Publications by authors named "Marc Gewillig"

244 Publications

Prenatal 3D-ultrasound diagnosis of isolated intrahepatic portal-systemic shunt with intact ductus venosus: A case report and literature review.

Radiol Case Rep 2021 May 16;16(5):1173-1178. Epub 2021 Mar 16.

Department of Development and Regeneration, Cluster Woman and Child, Group Biomedical Sciences, KU Leuven University of Leuven, Belgium.

We present a case of isolated intrahepatic portosystemic shunts with an aorto- hepatic-umbilical connection; prenatally diagnosed with 3D Doppler flow in a 27-year-old patient at 27 weeks of gestation. Fetal karyotyping was normal, detailed evaluation of the venous and cardiovascular system showed a patent ductus venosus and no other abnormalities. These fetuses with isolated intrahepatic shunts are at risk for intra-uterine growth restriction (27%), all cases had a good prognosis with live births. Postnatal follow-up to control shunt closure is vital as persistent shunts may lead to subsequent complications.
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http://dx.doi.org/10.1016/j.radcr.2021.02.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995476PMC
May 2021

Mid-Term Outcomes Following Percutaneous Pulmonary Valve Implantation Using the "Folded Melody Valve" Technique.

Circ Cardiovasc Interv 2021 Mar 17:CIRCINTERVENTIONS120009707. Epub 2021 Mar 17.

Cardiac Catheterization Laboratories, Sidra Heart Center, Sidra Medicine, Doha, Qatar (Y.B.).

Background: The folded valve is a manual shortening of the Melody device, which has been validated as a valuable therapeutic option for the management of dysfunctional right ventricular outflow tracts needing a short valved stent. In this article, we aimed to evaluate, in a multicenter cohort, the mid-term outcomes of patients in whom a percutaneous pulmonary valve implantation was performed using the folded valve technique.

Methods: A 2012 to 2018 retrospective multicenter study was performed in 7 European institutions. All patients who benefit from percutaneous pulmonary valve implantation with a folded Melody valve were included.

Results: A total of 49 patients (median age, 19 years [range 4-56], 63% male) were included. The primary percutaneous pulmonary valve implantation indication was right ventricular outflow tract stenosis (n=19; 39%), patched native right ventricular outflow tracts were the most common substrate (n=15; 31%). The folded technique was mostly used in short right ventricular outflow tracts (n=28; 57%). Procedural success was 100%. After a median follow-up of 28 months (range, 4-80), folded Melody valve function was comparable to the immediate postimplantation period (mean transvalvular peak velocity=2.6±0.6 versus 2.4±0.6 m/s, >0.1; only 2 patients had mild pulmonary regurgitation). Incidence rate of valve-related reinterventions was 2.1% per person per year (95% CI, 0.1%-3.9%). The probability of survival without valve-related reinterventions at 36 months was 90% (95% CI, 76%-100%).

Conclusions: The folded Melody valve is a safe technique with favorable mid-term outcomes up to 6.5 years after implantation, comparable with the usual Melody valve implantation procedure. Complications and reinterventions rates were low, making this technique relevant in selected patients.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.120.009707DOI Listing
March 2021

Pulmonary Valve Replacement in Tetralogy of Fallot: An Updated Meta-Analysis.

Ann Thorac Surg 2020 Dec 27. Epub 2020 Dec 27.

Department of Thoracic and Cardiovascular Surgery, West German Heart and Vascular Center, Essen, Germany.

Background: The benefits of pulmonary valve replacement (PVR) for pulmonary insufficiency in patients with repaired tetralogy of Fallot (TOF) are still incompletely understood, and optimal timing remains challenging.

Methods: We systematically reviewed databases (PubMed/MEDLINE, EMBASE, CENTRAL/CCTR, ClinicalTrials.gov, SciELO, LILACS, Google Scholar) and reference lists of relevant articles for studies about PVR in repaired TOF patients that reported any of the following outcomes: mortality and redo-PVR rates, right (RV) and left ventricular (LV) measures, QRS duration, cardiopulmonary exercise test (CPET) results, or brain natriuretic peptide (BNP). In addition to calculating the pooled treatment effects using a random effects meta-analysis, we evaluated the effect of pre-operative measures on PVR outcomes using meta-regressions.

Results: Eighty-four studies involving 7,544 patients met the eligibility criteria. Pooled mortality at 30 days, 5 year, and 10 year after PVR was 0.87% (80 studies; 63 of 7,253 patients), 2.7% (37 studies; 132 of 4,952 patients), and 6.2% (15 studies; 510 of 2,765 patients), respectively. Pooled 5 and 10 year re-PVR were 3.7% (23 studies; 141 of 3,755 patients) and 16.8% (16 studies; 172 of 3,035 patients), respectively. The results of the previous meta-analysis could be confirmed. In addition, it could be demonstrated that after PVR: 1) QRS duration, CPET results, and RV and LV longitudinal strain do not significantly change; 2) BNP decreases; and 3) greater indexed RV end-diastolic and end-systolic volumes are associated with lower chances of RV volume normalization after PVR.

Conclusions: This updated meta-analysis provides evidence about the benefits of PVR.
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http://dx.doi.org/10.1016/j.athoracsur.2020.11.040DOI Listing
December 2020

Pulmonary Vascular Reserve in Fontan Patients: Looking Upstream for the True Heart of the Matter.

J Am Coll Cardiol 2020 12;76(23):2764-2767

Congenital Cardiology, University Hospitals Leuven, Leuven, Belgium. Electronic address: https://twitter.com/alexvdbruaene.

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http://dx.doi.org/10.1016/j.jacc.2020.10.006DOI Listing
December 2020

Case Report: Disseminated Systemic Embolism of Lipiodol After Lymphography for Plastic Bronchitis After Fontan Repair.

Front Pediatr 2020 27;8:584185. Epub 2020 Oct 27.

Department of Pediatric and Congenital Cardiology, Leuven University Hospital, Leuven, Belgium.

