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J Am Coll Cardiol, 2001; 37:585-592 © 2001 by the American College of Cardiology Foundation |
a Congenital Cardiac Centre for Adults, University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada
Manuscript received January 25, 2000; revised manuscript received September 11, 2000, accepted October 16, 2000.
Reprint requests and correspondence: Dr. Samuel Siu, Toronto General Hospital, PMCC 3-526, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4
Sam.Siu{at}uhn.on.ca
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Abstract |
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The purpose of this study was to compare the clinical and echocardiographic features of adults who developed atrial tachyarrhythmias (ATs) late after a Fontan procedure with those who have remained free of arrhythmias.
BACKGROUND
Atrial tachyarrhythmias are a frequent complication of the Fontan operation. However, the outcomes in adult patients with AT who have had the Fontan operation have not been well defined.
METHODS
We reviewed the outcomes of 94 consecutive patients who underwent the Fontan operation between 1977 and 1994 and were followed as adults at the University of Toronto Congenital Cardiac Centre for Adults. Sixty patients had an atriopulmonary connection, 21 patients had an atrioventricular connection, and 13 patients received a lateral tunnel connection.
RESULTS
Thirty-nine patients (41%) had sustained AT (atrial fibrillation, atrial flutter or supraventricular tachycardia) after their Fontan procedure. Compared with patients who did not develop AT, those who did were more likely to develop heart failure (46% vs. 13%, p = 0.003) and right atrial thrombus (31% vs. 4%, p = 0.006), exhibit left atrial enlargement (mean [±SD] diameter: 44 ± 10 vs. 37 ± 9 mm, p = 0.002), exhibit right atrial enlargement (mean [±SD] volume: 139 ± 149 vs. 76 ± 54 ml, p = 0.040) and have moderate-to-severe systemic valve regurgitation (31% vs. 7%, p = 0.010). The mean survival time was not significantly different between the arrhythmia group and the arrhythmia-free group (21.2 ± 1.3 and 18.0 ± 0.7 years, respectively; p = 0.900).
CONCLUSIONS
Systemic atrioventricular valvular regurgitation and biatrial enlargement are commonly observed in patients who develop AT after the Fontan procedure. These patients are more likely to develop right atrial thrombus and heart failure.
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A number of risk factors for the development of late AT have been described, including poor preoperative functional class, previous atrial septectomy, preoperative AT, age at operation, the need for atrioventricular valve replacement, pulmonary artery (PA) reconstruction, right atrium (RA) to PA Fontan connection, early postoperative AT, postoperative sinus node dysfunction and length of follow-up (6,8,9,11,12).
Although these risk factors have been well described, the relation between the development of AT and subsequent clinical outcomes has not been well defined. In view of the reported incidence of AT after the Fontan procedure, it is important to relate the development of AT to other clinical outcomes such as heart failure, atrial thrombosis, pulmonary embolism, protein-losing enteropathy and death (4,7,9,13,14). The purpose of this study was to compare the clinical and echocardiographic features of adults who developed late AT with those who have remained free of arrhythmias.
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Methods |
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18 years old) who had a previous Fontan procedure, as identified from the University of Toronto Congenital Cardiac Centre for Adults (UTCCCA) computerized data base, were assessed there between June 1985 and September 1997. Patients at UTCCCA are followed according to standardized scheduling templates for clinic visits and cardiac investigations. For example, patients who have had the Fontan procedure undergo 12-lead electrocardiography and transthoracic echocardiography at the time of their annual clinic visit. The purpose of this study was to examine late outcomes; therefore, patients who did not survive beyond 30 days after the initial Fontan procedure were excluded. Baseline information, including demographic data, cardiac anatomy and operative reports, was obtained from a review of the patient’s medical records. Any clinical events that occurred after the patient’s initial Fontan operation, including heart failure, cardiac thrombus, pulmonary embolus, protein-losing enteropathy, cardiac reoperation and death, were recorded. Follow-up data were updated to December 31, 1997. The majority of patients in our data base were followed annually (n = 75 of 94) at the UTCCCA. Nineteen patients were not seen at UTCCCA during 1997, because they were followed by other centers of the Canadian Adult Congenital Heart (CACH) Network; member centers of the CACH network utilize the same standardized follow-up template as UTCCCA. The most recent follow-up information on these 19 patients was obtained from their local CACH center. The research Ethics Board of the Toronto General Hospital approved this study. Definitions. Cardiac anatomy was reviewed, and the principal lesion was defined as either tricuspid atresia or univentricular connection. The latter group included patients with a double-inlet left ventricle or right ventricle (RV). Fontan procedures were divided into three categories: atrioventricular connection (right atrial to right ventricular [RA-RV]), atriopulmonary connection (RA-PA) or lateral tunnel variant of total cavopulmonary connection (TCPC).
