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Coronary flow before and after surgical versus device closure of atrial septal defect
International Journal of Cardiology 135 (2009) 14 – 20 www.elsevier.com/locate/ijcard
Coronary flow before and after surgical versus device closure of atrial septal defect Elhadi H. Aburawi a,⁎, Ansgar Berg b , Erkki Pesonen a a
Department of Paediatrics, Division of Paediatric Cardiology, Lund University Hospital, Lund, Sweden, Gettingvägen, SE-221 85 Lund, Sweden b Institute of Clinical Medicine, Section of Paediatrics, Bergen University Hospital, Norway Received 4 October 2007; accepted 1 March 2008 Available online 1 July 2008
Abstract Background: Cardiopulmonary bypass (CPB) affects coronary flow after the operation. Surgical as compared to device closure of atrial septal defect (ASD) serves as a good model to clarify the effects of surgery with CPB on coronary flow. Methods: Coronary flow parameters were determined by transthoracic Doppler echocardiography before and after ASD closure. Thirteen children underwent surgery on CPB and fourteen children had device closure of their ASD under interventional cardiac catheterisation. Fourteen age-matched healthy controls were studied. Results: Left ventricular fractional shortening increased and cardiac output increased after the device closure but there were no significant changes after the surgery. After the surgery the mean diameter of left anterior descending coronary artery increased from 1.7 ± 0.6 to 2.1 ± 0.4 mm (p = 0.03), the peak flow velocity in diastole (PFVd) from 48 ± 10 to 70 ± 12 cm/s (p = 0.0001) and basal blood flow (BF) from 62 ± 18 to 105 ± 35 ml/min (p = 0.0001). Flow parameters in the right coronary artery increased similarly. In contrast, all coronary flow parameters decreased substantially after catheter interventions, but still remained significantly elevated as compared with controls. Conclusions: Surgery with cardiopulmonary bypass but not the device closure affects coronary flow beyond the pure effects of anatomical correction. Cardiac output increases after the device closure. The reported decrease of coronary flow reserve is obviously due to increased basal coronary flow. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Atrial septal defect; Coronary flow; Transthoracic Doppler echocardiography
1. Introduction Disturbed coronary flow is an important contributing factor to myocardium-related complications such as contractile dysfunction and arrhythmias [1], which often appear during the first week after cardiac surgery on cardiopulmonary bypass (CPB). The reported decrease of coronary flow reserve (CFR) after surgery with cardiopulmonary bypass (CPB) [2] might be due to increased coronary flow after the surgery [2,3]. CFR reflects the ability of coronary circulation
⁎ Corresponding author. Tel.: +46 46 17 82 61; fax: +46 46 17 81 50. E-mail address: [email protected] (E.H. Aburawi). 0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.03.046
to increase in response to increased cardiac metabolic demand. It is commonly expressed as the ratio of maximal or hyperaemic coronary flow to resting basal flow and has been reported to be decreased after CPB [2, 4–6]. Positron emission tomography technique has shown it to be decreased 1–3 weeks after surgery on CPB [2]. Intracoronary Doppler flow guide wire (IDGW) studies done 5–7 months after surgery showed improved but still low CFR as compared to presurgical values [7]. Myocardial ischemia/reperfusion has been shown to lead to coronary endothelial cell dysfunction [8]. In experimental models endothelial cell dysfunction after ischemia/reperfusion persists for at least 4–6 weeks [9,10]. The aim of this study is to assess the effect of device closure of ASD
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compared with the combined effects of cardiac surgery and CPB with cardioplegia on the coronary flow in children. 2. Subjects and methods Twenty seven children referred for ASD closure were investigated. Thirteen children at the mean age of 3.5 years (range 2–7 years) underwent surgery on CPB and fourteen children had a device closure of their ASD under interventional cardiac catheterisation at the mean age of 5 years (range 2–8 years). The patients were exposed to diagnostic radiation during the procedures for 5–8 min. No angiographies were done. Normal healthy control group consisted of 14 age-matched children. Written consent was obtained from the guardians of children enrolled in the study. The study protocol conforms to the principles outlined in the declaration of Helsinki [11]. The study was approved by the ethics committee for human research at the Lund University. Transthoracic Doppler echocardiography (TTDE) was performed on all children one day before and 5 ± 1 days postoperatively and one day after device closure. The exclusion criteria were clinical signs of infection/inflammation or CRP value N 0.8 mg/l prior to the procedures. 2.1. Transthoracic Doppler echocardiography TTDE examination was performed using Sequoia™ C512 (Acuson Mountain View, CA, USA) with 7–10 MHz transducer. Standard M- and B-mode and Doppler echocardiographic studies were performed for determining the anatomy and function of the heart. For coronary blood flow and flow velocity measurements the following adjustments were made in the ultrasound machine [12,13]: 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 15–40 cm/s before and 30–60 cm/s after surgery 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 left anterior descending artery (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 artery 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
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best quality envelope and pure sound throughout the cardiac cycle was chosen. Flow in the proximal half of the posterior descending coronary artery (PDA) located in the posterior interventricular groove was registered. 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. Because PDA runs almost parallel to the ultrasound beam it was impossible to measure its diameter. The internal dimension of the main right coronary artery (RCA) was measured and used in flow calculations instead. All images were saved on a magnetic–optic disc and reviewed in a slow-motion, and analyzed in single frame advance mode. The diameter of the aortic ring was measured in a long axis view by M-mode. Left ventricular fractional shortening was computed according to the standard formula [14]. Arterial blood pressure was measured by an automatic oscillometer cuff sphygmomanometer (Dynamap, Critikon Inc., Tampa, Florida, USA). The rate pressure product was calculated by multiplying heart rate with a systolic blood pressure [15]. The analysis package of the ultrasound unit was used for manual tracing of the spectral envelope. The flow velocity measurements across aortic valve were averaged over three consequent cardiac cycles. Diastolic peak flow velocity (PFVd), systolic peak flow velocity (PFVs), diastolic velocity time integral (VTId) and systolic velocity time integral (VTIs) were measured. Velocity–time integral/min was calculated by multiplying the sum of systolic and diastolic VTI (VTIs + d) with heart rate. Blood flow per minute was calculated as VTI/min multiplied with cross sectional area, where cross sectional area = π (coronary artery diameter / 2)2. The whole equation is: Blood flow (BF) ml/min = VTIs + d × Heart rate × π (coronary diameter / 2)2. 2.2. Cardiopulmonary bypass and cardioplegia Open-heart surgery was performed under mild to moderate hypothermic CPB (body temperature 28–32 °C). For myocardial protection, cold (+ 4 °C) hyperkalemic (K+ = 0.07 mmol/ml) blood cardioplegic solution was used. All patients had similar protocol for cardioplegia with antigrade perfusion of the coronary arteries to start with and then retrograde filling through the coronary sinus every 20 min during the CPB. 2.3. Postoperative treatment All children after CPB surgery received opioid derivatives in the form of intravenous ketobemidone hydrochloride during the first 2 to 3 days and then followed by oxicodon orally between 3 and 5 days postoperatively. However during the postoperative coronary flow studies these medications had already been stopped. None of our patients were on ACE-inhibitors, lanoxine, phenylepherine, beta-
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Table 1 Basic data of surgical and device closure groups.
