Sympathetic reinnervation, exercise performance and effects of ß-adrenergic blockade in cardiac transplant recipients

Frank M. Bengela,*, Peter Ueberfuhrb, Jessica Karjaa, Karin Schreibera, Stephan G. Nekollaa, Bruno Reichartb and Markus Schwaigera

a Nuklearmedizinische Klinik und Poliklinik der Technischen Universität München, Klinikum rechts der Isar, Ismaninger Str. 22, München 81675, Germany
b Herzchirurgische Klinik der Ludwig-Maximilians Universität München, Munich, Germany

Received March 21, 2004; revised June 24, 2004; accepted July 1, 2004 * Corresponding author. Tel.: +49 89 4140 2971; fax: +49 89 4140 4950 (E-mail: frank.bengel{at}lrz.tu-muenchen.de).


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
AIMS: To evaluate effects of ß-adrenergic receptor blockade on allograft performance, and to correlate these effects with sympathetic reinnervation.

METHODS AND RESULTS: Myocardial catecholamine storage capacity was determined in 12 non-rejecting transplant recipients using PET and C-11 adrenaline (epinephrine). Haemodynamics and left ventricular function were measured using radionuclide angiography at rest and during symptom-limited exercise before and after non-selective ß-blockade (propranolol iv). Exercise time and stress-induced increases of heart rate and LVEF before ß-blockade were significantly higher in reinnervated compared to denervated recipients. While resting LVEF remained unchanged, heart rate and blood pressure were generally reduced by ß-blockade, which was well tolerated by all patients. Exercise time and increases of heart rate and LVEF were more attenuated in reinnervated recipients. Differences of chronotropic and inotropic response to exercise between groups were no longer present following ß-blockade. Correlations between myocardial adrenaline retention, peak heart rate and increase of global, as well as regional ejection fraction during exercise were observed before, but not during ß-blockade.

CONCLUSION: Acute, non-selective ß-blockade is well tolerated by transplant recipients, but significantly attenuates beneficial functional effects of sympathetic reinnervation on exercise performance. The data suggest that reappearance of sympathetic nerve terminals is associated with reestablishment of intact pre-/postsynaptic interaction.


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
At cardiac transplantation, postganglionic sympathetic fibres are disrupted, causing cardiac sympathetic denervation. Denervation results in chronotropic incompetence1,2 and impairments of ventricular function,1,3 which contribute to limited exercise capacity. It has been speculated that presynaptic denervation influences postsynaptic adrenergic signal transduction. Increased catecholamine sensitivity has been described, but has mainly been attributed to loss of presynaptic neuronal uptake capacity.4 Overall postsynaptic ß-adrenergic receptor density has been found to be normal in allografts.5 Because of reliance of denervated hearts on circulating catecholamines, concerns have been raised against the therapeutic use of ß-blockers in transplant recipients. Some early studies have suggested detrimental effects of ß-blockade on exercise capacity, and attributed their observations to cardiac denervation.6–8 None of these studies, however, included methods to identify evidence of sympathetic reinnervation.

Reinnervation of the transplanted heart has been described in various studies using invasive measurements of transcardiac noradrenaline (norepinephrine) spillover, non-invasive imaging with radiolabelled catecholamine analogues, electrophysiologic measurements of heart rate variability, or clinical reappearance of anginal symptoms.9–13 Presence and extent of reinnervation are determined by multiple factors, including time after transplantation, duration of surgery, frequency of rejection, donor age and recipient age.14 Reinnervation remains incomplete and regionally limited,15,16 but physiological effects on myocardial blood flow and metabolism have been demonstrated.17–19 Recently, we have shown that reinnervation is associated with improved chronotropic and inotropic response to exercise and thereby enhances exercise performance.20 Although this and other studies21,22 documented the functional relevance of presynaptic sympathetic reinnervation for the transplanted heart, little is known about the interaction between restored presynaptic nerve terminals and postsynaptic adrenergic signal transduction.

