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Ventral cardiac denervation increased right coronary arterial blood flow
International Journal of Cardiology 114 (2007) 309 – 314 www.elsevier.com/locate/ijcard
Ventral cardiac denervation increased right coronary arterial blood flow Yoshio Ootaki, Keiji Kamohara, Masatoshi Akiyama, Firas Zahr, Michael W. Kopcak Jr., Raymond Dessoffy, Kiyotaka Fukamachi * Department of Biomedical Engineering, Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio, USA Received 19 September 2005; received in revised form 12 December 2005; accepted 14 December 2005 Available online 23 June 2006
Abstract Background: Cardiac denervation accompanied with coronary artery bypass surgery has been widely performed for the treatment of vasospastic angina associated with atherosclerotic coronary artery disease. However, the effect of cardiac denervation on phasic coronary blood flow patterns of the left anterior descending coronary artery (LAD), left circumflex coronary artery (LCX) and right coronary artery (RCA) remains unknown. This study aimed to investigate the effect of cardiac denervation on phasic coronary blood flow patterns of the LAD, LCX and RCA. Methods: Phasic coronary blood flow patterns were analyzed using three flow probes placed around the LAD, LCX and RCA with and without LAD stenosis. Ventral cardiac denervation (VCD) was performed in 8 pigs, and 16 pigs were used as control subjects. Autonomic activities before and after the VCD were quantified by wavelet analysis of heart rate variability. Results: The mean LAD flow (34.4 T 9.4 to 32.6 T 7.1 ml/min, p = 0.638) and mean LCX flow (26.3 T 10.2 to 27.2 T 6.0 ml/min, p = 0.825) showed no significant change after VCD, while the mean RCA flow (31.3 T 9.0 to 38.2 T 11.2 ml/min, p = 0.003) significantly increased. The hemodynamic variables in the VCD group were well maintained after creation of LAD stenosis, while they deteriorated in the control group. The low-frequency components, high-frequency components and their ratio did not change after VCD. Conclusions: VCD prevented the deterioration of cardiac function after creation of an LAD stenosis and resulted in an increase of the mean RCA flow. VCD did not affect autonomic nervous system activity. D 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Cardiac denervation; Coronary blood flow; Vasospastic angina
1. Introduction Cardiac denervation combined with coronary artery bypass surgery [1 –4] has been widely performed for the treatment of vasospastic angina associated with atherosclerotic coronary artery disease since Prinzmetal et al. [5] reported variant angina in 1959. Although cardiac denervation went out of use for patients with Prinzmetal’s angina due to the effectiveness of calcium antagonists, the ventral cardiac denervation (VCD) technique recently has been modified to prevent postoperative atrial fibrillation after coronary bypass grafting [6– 8]. Cardiac denervation has * Corresponding author. 9500 Euclid Avenue, Cleveland, OH 44195, USA. Tel.: +1 216 445 9344; fax: +1 216 444 9198. E-mail address: [email protected] (K. Fukamachi). 0167-5273/$ - see front matter D 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2005.12.011
also contributed to the postoperative clinical improvement following transmyocardial laser revascularization [9,10]. These studies revealed the effectiveness of cardiac denervation from the standpoint of the postoperative symptoms; however, its mechanism and its effects on the coronary blood flows and autonomic nervous activity are still unclear. Amano et al. [11] reported that a significant increase in the saphenous vein graft flow to the left anterior descending coronary artery (LAD) was observed after a combination of coronary artery bypass grafting and cardiac denervation in those patients with organic coronary artery disease. However, the effects of VCD on phasic coronary blood flow patterns of the LAD, left circumflex coronary artery (LCX) and right coronary artery (RCA) have not been assessed. The autonomic nervous system response to VCD remains
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unknown. The hypothesis of this study was that the simultaneous measurement of all three major coronary blood flows should show a significant change after VCD. Therefore, the objective of this study was to investigate the effects of VCD on coronary circulation and autonomic nervous system activity.
2.3. Ventral cardiac denervation
2. Materials and method
The animals were non-randomly divided into two groups. VCD was performed in 8 pigs (VCD group), and 16 pigs were used as control subjects (control group). VCD consisted of a circumferential incision in the adventitia around the ascending aorta and the main pulmonary artery. All fatty tissues within the aorta-pulmonary groove were also incised.
2.1. Animal model
2.4. Intraoperative hemodynamic assessment
Twenty-four pigs weighing 42.9 to 61.7 kg (50.1 T 5.4 kg) were used in this study. This study was approved by the Cleveland Clinic’s Institutional Animal Care and Use Committees, and all animals received humane care in accordance with the ‘‘Guide for the Care and Use of Laboratory Animals’’ published by the National Institutes of Health (National Institutes of Health publication 85-23, revised 1985).
Hemodynamic data were taken at baseline and after creation of LAD stenosis in the control group. Hemodynamic data were taken at baseline, after VCD and after creation of LAD stenosis in the VCD group. The LAD stenosis condition was induced by adjusting the tourniquet placed around the LAD distal to the flow probe to produce approximately a 50% reduction in the LADF. Heart rate, right atrial pressure, left atrial pressure, arterial pressure, coronary blood flows, and cardiac output were recorded.
2.2. Anesthesia and surgical preparation 2.5. Phasic coronary blood flow pattern The animal was anesthetized with an intramuscular injection of ketamine (20 mg/kg), and after intubation, the animal was ventilated through an endotracheal tube with a respirator. Anesthesia was maintained with isoflurane (0.5 –2.5%) until the end of the study. A venous catheter was placed in a peripheral vein to administer fluids. ECG leads were attached to the extremities to monitor cardiac vital signs. The settings of the respirator were adjusted as required based on the results of the arterial blood gas. The animal was placed on the surgical table in the supine position. A continuous infusion of lidocaine was started at the rate of 1 mg/kg/hr before neck incision. A right lateral neck incision was made to isolate the right carotid artery and the jugular vein. An arterial pressure monitoring line was inserted into the right carotid artery, and a venous infusion line and a right atrial pressure monitoring line were inserted through the right jugular vein. A median sternotomy was performed and the infusion rate of lidocaine was increased to 2 mg/kg/hr when the pericardium was opened. A left atrial pressure monitoring line was inserted from the left atrial appendage into the left atrium. The pulmonary artery was isolated for placement of a flow probe (16 mm, Transonic Systems Inc., Ithaca NY) to assess the cardiac output. The RCA, LAD and LCX were also isolated for placement of flow probes (SB-3.0 mm for LAD and LCX, SS-2.5 mm for RCA, Transonic Systems Inc.) in order to assess the coronary blood flow pattern throughout the experiment. The flow probes measured the cardiac output, LAD flow (LADF), LCX flow (LCXF) and RCA flow (RCAF). We obtained the total coronary blood flow (TCBF) by summing the three coronary flow values. A vascular tourniquet was placed distal to the flow probe of the LAD.
