Long-term outcomes of single-ventricle palliation for pulmonary atresia with intact ventricular septum: Fontan survivors remain at risk of late myocardial ischaemia and death

Long-term outcomes of single-ventricle palliation for pulmonary atresia with intact ventricular... Abstract OBJECTIVES The specific outcomes of patients with pulmonary atresia with intact ventricular septum late after Fontan palliation are unknown. Patients with smaller right ventricles and myocardial sinusoids are known to have worse survival in the first years of life. Whether the potential for coronary ischaemia affects the long-term outcomes of these patients after Fontan palliation is still unknown. METHODS All patients with pulmonary atresia with intact ventricular septum who underwent the Fontan procedure from 1984 to 2016 in Australia and New Zealand were identified, and preoperative, perioperative and follow-up data were collected. RESULTS Late follow-up data were available for 120 patients. The median length of follow-up after the Fontan procedure was 9.1 years (interquartile range 4.2–15.4 years). Late death occurred in 9% of patients (11/120). Six were sudden, unexpected deaths; 4 of those occurred in patients known to have right ventricle-dependent coronary circulation (RVDCC). Those with RVDCC had a higher incidence of sudden death (4/20 vs 2/100; P = 0.007). RVDCC was associated with late death (P = 0.01) and the development of myocardial ischaemia after Fontan completion (P < 0.001). The 10-year survival rate was 77% (95% confidence interval 56–100%) for patients with RVDCC vs 96% (95% confidence interval 92–100%) for patients without RVDCC. CONCLUSIONS Long-term survival of patients with pulmonary atresia with intact ventricular septum after the Fontan procedure is excellent, but patients with RVDCC remain susceptible to coronary ischaemia and sudden death. Closer surveillance and investigation for exercise-induced ischaemia may be necessary. Congenital heart disease, Fontan procedure, Pulmonary valve, Sinusoids, Right ventricular dependence INTRODUCTION Pulmonary atresia with intact ventricular septum (PA-IVS) is a condition with a wide variation of severity. The most favourable cases can be directed to biventricular repair whereas those at the most severe end of the disease spectrum are directed to single-ventricle palliation. Patients affected with its most severe form have small hypertrophied right ventricles and a tricuspid valve annulus of small dimensions [1–4]. The high pressures generated in these small right ventricular cavities can result commonly in the repermeation of myocardial sinusoids [5–9]. In up to 35% of patients with pulmonary atresia and an intact ventricular septum, the coronary blood flow becomes mainly dependent on perfusion from these sinusoids, to the extent that some of the patients have been described to be born with coronary ostial stenosis [6, 8–13]. Twenty percent of patients born with pulmonary atresia and an intact ventricular septum die within the first 2 years of life [2, 3, 11, 12, 14]. The presence of a smaller tricuspid valve annulus and the existence of coronary stenosis and right ventricle-dependent coronary circulation (RVDCC) have been identified as risk factors for early death. The specific outcomes of these patients have been limited to 10 years from birth, with only some follow-up after a Fontan circulation procedure. The Australian and New Zealand Fontan Registry, created in 2009, collects health information on all survivors of the Fontan procedure. We wanted to identify the late outcomes of patients with pulmonary atresia and an intact ventricular septum from the registry to elucidate whether potential coronary ischaemia may impact the late survival of this population. MATERIALS AND METHODS A retrospective analysis of the data of all patients with the primary diagnosis of pulmonary atresia and intact ventricular septum who have undergone a Fontan procedure in Australia and New Zealand was performed using The Australian and New Zealand Fontan Registry. The Australian and New Zealand Fontan Registry began in 2009 and includes only those patients in both countries who survived the hospital stay after a Fontan procedure [15]. The design of the registry was approved nationally by both countries and by local hospital ethics committees in each country. Approval for retrospective studies was covered within the application and waiver for consent was granted for retrospective studies. At the time of the study, there were 1449 patients included in the registry; 22 patients refused to participate. Due to the design of the registry, the review only included patients who underwent single-ventricle palliation via the Fontan operation but not via biventricular repair. A total of 128 children born between August 1972 and November 2012 were identified to have a diagnosis of PA-IVS. Patients who suffered early death, defined as death after Fontan completion but prior to hospital discharge, were excluded (5 patients). Patients with no follow-up information after Fontan completion were also excluded (3 patients). The remaining 120 patients constituted the core of the study. Of the 120 hospital survivors, 16 had an atriopulmonary (1984–1992) Fontan procedure; 17 had a lateral tunnel (1988–1997) procedure; and 87 had an extracardiac conduit Fontan (1997–2016) procedure. Two patients had undergone their Fontan procedures overseas. The characteristics of these patients are given in Table 1. Table 1: Patient characteristics Total (n = 120) RVDCC (n = 20) Non-RVDCC (n = 100) Male 60 (50) 12 (60) 48 (48) Dextrocardia 2 (2) 0 (0) 2 (2) Ebstein’s anomaly 4 (3) 1 (5) 3 (3) Birth weight (kg) 3.0 (2.6–3.4) 3.2 (2.8–3.8) 2.9 (2.5–3.3) Gestational age (weeks) 38 (37–40) 39 (38–40) 38 (37–40) Antenatal diagnosis 59 (49) 8 (40) 51 (51) TV z-score −3.2 (−3.9 to −2.2) −3.8 (−4.5 to −3.2) −3.1 (−3.7 to −2.2) RV hypoplasia  Mild 2 (2) 0 (0) 2 (2)  Moderate 31 (26) 4 (20) 27 (27)  Severe 87 (73) 16 (80) 71 (71) Myocardial sinusoids 83 (69) 20 (100) 63 (63) Pre-Fontan procedures  Age at Stage I (days) 4 (2–7) 6 (3.8–9.5) 4 (2–7)  Prior staging with BCPS 92 (77) 16 (80) 76 (76)  Age at Stage II (months)a 8.0 (5.2–14.3) 6.1 (4.3–8.2) 8.4 (5.5–14.5)  Pulmonary artery intervention 29 (24) 8 (40) 22 (21) Pre-Fontan haemodynamics  Pulmonary artery pressure (mmHg)b 11.0 (9.0–13.0) 10.0 (9.0–12.5) 11.0 (10.0–13.0)  Aortopulmonary or venovenous collaterals 53 (44) 13 (65) 40 (40)  Atrioventricular valve regurgitation ≥ moderate 12 (10) 4 (20) 8 (8) Fontan operative characteristics  Fenestration 48 (40) 8 (40) 41 (41)  Age at Fontan (years) 4.6 (3.6–6.0) 4.1 (3.5–4.9) 4.7 (3.6–6.1)  Fontan type   Extracardiac conduit 87 (73) 15 (75) 72 (72)   Lateral tunnel 17 (14) 2 (10) 15 (15)   Atriopulmonary 16 (13) 3 (15) 13 (13)  Concomitant procedures 40 (33) 6 (30) 34 (34)  Concomitant pulmonary artery reconstruction 20 (17) 3 (15) 17 (17)  Aortic cross-clamp time (min) 19.3 ± 27.4 17.1 ± 24.3 19.8 ± 28.3  Cardiopulmonary bypass time (min) 107.4 ± 42.5 89.2 ± 29.9 111.8 ± 44.0  ICU duration (days) 1 (1–2) 1 (1–2) 1 (1–2)  Length of hospital stay (days) 14 (10–20) 13.5 (10–19.3) 14 (10–21)  Chest tube duration (days) 9 (7–15) 9 (5.8–14.5) 9 (7–15.5) Total (n = 120) RVDCC (n = 20) Non-RVDCC (n = 100) Male 60 (50) 12 (60) 48 (48) Dextrocardia 2 (2) 0 (0) 2 (2) Ebstein’s anomaly 4 (3) 1 (5) 3 (3) Birth weight (kg) 3.0 (2.6–3.4) 3.2 (2.8–3.8) 2.9 (2.5–3.3) Gestational age (weeks) 38 (37–40) 39 (38–40) 38 (37–40) Antenatal diagnosis 59 (49) 8 (40) 51 (51) TV z-score −3.2 (−3.9 to −2.2) −3.8 (−4.5 to −3.2) −3.1 (−3.7 to −2.2) RV hypoplasia  Mild 2 (2) 0 (0) 2 (2)  Moderate 31 (26) 4 (20) 27 (27)  Severe 87 (73) 16 (80) 71 (71) Myocardial sinusoids 83 (69) 20 (100) 63 (63) Pre-Fontan procedures  Age at Stage I (days) 4 (2–7) 6 (3.8–9.5) 4 (2–7)  Prior staging with BCPS 92 (77) 16 (80) 76 (76)  Age at Stage II (months)a 8.0 (5.2–14.3) 6.1 (4.3–8.2) 8.4 (5.5–14.5)  Pulmonary artery intervention 29 (24) 8 (40) 22 (21) Pre-Fontan haemodynamics  Pulmonary artery pressure (mmHg)b 11.0 (9.0–13.0) 10.0 (9.0–12.5) 11.0 (10.0–13.0)  Aortopulmonary or venovenous collaterals 53 (44) 13 (65) 40 (40)  Atrioventricular valve regurgitation ≥ moderate 12 (10) 4 (20) 8 (8) Fontan operative characteristics  Fenestration 48 (40) 8 (40) 41 (41)  Age at Fontan (years) 4.6 (3.6–6.0) 4.1 (3.5–4.9) 4.7 (3.6–6.1)  Fontan type   Extracardiac conduit 87 (73) 15 (75) 72 (72)   Lateral tunnel 17 (14) 2 (10) 15 (15)   Atriopulmonary 16 (13) 3 (15) 13 (13)  Concomitant procedures 40 (33) 6 (30) 34 (34)  Concomitant pulmonary artery reconstruction 20 (17) 3 (15) 17 (17)  Aortic cross-clamp time (min) 19.3 ± 27.4 17.1 ± 24.3 19.8 ± 28.3  Cardiopulmonary bypass time (min) 107.4 ± 42.5 89.2 ± 29.9 111.8 ± 44.0  ICU duration (days) 1 (1–2) 1 (1–2) 1 (1–2)  Length of hospital stay (days) 14 (10–20) 13.5 (10–19.3) 14 (10–21)  Chest tube duration (days) 9 (7–15) 9 (5.8–14.5) 9 (7–15.5) Data expressed as n (%), mean ± SD or median (IQR). a 91 bidirectional cavopulmonary shunts, 2 bilateral BCPS, 1 Kawashima. b Data available for 104 patients. BCPS: bidirectional cavopulmonary shunt; ICU: intensive care unit; IQR: interquartile range; RV: right ventricle; RVDCC: right ventricle-dependent coronary circulation; SD: standard deviation; TV: tricuspid valve. Table 1: Patient characteristics Total (n = 120) RVDCC (n = 20) Non-RVDCC (n = 100) Male 60 (50) 12 (60) 48 (48) Dextrocardia 2 (2) 0 (0) 2 (2) Ebstein’s anomaly 4 (3) 1 (5) 3 (3) Birth weight (kg) 3.0 (2.6–3.4) 3.2 (2.8–3.8) 2.9 (2.5–3.3) Gestational age (weeks) 38 (37–40) 39 (38–40) 38 (37–40) Antenatal diagnosis 59 (49) 8 (40) 51 (51) TV z-score −3.2 (−3.9 to −2.2) −3.8 (−4.5 to −3.2) −3.1 (−3.7 to −2.2) RV hypoplasia  Mild 2 (2) 0 (0) 2 (2)  Moderate 31 (26) 4 (20) 27 (27)  Severe 87 (73) 16 (80) 71 (71) Myocardial sinusoids 83 (69) 20 (100) 63 (63) Pre-Fontan procedures  Age at Stage I (days) 4 (2–7) 6 (3.8–9.5) 4 (2–7)  Prior staging with BCPS 92 (77) 16 (80) 76 (76)  Age at Stage II (months)a 8.0 (5.2–14.3) 6.1 (4.3–8.2) 8.4 (5.5–14.5)  Pulmonary artery intervention 29 (24) 8 (40) 22 (21) Pre-Fontan haemodynamics  Pulmonary artery pressure (mmHg)b 11.0 (9.0–13.0) 10.0 (9.0–12.5) 11.0 (10.0–13.0)  Aortopulmonary or venovenous collaterals 53 (44) 13 (65) 40 (40)  Atrioventricular valve regurgitation ≥ moderate 12 (10) 4 (20) 8 (8) Fontan operative characteristics  Fenestration 48 (40) 8 (40) 41 (41)  Age at Fontan (years) 4.6 (3.6–6.0) 4.1 (3.5–4.9) 4.7 (3.6–6.1)  Fontan type   Extracardiac conduit 87 (73) 15 (75) 72 (72)   Lateral tunnel 17 (14) 2 (10) 15 (15)   Atriopulmonary 16 (13) 3 (15) 13 (13)  Concomitant procedures 40 (33) 6 (30) 34 (34)  Concomitant pulmonary artery reconstruction 20 (17) 3 (15) 17 (17)  Aortic cross-clamp time (min) 19.3 ± 27.4 17.1 ± 24.3 19.8 ± 28.3  Cardiopulmonary bypass time (min) 107.4 ± 42.5 89.2 ± 29.9 111.8 ± 44.0  ICU duration (days) 1 (1–2) 1 (1–2) 1 (1–2)  Length of hospital stay (days) 14 (10–20) 13.5 (10–19.3) 14 (10–21)  Chest tube duration (days) 9 (7–15) 9 (5.8–14.5) 9 (7–15.5) Total (n = 120) RVDCC (n = 20) Non-RVDCC (n = 100) Male 60 (50) 12 (60) 48 (48) Dextrocardia 2 (2) 0 (0) 2 (2) Ebstein’s anomaly 4 (3) 1 (5) 3 (3) Birth weight (kg) 3.0 (2.6–3.4) 3.2 (2.8–3.8) 2.9 (2.5–3.3) Gestational age (weeks) 38 (37–40) 39 (38–40) 38 (37–40) Antenatal diagnosis 59 (49) 8 (40) 51 (51) TV z-score −3.2 (−3.9 to −2.2) −3.8 (−4.5 to −3.2) −3.1 (−3.7 to −2.2) RV hypoplasia  Mild 2 (2) 0 (0) 2 (2)  Moderate 31 (26) 4 (20) 27 (27)  Severe 87 (73) 16 (80) 71 (71) Myocardial sinusoids 83 (69) 20 (100) 63 (63) Pre-Fontan procedures  Age at Stage I (days) 4 (2–7) 6 (3.8–9.5) 4 (2–7)  Prior staging with BCPS 92 (77) 16 (80) 76 (76)  Age at Stage II (months)a 8.0 (5.2–14.3) 6.1 (4.3–8.2) 8.4 (5.5–14.5)  Pulmonary artery intervention 29 (24) 8 (40) 22 (21) Pre-Fontan haemodynamics  Pulmonary artery pressure (mmHg)b 11.0 (9.0–13.0) 10.0 (9.0–12.5) 11.0 (10.0–13.0)  Aortopulmonary or venovenous collaterals 53 (44) 13 (65) 40 (40)  Atrioventricular valve regurgitation ≥ moderate 12 (10) 4 (20) 8 (8) Fontan operative characteristics  Fenestration 48 (40) 8 (40) 41 (41)  Age at Fontan (years) 4.6 (3.6–6.0) 4.1 (3.5–4.9) 4.7 (3.6–6.1)  Fontan type   Extracardiac conduit 87 (73) 15 (75) 72 (72)   Lateral tunnel 17 (14) 2 (10) 15 (15)   Atriopulmonary 16 (13) 3 (15) 13 (13)  Concomitant procedures 40 (33) 6 (30) 34 (34)  Concomitant pulmonary artery reconstruction 20 (17) 3 (15) 17 (17)  Aortic cross-clamp time (min) 19.3 ± 27.4 17.1 ± 24.3 19.8 ± 28.3  Cardiopulmonary bypass time (min) 107.4 ± 42.5 89.2 ± 29.9 111.8 ± 44.0  ICU duration (days) 1 (1–2) 1 (1–2) 1 (1–2)  Length of hospital stay (days) 14 (10–20) 13.5 (10–19.3) 14 (10–21)  Chest tube duration (days) 9 (7–15) 9 (5.8–14.5) 9 (7–15.5) Data expressed as n (%), mean ± SD or median (IQR). a 91 bidirectional cavopulmonary shunts, 2 bilateral BCPS, 1 Kawashima. b Data available for 104 patients. BCPS: bidirectional cavopulmonary shunt; ICU: intensive care unit; IQR: interquartile range; RV: right ventricle; RVDCC: right ventricle-dependent coronary circulation; SD: standard deviation; TV: tricuspid valve. The 120 patients had the following procedures before the Fontan procedure: Blalock–Taussig shunt (82), interventional catheter (62), central shunt (31), pulmonary artery reconstruction (20), pulmonary valvotomy (18), right ventricle outflow tract patch (13), Waterston shunt (5), tricuspid valve repair (3), mitral valve repair (2) and tricuspid valve repair (1). Long-term follow-up data were gathered from The Australian and New Zealand Fontan Registry. RVDCC was defined as the presence of stenosis of 2 or more main coronary arteries or coronary ostial atresia. RVDCC was assessed from preoperative coronary and right ventricular angiograms. Coronary artery stenosis was defined as more than 50% stenosis of the luminal surface of the vessel or if it was designated as significant in the cardiologist’s report. Patients with coronary atresia were included in this group. If data were missing from the registry, information was obtained from hospital databases and medical records. Preoperative, perioperative, postoperative and follow-up data were collected. Operative reports, discharge summaries and follow-up letters were reviewed retrospectively, as were echocardiographic reports, catheterisation reports, electrocardiograms (ECGs), cardiac magnetic resonance images, Holter monitor reports and exercise stress test reports. Significant events recorded were death, reintervention, protein losing enteropathy, arrhythmia, myocardial ischaemia (based on ECG changes, symptoms, exercise ECGs) and New York Heart Association (NYHA) Class III/IV. Early mortality includes all deaths prior to discharge after completion of the Fontan procedure. Late mortality includes deaths of patients who survived the hospital admission after the Fontan completion. Reintervention includes any surgical reoperation or transcatheter intervention after Fontan completion excluding fenestration closure. Fontan failure was defined as late death, Fontan takedown after hospital discharge, reoperation on the Fontan circuit, protein losing enteropathy, plastic bronchitis or NYHA Class III/IV at follow-up. An ischaemic event was defined as ST-segment changes or T-wave inversion that was determined to be a sign of ischaemia by the reporting cardiologist, an episode of chest pain or dyspnoea in association with ischaemic ECG changes, inducible ischaemia on an exercise tolerance test or elevated cardiac enzymes associated with angina or dyspnoea. Isolated ST-segment and T-wave changes in the absence of symptoms were not considered to be ischaemic for this study. Statistical analysis Analyses were performed in R (version 3.3.2; http://www.r-project.org/). Categorical data are summarised as counts and proportions (percentage). Continuous data are summarised as mean ± standard deviation or median [interquartile range (IQR)], depending on normality of distribution. The end-points examined for the 120 hospital survivors were late mortality, Fontan failure, late adverse event, reintervention or late mortality and myocardial ischaemia (based on ECG changes, symptoms, exercise ECGs). Survival and freedom from non-mortality end-points were estimated with 95% confidence intervals (CIs) using the Kaplan–Meier method. Survival and freedom from ischaemia according to RVDCC were plotted using the Kaplan–Meier method and compared by log-rank statistics in all patients. All P values less than 0.05 were considered statistically significant. Risk factors were examined using the Cox regression analyses from which hazard ratios (HRs) and 95% CIs were generated. The proportional hazards assumption was assessed based on the method of Harrell and Lee and via diagnostic plots. The proportional hazard assumption was met for all variables. The factors analysed are listed in Table 1. RESULTS A total of 128 patients underwent the Fontan procedure for PA-IVS. There were 5 deaths prior to discharge after Fontan completion, and 3 patients were lost to follow-up. Causes of death were stroke (2), sepsis (1), pneumonia (1) and pulmonary embolus (1). None of these patients had RVDCC. The 120 hospital survivors comprised the cohort for this study. They had an average of 3.2 ± 1.8 surgical procedures before the Fontan procedure. Fifty-two percent of the patients (62/120) underwent an average of 0.7 ± 0.8 interventional catheter procedures before the Fontan procedure. Patient characteristics are summarised in Table 1. The median follow-up time after Fontan completion was 9.1 years (IQR 4.2–15.4 years; mean 10.9 ± 8.1 years). The median age of the patients at the end of the follow-up period was 14.5 years (IQR 10.0–20.8 years; mean 15.9 ± 8.3 years). Follow-up data are summarised in Table 2. Of the 109 patients still alive, 76 patients (70%) and 32 patients (29%) were in NYHA functional classes I and II, respectively. One patient had ongoing palpitations, dyspnoea and chest pain (NYHA III). Forty-six patients (42%) participated in competitive or recreational sporting activities and 28 patients (26%) reported below average activity levels. Patients were prescribed a mean of 1.6 ± 0.9 cardiac medications, and patients with RVDCC were prescribed more medications (P = 0.02) (Table 2). Table 2: Follow-up data Clinical information at the last follow-up visit Total (n = 109) RVDCC (n = 15) Non-RVDCC (n = 94) NYHA 1.3 ± 0.5 1.3 ± 0.5 1.3 ± 0.5 Participation in a sporta 46 (42) 7 (47) 39 (42) Below average activity level 28 (26) 4 (27) 24 (26) Number of cardiovascular medications 1.6 ± 0.9 2.1 ± 1.0 1.5 ± 0.9  Anticoagulants 103 (95) 15 (100) 88 (94)  Beta-blockers 16 (15) 5 (33) 11 (12)  ACE inhibitors 26 (24) 6 (40) 20 (21)  Digoxin 4 (4) 1 (7) 3 (3)  Diuretics 9 (8) 2 (13) 7 (7) ECG ST-segment–T-wave changes 18 (17) 7 (47) 11 (12) Mitral valve regurgitation ≥ moderate 3 (3) 1 (7) 2 (2) Aortic valve regurgitation ≥ moderate 2 (2) 0 (0) 2 (2) Post-Fontan complications Total (n = 120) RVDCC (n = 20) Non-RVDCC (n = 100) Angina 26 (22) 10 (50) 16 (16) Syncope 15 (13) 6 (30) 9 (9) Arrhythmia 14 (12) 2 (10) 12 (12) Thromboembolic event 13 (11) 2 (10) 14 (14) PLE 4 (3) 1 (5) 3 (3) Late death 11 (9) 5 (25) 6 (6) Sudden death 6 (5) 4 (20) 2 (2) Clinical information at the last follow-up visit Total (n = 109) RVDCC (n = 15) Non-RVDCC (n = 94) NYHA 1.3 ± 0.5 1.3 ± 0.5 1.3 ± 0.5 Participation in a sporta 46 (42) 7 (47) 39 (42) Below average activity level 28 (26) 4 (27) 24 (26) Number of cardiovascular medications 1.6 ± 0.9 2.1 ± 1.0 1.5 ± 0.9  Anticoagulants 103 (95) 15 (100) 88 (94)  Beta-blockers 16 (15) 5 (33) 11 (12)  ACE inhibitors 26 (24) 6 (40) 20 (21)  Digoxin 4 (4) 1 (7) 3 (3)  Diuretics 9 (8) 2 (13) 7 (7) ECG ST-segment–T-wave changes 18 (17) 7 (47) 11 (12) Mitral valve regurgitation ≥ moderate 3 (3) 1 (7) 2 (2) Aortic valve regurgitation ≥ moderate 2 (2) 0 (0) 2 (2) Post-Fontan complications Total (n = 120) RVDCC (n = 20) Non-RVDCC (n = 100) Angina 26 (22) 10 (50) 16 (16) Syncope 15 (13) 6 (30) 9 (9) Arrhythmia 14 (12) 2 (10) 12 (12) Thromboembolic event 13 (11) 2 (10) 14 (14) PLE 4 (3) 1 (5) 3 (3) Late death 11 (9) 5 (25) 6 (6) Sudden death 6 (5) 4 (20) 2 (2) Data expressed as n (%) or mean ± SD. a As reported by patient or caregiver. ACE: angiotensin converting enzyme; ECG: electrocardiogram; NYHA: New York Heart Association; PLE: protein losing enteropathy; RVDCC: right ventricle-dependent coronary circulation; SD: standard deviation. Table 2: Follow-up data Clinical information at the last follow-up visit Total (n = 109) RVDCC (n = 15) Non-RVDCC (n = 94) NYHA 1.3 ± 0.5 1.3 ± 0.5 1.3 ± 0.5 Participation in a sporta 46 (42) 7 (47) 39 (42) Below average activity level 28 (26) 4 (27) 24 (26) Number of cardiovascular medications 1.6 ± 0.9 2.1 ± 1.0 1.5 ± 0.9  Anticoagulants 103 (95) 15 (100) 88 (94)  Beta-blockers 16 (15) 5 (33) 11 (12)  ACE inhibitors 26 (24) 6 (40) 20 (21)  Digoxin 4 (4) 1 (7) 3 (3)  Diuretics 9 (8) 2 (13) 7 (7) ECG ST-segment–T-wave changes 18 (17) 7 (47) 11 (12) Mitral valve regurgitation ≥ moderate 3 (3) 1 (7) 2 (2) Aortic valve regurgitation ≥ moderate 2 (2) 0 (0) 2 (2) Post-Fontan complications Total (n = 120) RVDCC (n = 20) Non-RVDCC (n = 100) Angina 26 (22) 10 (50) 16 (16) Syncope 15 (13) 6 (30) 9 (9) Arrhythmia 14 (12) 2 (10) 12 (12) Thromboembolic event 13 (11) 2 (10) 14 (14) PLE 4 (3) 1 (5) 3 (3) Late death 11 (9) 5 (25) 6 (6) Sudden death 6 (5) 4 (20) 2 (2) Clinical information at the last follow-up visit Total (n = 109) RVDCC (n = 15) Non-RVDCC (n = 94) NYHA 1.3 ± 0.5 1.3 ± 0.5 1.3 ± 0.5 Participation in a sporta 46 (42) 7 (47) 39 (42) Below average activity level 28 (26) 4 (27) 24 (26) Number of cardiovascular medications 1.6 ± 0.9 2.1 ± 1.0 1.5 ± 0.9  Anticoagulants 103 (95) 15 (100) 88 (94)  Beta-blockers 16 (15) 5 (33) 11 (12)  ACE inhibitors 26 (24) 6 (40) 20 (21)  Digoxin 4 (4) 1 (7) 3 (3)  Diuretics 9 (8) 2 (13) 7 (7) ECG ST-segment–T-wave changes 18 (17) 7 (47) 11 (12) Mitral valve regurgitation ≥ moderate 3 (3) 1 (7) 2 (2) Aortic valve regurgitation ≥ moderate 2 (2) 0 (0) 2 (2) Post-Fontan complications Total (n = 120) RVDCC (n = 20) Non-RVDCC (n = 100) Angina 26 (22) 10 (50) 16 (16) Syncope 15 (13) 6 (30) 9 (9) Arrhythmia 14 (12) 2 (10) 12 (12) Thromboembolic event 13 (11) 2 (10) 14 (14) PLE 4 (3) 1 (5) 3 (3) Late death 11 (9) 5 (25) 6 (6) Sudden death 6 (5) 4 (20) 2 (2) Data expressed as n (%) or mean ± SD. a As reported by patient or caregiver. ACE: angiotensin converting enzyme; ECG: electrocardiogram; NYHA: New York Heart Association; PLE: protein losing enteropathy; RVDCC: right ventricle-dependent coronary circulation; SD: standard deviation. Deaths Nine percent of patients (11/120) died a median of 9 years (IQR 5–16 years; mean 11.1 ± 8.3 years) after hospital discharge. Seven had an atriopulmonary, 1 had a lateral tunnel and 3 had an extracardiac conduit Fontan procedure. The mean age at death was 17 years. Five of the 11 deaths were in patients with known RVDCC. In all patients who underwent Fontan completion, survival by the Kaplan–Meier method at 5, 15 and 25 years was 98% (95% CI 96–99%), 88% (95% CI 80–97%) and 80% (95% CI 67–95%) at 25 years, respectively (Fig. 1). The cause of death was identified in 10 patients: sudden unexpected death (6), thromboembolic stroke (1), pulmonary embolism (1), protein losing enteropathy (1) and liver transplant rejection (1). In 1 patient, the cause of death was unknown. RVDCC was present in 5 (45%) of those who died and in 4 (67%) of those who died suddenly. Figure 1: View largeDownload slide Kaplan–Meier survival curves with 95% confidence intervals. Figure 1: View largeDownload slide Kaplan–Meier survival curves with 95% confidence intervals. There were 6 sudden unexpected deaths that occurred a median of 12 years (IQR 7–16 years; mean 12.3 ± 6.3 years) after the Fontan procedure. One patient died suddenly during exercise and 3 died suddenly at rest. The circumstances surrounding the death of the final 2 patients were unclear because those deaths were mostly unwitnessed and there was a lack of data. Four patients had symptoms of syncopal episodes; 2 had symptoms of angina; 2 had ischaemic ECG changes; and 1 patient had a cardiac arrest 1 month before his death. Four patients were known to have RVDCC. Two patients had been completely asymptomatic during their follow-up period. Autopsy showed a congenital anomaly of the right coronary artery with intimal and medical thickening in 1 patient and focal fibrosis of the myocardium thought to be related to ischaemia in another. Right ventricle-dependent coronary circulation Twenty (17%) patients were identified as having RVDCC. Five (25%) of these patients died; 4 (20%) had a sudden unexpected death, and 1 (5%) died of sepsis secondary to protein losing enteropathy. Of these, 2 had new ischaemic changes on ECG prior to their death, 1 experienced angina and 1 presented with angina followed by a syncopal event secondary to ventricular tachycardia. Only 1 of these required reinterventions in the form of Fontan revision. Overall, 10 patients (50%) experienced angina after Fontan and 6 (30%) had syncopal events. Patients with RVDCC had a higher risk of late death (P = 0.02) and sudden death (P = 0.007) (Table 2). Overall survival in patients with RVDCC was lower, with a 10-year survival rate of 77% (95% CI 56–100%) compared to 96% (95% CI 92–100%) (Fig. 2). Forty-seven percent of patients with RVDCC showed ischaemic ECG changes after Fontan completion compared to only 12% in the non-RVDCC group (P = 0.003). By univariable analysis, RVDCC was associated with death (HR 4.7, 95% CI 1.4–16; P = 0.01) and developing myocardial ischaemia after Fontan completion (HR 3.9, 95% CI 2–8; P < 0.001) (Table 3). Table 3: Results of univariable Cox proportional hazards analysis for late outcomes Variables Univariable HR 95% CI Late death  RVDCC 4.73 1.4–16  LCA stenosis 6.3 1.6–24  RCA stenosis 9 2.7–29  AP Fontan 4.9 1.4–18 Fontan failure  LCA stenosis 3.8 1.1–13  RCA stenosis 4 1.5–11 Myocardial ischaemia  RVDCC 3.9 2–7.6  LAD stenosis 4 2.1–7.8  RCA stenosis 2.9 1.4–5.9  TV z-score (per unit increase) 0.7 0.5–0.9  Fontan before 2000 0.4 0.2–0.9 Variables Univariable HR 95% CI Late death  RVDCC 4.73 1.4–16  LCA stenosis 6.3 1.6–24  RCA stenosis 9 2.7–29  AP Fontan 4.9 1.4–18 Fontan failure  LCA stenosis 3.8 1.1–13  RCA stenosis 4 1.5–11 Myocardial ischaemia  RVDCC 3.9 2–7.6  LAD stenosis 4 2.1–7.8  RCA stenosis 2.9 1.4–5.9  TV z-score (per unit increase) 0.7 0.5–0.9  Fontan before 2000 0.4 0.2–0.9 AP: atriopulmonary; CI: confidence interval; HR: hazard ratio; LAD: left anterior descending artery; LCA: left coronary artery; RCA: right coronary artery; RVDCC: right ventricle-dependent coronary circulation; TV: tricuspid valve. Table 3: Results of univariable Cox proportional hazards analysis for late outcomes Variables Univariable HR 95% CI Late death  RVDCC 4.73 1.4–16  LCA stenosis 6.3 1.6–24  RCA stenosis 9 2.7–29  AP Fontan 4.9 1.4–18 Fontan failure  LCA stenosis 3.8 1.1–13  RCA stenosis 4 1.5–11 Myocardial ischaemia  RVDCC 3.9 2–7.6  LAD stenosis 4 2.1–7.8  RCA stenosis 2.9 1.4–5.9  TV z-score (per unit increase) 0.7 0.5–0.9  Fontan before 2000 0.4 0.2–0.9 Variables Univariable HR 95% CI Late death  RVDCC 4.73 1.4–16  LCA stenosis 6.3 1.6–24  RCA stenosis 9 2.7–29  AP Fontan 4.9 1.4–18 Fontan failure  LCA stenosis 3.8 1.1–13  RCA stenosis 4 1.5–11 Myocardial ischaemia  RVDCC 3.9 2–7.6  LAD stenosis 4 2.1–7.8  RCA stenosis 2.9 1.4–5.9  TV z-score (per unit increase) 0.7 0.5–0.9  Fontan before 2000 0.4 0.2–0.9 AP: atriopulmonary; CI: confidence interval; HR: hazard ratio; LAD: left anterior descending artery; LCA: left coronary artery; RCA: right coronary artery; RVDCC: right ventricle-dependent coronary circulation; TV: tricuspid valve. Figure 2: View largeDownload slide Kaplan–Meier survival curves by RVDCC status. Log-rank test, P = 0.005. RVDCC: right ventricle-dependent coronary circulation. Figure 2: View largeDownload slide Kaplan–Meier survival curves by RVDCC status. Log-rank test, P = 0.005. RVDCC: right ventricle-dependent coronary circulation. Myocardial ischaemia Myocardial