(Circulation. 2000;101:2727.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Sympathetic Reinnervation of the Sinus Node and Exercise Hemodynamics After Cardiac Transplantation
From the Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis, Minn.
Correspondence to Robert F. Wilson, Box 508, UMHC, 420 Delaware St SE, Minneapolis, MN 54455.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background—Sympathetic cardiac reinnervation occurs variably after cardiac transplantation (CT) in humans. We hypothesized that sinus node reinnervation would partially restore normal chronotropic response to exercise.
Methods and Results—Thirteen recent CT recipients, 28 late CT
recipients (
1 year after CT), and 20 control subjects were studied.
Sinus node sympathetic reinnervation was determined by heart rate (HR)
change after tyramine injection into the artery that perfused the sinus
node. HR changes of <5 and 15 bpm were defined, respectively, as
denervation and marked reinnervation. During treadmill exercise, HR,
blood pressure, and expired O2 and CO2 were
measured. All early transplant recipients exhibited features typical of
denervation (basal HR, 88±2 bpm; peak HR, 132±4 bpm, peaking 1.8±0.3
minutes after exercise cessation and slowly declining after exercise).
A similar pattern was found in the 12 late transplant recipients with
persistent sinus node denervation. However, in patients with marked
reinnervation, exercise HR rose more (peak HR, 142±4 and 141±2 bpm),
peaked earlier after cessation of exercise (0.7±0.4 and 0.3±0.1
minute), and fell more rapidly. Exercise duration and maximal oxygen
consumption were not related significantly to reinnervation status, but
a trend existed for longer exercise time in markedly
reinnervated patients.
Conclusions—The present studies suggest that sympathetic reinnervation of the sinus node is accompanied by partial restoration of normal HR response to exercise. Both maximal oxygen consumption and exercise duration were markedly shorter in CT patients than in control subjects, and most of the difference was not related to innervation status.
Key Words: surgery • transplantation • tests • nervous system, sympathetic • exercise • cardiovascular diseases • reflex
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The sinus node is innervated richly by the parasympathetic and sympathetic nervous systems, both of which modulate heart rate during exercise.1 2 In normal individuals, heart rate increases abruptly at onset of exercise because of vagal parasympathetic withdrawal, rises progressively during exercise because of a combination of sympathetic neural and humoral drive, and falls rapidly after cessation of exercise because of withdrawal of neural sympathetic discharge.2 3
Cardiac transplantation results in total denervation of the donor heart, including the donor sinus node, which usually controls heart rate after transplantation.4 5 Denervation causes an increase in basal heart rate due to parasympathetic sectioning. Further increases in heart rate during exercise are dependent primarily on increases in plasma catecholamine concentration (eg, from adrenal secretion). This results in a slow, lumbering, and submaximal increase in heart rate during exercise. Typically, heart rate continues to rise after cessation of exercise as a result of delayed humoral catecholamine release. In recovery, heart rate falls slowly as plasma catecholamines are metabolized.
We and others have shown previously that left ventricular norepinephrine stores are absent early after orthotopic human cardiac transplantation but return gradually toward normal levels late after surgery.6 7 8 9 Reemergence of cardiac norepinephrine stores implies sympathetic reinnervation, because surgical interruption of the postganglionic sympathetic nerve axon invariably causes rapid depletion of norepinephrine within the nerve terminal.10 The return of norepinephrine stores can occur only if continuity exists between sympathetic ganglia that lie outside the transplanted tissue and cardiac nerve terminals. We also showed previously that ventricular reinnervation was accompanied by partial return of normal sympathetic neuronal effects on ventricular function (increase in inotropic state with neural stimulation) and by sympathetically mediated coronary vasoconstriction.11
In addition to ventricular reinnervation, sympathetic reinnervation of the sinus node was shown specifically by measurement of the change in heart rate that occurs after injection of tyramine into the artery that perfuses the sinus node.12 Although patients studied within 4 months of transplantation had no change in heart rate in response to tyramine (consistent with denervation), by 1 year after surgery, a majority of transplanted hearts exhibited an increase in heart rate with tyramine stimulation, which was indicative of limited sympathetic reinnervation.12
The physiological effects of reinnervation on sinus node function are not well defined. Limited studies performed soon after the advent of human cardiac transplantation suggested that the average heart rate response to exercise within the first 2 years after transplantation was typical of denervation.5 More recently, a fraction of transplant recipients have been shown to develop increased heart rate variability and enhanced heart rate falls after exercise, which suggests sinus node reinnervation.13 14 Because the occurrence and magnitude of sinus node sympathetic reinnervation varies greatly between patients and some patients develop concurrent sinus node dysfunction, effects of reinnervation have been difficult to delineate.15
Once we developed tools to assess sympathetic reinnervation of the sinus node in humans, we undertook the present studies to determine the physiological effects of sympathetic reinnervation on exercise hemodynamics, particularly on heart rate response during exercise. We hypothesized that sympathetic reinnervation would partially normalize heart rate response to exercise and improve exercise duration.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Patient Selection
The University of Minnesota Institutional Review Board approved all studies, and each patient was studied after informed consent was provided.
