|
Methods and Results Eleven symptom-free children were studied between 4 and 11 (median 6.0) years after the ASO. Flow velocity in the left anterior descending (LAD) and right coronary arteries (RCA) was measured with a 0.014-inch Doppler FloWire (Cardiometrics) before and after intracoronary injection of adenosine (0.5 µg/kg) and nitroglycerin (5 µg/kg). CFR was defined as the ratio of hyperemic to basal average peak velocity (APV). The median (range) CFR in the LAD was 3.7 (3.0 to 4.8) and 3.4 (2.9 to 4.8) in the RCA. The increase in APV after intracoronary injection of nitroglycerin was 300% (240% to 420%) in the LAD and 260% (190% to 460%) in the RCA. APV at rest was 15.0 (14.0 to 21.0) cm/s in the LAD and 16.0 (9.6 to 30.0) cm/s in the RCA. A linear relation was found between right ventricular systolic pressure and resting APV in the RCA (r=0.77, P=0.0056), and between resting APV and CFR (r=-0.61, P<0.05) in the RCA.
Conclusions The CFR and coronary vasoreactivity to nitroglycerin in children treated for transposition of the great arteries with the ASO was within normal limits. Increased right ventricular pressure and myocardial hypertrophy can cause increased resting coronary flow velocity in the RCA and affect CFR negatively.
Key Words: transposition of the great vessels surgery adenosine blood flow
| Introduction |
|---|
|
|
|---|
Coronary flow reserve (CFR) measures the extent to which coronary blood flow can be maximally increased above resting flow.3 Recent studies, performed with positron emission tomography (PET), have shown moderately to severely reduced global myocardial CFR in children treated for TGA with the ASO .46 Although these results are of great concern, they have not been confirmed by other available methods. The present study used intracoronary Doppler guidewire (IDGW) to measure resting coronary flow velocity and the reactivity of the coronary arteries to both epicardial and microvascular coronary vasodilators in children treated for TGA with the ASO.
| Methods |
|---|
|
|
|---|
Study Protocol
On day 1, the children underwent clinical examination, ECG, and echocardiography. On day 2, cardiac catheterization with selective coronary angiography was performed, followed by measurements of coronary flow velocity with an IDGW. Myocardial scintigraphy at rest was performed on day 3.
Echocardiographic Studies
Standard two-dimensional, Doppler, and M-mode echocardiography were performed in all children. Left ventricular shortening fraction and contractility were measured, and wall motion was described qualitatively.
Myocardial Single-Photon Emission Computed Tomography
Myocardial perfusion at rest was studied after an intravenous injection of 99mTc tetrofosmin. The dose was 3 MBq per kg body weight, with a minimum dose of 50 MBq. Approximately 60 minutes after injection, single-photon emission computed tomography (SPECT) was performed with a dual head
camera. Data were acquired in a 64x64 matrix, >180° from left posterior oblique to right anterior oblique during 20 minutes. The transaxial slices were realigned along the heart axis, and short-axis, vertical, and horizontal long-axis slices were obtained.
Cardiac Catheterization
The examination was performed under general anesthesia to maintain stable arterial blood gas values and hemodynamic conditions throughout the study. ECG and blood pressure were monitored continuously. The anesthesia was induced by intravenous thiopental, fentanyl, and rocuronium, and maintained with between 0.2% and 0.5% inhaled isoflurane. Right and left heart catheterization was performed with the use of 4F Judkins right and left coronary catheters. An intravenous bolus of heparin (50 U/kg) was given, and the coronary ostia then identified by small manual injections of contrast medium (Omnipaque, Nycomed) in the aortic root. After entering the coronary orifice, selective coronary angiography was performed by manual injection.