Systolic coronary flow was defined as the flow occurring in the period between the onset of rapid acceleration of TCBF associated with ventricular contraction and the onset of rapid acceleration of TCBF associated with ventricular relaxation. From the time-domain flow signal, the peak flow of the systolic and diastolic flow components was obtained. The time-flow integrals of the systolic and the diastolic flow components were also measured by the time-domain flow signal. The diastolic/systolic peak velocity ratios were calculated. Values for each parameter were obtained by averaging measurements from 7 to 10 consecutive cardiac cycles during temporary cessation of ventilation (Fig. 1). 2.6. Analysis of heart rate variability Ten minutes of autonomic activity before and after the VCD were quantified by wavelet analysis of heart rate variability as other investigators reported elsewhere [12,13]. In brief, time-domain analysis and spectral analysis of heart rate variability were performed using the MemCalc system (MemCalc Version 2.5, Suwa Trust CO, Tokyo, Japan) in each condition [14]. High frequency components (HF: 0.15 to 0.40 Hz) were defined as a marker of parasympathetic nervous activity, and low frequency components (LF: 0.04 to 0.15 Hz) related to a combination of parasympathetic and sympathetic nervous activities. The ratio of LF to HF (LF/ HF) was defined as an indicator of sympathetic nerve activity. 2.7. Statistical analysis The hemodynamic variables and ECG data were obtained using a PowerLab data acquisition system (AD
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Fig. 2. Mean coronary blood flow in the LAD, LCX and RCA before and after the ventral cardiac denervation (LAD = left anterior descending coronary artery, LCX = left circumflex coronary artery, RCA= right coronary artery.).
the VCD group and the control group. Differences were considered significant at p < 0.05. Fig. 1. Sample cardiovascular data (ECG = electrocardiogram, CO = cardiac output, LADF = left anterior descending coronary artery flow, LCXF = left circumflex coronary artery flow, RCAF = right coronary artery flow, TCBF = total coronary blood flow.).
Instruments Inc., Mountain View, CA) at 200 Hz and 1000 Hz, respectively, and analyzed using a custom-made visual basic program on Excel software (Excel 2000, Microsoft Corporation, CA). All values were expressed as mean T standard deviation. A paired Student’s t-test was used to assess the differences between the baseline, after the VCD and after creation of the LAD stenosis. An unpaired Student’s t-test and a chi-square test for independence were used to assess the differences between
3. Results VCD was successfully performed in all pigs in the VCD group. Table 1 shows hemodynamic data and coronary blood flows in the control group and the VCD group. After creation of the LAD stenosis, the systolic arterial pressure (85.3 T 6.6 mm Hg to 81.3 T 5.5 mm Hg, p = 0.026), mean arterial pressure (66.6 T 6.9 mm Hg to 62.3 T 5.5 mm Hg, p = 0.031), cardiac output (5.66 T 1.36 l/min to 5.06 T 1.17 l/ min, p = 0.009) and stroke volume (65.1 T12.6 ml to 55.4 T 9.3 ml, p = 0.001) significantly decreased, and the right atrial pressure (6.4 T 2.2 mm Hg to 7.3 T 2.3 mm Hg, p = 0.010) and the left atrial pressure (7.2 T 1.7 to 8.9 T 2.3
Table 1 Hemodynamic data Parameter
Control group (n = 16)
Body weight (kg) Sex (male/female) HR (bpm) mRAP (mm Hg) mLAP (mm Hg) sAP (mm Hg) dAP (mm Hg) mAP (mm Hg) CO (l/min) SV (ml) SVR (dyn sec cm 5) Mean TCBF (ml/min) Mean LADF (ml/min) Mean LCXF (ml/min) Mean RCAF (ml/min)
53.4 T 4.9 (49.3 – 61.7) 3/13 87 T 14 6.4 T 2.2 7.2 T 1.7 85.3 T 6.6 52.9 T 7.5 66.6 T 6.9 5.66 T 1.36 65.1 T12.6 874 T 209 113.5 T 36.8 35.9 T 13.3 29.9 T 14.4 47.7 T 22.8
Baseline
VCD group (n = 8) LAD stenosis
Baseline
After VCD
LAD stenosis
92 T 15 7.3 T 2.3* 8.9 T 2.3* 81.3 T 5.5* 50.3 T 6.2 62.3 T 5.5* 5.06 T 1.17* 55.4 T 9.3* 903 T 184 97.7 T 36.1* 17.6 T 6.0* 32.7 T 21.2 47.4 T 19.7
48.5 T 5.0. (42.9 – 61.6) 4/4 80 T 13 7.8 T 0.6 10.2 T 1.5. 82.5 T 10.8 54.2 T 10.4 65.9 T 11.0 5.40 T 0.43 69.0 T 10.2 860 T 124 92.0 T 21.0 34.4 T 9.4 26.3 T 10.2 31.3 T 9.0
82 T 14 7.9 T 1.1 9.5 T 1.5 83.4 T 9.7 53.0 T 6.1 65.7 T 7.6 5.56 T 0.54 69.0 T 12.5 834 T 93 98.0 T 20.6 32.6 T 7.1 27.2 T 6.0 38.2 T 11.2*
81 T15 8.1 T1.1 10.4 T 1.2 83.2 T 8.4 52.1 T 5.1 64.5 T 6.7 5.35 T 0.56 67.2 T 10.7. 851 T118 79.2 T 17.9* 15.2 T 4.4* 25.6 T 7.0 38.5 T 10.9*
VCD = ventral cardiac denervation, HR = heart rate, mRAP= mean right atrial pressure, mLAP= mean left atrial pressure, sAP= systolic arterial pressure, dAP= diastolic arterial pressure, mAP= mean arterial pressure, CO = cardiac output, SV = stroke volume, SVR = systemic vascular resistance, TCBF = total coronary blood flow, LADF = left anterior descending coronary artery flow, LCXF = left circumflex coronary artery flow, RCAF = right coronary artery flow. * p < 0.05 vs. baseline. . p < 0.05 vs. control.