Three groups of patients were studied. All patients underwent
uncomplicated orthotopic transplantation and were studied at the time
of routine, scheduled baseline angiography. The first group was
composed of 13 patients studied within 6 months of cardiac
transplantation (mean, 3.8±0.4 months; range, 2 to 6 months). A second
group was comprised of 28 patients who were studied 1 years after
transplantation (mean, 30±4 months; range, 12 to 60 months). All
patients were treated with immunosuppressive therapy similar to that
described previously.16 A third group was composed of 20
healthy control subjects in whom normal cardiac innervation was
presumed. An effort was made to match the age range of transplant
recipients. None of these subjects took medications or had known
medical illnesses.
Patients were excluded if they had diabetes mellitus, amyloidosis, or other diseases that could impair peripheral neural function. Additionally, patients with a resting heart rate >105 bpm and those unable to exercise for >5 minutes were excluded because further increases in heart rate might be limited, regardless of neural input.
Assessment of Sinus Node Reinnervation
Cardiac transplant recipients were brought to the cardiac
catheterization laboratory in a fasting state after
they were premedicated with diazepam (5 to 10 mg orally). After the
diagnostic procedure, sympathetic reinnervation of the
sinus node was assessed by injection of tyramine sequentially into left
and right coronary arteries and measurement of consequent
change in heart rate. Tyramine 4 µg/kg (Sigma F+D Division)
were injected into the right coronary artery, and 8 µg/kg was
injected into the left coronary artery. This dose of tyramine
was chosen because previous dose-response studies in dogs showed that
left coronary boluses of 8 to 10 µg/kg caused no significant
changes in arterial blood pressure but resulted in marked
cardiac norepinephrine release (
2-fold that elicited by
55 µg/kg of intravenously administered tyramine). The
dose was adjusted to 1 µg/kg for nondominant right coronary
arteries. Heart rate was recorded continuously for 1 minute before
and 2 minutes after each tyramine injection (until heart rate returned
to basal levels).
To assess the effect of tyramine on sinus node rate, maximal heart rate
within the first 2 minutes after tyramine injection (averaged over 3
beat periods) was subtracted from the heart rate measured during the
1-minute period preceding tyramine injection. To assess normal
variability in heart rate measurement, we previously measured basal
heart rate twice over a 3-minute period in 17 late transplant
recipients.12 Maximal change in heart rate without
intervention was +2±1 bpm (mean±SD; range, -3 to +4 bpm).
Consequently, a change in heart rate of +5 bpm was considered a
measurable response to tyramine (ie, outside 99% confidence limits of
normal variability). For purposes of analysis, change in heart
rate after tyramine administration in transplant recipients was defined
as none if heart rate rose <5 bpm, small-moderate if heart rate rose 5
to 14 bpm, and marked if heart rate increased 15 bpm.
Chronotropic Response to Exercise
To assess chronotropic response to exercise, each study
participant underwent treadmill exercise testing in an environmentally
controlled laboratory. All medications known to affect chronotropic
response to exercise were withdrawn at least 5 drug half-lives before
exercise testing (2 to 7 days for long-acting ß-adrenoceptor
antagonists), and subjects were studied in a 3-hour
postprandial state. A modified Bruce (Sheffield) treadmill exercise
protocol with standard 12-lead ECG monitoring (Quinton model Q5000) and
on-line, computerized expired breath-by-breath
CO2 and O2 monitoring
(Medgraphics Inc, model CPX-D) was used.17 18
Before exercise, an ECG was taken and arterial blood pressure (arm cuff), expired O2, and CO2 concentrations were measured. ECG and blood pressure measurements were obtained at 1-minute intervals from beginning of exercise until the patient was unable to exercise further (eg, due to fatigue or dyspnea). An ECG was recorded 30 seconds and 1 minute after exercise and every minute thereafter in the recovery period until heart rate returned to within 10% of basal levels or until 20 minutes had passed.
