J Thorac Cardiovasc Surg 2006;132:647-655
© 2006 The American Association for Thoracic Surgery
Surgery for Congenital Heart Disease |
Impaired cardiac autonomic nervous activity predicts sudden cardiac death in patients with operated and unoperated congenital cardiac disease
Astrid Lammersa,
Harald Kaemmerer, MD, PhDa,*,
Regina Hollweck, Dipl Statb,
Raphael Schneider, Dipl Ing (FH)c,
Petra Barthel, MDc,
Siegmund Braun, MDd,
Annette Wacker, MDa,
Silke Brodherr-Heberlein, MDa,
Michael Hauser, MDa,
Andreas Eicken, MDa,
Georg Schmidt, MD, PhDc,1,
John Hess, MD, PhDa
a Klinik für Kinderkardiologie und angeborene Herzfehler, Deutsches Herzzentrum München, Klinik an der Technischen Universität München, Germany
b Institut für Medizinische Statistik und Epidemiologie, Klinikum rechts der Isar der TU, München, Germany
c Erste Medizinische Klinik der Technischen Universität München, Klinikum Rechts der Isar, München, Germany
d Institut für Laboratoriumsmedizin, Deutsches Herzzentrum, München, Germany
Received for publication December 14, 2005; revisions received February 26, 2006; accepted for publication March 6, 2006.
* Address for reprints: Harald Kaemmerer, MD, PhD, FESC, Deutsches Herzzentrum München, Lazarettstr. 36, D-80636 München, Germany (Email: kaemmerer{at}dhm.mhn.de).
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Abstract
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OBJECTIVES: Sudden cardiac death is a leading cause of mortality in patients with congenital cardiac disease after surgical correction and is potentially preventable. The identification of patients at risk is therefore of major interest. We sought to assess the prognostic value of impaired cardiac autonomic nervous activity in patients with congenital cardiac disease.
METHODS: Forty-three consecutive patients with congenital cardiac disease were included in this prospective study. Parameters of heart rate turbulence and heart rate variability were calculated from Holter electrocardiograms. In addition, serum brain natriuretic peptide levels were measured. A combined end point of sudden cardiac death or nearly missed sudden cardiac death was used.
RESULTS: During a mean follow up of 27 ± 12.7 months, 5 patients died, and another 2 were successfully resuscitated. On univariate analysis, both brain natriuretic peptide levels and parameters of heart rate variability and heart rate turbulence were associated with impaired prognosis. On multivariate analysis, pathologic heart rate turbulence was found to be the strongest independent risk stratifier (hazard ratio, 61.5; P < .001).
CONCLUSIONS: Impaired cardiac autonomic nervous activity is associated with an increased risk of sudden cardiac death in congenital cardiac disease. Our results suggest that heart rate turbulence might be superior to established markers of cardiac autonomic dysfunction, such as heart rate variability. The combined use of heart rate turbulence, heart rate variability, and markers of neurohormonal activation, such as brain natriuretic peptide, might further improve the prognostic value.
Abbreviations and Acronyms BNP = B-type natriuretic peptide; CCD = congenital cardiac disease; CI = confidence interval; ECG = electrocardiography; HRT = heart rate turbulence; HRV = heart rate variability; HRVTI = heart rate variability triangular index; RMSSD = square root of the mean square differences of successive RR intervals; SDANN = standard deviation of mean values for all normal-to-normal intervals over 5 minutes; SDNN = standard deviation of all normal-to-normal intervals; TO = turbulence onset; TS = turbulence slope; VPB = ventricular premature beat
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Introduction
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Sudden cardiac death is a leading cause of mortality in patients with congenital cardiac disease (CCD) and is potentially preventable. The identification of patients at risk is therefore of major interest.
Cardiac autonomic nervous dysfunction is associated with an increased risk of death in noncongenital cardiovascular cohorts. Because cardiac autonomic nervous dysfunction is common in patients with CCD,1,2
we hypothesized that it might have similar prognostic implications in adolescents or adults with CCD and could be a means of assessing risk in this evolving population.