Measurements of Coronary Flow Velocity and Coronary Function
After coronary angiography, a 0.014-inch Doppler FloWire (Cardiometrics) was advanced into each target coronary artery. The position of the wire was adjusted to obtain the highest possible quality Doppler flow envelope and pure audio sound throughout the cardiac cycle. Continuous flow velocity profiles and audio signals, along with simultaneous ECG, were displayed on screen and recorded on videotape. Doppler flow velocity spectra were analyzed online by the signal analyzer (FloMap, Cardiometrics) to determine average peak velocity (APV), in which APV is the time-averaged value of the instantaneous peak velocity samples over the last 2 cardiac cycles. Diastolic (PFVd) and systolic peak flow velocity (PFVs) was measured off-line from the videotape and averaged over 3 cardiac cycles. Registrations were performed serially in the left anterior descending (LAD) branch of the left coronary artery and the RCA, respectively. After stable baseline signals were obtained in each vessel after angiography, hyperemic responses to adenosine and nitroglycerin (NTG) were determined. The drugs were given by a rapid bolus injection in the intracoronary catheter. Adenosine was always injected first (0.5 µg/kg). Because the optimal dose of intracoronary adenosine for children is not known, and maximal hyperemia had to be obtained, the measurement was repeated with a double dose (1.0 µg/kg) in the first children enrolled in the study. This did not result in higher CFR values in either LAD or RCA. The coronary flow velocity was allowed to return to baseline before NTG was injected (5 µg/kg). CFR was defined as the ratio of hyperemic APV after intracoronary injection of adenosine to basal APV.
Statistical Analysis
Results are presented as median (range). Comparison between coronary flow parameters at rest in the LAD and RCA were performed by Students t test for paired observations. Linear regression analysis was used to calculate correlation coefficients (r). A probability value <0.05 was considered significant.
| Results |
|---|
|
|
|---|
Intracoronary Doppler registrations could be obtained in the LAD in 9 of 11 subjects (Figure 1A) and in the RCA in all 11 subjects (Figure 1B).
|
Coronary Flow Velocity
Coronary flow velocities at rest in the LAD and RCA are shown in the Table. The APV and PFVd were similar in the 2 vessels, although PFVs was higher in the RCA (22.0 cm/s) than in the LAD (15.0 cm/s). The difference did not reach statistical significance (paired t test). There was a greater variability in APV in the RCA compared with the LAD (SD 6.8 cm/s versus 2.9 cm/s). There was a significant positive linear relation between right ventricular systolic pressure and RCA flow velocity at rest, both APV (r=0.77, P=0.0056, Figure 2) and PFVd (r=0.67, P=0.023). The patient with the highest resting APV (21.0 cm/s) in the LAD was found to have a small coronary fistula between the LAD and the pulmonary trunk.
|
|
Coronary Flow Reserve
The CFR values obtained by intracoronary adenosine injection and the coronary flow response to intracoronary NTG are shown in the Table, and examples of CFR registrations are shown in Figure 3A (LAD) and 3B (RCA). The 2 children with the lowest CFR in the RCA (2.9) had right ventricular hypertrophy, moderately increased right ventricular pressure, and the highest resting APV in the RCA. There was a significant negative linear relation between resting APV and CFR in the RCA (r=-0.61, P<0.05, Figure 4) The patient with the lowest CFR in the LAD (3.0) had the highest resting coronary flow velocity, and a small coronary fistula between the LAD and the pulmonary trunk.
