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Coronary flow dynamics in children after repair of Tetralogy of Fallot
International Journal of Cardiology 172 (2014) 122–126
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Coronary flow dynamics in children after repair of Tetralogy of Fallot Elhadi H. Aburawi a,c,⁎, Peter Munkhammar c, Marcus Carlsson d, Mohamed El-Sadig b, Erkki Pesonen c a
Departments of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, United Arab Emirates Institute of Public Health, College of Medicine and Health Sciences, United Arab Emirates University, United Arab Emirates c Departments of Pediatric Cardiology, Skåne University Hospital, Lund University, Sweden d Clinical Physiology and Nuclear Medicine, Skåne University Hospital, Lund University, Sweden b
a r t i c l e
i n f o
Article history: Received 25 November 2013 Received in revised form 15 December 2013 Accepted 30 December 2013 Available online 9 January 2014 Keywords: Coronary blood flow Fibrosis Post-surgery Right ventricular restrictive physiology Tetralogy of Fallot
a b s t r a c t Objectives: To assess the possible effect of a stiff right ventricle on the coronary flow (CF) in patients with postoperative Tetralogy of Fallot (TOF). Background: Right ventricular restrictive physiology i.e. forward flow during atrial contraction (RVRP), is characteristic to many patients with post-operative TOF. Methods: A total of 34 patients with TOF anatomically corrected through transatrial repair were included. Coronary flow parameters were registered with transthoracic Doppler echocardiography from posterior descending (PDCA) and left anterior descending (LAD) coronary arteries in the same patient in 24/34 (71%) patients. Twenty age-matched healthy children were used as controls. Cardiac magnetic resonance (CMR) imaging was used to detect myocardial fibrosis, RV volume, and RVRP. Results: The mean age at investigation was 10.2 ± 2.8 years. RV end diastolic and end systolic volumes indexed for BSA were larger in patients with RVRP (p = 0.002 and 0.008 respectively). Peak flow velocity in diastole and flow velocity time integral was increased in patients compared to controls. They were increased in the LAD in patients with fibrosis of RV (n = 11) compared to patients without fibrosis (n = 9) (p = 0.01 and 0.047 respectively). LAD coronary flow was especially increased in patients with RVRP (n = 9) as compared with those without (n = 11), (p = 0.006). Conclusions: Patients at mid-term followup after correction of TOF show increase of coronary flow. This increase is more pronounced in patients with fibrosis and RVRP of the RV. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease in childhood. Right ventricular restrictive physiology (RVRP) manifested as an antegrade flow in the pulmonary artery during atrial systole throughout the respiratory cycle is characteristic in many patients after corrective surgery for TOF. The stiff right ventricle (RV) after TOF repair may produce a restrictive physiology when the RV behaves as an almost passive conduit from the right atrium to pulmonary artery for pulmonary blood flow [1,2]. We have documented by cardiac magnetic resonance (CMR) imaging normal diastolic forward flow in pulmonary artery during atrial systole and determined a threshold of mean ≥ 2 SD of the percentage of forward flow during atrial contraction in healthy subjects as a limit for restrictive physiology [3]. There was a strong association between RVRP and right ventricular outflow
tract fibrosis assessed by late gadolinium contrast enhanced (LGE) CMR imaging [3]. One week after cardiopulmonary by-pass (CPB) coronary flow seems to be increased [4]. Coronary flow and, in particular, its diastolic component increases along with the increase of RV pressure [5]. The posterior descending coronary artery (PDCA) flow increases with the increase of right ventricular end diastolic pressure in children with atrial septal defect and pulmonary valve stenosis [6,7]. Coronary flow reserve measured from the right coronary artery (RCA) and left anterior descending coronary artery (LAD) have been reported to improve late after anatomical correction of TOF [8]. The effect of RVRP and fibrosis on coronary flow in patients with TOF after full correction has not been studied so far. The aim of this study was to investigate the coronary flow in patients with TOF after its anatomical correction. 2. Methods
⁎ Corresponding author at: Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, P. O. Box 17666, United Arab Emirates. Tel.: +971 3 7137 462; fax: +971 3 7672022. E-mail address: [email protected] (E.H. Aburawi). 0167-5273/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.12.188
This is a prospective study, carried out in Lund (Sweden) to assess the possible effect of a stiff right ventricle on the coronary flow (CF) in patients with post-operative Tetralogy of Fallot (TOF). Patients with anatomically corrected TOF through transatrial repair and those with pulmonary insufficiency (PI) on Doppler echocardiography, who did not have clinical signs of infection, were included. Patients with absent pulmonary valve, or
E.H. Aburawi et al. / International Journal of Cardiology 172 (2014) 122–126 who had undergone pulmonary valve replacement or those with residual pulmonary stenosis and pressure gradient N 25 mmHg on Doppler echocardiography, or who had associated atrioventricular septal defect, or double outlet right ventricle of Fallot type, or pulmonary atresia with ventricular septum defect (VSD) were excluded. A total of 34 patients were investigated at a mean age of 10.2 ± 2.8, (range 3–16) years. Twenty agematched healthy children were used as controls for coronary artery flow parameters. Forward flow as a percentage of the net forward flow during the cardiac cycle was calculated in a separate series of 12 healthy children (15 ± 3 years) with normal CMR referred for screening of arrhythmogenic right ventricular cardiomyopathy because of a family history of this disease. Standard M- and B-mode and -Doppler echocardiographic studies were performed by one of the investigators (PM) for determining the anatomy and function of the heart. Sequoia™ C512 (Acuson Mountain View, CA, USA) with 4 MHz transducer was used. Coronary flow measurements were performed by (EHA) within 1–2 days of CMR studies. A written consent was obtained from the guardians/parents of the children enrolled in the study. The study protocol conforms to the principles outlined in the declaration of Helsinki [9]. The local ethics committee at Lund University, Sweden approved the study.
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of 200 cm/s. As reported earlier [3] forward flow during atrial contraction in CMR above mean ± 2 SD of healthy subjects was set as a marker of restrictive physiology.
3. Statistical analyses Pearson's correlation analysis was used to test the correlation of QRS duration to fibrosis and right ventricular end-diastolic volume with flow parameters. RV volume was used as a surrogate for RV mass. Unpaired student's t-test was used for comparison between the groups with and without RVRP, with and without fibrosis and with healthy controls. Due to the small sample size and the abnormal distribution of the data the Mann–Whitney–Wilcoxon non-parametric test was used to confirm the results obtained using the parametric t-test. The intra-observer variability was calculated according to the British Standards Institution recommendation [12].