Measurement of Exercise Hemodynamic Parameters
Exercise heart rate response was characterized by the following
parameters: basal heart rate before exercise, heart rate at
each minute of exercise, heart rate at anaerobic threshold,
peak heart rate, and heart rate in recovery at 5 minutes after exercise
cessation. Additionally, heart rate was indexed to the predicted heart
rate on the basis of the age of the donor heart (from standard tables;
see Reference 17 ).
Assessment of Metabolic Parameters
Peak oxygen uptake (maximal oxygen consumption;
VO2max) was defined as the average value
obtained during the last 30 seconds of exercise. Anaerobic
threshold was determined noninvasively by 2 independent
investigators.18 Values for anaerobic
threshold determined by each observer varied by <10% in any patient.
Anaerobic threshold and exercise time at which
anaerobic threshold occurred were assessed by an average of
determinations from 2 observers.
Assessment of Humoral Catecholamine Response to
Exercise
In a subgroup of patients from each group, plasma
norepinephrine and epinephrine concentrations in a
peripheral arm vein were measured before exercise and at
peak exercise.19
Statistical Analysis
All data are presented as mean±SEM. Differences between
group means were assessed with ANOVA (Statview 4). A value of
P
0.05 was considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Sympathetic Reinnervation of Sinus Node
None of the 13 early transplant recipients had a significant increase in heat rate after tyramine injection (mean change, 1.6±0.3 bpm; range, 0 to 4 bpm), which indicated denervation (Figure 1
). Average increase in heart rate in
late transplant survivors was 12.5±2.0 bpm (range, -3 to 52 bpm). No
significant heart rate response to tyramine (<5-bpm heart rate change)
was found in 12 late transplant recipients, a small-moderate response
(5- to 14-bpm increase) was found in 5, and a marked (15 bpm)
increase was found in 11.
|
Exercise Hemodynamics and Effects of
Reinnervation
Heart Rate
Basal heart rate was higher in early and late transplant
recipients than in normal control subjects (Table 1). During exercise, heart rate in normal
subjects rose from 76±3 to 90±3 bpm within the first 2 minutes of
exercise. Thereafter, heart rate rose progressively, to 151±3 bpm at
anaerobic threshold and 178±4 bpm at the end of exercise.
After cessation of exercise, heart rate fell immediately in all
patients and was 64±3% of the peak heart rate by 5 minutes into the
recovery period.
|
In early transplant recipients, heart rate failed to rise significantly
in the first 2 minutes of exercise (88±3 bpm at rest and 92±3 bpm at
2 minutes), rose slowly to 109±4 bpm at anaerobic
threshold, and peaked at a lower heart rate at end of exercise (129±3
bpm; Table 1
). In 13 of 13 patients, heart rate continued to
rise after exercise, peaking an average of 1.8±0.3 minutes into the
recovery period. Unlike normal subjects, heart rate 5 minutes after
exercise was still 94±1% of the peak heart rate.
In persistently denervated late transplant recipients, heart rate also
was elevated at rest, failed to rise significantly in the first 2
minutes of exercise (85±3 bpm at rest and 90±3 bpm at 2 minutes;
Figure 2) and peaked at a lower heart
rate at end of exercise (126±5 bpm; Figure 3). In 10 of 12 patients, heart rate
continued to rise after exercise and peaked an average of 0.9±0.2
minutes into the recovery period. Heart rate 5 minutes into recovery
period was still 91±4% of peak heart rate.