Atrial tachyarrhythmias included any sustained episode of atrial flutter, atrial fibrillation or supraventricular tachycardia occurring at least 30 days after the patient’s Fontan operation. Patients with no evidence of sustained AT before and at least 30 days after their Fontan operation were deemed to be "arrhythmia-free."
Data from the patient’s most recent transthoracic echocardiogram were used to determine systemic ventricular systolic function, the degree of systemic atrioventricular valve regurgitation (AVVR) and atrial size. Echocardiography was performed by an experienced research sonographer who had no knowledge of the patients’ clinical data; an experienced echocardiographer (Dr. Siu) confirmed the sonographer’s assessments. Systolic function of the systemic ventricle on echocardiography was semiquantitatively assessed as normal to mildly impaired (estimated ejection fraction >40%) or moderately to severely impaired (<40%) (15). The magnitude of AVVR was also classified as either none/mild or moderate/severe using color flow Doppler criteria (16,17). Left atrial (LA) dimension was measured from the parasternal long-axis view. The maximal mediolateral or superoinferior RA dimensions were measured from the apical four-chamber view at end-systole. Right atrial volume was calculated using a validated prolate ellipsoid formula (18). Right atrial volumes were not assessed in patients with TCPC, because of the presence of the lateral tunnel.
Statistical analysis. Data were presented as the mean value ± SD; the median value and range were given if the data were not normally distributed. Patients were classified into two groups based on the occurrence of AT. A baseline comparison between the two groups was performed. Continuous variables were compared by using the Wilcoxon rank-sum test. Categoric variables were compared by using the chi-square or Fisher exact test, as appropriate. The proportion of patients with clinical events in the two groups was compared by log-rank analyses. The level of significance was set at p < 0.05 (two-sided). Survival for both groups was demonstrated by the Kaplan-Meier method. The predictive role of gender, age at Fontan procedure, development of late AT, original cardiac lesion and type of repair on mortality was examined using Cox proportional hazard regression analysis utilizing a stepwise backwards elimination algorithm (level of significance set at p < 0.05).
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There were 39 patients (41%) in the AT group and 55 patients (59%) in the arrhythmia-free group (Table 1); no patients in the arrhythmia-free group developed AT in the early postoperative period (within 30 days after the Fontan procedure). The principal cardiac lesion was tricuspid atresia. A significantly higher proportion of patients in the arrhythmia group had previous transposition of the great arteries, compared with the arrhythmia-free group. The Blalock-Taussig and Glenn shunts were the most common palliative procedures preceding the Fontan operation. Approximately 19% of patients had no palliative cardiovascular operation before their Fontan procedure. The majority (64%) of patients in this study had a RA-PA connection. The remaining patients received either a RA-RV conduit (22%) or TCPC (14%). A greater proportion of patients in the AT group received a RA-PA connection, compared with those in the arrhythmia-free group.
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Type and clinical presentation of late AT. Thirty-nine patients (41%) developed late AT. Six of these patients developed AT in the early postoperative period (within 30 days of the Fontan procedure) and redeveloped the same type of arrhythmia in the late postoperative period (atrial flutter in five and supraventricular tachycardia in one).