2.1. Coronary flow studies Transthoracic Doppler echocardiography (TTDE) registration was done in all (n = 34) patients and 20 age-matched healthy children. The following adjustments were made in the ultrasound machine for the coronary blood flow and flow velocity measurements [6,10,11]: Space-time in high frame rate (T1), wall filter was set at two thirds (F2) and the colour gain was adjusted to minimize colour flow signal scatter (gate 3). Colour Doppler mix was on. Pulsed Doppler of 4.5 MHz and sweep rate of 100 mm/s were used. Velocity setting of 30–60 cm/s was needed. Measurements were corrected for the angle between the Doppler beam and the coronary flow direction. True velocity was defined as the measured velocity divided by the cosine of the angle between the Doppler beam and the direction of blood. The internal dimension of the LAD was measured from the standard parasternal short-axis view at the R-wave. The callipers were applied to the internal borders 2–3 mm distal to the bifurcation of the left main coronary artery. The velocity scale was decreased to the minimum range and then gradually increased until colour signals were optimized within the vessel lumen. After finding good coronary flow signals, the pulsed Doppler sample volume was placed within the LAD 2–3 mm distal to the bifurcation of the left main coronary artery, and the sample volume was adjusted to 0.5–1.0 mm. A sample volume that gave the best quality envelope and pure sound throughout the cardiac cycle was chosen. An apical 4-chamber view was obtained. The probe was angulated anteriorly and rotated anticlockwise until the disappearance of right ventricle from the view. The technique was otherwise similar to that used in the registration of the flow in the LAD. The coronary flow parameters; peak flow velocity in diastole (PFVd), total systolic and diastolic flow velocity time integral (VTIt) and coronary flow (CF) were registered from LCA and PDCA. All images were saved on a magnetic–optic disc and reviewed in a slow motion, and analysed in single frame advance mode. The success rate for Doppler registration of flow in both coronary arteries in the same patient was 24/34 (71%). The PDCA runs almost parallel to its flow direction and to ultrasound beam. Therefore velocity registration in PDCA by Doppler is reliable but the diameter of PDCA cannot be measured. Therefore the internal dimension of the main right coronary artery (RCA) was measured instead from the standard parasternal short-axis view at the R-wave and used as estimate of PDCA diameter flow in flow calculation instead. Coronary flow was calculated (πr2 × VTI × heart rate, r = radius of the artery). 2.2. Reproducibility Test In ten children two recordings of LAD flow velocities were performed 15 min apart by the same observer (EHA). The paired data was analysed regarding peak flow velocity in diastole, and total systolic and diastolic velocity time integrals and LAD blood flow. The analyses of the Doppler tracings were performed offline, separately and independently of each other after 2 weeks. 2.3. Cardiac magnetic resonance imaging CMR imaging was done using a 1.5 T Philips Intera CV (Philips, Best, the Netherlands) (n = 27) and a 1.5 T Magnetom Vision (Siemens, Erlangen, Germany) (n = 4) to quantify RV volumes and to detect fibrosis in RVOT. In three patients CMR was not performed for logistical reasons. CMR images were ECG triggered and acquired at end expiratory apnoea. After scout images to obtain image planes cine CMR was performed covering the right ventricle. Typical image sequence parameters were: steady-state free-precession sequence, retrospective ECG triggering, acquired temporal resolution 47 ms reconstructed to 25 ms, echo time 1.4 ms, flip angle 60°and 8 mm slice thickness. Late gadolinium contrast enhanced (LGE) CMR imaging for fibrosis detection was obtained 10–20 min after intravenous administration of gadolinium-based contrast agent (Gd-DOTA or Gd DTPA, 0.2 mmol/kg body weight). The inversion time was set to null the signal from the viable myocardium. Typical sequence parameters were: inversion-recovery balanced turbo field echo, slice thickness, 8 mm; field of view, 340 mm; matrix, 126 × 256; repetition time, 3.14 ms; echo time, 1.58 ms. Flow CMR was performed using a non-segmented fast field echo velocity encoded sequence without echo sharing. Typical sequence parameters were: repetition time 10 ms, echo time 5 ms, flip angle 15°, slice thickness 6 mm, number of acquisitions 1, no parallel imaging and a velocity encoding gradient (VENC)
4. Results There were 34 patients; male to female ratio was 1.25. Their mean age at full corrective surgery was 8.0 ± 8.3 months (range 1 to 48 months) and their mean age at this study was 10.2 ± 2.8, (range 3– 16) years. There were no significant differences in age, BSA, heart rate, rate pressure product or QRS duration between those with and without RVRP, Table 1. RV end diastolic and end systolic volumes indexed for BSA were larger in patients with RVRP as compared with those without RVRP (p = 0.002 and 0.008 respectively). Pulmonary insufficiency was found in 44% of those with RVRP and in 55% without RVRP, (Table 1). Pulmonary artery end-diastolic flow was higher in patients with fibrosis (29 ± 25 ml/s) compared to patients without fibrosis (5 ± 17 ml/s, p = 0.003). The correlation of QRS duration to fibrosis was not significant (r = 0.2 and p = 0.6). Coronary flow study of both PDCA and LAD in the same patients was successful in 24/34 (71%), but the CMR imaging data was incomplete in 4 of them. Of the 20 patients who had CMR data and coronary flow parameters measured 9 had RVRP and 11 no RVRP. Fibrosis was found in 11 and 9 had no fibrosis. In the RVRP group (n = 9) all patients had fibrosis but in the fibrosis group (n = 11) there were 2 patients without RVRP. Right ventricular end-diastolic volume indexed for BSA as an indicator of right ventricular (RV) mass correlated with PFVd (r = 0.50, p = 0.01) and with VTIt (r = 0.44, p = 0.03) in the LAD. Posterior descending coronary artery PFVd, (Fig. 1A), VTIt, (Fig. 1B) and CF (Fig. 1C) Table 1 Demographic data in patients with both coronary flow and CMR data (n = 20).