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Table 2 Phasic coronary blood flow patterns Parameter
Baseline
After VCD
LADFm (ml/min) LADFs (ml/min) LADFd (ml/min) LADFd% (%) LADFpsf (ml/min) LADFpdf (ml/min) LADFpdf/psf LCXFm (ml/min) LCXFs (ml/min) LCXFd (ml/min) LCXFd% (%) LCXFpsf (ml/min) LCXFpdf (ml/min) LCXFpdf/psf RCAFm (ml/min) RCAFs (ml/min) RCAFd (ml/min) RCAFd% (%) RCAFpsf (ml/min) RCAFpdf (ml/min) RCAFpdf/psf
34.4 T 9.4 2.5 T 2.5 31.8 T 9.4 92.3 T 9.1 99.2 T 35.5 151.7 T 47.5 1.73 T 0.78 26.3 T 10.2 4.9 T 4.0 21.4 T 8.7 81.6 T 14.5 93.2 T 42.9 102.5 T 52.1 1.15 T 0.39 31.3 T 9.0 11.2 T 3.8 20.1 T 7.7 63.3 T 13.1 151.8 T 42.9 101.2 T 30.0 0.69 T 0.21
32.6 T 7.1 3.2 T 3.0 29.4 T 5.1 91.0 T 6.7 84.0 T 37.9 148.5 T 45.3 2.02 T 0.75 27.2 T 6.0 6.5 T 3.1 20.6 T 5.0 75.9 T 8.3 85.8 T 26.7 102.9 T 34.4 1.24 T 0.36 38.2 T 11.2* 14.4 T 6.6 23.8 T 6.2* 63.2 T 7.4 177.5 T 48.2* 132.3 T 21.2* 0.77 T 0.12
LADF = left anterior descending artery flow, LCXF = left circumflex artery flow, RCAF = right coronary artery flow, m = mean flow, s = systolic flow, d = diastolic flow, d% = diastolic fraction, psf = peak systolic flow, pdf = peak diastolic flow. * p < 0.05 baseline vs. after VCD.
mm Hg, p = 0.001) significantly increased in the control group, while these parameters were well maintained in the VCD group after creation of the LAD stenosis. The mean LADF (34.4 T 9.4 ml/min to 32.6 T 7.1 ml/min, p = 0.638) and mean LCXF (26.3 T 10.2 ml/min to 27.2 T 6.0 ml/min, p = 0.825) showed no significant change after VCD, while the mean RCAF (31.3 T 9.0 ml/min to 38.2 T 11.2 ml/min, p = 0.003) significantly increased (Fig. 2). Table 2 shows the phasic coronary blood flow patterns in the baseline and after VCD. There was no significant difference in the phasic coronary blood flow patterns in the LAD and LCX, while the diastolic RCAF (20.1 T 7.7 ml/min to 23.8 T 6.2 ml/min, p = 0.035), peak diastolic RCAF (101.2 T 30.0 ml/min to 132.3 T 21.2 ml/min, p = 0.003), and peak systolic RCAF (151.8 T 42.9 ml/min to 177.5 T 48.2 ml/ min, p = 0.024) significantly increased after VCD. There were no significant changes after VCD in the HF components (2.35 T 0.93 ms2 to 3.17 T 4.31 ms2, p= 0.578), LF components (0.43 T 0.25 ms2 to 0.35T 0.20 ms2, p = 0.611) or LF/HF ratio (0.25T 0.23 to 0.39 T 0.46, p = 0.238).
4. Discussion The present study analyzing hemodynamic data, phasic coronary blood flow patterns and heart rate variability revealed that (1) the mean LADF and LCXF were constant, while the mean RCAF increased after VCD; (2) the systolic RCAF, peak diastolic RCAF and peak systolic RCAF
increased after VCD; (3) the hemodynamic variables in the VCD group were well maintained after creation of LAD stenosis, while it deteriorated in the control group, and (4) the HF components, LF components and LF/HF ratio did not change after VCD. The autonomic nervous system anatomy was widely investigated not only in the extrapericardial space [15] but also in the intrapericardial space [16,17] and surface of the heart [18,19]. Pauza et al. reported [18] that from the arterial portion of the heart hilum (i.e., around the ascending aorta and pulmonary trunk) intrinsic nerves extend predominantly into the ventricle, while intrinsic nerves extend into the ventricle and atrium from the venous part of the heart hilum (i.e., around pulmonary veins and vena cavae). In addition, these intrinsic nerves proceed separately into regions of innervation in the ventricle and atrium by seven pathways: (1) left coronary, (2) right coronary, (3) ventral right atrial, (4) ventral left atrial, (5) left dorsal, (6) middle dorsal and (7) dorsal right atrial [19]. The right atrium was innervated by two subplexuses, the left atrium by three, the right ventricle by one and the left ventricle by three subplexuses [19]. According to this classification, the VCD procedure that we performed in this study involved all intrinsic nerves into the right ventricle and one third of the intrinsic nerves passing into the left ventricle. In this study, the mean LADF and LCXF were constant, while the mean RCAF increased after the VCD. These anatomical differences of the intrinsic nerves in the right ventricle and the left ventricle might be the cause for the difference in coronary blood flow seen after VCD. The mean RCAF, peak systolic RCAF and peak diastolic RCAF increased, while the diastolic fraction of the RCAF was constant in this study. In the RCA, diastolic flow is mainly regulated by arterial pressure, and systolic flow is mainly regulated by the pressure gradient between the arterial pressure and myocardial tissue pressure [20]. Since the hemodynamics before and after VCD were constant, the diastolic fraction of the RCAF was supposed to be constant in this study. Loss of sympathetic tone resulting in the blockade of a-adrenergic effect caused by VCD might play an important role in increasing the mean RCAF [21]. In the VCD group, the hemodynamic variables were well maintained after creation of the LAD stenosis, while the hemodynamic variables deteriorated in the control group. Since the mean RCAF increased after VCD, this increase might be an attempt to compensate for a shortage of coronary blood flow in the LAD. The effectiveness of transmyocardial laser revascularization due to the cardiac denervation was also reported [9,10]. Although the mechanism of transmyocardial laser revascularization is not well understood and questionable [22], some investigators reported that the increased coronary blood flow from the collateral arteries due to cardiac denervation might contribute to the experimental and clinical effectiveness observed following transmyocardial laser revascularization [23,24].
