(Circulation. 2000;102:2732.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Abnormal Cardiac Autonomic Nervous Activity After Right Ventricular Outflow Tract Reconstruction
From the Department of Pediatrics, National Cardiovascular Center, Osaka, Japan.
Correspondence to Hideo Ohuchi, MD, Department of Pediatrics, National Cardiovascular Center, 5-7-1, Fujishiro-dai, Suita, Osaka 565-8565, Japan.
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Abstract |
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Background—There are few studies of cardiac autonomic nervous activity (CANA) in patients with congenital heart disease.
Methods and Results—We
evaluated CANA in 54 patients after closure of an atrial/ventricular
septal defect (group A), 54 patients after successful right ventricular
outflow tract reconstruction (RVOTR) (group B1), 35 RVOTR patients with
residual stenosis (group B2), and 47 controls. Cardiac parasympathetic
nervous activity (PSNA) was estimated by heart rate (HR) change after
cholinergic blockade, HR variability, and arterial baroreflex
sensitivity (BRS). Cardiac sympathetic nervous activity was estimated
by the heart-to-mediastinum
123I-metaiodobenzylguanidine activity ratio
(H/M) and HR increase after isoproterenol infusion (ß). HR response
(
HR) and peak oxygen uptake
(
O2) were
measured by exercise test. There was no difference in ß among study
groups. Group A exhibited mildly impaired PSNA, which recovered 1 year
after surgery, and no change in H/M. Impaired PSNA and low H/M were
found in groups B1 and B2 compared with controls
(P<0.001), although the PSNA tended to recover 1 year
after re-RVOTR. In group B1, PSNA and ß were related to HR, and
BRS correlated inversely with the number of surgical procedures and age
at RVOTR and positively correlated with the follow-up period, whereas
HR correlated with peak
O2
(P<0.01 to 0.001).
Conclusions—After
RVOTR, postsynaptic ß-sensitivity is maintained and is important in
HR during exercise, as is PSNA, although ventricular sympathetic
denervation is common. Impaired PSNA immediately after RVOTR improves
with improved HR and results in future amelioration of aerobic
capacity, whereas ventricular sympathetic reinnervation is
uncertain.
Key Words: heart defects, congenital • nervous system, autonomic • exercise • heart rate • surgery
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Introduction |
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The blunted heart rate (HR) response during exercise in patients with congenital heart disease (CHD), especially those with complex CHD, is well demonstrated.1 2 3 4 Because the cardiac autonomic nervous system regulates HR,5 it is predictable that cardiac autonomic nervous activity (CANA) is abnormal in patients with CHD after definitive surgery. It is not known how much the sympathetic (SNA) and parasympathetic (PSNA) nervous activity are impaired and whether reinnervation occurs. Therefore, the purpose of our present study was as follows: (1) to evaluate PSNA and SNA in patients who have undergone right ventricular outflow tract reconstruction (RVOTR), which is a common procedure to correct CHD, and to compare the results with patients undergoing atrial or ventricular septal defect repair and with control subjects; (2) to investigate the relationships between CANA and clinical profiles, such as surgical procedure and HR response during exercise; and (3) to investigate the influence of surgery on both PSNA and SNA in these patients.
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Methods |
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Subjects in the Cross-Sectional Study
No patients were receiving inotropic, chronotropic, or antiarrhythmic medications. We studied 142 patients, who were divided into 4 groups. Group A consisted of 54 patients, 38 of whom had undergone closure of an atrial septal defect (ASD) and 16 of whom had closure of a ventricular septal defect (VSD). Group B1 consisted of 54 patients after RVOTR with no significant residual right ventricular outflow (pulmonary) stenosis. Group B2 consisted of 35 patients after RVOTR with significant residual pulmonary stenosis. Patients with a pressure gradient >30 mm Hg during cardiac catheterization or a transpulmonary valve flow velocity >3.0 m/s on Doppler echocardiography were included in this group. Group C, the controls, consisted of 47 patients with a history of Kawasaki disease but no stenotic coronary arterial lesions. None of the controls had abnormal findings on physical examination, chest radiograph, ECG, 2D echocardiogram, or treadmill exercise test. In the CHD groups, the follow-up period from the last operation to the time of study was
1
year. Antiplatelet agent was given to 3 patients in group B1.
(See
Table 1
.)
