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Background: In patients with transposition of the great arteries and an arterial switch operation (TGA-ASO) right ventricular outflow tract (RVOT) obstruction is a common complication requiring one or more RVOT interventions., Objectives: We aimed to assess cardiopulmonary exercise capacity and right ventricular function in patients stratified for type of RVOT intervention., Methods: TGA-ASO patients (≥16 years) were stratified by type of RVOT intervention. The following outcome parameters were included: predicted (%) peak oxygen uptake (peak VO2), tricuspid annular plane systolic excursion (TAPSE), tricuspid Lateral Annular Systolic Velocity (TV S'), right ventricle (RV)-arterial coupling (defined as TAPSE/RV systolic pressure ratio), and N-terminal proBNP (NT-proBNP)., Results: 447 TGA patients with a mean age of 25.0 (interquartile range (IQR) 21-29) years were included. Patients without previous RVOT intervention (n = 338, 76%) had a significantly higher predicted peak VO2 (78.0 ± 17.4%) compared to patients with single approach catheter-based RVOT intervention (73.7 ± 12.7%), single approach surgical RVOT intervention (73.8 ± 28.1%), and patients with multiple approach RVOT intervention (66.2 ± 14.0%, p = 0.021). RV-arterial coupling was found to be significantly lower in patients with prior catheter-based and/or surgical RVOT intervention compared to patients without any RVOT intervention (p = 0.029)., Conclusions: TGA patients after a successful arterial switch repair have a decreased exercise capacity. A considerable amount of TGA patients with either catheter or surgical RVOT intervention perform significantly worse compared to patients without RVOT interventions., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Clinical factors are used to estimate late complication risk in adults after atrial switch operation (AtrSO) for transposition of the great arteries (TGA), but heterogeneity in clinical course remains. We studied whether common genetic variants are associated with outcome and add value to a clinical risk score in TGA-AtrSO patients., Methods and Results: This multicenter study followed 133 TGA-AtrSO patients (aged 28 [IQR 24-35] years) for 13 (IQR 9-16) years and examined the association of genome-wide single-nucleotide polymorphisms (SNPs) with a composite endpoint of symptomatic ventricular arrhythmia, heart failure hospitalization, ventricular assist device implantation, heart transplantation, or mortality. Thirty-two patients (24%) reached the endpoint. The genome-wide association study yielded one genome-wide significant (p < 1 × 10 -8 ) locus and 18 suggestive loci (p < 1 × 10 -5 ). A genetic risk score constructed on the basis of independent SNPs with p < 1 × 10 -5 was associated with outcome after correction for the clinical risk score (HR = 1.26/point increase [95%CI 1.17-1.35]). Risk stratification improved with a combined risk score (clinical score + genetic score) compared to the clinical score alone (p = 2 × 10 -16 , C-statistic 0.95 vs 0.85). In 51 patients with a clinical intermediate (5-20%) 5-year risk of events, the combined score reclassified 32 patients to low (<5%) and 5 to high (>20%) risk. Stratified by the combined score, observed 5-year event-free survival was 100%, 79% and 31% for low, intermediate, and high-risk patients, respectively., Conclusions: Common genetic variants may explain some variation in the clinical course in TGA-AtrSO and improve risk stratification over clinical factors alone, especially in patients at intermediate clinical risk. These findings support the hypothesis that including genetic variants in risk assessment may be beneficial., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Patients with a Fontan circulation for single-ventricle physiology are at increased risk of developing thromboembolic events. Thromboembolic events can lead to failure of the Fontan circulation, chronic sequelae in case of stroke, and early mortality. Controversies exist regarding the substrates, risk factors, and optimal detection methods for thromboembolic events. Despite the major clinical implications, there is currently no consensus regarding the optimal antithrombotic therapy to prevent or treat thromboembolic events after the Fontan procedure. In this review we aimed to untangle the available literature regarding antithrombotic prophylaxis and treatment for pediatric and adult Fontan patients. A decision-tree algorithm for thromboprophylaxis in Fontan patients is proposed. Additionally, the current state of knowledge is reviewed with respect to the epidemiology, pathophysiology, and detection of thromboembolic events in Fontan patients, and important evidence gaps are highlighted., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Baffle complications, ie, leakage or stenosis, after an atrial switch operation (AtrSO) for transposition of the great arteries (TGA) are difficult to detect with the use of routine transthoracic echocardiography (TTE). We examined baffle interventions and the prevalence of baffle complications., Methods: This dual-centre study followed TGA-AtrSO patients for the occurrence of baffle interventions. In addition, in 2017-2019, prevalence of baffle complications was determined in patients undergoing routine contrast-enhanced (CE) TTE including various hemodynamic conditions and computed tomography (CT). Baffle leaks were defined as right-to-left shunting on CE-TTE and baffle stenosis as a systemic venous baffle diameter of < 10 mm on CT., Results: In total, 67 TGA-AtrSO patients