(Circulation. 1995;91:72-78.)
© 1995 American Heart Association, Inc.
Articles |
Evidence for Functional Sympathetic Reinnervation of Left Ventricle and Coronary Arteries After Orthotopic Cardiac Transplantation in Humans
From the Department of Medicine, University of Minnesota (Minneapolis).
Correspondence to Robert F. Wilson, MD, Box 508 UMHC, 420 Delaware St SE, Minneapolis, MN 55455.
 |
Abstract |
|---|
 Top Abstract IntroductionMethods Results Discussion References |
|---|
Background Structural sympathetic reinnervation of the transplanted human heart is believed to occur >1 year after cardiac transplantation. The functional effects of reinnervating neurons, however, are undefined.
Methods and Results To test directly for functional sympathetic
reinnervation, we measured left ventricular or coronary hemodynamics in
11 patients 
4 months after transplantation, in 45 patients 
1 year
after transplantation, and in 13 untransplanted, normally innervated
patients. Sympathetic neurons were stimulated with left coronary
injection of tyramine (10 µg/kg), which causes norepinephrine release
from intact sympathetic nerve terminals. Reinnervation was defined as a
measure of cardiac norepinephrine release after intracoronary tyramine
injection. Left ventricular pressure was measured before and at
1-minute intervals after tyramine with a micromanometer-tipped catheter
(Millar Instruments). Coronary blood flow velocity (CBFV) was measured
with a 3F Doppler catheter (Numed), and coronary artery cross-sectional
area was calculated using quantitative coronary angiography. In both
early patients and patients studied 4 months after transplantation
without reinnervation (late denervated), there was no change in left
ventricular function in response to tyramine (
dP/dt=31±61
and
49±54 mm Hg/s, respectively; P=NS). In transplant
recipients with reinnervation (late reinnervated), left ventricular
dP/dt rose significantly (dP/dt=210±97 mm Hg/s;
P<.05)
but less than in healthy patients (dP/dt=577±66 mm Hg/s;
P<.05). In both early and late denervated patients, there
was no change in CBFV in response to tyramine (CBFV=1.02±0.1 and
1.0±0.1xbasal, respectively; P=NS). In late
reinnervated
patients, CBFV fell significantly (CBFV=0.94±0.1xbasal;
P<.05). In healthy patients, CBFV fell even more
(CBFV=0.88±0.1xbasal; P<.05).
Conclusions Stimulation of reinnervating sympathetic neurons with tyramine in transplant recipients causes a significant but subnormal increase in dP/dt and a transient decrease in CBFV, suggesting that reinnervating sympathetic neurons can produce physiologically meaningful changes in left ventricular function and coronary artery tone.
Key Words: transplantation • nervous system, sympathetic • tyramine
|
Introduction |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Cardiac transplantation causes section of postganglionic neural axons innervating the heart and results in total cardiac denervation. Within days after transplantation, axonal degeneration caused by discontinuity with the nerve cell body1 (which resided outside the transplanted tissue block) leads to total depletion of cardiac norepinephrine stores2 and eventual disappearance of nerve terminals in the transplanted tissue3 (ie, wallerian degeneration).
Although sympathetic reinnervation occurs commonly in animal models, until very recently it was not believed to occur after human cardiac transplantation.4 5 6 Sympathetic reinnervation of transplanted human hearts, however, has been shown using two widely divergent methodologies.7 8 Studies from our laboratory have demonstrated that both tyramine (an agent that causes norepinephrine release from intact sympathetic nerve terminals) and sustained handgrip exercise (a reflex sympathetic stimulus) elicit norepinephrine release from the myocardium in the majority of transplant recipients surviving 1 or more years after transplantation.7 Patients studied less than 5 months after transplantation, however, failed to release norepinephrine from the myocardium in response to tyramine. Cardiac norepinephrine release could occur only if cardiac sympathetic neurons were contiguous with ganglionic nerve cell bodies in the nontransplanted thoracic ganglia and the central nervous system. In transplant recipients who demonstrated norepinephrine release, the magnitude of release increased for at least the first 5 years after transplantation, which suggests an ongoing process of sympathetic neural ingrowth. Using positron emission tomography, Schwaiger et al8 demonstrated uptake of a norepinephrine analogue (11C-hydroxyephedrine) in the anterolateral left ventricular wall in late transplant survivors but found no tracer uptake soon after transplantation.8 Taken together, these studies provide strong biochemical and spatial evidence for structural sympathetic reinnervation after human cardiac transplantation.
Studies in animals show that structural reinnervation causes partial return of sympathetic neural function.9 10 After reinnervation in dogs, heart rate and myocardial contractility increase during sympathetic stimulation with tyramine and during stellate ganglion excitation.9 10 The functional effects of reinnervation in humans have not been demonstrated, and several investigators have concluded from clinical studies that sympathetic reinnervation does not occur. Because sympathetic reinnervation is heterogeneous spatially and in magnitude, it is possible that the variability of response in late transplant recipients (some of whom were not reinnervated) might have precluded prior investigators from establishing the occurrence of functional reinnervation.