Thus, we sought to non-invasively evaluate effects of acute ß-adrenergic receptor blockade on allograft performance, and to correlate these effects with presence and extent of sympathetic reinnervation as quantified by positron emission tomography (PET). We speculated that, if reappearance of presynaptic nerve terminals is associated with restoration of pre-/postsynaptic interaction, ß-blockade would attenuate the previously observed beneficial chronotropic and inotropic effects of allograft reinnervation during exercise. On the contrary, if attenuation of exercise performance would turn out to be more pronounced in denervated, relative to reinnervated hearts, previous notions of a higher sensitivity to ß-blockade after denervation due to reliance on circulating catecholamines could be confirmed.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patients and study design
Twelve symptom-free, otherwise healthy cardiac transplant recipients (3 women, 9 men; age 58±9 years) were studied at 0.5–8.9 years after surgery. Transplantation was performed to treat ischaemic cardiomyopathy in 3, and idiopathic cardiomyopathy in 9 patients. Prior to inclusion, presence of acute rejection, significant transplant vasculopathy or allograft dysfunction was ruled out by clinical follow-up, echocardiography, coronary angiography and endomyocardial biopsy. No patient received medication known to interfere with pre- (antidepressants, clonidine, reserpine), or postsynaptic (ß- or α-adrenergic blockers or agonists) sympathetic nervous system. All other cardioactive drugs were discontinued 24 h before inclusion. Immunosuppressive therapy was not interrupted.

Using electrocardiographically gated equilibrium radionuclide angiography, allograft performance at rest and in response to standardized, symptom-limited exercise was determined before and after intravenous non-selective ß-adrenoceptor blockade on the same day. Presence and regional extent of reinnervation were quantified non-invasively on the next day using PET and C-11 adrenaline. Heart rate, blood pressure and 12-lead electrocardiogram were recorded continuously throughout all procedures. Prior to study inclusion, all patients signed written informed consent forms approved by the ethical committee of the medical faculty of the TU München.

Baseline assessment of left ventricular function and haemodynamics
Autologous erythrocytes were labelled with 800–1000 MBq of Tc-99m by combined in vivo/in vitro technique, and reinjected after purification. Following 5 min to allow for equilibrium, patients were positioned in a semi-upright position on a cycle ergometer table. Planar gated bloodpool images at rest (frame mode, 24 time bins, 3 min acquisition) were acquired in "best septal" left anterior oblique view using a small field of view gamma camera (Basicam, Siemens, Erlangen, Germany). Then, symptom-limited cycle ergometer exercise was started following a standardized protocol with 50 W initial workload. Imaging (parameters similar to rest) was commenced after 1 min in the stage to allow for haemodynamic stabilization, and continued for the remaining 3 min. Workload was increased by 50 W every 4 min until exhaustion. Similar to the first stage, imaging was performed in each stage after stabilization phase of 1 min. During the post-stress recovery phase, 3 min after exercise cessation, a final image was acquired.

ß-Adrenergic blockade and reassessment of left ventricular performance
Baseline measurements were followed by a 60 min break to allow for recovery. Then, patients were repositioned, and 0.1 mg/kg body weight of propranolol were administered intravenously as a short infusion over 10 min. Dosage was chosen based on previous results showing significantly attenuated heart rate response to isoprenaline as an indicator of sufficient ß-adrenergic blockade.23 A second series of radionuclide angiographic images at rest, under symptom-limited exercise and in recovery phase was commenced 10 min later.

PET
C-11 adrenaline was synthesised as previously described.24 PET imaging was performed using an ECAT EXACT scanner (CTI/Siemens, Knoxville, TN, USA). After adequate positioning, a transmission scan of 15 min was acquired for correction of photon attenuation. To measure perfusion, a 15 min static scan was performed 5 min after injection of 250–300 MBq of N-13 ammonia. After a break of 20 min to allow for radioactivity decay, 200–450 MBq of C-11 adrenaline were injected, and a dynamic imaging sequence (14 frames, 6x30, 2x60, 2x150, 2x300, 2x600 s) was acquired. To determine contribution of C-11 labelled metabolites to blood activity, venous blood samples were drawn at 1, 5, 10, 20 and 40 min after injection.

Data analysis
Left ventricular function
Radionuclide angiography was analysed according to international standards25 using commercial software (Gaede, Freiburg, Germany). Based on semi-automatic definition of regions of interest for left ventricle and background in end-systolic and end-diastolic frames, ventricular count rates throughout the cardiac cycle were obtained. Global left ventricular ejection fraction, regional ejection fraction in anteroseptal, lateral and inferoapical segments, and peak filling rate, a parameter of diastolic relaxation, were obtained.

