(Circulation. 2001;103:1881.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Myocardial Efficiency and Sympathetic Reinnervation After Orthotopic Heart Transplantation
A Noninvasive Study With Positron Emission Tomography
From Nuklearmedizinische Klinik und Poliklinik der Technischen Universität München (F.M.B., N.S., S.G.N., M.S.) and Herzchirurgische Klinik der Ludwig-Maximilians Universität München (P.U., B.R.), Munich, Germany.
Correspondence to Frank M. Bengel, MD, Nuklearmedizinische Klinik und Poliklinik der Technischen Universität München, Klinikum rechts der Isar, Ismaninger Str 22, 81675 München, Germany. E-mail frank.bengel{at}lrz.tu-muenchen.de
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Abstract |
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Background—The lack of cardiac catecholamine uptake and storage caused by sympathetic denervation may influence performance of the transplanted heart. Reinnervation, occurring late after transplantation, may partially resolve these effects. In this study, oxidative metabolism and its relation to cardiac work were compared in allografts and normal and failing hearts, and the effects of sympathetic reinnervation were evaluated.
Methods and Results—Twenty-seven nonrejecting, symptom-free transplant recipients, 11 healthy control subjects, and 10 patients with severe dilated cardiomyopathy underwent PET with 11C acetate for assessment of oxidative metabolism by the clearance constant k(mono) and radionuclide angiography or MRI for measurement of ventricular function, geometry, and work. Efficiency was estimated noninvasively by a work-metabolic index [WMI=(stroke volumexheart ratexsystolic pressure)/k(mono)]. In 14 of 27 transplants, presence of regional reinnervation was identified with PET and the catecholamine analogue 11C hydroxyephedrine (extent, 24±14% of left ventricle). The WMI was comparable in normal subjects and reinnervated and denervated transplants (6.2±2.3 versus 4.9±2.0 versus 4.9±1.2 · 106 mm Hg · mL; P=NS) and significantly lower in cardiomyopathy patients (3.0±1.3 · 106 mm Hg · mL; P<0.001). For normal subjects and transplant recipients, the WMI was significantly correlated with afterload (peripheral vascular resistance; r=-0.65, P<0.01), preload (end-diastolic volume; r=0.78, P<0.01), and stroke volume (r=0.81, P<0.01) but not with hydroxyephedrine retention (transplants only; r=0.09, P=NS).
Conclusions—After transplantation, cardiac efficiency is improved compared with failing hearts and comparable to normal hearts. Differences between denervated and reinnervated allografts were not surveyed. Additionally, the dependency on loading conditions and contractility was preserved, suggesting that normal regulatory interactions for efficiency are intact and that sympathetic tone does not play a role under resting conditions.
Key Words: transplantation • myocardium • nervous system, sympathetic • tomography
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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After orthotopic heart transplantation, performance of the allograft may be influenced by a variety of factors. Prolonged hypothermic ex vivo storage,1 episodes of rejection,2 effects of immunosuppressive therapy,3 and transplant vasculopathy4 may all alter the functional and metabolic state. Myocardial sympathetic denervation as the result of surgical interruption of postganglionic nerve fibers5 is another factor that has been discussed to influence allograft performance by a reduction of local myocardial catecholamine uptake, storage, and release6 7 and an impaired responsiveness to adrenergic stimulation.8 Conversely, reappearance of innervation, which has been demonstrated late after transplantation,6 7 may resolve changes in the denervated heart. Reinnervation, however, has been shown to remain incomplete and regionally limited.9 Currently, little is known about its physiological importance and its effects on metabolism, function, and efficiency of the transplanted heart.
Mechanical efficiency of the ventricle is defined as the fraction of total expended metabolic energy that is converted into external contractile work10 and has been used successfully to describe beneficial therapeutic effects in patients with heart failure.11 12 13 By taking into account the energy cost for a given level of cardiac output, efficiency may also be a very sensitive parameter to characterize performance of the transplanted heart. It has been previously described that overall oxidative energy metabolism in the transplanted heart is comparable to normal hearts.14 The relation between oxidative metabolism and the level of cardiac work, however, has not yet been investigated in detail.
The aim of this study was therefore 2-fold: (1) to evaluate efficiency of the nonrejecting, orthotopically transplanted heart compared with the normal and failing heart and (2) to assess the role of sympathetic reinnervation for regulation of allograft efficiency.
