Advance Publication by-J-STAGE Circulation Journal Official Journal of the Japanese Circulation Society http://www.j-circ.or.jp Ventricular Sympathetic Innervation in Patients With Transposition of the Great Arteries After Arterial Switch Operation and – Impact of Arterial Dissection and Coronary Reimplantation – Andreas Kuehn, MD; Manfred Vogt, MD, PhD; Markus Schwaiger, MD, PhD; Peter Ewert, MD, PhD; Michael Hauser, MD, PhD

Background: Coronary flow reserve (CFR) is reduced in patients with transposition of the great arteries (TGA) after the arterial switch operation (ASO). Dissection of the great arteries and coronary reimplantation may result in sym- pathetic denervation, with a negative effect on myocardial perfusion.

Methods and Results: 18 patients with TGA participated in the study; 9 had ASO (20.8±5.8 years). Controls were 9 patients after Rastelli procedure (22.1±6.8 years). Sympathetic innervation was measured by positron emission tomography using 11C epinephrine (EPI). Left ventricular EPI-retention ranged from 6.1% to 15.9%/min. Patients undergoing more than 1 operation had significantly reduced EPI-retention (P<0.001). EPI-retention and time interval after surgery correlated significantly (r=0.81, P<0.001) and was higher in patients undergoing surgery at an earlier age (P<0.001). No significant difference could be found between patients after ASO or Rastelli repair. Aortic cross- clamp time inversely correlated with EPI-retention (r=−0.72; P<0.001).

Conclusions: The ASO procedure had a negative effect on sympathetic innervation of the myocardium, but be- cause of reinnervation myocardial perfusion is not essentially altered by this mechanism. surgery and pro- longed aortic cross-clamp time have a negative effect on the norepinephrine content of cardiac sympathetic nerve terminals. Parameters such as ventricular performance and cardiopulmonary exercise capacity were unaffected by the degree of EPI-retention.

Key Words: Congenital heart disease; ; Positron emission tomography; Sympathetic nervous system

he arterial switch operation (ASO) is recognized as the The objective of the present investigation was to measure procedure of choice for the treatment of children with the integrity of myocardial sympathetic innervation in long-term T transposition of the great arteries (TGA).1,2 Although survivors of the ASO by PET-imaging using C-11 epinephrine sufficient growth of aortocoronary anastomoses has been dem- (EPI) as an analog of norepinephrine. The results were compared onstrated in animal3 and human studies,4,5 coronary dysfunc- with TGA patients after the Rastelli procedure, having the same tion with attenuation of the coronary flow reserve (CFR) and inborn cardiac anomaly but not having transection of the great stress-induced perfusion defects has been demonstrated in pre- arteries and coronary reimplantation.9 vious studies using positron emission tomography (PET).6 Clinicophysiologic parameters such as left ventricular func- Sympathetic nerves may be interrupted by the ASO with de- tion and treadmill exercise response were evaluated and corre- nervation of the heart. Several studies have demonstrated that lated with the extent of norepinephrine stores of the left . signals from cardiac efferent sympathetic nerves play an impor- tant role in modulating the ability of the coronary vasculature to dilate and thus increase the myocardial blood flow during Methods periods of activation of the sympathetic nervous system, such Study Population as physical activity or mental stress.7,8 A total of 18 patients with TGA without limitations precluding

Received January 5, 2014; revised manuscript received April 5, 2014; accepted April 9, 2014; released online May 30, 2014 Time for primary review: 30 days Department of Pediatric Cardiology and Congenital Heart Disease, Deutsches Herzzentrum Munich (A.K., M.V., P.E., M.H.); Nuklearmedizinische Klinik der Technischen Universität (M.S.), Munich, Germany Mailing address: Michael Hauser, MD, PhD, Department of Pediatric Cardiology and Congenital Heart Disease, Deutsches Herzzentrum, Franz-Schrank Strasse 2, 80638 Munich, Germany. E-mail: [email protected] ISSN-1346-9843 doi: 10.1253/circj.CJ-13-1594 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] Advance Publication by-J-STAGE KUEHN A et al.