|
|
| Discussion |
|---|
|
|
|---|
The coronary arteries in children treated with ASO for TGA are surgically relocated to the aortic root, and this may cause coronary flow abnormalities, even late after the operation.1,2,11 Myocardial perfusion defects found in asymptomatic survivors of the ASO have raised further concerns regarding the long-term function and patency of the coronary arteries in this patient group, recently supported by myocardial PET studies revealing reduced global myocardial CFR.4,6,12 Documented cases of true myocardial ischemia or sudden death in this patient group have however been exclusively associated with anatomic coronary stenosis.11,13
Coronary Flow Velocity at Rest
The resting LAD Doppler flow pattern found in this study was similar to previous observations in children and adults with normal coronary arteries.8,10,14,15 PET studies have indicated that myocardial blood flow at rest may be increased in subjects operated for TGA with the ASO.46 The basal flow velocities in both LAD and RCA in this study are lower than what has been reported in previous studies in children of comparable age and in adults, and this speaks strongly against increased coronary blood flow at rest.8,10,14 The peak systolic flow velocity was higher in the RCA than in the LAD (22.0 cm/s versus 15.0 cm/s) in our subjects. This agrees well with earlier animal studies, and may be explained by lower systolic pressure and lower intramyocardial resistance against coronary flow in the right ventricle.16
Right ventricular systolic pressure seems to affect both resting RCA flow velocity and CFR in the RCA. There was a positive linear relation between resting flow velocities in the RCA (both APV and PFVd) and right ventricular systolic pressure. A significant negative linear relation between APV at rest in the RCA and CFR was also found. The lowest CFR values in the RCA were found in the patients with increased right ventricular pressure, right ventricular hypertrophy, and high resting coronary flow velocity. RCA flow velocity at rest has been shown to have a positive correlation to systolic right ventricular pressure in children with congenital heart defects in one previous study.17 Left ventricular hypertrophy and increased left ventricular pressure has similarly been shown to be related to increased diastolic flow velocity at rest and reduced CFR in the LAD in several studies.18,19
Coronary Vasoreactivity
CFR can be measured with PET techniques, cine MR imaging, and Doppler ultrasound.4,6,17,20 It is well established that the normal adult heart can increase coronary flow/myocardial perfusion maximally by 2.5 to 4 times the resting value, but normal CFR values are different for each method and vasodilator used.4,10,20,21
Cardiac sympathetic nerves play a part in modulating the function of the coronary arteries.22 The ASO causes a loss of coronary adrenergic nerve supply, and it is conceivable that this might affect coronary vasoreactivity. The median (range) CFR for the subjects of this study was 3.7 (3.0 to 4.8) in the LAD, and 3.4 (2.9 to 4.8) in the RCA. The only available studies measuring CFR by IDGW in healthy children (aged 10 to 19 years) have shown mean values of 3.4 to 3.7.8,9 These CFR values are comparable to our results and indicate that the CFR, or more specifically the vasoreactivity of the myocardial microvasculature, is normal in our patient group.
It has further been speculated that the manipulation of the coronary arteries during the ASO, or development of fibrosis in the area of coronary reinsertion, may negatively affect the function of the proximal coronary vessels.4,6 NTG has predominant effects on the epicardial coronary arteries and a lesser effect on coronary resistance vessels <100 µm in diameter.23 In the present study, the median (range) increase in flow velocity after intracoronary administration of NTG was 300% (240% to 420%) for the LAD, and 260% (190% to 460%) for the RCA. There are no documented values for increase in coronary flow velocity after NTG administration in healthy children, but our results are comparable to values obtained in healthy adults.24,25
CFR Measured by Myocardial PET
CFR has been evaluated in children treated for TGA with the ASO in 3 recent studies with the use of PET for evaluation of global myocardial perfusion.46 Studies performed by the Munich group have found mean (SD) global myocardial CFR after intravenous administration of adenosine to be between 2.5 and 3.0 (0.6) in children examined 10 to 11 years after the ASO for TGA, compared with between 4.1 and 4.6 (0.9 and 1.0) in healthy adults.4,6 An additional PET study in a younger patient group examined 1.8 years after the ASO for TGA found global myocardial CFR to be only 1.19 (0.10) after intravenous administration of dipyridamole (0.56 mg/kg).5 The children had normal hemodynamics and the reduced CFR was interpreted as a reduced global vasoreactivity and speculated to be caused by the ASO or the cardiac malformation.