Age years 95% CI BSA m2 95% CI TAP Heart Rate bpm 95% CI RPP bpm ∗ mmHg 95% CI QRS duration msec 95% CI Arrythmia PI RVEDV/BSA ml/m2 95% CI RVESV/BSA ml/m2 95% CI
RVRP (n = 9)
Non-RVRP (n = 11)
p-Value
11 ± 2.6 (9.4–12.7) 1.2 ± 0.3 (1.0–1.4) 5 (56%) 71 ± 11 (63.4–78.4) 7469 ± 980 (6829–8109) 123 ± 29 (104–142) 3 (33%) 4 (44%) 158 ± 40 (132–184) 82 ± 31 (61.4–102.6)
10 ± 0.9 (9.9–10.1) 1.2 ± 0.4 (1.1–1.3) 2 (18%) 83 ± 15 (73.9–92.1) 8370 ± 1600 (7420–9320) 114 ± 25 (99.2–128.0) 5 (56%) 6 (55%) 99 ± 22 (134–182) 44 ± 12 (36.7–51.3)
0.57 0.9 – 0.06 0.12 0.8 – – 0.002 0.008
Data are presented as mean (±SD). bpm, beats per minute, BSA, body surface area, msec, millisecond, PI, pulmonary insufficiency, RPP, rate pressure product, RVEDV, right ventricular end-diastolic volume, RVESV, right ventricular end-systolic volume, RVRP, right ventricular restrictive physiology, and TAP, transannular patch.
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Fig. 3. Late gadolinium enhancement cardiac magnetic resonance image of a patient with fibrosis of the right ventricle (white arrows) and the site of VSD repair (black arrows) in the transversal view.
enhancement cardiac magnetic resonance image of a patient with fibrosis of the right ventricle and at the site of VSD repair is shown in Fig. 3. PFVd and VTIt were increased in the LAD in patients with fibrosis of RV (n = 11) compared to those without fibrosis (n = 9), (p = 0.01 and p = 0.047 respectively, Table 2) and in patients with RVRP (n = 9) as compared with those without (n = 11), (p = 0.006, Table 3). Linear regression analysis showed that LAD PFVd correlated with RVEDV and % fibrosis, (r = 0.53, p = 0.02 and r = 0.59, p = 0.008) (Fig. 4 A and B). Percentage of fibrosis correlated with RVEDV, r = 0.84 (Fig. 4C). In the multivariate analysis the correlations were not significant due to small data set. In Mann–Whitney–Wilcoxon non-parametric test, the correlation of LAD PFVd to RV mass (RVEDV) was not significant (p = 0.206) but very significant to RV fibrosis (p = 0.007) (Table 4). The reproducibility coefficient of variations were 5% for LAD coronary artery diameter, 12% for diastolic peak flow velocity, 7% for systolic peak flow velocity, 9% for the systolic and diastolic VTI, and 3% for LAD blood flow. The coefficient of variation for heart rate was 7%.
Fig. 1. Box-plots showing peak flow velocity in diastole (PFVd) (A), total systolic and diastolic velocity time integral (VTIt) (B) and coronary blood flow (CF) (C) in the posterior descending coronary artery. Whiskers indicate minimum and maximum values. All flow values were significantly larger in patients than in controls.
were larger in patients than controls (p = 0.02, p b 0.0001 and p b 0.0001 respectively). In the LAD PFV, VTIt and CF were increased compared to controls (p b 0.001 for all). Transthoracic Pulsed-wave Doppler signal of coronary flow velocity registration in LAD coronary artery is shown in Fig. 2. A late gadolinium
Table 2 Coronary flow data in patients with Tetralogy of Fallot with (n = 11) and without fibrosis (n = 9) compared to healthy controls (n = 20).
PDCA PFVd cm/s 95% C.I. VTIt cm 95% C.I. CF ml/s 95% C.I. LAD PFVd cm/s 95% C.I. VTIt cm 95% C.I. CF ml/s 95% C.I.
Fig. 2. Transthoracic Pulsed-wave Doppler signal of coronary flow velocity in left anterior descending (LAD) coronary artery in a Tetralogy of Fallot patient.
Fibrosis (n = 11)
No fibrosis (n = 9)
p-Value
Controls (n = 20)
*p-Value
37 (±6)
34 (±8)
0.38
31 (±4)
0.0017
(34.5–40.5) 16 (±3) (14.2–17.8) 43 (±10) (37.1–48.9)
(28.8–39.2) 16 (±4) (14.7–17.3) 36 (±6) (32.1–39.9)
72 (±16)
55 (±9)
(62.5–81.5) 46 (±16) (38.2–53.8) 75 (±16) (65.6–84.5)
(49.1–60.9) 33 (±7) (28.4–37.6) 63 (±10) (56.5–69.5)
0.80 0.10
0.010
0.047 0.079
(29.3–32.8) 10 (±2) (9.1–10.9) 21 (±4) (19.2–22.8)
48 (±9) (44.1–51.9) 10 (±2) (9.1–10.9) 34 (±7) (29.4–39.0)
**p-Value
0.15
b0.0001
b0.0001
b0.0001
b0.0001
b0.0001
0.044
b0.0001
b0.0001\
b0.0001
b0.0001
Data are presented as mean (±SD). LAD, Left anterior descending artery, PDCA, posterior descending coronary artery, PFVd, peak flow velocity in diastole, VTIt, total systolic and diastolic velocity time integral, and CF, coronary blood flow. *p-Value between fibrosis and controls. **p-Value between no-fibrosis and controls.
E.H. Aburawi et al. / International Journal of Cardiology 172 (2014) 122–126 Table 3 Coronary flow data in patients with Tetralogy of Fallot (n = 20), RVRP by CMR (n = 9), Non-RVRP (n = 11) and in healthy controls (n = 20).
PDCA PFVd cm/s 95% C.I. VTIt cm 95% C.I. CF ml/s 95% C.I. LAD PFVd cm/s 95% C.I. VTIt cm 95% C.I. CF ml/s 95% C.I.
RVRP (n = 9)
Non-RVRP (n = 11)
p-Value
38 (±6)
34 (±7)
0.25
(34.1–41.9) 16 (±3) (14.0–18.0) 44 (±10) (37.5–50.5)
(29.9–38.1) 16 (±4) (12.1–19.9) 36 (±7) (31.8–40.2)
74 (±17)
56 (±8)
(62.9–85.1) 48 (±17) (36.9–59.1) 72 (±16) (61.5–82.4)
(51.2–60.5) 34 (±6) (30.4–37.6) 68 (±14) (59.7–76.3)
0.84 0.06
0.006
0.02 0.52
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Table 4 Non-parametric Wilcoxon–Mann–Whitney test in patients with fibrosis (n = 11) and without fibrosis (n = 9).