The purpose of the present study was to determine if stimulation of reinnervating sympathetic neurons can produce physiologically meaningful changes in left ventricular function and coronary artery tone.
|
Methods |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Patient Selection
Three groups of patients were studied. The first group was composed of 11 patients who had undergone orthotopic cardiac transplantation within 4 months (mean, 3.2 months; range, 2 to 4 months) of the study. Each patient was treated with cyclosporin A, azathioprine, and glucocorticoid immunosuppression; the protocol is described elsewhere.11 Three patients had prior episodes of rejection based on serial endomyocardial biopsies and clinical course, but none had rejection at the time of the study. In this early transplant group, we assumed total sympathetic denervation on the basis of prior studies in 20 patients evaluated less than 4 months after transplantation in whom no evidence of reinnervation was found.7 12
The second group was composed of 46 patients studied 1 or more years after orthotopic cardiac transplantation (mean, 37.9 months; range, 12 to 96 months) and treated with immunosuppressive drugs similar to those described above. Eleven patients had at least one prior episode of rejection, but none had rejection at the time of the study.
The third group consisted of 13 patients undergoing coronary angiography for a chest pain syndrome or pre–lung transplantation evaluation in whom normal cardiac innervation was assumed. None had significant coronary artery disease (coronary diameter stenosis, >30% by visual inspection), pulmonary artery hypertension (mean pulmonary artery pressure, >25 mm Hg), hypoxemia (SaO2, <90%), or carbon dioxide retention (PCO2, >45 mm Hg).
Patients were excluded from any group if they had diabetes mellitus, amyloidosis, serum creatinine concentration of >2.0 mg/dL, or any other diseases known to impair peripheral neural function. Patients who were taking ß-adrenoreceptor antagonists, calcium channel antagonists, or nitrates had the drug withdrawn and held for at least five drug half-lives before the study.
From these patient groups, two catheterization research protocols were carried out during a routine surveillance cardiac catheterization. Each patient participated in only one protocol. All studies were approved by the University of Minnesota Institutional Review Board.
Catheterization Protocols
Assessment of Left
Ventricular Innervation
Five early transplant recipients, 13 late
transplant recipients,
and 3 normally innervated, untransplanted patients were studied. After
informed consent was obtained and patients were premedicated with
diazepam (5 to 10 mg PO), all patients were studied in a fasting state.
A pacing catheter (5F or 6F) was placed into the right atrium, and the
heart was paced at 100 beats per minute. A micromanometer catheter (6F
or 7F, Millar Instruments) was placed into the left ventricle via the
right femoral artery. The left main coronary artery was cannulated with
a 6F coronary catheter via the left femoral artery. In all late
transplant patients, the coronary sinus was cannulated with a 5F
catheter (model 7171, Cordis). Pressure from the left ventricle and the
ECG were monitored continuously. For subsequent off-line analysis
of left ventricular function, 10- to 20-second samples of left
ventricular pressure were recorded on-line to an IBM AT microcomputer
equipped with an analog-to-digital conversion board (AT-Codas, Data Q
Instruments), and pressure was digitized at 2-millisecond intervals.
Basal left ventricular pressure and ECG were recorded twice within 1 minute (without intervention) to assess measurement variability. In late transplant recipients, baseline paired blood samples from the left main coronary artery (via the guiding catheter) and coronary sinus blood were taken for plasma norepinephrine assay. Next, tyramine (10 µg/kg in 8 mL 0.9% saline, Sigma Chemical Co) was infused into the left coronary artery at approximately 1 mL/s as a bolus to elicit a cardiac norepinephrine release from intact sympathetic nerve terminals. This dosage was chosen based on previous studies demonstrating myocardial release of norepinephrine without systemic effects.7 12 Left ventricular pressure was recorded at 1-minute intervals for 8 minutes after tyramine administration.
After tyramine stimulation, 3 patients had an increase in heart rate over the paced rate. In each patient, the sinus node artery arose from the circumflex artery. To control for the effect of an increase in heart rate on left ventricular pressures, these patients were paced at the peak heart rate attained after tyramine. This was done after a waiting period of more than 8 minutes to allow left ventricular function to return to basal levels because we demonstrated in a previous study that left ventricular norepinephrine release and its effect on heart rate last less than 7 minutes.7 12 Left ventricular pressure then was recorded twice at 1-minute intervals. These pressures were considered to be basal conditions.
In late transplant recipients, paired left main coronary artery and coronary sinus blood samples were drawn 30 seconds, 1 minute, and 2 minutes after intracoronary tyramine administration to assess left ventricular norepinephrine release. (We have shown previously that peak norepinephrine release occurs within 1 minute after tyramine administration.7 ) The method has been described in detail elsewhere.12
Assessment of Coronary Artery
Reactivity
Six early transplant recipients, 33 late transplant
recipients,
and 10 normally innervated patients were studied. Following the routine
procedures described above, the coronary sinus was cannulated with a 5F
catheter as described above. A 5F or 6F pacing catheter was placed into
the right atrium, and the heart was paced at 100 beats per minute. The
left main coronary artery was cannulated with a 7F guiding catheter
(Cordis Corp). Through the guiding catheter, a 3F Doppler catheter
(Numed) was advanced into either the left anterior descending coronary
artery or left circumflex artery until an acceptable signal of coronary
blood flow velocity (CBFV) was obtained. The method has been described
in detail elsewhere.13 The left anterior descending
coronary artery was studied in 5 of 6 early and 24 of 32 late
transplant recipients and in 5 of 10 normally innervated patients.