The average age of onset of late AT was 26 years. The number of patients presenting with their first episode of AT in the age ranges of 5–9, 10–14, 15–19, 20–24, 25–29, 30–34, 35–40 and 41–45 years was 1, 3, 7, 7, 9, 4, 6 and 2, respectively. Patients developed their AT a mean duration of seven years after their Fontan procedure. Symptoms were present in 25 (64%) of 39 patients during their first presentation of arrhythmia and included palpitations (62%), fatigue (44%), dyspnea (23%), edema (21%), presyncope (21%) and syncope (3%). Eight of these patients (21%) first presented to an emergency ward; another nine patients first presented to their family physician; and eight patients developed their AT during their hospital stay. Fourteen patients were asymptomatic; their AT was detected during routine cardiology assessment.
Atrial fibrillation alone was observed in 12 (31%) of 39 patients, atrial flutter alone in 9 patients (23%) and other ATs in 15% of patients. The remaining 31% of patients in the arrhythmia group developed a combination of atrial flutter, atrial fibrillation and/or other atrial arrhythmias. The clinical (age at follow-up and age at the Fontan operation) and echocardiographic (atrial volume, moderate to severe AVVR or systemic systolic ventricular function) characteristics of the patients experiencing atrial flutter alone and atrial fibrillation alone were not significantly different. However, the small sample size (atrial fibrillation, n = 12; atrial flutter, n = 9) precludes further interpretation.
Two patients developed AT before, and continued to have arrhythmias, after their Fontan operation. Atrial tachyarrhythmia was chronic in 9 (23%) of the 39 patients and recurrent in 22 patients (56%). The remaining 21% of patients in the AT group had only one episode of documented AT during the study period. For those patients (n = 8) with only one episode of postoperative AT, the age at onset of the arrhythmia was 26 ± 7 years (range 17 to 38) at an interval of 8 ± 7 years (range 1.5 to 22.5) after the Fontan procedure.
Ten patients (26%) who developed AT received pacemakers, whereas 30 (77%) of the 39 patients were managed with antiarrhythmic medications, including propafenone, procainamide, sotalol, digoxin and amiodarone.
Echocardiographic features. Echocardiographic data were available for quantitation in 80 of the 94 patients. Systemic ventricular function and AVVR could be quantitated in 74 and 75 of these patients, respectively. Twenty-six percent of patients had a moderate to severe reduction in systolic function of the systemic ventricle; the majority of patients (74%) had mildly impaired to normal systemic ventricular function. There was a trend toward a higher proportion of patients with moderate to severely impaired systemic ventricular function in the AT group (38% vs. 17% in the arrhythmia-free group; p = 0.060). Thirteen (17%) of the 75 patients with echocardiographic data had moderate to severe AVVR. Moderate to severe AVVR was present in a higher proportion of patients in the arrhythmia group (31%), compared with those in the arrhythmia-free group (7%; p = 0.010). Six patients had both a moderate to severe reduction in systolic function and moderate to severe AVVR. Four of the six patients had an isolated episode of AT. When these patients were arrhythmia-free, they continued to have both moderate to severe AVVR and a moderate to severe reduction in systolic ventricular function at the last follow-up echocardiographic study in December 1997. Two other patients had chronic AT and continued to have both moderate to severe AVVR and systemic ventricular systolic dysfunction at follow-up.
The 13 patients with moderate to severe AVVR had significantly larger mean RA mediolateral (67 ± 21 vs. 50 ± 14 mm; p = 0.009), RA superoinferior (67 ± 22 vs. 52 ± 15 mm; p = 0.04) and LA dimensions (47 ± 9 vs. 38 ± 9 mm; p = 0.002), compared with the 59 patients without significant AVVR. There was no significant difference in age at the Fontan operation and the postoperative interval between patients with and those without hemodynamic residua (moderate to severe systemic ventricular dysfunction or AVVR). The group with hemodynamic residua had a higher proportion of patients with RA-PA Fontan procedures, compared with the group without these residua (80% vs. 55%; p = 0.017).