PET
Attenuation-corrected transaxial PET images were reconstructed by filtered back projection. Using volumetric sampling26 in static N-13 ammonia perfusion images, myocardial radioactivity was defined in 460 left ventricular segments, depicted in a polar map. Polar maps were normalized to maximum and used for qualitative assessment of regional perfusion. Myocardial segments were transferred to dynamic imaging sequence for C-11 adrenaline, and time activity curves were obtained. Arterial input function was derived from a small circular region of interest in left ventricular cavity and corrected for presence of C-11 labelled adrenaline metabolites, which were assayed from serial blood samples using Sep-Pak cartridges as previously described.27 Adrenaline retention was calculated as myocardial activity at 40 min divided by the integral of metabolite-corrected arterial blood curve. Global extent of reinnervation was quantified as percentage of polar map showing retention within 2.5 standard deviations of average segmental value of a normal database, composed of 7 healthy volunteers.27 Adrenaline retention was also assessed regionally in the anteroseptal, lateral and inferior wall, reflecting vascular territories of left anterior descending (LAD), circumflex (LCX) and right coronary artery (RCA).

Statistical analysis
Values are expressed as means±standard deviation. Relationship between pairs of continuous variables was described by Spearman's correlation co-efficient. Non-parametric Mann-Whitney U test was applied to compare results in denervated and reinnervated transplant recipients. Wilcoxon's signed rank test was applied to compare results before and after ß-blockade. Two-sided P-values <0.05 were initially defined as significant. To correct for inflation of type I error due to multiple testing, which may be an issue in serial testing of the same parameter (e.g., heart rate at rest, during stress, during recovery, at rest during ß-blockade, during stress during ß-blockade, during recovery during ß-blockade), the significance level for P was reduced to half its initial value in a stepwise fashion with each additional comparison (0.05–0.025, then to 0.0125 etc.).


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Sympathetic reinnervation
Myocardial integrity was confirmed in all transplant recipients by absence of perfusion defects (defined as N-13 ammonia uptake below 50% of maximum).

Mean global left ventricular adrenaline retention ranged from 4.2 to 14.6%/min, and maximal individual retention ranged from 5.8 to 30.3%/min. Regionally, myocardial adrenaline retention was highest in LAD territory (9.7±5.2%/min), followed by LCX (6.2±2.4%/min) and RCA (5.8±1.9%/min). Signs of reinnervation, defined as regional retention within 2.5 standard deviations of the average of healthy normals, were found in 8 patients. Reinnervated area ranged from 1% to 49% of left ventricle, and was mainly located in the anteroseptal wall (LAD territory). Four transplant recipients remained completely denervated. Characteristics of denervated and reinnervated transplant recipients are summarized in Table 1.


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Table 1. Characteristics of transplant recipients
 
Systemic haemodynamics, global left ventricular function and exercise performance at baseline
Global maximal myocardial adrenaline retention correlated significantly with increase of heart rate (r=0.59; P=0.048), peak heart rate (r=0.61; P=0.042), and peak rate pressure product (r=0.73; P=0.016) during exercise. Also, it tended to correlate with increase of global ejection fraction (r=0.59; P=0.05). Regional adrenaline retention was significantly correlated with increase of regional ejection fraction during exercise (r=0.46; P=0.007; Fig. 1).



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Fig. 1 Regression plots for the correlation between increase of global left ventricular ejection fraction (LVEF) or regional ejection fraction (rEF) during exercise and global, or regional, myocardial retention of C-11 adrenaline (EPI; epinephrine), respectively, before (left) and after (right) non-selective ß-adrenergic blockade. (Correlation between rEF and EPI before ß-blockade (bottom left) remains significant when outlyers at 120% rEF increase and/or at 20.4%/min EPI retention are removed).

 
Table 2 summarizes baseline results for heart rate, rate pressure product, global left ventricular ejection fraction and ventricular peak filling rate at rest, during exercise and in the recovery phase in subgroups of reinnervated and denervated patients. At rest, no significant differences were observed. During stress, reinnervated transplant recipients showed longer exercise time (P=0.041) higher increase of heart rate (P=0.034), higher peak heart rate (P=0.027) and higher peak rate-pressure product (P=0.011). The increase of global ejection fraction from baseline to peak exercise was also significantly higher (P=0.014). To avoid effects of differences in maximal exercise capacity, response of ejection fraction was normalized, and compared at an identical workload of 50 W, but ejection fraction increase remained consistently higher (P=0.017). Increase of peak filling rate during exercise was also higher (P=0.041). In the recovery phase, there was no change in heart rate compared to peak exercise, but an increase of ejection fraction in denervated patients, while reinnervated patients showed a reduction of heart rate and a mild reduction in global ejection fraction. As a consequence, stress-induced differences between both groups were no longer present (Fig. 2). Peak filling rate increased in both groups during recovery compared to stress.


