Fontan and Baudet [1] performed the successful functional. Ventricular Performance in Long-Term Survivors After Fontan Operation

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1 ORIGINAL ARTICLES: SURGERY: The Annals of Thoracic Surgery CME Program is located online at To take the CME activity related to this article, you must have either an STS member or an individual non-member subscription to the journal. Ventricular Performance in Long-Term Survivors After Fontan Operation Yuki Nakamura, MD, Toshikatsu Yagihara, MD, Koji Kagisaki, MD, Ikuo Hagino, MD, and Junjiro Kobayashi, MD Department of Cardiovascular Surgery, National Cardiovascular Center, Osaka, Japan Background. Ventricular function and arrhythmia in patients with Fontan circulation in long-term follow-up are still unknown. Methods. We retrospectively reviewed 48 patients who survived and were followed up for more than 15 years, among 110 patients who underwent Fontan operation in our institute from 1979 to Atriopulmonary connection was performed in 26 patients and total cavopulmonary connection in 22. The patients were categorized into right ventricle, left ventricle, and biventricle groups. Follow-up cardiac catheterization and exercise test were performed routinely every 5 years post surgery. Median age at Fontan operation was 5 years. Results. Mean follow-up was 18.5 years. Cardiac index in the total cavopulmonary connection group was higher than in the atriopulmonary connection group at 10 and 15 years post surgery (p < 0.05). Ejection fraction in the left-ventricle group was higher than in the right-ventricle group. End-diastolic volume at 5, 10, and 15 years was significantly lower than at 1 year (p < 0.05). End-diastolic pressure at 10 years was significantly higher than at 1 and 5 years (p < 0.05). Beyond 15 years, 6 patients developed ventricular tachycardia. The only significant risk factors for the onset of ventricular tachycardia in a multivariate analysis were age at Fontan operation and absolute age (p < 0.05). Conclusions. Long-term follow-up of patients demonstrated that postoperative ventricular systolic performance seemed to become steady. Ventricular tachycardia was detected 15 years post surgery, especially in older patients with older age at Fontan operation, possibly revealing a risk factor in the long-term postoperative period, thereby meriting further consideration. (Ann Thorac Surg 2011;91:172 80) 2011 by The Society of Thoracic Surgeons Accepted for publication July 14, Address correspondence to Dr Nakamura, Department of Cardiovascular Surgery, National Cardiovascular Center, 5-7-1, Fujishirodai, Suita, Osaka, , Japan; finitoyuki@msn.com. Fontan and Baudet [1] performed the successful functional repair of tricuspid atresia by atriopulmonary connection (APC) forty years ago, and 20 years have passed since de Leval and colleagues [2] reported the hemodynamic advantages of the total cavopulmonary connection (TCPC) over APC. Since then, long-term follow-up studies [3, 4] have been conducted that describe mortality and morbidity but not cardiopulmonary function. Ono and colleagues [3] described postoperative hemodynamics in 89 patients but their data did not show serial changes. As for tachyarrhythmia, supraventricular tachycardia occurring late after Fontan operation, especially after APC, has been widely reported. Mavroudis and colleagues [5] described in detail Fontan conversion with arrhythmia surgery for atrial fibrillation and atrial reentry tachycardia. Ventricular tachycardia (VT), however, has rarely been mentioned. The purpose of this study was to estimate serial changes in ventricular performance and cardiopulmonary function in patients with Fontan circulation for more than 15 years and identify risk factors related to the onset of VT. Patients and Methods Patients Between October 1979 and May 1992, 110 patients underwent Fontan operations at our institution. There were 26 hospital deaths and 18 late deaths. Causes of hospital deaths were Fontan circulation failure due to ventricular dysfunction or pulmonary condition in 19 patients and noncardiac event in 7 patients. Causes