Mean age and range (years) Haemoglobin (g %) ASD diameter (mm)
Surgery group (n = 13)
Device closure group (n = 14)
Before
After
Before
After
p-value
3.5 (2–7) 12.3 (11–13) 13 (8–23)
–
5 (2–8)
–
0.07
12 (11–13) 11 (8–16)
–
0.4
–
0.37⁎
11.9 (10–13) –
p-value
0.3
ASD = atrial septal defect, ⁎p-value between ASD size in surgical versus device closure groups.
blockers or any other vasoactive medications such as nitrate or dopamine during the intensive care management after day one postoperatively. Patients treated by cardiac catheterisation were not on any of the above medications. 2.4. Intra-observer variability In ten children two registrations of LAD flow velocities were performed 15 min apart by the same observer (EHA). The paired data was analyzed regarding peak flow diastolic and systolic velocities, velocity time integrals and LAD blood flow. The analyses of the Doppler tracings were performed off line, separately and independently of each other. 2.5. Statistics Paired Student's t test was used for comparison between the data before and after surgery. Simple and multiple regression analyses were used to calculate the correlation of the changes of PDA BF with right ventricular end-diastolic pressure (RVEDP) as well as pulmonary to systemic flow ratio (Qp/Qs). Statistical analyses were performed using Stat View (SAS Inst. 5.0) statistical software package. A p-value of b 0.05 was considered statistically significant. Results are presented as mean ± standard deviation. The intra-observer variability was statistically measured according to the British Standards Institution [16].
Left ventricular fractional shortening increased after the device closure from 35 ± 4% to 38.5 ± 5% and cardiac output from 595 ± 210 to 702 ± 170 ml/min/kg (p = 0.01 and 0.001 respectively) but there were no significant changes after the surgery (Table 2). Similarly, aorta VTI increased significantly after the device closure from 22 ± 5.5 to 26 ± 5 cm (p = 0.001), but was unchanged after surgery. After CPB surgery the mean diameter of LAD increased from 1.7 ± 0.6 to 2.1 ± 0.4 mm (p = 0.03), while it was the same after the device closure. LAD PFVd increased from 48 ± 10 to 70 ± 12 cm/s (p = 0.0001), BF from 62 ± 18 to 105 ± 35 ml/min (p = 0.0001), (Fig. 2) and VTId + s from 18 ± 4 to 24 ± 4 cm (p = 0.0003). RCA diameter increased from 1.5 ± 0.3to 1.9 ± 0.2 mm, p = 0.0003, and PDA PFVd from 42 ± 10 to 52 ± 8.8 cm/s, (p = 0.03). The estimated BF (RCA diameter used instead of PDA diameter in calculations) increased from 36 ± 18 to 74 ± 41 ml/min (p = 0.0008), and VT Id+ s from 13 ± 5 to 25 ± 15 cm (p = 0.005). All the flow measures decreased substantially after the device closure: LAD PFVd from 51 ± 9 to 40 ± 7 cm/s (p = 0.0001), BF from 66 ± 22 to 45 ± 18 ml/min (p b 0.0001) (Fig. 3) and VTId + s from 20 ± 2 to 16 ± 4.6 cm, p b 0.04. The RCA diameter decreased from 1.7 ± 0.24 to 1.6 ± 0.27 mm, (p = 0.2) and for the PDA PFVd decreased from 46 ± 7 to 30 ± 8 cm/s, (p = 0.0001), BF from 40 ± 18 to 30 ± 14 ml/min, p = 0.001 and VTId + s from 14 ± 4 to 12 ± 2 cm, p = 0.1. The coronary blood flow values of the healthy controls were for LAD lower than even after the device closure of the ASD: PFVd 30 ± 11 cm/s, BF 30 ± 11 ml/min and VTId + s 14 ± 5 cm, (p = 0.0001, p = 0.004 and p = 0.0001 respectively). The PDA parameters were lower than after the device closure PFVd 20 ± 5 cm/s, BF 20 ± 15 ml/min and VTId + s 10 ± 3 cm, (p = 0.0001, p = 0.003 and p = 0.0001 respectively). The actual flow data are presented in (Tables 3 and 4). The following coefficients of variation were obtained: 4.6%, for LAD's diameter, 11.7% for diastolic peak flow
3. Results Heart rate and rate pressure product did not change significantly after the procedures. Blood haemoglobin concentration was the same pre- and postoperatively (12.3 ± 0.7 versus 11.9 ± 0.9 g per 100 ml, p = 0.3). The mean diameter of ASD was in the surgical group slightly larger than in the device closure group, 13 ± 0.5.5 versus 11 ± 2.3 mm respectively (p = 0.37), (Table 1). The basal coronary flow was 66 in the older surgical and 62 ml/min in the younger device closure group (p = 0.3). Before the device closure, simple regression analysis showed a positive correlation between BF in PDA and RVEDP, (Fig. 1) as well as in Qp/Qs (n = 14, r = 0.67, p = 0.01 and r = 0.52, p = 0.06, respectively).
Fig. 1. Basal blood flow in posterior descending artery correlates with right ventricular end-diastolic pressure (r = 0.67, p = 0.01).
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Table 2 Haemodynamic data 1 day before and 5 ± 1 days after surgery and 1 day after device closure of ASD. Surgery (n = 13)
HR (beats/min) Systolic BP (mm Hg) Diastolic BP (mm Hg) RPP (mm Hg/min) CO (ml/min/kg) FS (%) Aorta VTI (cm)
Device Closure (n = 14)
Before
After
p-value
Before
After
p-value
96(12) 105(11) 52(7) 10081(1460) 460(140) 37(8) 18(3.8)
84(21) 102(11) 51(6) 8743(2427) 420(160) 40(5) 18(4)
0.18 0.02 0.6 0.08 0.3 0.37 0.8
99(9) 100(10) 59(7) 9970(1072) 595(210) 35(4) 22(5.5)
97(10) 100(8) 57(5) 9882(1026) 702(170) 38.5(5) 26(5)
0.5 0.8 0.08 0.6 0.001 0.01 0.001
Data are presented as mean (standard deviation). BP = Blood pressure, CO = cardiac output, CPB = cardiopulmonary bypass, FS = fractioning shortening, HR = heart rate, RPP = rate pressure product.
Our study shows that BF in the coronary arteries of ASD patients is increased and further elevated at least up to 6 days after the surgical closure of the defect under CPB. BF decreases after the device closure but not to normal. Because arteries have a certain maximal dilatory state they can reach, the increased basal flow after surgery leads to the decrease of CFR as reported earlier [2]. Our earlier work [3] showing the increased coronary BF after surgery for ventricular septal defect and atrioventricular septal defect and decreased BF after coarctation of aorta operations can be criticized because the diagnostic groups as well as the age of the patients were not similar. In the present study these aspects are taken into account. During the immediate post procedural period, systemic cardiac output increases after the device closure but not after the surgery. The ultrasound probes (4 and 5 MHz) we employed have an axial resolution of 0.1 mm, rendering thus the comparison
in diameter measurements possible. The success rate is significantly operator dependent. We succeeded always in LCA flow registration but the success rate for PDA was 90%. The TTDE assessment of coronary blood flow and flow velocity has been shown to correlate well with IDGW, positron emission tomography and coronary angiography measurements [13]. Measurement of coronary artery diameter by transthoracic echocardiography correlates well with those measured with quantitative coronary angiography [17,18]. The changes in the diameter of coronary arteries affect BF essentially because the area of the coronary artery lumen is related to the radius of the artery squared. The intra-observer coefficients of variation for Doppler flow parameters and even for flow volume were fairly low. They were comparable with earlier reports [16,19]. It may be assumed that the true fluctuations in Doppler coronary flow parameters are at least of the same range as the variation in heart rate coefficient of variation 7% which must be considered when the reproducibility of the method is evaluated. The measurements of flow in PDA do not always reflect only RCA flow. PDA is a continuation of the RCA in up to 70%, but it branches from the left circumflex coronary artery in about 10%. PDA, as a continuation of RCA, gets extra
Fig. 2. Basal coronary blood flow in the left anterior descending coronary artery, before and after surgical closure of ASD and in controls. The box plot displays the 25th percentile, median, and 75th percentile, as well as the 10th and 90th percentiles as horizontal lines outside the box.