ischaemia was noted in 43 patients (36%) through cardiology clinic reports, ECG and exercise testing. Myocardial ischaemia occurred in 36% of patients at a median of 6 years (IQR 2.1–8.5 years; mean 6.3 ± 5.6 years). Twenty-nine patients (24%) had ECG changes after Fontan completion that were suggestive of ischaemia. Fourteen patients (12%) completed an exercise tolerance test for investigation of myocardial ischaemia and showed inducible ischaemia through ECG changes and symptoms. Twenty-six patients (22%) suffered from angina. Sixty-four percent (7/11) of patients showed signs of ischaemia prior to death; 4 had ST depression and T-wave inversion on ECG, 2 suffered from ongoing angina and 1 patient had a syncopal episode associated with angina 1 month prior to his death. Of the 11 patients who died, 7 experienced ischaemia at a median of 4.8 years (IQR 1.4–8 years; mean 4.8 ± 4.2 years) and ischaemia preceded death by a median of 3.3 years (IQR 0.3–10.3 years; mean 7 ± 8.9 years). Patients who were found to have ischaemia had the following further examinations: cardiac magnetic resonance images (n = 13), exercise stress test (n = 17), cardiac catheterisation (n = 14) and cardiac computed tomography (n = 3). At the most recent follow-up visit, only 1 patient was known to be taking nitrates and 11 were taking beta-blockers. Four patients required Fontan revision, 3 patients had pacemakers inserted, 2 patients had fistula embolization, 2 patients had catheter ablation for arrhythmias and 1 patient had a coronary stent inserted. Overall freedom from myocardial ischaemia following Fontan completion was 81% (95% CI 74–89%) at 5 years, 63% (95% CI 53–74%) at 10 years and 47% (95% CI 35–63%) at 25 years. The 10-year freedom from ischaemia was significantly lower in patients with RVDCC compared to patients without RVDCC (15% vs 73%) (Fig. 3). Myocardial ischaemia (using ischaemia as a time-dependent covariate) was an independent predictor of death (HR 7.06, 95% CI 1.9–26.5; P = 0.004). Figure 3: View largeDownload slide Kaplan–Meier survival curves of freedom from new onset myocardial ischaemia following Fontan completion. Log-rank test, P <0.001. RVDCC: right ventricle-dependent coronary circulation. Figure 3: View largeDownload slide Kaplan–Meier survival curves of freedom from new onset myocardial ischaemia following Fontan completion. Log-rank test, P <0.001. RVDCC: right ventricle-dependent coronary circulation. Reinterventions Reintervention occurred in 26 patients (21.7%), consisting of pacemaker revision (n = 4), aortopulmonary and venovenous collateral embolization (n = 4), transcatheter ablation for arrhythmia (n = 3), Fontan circuit revision (n = 4), transcatheter pulmonary artery balloon dilatation (n = 2), pericardial/pleural effusion drainage (n = 2), closure of an atrial septal defect (n = 1), coronary artery stenting (n = 1), Fontan takedown and pulmonary valve replacement (n = 1), delayed sternal wire removal (n = 1), Bentall procedure (n = 1), balloon stenting of a Fontan conduit (n = 1) and a Fontan conversion (n = 1). Eleven patients went on to have another reintervention with 5 patients requiring 3 or more reinterventions. Overall freedom from reintervention following Fontan completion was 86% (95% CI 78–92%) at 5 years, 70% (95% CI 56–80%) at 15 years and 55% (95% CI 30–74%) at 25 years. Fontan failure Freedom from failure at 15, 20 and 25 years was 83% (95% CI 70–90%), 71% (95% CI 54–83%) and 60% (95% CI 37–76%), respectively. Risk factors predicting the occurrence of Fontan failure are listed in Table 3. DISCUSSION PA-IVS is a rare condition. It accounts for 1–3% of all congenital heart diseases and has an overall incidence of 4.5 cases per 100 000 live births [16]. Myocardial sinusoids have been reported to occur in 30–60% of patients with PA-IVS [4, 6, 11, 12, 14, 17–19]. The prevalence of RVDCC is thought to be in the range of 3–34% [4, 6, 9–13]. We demonstrated previously that these patients have a higher risk of death before reaching Fontan status. In our registry, 17% of the patients who had reached Fontan status were identified as having an RVDCC. The peculiarities of this coronary circulation are still unknown. It is unknown whether it may result in regional coronary ischaemia, especially during exercise. Our current study seems to indicate that coronary ischaemia remains a major issue for patients born with PA-IVS even late after Fontan completion. Ischaemic changes could be ultimately noted in almost all of those with an RVDCC. The incidence of sudden death also seemed to be increased in this subpopulation even though comparisons to patients with other conditions are difficult because of our current lack of data. It was long thought that up to a third of deaths occurring in patients with a Fontan circulation might be sudden and therefore likely related to arrhythmia, but these were probably overestimates [20]. In a recent publication by Khairy et al. [21] looking at modes of death in patients with a Fontan circulation, sudden death accounted for 9% of late deaths. A more recent large single-centre study found that 7% of deaths were due to sudden cardiac death [22]. In our study, sudden death accounted for 55% (6 of 11) of late deaths, although it is difficult to draw any reliable conclusions from this data because of the low event rate. A majority of late deaths occurred in children who had an atriopulmonary Fontan circulation. It is possible that this situation contributed to the outcomes of these patients. However, sudden death seemed to occur far more frequently in patients with RVDCC. The fact that coronary ischaemia was detected so much more frequently in these patients seems to support the relevance of RVDCC and consequent ischaemia in the pathogenesis of the sudden deaths observed. The presence of ostial coronary stenosis also seemed clearly associated with adverse outcomes. We believe that the increased risk of death and coronary ischaemia in patients with coronary ostial stenosis or RVDCC justifies a closer follow-up in those identified with such conditions. Conventional investigations with exercise studies should be performed as early as feasible. Angiography, whether it be invasive or computed tomography angiography, should be repeated in any patients whose coronary anatomy is uncertain. Holter monitoring should be checked regularly on several days to identify potentially fatal arrhythmias that may require further management. The possible diagnostic utility of stress dobutamine echocardiography and nuclear myocardial scans should also be investigated. As this stage, we have not identified solutions for those identified as having coronary ischaemia. Medical treatment may be effective. Education and keeping a defibrillator at home may be a solution. Because we do not know the exact mechanisms leading to sudden death, it is difficult to ascertain whether an internal defibrillator may be of use in these patients, but it may be an avenue worth investigating. Since the 1990s, indications to implant a defibrillator included a previous myocardial infarction and a left ventricular ejection fraction less than 30% [23]. Defibrillator therapy was associated with a 31% reduction in the risk of death. This indication was justified because this subgroup of patients had a 6% risk of sudden death within 5 years [24]. The risk of sudden death seems higher in those with an RVDCC. Finally, any patient detected to have a concerning ventricular arrhythmia burden could be a candidate for a heart transplant. CONCLUSION In conclusion, the long-term survival of patients with PA-IVS after the Fontan procedure remains excellent, but patients with RVDCC remain susceptible to myocardial ischaemia and sudden death. Closer surveillance and investigation for exercise-induced ischaemia may be necessary. The benefits of preventive implantation of a defibrillator should be investigated in patients with RVDCC who survive the Fontan procedure. ACKNOWLEDGEMENTS The authors sincerely acknowledge the help of Belinda Bortone (administrative support), Janina Chapman and all the Fontan Registry Research support staff for their support in data collection. Funding This work was supported by a National Health and Medical Research Council (NHMRC) Partnership Grant [1076849]. The contents of the published material are solely the responsibility of the individual authors. Yves d’Udekem is a Career Development Fellow of The National Heart Foundation Australia Program [CR 10M 5339] and NHMRC Clinician Practitioner Fellow [1082186]. Conflict of interest: none declared. REFERENCES 1 Daubeney PE , Wang D , Delany DJ , Keeton BR , Anderson RH , Slavik Z et al. Pulmonary atresia with intact ventricular septum: predictors of early and medium-term outcome in a population-based study . J Thorac Cardiovasc Surg 2005 ; 130 : 1071.e1. Google Scholar CrossRef Search ADS 2 Odim J , Laks H , Plunkett MD , Tung TC. Successful management of patients with pulmonary atresia with intact ventricular septum using a three tier grading system for right ventricular hypoplasia . Ann Thorac Surg 2006 ; 81 : 678 – 84 . Google Scholar CrossRef Search ADS PubMed 3 Liava’a M , Brooks P , Konstantinov I , Brizard C , d’Udekem Y. Changing trends in the management of pulmonary atresia with intact ventricular septum: the Melbourne experience . Eur J Cardiothorac Surg 2011 ; 40 : 1406 – 11 . Google Scholar PubMed 4 Hanley FL , Sade RM , Blackstone EH , Kirklin JW , Freedom RM , Nanda NC. Outcomes in neonatal pulmonary atresia with intact ventricular septum. A multiinstitutional study . J Thorac Cardiovasc Surg 1993 ; 105 : 406 – 23 , 24–7; discussion 23–4. 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Long-term outcomes of single-ventricle palliation for pulmonary atresia with intact ventricular septum: Fontan survivors remain at risk of late myocardial ischaemia and death