Blood samples were taken from the coronary sinus and left main
catheters to assess basal plasma norepinephrine concentration and
oxygen saturation (OSM3, Radiometer). Basal heart rate, blood pressure,
and CBFV were recorded, and an angiogram of the artery with the Doppler
catheter was obtained to assess epicardial coronary caliber.
After basal measurements, tyramine (10 µg/kg in 8 mL 0.9% saline, Sigma Chemical Co) was infused as a bolus at approximately 1 mL/s into the left coronary artery. Heart rate, blood pressure, and CBFV were monitored continuously. Paired left main and coronary sinus blood samples for norepinephrine were drawn at 30 seconds, 1 minute, and 2 minutes after intracoronary tyramine administration. In addition, 1 minute after tyramine administration paired blood samples for oxygen saturation measurement were drawn from the left main coronary and coronary sinus, and a repeat angiogram was then obtained.
Measurement of Plasma Norepinephrine Concentration
Blood
samples obtained from the left main coronary and coronary
sinus were centrifuged at 2000 rpm for 12 minutes. The plasma was
decanted and frozen at -70°C. Plasma norepinephrine concentration
was subsequently determined by a radioenzymatic method that has been
described elsewhere (Cat-a-Kit, Amersham Corp).14
Assessment of Cardiac Norepinephrine Release (Uptake)
Cardiac
release or uptake of norepinephrine was assessed
by subtracting the norepinephrine concentration in the blood entering
the heart through the left main coronary from the norepinephrine
concentration in the coronary sinus
([NE]CS-Ao).7 The effect of an intervention
on cardiac norepinephrine release (uptake) was assessed by subtracting
the cardiac norepinephrine release (uptake) during control conditions
from the cardiac norepinephrine release (uptake) during the
intervention ([NE]CS-Ao). In the late transplant
recipients, reinnervation was defined as
[NE]CS-Ao143 pg/mL (a threefold increase in the
measurement variability of [NE]CS-Ao).7 In
the early transplant patients, we assumed denervation based on the
previous finding from our laboratory that 20 patients previously tested
in this manner had no measurable norepinephrine
release.7 12 In healthy, nontransplanted patients, we
assumed that innervation was intact based on previous experience that
all patients meeting the entry criteria had marked norepinephrine
release.7 12
Assessment of Left Ventricular Function
At the time of
catheterization, left ventricular pressure was
digitized at 2-millisecond intervals and subsequently analyzed using
commercial software (Data Q Instruments) and additional software
developed in our laboratory. Left ventricular systolic and diastolic
pressures, dP/dt, and dP/dt normalized to instantaneous pressure
(dP/dt/P) were measured, and the time constant of early diastolic left
ventricular relaxation (
) was estimated according to the technique
of Weiss et al.15
Assessment of Coronary Artery Cross-sectional Area
Angiograms
of the coronary arteries were analyzed using
quantitative angiography, which was performed using the CAAS-Reiber
method (PIE DATA). The technique has been described in detail
elsewhere.16 17 In brief, the lumen of the artery at
the
position of blood flow velocity measurement (Doppler catheter tip
marker) was outlined using an automated edge-detection algorithm by an
operator who was blinded to the clinical and experimental data. The
lumen outline was corrected for magnification and radiographic
pin-cushion distortion. The mean lumen diameter was determined for
basal conditions and 1 minute after tyramine administration. Arteries
were assumed to be circular, and cross-sectional area was calculated
geometrically using the formula: cross-sectional area=(mean
diameter)2 · 
/4.
Assessment of Coronary Blood Flow
The effect of tyramine on
CBFV was expressed as the
fractional change in basal blood flow velocity. The change in coronary
blood flow was calculated as the quotient of (CBFV · arterial
cross-sectional area)after tyramine and
(CBFV · arterial cross-sectional area)basal. The change
in coronary artery resistance was calculated as the quotient of (mean
arterial pressureafter tyramine · coronary blood
flowbasal) and (mean arterial
pressurebasal · coronary blood flowafter
tyramine) (ie, the fractional change in the basal resistance).
Statistical Analysis
All data are presented as
mean±SD, except where noted
otherwise. Differences between the group mean values were assessed
using ANOVA (STATVIEW II). Paired differences were assessed
with a paired t test. Linear regression was determined by
the least-squares method, and correlation was expressed with a Pearson
correlation coefficient (STATVIEW II). Statistical
significance was defined as a value of P<.05.
|
Results |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Effects of Reinnervation on Left Ventricular Function
Left Ventricular Norepinephrine Release
Of the 13 late transplant recipients studied, 9 had a peak cardiac norepinephrine gradient (
[NE]CS-Ao) after tyramine
that exceeded 143 pg/mL, indicating left ventricular reinnervation. Of
patients with a significant norepinephrine release (ie, outside the
99% confidence limits for repeated measurements), the mean increase in
[NE]CS-Ao was 780±694 pg/mL (range, 187 to 1901
pg/mL).