Table 1. Treadmill Exercise Tolerance Test of Study Group Patients and Controls ASO Rastelli Normals n 9 9 20 Age (years) 20.8±5.8 22.1±6.8 21.9±4.2

V˙ O2max (ml · kg–1 · min–1) 35.6±2.98 33.9±3.85 36.2±4.1 RPP rest (mmHg/min) 7.332±1.658 7.576±1.376 7.947±1.786 RPP exercise (mmHg/min) 24.575±3.675 23.978±2.897 24.776±3.237

ASO, arterial switch operation; RPP, rate pressure product; V˙ O2max, maximal oxygen uptake.

exercise testing were included in the study: 9 were treated with Study Protocol and Testing ASO (group 1), and 9 were treated with the Rastelli procedure Clinical symptoms, exercise tolerance (by treadmill exercise as a control group (group 2). tolerance test), LV and RV function, wall motion analysis, For the clinical parameters (, treadmill ex- functionality of the homograft (by echocardiography), rhythm ercise response), 20 healthy age-matched volunteers (21.9±4.2 disturbances or ischemic changes on 12-channel ECG at rest years) served as a control group. and during/after exercise were assessed. The study protocol was approved and accepted by the insti- The clinical parameters were compared with those of the tutional review board of the Technical University of Munich. group of 20 age-matched healthy volunteers. All patients gave written informed consent to participate in the Treadmill Exercise Tolerance Test The patients were ex- study. ercised on a treadmill using the . To examine Group 1 9 young adults with TGA (age 20.8±5.8 years) their cardiopulmonary exercise capacity, noninvasive determi- participated in the study; 5 patients had a double outlet right nation of gas exchange parameters were used. Oxygen uptake ventricle (DORV) with subpulmonary ventricular septal de- (V˙ O2) and CO2 output (V˙ CO2) were measured by an automated fect (VSD, Taussig-Bing anomaly) and underwent 2-stage re- O2 and CO2 analyzer, the minute ventilation and the respira- pair with prior banding (PAB). tory rate were measured by pneumotachometer. The V-slope The ASO was performed at the age of 5.24±0.35 years, and method according to Beaver et al12 allowed for the determina- the mean time interval between PAB and ASO was 4.81±0.21 tion of the anaerobic threshold and the maximal V˙ O2 during years. In addition to ASO, all associated anomalies were cor- treadmill exercise. rected during the surgical procedure. One patient with DORV had to be reoperated after the ASO, Echocardiographic Studies because of severe aortic regurgitation, with implantation of a Standard cross-sectional, Doppler-, and M-mode echocardio- mechanical valve. graphic studies were performed in all patients and controls. LV The remaining 4 patients had d-TGA with VSD, which was shortening fraction, ejection fraction and contractility were mea- corrected early by ASO at an age of 0.35±0.12 years. sured at rest and immediately after exercise by previously The mean time interval between ASO and inclusion in the described methods.13 LV wall motion was analyzed by cross- study was 15.2±1.5 years for patients after 2-stage surgery, and sectional echocardiography using a 16-segment model advo- 19.7±1.5 years for patients after primary repair. cated by the American Society of Echocardiography.14 Surgery was performed in all patients under hypothermic cardiopulmonary bypass. For myocardial protection cold car- PET dioplegic solution was used. Mean extracorporeal bypass time PET was performed as previously described15–18 with an ECAT was 145.3±32.3 min; aortic cross-clamp time was 102.8±20.7 min. EXACT- or ECAT 951 scanner (CTI/Siemens, Knoxville, Surgical techniques for the ASO with VSD closure have been TN, USA). After acquisition of a transmission scan and qual- previously reported.10 The postoperative course was unremark- itative assessment of myocardial perfusion with 370 MBq 13-N able for all patients, with no clinical signs of ischemia. Coronary ammonia, 740 MBq of 11-C EPI was injected intravenously over morphology was unremarkable; no patient had an intramural a period of 30 min, and a dynamic imaging sequence was ac- course of the coronary arteries. quired. Group 2 9 young adults with TGA, VSD and RV outflow Volumetric sampling of myocardial radioactivity was used tract obstruction (age 22.1±6.8 years) participated as a control to calculate polar maps of myocardial 11-C EPI retention, group in the study. The mean age at the time of the Rastelli re- defined as cardiac activity at 30–40 min divided by the integral pair was 7.45±3.4 years; 1 patient had an aortopulmonary shunt of the arterial input function. operation at the age of 4 years, another had a Rashkind proce- On the basis of previously defined values in denerved pa- dure while newborn; 3 patients had to be reoperated because tients early after ,18,19 segments with re- of homograft stenosis. The mean time interval between the tention <7% per minute were defined as denervated according