Controls (n = 20)
*p-Value
31 (±4)
0.001
0.12
b0.0001
b0.0001
b0.0001
b0.0001
b0.0001
0.013
b0.0001
b0.0001
5. Discussion
b0.0001
b0.0001
Coronary flow was significantly increased in both PDCA and LAD at midterm follow-up after corrective surgery of TOF and it was further increased in patients with RVRP. RV end diastolic and end systolic volumes indexed for BSA were larger in patients with RVRP as compared with those without RVRP. Our present study suggests that CF is increased in post-operative TOF patients many years (mean 9.2 ± 2.9 years) after a full surgical correction. Increase in CF has previously been shown after surgery for transposition of the great arteries using intracoronary Doppler flow wire [13] and positron emission tomography [14]. We have reported earlier that CF increased after surgery for atrial septal defect with cardiopulmonary bypass one week after the operation whereas all coronary flow parameters decreased substantially after catheter interventions, but still remained significantly elevated as compared with controls [6]. CPB seems to initiate postoperative increase of coronary flow, not the surgery as such as demonstrated in our studies on pigs [15]. Interestingly, the correlation of fibrosis with LAD peak flow velocity was more significant than to RVEDV. Similarly increased coronary flow is seen in patients with endomyocardial fibrosis [16] and in hypertensive patients with microvascular angina demonstrating perivascular and myocardial fibrosis [17]. Fibrosis increases myocardial work and consequently coronary flow. Myocardial biopsies in patients with TOF indicate ultrastructural hypertrophic and degenerative changes. These changes are in the form of myoelastofibrous endocardial thickening characterized by elastic tissue hyperplasia, smooth muscle degeneration, and fibrous replacement with bundle formation [18]. Marked interstitial, perivascular and intermyocellular fibrosis are the other forms present in patients with right ventricular outflow tract obstruction and cellular hypertrophy. In patients with pulmonary valve stenosis [7] as well as in patients with elevated RV-pressure after arterial switch operation for transposition of the great arteries coronary flow is increased [19]. Patients with residual pulmonary stenosis were not included in the present series, which omits the role of stenosis as an explanation for the increase in CF. All patients had some pulmonary insufficiency, which might slightly elevate RVED pressure and therefore coronary flow. On the other hand the pulmonary artery pressure in TOF patients is small and elevates RVED pressure only marginally. The increase in LAD coronary circulation could be explained by RV fibrosis as the major blood supply of the interventricular septum is derived from the diagonally penetrating arteries from the LAD [20]. RV fibrosis is an essential coronary flow increasing factor as well as earlier CPB.
(29.2–32.8) 10 (±2) (9.1–10.9) 21 (±4) (19.3–22.8)
48 (±9) (44.1–51.9) 16 (±5) (13.8–18.2) 34 (±7) (31.0–37.0)
**p-Value
Data are presented as mean (±SD). LAD, Left anterior descending artery, PDCA, posterior descending coronary artery, RVRP, right ventricular restrictive physiology, PFVd, peak flow velocity in diastole, VTIt, total systolic and diastolic velocity time integral, and CF, coronary blood flow. *p-Value between RVRP and controls. **p-Value between non-RVRP and controls.
Mann–Whitney U
Wilcoxon W
Z
P (2-tailed)
P (1-tailed)
PDCA PFV cm/s VTI cm CF ml/s
28.5 38 23
64.5 74 59
−1.28 −0.5 −1.74
0.19 0.62 0.08
0.2 0.66 0.09
LAD PFV cm/s VTI cm CF (ml/s)
12.5 24 24.5
48.5 60 60.5
−2.6 −1.7 −1.6
0.009 0.098 0.11
0.007 0.11 0.11
LAD, Left anterior descending artery, PDCA, posterior descending coronary artery, PFVd, peak flow velocity in diastole, VTIt, total systolic and diastolic velocity time integral, and CF, coronary blood flow.
5.1. Limitation of the study Fig. 4. A–C. Linear regression analysis between LAD PFVd with RVEDV (A) and % of fibrosis (B) along with regression analysis of RVEDV with % of fibrosis (C).
The main limitation of the study is that we could not measure CFR by intravenous adenosine infusion as the consent was not obtained from
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the parents in spite of the ethical committee approval of the procedure. The sample size was small because the success rate of measuring CF parameters was low (71%). Due to the fact that the data is ‘continuous’ but was abnormally distributed we used the ‘t-test’ in the first instance because it is far more powerful for analysing ‘continuous’ data. Then, ‘nonparametric’ Mann–Whitney–Wilcoxon test was used as a ‘confirmatory’ test for the results obtained using the ‘t-test’. It is possible that PDCA flow data not reflects right coronary flow in all patients. PDCA is a continuation of the RCA in up to 70%, but it branches from the left circumflex coronary artery in about 10%. PDCA, as a continuation of RCA, gets extra flow from the left circumflex artery in 20%. Because PDCA runs almost parallel to flow direction it was impossible to measure the PDCA diameter. Instead, the main RCA diameter was used to estimate CF in PDCA. Because the diameter of PDCA is smaller than the origin of the right coronary and the diameter of artery in the origin of RCA is used the calculated volume of PDCA flow is larger than the real coronary flow. However, the differences between the groups can be shown using this estimate. RVEDV was used as an indirect marker of right ventricular mass because of difficulties in accurately quantifying RV mass due to trabeculations in RV. 6. Conclusions Patients at mid-term followup after correction of TOF show increase of coronary flow. This increase is more pronounced in patients with RVRP and fibrosis of the RV. The coronary flow increase in these patients may be due to previous surgery with cardiopulmonary by-pass and increased systolic workload against a stiff fibrotic myocardium and increased right ventricular volumes. The earlier reported decrease of coronary flow reserve after surgery might be due to increased basal coronary flow. These findings could provide new insights into the understanding of the pathophysiology of coronary blood flow and late complications in the postoperative patients with TOF. Acknowledgements We thank the Swedish Heart and Lung Foundation and the personnel of Skåne University Hospital and the Faculty of Medicine, Lund University for their financial support. We extend our gratitude to Mrs A. Maxedius, registered research nurse, for her assistance in patients' recruitment. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2013.12.188.