In each patient, the peak [NE]CS-Ao occurred within
1
minute of tyramine administration and declined somewhat at the 2-minute
sample, indicating that the peak response was sampled.
Measurement Variability for Parameters of Left Ventricular
Function
Paired measurements of left ventricular dP/dt, dP/dt/P, ,
systolic pressure, and end-diastolic pressure were
correlated closely (r=.98, .99, .86, .95, and .92,
respectively). The 95% confidence intervals for repeat measurements
were ±118 mm Hg/s, ±1.9 s-1, ±8.9
milliseconds, ±8.8
mm Hg, and ±2.3 mm Hg, respectively).
Basal
Hemodynamics
Under basal conditions, there were no significant
differences
among the four groups in any measurement of left ventricular function
(dP/dt, dP/dt/P, , systolic pressure, or end-diastolic
pressure; Table 1
and Fig 1A).
|
|
Effect of Tyramine on Left Ventricular Function
After tyramine administration, early transplant recipients showed
no significant change in left ventricular dP/dt, suggesting functional
denervation (Fig 1B
). The dP/dt in late persistently denervated
transplant patients also failed to change after tyramine, suggesting
persistent functional denervation. In late transplant recipients with
biochemical evidence of ventricular reinnervation (norepinephrine
release), however, dP/dt rose promptly and significantly after tyramine
stimulation (dP/dt=210±32 mm Hg/s). In normally innervated
patients, dP/dt rose even more after tyramine (dP/dt=577±38
mm Hg/s). In both late reinnervated transplant recipients and healthy
patients, the rise in dP/dt peaked 1 minute after tyramine
administration and fell to basal levels over the next 8 minutes (Fig
2).
|
In general, heart rate did not change after tyramine
infusion
(either because the sinoatrial nodal artery arose from the right
coronary artery or because the sinoatrial node was not reinnervated).
There were, however, 3 patients in whom a significant increase in heart
rate occurred, including 1 late denervated transplant recipient, 1 late
reinnervated transplant recipient, and 1 normally innervated patient.
When these patients were excluded from data analysis, the results
were not significantly different (dP/dt in late denervated
transplant recipients=75±11 mm Hg/s, in late reinnervated
patients=204±36 mm Hg/s, and in healthy
patients=615±5 mm Hg/s).
The dP/dt/P rose significantly
only in healthy patients. In late
reinnervated transplant recipients, however, increased
significantly, as did the peak systolic pressure. None of the other
parameters of left ventricular function changed significantly between
patient groups or in relation to basal values (Table 1).
Effects of Reinnervation on Coronary Artery Reactivity
Left Ventricular Norepinephrine Release
Of the 33 late
transplant recipients studied, 24 had a peak
cardiac norepinephrine gradient ([NE]CS-Ao) after
tyramine that exceeded 143 pg/mL, indicating left ventricular
reinnervation. Of patients with a significant increase, the mean change
in [NE]CS-Ao was 544±413 pg/mL (range, 151 to 1725
pg/mL).
Basal Hemodynamics
Under basal conditions,
there were no significant differences
among the four groups in heart rate, mean arterial pressure, arterial
cross-sectional area, or transcardiac arteriovenous oxygen difference
(Table 2).
|
Effects of Tyramine on Coronary
Artery Tone
Thirty seconds after tyramine administration, both late
reinnervated and healthy patients showed a significant decrease in CBFV
compared with patients studied early after transplantation (Figs
3 and 4). There were no significant changes
between groups in any other parameter. Of importance, mean arterial
pressure after tyramine was unchanged from basal values in each group
(Table 2).
|
|
One minute after tyramine administration,
CBFV rose to basal levels in
healthy patients and late reinnervated transplant recipients, even
though heart rate and arterial pressure were unchanged (Table
2).
Transcardiac arteriovenous oxygen difference tended to show increased
oxygen extraction in the late reinnervated transplant recipients and
normally innervated patients, but the difference did not reach
statistical significance. Coronary artery cross-sectional area 1 minute
after tyramine administration did not change in any group.
There was no relation in any group between the artery studied (left circumflex or left anterior descending coronary artery) and the change in CBFV 30 seconds after tyramine administration.
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
These data show that stimulation of reinnervating sympathetic neurons produces physiologically meaningful changes in both left ventricular function and coronary vasomotor tone, suggesting that clinically significant sympathetic reinnervation occurs in human cardiac transplant recipients. The present study also confirms previous studies in late heart transplant recipients demonstrating that tyramine causes myocardial release consistent with sympathetic reinnervation. These data demonstrate for the first time that sympathetic reinnervation after cardiac transplantation in humans has important physiological effects in terms of myocardial function and coronary artery tone. Although the effects in late transplant recipients were generally less than those seen in healthy control subjects, the magnitude of the response to neural stimulation varied significantly among late transplant recipients (from no response to near-normal changes). These results in humans are similar to those found in animal models of cardiac transplantation, which nearly uniformly demonstrate functional sympathetic neural reinnervation.9 10
Tyramine resulted in a transient reduction in CBFV in normally innervated patients and reinnervated transplant recipients, consistent with brief, rapid microvascular constriction because blood flow is regulated primarily in vessels <400 µm in diameter.18 The explanation for the transient coronary constriction in the setting of a more persistent norepinephrine release into the coronary sinus is not known. The change in blood flow velocity may reflect a balance of two effects of norepinephrine release: a direct microvascular constrictor effect and a metabolic dilator stimulus from increased myocardial metabolic demand due to an increase in inotropic state. Initial coronary constriction, therefore, might have been overridden by increased metabolic demand, returning coronary resistance to basal levels, but still higher than would be appropriate for the increased inotropic state. This view is supported by the trend for a widened transcardiac arteriovenous oxygen difference 1 minute after tyramine administration in late reinnervated and normal patients but not in late persistently denervated or early transplant recipients.