were followed to a median age of 38 (interquartile range 34-42) years, for a median of 9 (6-13) years. Baffle interventions were documented in 24 patients (36%). Cumulative risk of baffle interventions was 25% after 15 years of follow-up. Prevalence of baffle complications was determined in 29/67 patients. In total, 4 (14%) had patent baffles, 11 (38%) had leakage only, 5 (17%) had stenosis only, and 9 (31%) had both, while 24/29 (84%) were asymptomatic. Although baffle leaks were not associated with clinical characteristics, peak work rate during exercise TTE was lower in patients with vs without stenosis (89 ± 24 W vs 123 ± 21 W; P < 0.001)., Conclusions: Baffle complications are common in TGA-AtrSO. The cumulative risk of baffle interventions was 25% after 15 years of follow-up. CE-TTE uncovered asymptomatic baffle leakage in the majority of patients, especially with examination during exercise. CT revealed baffle stenosis in almost half of the patients, which was associated with decreased exercise tolerance. Awareness of these findings may alter clinical follow-up., (Copyright © 2021 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Sudden cardiac death (SCD) is the main preventable cause of death in patients with adult congenital heart disease (ACHD). Since robust risk stratification methods are lacking, we developed a risk score model to predict SCD in patients with ACHD: the PRospEctiVE study on implaNTable cardIOverter defibrillator therapy and suddeN cardiac death in Adults with Congenital Heart Disease (PREVENTION-ACHD) risk score model., Objective: The purpose of this study was to prospectively study predicted SCD risk using the PREVENTION-ACHD risk score model and actual SCD and sustained ventricular tachycardia/ventricular fibrillation (VT/VF) rates in patients with ACHD., Methods: The PREVENTION-ACHD risk score model assigns 1 point each to coronary artery disease, New York Heart Association class II/III heart failure, supraventricular tachycardia, systemic ejection fraction < 40%, subpulmonary ejection fraction < 40%, QRS duration ≥ 120 ms, and QT dispersion ≥ 70 ms. SCD risk was calculated for each patient. An annual predicted risk of ≥3% constituted high risk. The primary outcome was SCD or VT/VF after 2 years. The secondary outcome was SCD., Results: The study included 783 consecutive patients with ACHD (n=239 (31%) left-sided lesions; n=138 (18%) tetralogy of Fallot; n=108 (14%) closed atrial septal defect; median age 36 years; interquartile range 28-47 years; n=401 (51%) men). The PREVENTION-ACHD risk score model identified 58 high-risk patients. Eight patients (4 at high risk) experienced the primary outcome. The Kaplan-Meier estimates were 7% (95% confidence interval [CI] 0.1%-13.3%) in the high-risk group and 0.6% (95% CI 0.0%-1.1%) in the low-risk group (hazard ratio 12.5; 95% CI 3.1-50.9; P < .001). The risk score model's sensitivity was 0.5 and specificity 0.93, resulting in a C-statistic of 0.75 (95% CI 0.57-0.90). The hazard ratio for SCD was 12.4 (95% CI 1.8-88.1) (P = .01); the sensitivity and specificity were 0.5 and 0.92, and the C-statistic was 0.81 (95% CI 0.67-0.95)., Conclusion: The PREVENTION-ACHD risk score model provides greater accuracy in SCD or VT/VF risk stratification as compared with current guideline indications and identifies patients with ACHD who may benefit from preventive implantable cardioverter-defibrillator implantation., (Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Aortic root dilatation is common in adults with repaired tetralogy of Fallot (rTOF) and might lead to aortic dissection. However, little is known on progression of aortic dilatation and the effect of pharmaceutical treatment. This study aims to determine factors associated with aortic growth and investigate effects of losartan., Methods and Results: We performed a prespecified analysis from the 1:1 randomized, double-blind REDEFINE trial. Aortic root diameters were measured at baseline and after 2.0 ± 0.3 years of follow-up using cardiovascular magnetic resonance (CMR) imaging. A total of 66 patients were included (68% men, age 40 ± 12 years, baseline aortic root 37 ± 6 mm, 32% aortic dilatation (>40 mm)). There was a trend towards slow aortic root growth (+0.6 ± 2.3 mm after two years, p = 0.06) (n = 60). LV stroke volume was the only factor associated with both a larger baseline aortic root (β: 0.09 mm/ml (95% C.I.:0.02, 0.15), p = 0.010) and with aortic growth during follow-up (β: 0.04 mm/ml (95% C.I.:0.005, 0.066), p = 0.024), after correction for age, sex, and body surface area using linear regression analysis. No treatment effect of losartan was found (p = 0.17)., Conclusions: Aortic root dilatation was present in about one-third of rTOF patients. A larger LV stroke volume was associated with both a larger baseline aortic root and ongoing growth. Our findings provide no arguments for lower aortic diameter thresholds for prophylactic surgery compared to the general population., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Patients with systemic right ventricle (sRV), including transposition of great arteries (TGA) after atrial switch procedure and congenitally corrected transposition of great arteries (ccTGA), may require anticoagulation for thromboembolism (TE) prevention. In the absence of data on non-vitamin K antagonist oral anticoagulants (NOACs), vitamin K antagonists (VKAs) remain the agent of choice. We investigated the safety, efficacy and feasibility of NOACs treatment in adults with sRV in a worldwide study., Methods: This is an international multicentre