All measurements were performed noninvasively on the basis of imaging with PET and the radiotracers 11C acetate and 11C hydroxyephedrine (HED). Clearance kinetics of 11C acetate were used to quantify tricarboxylic acid cycle flux, which is directly related to overall myocardial oxidative metabolism.15 By a combination with noninvasive measures of cardiac function, a previously validated estimate of myocardial efficiency was derived.13 Additionally, the norepinephrine analogue 11C HED was used in transplant recipients to quantify presence and extent of sympathetic reinnervation.7 9
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Methods |
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Patients and Study Design
The study group consisted of 27 patients (6 women, 21 men; age, 55±10 years) at various time points after orthotopic heart transplantation (0.5 to 8.2 years; mean, 3.1±2.2 years). For inclusion in the study, patients had to be symptom-free. The presence of acute rejection, significant graft vessel disease, or impaired allograft function was ruled out by clinical follow-up, echocardiography, coronary angiography, and endomyocardial biopsy. None of the patients received medication known to interfere with presynaptic catecholamine uptake (eg, antidepressants, clonidine, reserpine), whereas only 4 had ß-adrenergic receptor blocking agents. ß-Blockers and all other cardioactive drugs were discontinued at least 24 hours before the study, whereas immunosuppressive therapy based on cyclosporine A was not interrupted.
In addition, 2 age-matched control groups consisting of 11 healthy normal subjects (7 women, 4 men; age, 51±9 years) without clinical or ECG evidence of heart disease and 10 patients with severe chronic idiopathic dilated cardiomyopathy (2 women, 8 men; age, 53±11 years) were studied. Results of these control groups have been reported in a previous study.16 Diagnosis of dilated cardiomyopathy was based on the absence of significant coronary artery disease and primary valvular disease during cardiac catheterization. Whereas healthy normal subjects had no medication, cardiomyopathy patients were studied under a standard therapy with ACE inhibitors, ß-blockers, and furosemide because of symptomatic heart failure.
Before inclusion in the study, all patients signed written informed consent forms approved by the ethics committee of the medical faculty of the TU München.
PET
Tracers were synthesized as previously
described.17 18
PET imaging was performed with an ECAT EXACT 47 or ECAT EXACT HR+
scanner (CTI/Siemens). After adequate positioning, a transmission scan
of 10 to 15 minutes was acquired for correction of photon attenuation.
To measure perfusion and oxidative metabolism, 300 to 400
MBq of 11C acetate was then injected as a
slow bolus over 30 seconds, and a dynamic imaging sequence of 21 frames
over 30 minutes (10x10, 1x60, 5x100, 3x180, and 2x300 seconds) was
initiated. In transplant recipients, presence or absence of sympathetic
reinnervation was assessed in the same session: After a break of 50
minutes to allow for decay of radioactivity, 600 MBq of
11C HED was injected, and a second dynamic
imaging sequence (14 frames, 6x30, 2x60, 2x150, 2x300, 2x600
seconds) was acquired. Heart rate and blood pressure were monitored
continuously throughout the imaging procedure by ECG and arm cuff
measurements.
Assessment of Left Ventricular
Function
Left ventricular (LV) function was
measured noninvasively on the same day either before or directly after
PET with tomographic radionuclide angiography (transplant recipients
and cardiomyopathy patients) or cine MRI (healthy
normal subjects). Both techniques have been shown to be reliable and
reproducible, and results have been demonstrated to correlate
closely.19 20
For radionuclide ventriculography, autologous erythrocytes were labeled with 800 to 1000 MBq of 99mTc by a combined in vivo/in vitro technique and reinjected after purification. After 5 minutes to allow for equilibrium, patients were positioned in a rotating triple-headed gamma camera (Multispect 3, Siemens), and an electrocardiographically gated tomographic acquisition was performed. MRI was performed with a 1.5-T Philips Gyroscan ACS2 or NT (Philips Medical Systems) with ECG-gated short-axis, multislice, multiphase cine gradient echo sequences.20
Data Analysis
PET
Attenuation-corrected transaxial PET images were
reconstructed by filtered backprojection. A previously validated
volumetric sampling tool21
was then applied to a summed data set of frames 11 to 12 of the imaging
sequence for 11C acetate to create polar
maps of static myocardial activity distribution at 2 to 4 minutes after
injection. These polar maps were normalized to their maximum and used
for qualitative assessment of regional myocardial
perfusion.22 Myocardial
sectors defined by the polar map were then transferred to the whole
dynamic sequence, and time-activity curves were obtained. The early
phase of 11C acetate washout was fitted
monoexponentially to obtain the constant
k(mono) as a previously
validated measure of oxidative
metabolism,15
expressed in another polar map. The average of
k(mono) for the whole map was
calculated to define global myocardial oxygen consumption.