Fig. 3. Basal coronary blood flow in the left anterior descending coronary artery, before and after device closure of ASD and in controls. The box plot displays the 25th percentile, median, and 75th percentile, as well as the 10th and 90th percentiles as horizontal lines outside the box.
velocity, 7% for systolic peak flow velocity, 9% for systolic and diastolic velocity time integral, and 3.3% for LAD blood flow. The coefficient of variation for heart rate was 7%. 4. Discussion
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Table 3 Parameters in left anterior descending coronary artery in surgical, device closure groups and in controls. Surgery (n = 13)
Diameter(mm) PFVd (cm/s) BF (ml/min) VTId + s (cm)
Device closure (n = 14)
Controls (n = 14)
Before
After
p-value
Before
After
p-value
1.7(0.3) 48(10) 62(18) 18(4)
2.1(0.4) 70(12) 105(35) 24(4)
0.03 0.0001 0.0001 0.0003
1.7(0.3) 51(9) 66(22) 20(2)
1.6(0.4) 40(7) 45(18) 16(5)
0.1 0.0001 0.0001 0.04
⁎p-value 1.7(0.2) 30(11) 30(8) 14(5)
0.09 0.0001 0.004 0.0001
Data are presented as mean (standard deviation). BF = blood flow, PFV = peak flow velocity, VTId + s = velocity time integral in diastole and systole. ⁎p-value between controls and patients after device closure.
flow from the left circumflex artery in 20%. Because PDA runs almost parallel to flow direction it was impossible to measure the PDA diameter. Instead, the main RCA diameter was used to estimate the BF in the PDA. LAD diameter and flow were measured at the same place. The patients in the surgical group were slightly, 1.5 year older than the intervention group, which might have had some effect on the results. However, basal flows in the two groups were almost equal before the procedures; 66 in the older surgical and 62 ml/min in the younger device closure group. ASD sizes in the surgical group were slightly larger than in the device closure group, but close to each other; according to the transthoracic echocardiography 13 and 11 mm respectively. Haemoglobin did not have any confounding effect of the results because blood haemoglobin concentration was the same before and after the procedures. CRP before the procedures was under 0.8 mg/l in all patients and therefore could not have any effect on basal flows. Cardiopulmonary bypass elicits an intense inflammatory reaction; CRP rises rapidly after surgery reaching a peak approximately 24–48 h after the surgery [20]. CRP has been reported to be an independent risk factor for coronary artery disease [21]. It reflects the degree of inflammation of the body and might affect coronary circulation. Data from both in vivo and in vitro studies using recombinant CRP do not give final answer of its effects. It might have possible dichotomous effects on the vasomotor tone and reactivity of conduit arteries [22]. However, the explanation for this contradictory result might be contamination of CRP extracts with other substances such as endotoxin and sodium azide [23].
Congenital heart disease cause several haemodynamic and functional changes that are likely to affect coronary blood flow [24–27]. The major determinant is the myocardial oxygen consumption which is affected by the heart rate, contractility and wall stress. Wall stress is related to ventricular pressure, chamber diameter and wall thickness [28]. The rate pressure product, describes myocardial oxygen demand [15]. Left ventricular shortening fraction and cardiac output increased after the device closure. We have shown earlier that longitudinal contractile function of the left ventricle decreases after surgery for ASD, but not after the device closure [29]. There was an increase of the blood flow in both main coronary arteries before closure of ASD. The coronary flow decreased after a closure of the defect with a device but still remained higher than in normal controls. These features suggest that the device closure is a preferred method for closing of ASD. After the cardiopulmonary bypass surgery the flow increased significantly. The mechanisms of increased coronary flow are unclear. Before the intervention the volume overload on the right side of the heart leads to increased secretion of atrial natriuretic peptide, which is a vasodilator factor [30]. Likewise the overflow through the lungs leads to increased shear stress of the endothelial cells of the pulmonary arteries which is a stimulus for the secretion of vasoactive substances such as prostacyclin [31]. The increase of coronary flow after CPB surgery and cardioplegia is probably due to the reduction of the myogenic reactivity of the coronary microcirculation [32–34]. The preconditioning effect of the cardioplegic solution on the
Table 4 Parameters in posterior descending coronary artery in surgical, device closure groups and in controls. Surgery (n = 13)
Diameter (mm) PFVd (cm/s) BF (ml/min) VTId + s (cm)
Device closure (n = 14)
Controls (n = 14)
Before
After
p-value
Before
After
p-value
1.5(0.3) 42(10) 36(18) 13(5)
1.9(0.2) 5(9) 74(41) 25(7)
0.0003 0.03 0.0008 0.0003
1.7(0.2) 46(7) 40(18) 14(4)
1.6(0.3) 30(8) 30(14) 12(2)
0.2 0.0001 0.0001 0.1
⁎p-value 1.6(0.2) 20(5) 20(5) 10(3)
0.8 0.0001 0.003 0.0001
Data are presented as mean (standard deviation). BF = blood flow, PFVd = peak flow velocity in diastole, VTId + s = velocity time integral in diastole and systole. ⁎p-value between controls and in patients after device closure.
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coronary circulation consisting of increased production of endothelial dilating prostanoids could be an additional phenomenon [35] even if the long duration of increased flow speaks against this possibility. Much of the present evidence attributes an important pathogenic role to TNF alpha via up regulation of the inducible form of nitric oxide synthase after CPB, which leads to abundant release of nitric oxide and dilatation of the coronary arteries [36]. Limitations of the study include that intravenous adenosine infusion could not be given to the patients because the consent from the parents was not obtained. Therefore the conclusion of possibly decreased coronary flow reserve after cardiopulmonary bypass surgery is based only on the physiological principle that increased basal BF leaves less capacity for further coronary dilatation. The recovery time after the surgery was longer than after device closure which might somewhat disturb the comparability of the flow values (5 versus 1 day). A longer postoperative follow up would have been indicated. However, this could not be done as the patients were discharged by day 1 after cardiac catheterisation and 7 to 8 days after surgery. In conclusion, the coronary flow is increased in patients with ASD. Cardiopulmonary bypass surgery initiates a further increase of coronary flow but the device closure decreases it due to anatomical correction of the defect. Cardiac output increases after the device closure but not immediately after CPB. Acknowledgements We thank the personnel of Lund University Hospital and the Faculty of Medicine, Lund University for financial support of this study.