Quantitation of LA dimension was feasible in 76 patients (81%) (Table 2). Measurements of RA dimension were feasible in 64 patients. The mediolateral and superoinferior RA dimensions exceeded the normal ranges in 80% and 75% of patients, respectively (19,20). The mean RA size and volume were higher in patients with AT. The mean LA size in the AT group was significantly larger than that in the arrhythmia-free group (44 ± 10 vs. 39 ± 9 mm; p = 0.002). Statistically significant differences in RA and LA sizes between the two groups were still present when patients with chronic AT were excluded from the analysis.
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Seven patients (7%) in the study had a documented episode of pulmonary embolus. Five of these patients were in the arrhythmia-free group. No significant difference was noted between the arrhythmia and arrhythmia-free groups with respect to the development of pulmonary embolus. Three (17%) of the 18 patients who developed RA thrombus or pulmonary emboli were already receiving either aspirin (n = 2) or warfarin (n = 1) at the time of diagnosis; in the months before the diagnosis of RA thrombus, there was difficulty maintaining adequate anticoagulation in the one patient receiving warfarin. More patients in the arrhythmia group were receiving aspirin or warfarin for either the prevention or treatment of RA thrombus, compared with the arrhythmia-free group (72% vs. 36%, p = 0.008). All patients with RA thrombus or pulmonary emboli were placed on long-term warfarin therapy.
Three patients developed protein-losing enteropathy (3%). No significant differences in the frequency were noted between the arrhythmia and arrhythmia-free groups.
Twenty-six patients underwent reoperation after the initial Fontan procedure (28%). Reoperation was required in 15 patients with arrhythmias (38%) and in 11 patients who were arrhythmia-free (20%) (p = 0.25). Fifteen (58%) of 26 patients underwent replacement of an obstructed Fontan connection. In these 15 patients, the origin and insertion of their new connection was the same as that of their original operation (RA-RV, RA-PA and TCPC in 11, 3 and 1 patients, respectively). As of December 1997, none of these patients had revision of a lateral tunnel or extracardiac Fontan connection. Four of six patients who had AT before their Fontan revision continued to have AT afterward; there was no recurrent AT in the remaining two patients. The other nine patients who underwent Fontan revisions did not have AT either before or after their revision.
Another three patients (12%) had a subaortic myectomy procedure, whereas two patients (8%) underwent heart transplantation. Five other patients underwent reoperation for closure of an atrial septal defect (n = 1), ligation of a Blalock-Taussig shunt (n = 1), ligation of a pulmonary arteriovenous fistula (n = 1), ligation of a Potts shunt (n = 1) or cryoablation in the RA for arrhythmia management (n = 1). One patient underwent systemic atrioventricular valve replacement for severe regurgitation; she was in the arrhythmia-free group. None of the patients undergoing reoperation had PA reconstruction. No statistically significant differences were noted regarding the type of post-Fontan operation performed in the arrhythmia and arrhythmia-free groups.
Nine patients in the study died beyond the immediate (30 days) postoperative period after their Fontan operation. The time of death ranged from 2 to 15 years after the patient’s Fontan operation. Four of the deaths were the result of progressive myocardial failure. One patient died from a stroke, whereas another experienced sudden death secondary to a presumed arrhythmia. Two deaths were from noncardiac causes. Information regarding the cause of death in one patient was unavailable. Multivariate Cox proportional hazard analysis did not identify statistically significant predictors of mortality. As shown in Figure 1, there was no significant difference in mean survival time from the time of operation between the arrhythmia and arrhythmia-free groups (21.2 ± 1.3 and 18.0 ± 0.7 years, respectively; p = 0.900). Five of the nine deaths were in the arrhythmia-free group.
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Discussion |
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Arrhythmias. The present study demonstrates a 41% occurrence of late AT after the Fontan operation, a finding consistent with previous reports (2–9). Importantly, a preliminary report from a multicenter study reported an even higher frequency (49%) of AT (10). Compared with other studies, our study examined adult survivors of the Fontan procedure as well as those who underwent this operation in adulthood. Our study also had a longer follow-up period for a majority of the group. Approximately two-thirds of our study group were followed for >10 years and 15% for >15 years. Other studies have demonstrated that length of follow-up is a risk factor for the development of AT (6,9,11). The relation between time and arrhythmia development is presumed to be mediated by progressive RA distention from long-standing elevation in RA pressures (11). Because the risk of developing atrial fibrillation and atrial flutter increases with time, it is likely there will be an increasing number of patients who have had the Fontan operation in whom atrial fibrillation and atrial flutter will develop. One patient in this study developed atrial fibrillation >20 years after the Fontan operation.
