Download Global Impairment of Cardiac Autonomic Nervous

Global Impairment of Cardiac Autonomic Nervous Activity
Late After the Fontan Operation
Constantinos H. Davos, MD, PhD; Darrel P. Francis, MRCP; Marjolein F.E. Leenarts, MD;
Sing-Chien Yap, MD; Wei Li, MD, PhD; Periklis A. Davlouros, MD;
Roland Wensel, MD; Andrew J.S. Coats, DM; Massimo Piepoli, MD, PhD;
Narayanswami Sreeram, MD; Michael A. Gatzoulis, MD, PhD
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Background—Atrial tachyarrhythmia is a common cause of morbidity and mortality in patients with univentricular
physiology undergoing the Fontan operation. We examined cardiac autonomic nervous activity, a predictor of
arrhythmia and sudden death in other cardiovascular disease, in patients late after the Fontan operation, employing heart
rate variability (HRV) and baroreflex sensitivity.
Methods and Results—We measured HRV and baroreflex sensitivity in 22 consecutive patients (8 male, age 26⫾9 years)
who had undergone the Fontan operation 13⫾6 years previously, and 22 age- and sex-matched healthy controls. Fontan
patients had significantly lower HRV (P⬍0.0001). Baroreflex sensitivity was measured by the ␣-index method (square
root of ratio of RR interval spectral power to systolic blood pressure (SBP) spectral power, in the LF and the HF band)
and was also significantly depressed in the Fontan group (P⬍0.0001 for both). Both low frequency (LF) and high
frequency (HF) components of HRV were reduced in the Fontan patients (P⬍0.0001), but there was interindividual
variation so that the LF/(LF⫹HF) ratio may be high, normal, or low, and decreased with increasing right atrial
dimensions (r⫽⫺0.62, P⫽0.006). Patients with a history of sustained atrial arrhythmia had a stronger baroreflex than
those without (P⫽0.005).
Conclusions—Autonomic nervous control of the heart is markedly deranged in patients late after the Fontan operation, with
reduced HRV and baroreflex sensitivity. A relative suppression of the sympathetic– compared with the parasympathetic–
system was observed in patients with marked right atrial dilation within the Fontan group. Furthermore, stronger baroreflexes
were seen in Fontan patients in association with a higher incidence of sustained atrial tachyarrhythmia, implying that sinus
node dysfunction is unlikely to be the dominant mechanism. Additional studies are clearly required to examine the prognostic
importance of impaired BRS and HRV in these patients. (Circulation. 2003;108[suppl II]:II-180-II-185.)
Key Words: fontan procedure 䡲 nervous system autonomic 䡲 baroreceptors
䡲 heart rate/heart rate variability 䡲 arrhythmias
P
atients with congenital heart disease of univentricular
physiology palliated with the Fontan operation frequently
suffer late complications, with atrial tachyarrhytmias being
prominent among them.1–3 These arrhythmias are difficult to
manage, and may significantly compromise cardiac output
and lead to increased morbidity and mortality.4 – 8 The pathophysiology of atrial tachyarrhythmia in this setting is not fully
understood and may involve the increased right atrial pressure after the Fontan procedure.3,9 –13
Deranged cardiac autonomic nervous activity (CANA) is a
well-recognized feature in heart failure patients, without
congenital heart disease.14 The degree of derangement is
associated with increased burden of cardiovascular morbidity
including arrhythmias (and sudden cardiac death) in a variety
of clinical settings,15–19 increased mortality, and worse overall
prognosis in coronary artery disease and heart failure patients.
Limited data exist on CANA in adults with congenital heart
disease20,21 after surgical repair of tetralogy of Fallot, and
even less in patients with single ventricle physiology after the
Fontan operation, mostly in pediatric patients.22 The aim of
our prospective study was to assess several aspects of CANA
late after the Fontan procedure in older patients (primarily
adults) and examine its relationship with cardiac physiology
and clinical status.