Lipiodol-based lymphangiography is not only a diagnostic tool for visualization of lymphatic disorders such as plastic bronchitis (PB), but also aims a therapeutic effect by embolizing lymph leakages. We performed such percutaneous lymphatic embolization for PB in a Fontan patient with proven absence of right-to-left shunt, and demonstrated important lymphatic abnormalities in the mediastinum. Shortly after the procedure, the patient developed severe convulsive seizures, revealing multiple cerebral embolisms of Lipiodol. Radiological images were impressive, yet the clinical neurological outcome was favorable. Lipiodol-based lymphography in Fontan patients with plastic bronchitis should be avoided as this subgroup is more likely to have developed lympho-pulmonary venous connections which allow systemic emboli.
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http://dx.doi.org/10.3389/fped.2020.584185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652765PMC
October 2020

Covered stent placement for treatment of coarctation of the aorta: immediate and long-term results.

Acta Cardiol 2020 Oct 28:1-9. Epub 2020 Oct 28.

Clinical Department of Cardiovascular diseases, University Hospitals Leuven, Leuven, Belgium.

Objectives: This study aimed to describe the safety and efficacy of covered stents in patients with coarctation of aorta (CoA) for immediate and long-term follow-up.

Background: Covered stents are increasingly being used in (re)CoA, mainly to reduce the risk of aortic wall injuries (AWI). However, limited data are available on intermediate and long-term outcome.

Methods: In 89 patients (67.4% male) with a mean age of 23.9 ± 15.8 (min max range 5.1-71.6) years were 102 covered stents implanted (January 2003 - December 2017). Short-term pre/post-implant hemodynamics and angiographic data were reported. Changes in blood pressure, the use of antihypertensive drugs and complications were recorded during follow-up.

Results: The procedural success rate was 100%. The mean invasive ascending-to-descending aorta systolic gradient under general anaesthesia decreased from 25 ± 16 mmHg to 4 ± 7 mmHg ( < 0.001). After a mean follow-up time of 6.6 ± 3.7 years, there was a persistent improvement of the mean systolic blood pressure gradient between right arm and leg (-7 ± 18 vs 38 ± 24 mmHg;  < 0.001). A larger proportion of patients required antihypertensive medication (33.7% vs 50.0%,  = 0.017) and needed ≥ 2 drugs (20.2% vs 27.4%,  = 0.066) to control blood pressure. Long-term adverse events were found in 4.5% of patients [covered stent fracture ( = 3), aneurysm formation ( = 2)].

Conclusions: Covered stent implantation for CoA is highly successful, safe and results in a persistent hemodynamic improvement in the immediate and long-term outcome. Lifelong follow-up with additional antihypertensive drug treatment is mandatory to maintain favourable hemodynamic results after stenting.

Condensed Abstract: Long-term follow-up data on covered stents in patients with coarctation of the aorta are scarce. A cohort of 89 patients was reviewed. The procedural implantation success rate was 100%. The invasive gradient decreased from 25 ± 16 mmHg to 4 ± 7 mmHg ( < 0.001). After follow-up of 6.6 ± 3.7 years, there was a persistent improvement of the clinical systolic blood pressure gradient (-7 ± 18 vs 38 ± 24 mmHg;  < 0.001). However, a larger proportion of patients required antihypertensive medication (33.7% vs 50.0%,  = 0.017). Covered stent implantation results in favourable hemodynamic effects, but lifelong follow-up with additional antihypertensive drug treatment is mandatory to maintain these results.
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http://dx.doi.org/10.1080/00015385.2020.1838126DOI Listing
October 2020

Inferior Vena Cava Diameter and Fontan-Related Nephropathy: Considerations About Clinical Usefulness and Physiology.

Pediatr Cardiol 2020 12 26;41(8):1811-1812. Epub 2020 Oct 26.

Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium.

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http://dx.doi.org/10.1007/s00246-020-02477-xDOI Listing
December 2020

Direct EBUS-guided transtracheal lymphosclerosis for plastic bronchitis after Fontan.

Catheter Cardiovasc Interv 2021 Feb 29;97(3):E371-E375. Epub 2020 Sep 29.

Department of Pediatric and Congenital Cardiology, Leuven University Hospital, Leuven, Belgium.

We report on a new puncture technique with direct transtracheal mediastinal lymphatic access to treat plastic bronchitis after Fontan repair. High resolution contrast-enhanced spiral CT identified enlarged lymph nodes in the paratracheal region. Inguinal intranodal Gadolinium Dynamic Contrast-enhanced Magnetic Resonance lymphangiography (DCMRL) confirmed the pathologic centrifugal lymph flow passing through these lymph nodes before leaking into the bronchial tree. The abnormal hypertrophic paratracheal, subcarinal, and hilar lymph nodes were punctured with a 22G needle through an endobronchial ultrasound bronchoscope. Occlusion of the lymph vessels was obtained by injecting a mixture of lipiodol/NBCA N-butyl cyanoacrylate (Histoacryl) 5/1 under fluoroscopic control. There was a total remission of PB with now 10 months of follow-up.
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http://dx.doi.org/10.1002/ccd.29284DOI Listing
February 2021

Systems genetics analysis identifies calcium-signaling defects as novel cause of congenital heart disease.

Genome Med 2020 08 28;12(1):76. Epub 2020 Aug 28.

Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3A, DK-2200, Copenhagen, Denmark.

Background: Congenital heart disease (CHD) occurs in almost 1% of newborn children and is considered a multifactorial disorder. CHD may segregate in families due to significant contribution of genetic factors in the disease etiology. The aim of the study was to identify pathophysiological mechanisms in families segregating CHD.

Methods: We used whole exome sequencing to identify rare genetic variants in ninety consenting participants from 32 Danish families with recurrent CHD. We applied a systems biology approach to identify developmental mechanisms influenced by accumulation of rare variants. We used an independent cohort of 714 CHD cases and 4922 controls for replication and performed functional investigations using zebrafish as in vivo model.

Results: We identified 1785 genes, in which rare alleles were shared between affected individuals within a family. These genes were enriched for known cardiac developmental genes, and 218 of these genes were mutated in more than one family. Our analysis revealed a functional cluster, enriched for proteins with a known participation in calcium signaling. Replication in an independent cohort confirmed increased mutation burden of calcium-signaling genes in CHD patients. Functional investigation of zebrafish orthologues of ITPR1, PLCB2, and ADCY2 verified a role in cardiac development and suggests a combinatorial effect of inactivation of these genes.