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Table 2. Haemodynamics and left ventricular function before ß-blockade
 


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Fig. 2 Heart rate and left ventricular ejection fraction (LVEF) in denervated and reinnervated transplant recipients at rest, at peak exercise stress, and during recovery 3 minutes after termination of exercise before (left) and after (right) non-selective ß-adrenergic blockade. * Indicates significant difference for the increase from rest to stress between reinnervated and denervated patients.

 
Analysis of regional ejection fraction confirmed the trend observed for global values: in the reinnervated group, regional ejection fraction in reinnervated anteroseptal segments increased from 31±14 to 57±4% (vs decrease from 57±12 to 53±4% in denervated patients; P=0.05), and decreased to 52±3% during recovery (vs increase to 57±15% for denervated group). No such differences in patterns were observed in mainly denervated inferoapical and lateral segments.

Systemic haemodynamics, global left ventricular function and exercise performance during ß-Blockade
During ß-blockade, baseline correlation between global maximal adrenaline retention and exercise response of global ejection fraction (r=0.16; P=0.59), as well as peak heart rate (r=0.52; P=0.09) was no longer observed. Also, correlation between regional adrenaline retention and ejection fraction was no longer present (r=0.04; P=0.82; Fig. 1). Interestingly, significant correlation between global adrenaline retention and heart rate increase (r=0.70; P=0.02) as well as peak rate pressure product (r=0.62; P=0.04) continued to exist.

Group results of haemodynamic and functional parameters during ß-blockade are summarized in Table 3. ß-Blockade resulted in significant reduction of resting heart rate (P=0.002) and rate-pressure product (P=0.002) by 10±7% and 16±10%, respectively. Resting ejection fraction remained unchanged. Exercise time was reduced by 15±8% (P=0.003). Additionally, peak heart rate (–22±8%; P=0.002), heart rate increase (–49±25%; P=0.002), peak rate pressure product (–34±12%; P=0.002) and peak ejection fraction (–8±10%; P=0.037) during exercise were attenuated. Lower heart rate (–19±9%; P=0.002) and rate pressure product (–20±2%; P=0.012) were also observed during recovery. Significant differences in haemodynamics and ejection fraction between reinnervated and denervated recipients, which were observed at baseline, were no longer present during ß-blockade (Fig. 2). Reduction of exercise time (P=0.022), peak heart rate (P=0.017), peak rate pressure product (P=0.017) and ejection fraction increase (P=0.034) during exercise was significantly higher in reinnervated compared to denervated transplant recipients, explaining the absence of significant differences in exercise performance during ß-blockade between groups. Additionally, no differences in regional ejection fraction between groups were observed for all segments. The innervation-specific pattern (increase from rest to stress, then mild decrease during recovery) in anteroseptal segments of reinnervated patients was no longer present.


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Table 3. Haemodynamics and left ventricular function during ß-blockade
 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
In summary, functional effects of sympathetic reinnervation on cardiac inotropy, chronotropy and lusitropy, which result in improved exercise capacity compared to denervated transplant recipients, were significantly attenuated by acute non-selective ß-adrenergic blockade, but ß-blockade was generally well-tolerated. These results suggest that beneficial effects of reinnervation are mediated via ß-adrenoceptors and that pre-/postsynaptic interaction is intact following reappearance of sympathetic nerve terminals.