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Coronary flow dynamics in children after repair of Tetralogy of Fallot Elhadi H. Aburawi a,c,⁎, Peter Munkhammar c, Marcus Carlsson d, Mohamed El-Sadig b, Erkki Pesonen c a
Departments of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, United Arab Emirates Institute of Public Health, College of Medicine and Health Sciences, United Arab Emirates University, United Arab Emirates c Departments of Pediatric Cardiology, Skåne University Hospital, Lund University, Sweden d Clinical Physiology and Nuclear Medicine, Skåne University Hospital, Lund University, Sweden b
a r t i c l e
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Article history: Received 25 November 2013 Received in revised form 15 December 2013 Accepted 30 December 2013 Available online 9 January 2014 Keywords: Coronary blood flow Fibrosis Post-surgery Right ventricular restrictive physiology Tetralogy of Fallot
a b s t r a c t Objectives: To assess the possible effect of a stiff right ventricle on the coronary flow (CF) in patients with postoperative Tetralogy of Fallot (TOF). Background: Right ventricular restrictive physiology i.e. forward flow during atrial contraction (RVRP), is characteristic to many patients with post-operative TOF. Methods: A total of 34 patients with TOF anatomically corrected through transatrial repair were included. Coronary flow parameters were registered with transthoracic Doppler echocardiography from posterior descending (PDCA) and left anterior descending (LAD) coronary arteries in the same patient in 24/34 (71%) patients. Twenty age-matched healthy children were used as controls. Cardiac magnetic resonance (CMR) imaging was used to detect myocardial fibrosis, RV volume, and RVRP. Results: The mean age at investigation was 10.2 ± 2.8 years. RV end diastolic and end systolic volumes indexed for BSA were larger in patients with RVRP (p = 0.002 and 0.008 respectively). Peak flow velocity in diastole and flow velocity time integral was increased in patients compared to controls. They were increased in the LAD in patients with fibrosis of RV (n = 11) compared to patients without fibrosis (n = 9) (p = 0.01 and 0.047 respectively). LAD coronary flow was especially increased in patients with RVRP (n = 9) as compared with those without (n = 11), (p = 0.006). Conclusions: Patients at mid-term followup after correction of TOF show increase of coronary flow. This increase is more pronounced in patients with fibrosis and RVRP of the RV. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease in childhood. Right ventricular restrictive physiology (RVRP) manifested as an antegrade flow in the pulmonary artery during atrial systole throughout the respiratory cycle is characteristic in many patients after corrective surgery for TOF. The stiff right ventricle (RV) after TOF repair may produce a restrictive physiology when the RV behaves as an almost passive conduit from the right atrium to pulmonary artery for pulmonary blood flow [1,2]. We have documented by cardiac magnetic resonance (CMR) imaging normal diastolic forward flow in pulmonary artery during atrial systole and determined a threshold of mean ≥ 2 SD of the percentage of forward flow during atrial contraction in healthy subjects as a limit for restrictive physiology [3]. There was a strong association between RVRP and right ventricular outflow
tract fibrosis assessed by late gadolinium contrast enhanced (LGE) CMR imaging [3]. One week after cardiopulmonary by-pass (CPB) coronary flow seems to be increased [4]. Coronary flow and, in particular, its diastolic component increases along with the increase of RV pressure [5]. The posterior descending coronary artery (PDCA) flow increases with the increase of right ventricular end diastolic pressure in children with atrial septal defect and pulmonary valve stenosis [6,7]. Coronary flow reserve measured from the right coronary artery (RCA) and left anterior descending coronary artery (LAD) have been reported to improve late after anatomical correction of TOF [8]. The effect of RVRP and fibrosis on coronary flow in patients with TOF after full correction has not been studied so far. The aim of this study was to investigate the coronary flow in patients with TOF after its anatomical correction. 2. Methods
⁎ Corresponding author at: Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, P. O. Box 17666, United Arab Emirates. Tel.: +971 3 7137 462; fax: +971 3 7672022. E-mail address: [email protected] (E.H. Aburawi). 0167-5273/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.12.188
This is a prospective study, carried out in Lund (Sweden) to assess the possible effect of a stiff right ventricle on the coronary flow (CF) in patients with post-operative Tetralogy of Fallot (TOF). Patients with anatomically corrected TOF through transatrial repair and those with pulmonary insufficiency (PI) on Doppler echocardiography, who did not have clinical signs of infection, were included. Patients with absent pulmonary valve, or
E.H. Aburawi et al. / International Journal of Cardiology 172 (2014) 122–126 who had undergone pulmonary valve replacement or those with residual pulmonary stenosis and pressure gradient N 25 mmHg on Doppler echocardiography, or who had associated atrioventricular septal defect, or double outlet right ventricle of Fallot type, or pulmonary atresia with ventricular septum defect (VSD) were excluded. A total of 34 patients were investigated at a mean age of 10.2 ± 2.8, (range 3–16) years. Twenty agematched healthy children were used as controls for coronary artery flow parameters. Forward flow as a percentage of the net forward flow during the cardiac cycle was calculated in a separate series of 12 healthy children (15 ± 3 years) with normal CMR referred for screening of arrhythmogenic right ventricular cardiomyopathy because of a family history of this disease. Standard M- and B-mode and -Doppler echocardiographic studies were performed by one of the investigators (PM) for determining the anatomy and function of the heart. Sequoia™ C512 (Acuson Mountain View, CA, USA) with 4 MHz transducer was used. Coronary flow measurements were performed by (EHA) within 1–2 days of CMR studies. A written consent was obtained from the guardians/parents of the children enrolled in the study. The study protocol conforms to the principles outlined in the declaration of Helsinki [9]. The local ethics committee at Lund University, Sweden approved the study.
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of 200 cm/s. As reported earlier [3] forward flow during atrial contraction in CMR above mean ± 2 SD of healthy subjects was set as a marker of restrictive physiology.
3. Statistical analyses Pearson's correlation analysis was used to test the correlation of QRS duration to fibrosis and right ventricular end-diastolic volume with flow parameters. RV volume was used as a surrogate for RV mass. Unpaired student's t-test was used for comparison between the groups with and without RVRP, with and without fibrosis and with healthy controls. Due to the small sample size and the abnormal distribution of the data the Mann–Whitney–Wilcoxon non-parametric test was used to confirm the results obtained using the parametric t-test. The intra-observer variability was calculated according to the British Standards Institution recommendation [12].