Methods
Patients
Twenty-two (8 male) patients with previous Fontan operations were
recruited from the Adult Congenital Heart Clinic of the Royal
Brompton Hospital, London, UK following informed consent. Ex-
From the Royal Brompton Adult Congenital Heart Programme, and Department of Clinical Cardiology, Royal Brompton Hospital and National Heart
and Lung Institute, Imperial College School of Medicine, London, UK, and Department of Cardiology, Wilhelmina Children’s Hospital, Utrecht, The
Netherlands
Correspondence to Michael A. Gatzoulis, M.D., Ph.D., Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. Phone: 44-207-351-8602,
Fax 44-207-351-8629, E-mail [email protected]
© 2003 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/01.cir.0000087946.47069.cb
II-180
Davos et al.
TABLE 1.
Cardiac Autonomic Nervous Activity and Fontan Operation
Heart Rate Variability Indices Assessed in the Study
Time Domain
Indices
SDNN
Standard deviation of all normal-to-normal RR intervals
RMSSD
Square root of the mean squared differences of
successive RR intervals
pNN50
Per cent of differences of successive RR intervals ⬎50
ms
Triangular index
Integral of the density distribution dived by the maximum
of the density distribution
Frequency Domain
Indices
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Transthoracic Echocardiography
Transthoracic echocardiography was performed using a Philips
Sonos 5500 (Andover) echocardiograph with a 2.5-MHz tranducer.
Subjects were examined at rest in the semilateral decubitus position.
Right and left atrial (RA and LA) sizes were measured off-line in 2
planes, transverse and supero-inferior, by a single investigator (WL)
blinded to the other data. For patients with a total cavo-pulmonary
connection type of Fontan–all of them intracrdiac–right atrial measurements were made on the actual true, native right atrium and not
on the intra-atrial baffle. Because of the heterogeneity of cardiac
anatomy, we used a qualitative, subjective assessment of systemic
ventricular dysfunction from multiview 2-dimentional echocardiography, graded from I to IV: I (absent), II (mild), III (moderate), and
IV (severe) as described previously.25 Atrio-ventricular valve regurgitation was also graded on a scale from I (absent) to IV (severe).
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VLF
Very low frequency (0.0033–0.04 Hz)
Statistical Analysis
LF
Low frequency (0.04–0.15 Hz)
HF
High frequency (0.15–0.4 Hz)
Data were expressed as frequency for the nominal variables and as
mean ⫾ SD for continuous variables. HRV and BRS indices with
skewed distributions were log transformed. Data were analyzed by
using Statview 5.0 (Abacus Concepts, SAS Institute). Differences
between the control and the patient subgroups were assessed by an
unpaired Student t test or by the Mann-Whitney rank-sum for data
that failed tests of normality. Variables that did not follow the normal
distribution were logarithmically transformed. Univariate and multivariate linear regression was used for determination of independent
predictors of the assessed variables. All of the tests were two-sided.
A probability value ⬍0.05 was considered significant.
clusion criteria included diabetes mellitus, permanent atrial arrhythmia, or ⬎2 ventricular ectopic beats per min during data acquisition,
the presence of a permanent pacemaker and clinical instability within
the preceding 3 months. Surgical details were obtained from operative notes. The patient symptomatic status was defined according to
the New York Heart Association (NYHA) functional classification.
Sustained arrhythmia was defined as arrhythmia that was clinically
apparent and was documented by ECG, a Holter recording, or ECG
strips before electrical cardioversion. Twenty-two age- and sexmatched normal controls, who had no significant past medical
history, no abnormalities on examination, and were not taking
regular medication, were also studied.