References [1] Hassanabad ZF, Furman BL, Parratt JR, Aughey E. Coronary endothelial dysfunction increases the severity of ischaemia-induced ventricular arrhythmias in rat isolated perfused hearts. Basic Res Cardiol 1998;93:241–9. [2] Donnelly 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;115:103–10. [3] Aburawi EH, Berg A, Liuba P, Pesonen E. Effects of cardiopulmonary bypass surgery on coronary flow in children assessed with transthoracic Doppler echocardiography. Am J Physiol Heart Circ Physiol 2007;293: H1138–43. [4] Hoffman JI. Maximal coronary flow and the concept of coronary vascular reserve. Circulation 1984;70:153–9. [5] Hoffman JI. Pediatric cardiovascular intensive care: myocardial perfusion. Progr Pediatr Cardiol 1995;4:117–23. [6] Coffman JD, Gregg DE. Reactive hyperaemia characteristics of the myocardium. Am J Physiol 1960;11:1143–9. [7] Harada K, Aoki M, Toyono M, Tamura M. Coronary flow velocity and coronary flow velocity reserve in children with ventricular septal defect. Tohoku J Exp Med 2004;202:77–85. [8] Ku DD. Coronary vascular reactivity after acute myocardial ischemia. Science 1982;218:576–8.
19
[9] Kaeffer N, Richard V, Francois A, Lallemand F, Henry JP, Thuillez C. Preconditioning prevents chronic reperfusion induced coronary endothelial dysfunction in rats. Am J Physiol 1996;271:H842–849. [10] Pearson PJ, Schaff HV, Vanhoutte PM. Long-term impairment of endothelium-dependent relaxations to aggregating platelets following reperfusion injury in canine coronary arteries. Circ res 1990;8:1921–7. [11] World Medical Association Declaration of Helsinki. Recommendations guiding physicians in biomedical research involving human subjects. Cardiovasc Res 1997;35:2–3. [12] Hozumi T, Yoshida K, Ogata Y, Morioka S, et al. Noninvasive assessment of significant left anterior descending coronary artery stenosis by coronary flow velocity reserve with transthoracic colour Doppler echocardiography. Circulation 1998;97:1557–62. [13] Saraste M, Koskenvuo J, Knuuti J, et al. Coronary flow reserve: measurement with transthoracic Doppler echocardiography is reproducible and comparable with positron emission tomography. Clin Physiol 2001;21:114–22. [14] Lewis RP, Sandler H. Relationship between changes in the left ventricular dimension and ejection fraction in man. Circulation 1971;44:548–57. [15] Baller D, Bretschneider HJ, Hellige G. A critical look at currently used indirect indices of myocardial oxygen consumption. Basic Res Cardiol 1981;76:163–81. [16] British Standards Institution. Precision of test methods, I: Guide for the determination and reproducibility for a standard test method. British Standard; 1979. p. 5479. [17] Kiviniemi TO, Saraste M, Koskenvuo JW, et al. Coronary artery diameter can be assessed reliably with transthoracic echocardiography. Am J Physiol Heart Circ Physiol 2004;286:H1515–1520. [18] Kurotobi S, Nagai T, Kawakami N, Sano T. Coronary diameter in normal infants, children and patients with Kawasaki disease. Pediatr Int 2002;44:1–4. [19] Oskarsson G, Pesonen E. Coronary blood flow in healthy neonates: effects of left ventricular function and mass. Pediatr Cardiol 2004;25:11–6. [20] Franke A, Lante W, Fackeldey V, et al. Pro-inflammatory cytokines after different kinds of cardio-thoracic surgical procedures: is what we see what we know? Eur J Cardiothorac Surg 2005;28:569–75. [21] Ridker Paul M. C-reactive protein, inflammation, and cardiovascular disease clinical update. Tex Heart Inst J 2005;32:384–6. [22] Sternik L, Samee S, Schaff HV, et al. C-reactive protein relaxes human vessels in vitro. Arterioscler Thromb Vasc Biol 2002;22:1865–8. [23] Zhong Y, Li SH, Liu SM, et al. C-Reactive protein upregulates receptor for advanced glycation end products expression in human endothelial cells. Hypertension 2006;48:504–11. [24] Kangos JJ, Ferrer MI, Francios RA, Blanc WA, Blumenthal S. Electrocardiographic changes associated with papillary muscle infarction in congenital heart disease. Am J Cardiol 1969;23:801–9. [25] Fogel MA, Rychik J, Vetter J, Donofrio MT, Jacobs M. Effect of volume unloading surgery on coronary flow dynamics in patients with aortic atresia. J Thorac Cardiovasc Surg 1997;113:718–26. [26] Hofstetter R, Zeike B, Messmer BJ, von Bernuth G. Echocardiographic evaluation of systolic left ventricular function in infants with critical aortic stenosis before and after valvotomy. Thorac Cardiovasc Surg 1990;38:236–40. [27] Hongo M, Goto T, Watanab N, et al. Relation of phasic coronary flow velocity profile to clinical and hemodynamic characteristics of patients with aortic valve disease. Circulation 1993;88:953–60. [28] Graham Jr TP, Covell JW, Sonnenblick EH, Ross Jr J, Braunwald E. Control of myocardial oxygen consumption: relative influence of contractile state and tension development. J Clin Inves 1968;47:375–85. [29] Hanseus KC, Bjorkhem G, Brodin LA, Pesonen E. Analysis of atrioventricular plane movements by Doppler tissue imaging and M-mode in children with atrial septal defects before and after surgical and device closure. Pediatr Cardiol 2002;23:152–9. [30] Nagaya N, Nishikimi T, Uematsu M, et al. Secretion patterns of brain natriuretic peptide and atrial natriuretic peptide in patients with or
20
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without pulmonary hypertension complicating atrial septal defect. Am Heart J 1998;136:297–301. [31] Muta H, Ishii M, Maeno Y, Akagi T, Kato H. Quantitative evaluation of the changes in plasma concentrations of cardiac natriuretic peptide before and after transcatheter closure of atrial septal defect. Acta Paediatr 2002;91:649–52. [32] Wang SY, Friedman M, Franklin A, Sellke FW. Myogenic reactivity of coronary resistance arteries after cardiopulmonary bypass and hyperkalemic cardioplegia. Circulation 1995;92:1590–6. [33] Khan TA, Bianchi C, Ruel M, et al. Mitogen-activated protein kinase inhibitor and cardioplegia–cardiopulmonary bypass reduce coronary myogenic tone. Circulation 2003;108:348–53.
[34] Sellke FW, Shafique T, Ely DL, Weintraub RM. Coronary endothelial injury after cardiopulmonary bypass and ischemic cardioplegia is mediated by oxygen-derived free radicals. Circulation 1993;88:395–400. [35] Sellke FW, Friedman M, Dai HB, et al. Mechanism causing coronary microvascular dysfunction following crystalloid cardioplegia and reperfusion. Cardiovasc Res 1993;27:1925–32. [36] Lamas S, Michel T, Brenner BM, Marsden PA. Nitric oxide synthesis in endothelial cells: evidence for a pathway inducible by TNF-alpha. Am J Physiol 1991;261:634–41.