Unlike other studies, ours predominantly included older variants of the Fontan operation, a procedure that did not exclude the RA from high systemic venous pressure. The majority of patients in this study had their Fontan operation performed from the late 1970s to the mid 1980s. Thus, the predominant types of Fontan procedures were RA-PA and RA-RV connections. The newer variants of the Fontan operation, such as the TCPC lateral tunnel or extracardiac Fontan connection, were not widely performed at our major referring institution until the late 1980s to mid 1990s, and were not well represented in this patient group. Although we also found that the AT group had a lower proportion of TCPC compared with the arrhythmia-free group, it is unclear whether the association between TCPC and a lower frequency of AT was a result of the relatively short follow-up period of these patients or the protection of the RA from elevated systemic venous pressures (9,10,14,21). Some have suggested a role for the extracardiac Fontan connection in view of the observation that atrial incisions themselves may be partly responsible for late AT (22). A recent study suggested that lateral tunnel conduit was associated with the lowest incidence of AT (12).
Atrial size. The mean RA size for the majority of patients who have had the Fontan operation was larger than normal, reflecting the elevated RA pressures in these patients. The mean RA size in Fontan patients who developed AT was significantly greater than that of the arrhythmia-free group, suggesting that RA distention contributed to the development of AT. In addition, the mean LA size in Fontan patients who developed AT was significantly larger than that of the arrhythmia-free group. Because the relation between LA dilation and the development of atrial fibrillation has been well documented in patients with acquired cardiac lesions, it is possible that LA distention also contributed to the development of AT in patients who have had the Fontan operation (23,24). The enlargement of the LA could be a consequence of systemic dysfunction or AVVR, both of which were more prevalent in this study’s arrhythmia group. This relation between LA size and the development of AT in patients who have had the Fontan operation has not been reported previously. The previously described relation between older age at operation and late AT is confirmed by our observation that the mean age at the Fontan procedure was higher in patients who developed AT than in those who did not (9,12). Older patients who do not have a Fontan circulation will be subjected to longer periods of hypoxia and ventricular volume overload, with resultant ventricular hypertrophy and abnormalities in diastolic filling. The development of systemic AVVR will result in further elevations in LA pressure, providing a stimulus for arrhythmia development.
Heart failure and systemic ventricular dysfunction. Fontan patients who developed AT had a significantly higher frequency of symptomatic heart failure compared with those without AT. Although most patients in this study who developed heart failure did so after their first episode of AT, the remaining patients developed heart failure without a documented arrhythmia or before the onset of AT. This suggests that heart failure can be a precipitant or a consequence of AT in the adult with Fontan physiology.
Cardiac thrombosis. Consistent with other reports, most of our patients’ thromboemboli originated in the venous circulation, with the majority of these located either in the true RA or within the Fontan conduit (25–31). Fontan patients who developed AT had a significantly higher frequency of RA thrombus. Twelve of the 14 patients who developed cardiac thrombus had AT. In nine of these patients, the cardiac thrombus was diagnosed after the onset of AT. Although the relation between AT and thrombus development is presumed to be mediated by increased stasis within the atria in the setting of diminished cardiac output, other studies of patients who have had the Fontan operation have reported the presence of prothrombotic coagulation abnormalities in protein C, antithrombin III, factor II, factor I and von Willebrand factor (6,32). Given the high incidence of AT and thromboembolism in the Fontan population, routine prophylactic anticoagulation with warfarin or antiplatelet agents has been suggested, despite the lack of clinical trials confirming the efficacy of such an approach (33). The one study examining the efficacy of prophylactic anticoagulation revealed a frequency of venous thrombosis of 7%, despite the use of warfarin for three months in the whole Fontan cohort (34).