Measurements
Patients were studied between 13:00 and 17:00 hour under standardized conditions, in a quiet room at a comfortable temperature. All
were fasted for at least 2 hours before testing and were not allowed
to smoke or drink alcohol- or caffeine-containing beverages for 24
hours before the study. All of the subjects rested supine for 15
minutes and then underwent 1 successive 20-minute recording at
rest.23 During this investigation, RR interval and blood pressure (BP)
were recorded. BP was measured by a Finapres device (model 2300;
Ohmeda), with the cuffed finger resting comfortably at the level of
the heart. The Finapres cuff was wrapped around the index finger of
the left hand. The subjects underwent several minutes of accustomisation to the Finapres, and the servo-adjust mechanism was turned
off before recording. The ECG was acquired from the limb lead with
the largest R wave (typically lead II). All of the data were sampled
at 1000 Hz on a computer using an analogue-to-digital converter
(National Instruments). The readings were saved into floppy disk and
analyzed off-line with custom designed software. The program
measured RR intervals and beat-to-beat systolic pressure while
ectopic beats were corrected by linear interpolation.23
HRV
HRV analysis was made on the 20-minute ECG recordings, and time
domain and frequency domain indexes were calculated (Table 1)
using our laboratory software.24
Baroreceptor Sensitivity
For the BRS assessment, we measured the average amplitude of
oscillations in RR interval and the average amplitude of oscillations
in SBP. Power spectral analysis was performed on the RR interval
and SBP data using an autoregressive algorithm. The ␣-index was
calculated as the square root of the ratio between RR and SBP
spectral power in the low frequency (0.04 – 0.15 Hz, ␣LF) and the
high frequency (0.04 – 0.15 Hz, ␣HF) band in the presence of an
adequate coherence (⬎0.5) between the RR interval and SBP as
assessed by cross-spectral analysis.24
Results
Patient Characteristics
Patient clinical and surgical characteristics are shown in
Table 2, their current medication in Table 3, and their
echocardiographic profile in Table 4. Ninety-one percent of
patients were in NYHA class I-II, whereas 14 (64%) patients
had a prior history of sustained atrial tachyarrhythmia.
HRV
All of the HRV indices in Fontan patients were significantly
reduced, compared with controls (Table 5 and Figure 1). The
time domain indices (SDNN, RMSSD, pNN50, and Triangular Index) were all reduced by at least 50%. Both LF and HF
were about three-fold reduced in Fontan patients, compared
with healthy controls. However, the mean relative balance of
LF and HF [expressed as LF/(LF⫹HF)] was not different
between Fontan patients and controls. There was a large
inter-individual variation so that the ratio of LF/(LF⫹HF)
could be high, normal, or low. Furthermore, there was a
negative correlation between the LF/(LF⫹HF) ratio and right
atrial transverse dimensions (r⫽⫺0.62, P⫽0.007, Figure 2)
and a borderline correlation with right atrial supero-inferior
dimensions (r⫽⫺0.46, P⫽0.05).
BRS
BRS in the Fontan patients was also markedly reduced (Table 5
and Figure 3). Fontan patients with a previous history of
sustained atrial tacharrhythmia in particular had a stronger
baroreflex (n⫽14, log aLF 0.83, log aHF 0.97) than the
remainder of Fontan patients (n⫽8, log aLF 0.36, log aHF 0.54,
P⫽0.01 and P⫽0.005, respectively). In contrast to HRV, BRS
was not related to any of the echocardiographic measurements.
There were no correlations between number of pre-Fontan
palliations and their type, years from palliation to Fontan completion, age at Fontan completion, years from Fontan completion
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September 9, 2003
TABLE 2. Clinical and surgical characteristics: Fontan Patients and
Healthy Controls
Fontan
Patients
Range
n
Controls
Range
n
Age, years
26.2⫾9.6
12.0–43.5
22
29.5⫾7.8
18.3–48.1
22
Female
26.3⫾10.6
12.0–43.5
14
30.6⫾8.2
18.3–47.1
14
Male
26.2⫾8.2
17.3–38.9
8
27.6⫾7.2
18.7–39.0
8
Variable
Tricuspid atresia
12* (54.5%)
Double inlet ventricle
5 (22.7%)
Atrial isomerism
2 (9.1%)
Pulmonary atresia/Intact septum
1 (4.5%)
Other
2 (9.1%)
Time after Fontan, years
13.1⫾5.7
4.8–24.1
Age at Fontan, years
13.2⫾8.1
1.8–28.9
Previous Palliations
18 (81.8%)
Blalock-Taussing shunt(s)
13** (72%)
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Glenn
2 (11%)
PA banding
1 (6%)
Other arterio-pulmonary shunt(s)
2 (11%)
Days from birth to 1st palliation
823⫾1510
1–6345
Years remained palliated
10.2⫾6.0
1.6–27.8
APC
10 (45.5%)
AVA
4 (18.2%)
TCPC
8 (36.3%)
Fontan revisions
4 (18.2%)
NYHA class
I
45.5%
II
45.5%
III
9%
%O2 saturation at rest
94.9⫾4.1
History of sustained atrial
tachyarrhythmia
14 (64%)
84–100
Mean values or frequency and percentages in ().