Conclusions: The study identifies abnormal calcium signaling as a novel pathophysiological mechanism in human CHD and confirms the complex genetic architecture underlying CHD.
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http://dx.doi.org/10.1186/s13073-020-00772-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453558PMC
August 2020

Critical Coarctation of the Aorta in Selective Fetal Growth Restriction and the Role of Coronary Stent Implantation.

Fetal Diagn Ther 2020 Jul 27:1-9. Epub 2020 Jul 27.

Department of Development and Regeneration, Cluster Woman and Child, Biomedical Sciences, KU Leuven, Leuven, Belgium,

Introduction: Monochorionic twins are at increased risk of congenital heart defects (CHDs). Up to 26% have a birth weight <1,500 g, a CHD requiring neonatal surgery, therefore, poses particular challenges.

Objective: The aim of the study was to describe pregnancy characteristics, perinatal management, and outcome of monochorionic twins diagnosed with critical coarctation of the aorta (CoA).

Methods: We included monochorionic twins diagnosed with critical CoA (2010-2019) at 2 tertiary referral centers, and we systematically reviewed the literature regarding CoA in monochorionic twins.

Results: Seven neonates were included. All were the smaller twin of pregnancies complicated by selective fetal growth restriction. The median gestational age at birth was 32 weeks (28-34). Birth weight of affected twins ranged as 670-1,800 g. One neonate underwent coarctectomy at the age of 1 month (2,330 g). Six underwent stent implantation, performed between day 8 and 40, followed by definitive coarctectomy between 4 and 9 months in 4. All 7 developed normally, except for 1 child with neurodevelopmental delay. Three co-twins had pulmonary stenosis, of whom 1 required balloon valvuloplasty. The literature review revealed 10 cases of CoA, all in the smaller twin. Six cases detected in the first weeks after birth were treated with prostaglandins alone, by repeated transcatheter angioplasty or by surgical repair, with good outcome in 2 out of 6.

Conclusions: CoA specifically affects the smaller twin of growth discordant monochorionic twin pairs. Stent implantation is a feasible bridging therapy to surgery in these low birth weight neonates.
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http://dx.doi.org/10.1159/000508305DOI Listing
July 2020

Outcome of arterial switch operation for transposition of the great arteries. A 35-year follow-up study.

Int J Cardiol 2020 10 26;316:94-100. Epub 2020 Apr 26.

Congenital and Structural Cardiology, University Hospitals Leuven, Leuven, Belgium; Department of Cardiovascular Sciences, Catholic University Leuven, Leuven, Belgium. Electronic address:

Background: Arterial switch operation (ASO) is today the first-choice surgical treatment for patients with transposition of the great arteries. Long-term outcome data still remain scarce. Moreover, the course of these patients is not uneventful. Therefore, we wanted to evaluate long-term outcome and determine on which variables to focus during follow-up.

Methods: Clinical records of 318 patients who underwent ASO between October 1981 and July 2018 were reviewed. Perioperative, post-operative, and interventional data were collected to determine mortality and the need for re-intervention. Descriptive statistics and Kaplan-Meier survival analysis were performed.

Results: Mean follow-up time was 11.1 SD 8.5 years (range 0-35) with a mean age of 12.5 SD 9.0 years (range 0-37) at latest follow-up. In-hospital mortality was 7.5% and overall survival 90.9% for a maximum follow-up time of 35 years. Causes of early mortality were cardiogenic shock, severe pulmonary hypertension, septic shock and multiple organ failure. Causes of late mortality were cardiogenic shock, severe pulmonary hypertension, pacemaker lead fracture and fire death. Re-intervention free survival at 5-year was 91.6%, at 10-year 90.7%, at 20-year 79.2%. For all survivors, the most frequent sequelae after ASO were pulmonary artery stenosis (80.9%), of which 13.5% needed an intervention. The threshold for intervening on lesions at the level of the pulmonary artery bifurcation was higher and the percutaneous re-intervention rate was higher for non-bifurcation lesions.

Conclusions: Despite a relatively high peri-operative mortality, TGA patients have an excellent overall long-term survival. However, a large proportion of patients requires re-interventions, mainly for pulmonary artery stenosis.
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http://dx.doi.org/10.1016/j.ijcard.2020.04.072DOI Listing
October 2020

Effect of xenon and dexmedetomidine as adjuncts for general anesthesia on postoperative emergence delirium after elective cardiac catheterization in children: study protocol for a randomized, controlled, pilot trial.

Trials 2020 Apr 3;21(1):310. Epub 2020 Apr 3.

Department of Anesthesiology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.

Background: Emergence delirium, a manifestation of acute postoperative brain dysfunction, is frequently observed after pediatric anesthesia and has been associated with the use of sevoflurane. Both xenon and dexmedetomidine possess numerous desirable properties for the anesthesia of children with congenital heart disease, including hemodynamic stability, lack of neurotoxicity, and a reduced incidence of emergence delirium. Combining both drugs has never been studied as a balanced-anesthesia technique. This combination allows the provision of anesthesia without administering anesthetic drugs against which the Food and Drug Administration (FDA) issued a warning for the use in young children.

Methods/design: In this phase-II, mono-center, prospective, single-blinded, randomized, controlled pilot trial, we will include a total of 80 children aged 0-3 years suffering from congenital heart disease and undergoing general anesthesia for elective diagnostic and/or interventional cardiac catheterization. Patients are randomized into two study groups, receiving either a combination of xenon and dexmedetomidine or mono-anesthesia with sevoflurane for the maintenance of anesthesia. The purpose of this study is to estimate the effect size for xenon-dexmedetomidine versus sevoflurane anesthesia with respect to the incidence of emergence delirium in children. We will also describe group differences for a variety of secondary outcome parameters including peri-interventional hemodynamics, emergence characteristics, incidence of postoperative vomiting, and the feasibility of a combined xenon-dexmedetomidine anesthesia in children.

Discussion: Sevoflurane is the most frequently used anesthetic in young children, but has been indicated as an independent risk factor in the development of emergence delirium. Xenon and dexmedetomidine have both been associated with a reduction in the incidence of emergence delirium. Combining xenon and dexmedetomidine has never been described as a balanced-anesthesia technique in children. Our pilot study will therefore deliver important data required for future prospective clinical trials.

