doi: 10.1161/01.cir.0000087946.47069.cb
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(Circulation. 2003;108:II-180.)
© 2003 American Heart Association, Inc.
Surgery for Congenital Heart Disease |
Global Impairment of Cardiac Autonomic Nervous Activity Late After the Fontan Operation
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 m.gatzoulis{at}rbh.nthames.nhs.uk
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Abstract |
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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.
Key Words: fontan procedure • nervous system autonomic • baroreceptors • heart rate/heart rate variability • arrhythmias
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Introduction |
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Patients 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.
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Methods |
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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. Exclusion 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 sex-matched 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
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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
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).
Statistical Analysis
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.
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Results |
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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.
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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).
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P<0.001, 
P<0.0001.
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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.
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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 to the time of the study, type of Fontan completion and NYHA class, and measured HRV or BRS indices.
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Discussion |
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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 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
Because global magnitude of HRV varies widely between subjects, evaluation of the balance between sympathetic and 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 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 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
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
Study Limitations
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.
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Conclusions |
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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.
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Acknowledgments |
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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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References |
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