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Since we did not directly measure the left ventricular function or collateral blood flow, further studies will be needed to clarify the effect of VCD on collateral blood flow. Analysis of the heart rate variability did not show any significant change after VCD. This fact might also be explained by not only the anatomical differences of the intrinsic nerves in the right ventricle and the left ventricle but also the surgical approaches. Methods employed to accomplish cardiac denervation varied with each investigator: thoracic ganglion by Galinanes et al. [25], autotransplantation by Bertland et al. [26], plexectomy by Bertrand et al. [3], ventral cardiac denervation including right and left pulmonary arteries by Betriu et al. [4], ventral cardiac denervation including dissection around the anterior wall of the right pulmonary artery by Amano et al. [11], and ventral cardiac denervation including dissection around superior vena cava by Melo et al. [6] and Alex et al. [8]. Extended dissection of the heart hilum can intercept the autonomic nervous fiber, though it introduces a risk of postoperative bleeding and prolonged operative time. Extended dissection might also affect the heart rate or heart rate variability after cardiac denervation. On the other hand, our VCD technique consisting of a circumferential incision in the adventitia around the ascending aorta and main pulmonary artery was a simple and effective method to induce a total blockade of the efferent nerve to the right ventricle. Since analysis of the heart rate variability did not show any significant change after VCD, it is difficult to determine whether VCD acts as a sympathetic block, parasympathetic block, afferent nerve block or efferent nerve block. Measurements of coronary blood flow and heart rate variability with sympathetic or parasympathetic blocking agents during the normal condition and the ischemic condition will be helpful to determine the mechanism of VCD. In clinical cases, iodine-123 metaiodobenzylguanidine imaging [27] might be useful to assess the regional effect of the VCD. For several reasons, the results produced from this study do not directly contribute to human clinical applications. An obvious limitation of this study is that our model was an acute, anesthetized, open-chest animal. These factors might affect the coronary blood flows and autonomic nervous system. Although concentration of the anesthetic can affect the autonomic nerve activity [28], the autonomic nerve activity was not altered with our VCD technique. According to the report by Pauza et al. in 2000 [19], the percentage of the ganglionated field that we blocked with our procedure represented about 10% of the total neurons in the heart. Therefore, the procedure might have a less pronounced effect on the heart rate and heart rate variability. Further studies will be required to clarify the effect of VCD on coronary circulation and autonomic nervous activity using a chronic VCD model. The second limitation of this study is that the anatomy and nervous system of the animal heart slightly differ from the normal human cardiac structure [29,30]. The third limitation is that the body weight of the
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control group (53.4 T 4.9 kg) and the VCD group (48.5 T 5.0 kg) showed a significant difference. The coronary blood flows were slightly higher in the control group. However, because these hemodynamic parameters showed no significant differences, and we did not directly compare hemodynamic data between the two groups, the results from this study might not be affected by the body size. To perform a human clinical study, serial surgical approaches depending on the serial assessment of the intrinsic nerves [19] will be needed. If VCD is proven beneficial for the coronary blood flow in human, this additional simple technique should be performed in conjunction with a major cardiac surgery procedure in patients suffering from Prinzmetal’s angina to prevent the need for medication throughout life. Since VCD is a very simple technique, the surgical risk for the additional VCD might be minimal. In conclusion, VCD prevented the deterioration of the cardiac function after creation of an LAD stenosis and resulted in an increase of the mean RCAF. VCD did not affect the autonomic nervous system activity. References [1] Grondin CM, Limet R. Sympathetic denervation in association with coronary artery grafting in patients with Prinzmetals’ angina. Ann Thorac Surg 1977;23:111 – 7. [2] Clark DA, Quint RA, Mitchell RL, Angell WW. Coronary artery spasm. Medical management, surgical denervation, and autotransplantation. J Thorac Cardiovasc Surg 1977;73:332 – 9. [3] Bertrand ME, Lablanche JM, Rousseau MF, Warembourg Jr HH, Stankowtak C, Soots G. Surgical treatment of variant angina: use of plexectomy with aortocoronary bypass. Circulation 1980;61:877 – 82. [4] Betriu A, Pomar JL, Bourassa MG, Grondin CM. Influence of partial sympathetic denervation on the results of myocardial revascularization in variant angina. Am J Cardiol 1983;51:661 – 7. [5] Prinzmetal M, Kennamer R, Merliss R, Wada T, Bor N. Angina pectoris: I. A variant form of angina pectoris. Am J Med 1959;27:375. [6] Melo J, Voigt P, Sonmez B, et al. Ventral cardiac denervation reduces the incidence of atrial fibrillation after coronary artery bypass grafting. J Thorac Cardiovasc Surg 2004;127:511 – 6. [7] Saltman AE. New-onset postoperative atrial fibrillation: a riddle wrapped in a mystery inside an enigma. J Thorac Cardiovasc Surg 2004;127:311 – 3. [8] Alex J, Rehman MU, Guvendik L. Ventral cardiac denervation: is it truly an effective prophylaxis against atrial fibrillation after coronary artery bypass grafting? J Thorac Cardiovasc Surg 2004;128:326 – 7. [9] Muxi A, Magrina J, Martin F, et al. Technetium 99m-labeled tetrofosmin and iodine 123-labeled metaiodobenzylguanidine scintigraphy in the assessment of transmyocardial laser revascularization. J Thorac Cardiovasc Surg 2003;125:1493 – 8. [10] Beek JF, van der Sloot JA, Huikeshoven M, et al. Cardiac denervation after clinical transmyocardial laser revascularization: short-term and long-term iodine 123-labeled meta-iodobenzylguanide scintigraphic evidence. J Thorac Cardiovasc Surg 2004;127:517 – 24. [11] Amano J, Suzuki A, Sunamori M. Effects of cardiac denervation on coronary and systemic circulation. Ann Thorac Surg 1994;57:928 – 32. [12] Takusagawa M, Komori S, Umetani K, et al. Alterations of autonomic nervous activity in recurrence of variant angina. Heart 1999;82:75 – 81. [13] Kanaya N, Hirata N, Kurosawa S, Nakayama M, Namiki A. Differential effects of propofol and sevoflurane on heart rate variability. Anesthesiology 2003;98:34 – 40.
