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J Thorac Cardiovasc Surg 2008;136:100-107
© 2008 The American Association for Thoracic Surgery
Surgery for Congenital Heart Disease |
a Medical University of South Carolina, Charleston, SC
b New England Research Institutes, Watertown, Mass
c University of Utah, Primary Children's Medical Center, Salt Lake City, Utah
d Children's Hospital Boston and Harvard Medical School, Boston, Mass
e Children's Hospital of New York, Columbia University, New York, NY
f Duke University School of Medicine, Durham, NC
g The Hospital for Sick Children, Toronto, Ontario, Canada
h National Heart, Lung, and Blood Institute, Bethesda, Md
i Children's Hospital of Philadelphia, Philadelphia, Pa
Received for publication September 14, 2007; revisions received November 29, 2007; accepted for publication December 18, 2007. * Address for reprints: Andrew D. Blaufox, MD, Children's Heart Center, Schneider Children's Hospital, 269-01 176th Ave, New Hyde Park, NY 11040. (Email: Ablaufox{at}nshs.edu).
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Abstract |
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Methods: The National Heart, Lung, and Blood Institute Pediatric Heart Network conducted a cross-sectional analysis of patients who had undergone a Fontan procedure at the 7 network centers. Analysis was based on 521 patients with an electrocardiogram (n = 509) and/or bicycle exercise test (n = 404). The Child Health Questionnaire parent report and the oxygen consumption at the anaerobic threshold were used as markers of functional outcome.
Results: Various Fontan procedures had been performed: intracardiac lateral tunnel (59%), atriopulmonary connection (14%), extracardiac later tunnel (13%), and extracardiac conduit (11%). Prior volume unloading surgery was performed in 389 patients: bidirectional Glenn (70%) and hemi-Fontan (26%). A history of atrial tachycardia was noted in 9.6% of patients and 13.1% of patients had a pacemaker. Lower resting heart rate and higher peak heart rate were each weakly associated with better functional status, as defined by higher anaerobic threshold (R = –0.18, P = .004, and R = 0.16, P = .007, respectively) and higher Child Health scores for physical functioning (R = –0.18, P < .001, and R = 0.17, P = .002, respectively). Higher anaerobic threshold was also independently associated with younger age and an abnormal P-axis. Resting bradycardia was not associated with anaerobic threshold or Child Health scores.
Conclusions: In pediatric patients (6–18 years) after the Fontan procedure, a lower resting heart rate and a higher peak heart rate are each independently associated with better physical function as measured by anaerobic threshold and Child Health scores. However, these correlations are weak, suggesting that other, nonrhythm and nonrate, factors may have a greater impact on the functional outcome of pediatric patients after the Fontan operation.
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Introduction |
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The incidence of late sinus node dysfunction after the Fontan operation has been reported to be about 15%1-3 but may occur in up to 44% of patients in selected series.4 The incidence of atrial tachycardia is 16% to 17% at approximately 5 years after the Fontan procedure1,5 and reaches 50% by 12 years.1 Further, sinus node dysfunction and atrial tachycardia can result in significant symptoms and comorbidities necessitating interventions, including medication,11 pacing,12 catheter ablation,13 and surgery,14 and may also be associated with an increased risk for late death.7,12,15,16 However, little is known about the impact of heart rate and rhythm disorders on the daily lives of pediatric patients who have undergone the Fontan operation. The goal of this study was to analyze heart rate and rhythm data from a large group of Fontan patients studied with a uniform protocol to define the incidence of heart rate and rhythm abnormalities in this patient population and to determine the impact of these abnormalities on quantifiable measures of functional outcome.
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Methods |
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Informed consent was obtained and data were collected at each of the participating centers according to the rules of each institution's internal review board.