prospective study, using data from the NOTE registry on adults with sRV taking NOACs between 2014 and 2019. The primary endpoints were TE and major bleeding (MB). The secondary endpoint was minor bleeding., Results: A total of 76 patients (42.5 ± 10.0 years, 76% male) with sRV (74% TGA, 26% ccTGA) on NOACs were included in the study. During a median follow-up of 2.5 years (IQR1.5-3.9), TE events occurred in 3 patients (4%), while no MB episodes were reported. Minor bleeding occurred in 9 patients (12%). NOAC treatment cessation rate was 1.4% (95%CI:0.3-4%) during the first year of follow-up. All the patients with TE events had a CHA 2 DS 2 -VASc score ≥ 2 and impaired sRV systolic function at baseline. The total incidence of major events during follow-up was significantly lower compared to historical use of VKAs or aspirin before study inclusion (1.4% (95%CI:0.29-4%) vs 6,9% (95%CI:2.5-15.2%); p = .01)., Conclusions: In this prospective study, NOACs appear to be well-tolerated, with excellent efficacy and safety at mid-term in patients with sRV., Competing Interests: Declaration of Competing Interest Dr. B.J. Bouma has received restricted research grant from Bristol-Myers Squibb and Pfizer. Prof. B.J.M. Mulder has received restricted research grants from Ingelheim-Boehringer, Bayer, and Daiichi Sankyo. The other Authors report no relationships that could be construed as a conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Predicting heart failure events in patients with a systemic right ventricle (sRV) due to transposition of the great arteries (TGA) is important for timely intensification of follow-up. This study assessed the value of strain compared with currently used parameters as predictor for heart failure-free survival in patients with sRV., Methods: In participants of a multicentre trial, speckle-tracking echocardiography (STE) was performed to assess global longitudinal strain (GLS), mechanical dispersion (MD), and postsystolic shortening (PSS). Cox regression was used to determine the association of STE parameters with the combined end point of progression of heart failure and death, compared with cardiovascular magnetic resonance (CMR) and computed tomography (CT) derived parameters., Results: Echocardiograms of 60 patients were analyzed (mean age 34 ± 11 years, 65% male, 35% congenitally corrected TGA). Mean GLS was -13.5 ± 2.9%, median MD was 49 (interquartile range [IQR] 30-76) ms, and 14 patients (23%) had PSS. During a median 8 (IQR 7-9) years, 15 patients (25%) met the end point. GLS, MD, and PSS were all associated with heart failure-free survival in univariable analysis. After correction for age, only GLS (optimal cutoff > -10.5%) and CMR/CT-derived sRV ejection fraction (optimal cutoff < 30%) remained associated with heart failure-free survival: hazard ratio (HR) 8.27, 95% confidence interval (CI) 2.50-27.41 (P < 0.001), and HR 4.34, 95% CI 1.48-12.74 (P = 0.007), respectively). Combining GLS and ejection fraction improved prediction, with patients with both GLS > -10.5% and sRV ejection fraction < 30% at highest risk (HR 19.69, 95% CI 4.90-79.13; P < 0.001)., Conclusions: The predictive value of GLS was similar to that of CMR/CT-derived ejection fraction. The combination of GLS and ejection fraction identified patients at highest risk of heart failure and death. Easily available STE parameters can be used to guide follow-up intensity and can be integrated into future risk prediction scores., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: 22q11.2 Deletion syndrome (22q11.2DS) is common in patients with tetralogy of Fallot (TOF) or pulmonary atresia with ventricular septal defect (PA/VSD) and is associated with worse outcomes in children. Whether this impaired prognosis is also translated into adulthood is unknown, as data in adult patients are limited. We aimed to compare long-term outcomes in adults with TOF or PA/VSD both with and without 22q11.2DS., Methods: This study prospectively followed a nationwide multicenter cohort of TOF or PA/VSD patients with genetically confirmed presence or absence of 22q11.2DS, from inclusion in the Dutch national CONCOR registry for adults with congenital heart disease (CHD) onward. Outcome measures included all-cause mortality, cardiac mortality, need for pulmonary valve replacement (PVR), ventricular arrhythmias (VA), pacemaker implantation, and ICD implantation., Results: In total, 479 patients were included (277 (58%) male, median age 28 [IQR; 21-37] years, 62 (13%) with PA/VSD, 34 (7%) with 22q11.2DS). During a median follow-up of 11 [IQR; 6-13] years, 52 (11%) patients died (8 with 22q11.2DS and 44 without 22q11.2DS). Patients with 22q11.2DS had significant decreased survival after 12 years (76% [95% CI; 62-93]) compared to patients without 22q11.2DS (89% [95% CI; 86-92], p = 0.008). 22q11.2DS was associated with increased risk of all-cause mortality and cardiac-mortality, independent of age, sex, and PA/VSD. No association was found between 22q11.2DS and late complications i.e. PVR, VA, pacemaker, or ICD implantation., Conclusions: Adults with TOF or PA/VSD with 22q11.2DS have a significantly worse survival than adults without this deletion. In patients with TOF or PA/VSD, genetic analysis for the presence of 22q11.2DS is important for risk stratification and genetic counseling., Competing Interests: Declaration of competing interest The authors D. Kauw, O.I. Woudstra, K. Van Engelen, F.J. Meijboom, B.J.M. Mulder, M.J. Schuuring and B.J. Bouma declare that they have no competing interests., (Copyright © 2020. Published by Elsevier B.V.)