Trial Registration: EudraCT, 2018-002258-56. Registered on 20 August 2018. https://www.clinicaltrialsregister.eu.
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http://dx.doi.org/10.1186/s13063-020-4231-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7126401PMC
April 2020

Right ventricular outflow tract prestenting with AndraStent XXL before percutaneous pulmonary valve implantation.

Arch Cardiovasc Dis 2020 Feb 18;113(2):113-120. Epub 2020 Feb 18.

Pôle des cardiopathies congénitales de l'enfant et de l'adulte, centre de référence malformations cardiaques congénitales complexes (M3C), hôpital Marie-Lannelongue, université Paris-Sud, université Paris-Saclay, 133, avenue de la Résistance, 92350 Le Plessis-Robinson, France.

Background: The indications for percutaneous pulmonary valve implantation (PPVI) have been extended to include large dysfunctional right ventricular outflow tracts (RVOTs). Prestenting of the RVOT is commonly performed before PPVI in order to ensure a stable landing zone. The AndraStent XXL (AndraMed GmbH, Reutlingen, Germany), a cobalt-chromium stent with semi-open cell design, has unique mechanical properties in this indication but is no longer available in France.

Aims: To assess the efficiency of AndraStent XXL before PPVI.

Methods: In this retrospective multicentre cohort study, 86 AndraStents XXL were implanted in 77 patients in 6 centres.

Results: PPVI was indicated mainly for pulmonary regurgitation (75.3%) in native or patched RVOT (88.3%). The stents were manually mounted on balloon catheters and delivered through sheaths using a conventional femoral approach. PPVI was performed successfully in 97.4% of patients after successful prestenting, generally during the same procedure (77.9%). There were no deaths associated with stent implantation, and four patients experienced five complications, mainly stent embolization, including one requiring surgery. Neither stent fracture nor dysfunction were observed in any patient during a mean follow-up of 19.2±8.7months. Stent analysis showed an excellent maximal stent expansion (97.1%) regardless of balloon size. A 22.3%±3.4 stent shortening with a 30mm balloon was observed.

Conclusions: Implantation of large cobalt-chromium AndraStent XXL stents is efficient for prestenting before PPVI.
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http://dx.doi.org/10.1016/j.acvd.2019.12.004DOI Listing
February 2020

Can ductus arteriosus morphology influence technique/outcome of stent treatment?

Catheter Cardiovasc Interv 2020 05 17;95(6):1149-1157. Epub 2020 Jan 17.

Department of Pediatric and Congenital Cardiology, University Hospitals Leuven, Leuven, Belgium.

Introduction: Results and outcomes of ductus arteriosus stenting vary widely. The aim of this study was to determine whether ductus morphology is associated with different procedural outcome.

Methods: Over an 18-year period, 123 patients presented with ductal dependent pulmonary blood flow. Results were retrospectively assessed based on radiographic anatomic features of the ductus arteriosus: Group 1: "straight" ductus arteriosus, typically seen in patients with Pulmonary atresia with intact septum (PA-IVS), Group 2: "intermediate" ductus arteriosus as seen in severe pulmonary stenosis (PS)-single ventricle, Group 3: "vertical" ductus arteriosus typically seen in patients with pulmonary atresia-ventricular septal defect, Group 4: ductus arteriosus arising from the aorta to a single lung, Group 5: ductus arteriosus arising from the innominate/subclavian artery to a single lung, Group 6: ductus arteriosus from innominate/subclavian artery to both lungs.

Results: Ductal stenting (DS) was attempted in 98 patients with 99 ducts. Successful stenting was possible in 83 patients. Success of DS was significantly different among the groups (p = .04, F = 5.41). Groups 1, 4, and 5 were "easy" with good success while Groups 2, 3, and 6 were complex and demanding. There were two deaths (after 5 and 7 days, respectively) that could be ascribed to DS. Elective re-interventions were performed in 34 ductuses (40%). Fifty three percent (n = 44/83) of successful ductus stents proceeded to further surgery and 20 ducts closed spontaneously in asymptomatic patients over time.

Conclusions: Ductus arteriosus morphology influences technique and determines complexity, safety, and final outcome of ductus arteriosus stenting.
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http://dx.doi.org/10.1002/ccd.28725DOI Listing
May 2020

Outcome of the Glenn procedure as definitive palliation in single ventricle patients.

Int J Cardiol 2020 03 18;303:30-35. Epub 2019 Nov 18.

Division of Structural and Congenital Cardiology, University Hospitals Leuven, Belgium; Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium. Electronic address:

Objectives: In selected single ventricle patients, a Glenn procedure (SV-Glenn) may be considered as definitive palliation. Either the patient is unsuited to progress to a Fontan circulation or a SV-Glenn circulation is preferred. This study aimed at describing the clinical course, and long-term mortality/morbidity of SV-Glenn patients.

Methods: All SV-Glenn patients followed at the University Hospitals Leuven before May 2018 were included. Patients who underwent, or were awaiting, TCPC completion and those who underwent a Glenn in the setting of a biventricular circulation one-and-a-half repair (OAHR), were excluded.

Results: Of 65 Glenn-only patients identified, 21 (32%) had OAHR, whereas 44 (68%) were SV-Glenn patients. Of SV-Glenn patients, 19 died within 6 months after the Glenn procedure. Of 25 SV-Glenn survivors, median age at Glenn was 6.3 (IQR 1.2-29.7) years. Eight were unsuited for TCPC completion; in 17 SV-Glenn was preferred over TCPC completion. Over a median follow-up time of 11 (IQR 3-18) years after the Glenn procedure, 5 (20%) patients died. At latest follow-up 10 (40%) had heart failure, 5 (20%) had atrial and 4 (16%) ventricular arrhythmias, 2 (8%) a thromboembolic event, 7 (28%) required pacemaker implantation, and 2 (8%) had infective endocarditis but none developed cirrhosis or protein-losing enteropathy. Mean saturation at latest follow-up was 87 ± 7%.