Although systolic left ventricular dP/dt increased significantly after
tyramine-induced norepinephrine release in late reinnervated transplant
recipients and healthy patients, the parameter of diastolic relaxation,
, unexpectedly increased in reinnervated transplant patients (Table
1). In contrast, normally innervated patients tended to have a
decrease
in (although not statistically significant). This finding in late
transplant recipients may seem contrary to the prior findings that
sympathetic stimulation improves diastolic relaxation. The increase in
, however, may be caused by regional differences in reinnervation
within the left ventricle.8 12 Heterogeneous changes
in
contraction velocity and relaxation might therefore increase the total
amount of time taken for relaxation to occur throughout the entire
ventricle, which would subsequently result in a higher value.
Potential Study Limitations
Although the present study
demonstrates that tyramine-induced
sympathetic stimulation affects ventricular function and coronary
vasomotor tone in both transplanted and healthy hearts, tyramine itself
is not an endogenous, physiological stimulus. We have shown previously,
however, that norepinephrine is released from regenerating sympathetic
neurons in transplanted hearts in response to sustained handgrip (a
reflex stimulus for sympathetic discharge) and that all patients with
reflexively induced norepinephrine release have tyramine-induced
norepinephrine release.7 Each of the parameters studied
(coronary blood flow and left ventricular function) are influenced
significantly by systemic hemodynamics. The use of reflex stimuli to
elicit cardiac sympathetic discharge in the present study would
have led to hemodynamically induced changes in coronary blood flow and
left ventricular function that would have been independent of the
effects of neural stimulation alone, making difficult the
interpretation of changes in left ventricular function or coronary
tone. By administering intracoronary tyramine, it is possible to
stimulate the cardiac sympathetic neurons without changing systemic
hemodynamics. The possibility that tyramine itself affected vasomotor
tone or left ventricular function is not likely as there was no
response to tyramine in transplant patients studied early after
transplantation or in those patients without ventricular norepinephrine
release late after transplantation.
Another potential limitation is that transplanted hearts may be supersensitive to adrenergic stimulation, amplifying the effects of neurally released norepinephrine. Several studies have documented an increased response of both human and animal transplanted hearts to adrenergic stimulation due to either an increase in ß-adrenoreceptor density or presynaptic supersensitivity.19 20 It is possible, therefore, that the observed changes in left ventricular function or coronary resistance in reinnervated transplant recipients were out of proportion to the degree of reinnervation. Alternatively, the expected response from a physiological neural discharge would be amplified similarly.
An unexpected result was the lack of constriction
of epicardial
coronary arteries in response to tyramine-induced norepinephrine
release in all patients, including the normally innervated control
patients. Tyramine failed to constrict the epicardial arteries of all
patients, including those normally innervated, suggesting that it is
not related to innervation status. This finding is surprising because
epicardial vasoconstriction has been demonstrated to occur after
physiological sympathetic stimulation in healthy
patients.21 One possible explanation is that angiography
was performed before the epicardial arteries constricted. In one prior
study, the coronary arteries of dogs were unchanged 1 minute after
infusion with methoxamine (a potent 
-agonist) but constricted by 2
minutes.22 It is also possible that sympathetically
induced conduit artery constriction occurs via release of multiple
neurotransmitters, and it is unclear whether tyramine causes release of
all of them, particularly neuropeptide
Y.23 24 25 In
addition, norepinephrine causes mixed - and ß-adrenergic
stimulation.26 Because none of the patients we studied
were taking ß-adrenoreceptor antagonists, it is possible that the
dilating effects of ß-adrenoreceptor stimulation balanced the
constricting effects of -adrenoreceptor stimulation.
Finally, reinnervation is regionally heterogeneous within the ventricle,12 27 28 and it is possible that some of the coronary arteries studied were not reinnervated, despite reinnervation elsewhere in the ventricle as demonstrated by norepinephrine release. Misclassification of individual arteries (reinnervated and denervated) would have decreased our ability to detect changes in vasoreactivity due to reinnervation. Similarly, reinnervation occurs in a base-to-apex distribution in a dog model,28 and it is likely that the distal perfusion fields of the arteries we studied were less reinnervated than the proximal beds.
Implications
The primary implication of the present study is
that
stimulation by tyramine of regenerating sympathetic neurons in
transplanted hearts can affect both left ventricular contractility and
coronary vasomotor tone in a manner similar to that seen in healthy
hearts. It is important, however, that the magnitude of the response of
coronary tone and left ventricular function was variable among
reinnervated patients. Therefore, one should anticipate wide variance
in the clinical manifestations of reinnervation.