Heart rate variability (HRV) is an established measure of cardiac autonomic nervous function. Pathologic HRV has been shown to be a powerful and independent predictor of adverse prognosis in patients with heart disease and in the general population.3 Recently, a novel parameter of cardiac autonomic nervous dysfunction, heart rate turbulence (HRT), has been introduced into clinical practice. Parameters of HRT have been shown to be powerful electrocardiography (ECG)–related risk predictors for mortality after myocardial infarction4-8 and in patients with chronic heart failure.9,10
To the best of our knowledge, there are no data regarding the prognostic significance of HRT and HRV in patients with CCD. The objective of the current study was to assess the prognostic value of these parameters for risk stratification in patients with CCD.
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Patients and Methods
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Forty-three consecutive patients with CCD (27 male and 16 female patients; mean age, 27.0 ± 12.7 years) who underwent 24-hour ECG recording for clinical reasons (previous arrhythmias, palpitations, or syncope) at our institution were enrolled in this prospective study. Patients with a preexisting cardiac pacemaker were excluded. All patients were continuously followed up at a specialized center for adults with CCD. Functional status of the patients was determined by a specialist in adult CCD using the Perloff classification.11
Baseline demographic data are shown in Tables 1 and 2.
We included 21 patients with a systemic right (morphologic) ventricle (20 atrial switch operations for transposition of the great arteries and 1 congenitally corrected transposition of the great arteries), 3 patients after late closure of an atrial septal defect (1 surgical and 2 interventional), 1 patient after repair of a complete atrioventricular septal defect, 5 patients with pulmonary atresia after allograft repair, 7 patients with single-ventricle physiology (2 with double-outlet right ventricle, 1 with double-inlet left ventricle, and 4 after Fontan-type repair), and 3 patients after repair of tetralogy of Fallot. In addition, there were 3 patients with miscellaneous lesions (1 patient with Ebstein's anomaly, 1 patient with repaired aortic coarctation, and 1 patient with aortic and mitral valve disease), as shown in Table 2. Twenty-one patients were in functional class I, 13 in class II, 3 in class III, and 6 in class IV. The vast majority of patients underwent corrective or palliative operations in infancy or childhood. Median time difference between surgical intervention and Holter monitoring was 18.3 years (interquartile range, 15.4-24.7 years).
A combined end point of sudden cardiac death or nearly missed sudden cardiac death was used. Sudden cardiac death was defined as death with documented ventricular fibrillation and unsuccessful resuscitation or unexpected death occurring in a short time period (generally at home).
Holter monitoring was performed for a mean of 23.1 ± 4.2 hours (Reynolds Pathfinder Software). The HRT parameters of turbulence onset (TO) and turbulence slope (TS) were calculated, as described previously.4 Briefly, HRT reflects the physiologic biphasic response of the sinus node to premature ventricular contractions, most likely because of an autonomous baroreflex.4,12-15 It consists of a short initial acceleration, followed by a deceleration of the heart rate. A premature ventricular ectopic beat causes a brief disturbance of the arterial blood pressure (low amplitude of the premature beat and high amplitude of the ensuing normal beat). When the autonomic control system is intact, this fleeting change is registered immediately, with an instantaneous response in the form of the HRT. If the autonomic control system is impaired, this reaction is either weakened or entirely missing. TO represents the percentage difference between the heart rate immediately after a ventricular premature beat (VPB) and the heart rate immediately preceding a VPB. It is calculated by using the following equation: TO = ([RR1 + RR2] – [RR-2 + RR-1])/(RR-2 + RR-1) * 100, with RR-2 and RR-1 being the first 2 normal intervals preceding the VPB and RR1 and RR2 being the first 2 normal intervals after the VPB. Initially, TO is determined for each individual VPB, followed by the determination of the average value of all individual measurements. Positive values for TO indicate deceleration, and negative values indicate acceleration of the sinus rhythm. Values 0 or greater were classified as pathologic.4
TS corresponds to the steepest slope of the linear regression line for each sequence of 5 consecutive normal intervals in the local tachogram. The TS calculations are based on the averaged tachogram and expressed in milliseconds per RR interval. Values of less than 2.5 ms were classified as pathologic.
From the same Holter recording, the following parameters of HRV were determined: standard deviation of all normal-to-normal intervals (SDNN), standard deviation of mean values for all normal-to-normal intervals over 5 minutes (SDANN), HRV triangular index (HRVTI; ie, the integral of the density distribution divided by the maximum density distribution), and square root of the mean square differences of successive RR intervals (RMSSD).