Heart rate, heart rhythm, and functional analysis—Patient sample
A total of 546 subjects were enrolled in the Fontan Cross-Sectional Study. Twenty-five patients were excluded from this analysis of heart rate and rhythm: In 17, neither an electrocardiogram (ECG) nor an exercise test was available; 7 had undergone surgical conversion of the Fontan circuit, which may have had an impact on arrhythmia development14; and 1 had second-degree atrioventricular block, leaving 521 subjects in the analytic data set.
Some additional exclusions were applied for selected heart rate and rhythm analyses. Patients with a pacemaker may have had a falsely elevated heart rate at rest and during exercise, whereas patients receivinging antiarrhythmic drugs may have had a falsely lowered heart rate. Thus the physiologic relationship between underlying heart rate and outcome in these patients might not be accurately identified. To avoid this possibility, we excluded from all heart rate analyses 34 subjects with a rate-responsive pacemaker (n = 5) and/or subjects who were currently treated with beta-blockers or class III antiarrhythmics (n = 30), and we excluded 43 subjects with a paced rhythm on resting ECG from the resting heart rate analysis.
Functional outcome measures
The Child Health Questionnaire (CHQ) Parent Report (CHQ-PF50) and the oxygen consumption (volume O2 · kg–1 · min–1) at the anaerobic threshold (VAT) during exercise testing were used as measures of functional outcome. The CHQ-PF50 provides physical (CHQ-p) and psychosocial (CHQ-ps) summary scores to describe the well-being of children 5 to 18 years of age.18 This instrument has been used extensively to establish functional outcome in normal children as well as pediatric patients with various diseases and is among the most reliable tools for this purpose.19 For this study, VAT was used as the marker for exercise performance because it is less effort dependent than other measures and reflects performance at lower levels of exercise.
ECG
A standard 12-lead ECG was performed in the supine position and recorded at 25-mm/s sweep speed with a 10 mm/mV-amplitude. All ECGs were performed at supine rest and before any exercise testing. Bradycardia was defined as a resting heart rate less than the fifth percentile for age.20
Exercise testing
A 12-lead ECG was continuously monitored during the exercise protocol. Arterial oxygen saturation was measured transcutaneously at rest and continuously during exercise. Maximal exercise testing was performed with a standard ramp protocol on an electronically braked cycle ergometer.21
Oxygen consumption and carbon dioxide production were measured continuously. VAT was measured by the V-slope method in those children in whom it could be accurately determined.
Peak heart rate percent predicted of normal for age was calculated as (peak heart rate/[220 – age]) x 100. Chronotropic index22 was calculated as (peak heart rate – resting heart rate)/(0.925 x [220 – age – resting heart rate]).
Statistical Analysis
Groups were defined by resting heart rate less than fifth percentile, peak heart rate less than 75% of predicted for age, history versus no history of atrial tachycardia, and current versus no pacemaker use. A Fisher exact test was used when comparing the distributions of a categorical variable by group and the Wilcoxon rank sum test was used for comparison of the distribution of most continuous variables. The Student t test was used to compare the distributions of resting heart rate. The Pearson rank correlation coefficient was used to estimate the association between pairs of continuous measures. Multivariate linear regression was used to identify independent predictors of functional outcome, defined as VAT and CHQ-p (physical) summary score.
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Results |
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Table 1 displays patient demographics. The mean age at enrollment was 11.9 ± 3.4 years (median 11.3) and at the Fontan procedure was 3.4 ± 1.9 years (median 2.8). There were more male (61%) than female patients. Of 389 patients who had undergone a staged second procedure, many more (70%) underwent the bidirectional Glenn than the hemi-Fontan. The intracardiac lateral tunnel was the most frequent form of Fontan procedure seen in these patients (59%), with the 3 other major forms being equally distributed among the remainder of the patients. Sixty-eight (13%) patients had a pacemaker at the time of the study. Fifty (10%) patients had a history of atrial tachycardia, defined as atrial tachycardia noted in the medical record or present on the study ECG or exercise test.