A second implication of the present study is that the use of transplanted hearts as a model of denervation is inappropriate unless the study is performed soon after cardiac transplantation. Previous studies in humans of left ventricular function or coronary vasomotor tone using chronically transplanted hearts as denervated controls will require reconsideration.
Finally, evidence in humans that severed sympathetic neurons can regenerate and have end-organ effects similar to those of normally innervated hearts has potential implications for other organ transplantation (lung, kidney, pancreas, and liver). The occurrence and effects of reinnervation in these conditions deserve study.
|
Acknowledgments |
|---|
We thank the Cardiac Transplantation and Cardiac Catheterization Teams of the University of Minnesota for their assistance in the performance of these studies. We also thank Thomas H. Rector, PhD, for his statistical assistance and Susan S. Meyer, BS, MBA, for her expertise in quantitative coronary angiography.
Received June 15, 1994; accepted August 9, 1994.
|
References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Stinson EB, Donge E, Iben AR, Shumway NE. Cardiac transplantation in man, III: surgical aspects. Am J Surg. 1969;118:182. [Medline] [Order article via Infotrieve]
2. Ebert PA, Sabiston DC. Pharmacologic quantitation of cardiac sympathetic reinnervation. Surgery. 1970;68:123-127. [Medline] [Order article via Infotrieve]
3. Norvell JE, Lower RR. Degeneration and reinnervation of the nerves of the heart after transplantation. Transplantation. 1973;15:337-344. [Medline] [Order article via Infotrieve]
4. Rowan RA, Billingham ME. Myocardial innervation in long-term heart transplant survivors: a quantitative ultrastructural survey. J Heart Transplant. 1988;7:448-452. [Medline] [Order article via Infotrieve]
5.
Cannom DS, Graham AF, Harrison DC. Electrophysiological
studies in the denervated transplanted heart. Circ Res. 1973;32:268-278.
6. Stinson EB, Schroder JS, Griepp RB, Shumway NE, Dong E. Observations on the behavior of recipient atria after cardiac transplantation in man. Am J Cardiol. 1972;30:615-622. [Medline] [Order article via Infotrieve]
7.
Wilson RF, Christensen BV, Olivari MT, Simon A, White CW,
Laxson DD. Evidence for structural sympathetic reinnervation after
orthotopic cardiac transplantation in humans. Circulation. 1991;83:1210-1220.
8. Schwaiger M, Hutchins GD, Kalff V, Rosenspire K, Hahka MS, Mallette S, Deeb GM, Abrams GD, Wieland D. Evidence for regional catecholamine uptake and storage sites in the transplanted human heart by positron emission tomography. J Clin Invest. 1991;87:1681-1690.
9. Willman VL, Cooper T, Hanlon CR. Return of neural responses after autotransplantation of the heart. Am J Physiol. 1964;207:187-189.
10. Kontos HA, Thames MD, Lower RR. Responses to electrical and reflex autonomic stimulation in dogs with cardiac transplantation before and after reinnervation. J Thorac Cardiovasc Surg. 1970;59:382-392. [Medline] [Order article via Infotrieve]
11. Olivari MT, Homans DC, Wilson RF, Kubo SH, Ring WS. Coronary artery disease in cardiac transplant patients receiving triple-drug immunosuppressive therapy. Circulation. 1989;80(suppl III):III-111-III-115.
12.
Wilson RF, Laxson DD, Christensen BV, McGinn AL, Kubo SH.
Regional differences in sympathetic reinnervation after human
orthotopic cardiac transplantation in man. Circulation. 1993;88:165-171.
13.
Wilson RF, Laughlin DE, Ackell PH, Chilian WM, Holida MD,
Hartley CJ, Armstrong ML, Marcus ML, White CW. Transluminal,
subselective measurement of coronary artery blood flow velocity and
vasodilator reserve in man. Circulation. 1985;72:82-92.
14. Passon PG, Peuler JD. A simplified radiometric assay for plasma norepinephrine and epinephrine. Anal Biochem. 1973;51:618-631. [Medline] [Order article via Infotrieve]
15. Weis JL, Frederiksen JW, Weisfeldt ML. Hemodynamic determinants of the time-course of fall in canine left ventricular pressure. J Clin Invest. 1976;58:751-776.
16. Langer A, Wilson RF. Comparison of manual versus automated edge detection for determining degrees of luminal narrowing by quantitative coronary angiography. Am J Cardiol. 1991;67:885-888. [Medline] [Order article via Infotrieve]
17. Reiber JHC, Kooijman CJ, Slager CJ, Gerbrands JJ, Schuurbiers JCH, DenBoer A, Wijns W, Serruys PW, Hugenholtz PG. Coronary artery dimensions from cineangiograms: methodology and validation of a computer-assisted analysis procedure. IEEE Trans Med Imag. 1984;MI-3:131-141.
18.
Vatner DE, Lavallee M, Amano J, Finizola A, Homcy CJ, Vatner
SF. Mechanisms of supersensitivity to sympathomimetic amines in the
chronically denervated heart of the conscious dog. Circ Res. 1985;57:55-64.