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
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1010-7940
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1873-734X
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10.1093/ejcts/ezy038
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Abstract

Abstract OBJECTIVES The specific outcomes of patients with pulmonary atresia with intact ventricular septum late after Fontan palliation are unknown. Patients with smaller right ventricles and myocardial sinusoids are known to have worse survival in the first years of life. Whether the potential for coronary ischaemia affects the long-term outcomes of these patients after Fontan palliation is still unknown. METHODS All patients with pulmonary atresia with intact ventricular septum who underwent the Fontan procedure from 1984 to 2016 in Australia and New Zealand were identified, and preoperative, perioperative and follow-up data were collected. RESULTS Late follow-up data were available for 120 patients. The median length of follow-up after the Fontan procedure was 9.1 years (interquartile range 4.2–15.4 years). Late death occurred in 9% of patients (11/120). Six were sudden, unexpected deaths; 4 of those occurred in patients known to have right ventricle-dependent coronary circulation (RVDCC). Those with RVDCC had a higher incidence of sudden death (4/20 vs 2/100; P = 0.007). RVDCC was associated with late death (P = 0.01) and the development of myocardial ischaemia after Fontan completion (P < 0.001). The 10-year survival rate was 77% (95% confidence interval 56–100%) for patients with RVDCC vs 96% (95% confidence interval 92–100%) for patients without RVDCC. CONCLUSIONS Long-term survival of patients with pulmonary atresia with intact ventricular septum after the Fontan procedure is excellent, but patients with RVDCC remain susceptible to coronary ischaemia and sudden death. Closer surveillance and investigation for exercise-induced ischaemia may be necessary. Congenital heart disease, Fontan procedure, Pulmonary valve, Sinusoids, Right ventricular dependence INTRODUCTION Pulmonary atresia with intact ventricular septum (PA-IVS) is a condition with a wide variation of severity. The most favourable cases can be directed to biventricular repair whereas those at the most severe end of the disease spectrum are directed to single-ventricle palliation. Patients affected with its most severe form have small hypertrophied right ventricles and a tricuspid valve annulus of small dimensions [1–4]. The high pressures generated in these small right ventricular cavities can result commonly in the repermeation of myocardial sinusoids [5–9]. In up to 35% of patients with pulmonary atresia and an intact ventricular septum, the coronary blood flow becomes mainly dependent on perfusion from these sinusoids, to the extent that some of the patients have been described to be born with coronary ostial stenosis [6, 8–13]. Twenty percent of patients born with pulmonary atresia and an intact ventricular septum die within the first 2 years of life [2, 3, 11, 12, 14]. The presence of a smaller tricuspid valve annulus and the existence of coronary stenosis and right ventricle-dependent coronary circulation (RVDCC) have been identified as risk factors for early death. The specific outcomes of these patients have been limited to 10 years from birth, with only some follow-up after a Fontan circulation procedure. The Australian and New Zealand Fontan Registry, created in 2009, collects health information on all survivors of the Fontan procedure. We wanted to identify the late outcomes of patients with pulmonary atresia and an intact ventricular septum from the registry to elucidate whether potential coronary ischaemia may impact the late survival of this population. MATERIALS AND METHODS A retrospective analysis of the data of all patients with the primary diagnosis of pulmonary atresia and intact ventricular septum who have undergone a Fontan procedure in Australia and New Zealand was performed using The Australian and New Zealand Fontan Registry. The Australian and New Zealand Fontan Registry began in 2009 and includes only those patients in both countries who survived the hospital stay after a Fontan procedure [15]. The design of the registry was approved nationally by both countries and by local hospital ethics committees in each country. Approval for retrospective studies was covered within the application and waiver for consent was granted for retrospective studies. At the time of the study, there were 1449 patients included in the registry; 22 patients refused to participate. Due to the design of the registry, the review only included patients who underwent single-ventricle palliation via the Fontan operation but not via biventricular repair. A total of 128 children born between August 1972 and November 2012 were identified to have a diagnosis of PA-IVS. Patients who suffered early death, defined as death after Fontan completion but prior to hospital discharge, were excluded (5 patients). Patients with no follow-up information after Fontan completion were also excluded (3 patients). The remaining 120 patients constituted the core of the study. Of the 120 hospital survivors, 16 had an atriopulmonary (1984–1992) Fontan procedure; 17 had a lateral tunnel (1988–1997) procedure; and 87 had an extracardiac conduit Fontan (1997–2016) procedure. Two patients had undergone their Fontan procedures overseas. The characteristics of these patients are given in Table 1. Table 1: Patient characteristics Total (n = 120) RVDCC (n = 20) Non-RVDCC (n = 100) Male 60 (50) 12 (60) 48 (48) Dextrocardia 2 (2) 0 (0) 2 (2) Ebstein’s anomaly 4 (3) 1 (5) 3 (3) Birth weight (kg) 3.0 (2.6–3.4) 3.2 (2.8–3.8) 2.9 (2.5–3.3) Gestational age (weeks) 38 (37–40) 39 (38–40) 38 (37–40) Antenatal diagnosis 59 (49) 8 (40) 51 (51) TV z-score −3.2 (−3.9 to −2.2) −3.8 (−4.5 to −3.2) −3.1 (−3.7 to −2.2) RV hypoplasia  Mild 2 (2) 0 (0) 2 (2)  Moderate 31 (26) 4 (20) 27 (27)  Severe 87 (73) 16 (80) 71 (71) Myocardial sinusoids 83 (69) 20 (100) 63 (63) Pre-Fontan procedures  Age at Stage I (days) 4 (2–7) 6 (3.8–9.5) 4 (2–7)  Prior staging with BCPS 92 (77) 16 (80) 76 (76)  Age at Stage II (months)a 8.0 (5.2–14.3) 6.1 (4.3–8.2) 8.4 (5.5–14.5)  Pulmonary artery intervention 29 (24) 8 (40) 22 (21) Pre-Fontan haemodynamics  Pulmonary artery pressure (mmHg)b 11.0 (9.0–13.0) 10.0 (9.0–12.5) 11.0 (10.0–13.0)  Aortopulmonary or venovenous collaterals 53 (44) 13 (65) 40 (40)  Atrioventricular valve regurgitation ≥ moderate 12 (10) 4 (20) 8 (8) Fontan operative characteristics  Fenestration 48 (40) 8 (40) 41 (41)  Age at Fontan (years) 4.6 (3.6–6.0) 4.1 (3.5–4.9) 4.7 (3.6–6.1)  Fontan type   Extracardiac conduit 87 (73) 15 (75) 72 (72)   Lateral tunnel 17 (14) 2 (10) 15 (15)   Atriopulmonary 16 (13) 3 (15) 13 (13)  Concomitant procedures 40 (33) 6 (30) 34 (34)  Concomitant pulmonary artery reconstruction 20 (17) 3 (15) 17 (17)  Aortic cross-clamp time (min) 19.3 ± 27.4 17.1 ± 24.3 19.8 ± 28.3  Cardiopulmonary bypass time (min) 107.4 ± 42.5 89.2 ± 29.9 111.8 ± 44.0  ICU duration (days) 1 (1–2) 1 (1–2) 1 (1–2)  Length of hospital stay (days) 14 (10–20) 13.5 (10–19.3) 14 (10–21)  Chest tube duration (days) 9 (7–15) 9 (5.8–14.5) 9 (7–15.5) Total (n = 120) RVDCC (n = 20) Non-RVDCC (n = 100) Male 60 (50) 12 (60) 48 (48) Dextrocardia 2 (2) 0 (0) 2 (2) Ebstein’s anomaly 4 (3) 1 (5) 3 (3) Birth weight (kg) 3.0 (2.6–3.4) 3.2 (2.8–3.8) 2.9 (2.5–3.3) Gestational age (weeks) 38 (37–40) 39 (38–40) 38 (37–40) Antenatal diagnosis 59 (49) 8 (40) 51 (51) TV z-score −3.2 (−3.9 to −2.2) −3.8 (−4.5 to −3.2) −3.1 (−3.7 to −2.2) RV hypoplasia  Mild 2 (2) 0 (0) 2 (2)  Moderate 31 (26) 4 (20) 27 (27)  Severe 87 (73) 16 (80) 71 (71) Myocardial sinusoids 83 (69) 20 (100) 63 (63) Pre-Fontan procedures  Age at Stage I (days) 4 (2–7) 6 (3.8–9.5) 4 (2–7)  Prior staging with BCPS 92 (77) 16 (80) 76 (76)  Age at Stage II (months)a 8.0 (5.2–14.3) 6.1 (4.3–8.2) 8.4 (5.5–14.5)  Pulmonary artery intervention 29 (24) 8 (40) 22 (21) Pre-Fontan haemodynamics  Pulmonary artery pressure (mmHg)b 11.0 (9.0–13.0) 10.0 (9.0–12.5) 11.0 (10.0–13.0)  Aortopulmonary or venovenous collaterals 53 (44) 13 (65) 40 (40)  Atrioventricular valve regurgitation ≥ moderate 12 (10) 4 (20) 8 (8) Fontan operative characteristics  Fenestration 48 (40) 8 (40) 41 (41)  Age at Fontan (years) 4.6 (3.6–6.0) 4.1 (3.5–4.9) 4.7 (3.6–6.1)  Fontan type   Extracardiac conduit 87 (73) 15 (75) 72 (72)   Lateral tunnel 17 (14) 2 (10) 15 (15)   Atriopulmonary 16 (13) 3 (15) 13 (13)  Concomitant procedures 40 (33) 6 (30) 34 (34)  Concomitant pulmonary artery reconstruction 20 (17) 3 (15) 17 (17)  Aortic cross-clamp time (min) 19.3 ± 27.4 17.1 ± 24.3 19.8 ± 28.3  Cardiopulmonary bypass time (min) 107.4 ± 42.5 89.2 ± 29.9 111.8 ± 44.0  ICU duration (days) 1 (1–2) 1 (1–2) 1 (1–2)  Length of hospital stay (days) 14 (10–20) 13.5 (10–19.3) 14 (10–21)  Chest tube duration (days) 9 (7–15) 9 (5.8–14.5) 9 (7–15.5) Data expressed as n (%), mean ± SD or median (IQR). a 91 bidirectional cavopulmonary shunts, 2 bilateral BCPS, 1 Kawashima. b Data available for 104 patients. BCPS: bidirectional cavopulmonary shunt; ICU: intensive care unit; IQR: interquartile range; RV: right ventricle; RVDCC: right ventricle-dependent coronary circulation; SD: standard deviation; TV: tricuspid valve. Table 1: Patient characteristics Total (n = 120) RVDCC (n = 20) Non-RVDCC (n = 100) Male 60 (50) 12 (60) 48 (48) Dextrocardia 2 (2) 0 (0) 2 (2) Ebstein’s anomaly 4 (3) 1 (5) 3 (3) Birth weight (kg) 3.0 (2.6–3.4) 3.2 (2.8–3.8) 2.9 (2.5–3.3) Gestational age (weeks) 38 (37–40) 39 (38–40) 38 (37–40) Antenatal diagnosis 59 (49) 8 (40) 51 (51) TV z-score −3.2 (−3.9 to −2.2) −3.8 (−4.5 to −3.2) −3.1 (−3.7 to −2.2) RV hypoplasia  Mild 2 (2) 0 (0) 2 (2)  Moderate 31 (26) 4 (20) 27 (27)  Severe 87 (73) 16 (80) 71 (71) Myocardial sinusoids 83 (69) 20 (100) 63 (63) Pre-Fontan procedures  Age at Stage I (days) 4 (2–7) 6 (3.8–9.5) 4 (2–7)  Prior staging with BCPS 92 (77) 16 (80) 76 (76)  Age at Stage II (months)a 8.0 (5.2–14.3) 6.1 (4.3–8.2) 8.4 (5.5–14.5)  Pulmonary artery intervention 29 (24) 8 (40) 22 (21) Pre-Fontan haemodynamics  Pulmonary artery pressure (mmHg)b 11.0 (9.0–13.0) 10.0 (9.0–12.5) 11.0 (10.0–13.0)  Aortopulmonary or venovenous collaterals 53 (44) 13 (65) 40 (40)  Atrioventricular valve regurgitation ≥ moderate 12 (10) 4 (20) 8 (8) Fontan operative characteristics  Fenestration 48 (40) 8 (40) 41 (41)  Age at Fontan (years) 4.6 (3.6–6.0) 4.1 (3.5–4.9) 4.7 (3.6–6.1)  Fontan type   Extracardiac conduit 87 (73) 15 (75) 72 (72)   Lateral tunnel 17 (14) 2 (10) 15 (15)   Atriopulmonary 16 (13) 3 (15) 13 (13)  Concomitant procedures 40 (33) 6 (30) 34 (34)  Concomitant pulmonary artery reconstruction 20 (17) 3 (15) 17 (17)  Aortic cross-clamp time (min) 19.3 ± 27.4 17.1 ± 24.3 19.8 ± 28.3  Cardiopulmonary bypass time (min) 107.4 ± 42.5 89.2 ± 29.9 111.8 ± 44.0  ICU duration (days) 1 (1–2) 1 (1–2) 1 (1–2)  Length of hospital stay (days) 14 (10–20) 13.5 (10–19.3) 14 (10–21)  Chest tube duration (days) 9 (7–15) 9 (5.8–14.5) 9 (7–15.5) Total (n = 120) RVDCC (n = 20) Non-RVDCC (n = 100) Male 60 (50) 12 (60) 48 (48) Dextrocardia 2 (2) 0 (0) 2 (2) Ebstein’s anomaly 4 (3) 1 (5) 3 (3) Birth weight (kg) 3.0 (2.6–3.4) 3.2 (2.8–3.8) 2.9 (2.5–3.3) Gestational age (weeks) 38 (37–40) 39 (38–40) 38 (37–40) Antenatal diagnosis 59 (49) 8 (40) 51 (51) TV z-score −3.2 (−3.9 to −2.2) −3.8 (−4.5 to −3.2) −3.1 (−3.7 to −2.2) RV hypoplasia  Mild 2 (2) 0 (0) 2 (2)  Moderate 31 (26) 4 (20) 27 (27)  Severe 87 (73) 16 (80) 71 (71) Myocardial sinusoids 83 (69) 20 (100) 63 (63) Pre-Fontan procedures  Age at Stage I (days) 4 (2–7) 6 (3.8–9.5) 4 (2–7)  Prior staging with BCPS 92 (77) 16 (80) 76 (76)  Age at Stage II (months)a 8.0 (5.2–14.3) 6.1 (4.3–8.2) 8.4 (5.5–14.5)  Pulmonary artery intervention 29 (24) 8 (40) 22 (21) Pre-Fontan haemodynamics  Pulmonary artery pressure (mmHg)b 11.0 (9.0–13.0) 10.0 (9.0–12.5) 11.0 (10.0–13.0)  Aortopulmonary or venovenous collaterals 53 (44) 13 (65) 40 (40)  Atrioventricular valve regurgitation ≥ moderate 12 (10) 4 (20) 8 (8) Fontan operative characteristics  Fenestration 48 (40) 8 (40) 41 (41)  Age at Fontan (years) 4.6 (3.6–6.0) 4.1 (3.5–4.9) 4.7 (3.6–6.1)  Fontan type   Extracardiac conduit 87 (73) 15 (75) 72 (72)   Lateral tunnel 17 (14) 2 (10) 15 (15)   Atriopulmonary 16 (13) 3 (15) 13 (13)  Concomitant procedures 40 (33) 6 (30) 34 (34)  Concomitant pulmonary artery reconstruction 20 (17) 3 (15) 17 (17)  Aortic cross-clamp time (min) 19.3 ± 27.4 17.1 ± 24.3 19.8 ± 28.3  Cardiopulmonary bypass time (min) 107.4 ± 42.5 89.2 ± 29.9 111.8 ± 44.0  ICU duration (days) 1 (1–2) 1 (1–2) 1 (1–2)  Length of hospital stay (days) 14 (10–20) 13.5 (10–19.3) 14 (10–21)  Chest tube duration (days) 9 (7–15) 9 (5.8–14.5) 9 (7–15.5) Data expressed as n (%), mean ± SD or median (IQR). a 91 bidirectional cavopulmonary shunts, 2 bilateral BCPS, 1 Kawashima. b Data available for 104 patients. BCPS: bidirectional cavopulmonary shunt; ICU: intensive care unit; IQR: interquartile range; RV: right ventricle; RVDCC: right ventricle-dependent coronary circulation; SD: standard deviation; TV: tricuspid valve. The 120 patients had the following procedures before the Fontan procedure: Blalock–Taussig shunt (82), interventional catheter (62), central shunt (31), pulmonary artery reconstruction (20), pulmonary valvotomy (18), right ventricle outflow tract patch (13), Waterston shunt (5), tricuspid valve repair (3), mitral valve repair (2) and tricuspid valve repair (1). Long-term follow-up data were gathered from The Australian and New Zealand Fontan Registry. RVDCC was defined as the presence of stenosis of 2 or more main coronary arteries or coronary ostial atresia. RVDCC was assessed from preoperative coronary and right ventricular angiograms. Coronary artery stenosis was defined as more than 50% stenosis of the luminal surface of the vessel or if it was designated as significant in the cardiologist’s report. Patients with coronary atresia were included in this group. If data were missing from the registry, information was obtained from hospital databases and medical records. Preoperative, perioperative, postoperative and follow-up data were collected. Operative reports, discharge summaries and follow-up letters were reviewed retrospectively, as were echocardiographic reports, catheterisation reports, electrocardiograms (ECGs), cardiac magnetic resonance images, Holter monitor reports and exercise stress test reports. Significant events recorded were death, reintervention, protein losing enteropathy, arrhythmia, myocardial ischaemia (based on ECG changes, symptoms, exercise ECGs) and New York Heart Association (NYHA) Class III/IV. Early mortality includes all deaths prior to discharge after completion of the Fontan procedure. Late mortality includes deaths of patients who survived the hospital admission after the Fontan completion. Reintervention includes any surgical reoperation or transcatheter intervention after Fontan completion excluding fenestration closure. Fontan failure was defined as late death, Fontan takedown after hospital discharge, reoperation on the Fontan circuit, protein losing enteropathy, plastic bronchitis or NYHA Class III/IV at follow-up. An ischaemic event was defined as ST-segment changes or T-wave inversion that was determined to be a sign of ischaemia by the reporting cardiologist, an episode of chest pain or dyspnoea in association with ischaemic ECG changes, inducible ischaemia on an exercise tolerance test or elevated cardiac enzymes associated with angina or dyspnoea. Isolated ST-segment and T-wave changes in the absence of symptoms were not considered to be ischaemic for this study. Statistical analysis Analyses were performed in R (version 3.3.2; http://www.r-project.org/). Categorical data are summarised as counts and proportions (percentage). Continuous data are summarised as mean ± standard deviation or median [interquartile range (IQR)], depending on normality of distribution. The end-points examined for the 120 hospital survivors were late mortality, Fontan failure, late adverse event, reintervention or late mortality and myocardial ischaemia (based on ECG changes, symptoms, exercise ECGs). Survival and freedom from non-mortality end-points were estimated with 95% confidence intervals (CIs) using the Kaplan–Meier method. Survival and freedom from ischaemia according to RVDCC were plotted using the Kaplan–Meier method and compared by log-rank statistics in all patients. All P values less than 0.05 were considered statistically significant. Risk factors were examined using the Cox regression analyses from which hazard ratios (HRs) and 95% CIs were generated. The proportional hazards assumption was assessed based on the method of Harrell and Lee and via diagnostic plots. The proportional hazard assumption was met for all variables. The factors analysed are listed in Table 1. RESULTS A total of 128 patients underwent the Fontan procedure for PA-IVS. There were 5 deaths prior to discharge after Fontan completion, and 3 patients were lost to follow-up. Causes of death were stroke (2), sepsis (1), pneumonia (1) and pulmonary embolus (1). None of these patients had RVDCC. The 120 hospital survivors comprised the cohort for this study. They had an average of 3.2 ± 1.8 surgical procedures before the Fontan procedure. Fifty-two percent of the patients (62/120) underwent an average of 0.7 ± 0.8 interventional catheter procedures before the Fontan procedure. Patient characteristics are summarised in Table 1. The median follow-up time after Fontan completion was 9.1 years (IQR 4.2–15.4 years; mean 10.9 ± 8.1 years). The median age of the patients at the end of the follow-up period was 14.5 years (IQR 10.0–20.8 years; mean 15.9 ± 8.3 years). Follow-up data are summarised in Table 2. Of the 109 patients still alive, 76 patients (70%) and 32 patients (29%) were in NYHA functional classes I and II, respectively. One patient had ongoing palpitations, dyspnoea and chest pain (NYHA III). Forty-six patients (42%) participated in competitive or recreational sporting activities and 28 patients (26%) reported below average activity levels. Patients were prescribed a mean of 1.6 ± 0.9 cardiac medications, and patients with