Rastelli repair and inclusion in the study was 17.65±4.9 years. to previous studies.15,17,18 Surgery was performed in all patients under hypothermic car- diopulmonary bypass. For myocardial protection cold cardio- Statistical Analysis plegic solution was used. Mean extracorporeal bypass time was Data were analyzed with SPSS version 16 (SPSS Inc, Chicago, 136.7±20.8 min; aortic cross-clamp time was 99.7±24.8 min. IL, USA). Mean and standard deviation (SD) were calculated Surgical techniques for the Rastelli operation have been previ- for all continuous variables. Differences between individual ously reported.11 The postoperative course was unremarkable groups were tested for significance by 1-way ANOVA, unpaired for all patients. t-test and the post hoc test. Linear regression was used to de- scribe relations between pairs of continuous variables. All tests of significance were 2-tailed, and P<0.05 was considered Advance Publication by-J-STAGE Sympathetic Innervation in TGA After ASO

Table 2. PET Data for Study Group Patients Table 3. Surgical Data of the Patients ASO Rastelli ASO Rastelli EPI-retention mean (%/min) 12.83±1.42 12.66±1.41 n 9 9 EPI-retention range (%/min) 6.1–14.8 6.5–15.9 Age (years) 20.8±5.8 22.1±6.8 EPI-retention <7%/min n=1 n=1 Age at operation (years) 1-stage: 0.35±0.12 7.45±3.4 2-stage: 5.25±0.35 EPI, epinephrine; PET, positron emission tomography. Other abbreviation as in Table 1. Coronary bypass time (min) 145.3±32.3 36.7±20.8 Aortic cross-clamp time (min) 102.8±20.7 99.7±24.8 Abbreviation as in Table 1. statistically significant.

those with primary repair (1-stage repair: 13.9±2.8%/min vs. Results 2-stage repair: 8.23±2.8%/min, P<0.001). Two patients had Treadmill Exercise Tolerance Test EPI-retention <7%/min, indicating complete denervation. One The patients (groups 1 and 2) were fully active and asymptom- of the patients, in the Rastelli group, had reoperation because atic; no patient was on cardioactive medication. of homograft stenosis; the other had a mechanical aortic valve All patients could be exercised to exhaustion and achieved implantation because of severe aortic insufficiency after ASO the anaerobic threshold; because the gas exchange ratio (RER) (Table 2). at peak exercise exceeded 1.0 in all individuals, we are confi- A significant positive correlation was found between EPI- dent that all patients and controls performed near maximal retention and the time interval between corrective surgery and exercise. Maximal oxygen uptake (V˙ O2 max: groups 1 and 2) was investigation for both patient groups (r=0.81, P<0.001); no within the normal range (34.2±6.9 ml · kg−1 · min−1) compared difference existed between groups 1 and 2. with the group of healthy volunteers (36.2±4.1 ml · kg−1 · min−1); Maximal EPI-retention was significant higher in patients despite a tendency to having lower V˙ O2 max in Rastelli patients, undergoing corrective at an earlier age than in there was no significant difference between the 2 patient groups those who had surgery in adolescence (P<0.001); again, there (35.6±2.98 vs. 33.9±3.85 ml · kg−1 · min−1, NS) (Table 1). was no significant difference between patients after ASO or None of the patients had ECG evidence of ischemia or ectopic Rastelli repair. activity during or after exercise. Clinical data such as weight, height, body mass index, LV All patients remained asymptomatic and did not complain ejection fraction at rest and after exercise, maximal oxygen of chest pain. uptake V˙ O2 max and ECG pattern at rest and during exercise did not correlate with EPI-retention and did not differ between Echocardiography groups 1 and 2. Echocardiographic measurements of fractional shortening and Baseline heart rate and rate pressure product (RPP) as an ejection fraction were normal in all patients. LV ejection frac- index of cardiac work at rest was within the normal range in tion and LV end-diastolic volume did not differ significantly all patients and there was no significant difference between between the patient subgroups with absent or positive EPI- groups 1 and 2. retention. No patient showed depressed contraction <0.45 in Heart rate and RPP at maximal exercise levels tended to be ejection fraction or regional wall motion abnormalities of the significantly higher in patients with higher EPI-retention LV at rest or after maximal exercise and there was no signifi- (P<0.001). cant difference detected in comparison with the healthy vol- Aortic cross-clamp time during corrective surgery inversely unteers. There was no evidence of hemodynamic abnormalities correlated with maximal EPI-retention (r= −0.72, P<0.001); such as relevant RV outflow tract obstruction, atrioventricular bypass time, time in the intensive care unit and ventilation regurgitation, aortic regurgitation or width of the ascending time did not correlate with sympathetic innervation (Table 3). .