of late deaths were Fontan circulation failure due to ventricular dysfunction in 4 patients, Fontan circulation failure due to pathway obstruction in 6 patients, intractable atrial tachycardia in 1 patient, noncardiac event in 3 patients, sudden death in 2 patients, and unknown cause in 2 patients. No patients in the late death group suffered from ventricular arrhythmia, excluding one patient with very poor preoperative ventricular function who died within a year. Overall survival after Fontan operation was 66% at 5 years, 64% at 10 years, and 62% at 15 years, respectively, and all the late 2011 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg NAKAMURA ET AL 2011;91: VENTRICULAR PERFORMANCE IN FONTAN 173 Table 1. Patient Characteristics Characteristics APC Group (26 patients) TCPC Group (22 patients) Difference p Value Total (48 patients) Median age at Fontan operation in years 4.6 (1 23) 5.7 (1.8 18) ns 5 (1 23) Morphology, n (%) LV group 19 (73.1) 5 (22.7) (50) TA/TS 15 (57.7) 4 (18.2) 19 (39.6) DILV 2 (7.7) 0 2 (4.2) PAIVS 2 (7.7) 0 2 (4.2) Other 0 1 (4.5) 1 (2.1) RV group 4 (15.4) 17 (77.3) (43.8) MA/MS 2 (7.7) 4 (18.2) 6 (12.5) DORV 0 1 (4.5) 1 (2.1) RI, CIRV 0 9 (40.9) 9 (18.8) RI, DIRV 0 2 (9.1) 2 (4.2) Unbalanced AV canal 0 1 (4.5) 1 (2.1) DIRV 1 (3.8) 0 1 (2.1) Other 1 (3.8) 0 1 (2.1) BV group 3 (11.5) 0 ns 3 (6.3) DORV 1 (3.8) 0 1 (2.1) Straddling AV valve 2 (7.7) 0 2 (4.2) Mean palliative procedures, n ns Mean follow-up period in years NYHA functional class at present I/II/III/IV 16/10/0/0 14/8/0/0 ns 30/18/0/0 APC atriopulmonary connection; AV atrioventricular; BV biventricular; CIRV common-inlet right ventricle; DILV double-inlet left ventricle; DIRV double-inlet right ventricle; DORV double-outlet right ventricle; LV left ventricle; MA mitral atresia; MS mitral stenosis; ns not significant; NYHA New York Heart Association; PAIVS pulmonary atresia with intact ventricular septum; RI right isomerism; RV right ventricle; TA tricuspid atresia; TCPC total cavopulmonary connection; TS tricuspid stenosis. deaths occurred within 15 years post surgery. The cohort studied consisted of 48 patients, excluding 26 hospital deaths, 18 late deaths, and 18 patients who were lost to follow-up. All the 48 patients were followed up for more than 15 years. Patient characteristics are shown in Table 1. In this period, we had preferred primary Fontan completion to a staged strategy, and the mean number of palliative procedures prior to Fontan operation was Interim bidirectional cavopulmonary anastomosis was performed in 6 patients. The median age at the time of Fontan operation was 5 years (range, 1 to 23 years). The main reason for patients of an older age requiring the surgery was late referral from other institutions. Since 1988, we had begun to apply TCPC-type procedure for Fontan completion, especially in patients with complex malformations such as heterotaxy syndrome, and it had been spread in all since Subsequently, 26 APC-type and 22 TCPC-type Fontan operations were included in this study. These patients were categorized into 3 groups based on ventricular morphology: those with a dominant right ventricle (RV) with or without a rudimentary left ventricle (group RV, 21 patients); those with a dominant left ventricle (LV) with or without a rudimentary right ventricle (group LV, 24 patients); and those with both right and left ventricles (group BV, 3 patients). We defined the BV group as patients with two ventricles in whom the volume of the smaller ventricle was either greater than 30% of the main ventricle or greater than 50% of its predicted normal value [6]. Surgical Procedures Fifty-three palliative procedures were performed in 35 patients. Atriopulmonary connection was performed by connecting the atrial appendage to the main pulmonary artery. The TCPC patients underwent either intraatrial anterior tunneling technique [7] using an equine pericardial patch (10 patients) or intraatrial grafting using a Gore-Tex tube graft (12 patients) (W. L. Gore and Assoc, Flagstaff, AZ). We have preferred Fontan completion without fenestration, and fenestration was not