In transplant recipients, myocardial activity of 11C HED was also sampled volumetrically. Additionally, the arterial input function was derived from a small circular region of interest in the LV cavity. Myocardial HED retention was calculated as activity at 40 minutes divided by the integral of the arterial blood curve.7 On the basis of results in denervated hearts,7 myocardium showing HED retention <7% per minute was defined as denervated. The global extent of reinnervation was quantified by the percentage of polar map showing retention above this threshold.9
Ventricular Function
For radionuclide angiography, tomographic data were
also reconstructed by filtered backprojection, and the volumetric
sampling tool was used for detection of endocardial borders in
end-systolic and end-diastolic phases, allowing
calculation of regional endocardial shortening in a polar map, and of
global LV volumes. Magnetic resonance images were analyzed by
commercially available software (MASS, University of Leiden, The
Netherlands). Contours for endocardial borders were drawn manually in
every phase of slices from apex to just below the valve plane. Then,
end-diastolic and end-systolic volumes were
calculated from the summation of these slices in
end-diastolic and end-systolic
phases.
Calculation of Hemodynamic
Parameters and Estimation of Myocardial Efficiency
Cardiac output was obtained by multiplying stroke
volume times heart rate. Systemic vascular resistance (SVR) was
estimated as mean arterial blood pressure divided by
cardiac output and converted to
dyne · s-5 · cm-5.23
LV stroke work was estimated by a stroke work index (SWI), the product of stroke volume and peak systolic blood pressure.13
Mechanical efficiency of the left ventricle, defined as the
relation between cardiac work and oxygen consumption, was noninvasively
estimated by combining stroke work data with data from
11C acetate PET. As previously
validated,13 the work-metabolic index (WMI) was calculated by
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Statistical Analysis
Values are expressed as mean±SD. Differences between
patient groups were assessed by 1-way factorial ANOVA and the post hoc
Fisher’s protected least significant differences test. Simple linear
regression analysis was performed to describe the relation
between continuous variables. A value of
P<0.05 was defined as
significant.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Sympathetic Reinnervation in Transplant Recipients
In transplants, maximal LV HED retention ranged from 3.4% to 16.1% per minute and was significantly correlated with time after transplantation (r=0.59; P<0.001). Fourteen of 27 patients showed HED retention above the threshold of 7% per minute, indicating sympathetic reinnervation. The extent of reinnervation in these patients ranged from 9% to 47% of the left ventricle (mean, 24±14). Thirteen of 27 transplant recipients remained sympathetically denervated. Both groups were matched for age (56±9 years for denervated versus 55±12 years for reinnervated patients; P<0.70) and the number of previously documented rejection episodes (1±1 versus 1±1; P=0.97).
Hemodynamics,
Ventricular Function, and Loading Conditions
Table 1
displays hemodynamic
parameters for both groups of transplant recipients
compared with normal subjects and cardiomyopathy
patients. Importantly, differences between reinnervated and
denervated transplant recipients were not observed.
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Compared with cardiomyopathy patients and normal subjects, the baseline heart rate was higher in transplant recipients. LV ejection fraction and volumes were comparable in transplants and normal subjects, except for a slightly lower end-diastolic volume and stroke volume in both transplant groups, whereas cardiomyopathy patients showed reduced ejection fraction and elevated volumes, as expected. SVR was substantially elevated in cardiomyopathy patients and was only marginally higher in innervated transplants compared with normal subjects.
Finally, cardiac work, estimated by the SWI, was significantly higher in both transplant groups compared with cardiomyopathy patients. Because of the difference in stroke volume, the SWI was slightly lower in transplants compared with normal subjects.
Global 11C Acetate
Kinetics and Myocardial Efficiency
Early uptake of 11C acetate
as a measure of myocardial perfusion was homogeneous in all
subjects. Perfusion defects, defined as regional uptake <50% of the
individual maximum, were not observed.