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Subjects in the Longitudinal Study
We investigated the change in CANA in 31 group A
patients (group X, age 14.3±6.1 years; ASD=28, VSD=3) and 19 group B2
patients (group Y, age 13.2±3.8 years; tetralogy of Fallot=8,
others=11). CANA was measured before (n=50) and 1 month (n=50) and 1
year (n=41) after the last definitive operation. In group X, ASD or VSD
closure was performed, whereas all group Y patients underwent re-RVOTR
because of progressive severe stenosis of the right ventricular outflow
tract.
Subgroup Analysis
To further investigate the influence of RVOTR on
CANA, we investigated 62 patients in groups B1 and B2 (group Z) who had
undergone 1 definitive RVOTR without re-RVOTR (age 14.3±3.7 years; age
at RVOTR 4.9±3.7 years; follow-up 9.6±3.6
years).
Cardiac Catheterization
Cardiac catheterization was performed in 102 CHD
patients and 41 controls. Parameters determined included central venous
and systolic right ventricular pressures, ejection fraction of the
right and left ventricles measured by cineventriculography, and cardiac
output by the Fick principle.
Measurement of Norepinephrine
and Natriuretic Peptides
An indwelling angiocatheter was inserted into the
antecubital vein for sampling. After 10 minutes’ rest, the plasma
norepinephrine (NE) level was determined by high-performance liquid
chromatography.6 The
plasma levels of atrial (ANP) and brain (BNP) natriuretic peptides were
assayed by
radioimmunoassay7 8
to evaluate the severity of hemodynamic impairment. ANP and BNP are
sensitive markers of failing ventricular pump
function.9
Measurement of HR Variability and
Arterial Baroreflex Sensitivity
Methodology for measuring HR variability (HRV)
and baroreflex sensitivity (BRS) was identical to that reported
previously.10 After
a 10-minute supine rest, ECG signals were recorded for an additional 5
minutes at a rate of 1000 samples per second. Beat-to-beat fluctuations
were transformed into frequency domains by a fast Fourier
transformation. Spectral HRV was expressed as a low-frequency (LF)
component at 0.04 to 0.15 Hz and a high-frequency (HF) component at
0.15 to 0.40 Hz, and the logarithmic values of the frequency
components, log LF and log HF, were
used.11 When
premature contractions were detected, removal of ectopy was
performed.12 After
HRV was measured, the bolus phenylephrine (1 to 4 µg/kg) injection
method was used to measure
BRS.10 ECG, arterial
blood pressure (by Finapres, Ohmeda), and respiration (by impedance
device) were recorded continuously on a multichannel recorder at a
speed of 100 mm/s until peak blood pressure was reached. The R-R
intervals obtained during expiration were plotted against the systolic
blood pressures of the preceding beats on a beat-to-beat basis. A
linear fit was performed to establish the linear portion of the line of
best fit. Only regression lines that were statistically significant
(P<0.05) were accepted for analysis. The final slope
(BRS)13 was obtained
by calculating the mean value of 2 measurements
(ms/mm Hg).
[123I]Metaiodobenzylguanidine
Scintigraphy
Metaiodobenzylguanidine (MIBG) scintigraphy was
performed in 81 CHD patients and 14 controls to evaluate myocardial
adrenergic nervous activity. There were no definitive criteria for
subject selection, but all patients did not undergo this scintigraphy
owing to the capacity of our laboratory. Seventy-four to 148 MBq of
MIBG was injected, and myocardial images were acquired with a
standard-field gamma camera equipped with a low-energy, parallel-hole
collimator. Static planar imaging was performed 15 minutes and 4 hours
after tracer injection, and to evaluate the myocardial accumulation of
MIBG, the heart-to–mediastinal activity ratio (H/M) was calculated.
Because MIBG is an analogue of NE and shares its uptake and storage
mechanisms, decreased MIBG uptake (low H/M) suggests decreased
sympathetic innervation, and it has been demonstrated in patients with
heart failure14 and
denervation caused by ischemia. Division of the cardiac sympathetic
nerves results in a low H/M, as occurs after cardiac
transplantation.15
Determination of Cardiac
Parasympathetic Nervous Tone and Postsynaptic
ß-Sensitivity
In 66 patients with CHD and 11 controls, atropine
(0.04 mg/kg) was administered intravenously to determine the cardiac
parasympathetic nervous tone (PNT) not less than 3 hours
postprandially. After at least a 10-minute rest, baseline HR was taken
as the control value. HR was recorded continuously at 25 mm/s on a
strip chart recorder, and the HR 1 minute after a full-dose atropine
infusion was determined. PNT was defined as the change in HR after
complete cholinergic blockade by atropine. Two minutes after the
atropine infusion, a continuous infusion of isoproterenol was
administered at a rate of 3
µg·kg-1·min-1
for 6 minutes, and ß was defined as the increase in HR from 1 minute
after full-dose atropine infusion to 6 minutes after isoproterenol
continuous infusion. In principle, we performed this approach in
series. After that, to investigate the influence of basal SNA on
PNT, propranolol (0.2 mg/kg) with atropine (8 to 10 µg/kg) was
administered to determine intrinsic HR in 14 of 66 patients (group A,
n=4; B1, n=1; B2, n=8; and C, n=1). These pharmacological studies were
limited to hospitalized patients with relatively preserved ventricular
function and without significant
tachyarrhythmias.