performed in any cases. Eighteen patients underwent 22 concomitant procedures in all; a Damus-Kaye-Stansel anastomosis in 2 patients, interventricular foramen enlargement in 2, subaortic myotomy in 1, common atrioventricular valve plasty in 4, tricuspid valve plasty in 1, reconstruction of pulmonary artery continuity using an equine pericardial patch in 4, pulmonary artery patch arterioplasty in 5, and total anomalous pulmonary venous connection repair in 3. Follow-Up Study We collected all preoperative and postoperative data from patients records in the National Cardiovascular Center. We have performed transthoracic echocardiog-

3 174 NAKAMURA ET AL Ann Thorac Surg VENTRICULAR PERFORMANCE IN FONTAN 2011;91: raphy examination in all patients at least once a year and we collected data about ejection fraction of the systemic ventricle, atrioventricular valve regurgitation, aortic valve regurgitation, and the presence of systemic ventricular outflow tract obstruction. Valve regurgitation was classified as trivial, mild, moderate, and severe. We performed cardiac catheterization routinely 1 and 5 years post surgery, and thereafter every 5 years. We performed an additional catheterization if we noticed some problems during the follow-up. Cardiac index (CI; L/min/m 2 ), ejection fraction (EF), end-diastolic volume (EDV; % of normal), end-diastolic pressure (EDP; mm Hg), and arterial blood saturation (Sao 2 ; %) were used for the assessment. Oxygen consumption was estimated from the age, gender, and heart rate data, and CI was measured using the Fick principle. The volumes of the ventricles were calculated using Simpsons rule or the area-length method. The EDV was expressed in terms of percent of predicted normal values estimated from body surface area. Ejection fraction was calculated as the ratio of stroke volume to EDV. The patients underwent an exercise test while hospitalized for cardiac catheterization. All patients exercised on a motor-driven, programmable treadmill (Q-5000 System; Quinton, Seattle, WA) and followed the protocol by Ohuchi and colleagues [6]. After a 3-minute warm-up period (1.5 km/min and 0% grade), treadmill speed and grade were increased at 30-second intervals in increments calculated to increase oxygen uptake by approximately 3.0 ml kg 1 min 1 per increment in normal subjects. We collected peak oxygen uptake (partial pressure of oxygen, venous [Pvo 2 ]) for the assessment, which was expressed in terms of percent of predicted normal values. Gender-adjusted and body weight-adjusted predicted normal values were determined using the formula derived from the normal data obtained at our center [8]. As for cardiac catheterization and exercise test, we included the data with the range of 2 years (the data were considered to belong to X years post surgery only if the test was performed between X 1 years and X 1 years post surgery). All the patients excluding 1 patient who went abroad from 12 years to 18 years post surgery underwent the Holter electrocardiographic test at least once a year after 10 years post surgery. An electrocardiograph was recorded continuously for 24 hours. We have routinely measured plasma concentration of brain natriuretic peptide (BNP) since The BNP was determined using immunoradiometric assays from ethylenediaminetetraacetic acid-aprotinin plasma and was measured in all patients at least once a year since Informed consent was obtained from all the patients and (or) their parents. The Ethics Committee of the National Cardiovascular Center approved the study protocol. Statistical Analysis Data were reported in median and interquartile ranges and in mean standard deviation. The Wilcoxon matched pairs test was used to estimate postoperative serial values. The cumulative freedom from VT was estimated by the Kaplan-Meier method. Univariate analysis using the Mann-Whitney test and multivariate analysis using Cox proportional hazard methods were performed to compare variables between the VT group and the non-vt group. A p value of less than 0.05 was regarded as statistically significant. Testing was performed using Dr. SPSS 2 statistical software (SPSS Inc, Chicago, IL). Results Mean follow-up period after Fontan operation was years. Mean age at last follow-up was years. A total of 4 patients, 1 in the APC group and 3 in the TCPC group, suffered from protein losing enteropathy. The patient in the APC group underwent Fontan conversion 14 years after APC-type Fontan operation, but protein losing enteropathy PLE persisted. As for thromboembolic events, 3 patients in the APC group suffered from brain infarction. Of the 26 patients in the APC group, 15 patients have suffered from atrial tachycardia or intraatrial reentry tachycardia, and 13 out of the 15 patients have undergone Fontan conversion so far. Three out of the 15 patients had also atrial fibrillation, and underwent a standard full maze procedure and pacemaker implantation concomitant with Fontan conversion procedure. We have applied Fontan conversion aggressively, and also in 18 patients in the APC group have undergone it. We had 4 patients who suffered from supraventricular tachycardia in the TCPC group, all of whom were patients with right isomerism. At final follow-up, 9 patients in the APC group and 1 patient in the TCPC group required antitachyarrhythmic drugs. Transthoracic echocardiography examination revealed mild aortic regurgitation in 1 patient and mild atrioventricular valve regurgitation in 2 patients. In the other 45 patients, aortic and atrioventricular valve regurgitation were less than mild during the follow-up. One patient suffered from systemic ventricular outflow tract obstruction (the peak systolic gradient across the outflow tract was 66 mm Hg by cardiac catheterization) and underwent relief of subaortic stenosis at Fontan conversion 10 years post surgery. Serial changes of CI, EF, EDV, EDP, and Sao 2 at cardiac catheterization were analyzed between the APC group and the TCPC group, or among the RV, LV, and BV groups. The CI in the APC group was significantly lower than in the TCPC group after 10 years post surgery; CI in the TCPC group has not changed significantly (Fig 1). The LV group showed a significantly higher EF than the RV group at 1 and 10 years post surgery (Fig 2). The EDV at 5 years was smaller than at 1 years post surgery, but thereafter EDV became steady (Fig 3). The EDP increased gradually until 10 years post surgery (Fig 4). The Sao 2 at 1 year was significantly lower than at 5, 10, and 15 years post surgery (p 0.001). The Sao 2 in the TCPC group was lower than in the APC group at 1 (p 0.001) and 10 years post surgery (p 0.05).

4 Ann Thorac Surg NAKAMURA ET AL 2011;91: VENTRICULAR PERFORMANCE IN FONTAN 175 Fig 1. Serial changes of cardiac index. ( TCPC; e APC.) Fig 3. Serial changes of end-diastolic volume (EDV) of the systemic ventricle. Serial changes of Pvo 2 during the exercise test are shown in Table 2. The Pvo 2 decreased serially, although not significantly. In the RV group, Pvo 2 at 10 years was significantly lower than at 5 years, and in the LV group, Pvo 2 at 15 years was significantly lower than at 10 years after Fontan operation. Beyond 15 years after Fontan operation, 6 patients (12.5%) developed nonsustained VT; 4 belonging to the APC group at 15, 22, 22, and 24 years post surgery (2 with tricuspid atresia, 1 with tricuspid stenosis, and 1 with double inlet LV), and 2 belonging to the TCPC group at 16 and 19 years post surgery (both with right isomerism heart). They developed VT at the age of 28, 29, 32, 32, 34, and 34 years old. We defined VT as 3 or more consecutive premature ventricular contractions. In all 6 patients, VT was detected during the Holter electrocardiographic monitoring test. No one experienced circulatory collapse. In all the patients, the heart rate was 100 to 150 beats per minute, the duration was 5 to 32 beats, and the frequency was 1 to 3 times per 24 hours. Of the 6 patients who suffered from VT, we performed an electrophysiologic study in one patient with severe Fig 2. Serial changes of ejection fraction of the systemic ventricle. ( left ventricle [LV]; e right ventricle [RV]; EF ejection fraction.) Fig 4. Serial changes of end-diastolic pressure (EDP) of the systemic ventricle.