|
|
In patients with mild-moderate sympathetic reinnervation of the sinus
node, basal heart rate was elevated compared with normally
innervated subjects (Table 1) and also rose little
within the first 2 minutes of exercise (94±4 bpm at rest and 101±6
bpm at 2 minutes). However, heart rates at anaerobic
threshold (121±9 bpm; Figures 4 and 5) and at peak exercise (142±7 bpm) were
significantly higher than observed in early or persistently denervated
late transplant recipients. Heart rate peaked at end of exercise in 3
of 5 patients, and mean time of peak heart rate was 0.7±0.4
minutes after cessation of exercise. Heart rate 5 minutes into the
recovery period (87±3% of peak heart rate) was significantly lower
than that found in early and denervated late transplant recipients but
higher than in normal subjects (Figure 6).
|
|
|
In markedly reinnervated transplant recipients, basal heart rate also was elevated and rose little in the first 2 minutes of exercise (87±3 bpm at rest and 96±3 bpm at 2 minutes). However, heart rates at anaerobic threshold (120±3 bpm) and peak exercise (141±2) were significantly higher than in early transplant recipients and late, persistently denervated transplanted patients. In only 3 of 11 patients did heart rate continue to rise after cessation of exercise and the mean time of peak heart rate was only 0.3±0.1 minutes after stopping exercise. Five minutes after exercise was stopped, heart rate had fallen to 80±2% of the peak rate (P<0.01 versus early and late denervated transplant recipients).
Blood Pressure
Diastolic blood pressure during basal conditions was
slightly higher in transplant recipients (all groups) than in normal
control patients (Table 2). In all
groups, diastolic blood pressure fell during exercise.
Systolic blood pressure at anaerobic threshold and
peak exercise increased more in normally innervated control
patients and in those with marked transplant reinnervation than in
early and late denervated transplant recipients.
|
Exercise Duration, Anaerobic Threshold, and Maximal
Oxygen Consumption
Basal oxygen consumption was similar in all groups (Table 3). Compared with healthy normal
subjects, transplantation was associated with a marked reduction in
exercise duration and VO2max, and this was
dependent on neither time elapsed since transplantation nor indices of
sinus node reinnervation (Figure 7).
Similarly, anaerobic threshold was reduced in both early
and late transplant recipients, without respect to indices of
reinnervation (although a trend occurred for greater
O2max in the markedly
reinnervated group).
|
|
Humoral Catecholamine Response to Exercise
Venous plasma norepinephrine and epinephrine
concentration at rest and peak exercise were similar in all groups.
Norepinephrine concentrations in early transplant
recipients and persistently denervated patients were 669±167 and
648±108 pg/mL and rose at peak exercise by 1846±937 and 1826±391
pg/mL, respectively. In mild-moderately and markedly
reinnervated patients, basal norepinephrine
concentrations of 850±245 and 590±110 pg/mL rose at peak exercise by
2675±748 and 1972±114 pg/mL, respectively. In normal subjects, basal
norepinephrine concentration was 544±44 pg/mL and rose by
2520±484 pg/mL by peak exercise.
Transplant recipients had reduced basal plasma epinephrine concentration (early transplant recipients, 9±8 pg/mL; late denervated patients, 24±15 pg/mL; mild-moderately reinnervated patients, 18±9 pg/mL; and markedly reinnervated patients, 26±8 pg/mL) compared with normal subjects (67±19 pg/mL; P<0.02). At peak exercise, plasma epinephrine concentration rose similarly in all transplant recipient groups (an increase of 61±51 pg/mL in early transplant recipients, 159±29 pg/mL in late denervated patients, 307±161 pg/mL in mild-moderately reinnervated patients, and 101±40 pg/mL in markedly reinnervated patients). In contrast, plasma epinephrine rose more in normal subjects (+504±161 pg/mL) than in late reinnervated transplant patients (P<0.05).
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The present studies show that sympathetic reinnervation of the sinus node after transplantation is accompanied by partial restoration of normal heart rate response to exercise and that degree of the normalization is related to extent of reinnervation (as detected by heart rate response to intracoronary tyramine). In patients with reinnervation, heart rate increased more, peaked near end of exercise, and after exercise fell more rapidly than in denervated patients. Duration of exercise and
O2max was not affected
significantly, although a trend existed for marked reinnervation to be
accompanied by longer exercise duration and higher
O2 at
anaerobic threshold and end of exercise.