Sympathetic Innervation Discussion The initial qualitative assessment of myocardial perfusion with As a result of major achievements in cardiac surgery and clini- 13-N ammonia was homogeneous in all patients. Perfusion cal care, a growing number of patients with congenital heart defects were not detected, confirming myocardial integrity at disease reach adulthood.2 Besides psychosocial factors, which the time of PET scanning. The presence and extent of cate- influence mental health,21 complications may arise from post- cholamine uptake in cardiac sympathetic nerve terminals were operative sequelae, residual defects and acquired comorbidi- evaluated with 11-C EPI, an analog of norepinephrine, that has ties. In particular, alterations in myocardial perfusion can be a the same mechanism of uptake and storage as the naturally concern in the long-term follow-up of patients with TGA after occurring neurotransmitter.19,20 the ASO. Several studies demonstrate attenuated myocardial LV myocardial EPI-retention as a measure of the inten- blood flow, impaired CFR and reversible stress-induced perfu- sity of innervation ranged from 6.1% to 15.9%/min (mean sion defects while the patients are clinically asymptomatic.6 12.74±3.8%/min) in all patients of groups 1 and 2. Several factors contribute to an alteration of myocardial No statistical significant difference could be found between blood flow, and impairment of the microcirculation seems to be patients of groups 1 and 2. The maximal LV EPI-retention in most likely. group 1 was 12.83±1.42%/min (range: 6.1–14.8%/min) and Abnormal vasomotor activity because of an increase in myo- 12.66±1.41%/min (range: 6.5–15.9%/min) in group 2. cardial oxygen demand, progredient intima proliferation induced Patients in both groups who had undergone more than 1 by coronary reimplantation, endothelial dysfunction, attenuated operation had a significant lower maximal EPI-retention than coronary perfusion pressure because of increased stiffness of Advance Publication by-J-STAGE KUEHN A et al. the ascending aortic wall,22 or reimplantation of the coronary the surface of the right and the dur- arteries out of the aortic sinus, and sympathetic denervation of ing cardiac surgery may damage sympathetic neuronal inner- the myocardium have to be discussed. vation; subclinical myocardial damage, such as ischemia dur- Coronary microcirculation is modulated through changes in ing cardiac surgery, may be another reason.35 arteriolar vascular resistance responding to alterations in blood The number of surgical procedures is another factor that af- flow, metabolic tissue demands and neurohumoral stimuli.23–25 fects sympathetic innervation of the myocardium. Only patients An increase in sympathetic activity produces dilatation of cor- undergoing more than 1 operation had EPI-retention <7%, onary resistance vessels and thus increases myocardial blood indicating complete denervation of the LV15,17,18 caused by flow.7,8 The increase in coronary flow response to sympathetic surgical injury as already mentioned. The higher age of the stimulation correlates with the magnitude of regional stores of subjects at the time of operation, the reduced ability for gen- norepinephrine in cardiac sympathetic nerve terminals, which erating sympathetic reinnervation and recurrent surgical dam- correlates with contractility, oxygen demand and reactive met- age are also possible explanations. abolic vasodilatation or direct activation of β-adrenergic recep- Kondo et al demonstrated that almost all patients operated tors on smooth muscle- and endothelial cells in the vessel wall. on in early infancy showed positive uptake of an norepineph- Coronary vasodilatation may also result from the direct stim- rine analog, which was observed in only half of those having ulation of alpha 2-adrenergic receptors in intact endothelial the operation in childhood or adolescents, suggesting there is cells and the release of nitric oxide, presumably through the a greater ability for sympathetic reinnervation in younger activation of local kinin synthesis.25,26 children.36 Postganglionic sympathetic nerve fibers, which travel from It is well known that neuronal regeneration is dependent on the stellate ganglia along the arterial structures to the myocar- neurotropins, which are produced and released by the target