Coronary flow before and after surgical versus device closure of atrial septal defect Elhadi H. Aburawi a,⁎, Ansgar Berg b , Erkki Pesonen a a
Department of Paediatrics, Division of Paediatric Cardiology, Lund University Hospital, Lund, Sweden, Gettingvägen, SE-221 85 Lund, Sweden b Institute of Clinical Medicine, Section of Paediatrics, Bergen University Hospital, Norway Received 4 October 2007; accepted 1 March 2008 Available online 1 July 2008
Abstract Background: Cardiopulmonary bypass (CPB) affects coronary flow after the operation. Surgical as compared to device closure of atrial septal defect (ASD) serves as a good model to clarify the effects of surgery with CPB on coronary flow. Methods: Coronary flow parameters were determined by transthoracic Doppler echocardiography before and after ASD closure. Thirteen children underwent surgery on CPB and fourteen children had device closure of their ASD under interventional cardiac catheterisation. Fourteen age-matched healthy controls were studied. Results: Left ventricular fractional shortening increased and cardiac output increased after the device closure but there were no significant changes after the surgery. After the surgery the mean diameter of left anterior descending coronary artery increased from 1.7 ± 0.6 to 2.1 ± 0.4 mm (p = 0.03), the peak flow velocity in diastole (PFVd) from 48 ± 10 to 70 ± 12 cm/s (p = 0.0001) and basal blood flow (BF) from 62 ± 18 to 105 ± 35 ml/min (p = 0.0001). Flow parameters in the right coronary artery increased similarly. In contrast, all coronary flow parameters decreased substantially after catheter interventions, but still remained significantly elevated as compared with controls. Conclusions: Surgery with cardiopulmonary bypass but not the device closure affects coronary flow beyond the pure effects of anatomical correction. Cardiac output increases after the device closure. The reported decrease of coronary flow reserve is obviously due to increased basal coronary flow. © 2008 Elsevier Ireland Ltd. All rights reserved. Keywords: Atrial septal defect; Coronary flow; Transthoracic Doppler echocardiography
1. Introduction Disturbed coronary flow is an important contributing factor to myocardium-related complications such as contractile dysfunction and arrhythmias [1], which often appear during the first week after cardiac surgery on cardiopulmonary bypass (CPB). The reported decrease of coronary flow reserve (CFR) after surgery with cardiopulmonary bypass (CPB) [2] might be due to increased coronary flow after the surgery [2,3]. CFR reflects the ability of coronary circulation
⁎ Corresponding author. Tel.: +46 46 17 82 61; fax: +46 46 17 81 50. E-mail address: [email protected] (E.H. Aburawi). 0167-5273/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2008.03.046
to increase in response to increased cardiac metabolic demand. It is commonly expressed as the ratio of maximal or hyperaemic coronary flow to resting basal flow and has been reported to be decreased after CPB [2, 4–6]. Positron emission tomography technique has shown it to be decreased 1–3 weeks after surgery on CPB [2]. Intracoronary Doppler flow guide wire (IDGW) studies done 5–7 months after surgery showed improved but still low CFR as compared to presurgical values [7]. Myocardial ischemia/reperfusion has been shown to lead to coronary endothelial cell dysfunction [8]. In experimental models endothelial cell dysfunction after ischemia/reperfusion persists for at least 4–6 weeks [9,10]. The aim of this study is to assess the effect of device closure of ASD
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compared with the combined effects of cardiac surgery and CPB with cardioplegia on the coronary flow in children. 2. Subjects and methods Twenty seven children referred for ASD closure were investigated. Thirteen children at the mean age of 3.5 years (range 2–7 years) underwent surgery on CPB and fourteen children had a device closure of their ASD under interventional cardiac catheterisation at the mean age of 5 years (range 2–8 years). The patients were exposed to diagnostic radiation during the procedures for 5–8 min. No angiographies were done. Normal healthy control group consisted of 14 age-matched children. Written consent was obtained from the guardians of children enrolled in the study. The study protocol conforms to the principles outlined in the declaration of Helsinki [11]. The study was approved by the ethics committee for human research at the Lund University. Transthoracic Doppler echocardiography (TTDE) was performed on all children one day before and 5 ± 1 days postoperatively and one day after device closure. The exclusion criteria were clinical signs of infection/inflammation or CRP value N 0.8 mg/l prior to the procedures. 2.1. Transthoracic Doppler echocardiography TTDE examination was performed using Sequoia™ C512 (Acuson Mountain View, CA, USA) with 7–10 MHz transducer. Standard M- and B-mode and Doppler echocardiographic studies were performed for determining the anatomy and function of the heart. For coronary blood flow and flow velocity measurements the following adjustments were made in the ultrasound machine [12,13]: 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 15–40 cm/s before and 30–60 cm/s after surgery 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 left anterior descending artery (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 artery 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
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best quality envelope and pure sound throughout the cardiac cycle was chosen. Flow in the proximal half of the posterior descending coronary artery (PDA) located in the posterior interventricular groove was registered. 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. Because PDA runs almost parallel to the ultrasound beam it was impossible to measure its diameter. The internal dimension of the main right coronary artery (RCA) was measured and used in flow calculations instead. All images were saved on a magnetic–optic disc and reviewed in a slow-motion, and analyzed in single frame advance mode. The diameter of the aortic ring was measured in a long axis view by M-mode. Left ventricular fractional shortening was computed according to the standard formula [14]. Arterial blood pressure was measured by an automatic oscillometer cuff sphygmomanometer (Dynamap, Critikon Inc., Tampa, Florida, USA). The rate pressure product was calculated by multiplying heart rate with a systolic blood pressure [15]. The analysis package of the ultrasound unit was used for manual tracing of the spectral envelope. The flow velocity measurements across aortic valve were averaged over three consequent cardiac cycles. Diastolic peak flow velocity (PFVd), systolic peak flow velocity (PFVs), diastolic velocity time integral (VTId) and systolic velocity time integral (VTIs) were measured. Velocity–time integral/min was calculated by multiplying the sum of systolic and diastolic VTI (VTIs + d) with heart rate. Blood flow per minute was calculated as VTI/min multiplied with cross sectional area, where cross sectional area = π (coronary artery diameter / 2)2. The whole equation is: Blood flow (BF) ml/min = VTIs + d × Heart rate × π (coronary diameter / 2)2. 2.2. Cardiopulmonary bypass and cardioplegia Open-heart surgery was performed under mild to moderate hypothermic CPB (body temperature 28–32 °C). For myocardial protection, cold (+ 4 °C) hyperkalemic (K+ = 0.07 mmol/ml) blood cardioplegic solution was used. All patients had similar protocol for cardioplegia with antigrade perfusion of the coronary arteries to start with and then retrograde filling through the coronary sinus every 20 min during the CPB. 2.3. Postoperative treatment All children after CPB surgery received opioid derivatives in the form of intravenous ketobemidone hydrochloride during the first 2 to 3 days and then followed by oxicodon orally between 3 and 5 days postoperatively. However during the postoperative coronary flow studies these medications had already been stopped. None of our patients were on ACE-inhibitors, lanoxine, phenylepherine, beta-
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Table 1 Basic data of surgical and device closure groups.