5 176 NAKAMURA ET AL Ann Thorac Surg VENTRICULAR PERFORMANCE IN FONTAN 2011;91: Table 2. Serial Changes of Peak Oxygen Uptake (% of Normal) at Exercise Test 5 Years (n 36) 10 Years (n 43) 15 Years (n 40) Overall patients APC group TCPC group a a LV group c 50 8 c RV group b 48 9 b BV group a, b, c p APC atriopulmonary connection; BV biventricular; LV left ventricle; RV right ventricle; TCPC total cavopulmonary connection. tricuspid stenosis. This patient underwent Fontan conversion 23 years after APC-type Fontan operation. Holter electrocardiographic monitoring test performed 3 years after Fontan conversion demonstrated frequent multiform PVCs (premature ventricular contractions) (20% of total heart beats) and nonsustained VT. By the endocardial activation mapping procedure, the site of the tachycardia was assumed to be in the free wall of the right ventricle. Catheter ablation caused transient (several minutes) disappearance of PVCs. After inducing aprindine, the patient was free of VT and the frequency of PVCs decreased remarkably. Cumulative freedom from VT was not significantly different between the APC and TCPC groups, or among the RV, LV, and BV groups. Preoperative, perioperative, and postoperative factors listed in Table 3 were tested for their impact on the occurrence of VT by univariate analysis. We classified surgical era as before 1987 and after 1988 because we had begun to apply the TCPC-type procedure since Age at Fontan operation (p 0.005), age at final follow-up (p 0.000), surgical era (p 0.013), follow-up period after Fontan operation (p 0.002), and maximum BNP at follow-up (p 0.046) were found to be significant risk factors. Age at Fontan operation was significantly higher in the VT group ( vs years). Age at final follow-up was significantly higher in the VT group ( vs years). As for surgical era, of the 15 patients in whom the Fontan operation was performed before 1987, 5 patients have developed VT; therefore, the odds ratio of VT between patients in whom the Fontan operation was performed before 1987 and after 1988 was 16. Follow-up period after the Fontan operation was significantly longer in the VT group ( vs years). The median maximum BNP at follow-up was PG/mL (range, 29.2 to 756.7) in the VT group and 48.9 PG/mL (range, 10.1 to 488.2) in the non-vt group. The EDP of the systemic ventricle was higher in the VT group 10 and 15 years post surgery, although not significantly. Preoperative EF was lower in the VT group, although not significantly (p 0.092). To evaluate the onset of VT, age at Fontan operation, and ventricular morphology, we examined preoperative EF and found that it had no correlation with age at Fontan operation; however, in the LV group, preoperative EF was significantly lower in the VT group (p 0.014) (Fig 5). These 5 significant values in a univariate analysis were entered in a multivariate analysis applying Cox proportional hazard methods using the onset of VT as a study endpoint. The median maximum BNP at follow-up was dichotomized into 2 groups, BNP of 50 PG/mL or greater and BNP less than 50 PG/mL, because the median maximum BNP at follow-up in all 48 patients was 49.8 PG/mL. In our cohort, age at final follow-up correlated proportionally with age at Fontan operation (R , p 0.000). Age at final follow-up also correlated proportionally with the follow-up period after Fontan operation (R , p 0.000). Therefore, we first entered age at Fontan operation, surgical era, follow-up period after Fontan operation, and maximum BNP at follow-up in a multivariate analysis. The only significant risk factor for the onset of VT in this multivariate analysis was age at Fontan operation (Table 4; multivariate analysis 1). Then we entered age at final follow-up, surgical era, and maximum BNP at follow-up in a multivariate analysis. The only significant risk factor for the onset of VT in this multivariate analysis was age at final follow-up (Table 4; multivariate analysis 2). We could not determine which was more significant of the two risk factors (age at Fontan operation and age at final follow-up) because absolute age correlated proportionally with age at Fontan operation in our cohort. The functional classification of patients determined according to the New York Heart Association (NYHA) (30 in class I and 18 in class II), maximum BNP, and Pvo 2 during the latest exercise test were evaluated as the parameters of cardiopulmonary function and the onset of VT (Fig 6). Although the patients with high maximum BNP at follow-up and low Pvo 2 during the latest