Comparison of CFR Measurements With IDGW and PET
Our findings of normal CFR and a normal flow velocity increase after intracoronary administration of NTG in both the LAD and RCA are in contradiction to earlier PET results showing moderately to severely reduced global myocardial CFR in patients treated for TGA with the ASO.46 Changes in coronary flow velocity measured with IDGW have been shown to be linearly related to absolute flow when the cross section of the vessel remains unchanged.26,27 When adenosine is administered intracoronary the epicardial vessels dilate, and the dilatation is linearly related to the increase in flow velocity.28 The CFR values obtained by this method are therefore lower than those obtained by measuring increases in global myocardial perfusion, as is done with the PET method. When this is taken into account, the CFR in our patients (3.4 to 3.7) is equal to the CFR obtained in healthy adults by PET (4.1 to 4.6).4,6
The results of the PET studies in children treated for TGA with the ASO are confounding, especially the extremely low CFR values found by Yates et al.5 The children studied were clinically asymptomatic, but would be expected to show signs of myocardial ischemia if they could only increase myocardial perfusion by 1.2 times the resting value. Exercise testing in a group of TGA children with reduced global myocardial CFR (mean value of 2.5) according to PET, did not show any sign of myocardial ischemia.6 Previous studies in which exercise testing has been performed in children operated for TGA with the ASO have shown that ECG changes suggestive of myocardial ischemia are rare.13
Open-heart surgery in the neonatal period may have a temporal adverse effect on the myocardium. Neonates operated for a ventricular septal defect, with entirely normal postoperative hemodynamics, had low CFR (1.5 to 1.6), according to a PET study performed
2 weeks after surgery.29 Studies measuring global myocardial CFR with the PET method in patients operated with open-heart surgery in the neonatal period have shown low CFR values, irrespective of the type of heart malformation or type of surgery.4,5,29 CFR in these studies has tended to be higher the older the subjects are at the time of examination. This opinion is further supported by the observation that children operated at an older age with reimplantation of the coronary arteries (Ross operation) have normal CFR, according to PET.6 This suggests that there is a link between decreased CFR and neonatal open-heart surgery, but not to coronary surgery as such.
The significance of reduced global myocardial CFR as measured by PET in children treated for TGA with the ASO is unclear, and should not be interpreted as proof of abnormal coronary function or increased risk of myocardial ischemia at long-term follow-up.
Coronary Angiography After ASO
Symptom-free patients treated for TGA with the ASO can have coronary stenosis or even occlusions.1,2 Our findings of an unsuspected total coronary occlusion in one of our patients and a coronary fistula in another show that coronary angiography may be of benefit for some patients, even if their clinical status and noninvasive studies do not give a suspicion of coronary abnormalites.30
Methodology
Cardiac catheterization was performed under anesthesia, maintained with low-dose inhaled isoflurane, unlikely to affect coronary flow. A higher dose of a similar drug, halothane, has not been shown to affect coronary flow reserve in children.8 Measurements of coronary flow velocity and CFR with the IDGW have been thoroughly validated, both in vitro and in vivo.26,27 The method has been reported to be safe, and there were no coronary complications in our study, neither during selective coronary angiography nor during intracoronary Doppler registration. To minimize systemic hemodynamic effects, we chose to give adenosine intracoronary in the indwelling coronary catheter. Adenosine has been shown to be superior to dipyridamole in inducing true maximal coronary flow, and normal values for CFR after adenosine injection are well established in adults.3,10,21,28 The dose given (0.5 µg adenosine/kg in both LAD and RCA) was estimated to be equivalent to the 12- and 18-µg doses used for respective vessels in adults. We took care to be sure that we were achieving true maximal flow velocity by administrating double adenosine doses in the first patients, and this did not result in a higher CFR than the dose of 0.5 µg/kg.