Reoperations. The development of arrhythmias was associated with an increased frequency of reoperations. This finding may be explained by the fact that over half of the operations were for replacement of obstructed Fontan conduits. Because arrhythmia development is associated with an increased frequency of RA thrombus, one could also expect a higher frequency of conduit replacements.
Pulmonary embolism. The frequency of pulmonary embolism in this study (10%) fell within the range (3% to 17%) of the few previous reports that examined this outcome (13,30,35). Although a higher frequency of pulmonary embolus in patients who develop AT might be expected, in this study, the frequency of pulmonary embolism was found to be similar in both the arrhythmia and arrhythmia-free groups. It is possible that due to our small sample size, the study lacked the power to reveal any difference in the frequency of this clinical event. Patients in the AT group may have developed fewer pulmonary emboli because more patients in the AT group were anticoagulated either for the prevention or diagnosis of RA thrombus.
Mortality. A study published from the Mayo Clinic, with a mean follow-up of four years, showed a significant number of late deaths (6 [26%] of 23) after the Fontan operation, attributable to arrhythmias (36). However, this was not the finding of our study. Only one of nine late deaths was due to a presumed arrhythmia, and there was no significant difference in the mortality rate between the arrhythmia and arrhythmia-free groups. Our findings are in agreement with Gewillig et al.’s study (7), which reported that none of their late deaths (3 of 78) was provoked by an arrhythmia. Although the lack of a statistically significant difference in mortality between patients with and those without AT may be a result of the modest sample size and length of follow-up after the development of arrhythmias (five years), it is possible that the mortality impact of AT in adults who have the Fontan procedure may be different from that of the pediatric population. For example, early arrhythmias after the Fontan procedure may be a reflection of baseline or residual hemodynamic aberrations, which are associated with a poor prognosis.
Study limitations. This was a retrospective study that included adult survivors of a childhood procedure who successfully made the transition from a pediatric to an adult institution. The sample size is modest, and the study may lack the power to determine a significant difference in frequency of pulmonary embolism or mortality between the two groups in the study. A larger patient sample will also allow elucidation of possible differences in baseline characteristics between patients presenting with isolated versus recurrent/chronic arrhythmias. Because routine transesophageal echocardiography was not performed in patients who had the Fontan procedure, the incidence of RA thrombus may have been underestimated in the arrhythmia-free group. This study may have over-represented the percentage of patients in whom these clinical events developed, because patients with symptoms may be more likely to seek their cardiologist and hence be referred to our center. However, the referral bias is minimized by the fact that our center is the main continuity clinic within metropolitan Toronto for adults who underwent the Fontan operation; also, our patients are seen annually. A retrospective study such as this would be unable to assess the frequency of paroxysmal AT, because the patient’s clinic evaluations were scheduled on an annual basis.
Clinical implications. Our study demonstrates that AT is commonly associated with the development of RA thrombus. Fontan patients in whom AT develops should be anticoagulated and screened for atrial thrombus with transesophageal echocardiography. The efficacy of routine anticoagulation in patients with Fontan physiology is being evaluated in an ongoing Canadian multicenter clinical trial. For patients with refractory arrhythmias, despite pharmacologic therapy, surgical revision of a lateral tunnel or extracardiac Fontan connection, combined with electrophysiologically guided cryoablation, can be considered. This approach may decrease the incidence of recurrent AT more than either technique alone (37).
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 B. Voss, F.-U. Sack, W. Saggau, S. Hagl, and R. Lange Atrial cardiomyoplasty in a Fontan circulation Eur. J. Cardiothorac. Surg., May 1, 2002; 21(5): 780 - 786. [Abstract] [Full Text] [PDF]
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C. Mavroudis, C. L. Backer, B. J. Deal, C. Johnsrude, and J. Strasburger Total cavopulmonary conversion and maze procedure for patients with failure of the Fontan operation J. Thorac. Cardiovasc. Surg., November 1, 2001; 122(5): 863 - 871. [Abstract] [Full Text] [PDF]
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