Conclusion: SV-Glenn patients represent a unique and heterogeneous patient population. Outcome was reasonable, although comorbidities, such as heart failure and arrhythmias were not uncommon. In SV-Glenn patients, 'classic' complications related to Fontan physiology, such as cirrhosis and protein-losing enteropathy, were absent.
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http://dx.doi.org/10.1016/j.ijcard.2019.10.031DOI Listing
March 2020

Providing a framework of principles for conceptualising the Fontan circulation.

Acta Paediatr 2020 04 8;109(4):651-658. Epub 2020 Jan 8.

Pediatric Cardiology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

The Fontan operation remains the final palliation for thousands of patients with complex congenital heart disease. By creating a Fontan circuit, control of cardiac output and congestion is wrested away from the ventricle and new haemodynamic forces take control. Understanding how to control the flow in the Fontan circuit will enable clinicians to improve patient management and possibly prevent future complications. CONCLUSION: This review proposes a framework of principles to conceptualise the functionality and limitations of a Fontan circulation.
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http://dx.doi.org/10.1111/apa.15098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155129PMC
April 2020

FUELing the Search for Medical Therapies in Late Fontan Failure.

Circulation 2020 02 17;141(8):652-654. Epub 2019 Nov 17.

Congenital Cardiology (A.v.d.B.), University Hospital Leuven, Belgium.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044512DOI Listing
February 2020

Percutaneous embolization of lymphatic fistulae as treatment for protein-losing enteropathy and plastic bronchitis in patients with failing Fontan circulation.

Catheter Cardiovasc Interv 2019 Dec 9;94(7):996-1002. Epub 2019 Oct 9.

Department of Paediatric and Congenital Cardiology, University Hospitals Leuven, Leuven, Belgium.

Background: To determine the feasibility and clinical result of selective embolization of hepatoduodenal or paratracheal lymphatics in Fontan patients with protein-losing enteropathy (PLE) or plastic bronchitis (PB).

Methods: Dilated lymph vessels in periportal (PLE) or paratracheal (PB) position were percutaneously punctured with a 22G Chiba needle. Intralymphatic position was confirmed by water soluble contrast injection with drainage to hepatoduodenal or tracheal fistulae. After flushing with 10% glucose solution, occlusion of hepatoduodenal or paratreacheal lymphatics was effected by injection of 1-4 cc mixture 4/1 of Lipiodol/n-butyl cyanoacrylate (n-BCA; Histoacryl).

Results: Seven patients with proven PLE were treated with periportal lymphatic embolization 10.7 (range: 6.6-13.5) years after the Fontan operation. The Fontan operation was performed at a median age of 3.7 (range: 2.9-5.7) years and PLE started a median of 3.1 (range: 0.9-4.7) years later. Five patients required a second procedure 2-8 months later. Complications were limited (spillage of glue in portal branch, transient cholangitis, and caustic duodenal bleeding). Six of seven patients reported significant improvement in quality of life and normalization of albumin levels after limited follow-up (p < .01). One patient (Fontan at 2.9 years; age 16.4 years) had PB for 2 years. Selective transthoracic cone-beam-directed puncture of left and right paratracheal lymphatics with n-BCA embolization of distal lymphatic fistulae resulted in lasting absence of tracheal casts (11 months).

Conclusions: Embolization of periportal/peritracheal lymphatics is a promising technique in Fontan patients with PLE/PB. Larger series are required to determine incidence and reasons of success/failure, with long-term results and effects on liver function.
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http://dx.doi.org/10.1002/ccd.28501DOI Listing
December 2019

A Cast of the Left Bronchial Tree.

Lung 2019 12 31;197(6):825-826. Epub 2019 Aug 31.

Peadiatric Cardiology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium.

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http://dx.doi.org/10.1007/s00408-019-00267-8DOI Listing
December 2019

Percutaneous obliteration of the right ventricle to avoid coronary damage by sinusoids in patients with pulmonary atresia intact ventricular septum during staged single ventricle palliation.

Catheter Cardiovasc Interv 2019 Nov 21;94(5):722-726. Epub 2019 Aug 21.

Department of Pediatric and Congenital Cardiology, University Hospitals Leuven, Leuven, Belgium.

Background And Aims: Suprasystemic pressure waves can damage the coronary arteries resulting in myocardial ischemia and excess early mortality. We aimed to reduce the coronary pressure wave through the sinusoids by abolishing RV volume with percutaneous devices.

Methods And Results: Four patients with PA-IVS and coronary sinusoids from the hypertensive rudimentary RV were evaluated at a median age 26.6 months (range: 2.7-51.7). Right ventricle coronary dependent flow to the left ventricular myocardium was excluded. All four patients had dual perfusion with competitive flow from the RV through the sinusoids to the coronary arteries. Devices used were: Amplatzer vascular plug II of 10-16 mm; 27 coils (diameter 5-15 mm) in the oldest patient. Right ventricular angiography after cavity obliteration showed no more significant coronary perfusion through the sinusoids. There were no complications or deaths. Only minor and transient changes in the levels of troponin were observed. Coronary angiography at pre-Fontan evaluation showed no progress of coronary abnormalities in two patients.

Conclusion: In selected patients with functionally single left ventricle, obliteration of the hypertensive RV cavity by percutaneous devices is safe and abolishes the systolic pressure wave in coronary sinusoids. When performed early, this may halt coronary damage and avoid excess mortality.
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http://dx.doi.org/10.1002/ccd.28457DOI Listing
November 2019

Vasoreactive Pulmonary Arterial Hypertension Manifesting With Misleading Epileptic Seizure: Diagnostic and Treatment Pitfalls.

Front Pediatr 2019 4;7:262. Epub 2019 Jul 4.

Pediatric Cardiology Unit and Centre Universitaire Romand de Cardiologie et Chirurgie Cardiaque Pédiatrique, Lausanne University Hospital (CHUV), Geneva University Hospitals (HUG), University of Geneva, Geneva, Switzerland.