RVDCC were prescribed more medications (P = 0.02) (Table 2). Table 2: Follow-up data Clinical information at the last follow-up visit Total (n = 109) RVDCC (n = 15) Non-RVDCC (n = 94) NYHA 1.3 ± 0.5 1.3 ± 0.5 1.3 ± 0.5 Participation in a sporta 46 (42) 7 (47) 39 (42) Below average activity level 28 (26) 4 (27) 24 (26) Number of cardiovascular medications 1.6 ± 0.9 2.1 ± 1.0 1.5 ± 0.9  Anticoagulants 103 (95) 15 (100) 88 (94)  Beta-blockers 16 (15) 5 (33) 11 (12)  ACE inhibitors 26 (24) 6 (40) 20 (21)  Digoxin 4 (4) 1 (7) 3 (3)  Diuretics 9 (8) 2 (13) 7 (7) ECG ST-segment–T-wave changes 18 (17) 7 (47) 11 (12) Mitral valve regurgitation ≥ moderate 3 (3) 1 (7) 2 (2) Aortic valve regurgitation ≥ moderate 2 (2) 0 (0) 2 (2) Post-Fontan complications Total (n = 120) RVDCC (n = 20) Non-RVDCC (n = 100) Angina 26 (22) 10 (50) 16 (16) Syncope 15 (13) 6 (30) 9 (9) Arrhythmia 14 (12) 2 (10) 12 (12) Thromboembolic event 13 (11) 2 (10) 14 (14) PLE 4 (3) 1 (5) 3 (3) Late death 11 (9) 5 (25) 6 (6) Sudden death 6 (5) 4 (20) 2 (2) Clinical information at the last follow-up visit Total (n = 109) RVDCC (n = 15) Non-RVDCC (n = 94) NYHA 1.3 ± 0.5 1.3 ± 0.5 1.3 ± 0.5 Participation in a sporta 46 (42) 7 (47) 39 (42) Below average activity level 28 (26) 4 (27) 24 (26) Number of cardiovascular medications 1.6 ± 0.9 2.1 ± 1.0 1.5 ± 0.9  Anticoagulants 103 (95) 15 (100) 88 (94)  Beta-blockers 16 (15) 5 (33) 11 (12)  ACE inhibitors 26 (24) 6 (40) 20 (21)  Digoxin 4 (4) 1 (7) 3 (3)  Diuretics 9 (8) 2 (13) 7 (7) ECG ST-segment–T-wave changes 18 (17) 7 (47) 11 (12) Mitral valve regurgitation ≥ moderate 3 (3) 1 (7) 2 (2) Aortic valve regurgitation ≥ moderate 2 (2) 0 (0) 2 (2) Post-Fontan complications Total (n = 120) RVDCC (n = 20) Non-RVDCC (n = 100) Angina 26 (22) 10 (50) 16 (16) Syncope 15 (13) 6 (30) 9 (9) Arrhythmia 14 (12) 2 (10) 12 (12) Thromboembolic event 13 (11) 2 (10) 14 (14) PLE 4 (3) 1 (5) 3 (3) Late death 11 (9) 5 (25) 6 (6) Sudden death 6 (5) 4 (20) 2 (2) Data expressed as n (%) or mean ± SD. a As reported by patient or caregiver. ACE: angiotensin converting enzyme; ECG: electrocardiogram; NYHA: New York Heart Association; PLE: protein losing enteropathy; RVDCC: right ventricle-dependent coronary circulation; SD: standard deviation. Table 2: Follow-up data Clinical information at the last follow-up visit Total (n = 109) RVDCC (n = 15) Non-RVDCC (n = 94) NYHA 1.3 ± 0.5 1.3 ± 0.5 1.3 ± 0.5 Participation in a sporta 46 (42) 7 (47) 39 (42) Below average activity level 28 (26) 4 (27) 24 (26) Number of cardiovascular medications 1.6 ± 0.9 2.1 ± 1.0 1.5 ± 0.9  Anticoagulants 103 (95) 15 (100) 88 (94)  Beta-blockers 16 (15) 5 (33) 11 (12)  ACE inhibitors 26 (24) 6 (40) 20 (21)  Digoxin 4 (4) 1 (7) 3 (3)  Diuretics 9 (8) 2 (13) 7 (7) ECG ST-segment–T-wave changes 18 (17) 7 (47) 11 (12) Mitral valve regurgitation ≥ moderate 3 (3) 1 (7) 2 (2) Aortic valve regurgitation ≥ moderate 2 (2) 0 (0) 2 (2) Post-Fontan complications Total (n = 120) RVDCC (n = 20) Non-RVDCC (n = 100) Angina 26 (22) 10 (50) 16 (16) Syncope 15 (13) 6 (30) 9 (9) Arrhythmia 14 (12) 2 (10) 12 (12) Thromboembolic event 13 (11) 2 (10) 14 (14) PLE 4 (3) 1 (5) 3 (3) Late death 11 (9) 5 (25) 6 (6) Sudden death 6 (5) 4 (20) 2 (2) Clinical information at the last follow-up visit Total (n = 109) RVDCC (n = 15) Non-RVDCC (n = 94) NYHA 1.3 ± 0.5 1.3 ± 0.5 1.3 ± 0.5 Participation in a sporta 46 (42) 7 (47) 39 (42) Below average activity level 28 (26) 4 (27) 24 (26) Number of cardiovascular medications 1.6 ± 0.9 2.1 ± 1.0 1.5 ± 0.9  Anticoagulants 103 (95) 15 (100) 88 (94)  Beta-blockers 16 (15) 5 (33) 11 (12)  ACE inhibitors 26 (24) 6 (40) 20 (21)  Digoxin 4 (4) 1 (7) 3 (3)  Diuretics 9 (8) 2 (13) 7 (7) ECG ST-segment–T-wave changes 18 (17) 7 (47) 11 (12) Mitral valve regurgitation ≥ moderate 3 (3) 1 (7) 2 (2) Aortic valve regurgitation ≥ moderate 2 (2) 0 (0) 2 (2) Post-Fontan complications Total (n = 120) RVDCC (n = 20) Non-RVDCC (n = 100) Angina 26 (22) 10 (50) 16 (16) Syncope 15 (13) 6 (30) 9 (9) Arrhythmia 14 (12) 2 (10) 12 (12) Thromboembolic event 13 (11) 2 (10) 14 (14) PLE 4 (3) 1 (5) 3 (3) Late death 11 (9) 5 (25) 6 (6) Sudden death 6 (5) 4 (20) 2 (2) Data expressed as n (%) or mean ± SD. a As reported by patient or caregiver. ACE: angiotensin converting enzyme; ECG: electrocardiogram; NYHA: New York Heart Association; PLE: protein losing enteropathy; RVDCC: right ventricle-dependent coronary circulation; SD: standard deviation. Deaths Nine percent of patients (11/120) died a median of 9 years (IQR 5–16 years; mean 11.1 ± 8.3 years) after hospital discharge. Seven had an atriopulmonary, 1 had a lateral tunnel and 3 had an extracardiac conduit Fontan procedure. The mean age at death was 17 years. Five of the 11 deaths were in patients with known RVDCC. In all patients who underwent Fontan completion, survival by the Kaplan–Meier method at 5, 15 and 25 years was 98% (95% CI 96–99%), 88% (95% CI 80–97%) and 80% (95% CI 67–95%) at 25 years, respectively (Fig. 1). The cause of death was identified in 10 patients: sudden unexpected death (6), thromboembolic stroke (1), pulmonary embolism (1), protein losing enteropathy (1) and liver transplant rejection (1). In 1 patient, the cause of death was unknown. RVDCC was present in 5 (45%) of those who died and in 4 (67%) of those who died suddenly. Figure 1: View largeDownload slide Kaplan–Meier survival curves with 95% confidence intervals. Figure 1: View largeDownload slide Kaplan–Meier survival curves with 95% confidence intervals. There were 6 sudden unexpected deaths that occurred a median of 12 years (IQR 7–16 years; mean 12.3 ± 6.3 years) after the Fontan procedure. One patient died suddenly during exercise and 3 died suddenly at rest. The circumstances surrounding the death of the final 2 patients were unclear because those deaths were mostly unwitnessed and there was a lack of data. Four patients had symptoms of syncopal episodes; 2 had symptoms of angina; 2 had ischaemic ECG changes; and 1 patient had a cardiac arrest 1 month before his death. Four patients were known to have RVDCC. Two patients had been completely asymptomatic during their follow-up period. Autopsy showed a congenital anomaly of the right coronary artery with intimal and medical thickening in 1 patient and focal fibrosis of the myocardium thought to be related to ischaemia in another. Right ventricle-dependent coronary circulation Twenty (17%) patients were identified as having RVDCC. Five (25%) of these patients died; 4 (20%) had a sudden unexpected death, and 1 (5%) died of sepsis secondary to protein losing enteropathy. Of these, 2 had new ischaemic changes on ECG prior to their death, 1 experienced angina and 1 presented with angina followed by a syncopal event secondary to ventricular tachycardia. Only 1 of these required reinterventions in the form of Fontan revision. Overall, 10 patients (50%) experienced angina after Fontan and 6 (30%) had syncopal events. Patients with RVDCC had a higher risk of late death (P = 0.02) and sudden death (P = 0.007) (Table 2). Overall survival in patients with RVDCC was lower, with a 10-year survival rate of 77% (95% CI 56–100%) compared to 96% (95% CI 92–100%) (Fig. 2). Forty-seven percent of patients with RVDCC showed ischaemic ECG changes after Fontan completion compared to only 12% in the non-RVDCC group (P = 0.003). By univariable analysis, RVDCC was associated with death (HR 4.7, 95% CI 1.4–16; P = 0.01) and developing myocardial ischaemia after Fontan completion (HR 3.9, 95% CI 2–8; P < 0.001) (Table 3). Table 3: Results of univariable Cox proportional hazards analysis for late outcomes Variables Univariable HR 95% CI Late death  RVDCC 4.73 1.4–16  LCA stenosis 6.3 1.6–24  RCA stenosis 9 2.7–29  AP Fontan 4.9 1.4–18 Fontan failure  LCA stenosis 3.8 1.1–13  RCA stenosis 4 1.5–11 Myocardial ischaemia  RVDCC 3.9 2–7.6  LAD stenosis 4 2.1–7.8  RCA stenosis 2.9 1.4–5.9  TV z-score (per unit increase) 0.7 0.5–0.9  Fontan before 2000 0.4 0.2–0.9 Variables Univariable HR 95% CI Late death  RVDCC 4.73 1.4–16  LCA stenosis 6.3 1.6–24  RCA stenosis 9 2.7–29  AP Fontan 4.9 1.4–18 Fontan failure  LCA stenosis 3.8 1.1–13  RCA stenosis 4 1.5–11 Myocardial ischaemia  RVDCC 3.9 2–7.6  LAD stenosis 4 2.1–7.8  RCA stenosis 2.9 1.4–5.9  TV z-score (per unit increase) 0.7 0.5–0.9  Fontan before 2000 0.4 0.2–0.9 AP: atriopulmonary; CI: confidence interval; HR: hazard ratio; LAD: left anterior descending artery; LCA: left coronary artery; RCA: right coronary artery; RVDCC: right ventricle-dependent coronary circulation; TV: tricuspid valve. Table 3: Results of univariable Cox proportional hazards analysis for late outcomes Variables Univariable HR 95% CI Late death  RVDCC 4.73 1.4–16  LCA stenosis 6.3 1.6–24  RCA stenosis 9 2.7–29  AP Fontan 4.9 1.4–18 Fontan failure  LCA stenosis 3.8 1.1–13  RCA stenosis 4 1.5–11 Myocardial ischaemia  RVDCC 3.9 2–7.6  LAD stenosis 4 2.1–7.8  RCA stenosis 2.9 1.4–5.9  TV z-score (per unit increase) 0.7 0.5–0.9  Fontan before 2000 0.4 0.2–0.9 Variables Univariable HR 95% CI Late death  RVDCC 4.73 1.4–16  LCA stenosis 6.3 1.6–24  RCA stenosis 9 2.7–29  AP Fontan 4.9 1.4–18 Fontan failure  LCA stenosis 3.8 1.1–13  RCA stenosis 4 1.5–11 Myocardial ischaemia  RVDCC 3.9 2–7.6  LAD stenosis 4 2.1–7.8  RCA stenosis 2.9 1.4–5.9  TV z-score (per unit increase) 0.7 0.5–0.9  Fontan before 2000 0.4 0.2–0.9 AP: atriopulmonary; CI: confidence interval; HR: hazard