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Figure 1). Among 470 patients with a P wave on the ECG, 20% had a low right atrial rhythm and 5% had a left atrial focus. Although 13% of patients had a pacemaker, during the resting supine ECG, only 63% of these were paced in the following modes: AAI(R) (69%), DDD(R) (28%), or DDIR (3%).
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Peak heart rate
The average peak heart rate during exercise testing in 371 patients was 157 ± 21 beats/min and was not associated with age (R = 0.07, 95% confidence interval –0.04 to 0.17; P = .211). Low peak heart rate, defined as less than 75% of predicted for age, was observed in 41% of patients. Mean change in heart rate (peak minus resting) was 83 ± 26 beats/min, and the mean chronotropic index (n = 340) was 0.67 ± 0.19 (median 0.70), with 73% having an abnormally low chronotropic index less than 0.8.
Multiple heart rate and rhythm abnormalities
Many subjects had multiple heart rate and rhythm abnormalities. Nine percent had a resting heart rate below the fifth percentile for age and nonsinus rhythm on resting ECG, and 10.9% had a resting heart rate below the fifth percentile for age plus a peak heart rate below 75% of predicted. However, 61% of the 96 patients who had a resting heart rate below the fifth percentile for age had a peak heart rate 75% of predicted or greater.
Functional Outcomes
Mean CHQ-p and CHQ-ps for the group were lower than those for historical healthy controls: CHQ-p was 45.4 ± 11.8 (median 49.3) versus 53.0 ± 8.8 for historical controls and CHQ-ps was 47.3 ± 10.9 (median 48.9) versus 51.2 ± 9.1 for historical controls.18,19 Mean VAT was low at 18.8 ± 6.4 mL · kg–1 · min–1.
Associations with Oxygen Consumption at the Anaerobic Threshold (VAT)
VAT was measured in 311 subjects. Higher VAT was weakly associated with lower resting heart rate (R = –0.18, 95% confidence interval –0.27 to –0.09; P = .004;
Figure 2, A) and higher peak heart rate (R = 0.16, 95% confidence interval 0.04 to 0.27; P = .07;
Figure 3, A). When the association between continuous predicted peak heart rate and VAT was examined, the strength and significance of the association was similar to the association between raw peak heart rate and VAT.
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Table 2). Although patients with an abnormal P-axis had a higher VAT than those with a normal axis (20.7 ± 6.8 vs 18.4 ± 6.2 mL · kg–1 · min–1; P = .02), VAT did not differ by predominant rhythm, including junctional rhythm, on resting ECG. VAT did not differ by history of atrial tachycardia status or by the use of antiarrhythmic medication. A multivariate model for VAT (n = 251) using age, rate, and rhythm variables demonstrated that younger age (0.77 mL · kg–1 · min–1 increase per 1-year decrease in age; P < .001), lower resting heart rate (0.91 mL · kg–1 · min–1 increase per 10 beats/min decrease at rest; P < .001), higher peak heart rate (0.44 mL · kg–1 · min–1 increase per 10 beats/min increase during exercise; P = .03), and an abnormal P-axis (2.59 mL · kg–1 · min–1 decrease if P-axis is between 0 and 90 degrees; P = .004) were independent predictors of better performance and accounted for 20% of the variation in VAT. Furthermore, the association between age and resting and peak heart rate was observed at all ages, without a difference between age groups (interaction P values .77 and 0.41, respectively).
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Associations with CHQ-ps Score
None of the heart rate and rhythm variables were associated with CHQ-ps.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsE-AcknowledgementsCore LaboratoriesReferences |
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Heart Rate and Functional Outcome
The most intriguing finding in this study is that, independent of age, lower resting heart rate was not associated with worsened functional outcome. Since heart rate normally falls with age and outcome usually worsens with age, the relationship between resting heart rate and outcome should be even stronger if age-adjusted heart rates were available for use or could be accurately derived from existing data. Further, despite a large number of patients with bradycardia, defined as a resting heart rate less than the fifth percentile for age, bradycardia was not associated with decreased functional status. On the surface, this finding appears to be at odds with previous studies that have associated sinus node dysfunction with lower physical performance. Sinus node dysfunction has often been broadly defined as various combinations of the following: nonsinus rhythm on resting ECG, low resting heart rate, low peak heart rate response to exercise, or long pauses.1-12,15,16,23,24 However, these prior studies have typically not separately analyzed the individual components of sinus node dysfunction, perhaps accounting for the differences with the findings in the present study.