A 5-year-old girl presented with acute nocturnal episodes of loss of consciousness following abdominal pain and crying. Epilepsy was primarily diagnosed but the course of the disease was suggestive of pulmonary hypertension. An adapted invasive assessment of pulmonary pressure and pharmacological challenge allowed for diagnosing vasoreactive pulmonary arterial hypertension. Initial treatment with sildenafil was not effective. Thus, calcium channel blockers were introduced when positive vasoreactivity was confirmed and permitted to stop the occurrence of the syncope and dramatically improved clinical status. At 2 years follow-up she is well without any complaint and in functional class I. Echocardiography shows a slightly enlarged but not hypertrophied right ventricle with a nearly normalized estimated right ventricular pressure. The last catheterization shows subnormal values of pulmonary arterial pressure (mean pulmonary artery pressure: 24 mmHg) and pulmonary vascular resistance (5, 4 Wood unitsm), normalizing with inhaled Nitric Oxide (mean pulmonary artery pressure of 14 mmHg and pulmonary vascular resistance of 1.5 Wood unitsm). Vasoreactive pulmonary arterial hypertension is a rare entity in children but it should not be misdiagnosed with seizures due to the presence of syncopal episodes. According to current knowledge, this form seems to have a better prognosis than non-reactive pulmonary arterial hypertension and the treatment of choice remains as calcium channel blockers. The management of this case was characterized by successive mishaps and potentially harmful mistakes and underscores the potential risk with pediatric PH evaluation in non-expert centers.
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http://dx.doi.org/10.3389/fped.2019.00262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6621927PMC
July 2019

Predicting 15-Year Mortality in Adults With Congenital Heart Disease Using Disease Severity and Functional Indices.

Can J Cardiol 2019 07 26;35(7):907-913. Epub 2019 Apr 26.

KU Leuven Department of Public Health and Primary Care, KU Leuven - University of Leuven, Leuven, Belgium; Institute of Health and Care Sciences, University of Gothenburg, Gothenburg, Sweden; Department of Pediatrics and Child Health, University of Cape Town, Cape Town, South Africa. Electronic address:

Background: Disease severity and functional indices are widely used for risk stratification of patients with congenital heart disease (CHD). The predictive value of these classification systems for assessing long-term mortality is unknown. We aimed to determine and compare the predictive value of disease severity and functional indices for 15-year mortality in adults with CHD.

Methods: Between 2000 and 2002, we categorized 629 patients with CHD (median age, 24 years; 60% were men) on 5 indices: disease complexity scores based on criteria of Task Force 1 of the 32nd Bethesda Conference; Disease Severity Index; New York Heart Association functional class; Ability Index; and Congenital Heart Disease Functional Index (CHDFI). Harrell's concordance statistics index (C-index) was calculated for each classification system through Cox hazard regression analysis to evaluate their performance on predicting all-cause and cardiac mortality over the subsequent 15 years.

Results: Over the 15-year follow-up period, 40 patients died, resulting in a mortality rate of 4.56 per 1000 person-years. The CHDFI showed the highest discrimination ability for all-cause mortality (C-index = 0.74; P < 0.001) and cardiac mortality (C-index = 0.76; P < 0.001). The C-index for the other classifications ranged from 0.58 to 0.71 for all-cause mortality and 0.55 to 0.67 for cardiac mortality. The CHDFI showed statistical superiority toward the Disease Severity Index (P < 0.01).

Conclusions: These results suggest that the Task Force 1 of the 32nd Bethesda Conference, New York Heart Association functional class, Ability Index, and CHDFI could aid in predicting long-term mortality. The CHDFI demonstrated the highest discrimination ability and emphasizes the importance to integrate both anatomic and physiological variables to predict long-term mortality.
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http://dx.doi.org/10.1016/j.cjca.2019.04.018DOI Listing
July 2019

Evaluation and Management of the Child and Adult With Fontan Circulation: A Scientific Statement From the American Heart Association.

Circulation 2019 Jul 1:CIR0000000000000696. Epub 2019 Jul 1.

It has been 50 years since Francis Fontan pioneered the operation that today bears his name. Initially designed for patients with tricuspid atresia, this procedure is now offered for a vast array of congenital cardiac lesions when a circulation with 2 ventricles cannot be achieved. As a result of technical advances and improvements in patient selection and perioperative management, survival has steadily increased, and it is estimated that patients operated on today may hope for a 30-year survival of >80%. Up to 70 000 patients may be alive worldwide today with Fontan circulation, and this population is expected to double in the next 20 years. In the absence of a subpulmonary ventricle, Fontan circulation is characterized by chronically elevated systemic venous pressures and decreased cardiac output. The addition of this acquired abnormal circulation to innate abnormalities associated with single-ventricle congenital heart disease exposes these patients to a variety of complications. Circulatory failure, ventricular dysfunction, atrioventricular valve regurgitation, arrhythmia, protein-losing enteropathy, and plastic bronchitis are potential complications of the Fontan circulation. Abnormalities in body composition, bone structure, and growth have been detected. Liver fibrosis and renal dysfunction are common and may progress over time. Cognitive, neuropsychological, and behavioral deficits are highly prevalent. As a testimony to the success of the current strategy of care, the proportion of adults with Fontan circulation is increasing. Healthcare providers are ill-prepared to tackle these challenges, as well as specific needs such as contraception and pregnancy in female patients. The role of therapies such as cardiovascular drugs to prevent and treat complications, heart transplantation, and mechanical circulatory support remains undetermined. There is a clear need for consensus on how best to follow up patients with Fontan circulation and to treat their complications. This American Heart Association statement summarizes the current state of knowledge on the Fontan circulation and its consequences. A proposed surveillance testing toolkit provides recommendations for a range of acceptable approaches to follow-up care for the patient with Fontan circulation. Gaps in knowledge and areas for future focus of investigation are highlighted, with the objective of laying the groundwork for creating a normal quality and duration of life for these unique individuals.
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http://dx.doi.org/10.1161/CIR.0000000000000696DOI Listing
July 2019

Heart Rate Reserve in Fontan Patients: Chronotropic Incompetence or Hemodynamic Limitation?