*Including 2 patients with pulmonary atresia.
**Including 1 patient with Both Blalock-Taussing and Waterstone shunts.
PA: pulmonary artery, APC: Atrio-pulmonary connection, AVA: Atrio-ventricular anastomosis, TCPC:
Total cavo-pulmonary connection.
to the time of the study, type of Fontan completion and
NYHA class, and measured HRV or BRS indices.
Discussion
This study shows that CANA as measured by HRV and BRS
is markedly deranged in patients late after the Fontan operation. Secondly, although LF and HF are overall severely
suppressed, there is differential suppression so that patients
with the greater degree of right atrial dilation have the most
severe suppression of LF (potentially sympathetic modulation), whereas those with lesser degree of right atrial dilation
have the most severe suppression of HF (potentially parasympathetic modulation). Thirdly, baroreflexes were significantly
more active in Fontan patients with previous history of
sustained atrial tachyarrhythmia.
Global Suppression of CANA
HRV is an index of multiple cyclical components swaying the
heart rate around its mean value. Nonspectral or time domain
parameters involve computing indices that are not directly
related to specific cycle lengths. This method offers a simple
means of defining patients with decreased variability in the mean
and SDs of R-R intervals. Spectral analysis can provide a more
detailed assessment of the modulation of the R-R interval. The
HF component of spectral analysis occurs at such a rapid cycle
time that only the parasympathetic arm of the autonomic
nervous system has sufficiently rapid modulatory capacity to be
imputed as the mediating control system. The LF component
occurs at a frequency at which the powerful sympathetic nervous
system influences are able to contribute importantly. Thus, the
LF pattern gives additional information about sympathetic modulation, although of course parasympathetic influences are involved.24 The suppression of HRV was not limited to the HF and
LF bands. There also appeared to be diminution of the VLF
band, of which the origin is currently incompletely elucidated.
This is evidence of global disruption of autonomic regulation.
BRS is a more specific measure of the ability of changes in BP
Davos et al.
TABLE 3.
Cardiac Autonomic Nervous Activity and Fontan Operation
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Current Medication: Fontan Patients
Overall Group
(n⫽22)
With History of Atrial
Arrhythmia
(n⫽14)
11 (50.0%)
11 (100%)
0 (0%)
Beta blockers
2 (9.1%)
2 (100%)
0 (0%)
ACE inhibitors
6 (27.3%)
4 (66.7%)
2 (33.3%)
Digoxin
1 (4.5%)
0 (0%)
1 (100%)
Calcium channel-blockers
1 (4.5%)
1 (100%)
0 (0%)
Drug
Amiodarone
Without History of Atrial
Arrhythmia
(n⫽8)
Diuretics
6 (27.3%)
5 (83.3%)
1 (16.7)
Aspirin
3 (13.6%)
2 (66.7%)
1 (33.3%)
Warfarin
18 (81.8%)
12 (66.7%)
6 (33.3%)
Nitrates
1 (4.5%)
1 (100%)
0 (0%)
Thyroxine
2 (9.1%)
2 (14.3%)
0 (0%)
Carbimazole
3 (13.6%)
3 (21.5%)
Number of patients and percentages in ().
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to produce changes in heart rate (which occurs through modulation of cardiac autonomic nervous outflow). We used a
well-validated noninvasive method, avoiding possible adverse
effects on patients and controls.23
There was markedly suppressed HRV (⬎50% reduction in
every measured variable) and BRS (⬇50% reduction) suggesting global disruption of cardiac autonomic nervous control. This was despite many patients being asymptomatic. The
disruption of HRV and BRS was unrelated to the age at (or
time since) the Fontan operation or previous palliations. Nor
did the type of Fontan surgery or the total number of surgical
procedures affect the HRV or BRS. These results are consistent with those of Ohuchi et al, who studied a pediatric
population of Fontan patients.22
Differential Effects of Sympathetic and
Vagal Modulation
TABLE 5. Heart Rate Variability and Baroreflex Sensitivity:
Fontan Patients and Healthy Controls
Fontan Patients
(n⫽22)
Controls
(n⫽22)
SDNN (ms)
35.2⫾21.6‡
74.1⫾23.6
RMSSD (ms)
31.2⫾29.8†
64.6⫾30.3
pNN50 (%)
13.0⫾22.2†
36.1⫾22.4
123.9⫾74.7‡
290.0⫾85.6
854.8⫾2055.9
846.8⫾496.6
Time domain indices of HRV
Triangular index
Because global magnitude of HRV varies widely between
subjects, evaluation of the balance between sympathetic and
TABLE 4.