Several previous studies have investigated effects of denervation on postsynaptic adrenergic components and catecholamine responsiveness. An increased sensitivity of denervated hearts to catecholamines has been described in animal studies28 and early human studies.23,29 This was initially thought to be consequence of ß-receptor upregulation. Studies in human myocardium, however, showed normal ß-receptor density,5 and other studies confirmed that adrenergic supersensitivity is due to lack of presynaptic neuronal uptake capacity rather than upregulation of ß-receptors.4,30 Despite normal overall ß-receptor density, shift from ß1 to ß2 subtype expression has been suggested.31 ß2-Adrenoceptors are thought to be mainly responsible for response to circulating catecholamines, and significantly contribute to chronotropic responsiveness in transplant recipients.31 All of these previous studies have in common, however, that the presence of myocardial reinnervation was not identified. Reinnervation has been shown to influence regional regulation of metabolism19 and contractility,20 but it has not been confirmed that these effects are mediated via ß-adrenergic receptors. Although the relative contribution of ß1- vs ß2-adrenoceptors and other steps of postsynaptic signal transduction were not investigated in detail, the present study is the first to demonstrate that restored presynaptic nerve terminals after cardiac transplantation are associated with re-established interaction of pre- and postsynaptic adrenergic components.

Because attenuating effects of nonselective ß-blockade were more pronounced in reinnervated than in denervated patients, the present data do not confirm previous notions that ß-blockade may be especially detrimental in denervated hearts due to dependency on circulating catecholamines.6–8 This hypothesis of early reports has already been challenged by other studies, which could not reproduce adverse effects of ß-blockade on exercise performance after transplantation.29,32 All patients tolerated ß-blockade well and concerns against the therapeutic use of ß-blockers in cardiac transplant recipients are not supported by our data, although it needs to be considered that acute high-dose ß-blockade was used in this study. Extrapolation to chronic treatment may be difficult, but interestingly, significant improvement of systolic allograft dysfunction during chronic ß-blocker therapy was described in a recent report.33

In contrast to previous studies where C-11-labelled hydroxyephedrine, a false neurotransmitter, was used for PET to determine sympathetic reinnervation,10,14,15,18–20 the recently introduced, more physiological tracer C-11 adrenaline was applied in this study. Its retention fraction in normal myocardium is higher than that of C-11 hydroxyephedrine, but correlates closely with the latter.27 While C-11 hydroxyephedrine is thought to primarily reflect capacity of presynaptic uptake-1 catecholamine transporter, C-11 adrenaline is thought to reflect not only neuronal uptake, but also metabolism and storage, and has thus been proposed as a more suitable and sensitive probe for the study of neuronal integrity.27 Consistently, previous findings of significant beneficial effects of sympathetic reinnervation, determined by C-11 hydroxyephedrine on chronotropic and inotropic response to exercise,20 were reproducible in the present study before ß-blockade in an albeit smaller group of transplant recipients.

In addition to effects of ß-blockade, this study includes information on haemodynamics and ventricular function in the early recovery phase as another aspect of exercise adaptation which has not been investigated in our previous studies. A specific pattern with continuously elevated heart rate and a further increase of ejection fraction after termination of exercise was observed in denervated, but not in reinnervated transplant recipients before ß-blockade. This may reflect the delayed response to circulating catecholamines, as suggested by previous observations.22 However, this pattern was also observed to some degree after ß-blockade in both groups, suggesting that other mechanisms such as ventricular unloading are also involved. Notably, heart rate in reinnervated recipients decreased to a larger extent than global ejection fraction during early recovery before ß-blockade. This may indicate a differential response of chronotropy and inotropy to ventricular unloading, but other factors such as regionally limited reinnervation, or technical issues related to acquisition of images over a period of 3 min which may attenuate maximally measurable functional parameters need to be considered. To which degree the chronotropic and inotropic adaptation in the recovery phase in reinnervated transplant recipients was comparable to normals cannot be answered in the present study due to a lack of healthy controls, but may be the topic of future investigations.

The dichotomous approach applied in this and previous studies,10,14,15,18–20 which divides patients into reinnervated and denervated, bears the limitation that a variety of different degrees of innervation is combined into one group. Results nevertheless are conclusive and correlation analysis on a continuous scale was performed to confirm group results. Finally, peak filling rates as diastolic parameters are co-registered with innervation for the first time, suggesting lusitropic effects of reinnervation. These parameters, however, should be interpreted with caution because they are highly sensitive to changes of heart rate during image acquisition, which impair reliability in the recovery phase, but also during exercise due to an often slow, but steady increase in transplant recipients.22 Other potential limitations related to the applied study protocol should be considered: firstly, individuals had to undergo a maximal exercise test twice within 1–2 h so that fatigue may have limited exercise performance in the second test. The complex study protocol and radionuclide decay did not allow for a longer break between both tests. Secondly, progressive exercise consisted of 4 minute stages to allow for stable and reproducible radionuclide image quality. Such relatively long stages may also contribute to leg fatigue before maximal cardiovascular stress. No objective measures of peak cardiovascular exercise were obtained, but individuals were encouraged to exercise until absolute subjective exhaustion. Although fatigue may have contributed to some of the general reduction of maximal haemodynamic response observed in the second test after ß-blockade, it cannot explain the significant interindividual variations related to sympathetic innervation. Additionally, functional results were also analysed at a standardized workload of 50 W to correct for differences in maximal exercise capacity.