Limitations
Rate of sinus node depolarization is controlled by a number of
factors other than sympathetic innervation. Circulating
catecholamines modulate heart rate. However, in the
subgroup of patients in whom plasma norepinephrine and
epinephrine concentrations during exercise were measured, we
found no difference between transplantation groups. Moreover, an excess
in humoral catecholamine response should be associated with
delayed heart rate peak and fall after exercise, the opposite of the
findings in reinnervated transplant recipients.
Within the heart, a small intrinsic nervous system (ie, ganglia and postganglionic fibers) exists that is primarily cholinergic, although it may also contain a small amount of catecholamine transmitters.1 20 Although it is possible that intracoronary tyramine elicited heart rate increases because of intracardiac neuronal release, absence of a tyramine-induced heart rate increase within the first 6 months after transplantation suggests that its effects were minimal. Moreover, in a previous in vivo study of transplanted human hearts, we showed that sustained handgrip by the recipient elicited intracardiac norepinephrine release, a reflex action that required an intact sympathetic connection between at least the spinal cord of the recipient and the donor heart.7
Heart rate response to exercise may also be affected by intrinsic sinus node disease, which can occur in late transplant recipients. Sinus node dysfunction would hide the effects of reinnervation on heart rate because its incidence might increase with time concurrently with reinnervation. However, progressive sympathetic reinnervation could protect somewhat against progressive effects of intrinsic sinus node disease.
In the present study, we did not assess vagal reinnervation of the sinus node, which, if present, might have altered heart rate response to exercise. Several factors argue against significant vagal reinnervation.21 22 Additionally, resting heart rate in the patients presented in the present study was similar in sympathetically reinnervated and persistently denervated patients, and heart rate did not rise importantly in the first 2 minutes of exercise (the usual timing of heart rate increase due to vagal withdrawal) in either group.2 3
The finding that reinnervation was not associated with a significant rise in exercise duration is not surprising, because total exercise time is related to a number of factors not influenced by cardiac reinnervation, such as steroid myopathy, progressive osteopenia, or peripheral vascular disease. Additionally, cardiac output during exercise is influenced profoundly by diastolic ventricular compliance, which can be reduced after transplantation.
Because the duration of exercise varied between patients, the sympathetic stimulus also could have been different. A variable sympathetic stimulus should make discernment of the effects of reinnervation on heart rate more difficult. We attempted to circumvent this problem by comparing the heart rate at similar relative metabolic activity levels (ie, anaerobic threshold).
Finally, effects of sympathetic reinnervation on exercise-induced heart rate increases may be exaggerated because of synaptic hypersensitivity.23 24 25 26 If some form of ß-adrenergic hypersensitivity is present, the physiological response to neurotransmitter release from a meager number of reinnervating fibers might be amplified significantly.
Comparison to Prior Work
After the initial transplantation experience in humans, many
investigators concluded that sympathetic reinnervation of the sinus
node did not occur.5 27 Additionally, a recent study
failed to show differences in chronotropic response to exercise over
time in transplant recipients.28 Two factors might account
for differences between the present study and those reported
previously. First, our patients were studied 5 years after
transplantation, whereas many previous reports included only patients
encountered within the first 2 years of surgery. Because reinnervation
is time dependent, our patients may have had greater reinnervation.
A second difference is that the previous inability to distinguish between patients with sinus node reinnervation and those without may have reduced the detection of this phenomenon that does not occur uniformly after transplantation. Concurrent development of sinus node dysfunction further hampers interpretation of chronotropic responses in individual patients. Third, closer examination of heart rate changes during exercise in individual patients reported previously suggests that some patients exhibited heart rate responses more typical of subjects with normal sympathetic innervation (peak heart rate at end of exercise and rapid fall thereafter).5 Given the results of the present study, it is possible that more-detailed physiological studies in those patients might have confirmed sympathetic reinnervation.
Implications
The principal implication of the present study is that
reinnervation of the sinus node causes a partial return of the normal
physiological response to exercise but the
magnitude of the effect is variable. In some patients,
near–normalization occurred of the sympathetically mediated heart rate
response to exercise, whereas in others, response was meager or
nonexistent. Many patients with marked reinnervation described the
return of a normal startle response characterized by sudden rapid
pounding of their heart immediately after a frightful event (eg, in
response to a car pulling out in front of the patient while he or she
was driving).