2.1. Coronary flow studies Transthoracic Doppler echocardiography (TTDE) registration was done in all (n = 34) patients and 20 age-matched healthy children. The following adjustments were made in the ultrasound machine for the coronary blood flow and flow velocity measurements [6,10,11]: Space-time in high frame rate (T1), wall filter was set at two thirds (F2) and the colour gain was adjusted to minimize colour flow signal scatter (gate 3). Colour Doppler mix was on. Pulsed Doppler of 4.5 MHz and sweep rate of 100 mm/s were used. Velocity setting of 30–60 cm/s was needed. Measurements were corrected for the angle between the Doppler beam and the coronary flow direction. True velocity was defined as the measured velocity divided by the cosine of the angle between the Doppler beam and the direction of blood. The internal dimension of the LAD was measured from the standard parasternal short-axis view at the R-wave. The callipers were applied to the internal borders 2–3 mm distal to the bifurcation of the left main coronary artery. The velocity scale was decreased to the minimum range and then gradually increased until colour signals were optimized within the vessel lumen. After finding good coronary flow signals, the pulsed Doppler sample volume was placed within the LAD 2–3 mm distal to the bifurcation of the left main coronary artery, and the sample volume was adjusted to 0.5–1.0 mm. A sample volume that gave the best quality envelope and pure sound throughout the cardiac cycle was chosen. An apical 4-chamber view was obtained. The probe was angulated anteriorly and rotated anticlockwise until the disappearance of right ventricle from the view. The technique was otherwise similar to that used in the registration of the flow in the LAD. The coronary flow parameters; peak flow velocity in diastole (PFVd), total systolic and diastolic flow velocity time integral (VTIt) and coronary flow (CF) were registered from LCA and PDCA. All images were saved on a magnetic–optic disc and reviewed in a slow motion, and analysed in single frame advance mode. The success rate for Doppler registration of flow in both coronary arteries in the same patient was 24/34 (71%). The PDCA runs almost parallel to its flow direction and to ultrasound beam. Therefore velocity registration in PDCA by Doppler is reliable but the diameter of PDCA cannot be measured. Therefore the internal dimension of the main right coronary artery (RCA) was measured instead from the standard parasternal short-axis view at the R-wave and used as estimate of PDCA diameter flow in flow calculation instead. Coronary flow was calculated (πr2 × VTI × heart rate, r = radius of the artery). 2.2. Reproducibility Test In ten children two recordings of LAD flow velocities were performed 15 min apart by the same observer (EHA). The paired data was analysed regarding peak flow velocity in diastole, and total systolic and diastolic velocity time integrals and LAD blood flow. The analyses of the Doppler tracings were performed offline, separately and independently of each other after 2 weeks. 2.3. Cardiac magnetic resonance imaging CMR imaging was done using a 1.5 T Philips Intera CV (Philips, Best, the Netherlands) (n = 27) and a 1.5 T Magnetom Vision (Siemens, Erlangen, Germany) (n = 4) to quantify RV volumes and to detect fibrosis in RVOT. In three patients CMR was not performed for logistical reasons. CMR images were ECG triggered and acquired at end expiratory apnoea. After scout images to obtain image planes cine CMR was performed covering the right ventricle. Typical image sequence parameters were: steady-state free-precession sequence, retrospective ECG triggering, acquired temporal resolution 47 ms reconstructed to 25 ms, echo time 1.4 ms, flip angle 60°and 8 mm slice thickness. Late gadolinium contrast enhanced (LGE) CMR imaging for fibrosis detection was obtained 10–20 min after intravenous administration of gadolinium-based contrast agent (Gd-DOTA or Gd DTPA, 0.2 mmol/kg body weight). The inversion time was set to null the signal from the viable myocardium. Typical sequence parameters were: inversion-recovery balanced turbo field echo, slice thickness, 8 mm; field of view, 340 mm; matrix, 126 × 256; repetition time, 3.14 ms; echo time, 1.58 ms. Flow CMR was performed using a non-segmented fast field echo velocity encoded sequence without echo sharing. Typical sequence parameters were: repetition time 10 ms, echo time 5 ms, flip angle 15°, slice thickness 6 mm, number of acquisitions 1, no parallel imaging and a velocity encoding gradient (VENC)
4. Results There were 34 patients; male to female ratio was 1.25. Their mean age at full corrective surgery was 8.0 ± 8.3 months (range 1 to 48 months) and their mean age at this study was 10.2 ± 2.8, (range 3– 16) years. There were no significant differences in age, BSA, heart rate, rate pressure product or QRS duration between those with and without RVRP, Table 1. RV end diastolic and end systolic volumes indexed for BSA were larger in patients with RVRP as compared with those without RVRP (p = 0.002 and 0.008 respectively). Pulmonary insufficiency was found in 44% of those with RVRP and in 55% without RVRP, (Table 1). Pulmonary artery end-diastolic flow was higher in patients with fibrosis (29 ± 25 ml/s) compared to patients without fibrosis (5 ± 17 ml/s, p = 0.003). The correlation of QRS duration to fibrosis was not significant (r = 0.2 and p = 0.6). Coronary flow study of both PDCA and LAD in the same patients was successful in 24/34 (71%), but the CMR imaging data was incomplete in 4 of them. Of the 20 patients who had CMR data and coronary flow parameters measured 9 had RVRP and 11 no RVRP. Fibrosis was found in 11 and 9 had no fibrosis. In the RVRP group (n = 9) all patients had fibrosis but in the fibrosis group (n = 11) there were 2 patients without RVRP. Right ventricular end-diastolic volume indexed for BSA as an indicator of right ventricular (RV) mass correlated with PFVd (r = 0.50, p = 0.01) and with VTIt (r = 0.44, p = 0.03) in the LAD. Posterior descending coronary artery PFVd, (Fig. 1A), VTIt, (Fig. 1B) and CF (Fig. 1C) Table 1 Demographic data in patients with both coronary flow and CMR data (n = 20).