ratio; LAD: left anterior descending artery; LCA: left coronary artery; RCA: right coronary artery; RVDCC: right ventricle-dependent coronary circulation; TV: tricuspid valve. Figure 2: View largeDownload slide Kaplan–Meier survival curves by RVDCC status. Log-rank test, P = 0.005. RVDCC: right ventricle-dependent coronary circulation. Figure 2: View largeDownload slide Kaplan–Meier survival curves by RVDCC status. Log-rank test, P = 0.005. RVDCC: right ventricle-dependent coronary circulation. Myocardial ischaemia Myocardial ischaemia was noted in 43 patients (36%) through cardiology clinic reports, ECG and exercise testing. Myocardial ischaemia occurred in 36% of patients at a median of 6 years (IQR 2.1–8.5 years; mean 6.3 ± 5.6 years). Twenty-nine patients (24%) had ECG changes after Fontan completion that were suggestive of ischaemia. Fourteen patients (12%) completed an exercise tolerance test for investigation of myocardial ischaemia and showed inducible ischaemia through ECG changes and symptoms. Twenty-six patients (22%) suffered from angina. Sixty-four percent (7/11) of patients showed signs of ischaemia prior to death; 4 had ST depression and T-wave inversion on ECG, 2 suffered from ongoing angina and 1 patient had a syncopal episode associated with angina 1 month prior to his death. Of the 11 patients who died, 7 experienced ischaemia at a median of 4.8 years (IQR 1.4–8 years; mean 4.8 ± 4.2 years) and ischaemia preceded death by a median of 3.3 years (IQR 0.3–10.3 years; mean 7 ± 8.9 years). Patients who were found to have ischaemia had the following further examinations: cardiac magnetic resonance images (n = 13), exercise stress test (n = 17), cardiac catheterisation (n = 14) and cardiac computed tomography (n = 3). At the most recent follow-up visit, only 1 patient was known to be taking nitrates and 11 were taking beta-blockers. Four patients required Fontan revision, 3 patients had pacemakers inserted, 2 patients had fistula embolization, 2 patients had catheter ablation for arrhythmias and 1 patient had a coronary stent inserted. Overall freedom from myocardial ischaemia following Fontan completion was 81% (95% CI 74–89%) at 5 years, 63% (95% CI 53–74%) at 10 years and 47% (95% CI 35–63%) at 25 years. The 10-year freedom from ischaemia was significantly lower in patients with RVDCC compared to patients without RVDCC (15% vs 73%) (Fig. 3). Myocardial ischaemia (using ischaemia as a time-dependent covariate) was an independent predictor of death (HR 7.06, 95% CI 1.9–26.5; P = 0.004). Figure 3: View largeDownload slide Kaplan–Meier survival curves of freedom from new onset myocardial ischaemia following Fontan completion. Log-rank test, P <0.001. RVDCC: right ventricle-dependent coronary circulation. Figure 3: View largeDownload slide Kaplan–Meier survival curves of freedom from new onset myocardial ischaemia following Fontan completion. Log-rank test, P <0.001. RVDCC: right ventricle-dependent coronary circulation. Reinterventions Reintervention occurred in 26 patients (21.7%), consisting of pacemaker revision (n = 4), aortopulmonary and venovenous collateral embolization (n = 4), transcatheter ablation for arrhythmia (n = 3), Fontan circuit revision (n = 4), transcatheter pulmonary artery balloon dilatation (n = 2), pericardial/pleural effusion drainage (n = 2), closure of an atrial septal defect (n = 1), coronary artery stenting (n = 1), Fontan takedown and pulmonary valve replacement (n = 1), delayed sternal wire removal (n = 1), Bentall procedure (n = 1), balloon stenting of a Fontan conduit (n = 1) and a Fontan conversion (n = 1). Eleven patients went on to have another reintervention with 5 patients requiring 3 or more reinterventions. Overall freedom from reintervention following Fontan completion was 86% (95% CI 78–92%) at 5 years, 70% (95% CI 56–80%) at 15 years and 55% (95% CI 30–74%) at 25 years. Fontan failure Freedom from failure at 15, 20 and 25 years was 83% (95% CI 70–90%), 71% (95% CI 54–83%) and 60% (95% CI 37–76%), respectively. Risk factors predicting the occurrence of Fontan failure are listed in Table 3. DISCUSSION PA-IVS is a rare condition. It accounts for 1–3% of all congenital heart diseases and has an overall incidence of 4.5 cases per 100 000 live births [16]. Myocardial sinusoids have been reported to occur in 30–60% of patients with PA-IVS [4, 6, 11, 12, 14, 17–19]. The prevalence of RVDCC is thought to be in the range of 3–34% [4, 6, 9–13]. We demonstrated previously that these patients have a higher risk of death before reaching Fontan status. In our registry, 17% of the patients who had reached Fontan status were identified as having an RVDCC. The peculiarities of this coronary circulation are still unknown. It is unknown whether it may result in regional coronary ischaemia, especially during exercise. Our current study seems to indicate that coronary ischaemia remains a major issue for patients born with PA-IVS even late after Fontan completion. Ischaemic changes could be ultimately noted in almost all of those with an RVDCC. The incidence of sudden death also seemed to be increased in this subpopulation even though comparisons to patients with other conditions are difficult because of our current lack of data. It was long thought that up to a third of deaths occurring in patients with a Fontan circulation might be sudden and therefore likely related to arrhythmia, but these were probably overestimates [20]. In a recent publication by Khairy et al. [21] looking at modes of death in patients with a Fontan circulation, sudden death accounted for 9% of late deaths. A more recent large single-centre study found that 7% of deaths were due to sudden cardiac death [22]. In our study, sudden death accounted for 55% (6 of 11) of late deaths, although it is difficult to draw any reliable conclusions from this data because of the low event rate. A majority of late deaths occurred in children who had an atriopulmonary Fontan circulation. It is possible that this situation contributed to the outcomes of these patients. However, sudden death seemed to occur far more frequently in patients with RVDCC. The fact that coronary ischaemia was detected so much more frequently in these patients seems to support the relevance of RVDCC and consequent ischaemia in the pathogenesis of the sudden deaths observed. The presence of ostial coronary stenosis also seemed clearly associated with adverse outcomes. We believe that the increased risk of death and coronary ischaemia in patients with coronary ostial stenosis or RVDCC justifies a closer follow-up in those identified with such conditions. Conventional investigations with exercise studies should be performed as early as feasible. Angiography, whether it be invasive or computed tomography angiography, should be repeated in any patients whose coronary anatomy is uncertain. Holter monitoring should be checked regularly on several days to identify potentially fatal arrhythmias that may require further management. The possible diagnostic utility of stress dobutamine echocardiography and nuclear myocardial scans should also be investigated. As this stage, we have not identified solutions for those identified as having coronary ischaemia. Medical treatment may be effective. Education and keeping a defibrillator at home may be a solution. Because we do not know the exact mechanisms leading to sudden death, it is difficult to ascertain whether an internal defibrillator may be of use in these patients, but it may be an avenue worth investigating. Since the 1990s, indications to implant a defibrillator included a previous myocardial infarction and a left ventricular ejection fraction less than 30% [23]. Defibrillator therapy was associated with a 31% reduction in the risk of death. This indication was justified because this subgroup of patients had a 6% risk of sudden death within 5 years [24]. The risk of sudden death seems higher in those with an RVDCC. Finally, any patient detected to have a concerning ventricular arrhythmia burden could be a candidate for a heart transplant. CONCLUSION In conclusion, the long-term survival of patients with PA-IVS after the Fontan procedure remains excellent, but patients with RVDCC remain susceptible to myocardial ischaemia and sudden death. Closer surveillance and investigation for exercise-induced ischaemia may be necessary. The benefits of preventive implantation of a defibrillator should be investigated in patients with RVDCC who survive the Fontan procedure. ACKNOWLEDGEMENTS The authors sincerely acknowledge the help of Belinda Bortone (administrative support), Janina Chapman and all the Fontan Registry Research support staff for their support in data collection. Funding This work was supported by a National Health and Medical Research Council (NHMRC) Partnership Grant [1076849]. The contents of the published material are solely the responsibility of the individual authors. Yves d’Udekem is a Career Development Fellow of The National Heart Foundation Australia Program [CR 10M 5339] and NHMRC Clinician Practitioner Fellow [1082186]. Conflict of interest: none declared. REFERENCES 1 Daubeney PE , Wang D , Delany DJ , Keeton BR , Anderson RH , Slavik Z et al. 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European Journal of Cardio-Thoracic SurgeryOxford University Press

Published: Feb 12, 2018

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