Objective: Little is known about the course of echocardiographic parameters used for the evaluation of valvular heart disease (VHD) during pregnancy, hampering interpretation of possible changes (physiological vs. pathophysiological). Therefore we studied the course of these parameters and ventricular function in pregnant women with aortic and pulmonary VHD., Methods: The cohort comprised 66 pregnant women enrolled in the prospective ZAHARA studies or evaluated by an identical protocol who had pulmonary VHD or aortic VHD (stenosis/prosthetic valve). The control group comprised 46 healthy pregnant women. Echocardiography was performed preconception, during pregnancy and 1 year postpartum. Peak gradient, mean gradient, aortic valve area (AVA)/effective orifice area (EOA), left ventricular ejection fraction (LVEF) and right ventricular function (RVF; TAPSE) were assessed., Results: Peak and mean gradients increased during pregnancy compared to preconception in women with aortic VHD and controls (p < 0.0125), but not in women with pulmonary VHD. AVA/EOA remained unchanged. Preconception and postpartum gradients were comparable in all groups. Mean LVEF was normal in pregnant women with VHD and controls. Mean TAPSE was lower (p < 0.001) in women with pulmonary VHD compared to women with aortic VHD and controls (<20 mm vs. ≥23 mm; p < 0.001). In women with pulmonary VHD a decrease of TAPSE was observed during pregnancy (p = 0.005)., Conclusion: Physiological changes during pregnancy lead to increased Doppler gradients in women with aortic VHD. This increase was not found in women with pulmonary VHD, probably caused by impaired RVF. Therefore, evaluation of RVF during pregnancy might be important to prevent underestimation of the degree of stenosis., Competing Interests: Declaration of competing interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Coronary artery disease (CAD) will increasingly determine outcome in the aging adult congenital heart disease (CHD) population. We aimed to determine sex-specific incidence of CAD in adult CHD patients throughout adulthood, compared to the general population., Methods and Results: We followed 11,723 adult CHD patients (median age 33 years; 49% male; 57% mild, 34% moderate, 9% severe CHD) from the Dutch CONCOR registry, and two age-sex-matched persons per patient from the general population for first CAD event in national registers (period 2002-2012). Incidence rates were estimated using smoothed hazard functions. CAD risk during follow-up, stratified by CHD severity, was compared using proportional subdistribution hazards regression. In ACHD patients, 103 CAD events (43 women) occurred over 60,456 person-years. Rates per 1000person-years increased from 0.3(95% confidence interval: 0.1-0.6) at age 20 to 5.8(3.7-8.9) at 70 years in female, and from 0.5(0.3-1.0) to 7.8(5.1-11.8) in male patients. Compared to the general population, relative risk was 12.0(2.5-56.3) in women and 4.6(1.7-12.1) in men aged 20 years. Relative risk declined with age, remaining significant up to age ~65 years in women and ~50 years in men. In patients with mild, moderate and severe CHD, CAD risk was 1.3(0.9-1.9), 1.6(1.0-2.5) and 2.9(1.3-6.9) times increased compared to the general population, respectively., Conclusions: We found increased CAD risk in adult CHD patients, with greater relative risk at younger age, in women and those with more severe CHD. These results underline the importance of screening for and treatment of CAD risk factors in these patients., Competing Interests: Declaration of competing interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2019. Published by Elsevier B.V.)

Background: Current guidelines consider vitamin K antagonists (VKA) the oral anticoagulant agents of choice in adults with atrial arrhythmias (AA) and moderate or complex forms of congenital heart disease, significant valvular lesions, or bioprosthetic valves, pending safety data on non-VKA oral anticoagulants (NOACs). Therefore, the international NOTE registry was initiated to assess safety, change in adherence and quality of life (QoL) associated with NOACs in adults with congenital heart disease (ACHD)., Methods: An international multicenter prospective study of NOACs in ACHD was established. Follow-up occurred at 6 months and yearly thereafter. Primary endpoints were thromboembolism and major bleeding. Secondary endpoints included minor bleeding, change in therapy adherence (≥80% medication refill rate, ≥6 out of 8 on Morisky-8 questionnaire) and QoL (SF-36 questionnaire)., Results: In total, 530 ACHD patients (mean age 47 SD 15 years; 55% male) with predominantly moderate or complex defects (85%), significant valvular lesions (46%) and/or bioprosthetic valves (11%) using NOACs (rivaroxaban 43%; apixaban 39%; dabigatran 12%; edoxaban 7%) were enrolled. The most common indication was AA (91%). Over a median follow-up of 1.0 [IQR 0.0-2.0] year, thromboembolic event rate was 1.0% [95%CI 0.4-2.0] (n = 6) per year, with 1.1% [95%CI 0.5-2.2] (n = 7) annualized rate of major bleeding and 6.3% [95%CI 4.5-8.5] (n = 37) annualized rate of minor bleeding. Adherence was sufficient during 2 years follow-up in 80-93% of patients. At 1-year follow-up, among the subset of previous VKA-users who completed the survey (n = 33), QoL improved in 6 out of 8 domains (p ≪ 0.05)., Conclusions: Initial results from our worldwide prospective study suggest that NOACs are safe and may be effective for thromboembolic prevention in adults with heterogeneous forms of congenital heart disease., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) have several advantages over VKAs that render them an attractive option for adults with congenital heart disease (CHD). Efficacy and safety data specific to the adult CHD population are emerging. Herein, we synthesize the growing literature regarding NOACs in adults with CHD and attempt to identify subgroups for which it appears reasonable to extrapolate data from populations without CHD. Small observational studies suggest that NOACs are safe and effective in selected adults with CHD. NOACs are contraindicated in patients with a mechanical valve, in those with mitral or tricuspid valve stenosis with enlarged and diseased atria, with or without a mitral or tricuspid bioprosthesis, and after recent cardiac surgery (< 3 months). There is