Study Limitations
Intracoronary measurements of coronary flow velocity and CFR in healthy children of the same age could not be included in our study due to ethical constraints, but normal values for healthy children and adults obtained by the same technique are available and can be used as comparison.810
Because both adenosine and NTG are endothelium-independent vasodilators, the present study did not evaluate coronary endothelial function. That would require intracoronary injection of acetylcholine, and because this drug may cause coronary spasms and other serious side effects, we found the risk of this procedure unacceptable for our study group.8
Conclusions
Intracoronary Doppler measurements of CFR and coronary vasoreactivity to NTG in children treated for TGA with the ASO do not indicate any negative long-term effects of either the operation or the cardiac malformation on coronary function. Residual lesions of hemodynamic significance causing myocardial hypertrophy, however, may have adverse effects on CFR in these patients.
| Acknowledgments |
|---|
Received March 18, 2002; revision received July 11, 2002; accepted July 11, 2002.
| References |
|---|
|
|
|---|
2. Bonnet D, Bonhoeffer P, Piechaud J-F, et al. Long-term fate of the coronary arteries after the arterial switch operation in newborns with transposition of the great arteries. Heart. 1996; 76: 274279.
3. Hoffman JIE. A critical review of coronary reserve. Circulation. 1987; 75: I611.[Medline] [Order article via Infotrieve]
4. Bengel FM, Hauser M, Duvernoy CS, et al. Myocardial blood flow and coronary flow reserve late after anatomical correction of transposition of the great arteries. J Am Coll Cardiol. 1998; 32: 19551961.
5. Yates RW, Marsden PK, Badawi RD, et al. Evaluation of myocardial perfusion using positron emission tomography in infants following a neonatal arterial switch operation. Pediatr Cardiol. 2000; 21: 111118.[CrossRef][Medline] [Order article via Infotrieve]
6. Hauser M, Bengel FM, Kuhn A, et al. Myocardial blood flow and flow reserve after coronary reimplantation in patients after arterial switch and Ross operation. Circulation. 2001; 103: 18751880.
7. Yacoub MH, Radley-Smith R. Anatomy of the coronary arteries in transposition of the great arteries and methods for their transfer in anatomical correction. Thorax. 1978; 33: 418424.
8. Giulia Gagliardi M, Crea F, Polletta B, et al. Coronary microvascular endothelial dysfunction in transplanted children. Eur Heart J. 2001; 22: 254260.
9. Itoi T, Oka T, Hamaoka K. Abnormal coronary flow reserve in a 13-year-old girl with an absent left circumflex coronary artery. Pediatr Cardiol. 2001; 22: 165166.[CrossRef][Medline] [Order article via Infotrieve]
10. Kern MJ, Bach RG, Mechem CJ, et al. Variations in normal coronary vasodilatory reserve stratified by artery, gender, heart transplantation and coronary artery disease. J Am Coll Card. 1996; 28: 11541160.[Abstract]
11. Tsuda E, Imakita M, Yagihara T, et al. Late death after arterial switch operation for transposition of the great arteries. Am Heart J. 1992; 124: 15511557.[CrossRef][Medline] [Order article via Infotrieve]
12. Vogel M, Smallhorn JF, Gilday D, et al. Assessment of myocardial perfusion in patients after the arterial switch operation. J Nucl Med. 1991; 32: 237241.
13. Massin M, Hovels-Gurich H, Dabrits S, et al. The results of the Bruce treadmill test in children after arterial switch operation for simple transposition of the great arteries. Am J Cardiol. 1998; 81: 5660.[CrossRef][Medline] [Order article via Infotrieve]
14. Hamaoka K, Onouchi Z, Ohmochi Y, et al. Coronary arterial flow-velocity dynamics in children with angiographically normal coronary arteries. Circulation. 1995; 92: 24572462.
15. Jureidini SB, Marino CJ, Waterman B, et al. Transthoracic Doppler echocardiography of normally originating coronary arteries in children. J Am Soc Echocardiogr. 1998; 11: 409420.[CrossRef][Medline] [Order article via Infotrieve]
16. Lowensohn HS, Khouri EM, Gregg DE, et al. Phasic right coronary artery blood flow in conscious dogs with normal and elevated right ventricular pressures. Circ Res. 1976; 39: 760776.