dium, are transected in patients undergoing ASO,27,28 resulting tissue;37 aging has been suggested to be associated with re- in axonal degeneration and depletion of norepinephrine from duced availability of target-derived neurotropin factors,38 which nerve terminals. may explain the relationship between sympathetic reinnervation It is hypothesized that dissection of the great arteries and and the age of the patient. Reduced availability and synthesiz- coronary reimplantation may have some adverse effect on myo- ing capacity of neurotropins may be responsible for the lower cardial perfusion contributing to an attenuated CFR, which cre- degree of reinnervation in cases of more frequent operations.33 ates potential for a mismatch between perfusion and energy Aortic cross-clamp time negatively correlated with EPI- demand.6 retention in both patient groups. During aortic cross-clamping In our study, there were signs of reinnervation in most of there is reversible subendocardial ischemia, leading to hibernat- the patients after ASO and only 1 patient in each group showed ing myocardium, which affects sympathetic nerve function.39 complete denervation with EPI-retention <7%/min, indicating Functional denervation has been observed after brief coronary complete denervation as demonstrated in patients early after occlusion,40,41 as well as in viable risk areas of reperfused myo- heart transplantation. cardial infarcts,42 which supports the view that sympathetic nerve There was no difference in the intensity of EPI-retention function is exquisitely sensitive to ischemia. between patients after ASO or after Rastelli repair, indicating The parasympathetic and sympathetic postganglionic path- that sympathetic denervation is not the major point contribut- ways to the sinoatrial node follow the free wall of the right ing to impairment of myocardial blood flow and CFR in long- atrium and thus are vulnerable to surgical interventions such term survivors of the ASO. as incision or cannulation of the right atrium during open heart Initially after the ASO, there is relevant sympathetic dener- surgery; this regional injury may induce cardiac , vation leading to an attenuation of myocardial perfusion, as has but sympathetic innervation of the ventricular myocardium is been demonstrated in animal models29 and clinical studies.30 not likely to be affected.43 Early denervation supersensitivity29 and inhomogeneity of PAB did not attenuate sympathetic innervation of the ven- sympathetic innervation, which is likely to be present during tricular myocardium; in animal models it has been demonstrated the reinnervation phase,31,32 predispose to arrhythmias, which that ventricular hypertrophy induced by PAB with slowly pro- occur in 9.6% of 1-year survivors.31 gressive pressure overload is not associated with depression of Regrowth of nerve fibers takes time and it is apparent that sympathetic innervation.44 the intensity of myocardial EPI-retention, which represents The present study showed that both the heart rate response sympathetic reinnervation, is positively correlated to the length to exercise and RPP as an index of cardiac work were attenu- of time after surgery. Patients operated on at an earlier age had ated in patients with reduced or absent EPI-uptake. Similar find- positive EPI-retention more frequently and more extensively ings have been obtained in patients after transplantation, where than those operated on at an older age. the magnitude of peak heart rate and oxygen consumption Similar findings have been demonstrated in patients after correlated with the presence or absence of sympathetic rein- transplantation.33 nervation.45 The fact that patients after Rastelli repair had a similar pat- The right stellate cardiopulmonary nerves, including the sym- tern of EPI-retention as patients after ASO, and the fact that a pathetic and parasympathetic axons, travel along the postero- Rastelli patient had complete denervation indicates that the medial surface of the superior vena cava;28 sympathetic as well process of sympathetic denervation and reinnervation also takes as parasympathetic innervation from the right stellate cardio- place in patients who do not undergo arterial transection and pulmonary nerves to the sinus node may be compromised in coronary reimplantation. patients after ASO or Rastelli