In conclusion, results of this study give further insights into exercise physiology of the transplanted heart. Beneficial effects of sympathetic reinnervation on exercise performance are predominantly mediated via ß-adrenergic receptors, and restored presynaptic innervation is paralleled by intact pre-/postsynaptic interaction.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Kao AC, Van TPr, Shaeffer MG, et al. Central and peripheral limitations to upright exercise in untrained cardiac transplant recipients Circulation 1994;89:2605-2615.[Abstract]
  2. Quigg RJ, Rocco MB, Gauthier DF, et al. Mechanism of the attenuated peak heart rate response to exercise after orthotopic cardiac transplantation J Am Coll Cardiol 1989;14:338-344.[Medline]
  3. Paulus WJ, Bronzwaer JGF, Felice H, et al. Deficient acceleration of left ventricular relaxation during exercise after heart transplantation Circulation 1992;86:1175-1185.[Abstract]
  4. von Scheidt W, Böhm M, Schneider B, et al. Isolated presynaptic inotropic ß-adrenergic supersensitivity of the transplanted denervated human heart in vivo Circulation 1992;85:1056-1063.[Abstract]
  5. Denniss AR, Marsh JD, Quigg RJ, et al. Beta-adrenergic receptor number and adenylate cyclase function in denervated transplanted and cardiomyopathic human hearts Circulation 1989;79:1028-1034.[Abstract]
  6. Bexton RS, Milne JR, Cory-Pearce R, et al. Effect of beta blockade on exercise response after cardiac transplantation Br Heart J 1983;49:584-588.[Abstract]
  7. Kushwaha SS, Banner NR, Patel N, et al. Effect of beta blockade on the neurohumoral and cardiopulmonary response to dynamic exercise in cardiac transplant recipients Br Heart J 1994;71:431-436.[Abstract]
  8. Verani MS, Nishimura S, Mahmarian JJ, et al. Cardiac function after orthotopic heart transplantation: response to postural changes, exercise, and beta-adrenergic blockade J Heart Lung Transplant 1994;13:181-193.[Medline]
  9. DeMarco T, Dae M, Yuen GM, et al. Iodine-123 metaiodobenzylguanidine scintigraphic assessment of the transplanted human heart: evidence for late reinnervation J Am Coll Cardiol 1995;25:927-931.[CrossRef][Medline]
  10. Schwaiger M, Hutchins GD, Kalff V, et al. Evidence for regional catecholamine uptake and storage sites in the transplanted human heart by positron emission tomography J Clin Invest 1991;87:1681-1690.[Medline]
  11. Stark RP, McGinn AL, Wilson RF. Chest pain in cardiac-transplant recipients. Evidence of sensory reinnervation after cardiac transplantation N Engl J Med 1991;324:1791-1794.[Medline]
  12. Kaye DM, Esler M, Kingwell B, et al. Functional and neurochemical evidence for partial cardiac sympathetic reinnervation after cardiac transplantation in humans Circulation 1993;88:1110-1118.[Abstract]
  13. Wilson RF, Christensen BV, Olivari MT, et al. Evidence for structural sympathetic reinnervation after orthotopic cardiac transplantation in humans Circulation 1991;83:1210-1220.[Abstract]
  14. Bengel FM, Ueberfuhr P, Hesse T, et al. Clinical determinants of ventricular sympathetic reinnervation after orthotopic heart transplantation Circulation 2002;106:831-835.[Abstract/Free Full Text]
  15. Bengel FM, Ueberfuhr P, Ziegler SI, et al. Serial assessment of sympathetic reinnervation after orthotopic heart transplantation - A longitudinal study using positron emission tomography and C-11 hydroxyephedrine Circulation 1999;99:1866-1871.[Abstract/Free Full Text]
  16. Wilson RF, Laxson DD, Christensen BV, et al. Regional differences in sympathetic reinnervation after human orthotopic cardiac transplantation Circulation 1993;88:165-171.[Abstract]