currently insufficient evidence to recommend NOACs in patients with a Fontan circulation or cyanotic CHD. Growing literature supports the use of NOACs in patients without CHD who have various forms of valvular heart disease. Therefore, when an indication for oral anticoagulation is established, it appears reasonable to consider a NOAC instead of a VKA in adults with CHD lesions analogous to isolated mitral regurgitation, tricuspid regurgitation, or aortic regurgitation or stenosis. The NOAC agent selected and the prescribed dose should be tailored according to bleeding risk, body weight, renal function, and comedications, especially antiepileptic drugs. The decision to initiate a NOAC should be shared between the patient and care provider. Large-scale research studies are required to further assess safety and efficacy in selected patient subgroups., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Several studies have reported changes in electrocardiographic variables after atrial septal defect (ASD) closure. However no temporal electro-and vectorcardiographic changes have been described from acute to long-term follow-up at different ages. We aimed to study electrical remodeling after percutaneous ASD closure in pediatric and adult patients., Methods: ECGs of 69 children and 75 adults (median age 6 [IQR 4-11] years and 45 [IQR 33-54] years, respectively) were retrospectively selected before percutaneous ASD closure and at acute (1-7 days), intermediate (4-14 weeks) and late (6-18 months) follow-up. Apart from electrocardiographic variables, spatial QRS-T angle and ventricular gradient (VG) were derived from mathematically-synthesized vectorcardiograms., Results: In both pediatric and adult patients, the heart rate decreased immediately post-closure, which persisted to late follow-up. The P-wave amplitude also decreased acutely post-closure, but remained unchanged at later follow-up. The PQ duration shortened immediately in children and at intermediate follow-up in adults. The QRS duration and QTc interval decreased at intermediate-term follow-up in both children and adults. In both groups the spatial QRS-T angle decreased at late follow-up. The VG magnitude increased at intermediate follow-up in children and at late follow-up in adults, after an initial decrease in children., Conclusion: In both pediatric and adult ASD patients, electrocardiographic changes mainly occurred directly after ASD closure except for shortening of QRS duration and QTc interval, which occurred at later follow-up. Adults also showed late changes in PQ duration. At 6-to-18 month post-closure, the spatial QRS-T angle decreased, reflecting increased electrocardiographic concordance. The initial acute decrease in VG in children, which was followed by a significant increase, may be the effect of action potential duration dynamics directly after percutaneous ASD closure., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: This study describes the different types of congenital vascular rings according to their anatomy, symptoms, and age at clinical onset and reports the surgical outcomes., Methods: A retrospective observational database study was conducted, reviewing the medical charts of 69 adult survivors with a history of a vascular ring, identified from the Dutch Congenital Cor vitia database., Results: Median age at presentation was 8.5 years (0-53.0 years). Thirty patients (43.5%) had a "left aortic arch with aberrant right subclavian artery," 21 patients (30.4%) a "double aortic arch," and 16 patients (23.2%) a "right aortic arch with aberrant left subclavian artery." The main symptomatology at presentation comprised respiratory symptoms (82.9%). Almost three-quarters of patients were also diagnosed with asthma/bronchial hyperreactivity. Patients with a double aortic arch had more symptoms than patients with a left aortic arch with aberrant right subclavian artery and right aortic arch with aberrant left subclavian artery (P < 0.001), requiring surgery most often (P < 0.001). In patients with childhood onset of symptoms, preoperative spirometry (ie, peak expiratory flows) was more often abnormal as compared with adult patients (P = 0.007). Surgery was performed in 42.0% of all patients at a median age of 17 years (0-63.0 years). Twenty-four (92.3%) of the operated patients showed improvement or complete relief of symptoms shortly after surgery. Of 26 asymptomatic nonoperated patients, 3 patients (11.5%) eventually developed symptoms., Conclusions: The low incidence of vascular rings, their anatomic heterogeneity, and a wide range of common symptoms often lead to misdiagnosis. Clinical awareness is warranted as a large subset of patients could benefit from surgery, even at an adult age., (Copyright © 2018 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objectives: In the VAL-SERVE (Valsartan in Systemic Right Ventricle) trial, three-year valsartan treatment improved systemic ventricular function only in symptomatic patients with congenitally or with an atrial switch corrected transposition of the great arteries. The aim of the current study was to investigate the longer-term clinical outcomes after valsartan treatment., Methods: From 2006 to 2009, 88 adults were randomly allocated 1:1 to either valsartan or placebo for three consecutive years. Endpoints were defined as overall survival and freedom from clinical events (arrhythmia, heart failure, tricuspid valve surgery, death)., Results: Cardiac drug use and median follow-up after trial close-out (8.3 years) was similar between the randomization groups. Six patients (valsartan n = 3, placebo n = 3) died in 364 and 365 person-years (P = 0.999). No difference in the composite or separate clinical endpoints was found between the randomization groups, with corresponding long-term event-free survival rates of 50% and 34%. Nevertheless, in symptomatic patients valsartan significantly reduced the risk for events compared to placebo (HR 0.37, 95% CI 0.17-0.92). Analysis for repeated events and on-treatment analysis with any renin-angiotensin-aldosterone-system-inhibitor did not alter these results., Conclusions: Valsartan treatment in systemic RV patients did not result in improved survival at longer-term follow-up, but was associated with decreased risk of events in symptomatic patients., (Copyright © 2018. Published by Elsevier B.V.)