repair. Chronotropic action be- Potential mechanisms are transient myocardial deteriora- cause of norepinephrine release into the sinus node artery may tion34 and surgical damage.35 Sympathetic nerves also pass along be attenuated by such surgical procedures.46 Clinical param- the posteromedial surface of the superior vena cava, the right eters such as ventricular performance on exercise and cardio- atrium and both the ascending aorta and the main pulmonary pulmonary exercise capacity were unaffected by the degree of artery and pulmonary veins.28 Transection and dissection of LV EPI-retention. cardiac structures and removal of the overlying Nevertheless, the paucity of sympathetic reinnervation may Advance Publication by-J-STAGE Sympathetic Innervation in TGA After ASO have long-term physiological and clinical consequences car- school aged children. Circ J 2008; 8: 1291 – 1295. diovascular surgery. 6. Hauser M, Bengel FM, Kühn A, Sauer U, Zylla S, Braun SL, et al. Myocardial blood flow and flow reserve after coronary reimplantation in patients after arterial switch and Ross operation. Circulation 2001; Clinical Implications 103: 1875 – 1880. The study results showed that open heart surgery should be 7. Zeiher AM, Drexler H, Wollschlaer H, Saurbier B, Just H. Coronary performed as early as possible, because sympathetic reinnerva- vasomotion in response to sympathetic stimulation in humans: Im- tion is more likely in children having corrective cardiac sur- portance of the functional integrity of the endothelium. J Am Coll Cardiol 1989; 14: 1181 – 1190. gery in early infancy. The negative influence of cardiopulmo- 8. Zeiher AM, Drexler H, Wollschlaeger H, Just H. Endothelial dysfunc- nary bypass should be taken into consideration, as we could tion of the coronary microvasculature is associated with coronary blood demonstrate a negative correlation between aortic cross-clamp flow regulation in patients with early atherosclerosis. Circulation 1991; time and sympathetic innervation; if possible, prolonged aortic 84: 1984 – 1992. 9. Wu KL, Wang JK, Lin MT, Chen CA, Wu ET, Chiu SN, et al. Left cross-clamp time should be avoided. ventricular outflow tract obstruction in complete transposition of the great arteries: Echocardiography criteria for surgical strategies. Circ J Study Limitations 2010; 74: 1214 – 1218. The study population was small, which is a major limitation 10. Di Donato RM, Wernovsky G, Walsh EP, Colan SD, Lang P, Wessel DL, et al. Results for the arterial switch operation for transposition of the study; the clinical variation was wide, but all patients of the great arteries with ventricular septal defect: Surgical consider- after ASO had dissection of the great arteries, which is thought ations and midterm follow-up data. Circulation 1989; 80: 1689 – 1705. to be the main reason for sympathetic denervation of the ven- 11. Rastelli GC, Wallace RB, Ongley PA. Complete repair of transposi- tricular myocardium with consecutive impaired myocardial tion of the great arteries with pulmonary stenosis: A review and re- blood flow. From the ethical point of view it was not accept- port of a case corrected by using a new surgical technique. Circula- tion 1969; 39: 83 – 95. able to investigate children younger than 18 years of age, be- 12. Beaver WL, Wassermann K, Whipp BJ. A new method for detecting cause of the exposure to radiation and the fact that the clinical anaerobic threshold by gas exchange. J Appl Physiol 1986; 60: 2020 – impact of the study had no direct therapeutic consequence for 2027. the individual patient; because of that, according to the instruc- 13. Colan SD, Borow KM, Neumann A. Left ventricular end-systolic wall stress velocity of fiber shortening relation: A load independent tions of the ethical committee, only patients older than 18 years index of myocardial contractility. J Am Coll Cardiol 1984; 4: 715 – of age were included in the study. 724. 