19.
Yusuf Y, Theodoropolous S, Mathias CJ, Dhalla N, Wittes J,
Mitchell A, Yacoub M. Increased sensitivity of the denervated
transplanted human heart to isoprenaline before and after
ß-adrenergic blockade. Circulation. 1987;75:696-704.
20.
Brown BG, Lee AB, Bolson EL, Dodge HT. Reflex constriction of
significant coronary artery stenosis as a mechanism contributing to
ischemic left ventricular dysfunction during isometric exercise.
Circulation. 1984;70:18-24.
21. Vatner SF, Pagani M, Manders T, Pasipoularides AD. Alpha adrenergic vasoconstriction and nitroglycerin vasodilation of large coronary arteries in the conscious dog. J Clin Invest. 1980;65:5-14.
22. Haass M, Hoch M, Richardt G, Schomig A. Neuropeptide Y differentiates between exocytotic and nonexocytotic noradrenaline release in the guinea-pig heart. Naunyn Schmiedebergs Arch Pharmacol. 1989;340:509-515. [Medline] [Order article via Infotrieve]
23. Franco-Cereceda A, Saria A, Lundberg JM. Differential release of calcitonin gene-related peptide and neuropeptide Y from the isolated heart by capsaicin, ischemia, nicotine, bradykinin and oubain. Acta Physiol Scand. 1989;135:173-187. [Medline] [Order article via Infotrieve]
24. Cheng JT, Shen CL. Release of neuropeptide Y induced by tyramine in the isolated vas deferens of rat. Naunyn Schmeidebergs Arch Pharmacol. 1987;335:255-260. [Medline] [Order article via Infotrieve]
25. Ahlquist RD. A study of the adrenotropic receptors. Am J Physiol. 1948;153:586-600.
26. Kaye M. Denervation and reinnervation of the heart. In: Randall W, ed. Neural Regulation of the Heart. New York, NY: Oxford University Press; 1977:278-306.
27. Kaye M, Wells D, Tyce G. Nerve growth factor enhanced reinnervation of surgically denervated canine heart. Am J Physiol. 1979;236:H624-H628.
28.
Chilian WM, Harrison DG, Haws CW, Snyder WD, Marcus ML.
Adrenergic coronary tone during submaximal exercise in the dog is
produced by circulating catecholamines. Circ Res. 1986;58:68-82.
This article has been cited by other articles:
 |
|
 |
|
  J. M. Scott, B. T. A. Esch, M. J. Haykowsky, D. E. R. Warburton, M. Toma, A. Jelani, D. Taylor, I. Paterson, D. Poppe, Y. Liang, et al. Cardiovascular responses to incremental and sustained submaximal exercise in heart transplant recipients Am J Physiol Heart Circ Physiol, February 1, 2009; 296(2): H350 - H358. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Ovchinnikov, G. Suzuki, J. M. Canty Jr., and J. A. Fallavollita Blunted functional responses to pre- and postjunctional sympathetic stimulation in hibernating myocardium Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1719 - H1728. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Pachon M, E. I. Pachon M, J. C. Pachon M, T. J. Lobo, M. Z. Pachon, R. N.A. Vargas, and A. D. Jatene "Cardioneuroablation" - new treatment for neurocardiogenic syncope, functional AV block and sinus dysfunction using catheter RF-ablation Europace, January 1, 2005; 7(1): 1 - 13. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Jacob, F. Costa, S. Vincent, D. Robertson, and I. Biaggioni Neurovascular Dissociation With Paradoxical Forearm Vasodilation During Systemic Tyramine Administration Circulation, May 20, 2003; 107(19): 2475 - 2479. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. M. Bengel, P. Ueberfuhr, N. Schiepel, S. G. Nekolla, B. Reichart, and M. Schwaiger Effect of Sympathetic Reinnervation on Cardiac Performance after Heart Transplantation N. Engl. J. Med., September 6, 2001; 345(10): 731 - 738. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Winnicki, B. G. Phillips, V. Accurso, P. van de Borne, A. Shamsuzzaman, K. Patil, K. Narkiewicz, and V. K. Somers Independent Association Between Plasma Leptin Levels and Heart Rate in Heart Transplant Recipients Circulation, July 24, 2001; 104(4): 384 - 386. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Odaka, W. von Scheidt, S. I. Ziegler, P. Ueberfuhr, S. G. Nekolla, B. Reichart, F. M. Bengel, and M. Schwaiger Reappearance of Cardiac Presynaptic Sympathetic Nerve Terminals in the Transplanted Heart: Correlation Between PET Using 11C-Hydroxyephedrine and Invasively Measured Norepinephrine Release J. Nucl. Med., July 1, 2001; 42(7): 1011 - 1016. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. F. Wilson, T. H. Johnson, G. C. Haidet, S. H. Kubo, and M. Mianuelli Sympathetic Reinnervation of the Sinus Node and Exercise Hemodynamics After Cardiac Transplantation Circulation, June 13, 2000; 101(23): 2727 - 2733. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Uberfuhr, S. Ziegler, M. Schwaiblmair, B. Reichart, and M. Schwaiger Incomplete sympathic reinnervation of the orthotopically transplanted human heart: Observation up to 13 years after heart transplantation Eur. J. Cardiothorac. Surg., February 1, 2000; 17(2): 161 - 168. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Galatius, H. Wroblewski, V. B. Sorensen, P. Bie, H. Arendrup, and J. Kastrup Calf blood flow during prolonged tilt in idiopathic dilated cardiomyopathy and after cardiac transplantation Am J Physiol Heart Circ Physiol, January 1, 2000; 278(1): H239 - H248. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Pasic, M. Musci, H. Siniawski, O. Grauhan, B. Edelmann, T. Tedoriya, Y. Weng, and R. Hetzer THE COX MAZE III PROCEDURE: PARALLEL NORMALIZATION OF SINUS NODE DYSFUNCTION, IMPROVEMENT OF ATRIAL FUNCTION, AND RECOVERY OF THE CARDIAC AUTONOMIC NERVOUS SYSTEM J. Thorac. Cardiovasc. Surg., August 1, 1999; 118(2): 287 - 296. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Buvry, Y.-R. Yang, R. Tavakoli, and N. Frossard Calcitonin Gene-Related Peptide-Immunoreactive Nerves and Neuroendocrine Cells after Lung Transplantation in the Rat Am. J. Respir. Cell Mol. Biol., June 1, 1999; 20(6): 1268 - 1273. [Abstract] [Full Text]
|
|
|
|
|
|
F. M. Bengel, P. Ueberfuhr, S. I. Ziegler, S. Nekolla, B. Reichart, and M. Schwaiger Serial Assessment of Sympathetic Reinnervation After Orthotopic Heart Transplantation : A Longitudinal Study Using PET and C-11 Hydroxyephedrine Circulation, April 13, 1999; 99(14): 1866 - 1871. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Richard, J.-C. Verdier, A. Duvallet, S.-P. Rosier, P. Leger, A. Nignan, and M. Rieu Chronotropic competence in endurance trained heart transplant recipients: heart rate is not a limiting factor for exercise capacity J. Am. Coll. Cardiol., January 1, 1999; 33(1): 192 - 197. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Hunt Current Status of Cardiac Transplantation JAMA, November 18, 1998; 280(19): 1692 - 1698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Kondo, M. Nakazawa, K. Momma, and K. Kusakabe Sympathetic Denervation and Reinnervation After Arterial Switch Operation for Complete Transposition Circulation, June 23, 1998; 97(24): 2414 - 2419. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Bernardi, C. Valenti, J. Wdowczyck-Szulc, A. W. Frey, M. Rinaldi, G. Spadacini, C. Passino, L. Martinelli, M. Vigano, and G. Finardi Influence of Type of Surgery on the Occurrence of Parasympathetic Reinnervation After Cardiac Transplantation Circulation, April 14, 1998; 97(14): 1368 - 1374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Arrowood, A. J. Minisi, E. Goudreau, A. B. Davis, and A. L. King Absence of Parasympathetic Control of Heart Rate After Human Orthotopic Cardiac Transplantation Circulation, November 18, 1997; 96(10): 3492 - 3498. [Abstract] [Full Text]
|
|
|
|
|
|
M. M. Givertz, L. H. Hartley, and W. S. Colucci Long-term Sequential Changes in Exercise Capacity and Chronotropic Responsiveness After Cardiac Transplantation Circulation, July 1, 1997; 96(1): 232 - 237. [Abstract] [Full Text]
|
|
|
|
|
|
J. Bartunek, A. M. Shah, M. Vanderheyden, and W. J. Paulus Dobutamine Enhances Cardiodepressant Effects of Receptor-Mediated Coronary Endothelial Stimulation Circulation, January 7, 1997; 95(1): 90 - 96. [Abstract] [Full Text]
|
|
|
|
|
|
S. Singh, P. I. Johnson, R. E. Lee, E. Orfei, V. A. Lonchyna, H. J. Sullivan, A. Montoya, H. Tran, W. H. Wehrmacher, and R. D. Wurster TOPOGRAPHY OF CARDIAC GANGLIA IN THE ADULT HUMAN HEART J. Thorac. Cardiovasc. Surg., October 1, 1996; 112(4): 943 - 953. [Abstract] [Full Text]
|
|
|
|
|
|
L. Bernardi, B. Bianchini, G. Spadacini, S. Leuzzi, F. Valle, E. Marchesi, C. Passino, A. Calciati, M. Vigano, M. Rinaldi, et al. Demonstrable Cardiac Reinnervation After Human Heart Transplantation by Carotid Baroreflex Modulation of RR Interval Circulation, November 15, 1995; 92(10): 2895 - 2903. [Abstract] [Full Text]
|
|
|
|
|
|
W. J. Paulus, P. J. Vantrimpont, and A. M. Shah Paracrine Coronary Endothelial Control of Left Ventricular Function in Humans Circulation, October 15, 1995; 92(8): 2119 - 2126. [Abstract] [Full Text]
|
|
|
|
 |
|
 P. Haouzi, B. Chenuel, and B. Chalon Effects of body position on the ventilatory response following an impulse exercise in humans J Appl Physiol, April 1, 2002; 92(4): 1423 - 1433. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||