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Ventral cardiac denervation increased right coronary arterial blood flow Yoshio Ootaki, Keiji Kamohara, Masatoshi Akiyama, Firas Zahr, Michael W. Kopcak Jr., Raymond Dessoffy, Kiyotaka Fukamachi * Department of Biomedical Engineering, Lerner Research Institute, The Cleveland Clinic, Cleveland, Ohio, USA Received 19 September 2005; received in revised form 12 December 2005; accepted 14 December 2005 Available online 23 June 2006
Abstract Background: Cardiac denervation accompanied with coronary artery bypass surgery has been widely performed for the treatment of vasospastic angina associated with atherosclerotic coronary artery disease. However, the effect of cardiac denervation on phasic coronary blood flow patterns of the left anterior descending coronary artery (LAD), left circumflex coronary artery (LCX) and right coronary artery (RCA) remains unknown. This study aimed to investigate the effect of cardiac denervation on phasic coronary blood flow patterns of the LAD, LCX and RCA. Methods: Phasic coronary blood flow patterns were analyzed using three flow probes placed around the LAD, LCX and RCA with and without LAD stenosis. Ventral cardiac denervation (VCD) was performed in 8 pigs, and 16 pigs were used as control subjects. Autonomic activities before and after the VCD were quantified by wavelet analysis of heart rate variability. Results: The mean LAD flow (34.4 T 9.4 to 32.6 T 7.1 ml/min, p = 0.638) and mean LCX flow (26.3 T 10.2 to 27.2 T 6.0 ml/min, p = 0.825) showed no significant change after VCD, while the mean RCA flow (31.3 T 9.0 to 38.2 T 11.2 ml/min, p = 0.003) significantly increased. The hemodynamic variables in the VCD group were well maintained after creation of LAD stenosis, while they deteriorated in the control group. The low-frequency components, high-frequency components and their ratio did not change after VCD. Conclusions: VCD prevented the deterioration of cardiac function after creation of an LAD stenosis and resulted in an increase of the mean RCA flow. VCD did not affect autonomic nervous system activity. D 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Cardiac denervation; Coronary blood flow; Vasospastic angina
1. Introduction Cardiac denervation combined with coronary artery bypass surgery [1 –4] has been widely performed for the treatment of vasospastic angina associated with atherosclerotic coronary artery disease since Prinzmetal et al. [5] reported variant angina in 1959. Although cardiac denervation went out of use for patients with Prinzmetal’s angina due to the effectiveness of calcium antagonists, the ventral cardiac denervation (VCD) technique recently has been modified to prevent postoperative atrial fibrillation after coronary bypass grafting [6– 8]. Cardiac denervation has * Corresponding author. 9500 Euclid Avenue, Cleveland, OH 44195, USA. Tel.: +1 216 445 9344; fax: +1 216 444 9198. E-mail address: [email protected] (K. Fukamachi). 0167-5273/$ - see front matter D 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2005.12.011
also contributed to the postoperative clinical improvement following transmyocardial laser revascularization [9,10]. These studies revealed the effectiveness of cardiac denervation from the standpoint of the postoperative symptoms; however, its mechanism and its effects on the coronary blood flows and autonomic nervous activity are still unclear. Amano et al. [11] reported that a significant increase in the saphenous vein graft flow to the left anterior descending coronary artery (LAD) was observed after a combination of coronary artery bypass grafting and cardiac denervation in those patients with organic coronary artery disease. However, the effects of VCD on phasic coronary blood flow patterns of the LAD, left circumflex coronary artery (LCX) and right coronary artery (RCA) have not been assessed. The autonomic nervous system response to VCD remains
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unknown. The hypothesis of this study was that the simultaneous measurement of all three major coronary blood flows should show a significant change after VCD. Therefore, the objective of this study was to investigate the effects of VCD on coronary circulation and autonomic nervous system activity.
2.3. Ventral cardiac denervation
2. Materials and method
The animals were non-randomly divided into two groups. VCD was performed in 8 pigs (VCD group), and 16 pigs were used as control subjects (control group). VCD consisted of a circumferential incision in the adventitia around the ascending aorta and the main pulmonary artery. All fatty tissues within the aorta-pulmonary groove were also incised.
2.1. Animal model
2.4. Intraoperative hemodynamic assessment
Twenty-four pigs weighing 42.9 to 61.7 kg (50.1 T 5.4 kg) were used in this study. This study was approved by the Cleveland Clinic’s Institutional Animal Care and Use Committees, and all animals received humane care in accordance with the ‘‘Guide for the Care and Use of Laboratory Animals’’ published by the National Institutes of Health (National Institutes of Health publication 85-23, revised 1985).
Hemodynamic data were taken at baseline and after creation of LAD stenosis in the control group. Hemodynamic data were taken at baseline, after VCD and after creation of LAD stenosis in the VCD group. The LAD stenosis condition was induced by adjusting the tourniquet placed around the LAD distal to the flow probe to produce approximately a 50% reduction in the LADF. Heart rate, right atrial pressure, left atrial pressure, arterial pressure, coronary blood flows, and cardiac output were recorded.
2.2. Anesthesia and surgical preparation 2.5. Phasic coronary blood flow pattern The animal was anesthetized with an intramuscular injection of ketamine (20 mg/kg), and after intubation, the animal was ventilated through an endotracheal tube with a respirator. Anesthesia was maintained with isoflurane (0.5 –2.5%) until the end of the study. A venous catheter was placed in a peripheral vein to administer fluids. ECG leads were attached to the extremities to monitor cardiac vital signs. The settings of the respirator were adjusted as required based on the results of the arterial blood gas. The animal was placed on the surgical table in the supine position. A continuous infusion of lidocaine was started at the rate of 1 mg/kg/hr before neck incision. A right lateral neck incision was made to isolate the right carotid artery and the jugular vein. An arterial pressure monitoring line was inserted into the right carotid artery, and a venous infusion line and a right atrial pressure monitoring line were inserted through the right jugular vein. A median sternotomy was performed and the infusion rate of lidocaine was increased to 2 mg/kg/hr when the pericardium was opened. A left atrial pressure monitoring line was inserted from the left atrial appendage into the left atrium. The pulmonary artery was isolated for placement of a flow probe (16 mm, Transonic Systems Inc., Ithaca NY) to assess the cardiac output. The RCA, LAD and LCX were also isolated for placement of flow probes (SB-3.0 mm for LAD and LCX, SS-2.5 mm for RCA, Transonic Systems Inc.) in order to assess the coronary blood flow pattern throughout the experiment. The flow probes measured the cardiac output, LAD flow (LADF), LCX flow (LCXF) and RCA flow (RCAF). We obtained the total coronary blood flow (TCBF) by summing the three coronary flow values. A vascular tourniquet was placed distal to the flow probe of the LAD.