14. Ewy GA, Ronan JA, Appleton CP. ACC/AHA guidelines for the clinical application of echocardiography: A report of the American Conclusions College of Cardiology/AHA Task Force on assessment of diagnosis and therapeutic cardiovascular procedures. J Am Coll Cardiol 1990; We found that sympathetic reinnervation occurs in most of the 16: 1505 – 1528. long-term survivors after ASO. There exists no difference in 15. Bengel FM, Ueberfuhr P, Ziegler SI, Nekolla S, Reichart B, EPI-retention between patients after ASO or Rastelli repair, so Schwaiger M. Serial assessment of sympathetic reinnervation after orthotopic heart transplantation: A longitudinal study using positron factors other than arterial transection and coronary reimplanta- emission tomography and C-11 hydroxyephedrine. Circulation 1999; tion may influence sympathetic innervation of the myocardium. 99: 1866 – 1871. The older the patients were at the time of operation, the more 16. Bengel FM, Ueberfuhr P, Schiepel N, Nekolla S, Reichard B, operations they undergo and the longer the aortic cross-clamping Schwaiger M. Myocardial efficiency and sympathetic reinnervation lasts, the more diminished is EPI-retention as indicator of sym- after orthotopic heart transplantation: A noninvasive study using posi- tron emission tomography. Circulation 2001; 103: 1881 – 1886. pathetic reinnervation. 17. Bengel FM, Ueberfuhr P, Schiepel N, Nekolla S, Reichard B, Ventricular performance and cardiopulmonary exercise ca- Schwaiger M. Effect of sympathetic reinnervation on cardiac perfor- pacity did not correlate with EPI-retention; only peak heart rate mance after heart transplantation. N Engl J Med 2001; 345: 731 – and RPP at maximal exercise level positive correlated with the 738. 18. Uebrfuhr P, Ziegler S, Schwaiblmair M, Reichard B, Schwaiger M. degree of sympathetic reinnervation. Incomplete sympathetic reinnervation of the orthotopically transplant- It is unlikely that reduced CFR is related exclusively to an ed human heart: Observations to 13 years after heart transplantation. impairment of myocardial sympathetic innervation in long-term Eur J Cardiothorac Surg 2000; 17: 161 – 168. survivors of ASO; a multifactorial pathomechanism has to be 19. Schwaiger M, Hutchins GD, Kalff V, Rosenspire K, Haka MS, Mallette S, et al. Evidence for regional catecholamine uptake and storage sites discussed. in the transplanted human heart by positron emission tomography. J Clin Invest 1991; 87: 1681 – 1690. Disclosures 20. Schwaiger M, Kalff V, Rosenspire K, Haka MS, Molina E, Hutchins None. GD, et al. Noninvasive evaluation of sympathetic nervous system in human heart by positron emission tomography tomography. Circula- tion 1990; 82: 457 – 464. References 21. Enomoto J, Nakazawa J, Mizuno Y, Shirai T, Ogawa J, Niwa K. . 1 Losay J, Planche C, Gerardin C, Lacour-Gayet F, Bruniaux J, Kachaner Psychosocial factors influencing mental health in adults with con- J. Midterm surgical results of arterial switch operation for transposi- genital heart disease. Circ J 2013; 77: 749 – 755. tion of the great arteries with intact ventricular septum. Circulation 22. Hauser M, Kuehn A, Petzuch K, Wolf P, Vogt M. Elastic properties 1990; 82(Suppl 4): 146 – 150. of the ascending aorta in healthy children and adolescents: Age-re- 2. Le Gloan L, Mercier LA, Dore A, Marcotte F, Ibrahim R, Mongeon lated reference values for aortic stiffness and distensibility obtained FP, et al. Recent advances in adult congenital heart disease. Circ J on M-mode echocardiography. Circ J 2013; 77: 3007 – 3014. 2011; 75: 2287 – 2295. 23. Berne RM. Regulation of coronary blood flow. Physiol Rev 1964; 3. Brutel de la Riviere A, Quaegebeur JM, Hennis PJ, Brutel de la 44: 1 – 29. Riverie G, Huysmans HA, Brom AG. Growth of an aorto-coronary 24. Vanhoutte PM, editor. Vasodilatation: Vascular smooth muscle, pep- anastomosis: An experimental study in pigs. J Thorac Cardiovasc tides, autonomic nerves, and endothelium. New York: Raven Press, Surg 1983; 86: 393 – 399. 1988. 4. Arensmann FW, Sievers HH, Lange P, Radley-Smith R, Bernhard 25. Young MA, Knight DR, Varner SF. Autonomic control of large A, Heintzen P, et al. Assessment of coronary and aortic anastomosis coronary arteries and resistance vessels. Prog Cardiovasc Dis 1987; after anatomin correction of transposition of the great arteries. J Tho- 30: 211 – 234. rac Cardiovasc Surg 1985; 90: 597 – 604. 26. Graves J, Poston L. Beta-adrenoceptor agonist mediated relaxation 5. Murakami T, Takei K, Ueno M, Takeda A, Yakuwa S, Nakazawa M. of rat isolated resistance arteries: A role for the endothelium and Aortic reservoir function after arterial switch operation in elemantary nitric oxide. Br J Pharmacol 1993; 108: 631 – 637. Advance Publication by-J-STAGE KUEHN A et al.