Patients' blood samples were collected in ethylenediamine tetraacetic acid tubes. B-type natriuretic peptide (BNP) was immediately determined by using a commercial fluorescence immunoassay (Triage BNP test; Biosite, San Diego, Calif). The measurable range of the Triage BNP test is from 5 to 1300 pg/mL.
All patients received extensive information about the aim of the study and provided informed written consent, and this study was approved by the local ethics committee.
All values are presented as means ± standard deviation. Comparisons between groups were made by using the Mann-Whitney U test, the 
2 test, or the Fisher exact test, as appropriate. Pearson correlation coefficients are calculated to assess the relationship between parameters of HRV and HRT. The relationship between covariables and survival was initially studied with univariate Cox proportional hazard analysis. Significant parameters were subsequently included into a multivariate Cox proportional hazard model in a stepwise forward selection procedure. The hazard ratio with the 95% confidence interval (CI) and P values are presented. Hazard ratios for continuous variables apply per unit of the analyzed variable. In addition, Kaplan-Meier cumulative survival plots were constructed to illustrate the results. All tests are performed 2-tailed. StatView 5.0 (Abacus Concepts, Inc, Berkeley, Calif) was used for statistical analysis. Areas under the curve for sensitivity and specificity were constructed with MedCalc 5.0 software (MedCalc Software, Mariakerke, Belgium) to compare different predictive values.
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Results
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Clinical Follow-up
The mean follow-up was 27 ± 9 months. Five patients died suddenly during follow-up (10 days to 29 months), and 2 additional patients had a cardiac arrest and were successfully resuscitated (both with documented ventricular fibrillation during resuscitation).
Heart Rate Turbulence
Twenty-two patients had normal TO and TS values. Another 6 patients had no ventricular ectopic beats during Holter monitoring and were classified as "normal" (in accordance with previous studies).4,5 HRT was pathologic in 15 patients. An isolated pathologic TO was found in 6 patients, and 3 patients had an isolated pathologic TS. Pathologic values of both TO and TS were seen in 6 patients. All patients with pathologic TO and TS died (4/6) or were successfully resuscitated (2/6). In contrast, only 1 patient (1/37) with normal TO and TS died during follow-up (2 = 12.9, P = .0003, Figure 1). The individual area under the curve values for parameters of HRT are listed in Table 3. The relationship between event-free survival and HRT parameters is illustrated in Figure 2.
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Figure 1. Kaplan-Meier plot for patients in 3 different heart rate turbulence subgroups: TO and TS normal, TO or TS pathologic, and TO and TS pathologic. TO, Turbulence onset; TS, turbulence slope.
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TABLE 3. Receiver operating characteristic analysis for BNP, parameters of heart rate turbulence, and parameters of heart rate variability
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Figure 2. Clustered dot plot illustrating the relationship between event-free survival and TO or TS values. The horizontal lines indicate the cutoff values (0 and 2.5). TO, Turbulence onset; TS, turbulence slope.
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Heart Rate Variability
Mean values for all parameters of HRV were significantly higher in event-free survivors compared with those in patients who died suddenly or had a cardiac arrest (SDNN: 154.3 ± 82.2 vs 61.7 ± 31.6, P < .001; SDANN: 140.8 ± 82.2 vs 44.4 ± 26.1, P < .001; RMSDD: 34.8 ± 19.0 vs 18.8 ± 9.6, P = .02; HRVTI: 38.5 ± 20.4 vs 13.1 ± 6.1, P < .001). Receiver operating characteristics curve analysis identified a SDNN cutoff value of 72 or greater as being the best predictor of event-free survival (sensitivity, 71.4%; specificity, 97.1%). For the other parameters of HRV, the calculated cutoff values are an SDANN of 60.0 or greater (sensitivity, 85.7%; specificity, 97.1%), an RMSSD of 26 or greater (sensitivity, 85.7%; specificity, 60.0%), and an HRVTI of 24 or greater (sensitivity, 100%; specificity, 74.3%), respectively (Figure 3). The individual area under the curve values for parameters of HRV are listed in Table 3.