exercise test had a tendency to be in low functional class, we could not figure out the correlation between the onset of VT and these parameters. Comment In this study we analyzed the serial changes in parameters at cardiac catheterization and exercise test every 5 years in Fontan patients post surgery. We admit that the parameters measured did not reflect actual functional class because cardiac catheterization was performed with the patient under sedation [9]. Nonetheless, we could find the trend of cardiopulmonary parameters during the 15-year follow-up. Cardiac index in the APC group began to decrease after 10 years post surgery. It was lower than CI in the TCPC group after 10 years, suggesting APC as failing Fontan circulation [10]. With regard to ventricular systolic function, we measured only EF. In our cohort, ventricular systolic function estimated by EF seemed to be preserved. The EF had not changed significantly during the 15-year follow-up, but the LV group showed a significantly higher EF than the RV group post surgery, as previously reported [9]. In our

6 Ann Thorac Surg NAKAMURA ET AL 2011;91: VENTRICULAR PERFORMANCE IN FONTAN 177 Table 3. Factors Tested for Impact on the Occurrence of Ventricular Tachycardia Factors Parameters p (Univariate) Preoperative factors Patient demographics Age at Fontan operation Sex 0.13 Morphology Ventricular morphology 0.34 Palliative procedures Number of palliative procedures 0.87 Preoperative hemodynamics on cardiac catheterization Ejection fraction of the systemic ventricle Systemic ventricular end-diastolic volume 0.43 Arterial blood saturation 0.52 Perioperative factors Type of Fontan operation 0.52 Surgical era Operation time 0.18 Extracorporeal circuit time 0.21 Myocardial ischemia time 0.79 Postoperative factors: Age Age at final follow-up Follow-up Follow-up period after Fontan operation Postoperative hemodynamics on cardiac catheterization at 1 year after operation Postoperative hemodynamics on cardiac catheterization at 5 years after operation Postoperative hemodynamics on cardiac catheterization at 10 years after operation Postoperative hemodynamics on cardiac catheterization at 15 years after operation Cardiac index 0.8 Ejection fraction of the systemic ventricle 0.48 Systemic ventricular end-diastolic volume 0.64 Systemic ventricular end-diastolic 0.84 pressure Cardiac index 0.19 Ejection fraction of the systemic ventricle 0.2 Systemic ventricular end-diastolic volume 0.48 Systemic ventricular end-diastolic 0.36 pressure Cardiac index 0.49 Ejection fraction of the systemic ventricle 0.98 Systemic ventricular end-diastolic volume 0.52 Systemic ventricular end-diastolic pressure Cardiac index Ejection Fraction of the systemic ventricle 0.55 Systemic ventricular end-diastolic volume 0.62 Systemic ventricular end-diastolic pressure Findings at exercise test at 5 years after operation Peak oxygen uptake 0.11 Findings at exercise test at 10 years after operation Peak oxygen uptake 0.47 Findings at exercise test at 15 years after operation Peak oxygen uptake 0.64 Clinical symptoms New York Heart Association functional 0.5 class Neurohumoral factor Brain natriuretic peptides Medications Beta blocker 0.14 Angiotensin converting enzyme inhibitor 0.91 group, significant change in EF between before and 1 year after Fontan operation was recognized only in the RV group, suggesting the impact of ventricular morphology on changes in EF in the short-term postoperative period. Because EF measured at cardiac catheterization is a load-dependent index, it may fail to reflect major changes in contractility [11]. Senzaki and colleagues [12] reported that the global ventricular contractile function estimated by cardiac catheterization remains preserved in Fontan patients who are asymptomatic with good functional status, and that CI and fractional shortening are significantly lower in Fontan patients as a result of the increased afterload. With regard to ventricular diastolic function, we measured only EDP. In our cohort, ventricular diastolic function estimated by EDP seemed to decline gradually. End-diastolic pressure had increased gradually and stabilized after 10 years post surgery. The EDP measured at cardiac catheterization is a predictor of only late diastolic function. Ventricular diastolic dysfunction in Fontan pa-