Exercise Protocol
All subjects exercised to the end of their tolerance
on a motor-driven, programmable treadmill (Q-5000 system, Quinton)
using a 30-second incremental protocol described
previously.1 10 16
Endurance time (in minutes) and peak oxygen uptake
(O2,
mL·kg-1·min-1)
were measured.
A 12-lead ECG was recorded at rest and throughout exercise
and used to determine HR. Ventilation and gas exchange were measured by
a computerized breath-by-breath method. The subjects breathed through a
tight-fitting mask connected to a hot-wire anemometer (Riko AS500,
Minato Medical Science) to measure inspired and expired volume
continuously. A mass spectrometer (MG-300, Perkins Elmer) was used to
continuously measure O2 and
CO2 partial pressures. In the breath-by-breath
protocol, ventilatory equivalents for oxygen and carbon dioxide, as
well as respiratory gas exchange ratio, were computed in real time and
displayed with the HR and
O2 on a
monitor.
Change in HR from rest to peak exercise (HR) was
calculated.
Informed Consent
In CHD groups, after adequate explanation of the
purpose of the study and clinical significance (mentioned in the
clinical implication), informed consent was obtained from all subjects
and/or their parents. In controls who had performed MIBG scintigraphy
and pharmacological evaluation, we asked them and/or their parents to
take part in the present study as a volunteer, and we obtained consent
for 11 pharmacological and 14 MIBG scintigraphic evaluations. The study
protocol was approved by the ethics committee of the National
Cardiovascular Center.
Statistical Analysis
Differences in hemodynamic variables, parameters of
CANA, and cardiorespiratory variables during exercise were evaluated by
a factorial 1-way ANOVA with Scheffé’s procedure. Simple regression
analysis was used to determine correlations between HR response and
other parameters. Change in CANA after surgery was evaluated with a
paired t test or Wilcoxon signed rank test.
Correlation between number of surgical procedures and indices of CANA
was evaluated by Spearman rank correlation analysis. Univariate and
stepwise multivariate linear regression analyses were used to detect
independent indices affecting the change of CANA during follow-up. Data
are expressed as mean±SD. A P value of <0.05 was
considered statistically
significant.
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Results |
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Hemodynamic Variables and Natriuretic Peptides
All hemodynamic variables in groups B1 and B2, except right ventricular ejection fraction, were abnormal compared with those from groups A and C. A significant increase in systolic right ventricular pressure was observed in group B2, but no obstructive pulmonary arterial lesions were demonstrated (pulmonary arterial resistance <3.0 U/m2). Natriuretic peptides were significantly higher in CHD groups, which suggests the presence of mild heart failure. (See Table 1
.)
Cardiac Autonomic Nervous Activity
There was no difference in ß among the 4 groups (see
Table 2). In group A, HRV and BRS were significantly lower
than in controls, but the decrease was small compared with that in
groups B1 and B2. Other variables did not differ from those in
controls. In contrast, groups B1 and B2 exhibited extremely low values
of CANA, but the degree of pulmonary stenosis did not correlate with
any indices of CANA except ß (r=0.40,
P<0.05).
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Influence of the Number of Surgical Procedures,
Age at Time of RVOTR, and Follow-Up Period on CANA
In group Z, log LF, BRS, and PNT were significantly
higher in patients without prior palliative surgeries than in patients
with prior palliative surgeries (log LF, P<0.005;
BRS, P<0.0001; and PNT, P<0.005).
Although log HF and H/M tended to be higher in the former group than
the latter (log HF, P<0.07; H/M,
P<0.08), no difference in ß was observed between
the 2 groups. Log LF, BRS, and PNT correlated inversely with the
number of surgical procedures (P<0.05 to 0.0001; BRS
is shown in
Figure 1), whereas age at the time of RVOTR also inversely
correlated with log LF, BRS, and ß (P<0.05 to
0.01). BRS significantly correlated with the follow-up duration after
RVOTR (BRS, r=0.42, P=0.001;
Figure 2). However, no significant correlation was
demonstrated between H/M and follow-up duration
(Figure 3). Among these 3 factors, the number of surgical
procedures and age at the time of RVOTR were the independent indices of
BRS. However, no predictive indices for H/M were
determined.