Background: The purpose of this prospective randomised controlled trial was to assess whether home-based, self-selected exercise training is safe, results in high compliance and improves exercise capacity in symptomatic adults with congenital heart disease (CHD)., Methods: Forty adults with moderate or severe CHD (40 ± 12 years, 56% male, New York Heart Association [NYHA] II/III 37/3) were randomly assigned, stratified by CHD complexity, either to home-based exercise training or usual care. The exercise training protocol consisted of three exercise sessions per week for six consecutive months. Patients were free to choose any sports of their preference., Results: Thirty-four patients (each randomisation group n = 17) completed the protocol and were analysed. The majority was involved in high-dynamic sports (76%); none had to discontinue the training programme due to exercise-related adverse events. More than 70% adhered to the exercise programme at or above the target training level. Peak VO 2 increased significantly in the exercise group by +1.7 ± 2.7 ml∙kg∙min -1 (p = 0.025), whereas it remained unchanged in the control group by +0.8 ± 2.2 ml∙kg∙min -1 (p = 0.184). No significant changes were found in serum N-Terminal pro-brain natriuretic peptide levels or quality of life in either randomisation group or between groups., Conclusions: In symptomatic adults with moderate or severe CHD, home-based exercise training of their preference appeared safe, with good compliance and favourable effects on exercise capacity. Our results demonstrate that it is appropriate to stimulate our patients to regularly perform moderate to vigorous physical activities, in absence of medical restrictions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aims: Adult congenital heart disease (ACHD) patients are at increased risk of sudden cardiac death and out-of-hospital cardiac arrest (OHCA). Currently, insufficient data exist on outcome, causes and circumstances of OHCA of ACHD patients resuscitated for OHCA. We investigate these parameters in ACHD patients in comparison to OHCA in the general population., Methods and Results: We identified ACHD patients with OHCA by linking data from a Dutch nationwide registry of ACHD patients (CONCOR, n = 15,727), and ARREST, a cohort of OHCA cases (n = 17,868). 62 ACHD patients with OHCA were identified. Ventricular septal defect (n = 11), bicuspid aortic valve (n = 10) and atrial septal defect (n = 8) were the most common diagnoses. We included OHCA cases from the general population as controls. ACHD patients were younger than controls (n = 11,624) at the time of OHCA (47 (SD ± 17) years vs. 66 (SD ± 15) years, respectively, p < 0.001), and more often had a shockable initial rhythm (67% vs 40%, respectively, p < 0.001). A cardiac cause of OHCA was identified in 76% of ACHD patients, with only 7% due to myocardial infarction or ischemia. Survival was better in ACHD patients than in controls (44% vs. 19%, p < 0.001), but this difference disappeared after correction for age, gender, witnessed arrest, bystander resuscitation, public location and shockable rhythm., Conclusions: OHCA in ACHD patients occurs at young age, is rarely caused by ischemia and occurs mainly in patients with simple congenital defects. Risk stratification efforts should therefore not be restricted to ACHD patients with severe congenital defects., (Copyright © 2018. Published by Elsevier B.V.)

Background: Proximal aortic dilatation in certain congenital heart diseases (CHD) prompts concerns about dissection and consideration of prophylactic surgery. To evaluate contemporary prophylactic practice, we determined incidence of aortic dissection and prophylactic surgery in aortopathy-associated CHD, compared to Marfan syndrom (MFS) and controls., Methods and Results: We followed patients from the CONCOR adult CHD registry (2002-2015), with a native proximal aorta and aortopathy-associated CHD, comprising bicuspid aortic valve/aortic stenosis ('BAV/AS'; n = 2239) and aortic coarctation/conotruncal defects/univentricular heart/ventricular septal defect ('At-risk CHD'; n = 5439). As reference, we selected MFS (n = 356) and 'Control' (atrial septal defect, pulmonary stenosis; n = 2940) patients. Cumulative incidences of dissection and prophylactic proximal aortic replacement - considered competing events - were determined, and compared corrected for age and sex. Median follow-up was 6.7 years. Ten-year dissection-incidence was 0.3% (95%CI: 0.0-0.7) in BAV/AS and 0.2% (0.0-0.3) in At-risk CHD, both significantly lower than in MFS (4.1%; 1.8-6.4) and similar to Controls (0.1%; 0.0-0.3). Ten-year prophylactic-surgery incidence was 9.3% (7.6-11.0) in BAV/AS and 0.7% (0.5-1.0) in At-risk CHD, both significantly lower than in MFS (21.3%; 16.3-26.3) and higher than in Controls (0.1%; 0.0-0.3)., Conclusions: In contemporary practice, aortic-dissection incidence is low in adults with aortopathy-associated CHDs, while prophylactic-surgery incidence is high in BAV/AS. To reduce surgical burden, BAV/AS patients could benefit from more individualised prophylactic-surgery algorithms., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Current guidelines on oral anticoagulation (OAC) in adults with congenital heart disease (ACHD) and atrial arrhythmias (AA) consist of heterogeneous and divergent recommendations with limited level of evidence, possibly leading to diverse OAC management and different outcomes. Therefore, we aimed to evaluate real-world implementation and outcome of three guidelines on OAC management in ACHD patients with AA., Methods: The ESC GUCH 2010, PACES/HRS 