Systolic coronary flow was defined as the flow occurring in the period between the onset of rapid acceleration of TCBF associated with ventricular contraction and the onset of rapid acceleration of TCBF associated with ventricular relaxation. From the time-domain flow signal, the peak flow of the systolic and diastolic flow components was obtained. The time-flow integrals of the systolic and the diastolic flow components were also measured by the time-domain flow signal. The diastolic/systolic peak velocity ratios were calculated. Values for each parameter were obtained by averaging measurements from 7 to 10 consecutive cardiac cycles during temporary cessation of ventilation (Fig. 1). 2.6. Analysis of heart rate variability Ten minutes of autonomic activity before and after the VCD were quantified by wavelet analysis of heart rate variability as other investigators reported elsewhere [12,13]. In brief, time-domain analysis and spectral analysis of heart rate variability were performed using the MemCalc system (MemCalc Version 2.5, Suwa Trust CO, Tokyo, Japan) in each condition [14]. High frequency components (HF: 0.15 to 0.40 Hz) were defined as a marker of parasympathetic nervous activity, and low frequency components (LF: 0.04 to 0.15 Hz) related to a combination of parasympathetic and sympathetic nervous activities. The ratio of LF to HF (LF/ HF) was defined as an indicator of sympathetic nerve activity. 2.7. Statistical analysis The hemodynamic variables and ECG data were obtained using a PowerLab data acquisition system (AD
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Fig. 2. Mean coronary blood flow in the LAD, LCX and RCA before and after the ventral cardiac denervation (LAD = left anterior descending coronary artery, LCX = left circumflex coronary artery, RCA= right coronary artery.).
the VCD group and the control group. Differences were considered significant at p < 0.05. Fig. 1. Sample cardiovascular data (ECG = electrocardiogram, CO = cardiac output, LADF = left anterior descending coronary artery flow, LCXF = left circumflex coronary artery flow, RCAF = right coronary artery flow, TCBF = total coronary blood flow.).
Instruments Inc., Mountain View, CA) at 200 Hz and 1000 Hz, respectively, and analyzed using a custom-made visual basic program on Excel software (Excel 2000, Microsoft Corporation, CA). All values were expressed as mean T standard deviation. A paired Student’s t-test was used to assess the differences between the baseline, after the VCD and after creation of the LAD stenosis. An unpaired Student’s t-test and a chi-square test for independence were used to assess the differences between
3. Results VCD was successfully performed in all pigs in the VCD group. Table 1 shows hemodynamic data and coronary blood flows in the control group and the VCD group. After creation of the LAD stenosis, the systolic arterial pressure (85.3 T 6.6 mm Hg to 81.3 T 5.5 mm Hg, p = 0.026), mean arterial pressure (66.6 T 6.9 mm Hg to 62.3 T 5.5 mm Hg, p = 0.031), cardiac output (5.66 T 1.36 l/min to 5.06 T 1.17 l/ min, p = 0.009) and stroke volume (65.1 T12.6 ml to 55.4 T 9.3 ml, p = 0.001) significantly decreased, and the right atrial pressure (6.4 T 2.2 mm Hg to 7.3 T 2.3 mm Hg, p = 0.010) and the left atrial pressure (7.2 T 1.7 to 8.9 T 2.3
Table 1 Hemodynamic data Parameter
Control group (n = 16)
Body weight (kg) Sex (male/female) HR (bpm) mRAP (mm Hg) mLAP (mm Hg) sAP (mm Hg) dAP (mm Hg) mAP (mm Hg) CO (l/min) SV (ml) SVR (dyn sec cm 5) Mean TCBF (ml/min) Mean LADF (ml/min) Mean LCXF (ml/min) Mean RCAF (ml/min)
53.4 T 4.9 (49.3 – 61.7) 3/13 87 T 14 6.4 T 2.2 7.2 T 1.7 85.3 T 6.6 52.9 T 7.5 66.6 T 6.9 5.66 T 1.36 65.1 T12.6 874 T 209 113.5 T 36.8 35.9 T 13.3 29.9 T 14.4 47.7 T 22.8
Baseline
VCD group (n = 8) LAD stenosis
Baseline
After VCD
LAD stenosis
92 T 15 7.3 T 2.3* 8.9 T 2.3* 81.3 T 5.5* 50.3 T 6.2 62.3 T 5.5* 5.06 T 1.17* 55.4 T 9.3* 903 T 184 97.7 T 36.1* 17.6 T 6.0* 32.7 T 21.2 47.4 T 19.7
48.5 T 5.0. (42.9 – 61.6) 4/4 80 T 13 7.8 T 0.6 10.2 T 1.5. 82.5 T 10.8 54.2 T 10.4 65.9 T 11.0 5.40 T 0.43 69.0 T 10.2 860 T 124 92.0 T 21.0 34.4 T 9.4 26.3 T 10.2 31.3 T 9.0
82 T 14 7.9 T 1.1 9.5 T 1.5 83.4 T 9.7 53.0 T 6.1 65.7 T 7.6 5.56 T 0.54 69.0 T 12.5 834 T 93 98.0 T 20.6 32.6 T 7.1 27.2 T 6.0 38.2 T 11.2*
81 T15 8.1 T1.1 10.4 T 1.2 83.2 T 8.4 52.1 T 5.1 64.5 T 6.7 5.35 T 0.56 67.2 T 10.7. 851 T118 79.2 T 17.9* 15.2 T 4.4* 25.6 T 7.0 38.5 T 10.9*
VCD = ventral cardiac denervation, HR = heart rate, mRAP= mean right atrial pressure, mLAP= mean left atrial pressure, sAP= systolic arterial pressure, dAP= diastolic arterial pressure, mAP= mean arterial pressure, CO = cardiac output, SV = stroke volume, SVR = systemic vascular resistance, TCBF = total coronary blood flow, LADF = left anterior descending coronary artery flow, LCXF = left circumflex coronary artery flow, RCAF = right coronary artery flow. * p < 0.05 vs. baseline. . p < 0.05 vs. control.