One possible explanation for the association between resting heart rate and functional outcome is that a high resting heart rate is an indicator of a poor functional state, perhaps resulting from low cardiac output and reflex sympathetic stimulation. Conversely, we speculate that a low resting heart rate may confer mechanical advantages to the Fontan ventricle. This may be related to longer diastolic filling times supporting the preload dependency of the Fontan circulation or to improvement in load-independent diastolic mechanics. Of note, very few patients had a resting heart rate above the 95th percentile for age. The data in this study do not address whether a low resting heart rate is part of a compensatory mechanism; however, previous authors have proposed that resting bradycardia in Fontan patients may be more likely to be the result of surgical or functional autonomic derangements, with selective reduction of cardiac sympathetic activation rather than sinus node dysfunction.25 Any link between autonomic function and the association between higher CHQ-p score and lower heart rate will need to be substantiated in further studies.
The role of peak heart rate in these patients may be more complex. It is clear that the population had an abnormal heart rate response to exercise, with 73% of subjects having an abnormally low chronotropic index. The chronotropic index may be a better representation of the expected peak heart rate response to exercise than the formula (peak heart rate = 220 – age [years]).22 It is less clear whether the abnormal chronotropy is due to intrinsic sinus node dysfunction, autonomic derangements, or other mechanisms. Regardless of the etiology, a higher peak heart rate was associated with a higher VAT and a higher CHQ-p. Although this relationship was found to be weak in this group of Fontan patients, its existence is no different from that in patients with normal hearts,26 in whom increasing heart rate is the most important mechanism for augmenting cardiac output during exercise.
Although other studies have demonstrated that pacing is indicated in Fontan patients with symptomatic bradycardia,1,3,4 the clinical message from this study might be that good functional outcomes in patients with low resting heart rates suggests that placement of a pacemaker for asymptomatic bradycardia might not improve clinical status and may warrant very careful reconsideration. Inasmuch as a higher peak heart rate was also correlated with better functional outcome, failure to increase heart rate during exercise may be a better indicator of pacemaker necessity, but this needs to be evaluated in a prospective manner.
Heart Rate and Rhythm Abnormalities
Despite the more recent surgical era represented in the present study, the high incidence of heart rate and rhythm abnormalities in this Fontan population is consistent with that reported by previous authors.1-10 In the present study, 27% of patients had resting heart rates below the fifth percentile for age, 31% had a nonsinus rhythm on resting ECG, and 41% had a peak heart rate less than 75% of predicted. Previous studies defined sinus node dysfunction as having any one of these abnormalities,1-3 with a prevalence of up to 44% in select series.4 Fishberger and associates7 reported that 9.2% of Fontan patients had a pacemaker after a mean follow-up of 6 years, similar to the 13% prevalence during a follow-up of about 8.5 years in this study. Interestingly, the incidence of atrial tachycardia in the present study was lower than reported in prior studies despite a longer follow-up period (9.6% at 8.5 years compared with 16% to 17% at 5 years).1,5 Thus the impact of the more recent era may have been greater on the development of atrial tachycardia than on other heart rate and rhythm abnormalities.