The clearance constant
k(mono) as a measure of
oxidative metabolism was not different in
innervated and denervated transplant recipients and was
comparable to normal subjects (0.060±0.015 per minute in normal
subjects versus 0.055±0.014 per minute in denervated transplants and
0.060±0.010 per minute in reinnervated transplants;
P=NS), whereas it was
significantly lower in cardiomyopathy patients
(0.040±0.011 per minute,
P<0.001)
(Figure 1).
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The WMI as an estimate of cardiac efficiency was also
similar in denervated and innervated transplant recipients
and comparable to normal subjects
(6.2±2.3 · 106 mm Hg · mL in
normal subjects versus
4.9±1.2 · 106 mm Hg · mL in
denervated and 4.9±2.0 · 106
mm Hg · mL in reinnervated transplants;
P=NS) but significantly reduced
in cardiomyopathy patients
(3.0±1.3 · 106 mm Hg · mL;
P<0.01)
(Figure 1
).
Determinants of Myocardial Efficiency
For normal subjects as well as transplant recipients,
the WMI was significantly inversely correlated with SVR as a measure of
afterload and positively correlated with end-diastolic
volume as an estimate of preload. Additionally, there was a positive
correlation with stroke volume as a measure of
contractility
(Figure 2). The interrelation between these
parameters in subgroups is shown in
Table 2.
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Parameters of sympathetic reinnervation such as
mean HED retention
(Figure 3) were not correlated with the WMI in transplant
recipients.
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Regional Analysis of
Catecholamine Uptake, Oxidative Metabolism, and
Wall Motion
In addition to global analysis, HED retention,
qualitative perfusion, k(mono),
and endocardial shortening were regionally analyzed by regions
of interest encompassing the vascular territories for the left anterior
descending (LAD), left circumflex (LCX), and right coronary
artery (RCA).
Results are summarized in
Table 3. Reinnervation occurred mainly in the LAD
territory, where the difference in HED retention between denervated and
reinnervated transplants was highly significant. Smaller
but also significant differences were observed for the LCX and RCA.
Despite these differences in HED retention, no regional differences for
perfusion, k(mono), or
endocardial shortening were observed between
groups.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In summary, performance of the transplanted heart was significantly improved compared with the failing heart and was comparable to healthy individuals. Normal regulatory mechanisms for efficiency, namely the dependency on loading conditions and contractility, remained intact after transplantation, whereas the presence or absence of sympathetic reinnervation did not have an influence under resting conditions.
The concept of efficiency, which includes not only information about cardiac output but also about the concomitant energy cost, has been mainly used in heart failure to understand and optimize effects of medical therapy.10 11 12 13 24 Efficiency is usually quantified by complex invasive measurements of cardiac work and oxygen consumption, which limit its clinical application. Recently, however, an approach for noninvasive estimation based on PET imaging with 11C acetate has been introduced and validated.13 In the present study, this noninvasive method was applied to characterize effects of heart transplantation as a therapeutic option for terminal heart failure. After transplantation, a variety of factors may affect cardiac work, oxygen consumption, and thus efficiency.
First, the hemodynamic situation of the transplanted heart is different. The baseline heart rate is elevated, mainly because of a lack of parasympathetic control of the sinus node.5 Blood pressure and ventricular afterload also may be increased as the result of elevated plasma catecholamine levels25 or due to effects of cyclosporine immunosuppression.3 Despite hemodynamic differences, however, efficiency of transplant allografts remained within the normal range in the present study. Furthermore, the relation between efficiency and loading conditions as well as contractile state, a previously described normal regulatory interaction,24 remained intact after transplantation. Efficiency was also significantly improved compared with failing hearts, so that results of previous studies reporting only minor improvements in exercise performance after transplantation26 cannot be attributed to a lack of improvement of cardiac efficiency.
Second, the metabolic profile of the transplanted heart may differ from normal hearts. It has previously been shown that nonrejecting allografts utilize higher amounts of glucose as a substrate. This observation was largely attributed to sympathetic denervation and led to the conclusion that the transplanted heart may be metabolically inefficient, requiring greater amounts of substrate to maintain cardiac work.27 Consistent with previous work,14 however, overall flux through the tricarboxylic acid cycle as the final common pathway for all substrates was found to be comparable to normal subjects in the present study, suggesting a substrate shift from fatty acids to glucose rather than an overall increased energy demand as explanation for higher glucose utilization rates. Normal values for the WMI give further evidence against the hypothesis of general metabolic inefficiency after transplantation.