parasympathetic modulation can be helped by addressing a
ratio such as LF/(LF⫹HF). This can have a value between
almost 1 (indicating LF power much larger than HF power)
and 0 (indicating HF power much larger than LF power), with
a value of 0.5 indicating an equal balance. In our study we
Echocardiographic Characteristics: Fontan Patients
Frequency domain indices of HRV
VLF (ms2)
log VLF
2.2⫾0.8*
2.8⫾0.3
LF (ms2)
254.3⫾400.7‡
788.0⫾505.8
Mean
Standard
Deviation
Range
n
Supero-inferior
5.6
1.7
3.2–8.9
18
Transverse
5.4
1.9
3.0–8.8
18
␣-LF (ms/mmHg)
7.6⫾10.5‡
Supero-inferior
4.9
1.3
3.3–8.0
16
log ␣-LF
0.7⫾0.4‡
1.1⫾0.2
Transverse
3.1
0.8
2.3–4.7
16
␣-HF (ms/mmHg)
9.3⫾8.8‡
29.6⫾16.1
log ␣-HF
0.8⫾0.4‡
1.4⫾0.2
Variable
log LF
RA dimension (cm)
log HF
LA dimension (cm)
AVVR
Not present
12 (54.5%)
Mild
8 (36.4%)
Moderate
2 (9.1%)
Systemic ventricular dysfunction
Absent
HF (ms2)
14 (63.7%)
Mild
3 (13.6%)
Moderate
3 (13.6%)
Severe
2 (9.1%)
RA: Right atrium, LA: Left atrium, AVVR: Atrio-ventricular valve regurgitation.
LF/(LF⫹HF)
1.8⫾0.8‡
2.8⫾0.4
263.0⫾668.2‡
852.9⫾682.3
1.9⫾0.7‡
2.8⫾0.4
0.50⫾0.16
0.50⫾0.21
Baroreflex Sensitivity
14.3⫾5.4
HRV: heart rate variability; RR: mean duration of RR interval; SDNN: standard
deviation of all RR intervals; RMSSD: square root of the mean squared
differences of successive RR intervals; pNN50: percent of differences of
successive RR intervals ⬎50 ms; Triangular index: integral of the density
distribution divided by the maximum of the density distribution; VLF: very low
frequency; LF: low frequency; HF: high frequency; ␣: alpha index, square root
of the ratio between RR and SBP spectral powers in the VLF (␣-VLF), LF (␣-LF)
and HF (␣-HF) band in spectral analysis. Values are mean⫾SD.
*P⬍0.01.
†P⬍0.001.
‡P⬍0.0001 vs controls.
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Circulation
September 9, 2003
Figure 3. Baroreflex sensitivity: Fontan patients versus healthy
controls. P⬍0.001 for all measures.
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there is a process common to both right atrial dilation and
depression of sympathetic modulation. Indeed, the former
may cause the latter, although the current observational study
would not be able to confirm causality. Clearly, however,
there must be other processes depressing CANA, because at
least one alternative mechanism must be invoked to explain
suppression of HF. Overt or occult damage occurring at or
around the time of surgery is a plausible candidate.22
BRS and Atrial Arrhythmia
Figure 1. Heart rate variability: Fontan patients versus healthy
controls. Upper panel: time domain indices. Lower panel: frequency domain indices. *P⬍0.01, †P⬍0.001, ‡P⬍0.0001.
found that the mean value of LF/(LF⫹HF) was not significantly different between the Fontan patients and the controls,
although the Fontan patients had a slightly wider dispersion
of values (95% CI: 0.08 – 0.93 versus 0.19 – 0.82). This
dispersion arose from differential suppression of LF and HF
in different individual patients. The individual values of
LF/(LF⫹HF) were inversely correlated with right atrial
dimensions. This is in contrast to the study by Ohuchi et al,
who failed to show any relationship between autonomic
nervous dysfunction and underlying heamodynamics in their
study of pediatric patients. Longer length of follow-up from
the Fontan completion between the 2 studies is almost
certainly responsible. We interpret our data as evidence that
Figure 2. Correlation between the LF/(LF⫹HF) ratio and right
atrial dimension: Fontan patients.