J Am Heart Assoc 2019 05;8(9):e012008

1 Department of Cardiovascular Sciences KU Leuven Leuven Belgium.

Background Patients with a Fontan circulation achieve lower peak heart rates ( HR ) during exercise. Whether this impaired chronotropic response reflects pathology of the sinoatrial node or is a consequence of altered cardiac hemodynamics is uncertain. We evaluated the adequacy of HR acceleration throughout exercise relative to metabolic demand and cardiac output in patients with a Fontan circulation relative to healthy controls. Methods and Results Thirty subjects (20 healthy controls and 10 Fontan patients) underwent cardiac magnetic resonance imaging with simultaneous invasive pressure recording via a pulmonary and radial artery catheter during supine bicycle exercise to near maximal exertion. Adequacy of cardiac index, stroke volume, and HR reserve was assessed by determining the exercise-induced increase (∆) in cardiac index, stroke volume, and HR relative to the increase in oxygen consumption ( VO ). HR reserve was lower in Fontan patients compared with controls (71±21 versus 92±15 bpm; P=0.001). In contrast, increases in HR relative to workload and VO were higher than in controls. The change in cardiac index relative to the change in VO (∆cardiac index/∆ VO ) was similar between groups, but Fontan patients had increased ∆ HR /∆ VO and reduced ∆ stroke volume/∆ VO compared with controls. There was an early and marked reduction in stroke volume during exercise in Fontan patients corresponding with a plateau in cardiac output at a low peak HR . Conclusions In Fontan patients, the chronotropic response is appropriate relative to exercise intensity, implying normal sinoatrial function. However, premature reductions in ventricular filling and stroke volume cause an early plateau in cardiac output beyond which further increases in HR would be physiologically implausible. Thus, abnormal cardiac filling rather than sinoatrial node dysfunction explains the diminished HR reserve in Fontan patients.
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http://dx.doi.org/10.1161/JAHA.119.012008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512107PMC
May 2019

Acute and midterm outcomes of the post-approval MELODY Registry: a multicentre registry of transcatheter pulmonary valve implantation.

Eur Heart J 2019 07;40(27):2255-2264

Department of Congenital Heart Disease-Pediatric Cardiology, German Heart Institute Berlin, Augustenburger Platz 1, Berlin, Germany.

Aims: The post-approval MELODY Registry aimed to obtain multicentre registry data after transcatheter pulmonary valve implantation (TPVI) with the Melody™ valve (Medtronic plc.) in a large-scale cohort of patients with congenital heart disease (CHD).

Methods And Results: Retrospective analysis of multicentre registry data after TPVI with the Melody™ valve. Eight hundred and forty-five patients (mean age: 21.0 ± 11.1 years) underwent TPVI in 42 centres between December 2006 and September 2013 and were followed-up for a median of 5.9 years (range: 0-11.0 years). The composite endpoint of TPVI-related events during follow-up (i.e. death, reoperation, or reintervention >48 h after TPVI) showed an incidence rate of 4.2% per person per year [95% confidence interval (CI) 3.7-4.9]. Transcatheter pulmonary valve implantation infective endocarditis (I.E.) showed an incidence rate of 2.3% per person per year (95% CI 1.9-2.8) and resulted in significant morbidity and in nine deaths. In multivariable Cox proportional hazard models, the invasively measured residual right ventricle (RV)-to-pulmonary artery (PA) pressure gradient (per 5 mmHg) was associated with the risk of the composite endpoint (adjusted hazard ratio: 1.21, 95% CI 1.12-1.30; P < 0.0001) and the risk of TPVI I.E. (adjusted hazard ratio: 1.19, 95% CI 1.07-1.32; P = 0.002). Major procedural complications (death, surgical, or interventional treatment requirement) occurred in 0.5%, 1.2%, and 2.0%, respectively. Acutely, the RV-to-PA pressure gradient and the percentage of patients with pulmonary regurgitation grade >2 improved significantly from 36 [interquartile range (IQR) 24-47] to 12 (IQR 7-17) mmHg and 47 to 1%, respectively (P < 0.001 for each).

Conclusion: The post-approval MELODY Registry confirms the efficacy of TPVI with the Melody™ valve in a large-scale cohort of CHD patients. The residual invasively measured RV-to-PA pressure gradient may serve as a target for further improvement in the composite endpoint and TPVI I.E. However, TPVI I.E. remains a significant concern causing significant morbidity and mortality.
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http://dx.doi.org/10.1093/eurheartj/ehz201DOI Listing
July 2019

Creation of the Fontan circulation in sheep: a survival model.

Interact Cardiovasc Thorac Surg 2019 07;29(1):15-21

Department of Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium.

Objectives: Patients with a single ventricle survive thanks to the Fontan palliation. Nevertheless, there is a growing number of Fontan patients with progressive heart failure. To validate therapeutic options in these patients, we developed a chronic Fontan large animal model.

Methods: A Fontan circulation was surgically created in 15 sheep. The superior vena cava was anastomosed end-to-side to the pulmonary artery. The inferior vena cava was connected to the pulmonary artery by an ePTFE conduit, and the inferior vena cava-right atrium junction was ligated.

Results: Total cavopulmonary connection was successfully performed in all 15 animals. After creation of the Fontan circulation, central venous pressure increased from 4 [interquartile range (IQR) 3-6] mmHg to 16 (IQR 14-17) mmHg, mean arterial blood pressure decreased from 68 (IQR 54-75) mmHg to 52 (IQR 50-61) mmHg and cardiac output decreased from 5.1 (IQR 4.6-6.8) l/min to 1.7 (IQR 1.3-2.7) l/min. Five animals were electively sacrificed after a follow-up period of 21 weeks.

Conclusions: These results demonstrate that it is feasible to create a chronic animal model with unsupported Fontan circulation. This animal model not only opens perspectives to investigate the pathophysiology of the failing Fontan circulation, but also provides the possibility to study therapeutic options such as the effect of mechanical circulatory support in the failing Fontan physiology.
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http://dx.doi.org/10.1093/icvts/ivz022DOI Listing
July 2019

Paradoxical nonreentrant tachycardia induced by iatrogenic atrioventricular block.

Acta Cardiol 2019 Oct 8;74(5):423-424. Epub 2019 Feb 8.

Department of Cardiology and Pediatric Cardiology, University Hospital Leuven , Belgium.

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http://dx.doi.org/10.1080/00015385.2018.1521556DOI Listing
October 2019

An In Vitro Model of a Parallel-Plate Perfusion System to Study Bacterial Adherence to Graft Tissues.