Finally, studies assessing the effects of the sympathetic nervous system on heart rate should not presume that the sinus node is denervated or that there is uniform reinnervation after transplantation. Compelling evidence now exists for limited sinus node sympathetic reinnervation, and the present study demonstrates that the phenomenon has physiological importance.
|
Acknowledgments |
|---|
The authors express thanks to the faculty and staff of the Cardiac Catheterization Laboratory of the University of Minnesota for their invaluable assistance in determining sinus node reinnervation by tyramine challenge.
|
Footnotes |
|---|
1 Dr Haidet died on April 9, 1999.
Received August 23, 1999; revision received December 7, 1999; accepted January 3, 2000.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
-
Stotler WA, McMahon T. The innervation and
structure of the conductive system of the human heart. J
Comp Neurol. 1947;87:57–83.
-
Hammond HK, Froelicher VF. Normal and abnormal heart
rate responses to exercise. Prog Cardiovasc Dis. 1985;27:271–296.[Medline]
[Order article via Infotrieve]
-
Detrano R, Froelicher VF. Exercise testing: uses and
limitations considering recent studies. Prog Cardiovasc Dis. 1988;31:173–204.[Medline]
[Order article via Infotrieve]
-
Cooper T, Willman VL, Jellinek M, et
al. Heart autotransplantation: effect on myocardial
catecholamine and histamine. Science. 1962;13:40–41.
-
Stinson EB, Griepp RB, Schroeder JS, et al.
Hemodynamic observations one and two years after
cardiac transplantation in man. Circulation. 1972;45:1183–1194.
[Abstract/Free Full Text]
-
Kaye MP, Randall WC, Hageman GR, et al. Chronology and
mode of reinnervation of the surgically denervated canine heart:
functional and chemical correlates. Am J Physiol. 1977;233:H431–H437.
-
Wilson RF, Christensen BV, Simon A, et al. Evidence
for structural sympathetic reinnervation after human orthotopic cardiac
transplantation. Circulation. 1991;83:1210–1220.
[Abstract/Free Full Text]
-
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.
-
De Marco T, Dae M, Yuen-Green MSF, et al. Iodine-123
metaiodobenzylguanidine scintigraphic
assessment of the transplanted human heart: evidence for late
reinnervation. J Am Coll Cardiol. 1995;927–931.
-
von Euler US, Lishajko F. Effect of directly and
indirectly acting sympathomimetic amines on adrenergic transmitter
granules. Acta Physiol Scand. 1968;73:78–92.[Medline]
[Order article via Infotrieve]
-
Burke MN, McGinn AL, Homans DC, et al. Evidence for
functional sympathetic reinnervation of the left ventricle and
coronary arteries after orthotopic cardiac transplantation in
humans. Circulation. 1995;91:72–78.
[Abstract/Free Full Text]
-
Wilson RF, Laxson DL, Christensen BV, et al. Regional
differences in sympathetic reinnervation after human orthotopic cardiac
transplantation. Circulation. 1993;88:165–171.
[Abstract/Free Full Text]
-
Ramaekers D, Ector H, VanHaecke J, et al. Heart rate
variability after cardiac transplantation in humans. Pacing Clin
Electrophysiol. 1996;19:2112–2118.[Medline]
[Order article via Infotrieve]
-
Scott CD, Dark JH, McComb JM. Evolution of the
chronotropic response to exercise after cardiac transplantation.
Am J Cardiol. 1995;76:1292–1296.[Medline]
[Order article via Infotrieve]
-
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]
-
Olivari MT, Homans DC, Wilson RF, et al.
Coronary artery disease in cardiac transplant patients
receiving triple-drug immunosuppressive therapy.
Circulation. 1989;80:111–115.
-
Sheffield LT. Graded exercise test (GTX) for
ischemic heart disease. In: Exercise Testing and Training
of Apparently Healthy Individuals: A Handbook for Physicians.
Dallas, Tex: American Heart Association Committee on Exercise;
1972:35S–38S.
-
Bruce RA, Kusumi F, Hosmer D. Maximal oxygen intake and
normographic assessment of functional aerobic impairment. Am
Heart J. 1973;85:546–562.[Medline]
[Order article via Infotrieve]
-
Passon PG, Peuler JD. A simplified radiometric assay
for plasma norepinephrine and epinephrine.