Limitations
Despite the important findings presented here, this study has several limitations. First, since the study was observational, causality cannot be inferred from the associations identified. Second, although this study suggests that lower resting and higher peak heart rates may be beneficial in Fontan patients, these variables accounted for only 8% of the variance in CHQ-p, indicating that other factors may be more important in determining CHQ-p than heart rate. Third, the associations found between heart rate and CHQ-p or VAT arose from a subsample of the study cohort, which excluded patients who were paced and those receiving antiarrhythmic medication. Inasmuch as the study design did not allow for the reprogramming of pacemakers so that underlying rhythm could be manifest when assessing heart rate, it is unknown whether the relationships between underlying heart rate and CHQ-p or VAT would have been different in those patients with a pacemaker. However, despite exclusion of paced patients in the heart rate analysis, a large number of patients without a pacemaker had bradycardia and were included in the analysis, indicating that the results are reasonably applicable to most Fontan patients. It is possible that the patients with pacemakers may have had more profound bradycardia than the bradycardic patients without pacemakers. Thus excluding paced patients does not necessarily negate the relationship between resting heart rate and outcome for even the paced patients. Fourth, there was not a core laboratory for the ECG or exercise testing interpretation, so that institutional variability could have influenced the results. Fifth, a definition of atrial tachycardia based on chart review, study ECG, or exercise test may have underestimated the incidence of this problem compared with methods such as 24-hour ECG monitoring and electrophysiology study. Finally, associations with VAT have to be interpreted cautiously inasmuch as only 311 patients had valid VATs reported. For subjects who underwent exercise testing, those with a VAT measurement had better physical functioning on CHQ than those without a VAT measurement. In general, the analyses of VAT as an outcome measure for Fontan subjects are based on an older and possibly somewhat healthier cohort than the other findings. Inability to reach VAT may be an important determinant of functional outcome by itself.
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Conclusions |
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E-Acknowledgements |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsE-AcknowledgementsCore LaboratoriesReferences |
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Data Coordinating Center: New England Research Institutes, Lynn Sleeper, Steven Colan, Paul Mitchell, Gloria Klein, Dianne Gallagher, Patty Connell, Lisa Wruck
Network Chair: Lynn Mahony, University of Texas Southwestern Medical Center
Clinical Site Investigators: Children's Hospital Boston, Jane Newburger (PI), Stephen Roth, Roger Breitbart, Renee Margossian, Andrew Powell, Jonathan Rhodes, Jodi Elder, Ellen McGrath; Children's Hospital of New York, Welton M. Gersony (PI), Seema Mital, Beth Printz, Ashwin Prakash, Darlene Servedio; Children's Hospital of Philadelphia, Victoria Vetter (PI), Bernard J. Clark, Mark Fogel, Steven Paridon, Jack Rychik, Margaret Harkins, Jamie Koh; Duke University, Page A. W. Anderson (PI), Rene Herlong, Lynne Hurwitz, Jennifer S. Li, Ann Marie Nawrocki; Medical University of South Carolina, J. Philip Saul (PI), Andrew M. Atz, Andrew D. Blaufox, Girish Shirali, Jon Lucas, Amy Blevins; Primary Children's Medical Center, Salt Lake City, Utah, LuAnn Minich (PI), Richard Williams, Linda Lambert, Michael Puchalski; Hospital for Sick Children, Toronto, Brian McCrindle (PI), Timothy Bradley, Kevin Roman, Jennifer Russell, Shi-Joon Yoo, Elizabeth Radojewski, Nancy Slater
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Core Laboratories |
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Echocardiography, Children's Hospital Boston: Steven Colan (Director), Marcy Schwartz, Renee Margossian
Protocol Review Committee: Michael Artman, Chair; Judith Massicot-Fisher, Executive Secretary; Erle Austin, Daniel Bernstein, Timothy Feltes, Julie Johnson, Jeffrey Krischer, G. Paul Matherne, Anne Murphy, ad hoc, Anne Rowley, ad hoc
Data and Safety Monitoring Board: John Kugler, Chair; Tracey R. Hoke, Executive Secretary; Kathryn Davis, David J. Driscoll, Mark Galantowicz, Sally A. Hunsberger, Thomas J. Knight, Catherine L. Webb, Lawrence Wissow.
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Footnotes |
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References |
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