2014 and ESC atrial fibrillation (AF) 2016 guidelines were assessed for implementation. ACHD patients with recurrent or sustained non-valvular AA from 5 tertiary centers were identified using a national ACHD registry. After two years of prospective follow-up, thromboembolism, major bleeding and death were assessed., Results: In total, 225 adults (mean age 54±15years, 55% male) with various defects (simple 43%; moderate 37%; complex 20%) and AA were included. Following the most strict indication (OAC is recommended in all three guidelines), one should treat a mere 37% of ACHD patients with AA, whereas following the least strict indication (OAC is recommended in any one of the three guidelines), one should treat 98% of patients. The various guidelines were implemented in 54-80% of patients. From all recommendations, Fontan circulation, CHA2DS2-VASc≥1 and AF were independently associated with OAC prescription. Superiority of any guideline in identifying outcome (n=15) could not be demonstrated., Conclusions: The implementation of current guidelines on OAC management in ACHD patients with AA is low, probably due to substantial heterogeneity among guidelines. OAC prescription in daily practice was most consistent in patients with AF and CHA2DS2-VASc≥1 or Fontan circulation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aim: To determine the prevalence of unidentified bicuspid aortic valve (BAV) or aortic dilatation (>40mm) in first degree relatives (FDR) of patients with isolated BAV in a general hospital., Methods and Results: Patients with isolated BAV received information advising cardiac screening of their FDR. Referred and screened were 134 FDR of 54 adult index patients with isolated BAV (median 2 per index patient). FDR's mean age was 49years (range 16-83years) and 41% were male. They comprised 5 parents (3.7%), 52 siblings (39%) and 77 offspring (57%). Among these FDR, the prevalence of BAV was 6.0% (8 patients). In FDR without BAV, 10 (7.5%) had aortic dilatation. 'Familial BAV' was present in 9/54 families (17%)., Conclusion: In a general hospital, screening of FDR of patients with isolated BAV resulted in a substantial yield of 13% new cases with BAV or aortic dilatation without BAV., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Background: Atrioventricular septal defect (AVSD) has an incidence of 4-5.3 per 10.000 live births and is associated with Down syndrome (DS). Data on arrhythmias and sudden cardiac death (SCD) after AVSD correction is scarce., Aim: To analyse the incidence of post-operative arrhythmias and SCD after AVSD correction and explore risk factors., Methods: This is a retrospective multicenter study including patients after biventricular AVSD correction. Univariate and multivariate analyses were performed to explore risk factors., Results: A total of 415 patients were included with a mean follow-up duration of 9years (range; <30days-47years). Early post-operative SVTs were documented in 33 patients (8%) and late post-operative SVTs in 15 patients (3.6%). Non-syndromic AVSD (p=0.022, HR=2.64; 95% CI=1.15-6.04) and cAVSD (p=0.005, HR=3.7; 95% CI=1.39-7.51) were independent risk factors for early post-operative SVTs and significant more late post-operative SVTs occurred in non-syndromic patients (p=0.016, HR=6.38; 95% CI=1.42-28.71) and in pAVSD (p=0.045, HR=3.703; 95% CI=1.03-13.32). Fifteen patients (3.6%) received a pacemaker. Non-syndromic AVSD (p=0.008, HR=15.82; 95% CI=2.04-122.47), pAVSD (p=0.017, HR=6.26; 95% CI=1.39-28.28) and re-operation (p=0.007, HR=4.911; 95% CI=1.54-15.64) were independent risk factors for postoperative pacemaker implantation. Late life-threatening ventricular arrhythmias and SCD occurred in 0.5% and 1.7% respectively., Conclusion: There is good long-term survival after AVSD correction and incidence of SCD is low. Non-syndromic AVSD and cAVSD are independent risk factors for early post-operative SVTs. Non-syndromic AVSD patients have significant more early 3rd degree AVB and late post-operative SVTs. Non-syndromic patients with partial AVSD who have undergone reoperation have a significant higher risk of pacemaker implantation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: Women with repaired coarctation of the aorta (rCoA) are at risk of hypertensive disorders and other complications during pregnancy. Hypertensive disorders in pregnant women are associated with inadequate uteroplacental flow, which is related to adverse offspring outcome. The aim of this study was to investigate the relationship of maternal cardiac function, placental function and pregnancy complications in women with rCoA., Methods: We included 49 pregnant women with rCoA and 69 controls from the prospective ZAHARA-studies (Zwangerschap bij Aangeboren HARtAfwijkingen, pregnancy in congenital heart disease). Clinical evaluation, echocardiography and uteroplacental Doppler flow (UDF) measurements were performed at 20 and 32weeks gestation. Univariable regression analysis was performed., Results: Comparison of rCoA and healthy women. In women with rCoA, tricuspid annular plane systolic excursion (TAPSE) decreased during pregnancy (25.7mm to 22.8mm, P=0.006). UDF indices and pregnancy complication rates were similar in both groups. Offspring of rCoA women had lower birth weight (3233g versus 3578g, P=0.001), which was associated with β-blocker use during pregnancy (β=-418.0, P=0.01). Association of cardiac function and UDF. Right ventricular (RV) function before pregnancy (TAPSE) and at 20weeks gestation (TAPSE and RV fractional area change) were associated with impaired UDF indices (umbilical artery