7 178 NAKAMURA ET AL Ann Thorac Surg VENTRICULAR PERFORMANCE IN FONTAN 2011;91: Fig 6. New York Heart Association (NYHA) functional class, maximum brain natriuretic peptide (BNP), and partial pressure of oxygen, venous (PVo 2 ) during the latest exercise test, and the onset of ventricular tachycardia (VT). Fig 5. Preoperative ejection fraction (EF) and age at Fontan operation in the left ventricle (LV) group. (Πnon-ventricular tachycardia in LV group; ventricular tachycardia in LV group.) tients has been studied extensively. It might be caused by the development of asynchronous ventricular relaxation resulting from an acute preload reduction and the development of a hypertrophic systemic ventricle [13]. Ventricular diastolic dysfunction seems to progress late after Fontan operation, and it cannot be simply explained by hypertrophy because a ventricular mass to volume ratio seems to regress during follow-up [14]. In our study, the process of volume reduction was completed between 1 and 5 years post surgery because EDV at 1 year was larger than at 5 years post surgery, and EDV had stabilized after 5 years post surgery. However, EDP at 10 years was significantly higher than at 5 years, suggesting that not only preload reduction but also some other factor was related to ventricular diastolic dysfunction. Considering our data and the reports we have cited, ventricular Table 4. Factors Tested for Impact on the Occurrence of Ventricular Tachycardia by Multivariate Analysis Factors Odds Ratio p Value Multivariate analysis 1 Age at Fontan operation (year) Surgical era (before 1987) Follow-up period after Fontan operation (year) Maximum brain natriuretic peptide ( 50 pg/ml) Multivariate analysis 2 Age at final follow-up Surgical era (before 1987) Maximum brain natriuretic peptide ( 50 pg/ml) systolic function appears to be relatively well preserved in a 15-year follow-up, whereas ventricular diastolic dysfunction appears to progress gradually. With regard to Sao 2, it was lower in the TCPC group than that in the APC group probably due to desaturation caused by right-left shunt of coronary sinus flow [7]. The increase in Sao 2 in each group during follow-up suggested the impact of spontaneous closure of intraatrial baffle leak and collaterals on Sao 2. Beyond 15 years after Fontan operation, 6 older patients (12.5%) with a higher age at Fontan operation developed VT, irrespective of ventricular function estimated by cardiac catheterization. All the patients with VT were in a relatively good functional class (NYHA class I or II). We did not find any reports describing ventricular tachycardia in Fontan patients with a relatively good functional class on a long-term follow-up. There have been many studies on ventricular arrhythmias in congenital heart defects, especially in patients with tetralogy of Fallot (TOF). Recently, many research centers devoted to the study of cardiovascular disease have conducted electrophysiologic studies on patients with repaired TOF and successfully identified ventricular arrhythmogenic areas, but in almost all cases these were localized in the surgically corrected area [15]. Myocardial fibrosis has been found in patients who died suddenly after definitive repair of TOF, which produced reentry circuits for VT [16]. Ventricular arrhythmias have also been detected in unrepaired TOF patients and a significant increase in ventricular arrhythmia with increasing age has been noted [17]. This has led to the conclusion that the surgical procedure is not the only cause for the production of arrhythmogenic areas. Chowdhury and colleagues [18] examined surgically resected crista supraventricularis muscle in TOF patients and found that age at repair, cyanosis, and elevated EDP were risk factors for pathologic changes, and that age at repair had

8 Ann Thorac Surg NAKAMURA ET AL 2011;91: VENTRICULAR PERFORMANCE IN FONTAN 179 a significant influence on the presence of ventricular arrhythmias. Volume overload might be a cause of myocardial fibrosis, as in adult patients with aortic regurgitation and congestive heart failure [19, 20], although few studies have described myocardial fibrosis in volumeoverloaded hearts with congenital heart defects. In our study, parameters during the postoperative course, including ventricular performance estimated by cardiac catheterization and transthoracic echocardiography and cardiopulmonary function estimated by exercise test, did not correlate with onset of VT without maximum BNP at follow-up. Evaluation of BNP in Fontan patients is still uncertain, unlike that in patients with acquired heart disease. Bolger and colleagues [21] found that the degree of neurohormonal activation relates closely to NYHA functional class and to the systemic ventricular function in