Age years 95% CI BSA m2 95% CI TAP Heart Rate bpm 95% CI RPP bpm ∗ mmHg 95% CI QRS duration msec 95% CI Arrythmia PI RVEDV/BSA ml/m2 95% CI RVESV/BSA ml/m2 95% CI
RVRP (n = 9)
Non-RVRP (n = 11)
p-Value
11 ± 2.6 (9.4–12.7) 1.2 ± 0.3 (1.0–1.4) 5 (56%) 71 ± 11 (63.4–78.4) 7469 ± 980 (6829–8109) 123 ± 29 (104–142) 3 (33%) 4 (44%) 158 ± 40 (132–184) 82 ± 31 (61.4–102.6)
10 ± 0.9 (9.9–10.1) 1.2 ± 0.4 (1.1–1.3) 2 (18%) 83 ± 15 (73.9–92.1) 8370 ± 1600 (7420–9320) 114 ± 25 (99.2–128.0) 5 (56%) 6 (55%) 99 ± 22 (134–182) 44 ± 12 (36.7–51.3)
0.57 0.9 – 0.06 0.12 0.8 – – 0.002 0.008
Data are presented as mean (±SD). bpm, beats per minute, BSA, body surface area, msec, millisecond, PI, pulmonary insufficiency, RPP, rate pressure product, RVEDV, right ventricular end-diastolic volume, RVESV, right ventricular end-systolic volume, RVRP, right ventricular restrictive physiology, and TAP, transannular patch.
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Fig. 3. Late gadolinium enhancement cardiac magnetic resonance image of a patient with fibrosis of the right ventricle (white arrows) and the site of VSD repair (black arrows) in the transversal view.
enhancement cardiac magnetic resonance image of a patient with fibrosis of the right ventricle and at the site of VSD repair is shown in Fig. 3. PFVd and VTIt were increased in the LAD in patients with fibrosis of RV (n = 11) compared to those without fibrosis (n = 9), (p = 0.01 and p = 0.047 respectively, Table 2) and in patients with RVRP (n = 9) as compared with those without (n = 11), (p = 0.006, Table 3). Linear regression analysis showed that LAD PFVd correlated with RVEDV and % fibrosis, (r = 0.53, p = 0.02 and r = 0.59, p = 0.008) (Fig. 4 A and B). Percentage of fibrosis correlated with RVEDV, r = 0.84 (Fig. 4C). In the multivariate analysis the correlations were not significant due to small data set. In Mann–Whitney–Wilcoxon non-parametric test, the correlation of LAD PFVd to RV mass (RVEDV) was not significant (p = 0.206) but very significant to RV fibrosis (p = 0.007) (Table 4). The reproducibility coefficient of variations were 5% for LAD coronary artery diameter, 12% for diastolic peak flow velocity, 7% for systolic peak flow velocity, 9% for the systolic and diastolic VTI, and 3% for LAD blood flow. The coefficient of variation for heart rate was 7%.
Fig. 1. Box-plots showing peak flow velocity in diastole (PFVd) (A), total systolic and diastolic velocity time integral (VTIt) (B) and coronary blood flow (CF) (C) in the posterior descending coronary artery. Whiskers indicate minimum and maximum values. All flow values were significantly larger in patients than in controls.
were larger in patients than controls (p = 0.02, p b 0.0001 and p b 0.0001 respectively). In the LAD PFV, VTIt and CF were increased compared to controls (p b 0.001 for all). Transthoracic Pulsed-wave Doppler signal of coronary flow velocity registration in LAD coronary artery is shown in Fig. 2. A late gadolinium
Table 2 Coronary flow data in patients with Tetralogy of Fallot with (n = 11) and without fibrosis (n = 9) compared to healthy controls (n = 20).
PDCA PFVd cm/s 95% C.I. VTIt cm 95% C.I. CF ml/s 95% C.I. LAD PFVd cm/s 95% C.I. VTIt cm 95% C.I. CF ml/s 95% C.I.
Fig. 2. Transthoracic Pulsed-wave Doppler signal of coronary flow velocity in left anterior descending (LAD) coronary artery in a Tetralogy of Fallot patient.
Fibrosis (n = 11)
No fibrosis (n = 9)
p-Value
Controls (n = 20)
*p-Value
37 (±6)
34 (±8)
0.38
31 (±4)
0.0017
(34.5–40.5) 16 (±3) (14.2–17.8) 43 (±10) (37.1–48.9)
(28.8–39.2) 16 (±4) (14.7–17.3) 36 (±6) (32.1–39.9)
72 (±16)
55 (±9)
(62.5–81.5) 46 (±16) (38.2–53.8) 75 (±16) (65.6–84.5)
(49.1–60.9) 33 (±7) (28.4–37.6) 63 (±10) (56.5–69.5)
0.80 0.10
0.010
0.047 0.079
(29.3–32.8) 10 (±2) (9.1–10.9) 21 (±4) (19.2–22.8)
48 (±9) (44.1–51.9) 10 (±2) (9.1–10.9) 34 (±7) (29.4–39.0)
**p-Value
0.15
b0.0001
b0.0001
b0.0001
b0.0001
b0.0001
0.044
b0.0001
b0.0001\
b0.0001
b0.0001
Data are presented as mean (±SD). LAD, Left anterior descending artery, PDCA, posterior descending coronary artery, PFVd, peak flow velocity in diastole, VTIt, total systolic and diastolic velocity time integral, and CF, coronary blood flow. *p-Value between fibrosis and controls. **p-Value between no-fibrosis and controls.
E.H. Aburawi et al. / International Journal of Cardiology 172 (2014) 122–126 Table 3 Coronary flow data in patients with Tetralogy of Fallot (n = 20), RVRP by CMR (n = 9), Non-RVRP (n = 11) and in healthy controls (n = 20).
PDCA PFVd cm/s 95% C.I. VTIt cm 95% C.I. CF ml/s 95% C.I. LAD PFVd cm/s 95% C.I. VTIt cm 95% C.I. CF ml/s 95% C.I.
RVRP (n = 9)
Non-RVRP (n = 11)
p-Value
38 (±6)
34 (±7)
0.25
(34.1–41.9) 16 (±3) (14.0–18.0) 44 (±10) (37.5–50.5)
(29.9–38.1) 16 (±4) (12.1–19.9) 36 (±7) (31.8–40.2)
74 (±17)
56 (±8)
(62.9–85.1) 48 (±17) (36.9–59.1) 72 (±16) (61.5–82.4)
(51.2–60.5) 34 (±6) (30.4–37.6) 68 (±14) (59.7–76.3)
0.84 0.06
0.006
0.02 0.52
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Table 4 Non-parametric Wilcoxon–Mann–Whitney test in patients with fibrosis (n = 11) and without fibrosis (n = 9).