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Table 2 Phasic coronary blood flow patterns Parameter
Baseline
After VCD
LADFm (ml/min) LADFs (ml/min) LADFd (ml/min) LADFd% (%) LADFpsf (ml/min) LADFpdf (ml/min) LADFpdf/psf LCXFm (ml/min) LCXFs (ml/min) LCXFd (ml/min) LCXFd% (%) LCXFpsf (ml/min) LCXFpdf (ml/min) LCXFpdf/psf RCAFm (ml/min) RCAFs (ml/min) RCAFd (ml/min) RCAFd% (%) RCAFpsf (ml/min) RCAFpdf (ml/min) RCAFpdf/psf
34.4 T 9.4 2.5 T 2.5 31.8 T 9.4 92.3 T 9.1 99.2 T 35.5 151.7 T 47.5 1.73 T 0.78 26.3 T 10.2 4.9 T 4.0 21.4 T 8.7 81.6 T 14.5 93.2 T 42.9 102.5 T 52.1 1.15 T 0.39 31.3 T 9.0 11.2 T 3.8 20.1 T 7.7 63.3 T 13.1 151.8 T 42.9 101.2 T 30.0 0.69 T 0.21
32.6 T 7.1 3.2 T 3.0 29.4 T 5.1 91.0 T 6.7 84.0 T 37.9 148.5 T 45.3 2.02 T 0.75 27.2 T 6.0 6.5 T 3.1 20.6 T 5.0 75.9 T 8.3 85.8 T 26.7 102.9 T 34.4 1.24 T 0.36 38.2 T 11.2* 14.4 T 6.6 23.8 T 6.2* 63.2 T 7.4 177.5 T 48.2* 132.3 T 21.2* 0.77 T 0.12
LADF = left anterior descending artery flow, LCXF = left circumflex artery flow, RCAF = right coronary artery flow, m = mean flow, s = systolic flow, d = diastolic flow, d% = diastolic fraction, psf = peak systolic flow, pdf = peak diastolic flow. * p < 0.05 baseline vs. after VCD.
mm Hg, p = 0.001) significantly increased in the control group, while these parameters were well maintained in the VCD group after creation of the LAD stenosis. The mean LADF (34.4 T 9.4 ml/min to 32.6 T 7.1 ml/min, p = 0.638) and mean LCXF (26.3 T 10.2 ml/min to 27.2 T 6.0 ml/min, p = 0.825) showed no significant change after VCD, while the mean RCAF (31.3 T 9.0 ml/min to 38.2 T 11.2 ml/min, p = 0.003) significantly increased (Fig. 2). Table 2 shows the phasic coronary blood flow patterns in the baseline and after VCD. There was no significant difference in the phasic coronary blood flow patterns in the LAD and LCX, while the diastolic RCAF (20.1 T 7.7 ml/min to 23.8 T 6.2 ml/min, p = 0.035), peak diastolic RCAF (101.2 T 30.0 ml/min to 132.3 T 21.2 ml/min, p = 0.003), and peak systolic RCAF (151.8 T 42.9 ml/min to 177.5 T 48.2 ml/ min, p = 0.024) significantly increased after VCD. There were no significant changes after VCD in the HF components (2.35 T 0.93 ms2 to 3.17 T 4.31 ms2, p= 0.578), LF components (0.43 T 0.25 ms2 to 0.35T 0.20 ms2, p = 0.611) or LF/HF ratio (0.25T 0.23 to 0.39 T 0.46, p = 0.238).
4. Discussion The present study analyzing hemodynamic data, phasic coronary blood flow patterns and heart rate variability revealed that (1) the mean LADF and LCXF were constant, while the mean RCAF increased after VCD; (2) the systolic RCAF, peak diastolic RCAF and peak systolic RCAF
increased after VCD; (3) the hemodynamic variables in the VCD group were well maintained after creation of LAD stenosis, while it deteriorated in the control group, and (4) the HF components, LF components and LF/HF ratio did not change after VCD. The autonomic nervous system anatomy was widely investigated not only in the extrapericardial space [15] but also in the intrapericardial space [16,17] and surface of the heart [18,19]. Pauza et al. reported [18] that from the arterial portion of the heart hilum (i.e., around the ascending aorta and pulmonary trunk) intrinsic nerves extend predominantly into the ventricle, while intrinsic nerves extend into the ventricle and atrium from the venous part of the heart hilum (i.e., around pulmonary veins and vena cavae). In addition, these intrinsic nerves proceed separately into regions of innervation in the ventricle and atrium by seven pathways: (1) left coronary, (2) right coronary, (3) ventral right atrial, (4) ventral left atrial, (5) left dorsal, (6) middle dorsal and (7) dorsal right atrial [19]. The right atrium was innervated by two subplexuses, the left atrium by three, the right ventricle by one and the left ventricle by three subplexuses [19]. According to this classification, the VCD procedure that we performed in this study involved all intrinsic nerves into the right ventricle and one third of the intrinsic nerves passing into the left ventricle. In this study, the mean LADF and LCXF were constant, while the mean RCAF increased after the VCD. These anatomical differences of the intrinsic nerves in the right ventricle and the left ventricle might be the cause for the difference in coronary blood flow seen after VCD. The mean RCAF, peak systolic RCAF and peak diastolic RCAF increased, while the diastolic fraction of the RCAF was constant in this study. In the RCA, diastolic flow is mainly regulated by arterial pressure, and systolic flow is mainly regulated by the pressure gradient between the arterial pressure and myocardial tissue pressure [20]. Since the hemodynamics before and after VCD were constant, the diastolic fraction of the RCAF was supposed to be constant in this study. Loss of sympathetic tone resulting in the blockade of a-adrenergic effect caused by VCD might play an important role in increasing the mean RCAF [21]. In the VCD group, the hemodynamic variables were well maintained after creation of the LAD stenosis, while the hemodynamic variables deteriorated in the control group. Since the mean RCAF increased after VCD, this increase might be an attempt to compensate for a shortage of coronary blood flow in the LAD. The effectiveness of transmyocardial laser revascularization due to the cardiac denervation was also reported [9,10]. Although the mechanism of transmyocardial laser revascularization is not well understood and questionable [22], some investigators reported that the increased coronary blood flow from the collateral arteries due to cardiac denervation might contribute to the experimental and clinical effectiveness observed following transmyocardial laser revascularization [23,24].