adults with congenital heart disease, including singleventricle physiology. Larsson and colleagues [22] found that neurohormonal activation related to NYHA functional class but not to ventricular function and exercise capacity in Fontan patients. Inai and colleagues [23] reported that BNP levels were neither determinants of exercise tolerance nor prognostic predictors in Fontan patients. Considering that our cohort presented VT only after 15 years post surgery, there might be additional postoperative factors related to the onset of VT other than maximum BNP at follow-up. In our study, none of the 6 patients who developed VT had undergone procedures in the ventricles. The only significant risk factors for the onset of VT in a multivariate analysis were age at Fontan operation and age itself. In 6 patients who developed VT, the interval between Fontan operation and the onset of VT correlated inversely with age at Fontan operation. We could not determine which was more significant of the two risk factors because absolute age correlated proportionally with age at Fontan operation in our cohort. However, we could suspect that pathologic changes caused by longstanding cyanosis and volume overload before Fontan operation might produce arrhythmogenic areas, resulting in VT with an additional postoperative factor, age itself, in patients when they got close to their thirties. As for Pvo 2 during the exercise test, Fredriksen and colleagues [24] performed an exercise test in 52 adult patients with a Fontan circulation who performed APCtype Fontan operation. They described that age at surgery was the single most important predictor of Pvo 2 in patients with a Fontan circulation and that no effect of time since repair was found. In our study, we checked serial changes of Pvo 2 during the exercise test and we could find no relationship between Pvo 2 and age at Fontan operation. The Pvo 2 decreased serially, although overall, not significantly. In the RV group Pvo 2 at 10 years was significantly lower than at 5 years, and in the LV group Pvo 2 at 15 years was significantly lower than at 10 years after Fontan operation. We suspect that the difference between the Fredriksen and colleagues study and ours came from the difference in the distribution of patients age (our patients were much younger). Our study has some limitations. First, the cohort studied was a heterogeneous group. We categorized patients into three groups based on ventricular morphology, but in each group morphologic conditions were diverse. Second, cardiac catheterization was performed with the patient under sedation such that the parameters measured did not reflect functional class [9]. Third, the cohort consisted of selected patients who could survive for more than 15 years after Fontan operation; therefore, data of patients who died or were lost to follow-up were missing. Fourth, we had only one or two years of follow-up after the onset of VT in these patients; therefore, whether VT patients have shorter life expectancy or not was not determined by our study. But we should be very careful of VT in Fontan patients and take measures to deal with it. For example, we should consider implantable cardioverter defibrillator implantation in selected Fontan patients when we perform Fontan conversion, although we have had no experience of it so far. In patients with Fontan circulation for more than 15 years, ventricular systolic function appears to be relatively well preserved, whereas ventricular diastolic dysfunction appears to progress gradually. Some older patients with a higher age at the time of the procedure developed VT after 15 years post surgery irrespective of ventricular function estimated by cardiac catheterization. Cumulative freedom from VT was not significantly different between the APC and TCPC groups, or among the RV, LV, and BV groups. In our study, we could not find the postoperative risk factors for the onset of VT other than age itself. The advent of VT might be a key event in longer postoperative periods. Further studies are needed to investigate VT in Fontan patients. References 1. Fontan F, Baudet E. Surgical repair of tricuspid atresia. Thorax 1971;26: de Leval MR, Kilner PK, Gewillig M, Bull C. Total cavopulmonary connection: a logical alternative to atriopulmonary connection for complex Fontan operations. Experimental studies and early clinical experience. J Thorac Cardiovasc Surg 1988;96: Ono M, Boethig D, Goerler H, Lange M, Westhoff-Bleck M, Breymann T. 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