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Figure 3. Clustered dot plot illustrating the relationship between event-free survival and parameters of heart rate variability. The horizontal lines indicate the optimal cutoff value calculated on receiver operating curve analysis. SDNN, Standard deviation of all normal-to-normal intervals; SDANN, standard deviation of mean values for all normal-to-normal intervals over 5 minutes; RMSSD, square root of the mean square differences of successive RR intervals; HRVTI, heart rate variability triangular index.
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Correlation Between HRT and HRV
The correlation coefficients between parameters of HRT and HRV are listed in Table 4. Correlations between 0.49 and 0.76 were found between TS and all parameters of HRV. In contrast, there was no correlation between TO and TS and between TO and HRV parameters.
B-type Natriuretic Peptide
The mean BNP level was 266.4 ± 412.9 pg/mL. Survivors without cardiac arrest demonstrated a significantly lower serum pg/mL level (111.3 ± 237.2 mg/L) compared with patients who died or had a cardiac arrest during follow-up (997.7 ± 227.4 pg/mL, P < .0001, Figure 4). Receiver operating characteristics curve analysis identified a BNP value of greater than 491 pg/mL as being the best predictor of mortality or cardiac arrest (sensitivity, 100%; specificity, 97%). All patients who died and had BNP levels of greater than 491 pg/dL at the time of initial investigation died during follow-up, and 1 patient with a pg/mL level of 1300 pg/mL survived.
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Figure 4. Clustered dot plot illustrating the relationship between event-free survival and serum B-type natriuretic peptide levels. The horizontal lines indicate the optimal cutoff value calculated on receiver operator characteristic analysis.
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Predictors of Mortality and Cardiac Arrest
On univariate analysis, BNP, TS as a continuous variable, pathologic TO, pathologic TS, pathologic TO and TS, SDNN, SDANN, and HRVTI were associated with mortality and cardiac arrest (Table 5). In addition, functional status and a history of clinical arrhythmia were predictive of adverse outcomes on univariate analysis. Furthermore, TO as a continuous variable and RMSDD were not predictive of an adverse outcome. Parameters significantly predicting adverse outcome in univariate analysis were subsequently included in a multivariate Cox proportional hazard analysis. In contrast, parameters derived from resting ECGs (QRS duration and QT interval), as well as frequency of ventricular extrasystoles and ventricular tachycardia on 24-hour ECGs, were not predictive of outcome on univariate analysis. When TO and TS were included as continuous parameters, BNP was found to be the strongest predictor of survival/cardiac arrest (hazard ratio, 1.003; 95% CI, 1.001-1.005; P = .0006). However, when pathologic TO and TS was included as a nominal variable (0 = TO or TS normal, 1 = TO and TS pathologic), pathologic TO and TS was the only independent predictor of all-cause mortality/cardiac arrest in multivariate analysis (hazard ratio, 59.3; 95% CI, 7.2-524.2; P < .0003; Table 6).
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Discussion
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Ventricular arrhythmia and sudden cardiac death are leading causes of mortality in patients with CCD.16,17 Risk stratification is of major importance because it might have therapeutic implications (eg, implantable cardioverter defibrillator implantation). The results of this prospective study show for the first time that pathologic parameters of cardiac autonomic nervous activity are associated with impaired prognosis in patients with CCD. This finding is consistent with results reported in noncongenital cardiac patients.
HRV and HRT
HRV reflects the influence of the autonomic nervous system on the heart, resulting in a fluctuation of the heart rate around its mean value.2,3 Pathologic HRV has been shown to be a powerful and independent predictor of adverse prognosis in patients with heart disease and in the general population.3 In the UK Heart Study18 a reduction in a parameter of HRV, the SDNN, was the most powerful predictor of mortality caused by progressive heart failure. Decreased HRV after myocardial infarction is associated with a markedly increased mortality.19 Similarly, HRT has been identified as an important independent predictor for mortality after myocardial infarction. Parameters of HRT were positively correlated with mortality in the population of the multicenter postinfarction programs, the population of the control group of the European Myocardial Infarct Amiodarone Trial, and the population of the Autonomic Tone And Reflexes After Myocardial Infarction study.4,9,10 The European Myocardial Infarct Amiodarone Trial study showed TS as an independent predictor of mortality. In the Multicenter Post Infarction Program (MPIP) and Autonomic Tone And Reflexes After Myocardial Infarction study TS was, after left ventricular ejection fraction, the second most important predictor of mortality.4-6
Prognostic Value of BNP
It has been demonstrated that BNP levels are associated with impaired survival in patients with heart failure of various causes.20,21 Recently, Book and colleagues22 demonstrated that BNP levels are increased in patients with CCD with right ventricular failure, which in itself is an ominous sign in this population.23 Our results suggest that high BNP values might be also be related to sudden cardiac death in patients with CCD.