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Since we did not directly measure the left ventricular function or collateral blood flow, further studies will be needed to clarify the effect of VCD on collateral blood flow. Analysis of the heart rate variability did not show any significant change after VCD. This fact might also be explained by not only the anatomical differences of the intrinsic nerves in the right ventricle and the left ventricle but also the surgical approaches. Methods employed to accomplish cardiac denervation varied with each investigator: thoracic ganglion by Galinanes et al. [25], autotransplantation by Bertland et al. [26], plexectomy by Bertrand et al. [3], ventral cardiac denervation including right and left pulmonary arteries by Betriu et al. [4], ventral cardiac denervation including dissection around the anterior wall of the right pulmonary artery by Amano et al. [11], and ventral cardiac denervation including dissection around superior vena cava by Melo et al. [6] and Alex et al. [8]. Extended dissection of the heart hilum can intercept the autonomic nervous fiber, though it introduces a risk of postoperative bleeding and prolonged operative time. Extended dissection might also affect the heart rate or heart rate variability after cardiac denervation. On the other hand, our VCD technique consisting of a circumferential incision in the adventitia around the ascending aorta and main pulmonary artery was a simple and effective method to induce a total blockade of the efferent nerve to the right ventricle. Since analysis of the heart rate variability did not show any significant change after VCD, it is difficult to determine whether VCD acts as a sympathetic block, parasympathetic block, afferent nerve block or efferent nerve block. Measurements of coronary blood flow and heart rate variability with sympathetic or parasympathetic blocking agents during the normal condition and the ischemic condition will be helpful to determine the mechanism of VCD. In clinical cases, iodine-123 metaiodobenzylguanidine imaging [27] might be useful to assess the regional effect of the VCD. For several reasons, the results produced from this study do not directly contribute to human clinical applications. An obvious limitation of this study is that our model was an acute, anesthetized, open-chest animal. These factors might affect the coronary blood flows and autonomic nervous system. Although concentration of the anesthetic can affect the autonomic nerve activity [28], the autonomic nerve activity was not altered with our VCD technique. According to the report by Pauza et al. in 2000 [19], the percentage of the ganglionated field that we blocked with our procedure represented about 10% of the total neurons in the heart. Therefore, the procedure might have a less pronounced effect on the heart rate and heart rate variability. Further studies will be required to clarify the effect of VCD on coronary circulation and autonomic nervous activity using a chronic VCD model. The second limitation of this study is that the anatomy and nervous system of the animal heart slightly differ from the normal human cardiac structure [29,30]. The third limitation is that the body weight of the
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control group (53.4 T 4.9 kg) and the VCD group (48.5 T 5.0 kg) showed a significant difference. The coronary blood flows were slightly higher in the control group. However, because these hemodynamic parameters showed no significant differences, and we did not directly compare hemodynamic data between the two groups, the results from this study might not be affected by the body size. To perform a human clinical study, serial surgical approaches depending on the serial assessment of the intrinsic nerves [19] will be needed. If VCD is proven beneficial for the coronary blood flow in human, this additional simple technique should be performed in conjunction with a major cardiac surgery procedure in patients suffering from Prinzmetal’s angina to prevent the need for medication throughout life. Since VCD is a very simple technique, the surgical risk for the additional VCD might be minimal. In conclusion, VCD prevented the deterioration of the cardiac function after creation of an LAD stenosis and resulted in an increase of the mean RCAF. VCD did not affect the autonomic nervous system activity. References [1] Grondin CM, Limet R. Sympathetic denervation in association with coronary artery grafting in patients with Prinzmetals’ angina. Ann Thorac Surg 1977;23:111 – 7. [2] Clark DA, Quint RA, Mitchell RL, Angell WW. Coronary artery spasm. Medical management, surgical denervation, and autotransplantation. J Thorac Cardiovasc Surg 1977;73:332 – 9. [3] Bertrand ME, Lablanche JM, Rousseau MF, Warembourg Jr HH, Stankowtak C, Soots G. Surgical treatment of variant angina: use of plexectomy with aortocoronary bypass. Circulation 1980;61:877 – 82. [4] Betriu A, Pomar JL, Bourassa MG, Grondin CM. Influence of partial sympathetic denervation on the results of myocardial revascularization in variant angina. Am J Cardiol 1983;51:661 – 7. [5] Prinzmetal M, Kennamer R, Merliss R, Wada T, Bor N. Angina pectoris: I. A variant form of angina pectoris. Am J Med 1959;27:375. [6] Melo J, Voigt P, Sonmez B, et al. Ventral cardiac denervation reduces the incidence of atrial fibrillation after coronary artery bypass grafting. J Thorac Cardiovasc Surg 2004;127:511 – 6. [7] Saltman AE. New-onset postoperative atrial fibrillation: a riddle wrapped in a mystery inside an enigma. J Thorac Cardiovasc Surg 2004;127:311 – 3. [8] Alex J, Rehman MU, Guvendik L. Ventral cardiac denervation: is it truly an effective prophylaxis against atrial fibrillation after coronary artery bypass grafting? J Thorac Cardiovasc Surg 2004;128:326 – 7. [9] Muxi A, Magrina J, Martin F, et al. Technetium 99m-labeled tetrofosmin and iodine 123-labeled metaiodobenzylguanidine scintigraphy in the assessment of transmyocardial laser revascularization. J Thorac Cardiovasc Surg 2003;125:1493 – 8. [10] Beek JF, van der Sloot JA, Huikeshoven M, et al. Cardiac denervation after clinical transmyocardial laser revascularization: short-term and long-term iodine 123-labeled meta-iodobenzylguanide scintigraphic evidence. J Thorac Cardiovasc Surg 2004;127:517 – 24. [11] Amano J, Suzuki A, Sunamori M. Effects of cardiac denervation on coronary and systemic circulation. Ann Thorac Surg 1994;57:928 – 32. [12] Takusagawa M, Komori S, Umetani K, et al. Alterations of autonomic nervous activity in recurrence of variant angina. Heart 1999;82:75 – 81. [13] Kanaya N, Hirata N, Kurosawa S, Nakayama M, Namiki A. Differential effects of propofol and sevoflurane on heart rate variability. Anesthesiology 2003;98:34 – 40.
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