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Change in CANA After Operation
In group X, log HF and BRS decreased 1 month after
definitive repair, but both values increased significantly 1 year after
surgery (P<0.001). BRS increased significantly
compared with its preoperative value, whereas no change in H/M was
observed. In group Y, log HF, BRS, and H/M decreased significantly 1
month after re-RVOTR (P<0.05 to 0.01). Log HF
increased significantly (P<0.05), and the value of
BRS tended to increase (P<0.1). H/M was unchanged 1
year after re-RVOTR compared with its value 1 month after surgery. (See
Table 3.)
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HR Response During Exercise and Exercise
Capacity
Because the gas exchange ratio at peak exercise
exceeded 1.00 in all patients, we are confident that all patients
performed near-maximal exercise. Endurance time and peak
O2 were
significantly lower than for controls in all CHD groups. HR was
significantly lower in any CHD group, especially B1 and B2, than in
controls. (See
Table 4.)
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Peak HR and HR correlated well with peak
O2 in group
B1
(Figure 4). However, no significant relationship was
demonstrated between HR and peak
O2 in groups
A and B2.
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Relationship Between CANA and HR
Response
All indices of CANA except H/M correlated with HR in
groups A and B1, whereas these correlations were weak in group B2.
PNT and ß correlated more closely with HR in group B1. (See
Table 5.)
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Influence of Basal SNA on PNT
PNT (27±17) was significantly greater than the
difference in HR between intrinsic HR and HR after full dose of
atropine (20±15, P<0.005), which is considered a
true PSNA, but correlation between the 2 variables was very
tight (r=0.92,
P<0.0001).
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Discussion |
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Our major findings are as follows. First, relatively severe sympathetic denervation of the ventricle is common after RVOTR, relating to the number of surgical procedures and not to ventricular function. Ventricular sympathetic reinnervation after RVOTR is uncertain. In addition, there is a small contribution of the sympathetic denervation to HR response during exercise. Second, with regard to the sinus node, ß is relatively maintained in the majority of these patients, whereas impaired PSNA immediately after surgery recovers 1 year later. Both ß and the recovery in PSNA are crucial to the HR response during exercise and are a major determinant of individual exercise capacity in these patients long after definitive RVOTR.
Abnormal CANA
Possible explanations for the sympathetic denervation
of the ventricle include ventricular
failure17 and/or
surgery-related damage. Because H/M did not correlate with NE,
natriuretic peptides, or ventricular function but correlated closely
with the number of surgical procedures, the latter explanation is more
likely. Surgical damage includes 2 factors: one is direct damage due to
transection and/or dissection, and the other is subclinical myocardial
damage, such as ischemia during cardiac surgery. Central sympathetic
and parasympathetic cardiopulmonary nerves pass along the posteromedial
surface of the superior vena cava, the right atrium, and both the
ascending aorta and main pulmonary artery. Many small nerves arise from
the cardiopulmonary plexuses and innervate the adjacent atria, aorta,
pulmonary artery, and pulmonary
veins.18
Consequently, removal of pericardium overlying the surface of the right
atrium and the superior vena cava during cardiac surgery must cause
abnormal CANA even in patients with an ASD or VSD. In addition to
vulnerability of the cardiac sympathetic nerves to
ischemia,19 direct
damage of CANA may be inevitable. Significant deterioration of PSNA
immediately after closure of an ASD or VSD, although it soon recovers,
supports this hypothesis. Because there is no change in H/M after
closure of an ASD or VSD, possibly the surgical technique used for
RVOTR and/or surgical time is responsible for sympathetic denervation
of the ventricle. Even in an initial RVOTR (although re-RVOTR in the
present study), extensive surgical manipulation, such as transection
and/or dissection of the main and branch pulmonary arteries, is
sometimes needed to repair stenosis of the right ventricular outflow
tract and is both time consuming and potentially traumatic to adjacent
innervation. Hence, significant sympathetic denervation must be
associated with re-RVOTR and probably also with first RVOTR. Our study
also supports this possibility, because a significant decrease in H/M
immediately after re-RVOTR was demonstrated. Finally, preoperative
hypoxia may be related to sympathetic denervation because of its
vulnerability to ischemia.