27. Warnes CA. Transposition of the great arteries. Circulation 2006; plete transposition. Circulation 1998; 97: 2414 – 2419. 114: 2699 – 2709. 37. Terenghi G. Peripheral nerve regeneration and neurotropic factors. J 28. Janes RD, Brandy JC, Hopkins DA, Jonas RA, Mavroudis C, Anat 1999; 194: 1 – 14. Blackstone EH. Anatomy of human extrinsic cardiac nerves and 38. Dickason AK, Isaacson LG. Plasticity of aged perivascular axons ganglia. Am J Cardiol 1986; 57: 299 – 309. following exogenous NGF: Analysis of catecholamines. Neurobiol 29. Falkenberg C, Hallhagen S, Nilsson K, Nilssn B, Östmann-Smith I. Aging 2002; 23: 125 – 134. A study of the physiological consequences of sympathetic denerva- 39. Luisi AJ, Fallavollita JA, Suzuki G, Canty JM. Spatial inhomogen- tion of the heart caused by the arterial switch procedure. Cardiol ity of sympathetic nerve function in hibernating myocardium. Circu- Young 2010; 20: 150 – 158. lation 2002; 106: 779 – 781. 30. Di Carli MF, Tobes MC, Mangner T, Levine AB, Muzik O, 40. Ciuffo AA, Ouyang P, Becker LC, Levin L, Weisfeldt ML. Reduc- Chakroborty P, et al. Effects of cardiac sympathetic innervation in tion of sympathetic inotropic response after ischemia in dogs: Con- coronary blood flow. N Engl J Med 1997; 336: 1208 – 1216. tributor to stunned myocardium. J Clin Invest 1985; 75: 1504 – 1509. 31. Hayashi G, Kurosaki K, Echigo S, Kado H, Fukushima N, Yokota 41. Guttermann DD, Morgan DA, Miller FJ. Effect of brief myocardial M, et al. Prevalence of arrhythmias and their risk factors mid- and ischemia on sympathetic coronary vasoconstriction. Circ Res 1992; long-term after the arterial switch operation. Pediatr Cardiol 2006; 7: 960 – 969. 27: 689 – 694. 42. Matsunari I, Schricke U, Bengel FM, Haase HU, Barthel P, Schmidt 32. Ueberfuhr P, Frey AW, Reichart B. Vagal reinnervation in the long G, et al. Extent of cardiac sympathetic neuronal damage is determined term after orthotopic heart transplantation. J Heart Lung Transplant by the area of ischemia in patients with acute coronary syndromes. 2000; 19: 946 – 950. Circulation 2000; 101: 2579 – 2585. 33. Bengel FM, Ueberfuhr P, Hesse T, Schiepel N, Ziegler SI, Scholz S, 43. Randall WC, Wurster RD, Duff M, O’Toole MF, Wehrmacher W. et al. Clinical determinants of ventricular sympathetic reinnervation Surgical interruption of postganglionic innervation of the sinoatrial after orthotopic heart transplantation. Circulation 2002; 106: nodal region. J Thorac Cardiovasc Surg 1991; 101: 66 – 67. 831 – 835. 44. Lindpaintner K, Lund DD, Schmid PG. Role of myocardial hyper- 34. Miurata K, Kusachi S, Murakami T, Nogami K, Murakami M, Hirohata trophy in tropic stimulation of sympathetic cardiac inervation. J S, et al. Relation of iodine-123 metaiodobenzylguanidine myocar- Cardiovasc Pharmacol 1987; 10: 211 – 220. dial scintigrapy to endomyocardial findings in patients with 45. Ueberfuhr P, Ziegler S, Schwaiblmair M, Nekolla S, Janka S, dilated . Clin Cardiol 1997; 20: 61 – 66. Reichart B, et al. Functional significance of the sympathetic re-inner- 35. Ohuchi H, Suzuki H, Toyohara K, Tatsumi K, Ono Y, Arakaki Y, et vated orthotopically transplanted heart (abstract). Circulation 1994; al. Abnormal cardiac autonomic nervous activity after right ventricu- 94(Suppl I): I-291. lar outflow tract reconstruction. Circulation 2000; 102: 2732 – 2738. 46. Wilson RF, Laxson DD, Christensen BV, McGinn AL, Kubo SH. 36. Kondo C, Nakazawa M, Momma K, Kusakabe K. Sympathetic de- Regional differences in sympathetic reinnervation after human or- nervation and reinnervation after arterial switch operation for com- thotopic cardiac transplantation. Circulation 1993; 88: 165 – 171.