Anal Biochem.. 1973;51:618–631.[Medline]
[Order article via Infotrieve]
-
Ellison JP, Hibbs RG. An ultrastructural study of
mammalian cardiac ganglia. J Mol Cell Cardiol. 1976;8:88–101.
-
Morgan-Hughes NJ, Kenny RA, Scott CD, et al.
Vasodepressor reactions after orthotopic cardiac transplantation:
relationship to reinnervation status. Clin Auton Res. 1994;4:125–129.[Medline]
[Order article via Infotrieve]
-
Arrowood JA, Goudreau E, Minisi AJ, et al. Evidence
against reinnervation of cardiac vagal afferents after human orthotopic
cardiac transplantation. Circulation. 1995;92:402–408.
[Abstract/Free Full Text]
-
Vatner DE, Lavallee M, Amano J, et al. Mechanisms of
supersensitivity in the chronically denervated heart of the conscious
dog. Circ Res. 1985;57:55–64.
[Abstract/Free Full Text]
-
Yusuf S, Theodoropoulos S, Mathias CJ, et al. Increased
sensitivity of the denervated transplanted human heart to isoprenaline
both before and after ß-adrenergic blockade.
Circulation. 1987;75:606–704.
-
Denniss AR, Marsh JD, Quigg RJ, et al.
ß-adrenergic receptor number and adenylate cyclase
function in denervated transplanted and cardiomyopathic
human hearts. Circulation. 1989;79:1028–1034.
[Abstract/Free Full Text]
-
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/Free Full Text]
-
Pope SE, Stinson EB, Daughters GT, et al. Exercise
response of the denervated heart in long-term cardiac transplant
recipients. Am J Cardiol. 1980;46:213–218.[Medline]
[Order article via Infotrieve]
-
Givertz MM, Hartley LH, Colucci WS. Long-term
sequential changes in exercise capacity and chronotropic responsiveness
after cardiac transplantation. Circulation. 1997;96:232–237.
[Abstract/Free Full Text]
This article has been cited by other articles:
 |
|
 |
|
  M. Mabuchi, M. Imamura, N. Kubo, K. Morita, K. Noriyasu, T. Tsukamoto, K. Yasuda, and N. Tamaki Sympathetic Denervation and Reinnervation After the Maze Procedure J. Nucl. Med., July 1, 2005; 46(7): 1089 - 1094. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. M. Bengel, P. Ueberfuhr, J. Karja, K. Schreiber, S. G. Nekolla, B. Reichart, and M. Schwaiger Sympathetic reinnervation, exercise performance and effects of {beta}-adrenergic blockade in cardiac transplant recipients Eur. Heart J., October 1, 2004; 25(19): 1726 - 1733. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. Lovric, V. Avbelj, R. Trobec, D. Zorman, P. Rakovec, S. Hojker, B. Gersak, and M. Milcinski Sympathetic reinnervation after heart transplantation, assessed by iodine-123 metaiodobenzylguanidine imaging, and heart rate variability Eur. J. Cardiothorac. Surg., October 1, 2004; 26(4): 736 - 741. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. M. Bengel, P. Ueberfuhr, T. Hesse, N. Schiepel, S. I. Ziegler, S. Scholz, S. G. Nekolla, B. Reichart, and M. Schwaiger Clinical Determinants of Ventricular Sympathetic Reinnervation After Orthotopic Heart Transplantation Circulation, August 13, 2002; 106(7): 831 - 835. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. van de Borne, J. Neubauer, M. Rahnama, J.-L. Jansens, N. Montano, A. Porta, V. K. Somers, and J. P. Degaute Differential Characteristics of Neural Circulatory Control: Early Versus Late After Cardiac Transplantation Circulation, October 9, 2001; 104(15): 1809 - 1813. [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]
|
|
|
|
 |
|
 D. J. Christini, J. Walden, and J. M. Edelberg Direct biologically based biosensing of dynamic physiological function Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2006 - H2010. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. M. Bengel, P. Ueberfuhr, N. Schiepel, S. G. Nekolla, B. Reichart, and M. Schwaiger Myocardial Efficiency and Sympathetic Reinnervation After Orthotopic Heart Transplantation : A Noninvasive Study With Positron Emission Tomography Circulation, April 10, 2001; 103(14): 1881 - 1886. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||