Although it is unclear whether abnormal CANA of the sinus node results from cardiac nerve denervation, well-maintained ß may be further proof that the major cause of abnormal CANA is cardiac nerve denervation, because a similar observation has been reported after cardiac transplantation.20 As shown in the ventricle, subclinical ischemia during cardiac surgery may cause abnormal CANA in the sinus node. In addition, the significant inverse correlation between age at the time of RVOTR and HRV, BRS, and ß suggests some influence of preoperative factors, including hypoxia, on postoperative CANA.
Reinnervation of Cardiac Autonomic
Nerves
Significant sympathetic reinnervation of the ventricle
was not shown in patients after 1-staged RVOTR. Possible sympathetic
reinnervation in infants after an arterial switch operation has been
demonstrated.4 The
higher age of our subjects compared with that study may explain the
different outcome. However, because some studies have demonstrated
sympathetic reinnervation in adults after cardiac
transplantation,21
it may be anticipated that sympathetic reinnervation occurs in patients
after RVOTR.
CANA of the sinus node followed a quite different course from that of the ventricle. In addition to well-maintained ß, PSNA improves, at least during the first year after closure of ASD or VSD. Abolition of the intracardiac shunt may improve PSNA in these patients. Even in patients after RVOTR, the present study demonstrated recovery in PSNA, and the significant positive correlation between BRS and the follow-up period also suggests further parasympathetic reinnervation long after RVOTR. Hemodynamic improvement could explain this, but this seems unlikely because the rate of sympathetic reinnervation is slow, as in the ventricle, even in cardiac transplant patients who enjoy a remarkable hemodynamic improvement. Parasympathetic reinnervation, along with sympathetic reinnervation, occurs in cardiac transplant patients22 ; therefore, the most likely mechanism for temporary deterioration with subsequent recovery of PSNA along with maintained ß may be surgery-related subclinical damage of the sinus node based on ischemia, rather than denervation as occurs in the ventricle. Accepting the evidence that nerves regenerate only if they are cut,23 the type of surgery used, ie, the extent to which the cardiac parasympathetic and/or sympathetic nerve fibers are cut, may also determine the degree of cardiac nerve reinnervation in these patients.
HR Response During Exercise and CANA
Impaired CANA is one of the serious consequences of
RVOTR because it is closely related to exercise capacity. We have
demonstrated, for the first time, the close relationship between ß
and HR response during exercise. Although the mechanism of impaired ß
is undetermined, downregulation of the
ß-receptor24 is
unlikely because ß did not correlate with NE. If cardiac
parasympathetic reinnervation occurs, late improved exercise capacity
may be expected in patients long after RVOTR. The weak relationship
between HR and CANA in group A is probably due to the smaller range
of peak O2,
ie, there were few patients with low aerobic
capacity.
Study Limitations
The present study is limited by the small number of
patients in the longitudinal study. Another important issue is the
method of evaluating CANA. Direct stimulation of the sympathetic nerves
of the sinus node and the ventricle with tyramine is
preferable,21 and a
future study investigating the correlation between indices obtained by
direct stimulation and those used in our study is needed. Because the
increase in HR after a full dose of atropine and propranolol strongly
correlates with PNT, we believe that basal SNA has no major influence
on the present results. PSNA may be somewhat underestimated by log
HF,25 because
patients who underwent several surgical procedures showed a restrictive
ventilatory impairment. In contrast, BRS may be a more valid approach
to estimate PSNA, because its value is uninfluenced by respiration, and
this reflex directly activates the cardiac parasympathetic
nerves26 and is
almost abolished by
atropine.27
Clinical Implication
When monitoring adults after RVOTR, in addition to the
greater contribution of CANA to exercise capacity, we should also be
aware that they may not complain of chest pain even if they develop
ischemic heart disease because of cardiac nerve denervation, as occurs
in patients after cardiac transplantation. This may apply to other
kinds of CHD, including patients after the arterial switch operation
and postoperative complex CHD. Another important and serious concern is
the relationship between arrhythmia and CANA. Arrhythmias have been
implicated in sudden cardiac death long after
RVOTR28 ; therefore,
further studies of life-threatening arrhythmias and their relationship
to CANA are
needed.
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Acknowledgments |
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We thank Drs Peter M. Olley, Professor of Pediatrics, University of Alberta, and Setsuko Olley for assistance in preparing the manuscript and also thank Dr Hiroshi Takaki, Department of Cardiovascular Dynamics, National Cardiovascular Center Research Institute, for data analysis of HRV.
Received April 7, 2000; revision received June 29, 2000; accepted July 16, 2000.
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Fallot repair: is it really as simple as measuring ECG intervals?
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