  17. DiCarli MF, Tobes MC, Mangner T, et al. Effects of cardiac sympathetic innervation on coronary blood flow N Engl J Med 1997;336:1208-1215.[Abstract/Free Full Text]
  18. Bengel FM, Ueberfuhr P, Schiepel N, et al. Myocardial efficiency and sympathetic reinnervation after orthotopic heart transplantation. A noninvasive study using positron emission tomography Circulation 2001;103:1881-1886.[Abstract/Free Full Text]
  19. Bengel FM, Ueberfuhr P, Ziegler SI, et al. Noninvasive assessment of the effect of cardiac sympathetic innervation on metabolism of the human heart Eur J Nucl Med 2000;27:1650-1657.[CrossRef][Medline]
  20. Bengel FM, Ueberfuhr P, Schiepel N, et al. Effect of sympathetic reinnervation on cardiac performance after heart transplantation N Engl J Med 2001;345:731-738.[Abstract/Free Full Text]
  21. Schwaiblmair M, von Scheidt W, Uberfuhr P, et al. Functional significance of cardiac reinnervation in heart transplant recipients J Heart Lung Transplant 1999;18:838-845.[CrossRef][Medline]
  22. Wilson RF, Johnson TH, Haidet GC, et al. Sympathetic reinnervation of the sinus node and exercise haemodynamics after cardiac transplantation Circulation 2000;101:2727-2733.[Abstract/Free Full Text]
  23. Yusuf S, Theodoropoulos S, Mathias CJ, et al. Increased sensitivity of the denervated transplanted human heart to isoprenaline both before and after beta-adrenergic blockade Circulation 1987;75:696-704.[Abstract]
  24. Chakraborty PK, Gildersleeve DL, Jewett DM, et al. High yield synthesis of high specific activity R- (-)-[11C]epinephrine for routine PET studies in humans Nucl Med Biol 1993;20:939-944.[CrossRef][Medline]
  25. Imaging guidelines for nuclear cardiology procedures. American Society of Nuclear Cardiology. Equilibrium gated blood pool imaging protocols. J. Nucl. Cardiol. 1996;3:G26-29.
  26. Nekolla SG, Miethaner C, Nguyen N, et al. Reproducibility of polar map generation and assassment of defect severity and extent assessment in myocardial perfusion imaging using positron emission tomography Eur J Nucl Med 1998;25:1313-1321.[CrossRef][Medline]
  27. Munch G, Nguyen NT, Nekolla S, et al. Evaluation of sympathetic nerve terminals with [(11)C]epinephrine and [(11)C]hydroxyephedrine and positron emission tomography Circulation 2000;101:516-523.[Abstract/Free Full Text]
  28. Vatner DE, Lavallee M, Amano J, et al. Mechanisms of supersensitivity to sympathomimetic amines in the chronically denervated heart of the conscious dog Circ Res 1985;57:55-64.[Abstract]
  29. Borow KM, Neumann A, Arensman FW, et al. Cardiac and peripheral vascular responses to adrenoceptor stimulation and blockade after cardiac transplantation J Am Coll Cardiol 1989;14:1229-1238.[CrossRef][Medline]
  30. Gilbert EM, Eiswirth CC, Mealey PC, et al. ß-adrenergic supersensitivity of the transplanted human heart is presynaptic in origin Circulation 1989;79:344-349.[Abstract]
  31. Leenen FH, Davies RA, Fourney A. Role of cardiac beta 2-adrenergic responses to exercise in cardiac transplant patients Circulation 1995;91:685-690.[Abstract/Free Full Text]
  32. Yusuf S, Theodoropoulos S, Dhalla N, et al. Influence of beta blockade on exercise capacity and heart rate response after human orthotopic and heterotopic cardiac transplantation Am J Cardiol 1989;64:636-641.[CrossRef][Medline]
  33. Gardner RS, McGowan J, McDonagh TA. Left ventricular systolic dysfunction in a cardiac transplant recipient treated with carvedilol Eur J Heart Fail 2002;4:377-379.[CrossRef][Medline]




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