Mean age and range (years) Haemoglobin (g %) ASD diameter (mm)
Surgery group (n = 13)
Device closure group (n = 14)
Before
After
Before
After
p-value
3.5 (2–7) 12.3 (11–13) 13 (8–23)
–
5 (2–8)
–
0.07
12 (11–13) 11 (8–16)
–
0.4
–
0.37⁎
11.9 (10–13) –
p-value
0.3
ASD = atrial septal defect, ⁎p-value between ASD size in surgical versus device closure groups.
blockers or any other vasoactive medications such as nitrate or dopamine during the intensive care management after day one postoperatively. Patients treated by cardiac catheterisation were not on any of the above medications. 2.4. Intra-observer variability In ten children two registrations of LAD flow velocities were performed 15 min apart by the same observer (EHA). The paired data was analyzed regarding peak flow diastolic and systolic velocities, velocity time integrals and LAD blood flow. The analyses of the Doppler tracings were performed off line, separately and independently of each other. 2.5. Statistics Paired Student's t test was used for comparison between the data before and after surgery. Simple and multiple regression analyses were used to calculate the correlation of the changes of PDA BF with right ventricular end-diastolic pressure (RVEDP) as well as pulmonary to systemic flow ratio (Qp/Qs). Statistical analyses were performed using Stat View (SAS Inst. 5.0) statistical software package. A p-value of b 0.05 was considered statistically significant. Results are presented as mean ± standard deviation. The intra-observer variability was statistically measured according to the British Standards Institution [16].
Left ventricular fractional shortening increased after the device closure from 35 ± 4% to 38.5 ± 5% and cardiac output from 595 ± 210 to 702 ± 170 ml/min/kg (p = 0.01 and 0.001 respectively) but there were no significant changes after the surgery (Table 2). Similarly, aorta VTI increased significantly after the device closure from 22 ± 5.5 to 26 ± 5 cm (p = 0.001), but was unchanged after surgery. After CPB surgery the mean diameter of LAD increased from 1.7 ± 0.6 to 2.1 ± 0.4 mm (p = 0.03), while it was the same after the device closure. LAD PFVd increased from 48 ± 10 to 70 ± 12 cm/s (p = 0.0001), BF from 62 ± 18 to 105 ± 35 ml/min (p = 0.0001), (Fig. 2) and VTId + s from 18 ± 4 to 24 ± 4 cm (p = 0.0003). RCA diameter increased from 1.5 ± 0.3to 1.9 ± 0.2 mm, p = 0.0003, and PDA PFVd from 42 ± 10 to 52 ± 8.8 cm/s, (p = 0.03). The estimated BF (RCA diameter used instead of PDA diameter in calculations) increased from 36 ± 18 to 74 ± 41 ml/min (p = 0.0008), and VT Id+ s from 13 ± 5 to 25 ± 15 cm (p = 0.005). All the flow measures decreased substantially after the device closure: LAD PFVd from 51 ± 9 to 40 ± 7 cm/s (p = 0.0001), BF from 66 ± 22 to 45 ± 18 ml/min (p b 0.0001) (Fig. 3) and VTId + s from 20 ± 2 to 16 ± 4.6 cm, p b 0.04. The RCA diameter decreased from 1.7 ± 0.24 to 1.6 ± 0.27 mm, (p = 0.2) and for the PDA PFVd decreased from 46 ± 7 to 30 ± 8 cm/s, (p = 0.0001), BF from 40 ± 18 to 30 ± 14 ml/min, p = 0.001 and VTId + s from 14 ± 4 to 12 ± 2 cm, p = 0.1. The coronary blood flow values of the healthy controls were for LAD lower than even after the device closure of the ASD: PFVd 30 ± 11 cm/s, BF 30 ± 11 ml/min and VTId + s 14 ± 5 cm, (p = 0.0001, p = 0.004 and p = 0.0001 respectively). The PDA parameters were lower than after the device closure PFVd 20 ± 5 cm/s, BF 20 ± 15 ml/min and VTId + s 10 ± 3 cm, (p = 0.0001, p = 0.003 and p = 0.0001 respectively). The actual flow data are presented in (Tables 3 and 4). The following coefficients of variation were obtained: 4.6%, for LAD's diameter, 11.7% for diastolic peak flow
3. Results Heart rate and rate pressure product did not change significantly after the procedures. Blood haemoglobin concentration was the same pre- and postoperatively (12.3 ± 0.7 versus 11.9 ± 0.9 g per 100 ml, p = 0.3). The mean diameter of ASD was in the surgical group slightly larger than in the device closure group, 13 ± 0.5.5 versus 11 ± 2.3 mm respectively (p = 0.37), (Table 1). The basal coronary flow was 66 in the older surgical and 62 ml/min in the younger device closure group (p = 0.3). Before the device closure, simple regression analysis showed a positive correlation between BF in PDA and RVEDP, (Fig. 1) as well as in Qp/Qs (n = 14, r = 0.67, p = 0.01 and r = 0.52, p = 0.06, respectively).
Fig. 1. Basal blood flow in posterior descending artery correlates with right ventricular end-diastolic pressure (r = 0.67, p = 0.01).
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Table 2 Haemodynamic data 1 day before and 5 ± 1 days after surgery and 1 day after device closure of ASD. Surgery (n = 13)
HR (beats/min) Systolic BP (mm Hg) Diastolic BP (mm Hg) RPP (mm Hg/min) CO (ml/min/kg) FS (%) Aorta VTI (cm)
Device Closure (n = 14)
Before
After
p-value
Before
After
p-value
96(12) 105(11) 52(7) 10081(1460) 460(140) 37(8) 18(3.8)
84(21) 102(11) 51(6) 8743(2427) 420(160) 40(5) 18(4)
0.18 0.02 0.6 0.08 0.3 0.37 0.8
99(9) 100(10) 59(7) 9970(1072) 595(210) 35(4) 22(5.5)
97(10) 100(8) 57(5) 9882(1026) 702(170) 38.5(5) 26(5)
0.5 0.8 0.08 0.6 0.001 0.01 0.001
Data are presented as mean (standard deviation). BP = Blood pressure, CO = cardiac output, CPB = cardiopulmonary bypass, FS = fractioning shortening, HR = heart rate, RPP = rate pressure product.
Our study shows that BF in the coronary arteries of ASD patients is increased and further elevated at least up to 6 days after the surgical closure of the defect under CPB. BF decreases after the device closure but not to normal. Because arteries have a certain maximal dilatory state they can reach, the increased basal flow after surgery leads to the decrease of CFR as reported earlier [2]. Our earlier work [3] showing the increased coronary BF after surgery for ventricular septal defect and atrioventricular septal defect and decreased BF after coarctation of aorta operations can be criticized because the diagnostic groups as well as the age of the patients were not similar. In the present study these aspects are taken into account. During the immediate post procedural period, systemic cardiac output increases after the device closure but not after the surgery. The ultrasound probes (4 and 5 MHz) we employed have an axial resolution of 0.1 mm, rendering thus the comparison
in diameter measurements possible. The success rate is significantly operator dependent. We succeeded always in LCA flow registration but the success rate for PDA was 90%. The TTDE assessment of coronary blood flow and flow velocity has been shown to correlate well with IDGW, positron emission tomography and coronary angiography measurements [13]. Measurement of coronary artery diameter by transthoracic echocardiography correlates well with those measured with quantitative coronary angiography [17,18]. The changes in the diameter of coronary arteries affect BF essentially because the area of the coronary artery lumen is related to the radius of the artery squared. The intra-observer coefficients of variation for Doppler flow parameters and even for flow volume were fairly low. They were comparable with earlier reports [16,19]. It may be assumed that the true fluctuations in Doppler coronary flow parameters are at least of the same range as the variation in heart rate coefficient of variation 7% which must be considered when the reproducibility of the method is evaluated. The measurements of flow in PDA do not always reflect only RCA flow. PDA is a continuation of the RCA in up to 70%, but it branches from the left circumflex coronary artery in about 10%. PDA, as a continuation of RCA, gets extra
Fig. 2. Basal coronary blood flow in the left anterior descending coronary artery, before and after surgical closure of ASD and in controls. The box plot displays the 25th percentile, median, and 75th percentile, as well as the 10th and 90th percentiles as horizontal lines outside the box.