Progressive transplant vasculopathy and repeated myocardial damage caused by acute rejection are major complications after transplantation and may alter allograft performance. The present study, however, was designed to characterize cardiac efficiency in transplant recipients with an uncomplicated course and to evaluate the additional role of sympathetic reinnervation. Patients with acute rejection, vasculopathy, or allograft failure were excluded. Future studies may focus on effects of these short- and long-term complications, and new therapeutic approaches may be optimized with serial noninvasive measurements of efficiency.
With the use of different techniques, a variety of previous studies have demonstrated that sympathetic reinnervation of both sinus node and myocardium does occur late after transplantation. It has also been shown that reinnervation remains regionally heterogeneous.6 7 9 28 Consistently, with the use of PET methodology, which allows direct detection of reappearing myocardial catecholamine uptake and storage, evidence of incomplete reinnervation was found in the present study. Previous work has shown that sympathetic reinnervation contributes to partial restoration of exercise capacity29 and plays a role for regulation of myocardial blood flow and metabolism.30 31 In the present study, however, cardiac work, oxygen consumption, and efficiency at rest were not different between reinnervated and denervated transplant recipients. Additionally, there was no regional difference for contractile performance or oxygen consumption in reinnervated and denervated territories. These results further confirm that efficiency of the allograft is mainly regulated by intrinsic mechanisms other than sympathetic innervation and that reappearance of sympathetic nerve terminals does not play a major regulatory role under resting conditions.
Conclusions
Cardiac work, oxygen consumption, and efficiency of the
transplanted heart are similar to normal hearts at rest and are
significantly improved compared with the failing heart. Intrinsic
regulatory interactions between efficiency, preload, afterload, and
contractility remain intact despite sympathetic
denervation early after transplantation. Additionally, the occurrence
of sympathetic reinnervation did not have global or regional effects on
oxidative metabolism, contractile function, and efficiency
at rest. The performance of physical exercise is of limited
feasibility during PET imaging because of the high likelihood of motion
artifacts; therefore, further studies with other techniques may be
performed in the future to evaluate the
physiological role of reinnervation under stress
conditions.
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Acknowledgments |
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The authors would like to thank the PET technologists and the cyclotron staff of the TU Muenchen for excellent performance of PET studies and reliable production of radiotracers. Also, the organizational help of G. Schuepferling is greatly appreciated.
Received September 28, 2000; revision received December 15, 2000; accepted December 28, 2000.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. See YP, Weisel RD, Mickle DA, et al. Prolonged hypothermic cardiac storage for transplantation: the effects on myocardial metabolism and mitochondrial function. J Thorac Cardiovasc Surg. 1992;104:817–824.[Abstract]
2. Kirklin JK, Naftel DC, Bourge RC, et al. Rejection after cardiac transplantation: a time-related risk factor analysis. Circulation. 1992;86(suppl II):II-236–II-241.
3. Scherrer U, Vissing SF, Morgan BJ, et al. Cyclosporine-induced sympathetic activation and hypertension after heart transplantation. N Engl J Med. 1990;323:693–699.[Abstract]
4. Gao SZ, Alderman EL, Schroeder ES, et al. Accelerated coronary vascular disease in the heart transplant patient: coronary angiographic findings. J Am Coll Cardiol. 1990;16:586–595.[Abstract]
5.
Bristow MR. The
surgically denervated, transplanted human heart.
Circulation. 1990;82:658–660.
6.
Wilson RF,
Christensen BV, Olivari MT, et al. Evidence for structural sympathetic
reinnervation after orthotopic cardiac transplantation in humans.
Circulation. 1991;83:1210–1220.
7. 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.
8.
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.
9.
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.
10. Bing R, Hammond M, Handelsman J, et al. The measurement of coronary blood flow, oxygen consumption, and efficiency of the left ventricle in man. Am Heart J. 1949;38:1–24.[Medline] [Order article via Infotrieve]
11.
Eichhorn EJ,
Bedotto JB, Malloy CR, et al. Effect of ß-adrenergic blockade on
myocardial function and energetics in congestive heart failure.