Prognostic Value of Impaired Cardiac Autonomic Function in Patients With CCD
Deranged cardiac autonomic nervous activity has been demonstrated in patients with CCD with different underlying cardiac conditions.1,2 However, the prognostic value of a pathologic cardiac autonomic function in patients with CCD is unknown.
The results of the present study suggest for the first time that parameters of HRV and HRT are predictive of survival in patients with CCD. Our results show that parameters of HRV are predictors of sudden cardiac death or cardiac arrest. Similarly, measures of HRT, TO and TS, provided important prognostic information. In addition, HRT and heart rate slope carried additional prognostic information to each other and to other parameters of cardiac autonomic nervous function. In this study the combination of TO and TS was a strong risk predictor, even after adjustment for other parameters of cardiac autonomic nervous function, functional status, clinical history of arrhythmia, and neurohormonal activity. The combination of pathologic TO and TS emerged as the strongest independent predictor of sudden cardiac death or cardiac arrest, associated with a 59-fold increased risk of sudden cardiac death or cardiac arrest. Several mechanisms might account for the prognostic value of HRT (and thus autonomic dysfunction) in patients with CCD. It has been reported that autonomic dysfunction is associated with increased sympathetic activity, neuroendocrine activation, increased cytokine levels, and parasympathetic withdrawal, each representing an ominous sign in patients with chronic heart disease.24-26 It appears likely that the remarkable prognostic information provided by parameters of autonomic dysfunction is thus due a combination of the prognostic value of these pathophysiologic variables.
Study Limitations
This study was performed at a tertiary care center for CCD. Thus the sample of patients does not represent the typical population of CCD seen by a general practitioner or cardiologist. The prevalence of patients at risk in our institution is likely to be higher than either that in regional hospitals or that in departments of cardiology. In addition, the patient group might be biased toward more symptomatic patients. The main limitation of our study is the small number of patients included. Therefore larger studies are necessary to determine the prognostic value of HRT and HRV not only on short-term but also on long-term prognosis in patients with CCD. In addition, we cannot exclude the possibility that the patients in the study could be a biased sample, favoring those with systemic right ventricles. A larger study might allow sufficient power to identify the prognostic value of HRT within individual anatomic subgroups of congenital heart disease.
We used time domain parameters of HRV. Spectral analysis might provide a more detailed analysis of HRV, further increasing the prognostic power of HRV parameters. However, the prognostic value of HRV parameters measured in the time domain is well recognized in noncongenital cohorts.19 Furthermore, unlike spectral analysis, this method offers a simple means of identifying patients with decreased variability and is widely clinically available.
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Conclusions
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CCD is associated with cardiac autonomic dysfunction, which can be quantified by measuring HRT and HRV. These parameters are powerful ECG-related risk predictors for sudden cardiac death not only in acquired cardiac disease but also in CCD. The present study verifies for the first time that HRT and HRV, alone or in combination with other parameters of neurohormonal activation, might be suitable predictors of prognosis in patients with CCD. Larger studies are required to confirm the predictive value of these parameters and potentially develop prognostication scores.
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Footnotes
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1 Georg Schmidt reports owning patents for Heart Rate Turbulence, licensed to Biotronik and GE Medical; he also reports consulting and lecture fees from GE Medical. 
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References
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- Davos CH, Davlouros PA, Wensel R, et al. Global impairment of cardiac autonomic nervous activity late after repair of tetralogy of Fallot. Circulation 2002;106(suppl):I69-I75.
- Davos CH, Francis DP, Leenarts MF, et al. Global impairment of cardiac autonomic nervous activity late after the Fontan operation. Circulation 2003;108(suppl):II180-II185.
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- Schmidt G, Malik M, Barthel P, et al. Heart-rate turbulence after ventricular premature beats as a predictor of mortality after acute myocardial infarction. Lancet 1999;353:1390-1396.[Medline]
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Abstract
Introduction