Fig. 3. Basal coronary blood flow in the left anterior descending coronary artery, before and after device closure of ASD and in controls. The box plot displays the 25th percentile, median, and 75th percentile, as well as the 10th and 90th percentiles as horizontal lines outside the box.
velocity, 7% for systolic peak flow velocity, 9% for systolic and diastolic velocity time integral, and 3.3% for LAD blood flow. The coefficient of variation for heart rate was 7%. 4. Discussion
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Table 3 Parameters in left anterior descending coronary artery in surgical, device closure groups and in controls. Surgery (n = 13)
Diameter(mm) PFVd (cm/s) BF (ml/min) VTId + s (cm)
Device closure (n = 14)
Controls (n = 14)
Before
After
p-value
Before
After
p-value
1.7(0.3) 48(10) 62(18) 18(4)
2.1(0.4) 70(12) 105(35) 24(4)
0.03 0.0001 0.0001 0.0003
1.7(0.3) 51(9) 66(22) 20(2)
1.6(0.4) 40(7) 45(18) 16(5)
0.1 0.0001 0.0001 0.04
⁎p-value 1.7(0.2) 30(11) 30(8) 14(5)
0.09 0.0001 0.004 0.0001
Data are presented as mean (standard deviation). BF = blood flow, PFV = peak flow velocity, VTId + s = velocity time integral in diastole and systole. ⁎p-value between controls and patients after device closure.
flow from the left circumflex artery in 20%. Because PDA runs almost parallel to flow direction it was impossible to measure the PDA diameter. Instead, the main RCA diameter was used to estimate the BF in the PDA. LAD diameter and flow were measured at the same place. The patients in the surgical group were slightly, 1.5 year older than the intervention group, which might have had some effect on the results. However, basal flows in the two groups were almost equal before the procedures; 66 in the older surgical and 62 ml/min in the younger device closure group. ASD sizes in the surgical group were slightly larger than in the device closure group, but close to each other; according to the transthoracic echocardiography 13 and 11 mm respectively. Haemoglobin did not have any confounding effect of the results because blood haemoglobin concentration was the same before and after the procedures. CRP before the procedures was under 0.8 mg/l in all patients and therefore could not have any effect on basal flows. Cardiopulmonary bypass elicits an intense inflammatory reaction; CRP rises rapidly after surgery reaching a peak approximately 24–48 h after the surgery [20]. CRP has been reported to be an independent risk factor for coronary artery disease [21]. It reflects the degree of inflammation of the body and might affect coronary circulation. Data from both in vivo and in vitro studies using recombinant CRP do not give final answer of its effects. It might have possible dichotomous effects on the vasomotor tone and reactivity of conduit arteries [22]. However, the explanation for this contradictory result might be contamination of CRP extracts with other substances such as endotoxin and sodium azide [23].
Congenital heart disease cause several haemodynamic and functional changes that are likely to affect coronary blood flow [24–27]. The major determinant is the myocardial oxygen consumption which is affected by the heart rate, contractility and wall stress. Wall stress is related to ventricular pressure, chamber diameter and wall thickness [28]. The rate pressure product, describes myocardial oxygen demand [15]. Left ventricular shortening fraction and cardiac output increased after the device closure. We have shown earlier that longitudinal contractile function of the left ventricle decreases after surgery for ASD, but not after the device closure [29]. There was an increase of the blood flow in both main coronary arteries before closure of ASD. The coronary flow decreased after a closure of the defect with a device but still remained higher than in normal controls. These features suggest that the device closure is a preferred method for closing of ASD. After the cardiopulmonary bypass surgery the flow increased significantly. The mechanisms of increased coronary flow are unclear. Before the intervention the volume overload on the right side of the heart leads to increased secretion of atrial natriuretic peptide, which is a vasodilator factor [30]. Likewise the overflow through the lungs leads to increased shear stress of the endothelial cells of the pulmonary arteries which is a stimulus for the secretion of vasoactive substances such as prostacyclin [31]. The increase of coronary flow after CPB surgery and cardioplegia is probably due to the reduction of the myogenic reactivity of the coronary microcirculation [32–34]. The preconditioning effect of the cardioplegic solution on the
Table 4 Parameters in posterior descending coronary artery in surgical, device closure groups and in controls. Surgery (n = 13)
Diameter (mm) PFVd (cm/s) BF (ml/min) VTId + s (cm)
Device closure (n = 14)
Controls (n = 14)
Before
After
p-value
Before
After
p-value
1.5(0.3) 42(10) 36(18) 13(5)
1.9(0.2) 5(9) 74(41) 25(7)
0.0003 0.03 0.0008 0.0003
1.7(0.2) 46(7) 40(18) 14(4)
1.6(0.3) 30(8) 30(14) 12(2)
0.2 0.0001 0.0001 0.1
⁎p-value 1.6(0.2) 20(5) 20(5) 10(3)
0.8 0.0001 0.003 0.0001
Data are presented as mean (standard deviation). BF = blood flow, PFVd = peak flow velocity in diastole, VTId + s = velocity time integral in diastole and systole. ⁎p-value between controls and in patients after device closure.
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coronary circulation consisting of increased production of endothelial dilating prostanoids could be an additional phenomenon [35] even if the long duration of increased flow speaks against this possibility. Much of the present evidence attributes an important pathogenic role to TNF alpha via up regulation of the inducible form of nitric oxide synthase after CPB, which leads to abundant release of nitric oxide and dilatation of the coronary arteries [36]. Limitations of the study include that intravenous adenosine infusion could not be given to the patients because the consent from the parents was not obtained. Therefore the conclusion of possibly decreased coronary flow reserve after cardiopulmonary bypass surgery is based only on the physiological principle that increased basal BF leaves less capacity for further coronary dilatation. The recovery time after the surgery was longer than after device closure which might somewhat disturb the comparability of the flow values (5 versus 1 day). A longer postoperative follow up would have been indicated. However, this could not be done as the patients were discharged by day 1 after cardiac catheterisation and 7 to 8 days after surgery. In conclusion, the coronary flow is increased in patients with ASD. Cardiopulmonary bypass surgery initiates a further increase of coronary flow but the device closure decreases it due to anatomical correction of the defect. Cardiac output increases after the device closure but not immediately after CPB. Acknowledgements We thank the personnel of Lund University Hospital and the Faculty of Medicine, Lund University for financial support of this study.