pulsatility index at 20weeks β=-0.02, P=0.01, resistance index at 20 and 32weeks β=-0.01, P=0.02 and β=-0.02, P=0.01 and uterine artery pulsatility and resistance index at 20weeks gestation β=-0.02, P=0.05 and β=-0.01, P=0.02)., Conclusions: Women with rCoA tolerate pregnancy well. However, RV function is altered and is associated with impaired placentation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Adults with congenital heart disease (ACHD) are affected by atrial arrhythmias (AA). To elucidate the impact of AA on prognosis, we aimed to determine the impact of AA on death, heart failure and stroke in ACHD patients in a prospective nationwide clinical registry., Methods: All patients aged ≥18years included in the CONCOR registry per October 1st 2015 were analysed. Prior AA was defined as atrial fibrillation, atrial flutter or unspecified AA before inclusion in CONCOR and new-onset AA as a first documented AA during follow-up. The outcomes were death, first stroke and first admission for heart failure (HF)., Results: The study cohort comprised 14,224 patients (baseline median age 33.6 [IQR 23-47], male 49.5%, AA n=1501, complex defect 10.3%, repaired defect 58.9%). Median follow-up was 6.5years [IQR 3-10]. Adjusting for age, sex, repair status and defect severity, patients with prior AA had higher mortality and more HF admissions, but no increased risk of stroke compared to those without AA (HR=2.11; 95% CI=1.79-2.49; p<0.001, HR=4.06; 95% CI=2.66-6.19; p<0.001 and HR=1.09; 95% CI=0.71-1.68; p=0.698, respectively). New-onset AA during follow-up was significantly associated with stroke (HR=2.04; 95% CI=1.05-3.96; p=0.036)., Conclusions: ACHD patients with prior AA have a 2-fold increased risk of death and a 4-fold increased risk of heart failure, but no increased risk for stroke compared to those without AA. Defect severity and age appear to be more important risk factors for stroke than prior AA. Stroke risk is increased only after conversion of new onset AA., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Little is known on the clinical course of tricuspid regurgitation (TR) in patients with repaired tetralogy of Fallot (rTOF) and which patients are at particular risk. This study aims to determine TR course, characteristics associated with TR progression, and the prognostic relevance of TR in rTOF patients., Methods: In this dualcenter cohort study, rTOF patients from a prospective national registry with ≥1 cardiac magnetic resonance imaging study and ≥2 echocardiograms available were included. Clinical and imaging data were collected. Cox hazards regression analysis was used to assess patient characteristics associated with progression to severe TR and whether severe TR was associated with the combined clinical endpoint of tachyarrhythmia, heart failure, and death, as time-dependent factor., Results: A total of 216 patients were included (57% men, age 34±12years); 11 patients (5%) had severe TR at baseline. During 7.6±3.5years of follow-up, progression to severe TR occurred in 15 patients (7%). NYHA class ≥2 (HR 5.38, 95%-C.I. 1.91-15.16, p=0.001) and moderate baseline TR (HR 13.10, 95%-C.I. 2.95-58.21, p=0.001) were independently associated with progression to severe TR. Adverse events occurred in 47 patients (22%). The occurrence of severe TR was independently associated with adverse events (HR 3.48, 95%-C.I. 1.68-7.21, p=0.001)., Conclusions: In this study, severe TR was present in 12% of adult rTOF patients during 7.6years, and progression to severe TR was most likely in symptomatic patients with moderate baseline TR. In these patients, close surveillance is warranted, because the occurrence of severe TR was associated with worse prognosis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Adult patients with pulmonary arterial hypertension due to congenital heart disease (PAH-CHD) suffer from high mortality. This underlines the importance of adequate risk stratification to guide treatment decisions. Several baseline parameters are associated with mortality, however, their prognostic value may weaken after years of follow-up. Therefore we investigated the prognostic value of serial changes in standard clinical parameters in PAH-CHD., Methods: In this prospective observational cohort study we included consecutive PAH-CHD adults, between 2005 and 2016. Control visits to the outpatient clinic were standardized, including functional, biochemical and echocardiographic tests, according to the guidelines. The prognostic value of serial changes was determined with time-dependent Cox regression., Results: Ninety-two patients with PAH-CHD were included (age 43±15years, 34% male, 38% Down, 73% Eisenmenger). During a median follow-up of 6.0 (IQR 3.7-9.3) years, 35 (38%) patients died. Serial changes in World Health Organization functional classification (WHO-FC, HR 18.34 for onset class IV), six-minute walk distance (6-MWD, HR 0.65 per 50m), oxygen saturation at peak exercise (peak SaO 2 , HR 0.74 per 5%), NTproBNP (HR 2.25 per 1000ng/l) and echocardiographic right ventricular function (TAPSE, HR 0.80 per 0.5cm) significantly predicted mortality. Moreover, serial changes in these parameters were more potent predictors compared to baseline parameters, based on reduction in -2 log likelihood., Conclusions: Serial changes in standard clinical parameters have more prognostic value compared to baseline parameters in PAH-CHD. Our results emphasize the importance of screening for serial changes since periodical assessment could guide treatment decisions to delay disease progression., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)