17. Watanabe N, Awa S, Akagi M, et al. Effects of heart rate and right ventricular pressure on right coronary arterial flow and its systolic versus diastolic distribution in a variety of congenital heart disease in children. Pediatr Int. 2000; 42: 476482.[CrossRef][Medline] [Order article via Infotrieve]
18. Hildick-Smith DJR, Shapiro LM. Coronary flow reserve improves after aortic valve replacement for aortic stenosis: an adenosine transthoracic echocardiography study. J Am Coll Cardiol. 2000; 36: 18891896.
19. Oskarsson G, Pesonen E. Coronary flow abnormalities in neonates with aortic stenosis. J Pediatrics. 2000; 137: 875877.[CrossRef][Medline] [Order article via Infotrieve]
20. Sakuma H, Koskenvuo JW, Niemi P, et al. Assessment of coronary flow reserve using fast velocity-encoded cine MR imaging: validation study using positron emission tomography. Am J Roentgenol. 2000; 175: 10291033.
21. Lim HE, Shim WJ, Rhee H, et al. Assessment of coronary flow reserve with transthoracic Doppler echocardiography: comparison among adenosine, standard-dose dipyridamole, and high-dose dipyridamole. J Am Soc Echocardiogr. 2000; 13: 264270.[CrossRef][Medline] [Order article via Infotrieve]
22. DiCarli MF, Tobes MC, Mangner T, et al. Effects of cardiac sympathetic innervation on coronary blood flow. N Engl J Med. 1997; 366: 12081215.
23. Harrison DG, Bates JN. The nitrovasodilators: new ideas about old drugs. Circulation. 1993; 87: 14611467.
24. Egashira K, Inou T, Hirooka Y, et al. Evidence of impaired endothelium dependent coronary vasodilation in patients with angina pectoris and normal coronary angiograms. N Engl J Med. 1993; 328: 16591664.
25. Simonetti I, Rossen JD, Winniford MD, et al. Biphasic effects of nitroglycerin on coronary hemodynamics in normal subjects. Z Kardiol. 1989; 78: 5255.[Medline] [Order article via Infotrieve]
26. Marcus ML, Wilson RF, White CW. Methods of measurement of myocardial blood flow in patients: a critical review. Circulation. 1987; 76: 245253.
27. Doucette JW, Corl PD, Payene HM, et al. Validation of a Doppler guide wire for intravascular measurement of coronary artery flow velocity. Circulation. 1992; 85: 18991911.
28. Lupi A, Buffon A, Finocchiaro ML, et al. Mechanisms of adenosine-induced epicardial coronary artery dilatation. Eur Heart J. 1997; 18: 614617.
29. Donelly JP, Raffel DM, Shulkin BL, et al. Resting coronary flow and coronary flow reserve in human infants after repair or palliation of congenital heart defects as measured by positron emission tomography. J Thorac Cardiovasc Surg. 1998; 115: 103110.
30. Mavroudis C, Backer CL, Duffy E, et al. Pediatric coronary artery bypass for Kawasaki, congenital, post arterial switch, and iatrogenic lesions. Ann Thorac Surg. 1999; 68: 506512.
This article has been cited by other articles:
![]() |
S. M. Paridon, B. S. Alpert, S. R. Boas, M. E. Cabrera, L. L. Caldarera, S. R. Daniels, T. R. Kimball, T. K. Knilans, P. A. Nixon, J. Rhodes, et al. Clinical Stress Testing in the Pediatric Age Group: A Statement From the American Heart Association Council on Cardiovascular Disease in the Young, Committee on Atherosclerosis, Hypertension, and Obesity in Youth Circulation, April 18, 2006; 113(15): 1905 - 1920. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. G. Gagliardi, R. Adorisio, F. Crea, P. Versacci, R. Di Donato, and S. P. Sanders Abnormal Vasomotor Function of the Epicardial Coronary Arteries in Children Five to Eight Years After Arterial Switch Operation: An Angiographic and Intracoronary Doppler Flow Wire Study J. Am. Coll. Cardiol., October 18, 2005; 46(8): 1565 - 1572. [Abstract] [Full Text] [PDF] |
||||
![]() |
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] |
||||
![]() |
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] |
||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Circulation Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search Copyright © 2002 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. |