J Vis Exp 2019 01 7(143). Epub 2019 Jan 7.

Cardiovascular Developmental Biology, Department of Cardiovascular Sciences, KU Leuven.

Various valved conduits and stent-mounted valves are used for right ventricular outflow tract (RVOT) valve replacement in patients with congenital heart disease. When using prosthetic materials however, these grafts are susceptible to bacterial infections and various host responses. Identification of bacterial and host factors that play a vital role in endovascular adherence of microorganisms is of importance to better understand the pathophysiology of the onset of infections such as infective endocarditis (IE) and to develop preventive strategies. Therefore, the development of competent models to investigate bacterial adhesion under physiological shear conditions is necessary. Here, we describe the use of a newly designed in vitro perfusion chamber based on parallel plates that allows the study of bacterial adherence to different components of graft tissues such as exposed extracellular matrix, endothelial cells and inert areas. This method combined with colony-forming unit (CFU) counting is adequate to evaluate the propensity of graft materials towards bacterial adhesion under flow. Further on, the flow chamber system might be used to investigate the role of blood components in bacterial adhesion under shear conditions. We demonstrated that the source of tissue, their surface morphology and bacterial species specificity are not the major determining factors in bacterial adherence to graft tissues by using our in-house designed in vitro perfusion model.
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http://dx.doi.org/10.3791/58476DOI Listing
January 2019

Mid-Term Valve-Related Outcomes After Transcatheter Tricuspid Valve-in-Valve or Valve-in-Ring Replacement.

J Am Coll Cardiol 2019 01;73(2):148-157

Mayo Clinic, Rochester, Minnesota.

Background: Transcatheter aortic and pulmonary valves have been used to treat stenosis or regurgitation after prior surgical tricuspid valve (TV) replacement or repair. Little is known about intermediate-term valve-related outcomes after transcatheter tricuspid valve replacement (TTVR), including valve function, thrombus, and endocarditis.

Objectives: The authors sought to evaluate mid-term outcomes in a large cohort of patients who underwent TTVR after surgical TV repair or replacement, with a focus on valve-related outcomes.

Methods: Patients who underwent TTVR after prior surgical TV replacement or repair were collected through an international registry. Time-related outcomes were modeled and risk factors assessed.

Results: Data were collected for 306 patients who underwent TTVR from 2008 through 2017 at 80 centers; 52 patients (17%) had a prior history of endocarditis. Patients were followed for a median of 15.9 months after implantation (0.1 to 90 months), with 64% of patients estimated to be alive without TV reintervention or a valve-related event at 3 years. The cumulative 3-year incidence of death, reintervention, and valve-related adverse outcomes (endocarditis, thrombosis, or significant dysfunction) were 17%, 12%, and 8%, respectively. Endocarditis was diagnosed in 8 patients 2 to 29 months after TTVR, for an annualized incidence rate of 1.5% per patient-year (95% confidence interval: 0.45% to 2.5%). An additional 8 patients were diagnosed with clinically relevant valve thrombosis, 3 in the short term, 2 within 2 months, and 3 beyond 6 months. Only 2 of these 8 patients received anticoagulant therapy before thrombus detection (p = 0.13 vs. patients without thrombus). Prior endocarditis was not a risk factor for reintervention, endocarditis, or valve thrombosis, and there was no difference in valve-related outcomes according to TTVR valve type.

Conclusions: TV dysfunction, endocarditis, and leaflet thrombosis were uncommon after TTVR. Patients with prior endocarditis were not at higher risk for endocarditis or other adverse outcomes after TTVR, and endocarditis occurred with similar frequency in different valve types. Though rare, leaflet thrombosis is an important adverse outcome, and further study is necessary to determine the appropriate level of prophylactic therapy after TTVR.
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http://dx.doi.org/10.1016/j.jacc.2018.10.051DOI Listing
January 2019

Whole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot.

Circ Res 2019 02;124(4):553-563

From the Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, Manchester Academic Health Science Centre, University of Manchester, United Kingdom (D.J.P., S.G.W., R.M.M., E.F., B.D.K.).

Rationale: Familial recurrence studies provide strong evidence for a genetic component to the predisposition to sporadic, nonsyndromic Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease phenotype. Rare genetic variants have been identified as important contributors to the risk of congenital heart disease, but relatively small numbers of TOF cases have been studied to date.

Objective: We used whole exome sequencing to assess the prevalence of unique, deleterious variants in the largest cohort of nonsyndromic TOF patients reported to date.

Methods And Results: Eight hundred twenty-nine TOF patients underwent whole exome sequencing. The presence of unique, deleterious variants was determined; defined by their absence in the Genome Aggregation Database and a scaled combined annotation-dependent depletion score of ≥20. The clustering of variants in 2 genes, NOTCH1 and FLT4, surpassed thresholds for genome-wide significance (assigned as P<5×10) after correction for multiple comparisons. NOTCH1 was most frequently found to harbor unique, deleterious variants. Thirty-one changes were observed in 37 probands (4.5%; 95% CI, 3.2%-6.1%) and included 7 loss-of-function variants 22 missense variants and 2 in-frame indels. Sanger sequencing of the unaffected parents of 7 cases identified 5 de novo variants. Three NOTCH1 variants (p.G200R, p.C607Y, and p.N1875S) were subjected to functional evaluation, and 2 showed a reduction in Jagged1-induced NOTCH signaling. FLT4 variants were found in 2.4% (95% CI, 1.6%-3.8%) of TOF patients, with 21 patients harboring 22 unique, deleterious variants. The variants identified were distinct to those that cause the congenital lymphoedema syndrome Milroy disease. In addition to NOTCH1, FLT4 and the well-established TOF gene, TBX1, we identified potential association with variants in several other candidates, including RYR1, ZFPM1, CAMTA2, DLX6, and PCM1.

Conclusions: The NOTCH1 locus is the most frequent site of genetic variants predisposing to nonsyndromic TOF, followed by FLT4. Together, variants in these genes are found in almost 7% of TOF patients.
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http://dx.doi.org/10.1161/CIRCRESAHA.118.313250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377791PMC
February 2019