References [1] Hassanabad ZF, Furman BL, Parratt JR, Aughey E. Coronary endothelial dysfunction increases the severity of ischaemia-induced ventricular arrhythmias in rat isolated perfused hearts. Basic Res Cardiol 1998;93:241–9. [2] Donnelly 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;115:103–10. [3] Aburawi EH, Berg A, Liuba P, Pesonen E. Effects of cardiopulmonary bypass surgery on coronary flow in children assessed with transthoracic Doppler echocardiography. Am J Physiol Heart Circ Physiol 2007;293: H1138–43. [4] Hoffman JI. Maximal coronary flow and the concept of coronary vascular reserve. Circulation 1984;70:153–9. [5] Hoffman JI. Pediatric cardiovascular intensive care: myocardial perfusion. Progr Pediatr Cardiol 1995;4:117–23. [6] Coffman JD, Gregg DE. Reactive hyperaemia characteristics of the myocardium. Am J Physiol 1960;11:1143–9. [7] Harada K, Aoki M, Toyono M, Tamura M. Coronary flow velocity and coronary flow velocity reserve in children with ventricular septal defect. Tohoku J Exp Med 2004;202:77–85. [8] Ku DD. Coronary vascular reactivity after acute myocardial ischemia. Science 1982;218:576–8.
19
[9] Kaeffer N, Richard V, Francois A, Lallemand F, Henry JP, Thuillez C. Preconditioning prevents chronic reperfusion induced coronary endothelial dysfunction in rats. Am J Physiol 1996;271:H842–849. [10] Pearson PJ, Schaff HV, Vanhoutte PM. Long-term impairment of endothelium-dependent relaxations to aggregating platelets following reperfusion injury in canine coronary arteries. Circ res 1990;8:1921–7. [11] World Medical Association Declaration of Helsinki. Recommendations guiding physicians in biomedical research involving human subjects. Cardiovasc Res 1997;35:2–3. [12] Hozumi T, Yoshida K, Ogata Y, Morioka S, et al. Noninvasive assessment of significant left anterior descending coronary artery stenosis by coronary flow velocity reserve with transthoracic colour Doppler echocardiography. Circulation 1998;97:1557–62. [13] Saraste M, Koskenvuo J, Knuuti J, et al. Coronary flow reserve: measurement with transthoracic Doppler echocardiography is reproducible and comparable with positron emission tomography. Clin Physiol 2001;21:114–22. [14] Lewis RP, Sandler H. Relationship between changes in the left ventricular dimension and ejection fraction in man. Circulation 1971;44:548–57. [15] Baller D, Bretschneider HJ, Hellige G. A critical look at currently used indirect indices of myocardial oxygen consumption. Basic Res Cardiol 1981;76:163–81. [16] British Standards Institution. Precision of test methods, I: Guide for the determination and reproducibility for a standard test method. British Standard; 1979. p. 5479. [17] Kiviniemi TO, Saraste M, Koskenvuo JW, et al. Coronary artery diameter can be assessed reliably with transthoracic echocardiography. Am J Physiol Heart Circ Physiol 2004;286:H1515–1520. [18] Kurotobi S, Nagai T, Kawakami N, Sano T. Coronary diameter in normal infants, children and patients with Kawasaki disease. Pediatr Int 2002;44:1–4. [19] Oskarsson G, Pesonen E. Coronary blood flow in healthy neonates: effects of left ventricular function and mass. Pediatr Cardiol 2004;25:11–6. [20] Franke A, Lante W, Fackeldey V, et al. Pro-inflammatory cytokines after different kinds of cardio-thoracic surgical procedures: is what we see what we know? Eur J Cardiothorac Surg 2005;28:569–75. [21] Ridker Paul M. C-reactive protein, inflammation, and cardiovascular disease clinical update. Tex Heart Inst J 2005;32:384–6. [22] Sternik L, Samee S, Schaff HV, et al. C-reactive protein relaxes human vessels in vitro. Arterioscler Thromb Vasc Biol 2002;22:1865–8. [23] Zhong Y, Li SH, Liu SM, et al. C-Reactive protein upregulates receptor for advanced glycation end products expression in human endothelial cells. Hypertension 2006;48:504–11. [24] Kangos JJ, Ferrer MI, Francios RA, Blanc WA, Blumenthal S. Electrocardiographic changes associated with papillary muscle infarction in congenital heart disease. Am J Cardiol 1969;23:801–9. [25] Fogel MA, Rychik J, Vetter J, Donofrio MT, Jacobs M. Effect of volume unloading surgery on coronary flow dynamics in patients with aortic atresia. J Thorac Cardiovasc Surg 1997;113:718–26. [26] Hofstetter R, Zeike B, Messmer BJ, von Bernuth G. Echocardiographic evaluation of systolic left ventricular function in infants with critical aortic stenosis before and after valvotomy. Thorac Cardiovasc Surg 1990;38:236–40. [27] Hongo M, Goto T, Watanab N, et al. Relation of phasic coronary flow velocity profile to clinical and hemodynamic characteristics of patients with aortic valve disease. Circulation 1993;88:953–60. [28] Graham Jr TP, Covell JW, Sonnenblick EH, Ross Jr J, Braunwald E. Control of myocardial oxygen consumption: relative influence of contractile state and tension development. J Clin Inves 1968;47:375–85. [29] Hanseus KC, Bjorkhem G, Brodin LA, Pesonen E. Analysis of atrioventricular plane movements by Doppler tissue imaging and M-mode in children with atrial septal defects before and after surgical and device closure. Pediatr Cardiol 2002;23:152–9. [30] Nagaya N, Nishikimi T, Uematsu M, et al. Secretion patterns of brain natriuretic peptide and atrial natriuretic peptide in patients with or
20
E.H. Aburawi et al. / International Journal of Cardiology 135 (2009) 14–20
without pulmonary hypertension complicating atrial septal defect. Am Heart J 1998;136:297–301. [31] Muta H, Ishii M, Maeno Y, Akagi T, Kato H. Quantitative evaluation of the changes in plasma concentrations of cardiac natriuretic peptide before and after transcatheter closure of atrial septal defect. Acta Paediatr 2002;91:649–52. [32] Wang SY, Friedman M, Franklin A, Sellke FW. Myogenic reactivity of coronary resistance arteries after cardiopulmonary bypass and hyperkalemic cardioplegia. Circulation 1995;92:1590–6. [33] Khan TA, Bianchi C, Ruel M, et al. Mitogen-activated protein kinase inhibitor and cardioplegia–cardiopulmonary bypass reduce coronary myogenic tone. Circulation 2003;108:348–53.
[34] Sellke FW, Shafique T, Ely DL, Weintraub RM. Coronary endothelial injury after cardiopulmonary bypass and ischemic cardioplegia is mediated by oxygen-derived free radicals. Circulation 1993;88:395–400. [35] Sellke FW, Friedman M, Dai HB, et al. Mechanism causing coronary microvascular dysfunction following crystalloid cardioplegia and reperfusion. Cardiovasc Res 1993;27:1925–32. [36] Lamas S, Michel T, Brenner BM, Marsden PA. Nitric oxide synthesis in endothelial cells: evidence for a pathway inducible by TNF-alpha. Am J Physiol 1991;261:634–41.