Patients from our study with a history of sustained artrial
tachyarrhythmia had significantly more sensitive baroreflexes,
indicating a greater propensity for modulation of the sinus node
rate in response to changes in arterial BP. This is inconsistent
with the hypothesis that sinus node damage is a dominant
mechanism predisposing to atrial tachyarrhythmia in this population, because any such damage would be expected to reduce
(rather than increase) the ability of the node to respond to
autonomic modulation.11 Why this relationship exists between
prior atrial tachyarrhythmia and higher baroreflex gain remains
unclear and it would seem counterintuitive, especially when
examined in the context of data from patients with myocardial
infarction. It is purely speculative, but when baroreflex gain is
stronger, disturbances in BP could more easily engender dramatic changes in heart rate, which act as a precursor to atrial
ectopy, which in turn may trigger atrial tachyarrhythmia. However, such an explanation is tenuous and would need additional
corroboration. Why Fontan patients might be different from
others at risk of atrial arrhythmia is unknown. It is certainly far
from proven that relatively preserved BRS actually causes atrial
arrhythmia. Causation could be in the opposite direction, or there
could be a common cause to both. Data on this question is
currently lacking.
Both ␣LF and ␣HF were markedly depressed in the Fontan
patients. ␣LF is a better gauge of BRS than ␣HF, because the
response time of the arterial baroreflex corresponds better to
the cyclical pattern of LF than to that of HF. Although both
␣ measures were depressed, there seemed to be a trend to
greater depression of ␣HF, suggesting a global autonomic
abnormality rather than a very specific baroreflex defect
Davos et al.
Cardiac Autonomic Nervous Activity and Fontan Operation
Study Limitations
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We could not examine direct influence of surgical procedures on
CANA, because preoperative and immediate postoperative
HRV and BRS data were not available. Trying to keep the study
noninvasive and needle-free, we did not assess catecholamine
levels or muscle sympathetic nerve activity. Many of our
patients were on amiodarone or other anti-arrhythmic medication, which would have been unethical to discontinue in preparation for assessing the CANA. Furthermore, exclusion of
patients with previous arrhythmia from the study would have
given us a biased population, not representative of the true
clinical spectrum of patients late after the Fontan operation.
Therefore, we cannot be certain that medication did not contribute to the effects seen and reported here. Additional predictors of
CANA dysfunction after the Fontan procedure may exist, and be
identified with a larger patient sample and longer period of
observation in future studies. Furthermore, the potential effects
of atrio-pulmonary to total cavo-pulmonary Fontan conversion
and heart transplantation on CANA in patients with univentricular physiology need prospective assessment.
Conclusions
CANA is markedly depressed in patients late after the Fontan
operation, with both HRV and BRS reduced by ⬎50%.
Patients with marked right atrial dilation had more marked
suppression of their sympathetic compared with the parasympathetic system. Furthermore, stronger baroreflexes seem to
be associated with a higher (rather than lower) incidence of
sustained atrial tachyarrhythmia, implying that sinus node
dysfunction may not be the dominant pathogenetic mechanism involved in late arrhythmogenesis in these patients.
Additional studies are clearly required to assess the prognostic value of abnormal CANA in patients with univentricular
physiology late after the Fontan procedure.
Acknowledgments
CD and PD received support both from the Hellenic Society of
Cardiology, Athens, Greece and the Clinical Research Committee,
Royal Brompton Hospital, London, UK. DF received support from
the British Heart Foundation, UK.
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Global Impairment of Cardiac Autonomic Nervous Activity Late After the Fontan
Operation
Constantinos H. Davos, Darrel P. Francis, Marjolein F.E. Leenarts, Sing-Chien Yap, Wei Li,
Periklis A. Davlouros, Roland Wensel, Andrew J.S. Coats, Massimo Piepoli, Narayanswami
Sreeram and Michael A. Gatzoulis
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Circulation. 2003;108:II-180-II-185
doi: 10.1161/01.cir.0000087946.47069.cb
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