Controls (n = 20)
*p-Value
31 (±4)
0.001
0.12
b0.0001
b0.0001
b0.0001
b0.0001
b0.0001
0.013
b0.0001
b0.0001
5. Discussion
b0.0001
b0.0001
Coronary flow was significantly increased in both PDCA and LAD at midterm follow-up after corrective surgery of TOF and it was further increased in patients with RVRP. RV end diastolic and end systolic volumes indexed for BSA were larger in patients with RVRP as compared with those without RVRP. Our present study suggests that CF is increased in post-operative TOF patients many years (mean 9.2 ± 2.9 years) after a full surgical correction. Increase in CF has previously been shown after surgery for transposition of the great arteries using intracoronary Doppler flow wire [13] and positron emission tomography [14]. We have reported earlier that CF increased after surgery for atrial septal defect with cardiopulmonary bypass one week after the operation whereas all coronary flow parameters decreased substantially after catheter interventions, but still remained significantly elevated as compared with controls [6]. CPB seems to initiate postoperative increase of coronary flow, not the surgery as such as demonstrated in our studies on pigs [15]. Interestingly, the correlation of fibrosis with LAD peak flow velocity was more significant than to RVEDV. Similarly increased coronary flow is seen in patients with endomyocardial fibrosis [16] and in hypertensive patients with microvascular angina demonstrating perivascular and myocardial fibrosis [17]. Fibrosis increases myocardial work and consequently coronary flow. Myocardial biopsies in patients with TOF indicate ultrastructural hypertrophic and degenerative changes. These changes are in the form of myoelastofibrous endocardial thickening characterized by elastic tissue hyperplasia, smooth muscle degeneration, and fibrous replacement with bundle formation [18]. Marked interstitial, perivascular and intermyocellular fibrosis are the other forms present in patients with right ventricular outflow tract obstruction and cellular hypertrophy. In patients with pulmonary valve stenosis [7] as well as in patients with elevated RV-pressure after arterial switch operation for transposition of the great arteries coronary flow is increased [19]. Patients with residual pulmonary stenosis were not included in the present series, which omits the role of stenosis as an explanation for the increase in CF. All patients had some pulmonary insufficiency, which might slightly elevate RVED pressure and therefore coronary flow. On the other hand the pulmonary artery pressure in TOF patients is small and elevates RVED pressure only marginally. The increase in LAD coronary circulation could be explained by RV fibrosis as the major blood supply of the interventricular septum is derived from the diagonally penetrating arteries from the LAD [20]. RV fibrosis is an essential coronary flow increasing factor as well as earlier CPB.
(29.2–32.8) 10 (±2) (9.1–10.9) 21 (±4) (19.3–22.8)
48 (±9) (44.1–51.9) 16 (±5) (13.8–18.2) 34 (±7) (31.0–37.0)
**p-Value
Data are presented as mean (±SD). LAD, Left anterior descending artery, PDCA, posterior descending coronary artery, RVRP, right ventricular restrictive physiology, PFVd, peak flow velocity in diastole, VTIt, total systolic and diastolic velocity time integral, and CF, coronary blood flow. *p-Value between RVRP and controls. **p-Value between non-RVRP and controls.
Mann–Whitney U
Wilcoxon W
Z
P (2-tailed)
P (1-tailed)
PDCA PFV cm/s VTI cm CF ml/s
28.5 38 23
64.5 74 59
−1.28 −0.5 −1.74
0.19 0.62 0.08
0.2 0.66 0.09
LAD PFV cm/s VTI cm CF (ml/s)
12.5 24 24.5
48.5 60 60.5
−2.6 −1.7 −1.6
0.009 0.098 0.11
0.007 0.11 0.11
LAD, Left anterior descending artery, PDCA, posterior descending coronary artery, PFVd, peak flow velocity in diastole, VTIt, total systolic and diastolic velocity time integral, and CF, coronary blood flow.
5.1. Limitation of the study Fig. 4. A–C. Linear regression analysis between LAD PFVd with RVEDV (A) and % of fibrosis (B) along with regression analysis of RVEDV with % of fibrosis (C).
The main limitation of the study is that we could not measure CFR by intravenous adenosine infusion as the consent was not obtained from
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the parents in spite of the ethical committee approval of the procedure. The sample size was small because the success rate of measuring CF parameters was low (71%). Due to the fact that the data is ‘continuous’ but was abnormally distributed we used the ‘t-test’ in the first instance because it is far more powerful for analysing ‘continuous’ data. Then, ‘nonparametric’ Mann–Whitney–Wilcoxon test was used as a ‘confirmatory’ test for the results obtained using the ‘t-test’. It is possible that PDCA flow data not reflects right coronary flow in all patients. PDCA is a continuation of the RCA in up to 70%, but it branches from the left circumflex coronary artery in about 10%. PDCA, as a continuation of RCA, gets extra flow from the left circumflex artery in 20%. Because PDCA runs almost parallel to flow direction it was impossible to measure the PDCA diameter. Instead, the main RCA diameter was used to estimate CF in PDCA. Because the diameter of PDCA is smaller than the origin of the right coronary and the diameter of artery in the origin of RCA is used the calculated volume of PDCA flow is larger than the real coronary flow. However, the differences between the groups can be shown using this estimate. RVEDV was used as an indirect marker of right ventricular mass because of difficulties in accurately quantifying RV mass due to trabeculations in RV. 6. Conclusions Patients at mid-term followup after correction of TOF show increase of coronary flow. This increase is more pronounced in patients with RVRP and fibrosis of the RV. The coronary flow increase in these patients may be due to previous surgery with cardiopulmonary by-pass and increased systolic workload against a stiff fibrotic myocardium and increased right ventricular volumes. The earlier reported decrease of coronary flow reserve after surgery might be due to increased basal coronary flow. These findings could provide new insights into the understanding of the pathophysiology of coronary blood flow and late complications in the postoperative patients with TOF. Acknowledgements We thank the Swedish Heart and Lung Foundation and the personnel of Skåne University Hospital and the Faculty of Medicine, Lund University for their financial support. We extend our gratitude to Mrs A. Maxedius, registered research nurse, for her assistance in patients' recruitment. Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2013.12.188.
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