Circulation. 1990;82:473–483.
12.
Baxley W, Dodge
H, Rackley C, et al. Left ventricular mechanical efficiency
in man with heart disease.
Circulation. 1977;55:564–568.
13. Beanlands RS, Bach DS, Raylman R, et al. Acute effects of dobutamine on myocardial oxygen consumption and cardiac efficiency measured using carbon-11 acetate kinetics in patients with dilated cardiomyopathy. J Am Coll Cardiol. 1993;22:1389–1398.[Abstract]
14. Bengel FM, Ueberfuhr P, Nekolla S, et al. Oxidative metabolism of the transplanted human heart assessed by positron emission tomography using C-11 acetate. Am J Cardiol. 1999;83:1503–1505.[Medline] [Order article via Infotrieve]
15.
Armbrecht JJ,
Buxton DB, Schelbert HR. Validation of [1–11C]acetate as a tracer
for noninvasive assessment of oxidative metabolism with
positron emission tomography in normal, ischemic,
postischemic, and hyperemic canine
myocardium.
Circulation. 1990;81:1594–1605.
16. Bengel FM, Permanetter B, Ungerer M, et al. Noninvasive estimation of myocardial efficiency using positron emission tomography and C-11 acetate: comparison between the normal and failing human heart. Eur J Nucl Med. 2000;27:319–326.[Medline] [Order article via Infotrieve]
17.
Rosenspire KC,
Haka MS, Van Dort M, et al. Synthesis and preliminary evaluation of
carbon-11-meta-hydroxyephedrine: a false transmitter agent for heart
neuronal imaging. J Nucl
Med. 1990;31:1328–1334.
18. Pike VW, Eakins MN, Allan RM, et al. Preparation of (1–11C) acetate: an agent for the study of myocardial metabolism by positron emission tomography. Int J Appl Radiat Isot. 1982;33:505–512.[Medline] [Order article via Infotrieve]
19.
Bengel FM,
Nekolla SG, Ibrahim T, et al. Effect of thyroid hormones on cardiac
function, geometry and oxidative metabolism assessed
noninvasively by positron emission tomography and magnetic resonance
imaging. J Clin Endocrinol
Metab. 2000;85:1822–1827.
20. Baur LHB, Schipperheyn JJ, van der Velde EA, et al. Reproducibility of left ventricular size, shape and mass with echocardiography, magnetic resonance imaging and radionuclide angiography in patients with anterior wall infarction. Int J Card Imaging. 1996;12:233–240.[Medline] [Order article via Infotrieve]
21. Nekolla SG, Miethaner C, Nguyen N, et al. Reproducibility of polar map generation and assessment of defect severity and extent assessment in myocardial perfusion imaging using positron emission tomography. Eur J Nucl Med. 1998;25:1313–1321.[Medline] [Order article via Infotrieve]
22.
Gropler RJ,
Siegel BA, Geltman EM. Myocardial uptake of carbon-11-acetate as an
indirect estimate of regional myocardial blood flow.
J Nucl Med. 1991;32:245–251.
23.
Guyton AC. The
relationship of cardiac output and arterial pressure
control. Circulation. 1981;64:1079–1088.
24. Suga H, Igarashi Y, Yamada O, et al. Mechanical efficiency of the left ventricle as a function of preload, afterload and contractility. Heart Vessels. 1985;1:3–8.[Medline] [Order article via Infotrieve]
25. 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.[Abstract]
26.
Stevenson LW,
Sietsema K, Tillisch JH, et al. Exercise capacity for survivors of
cardiac transplantation or sustained medical therapy for stable heart
failure. Circulation. 1990;81:78–85.
27. Rechavia E, de Silva R, Kushwaha SS, et al. Enhanced myocardial 18F-2-fluoro-2-deoxyglucose uptake after orthotopic heart transplantation assessed by positron emission tomography. J Am Coll Cardiol. 1997;30:533–538.[Abstract]
28.
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.
29.
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.
30.
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.
31. Bengel FM, Ueberfuhr P, Ziegler SI, et al. Non-invasive assessment of the effect of cardiac sympathetic innervation on metabolism of the human heart. Eur J Nucl Med. 2000;27:1650–1657. [Medline] [Order article via Infotrieve]
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