Publications by authors named "Julie De Backer"

142 Publications

Influenza vaccination in congenital heart disease in the pre-COVID19 era: Coverage rate, patient characteristics and outcome.

Can J Cardiol 2021 May 4. Epub 2021 May 4.

Department of Pediatric Cardiology, Ghent University Hospital, Ghent, Belgium.

Background: Influenza vaccination is the most commonly recommended immune prevention strategy. However, data on influenza vaccination in patients with congenital heart disease (CHD) is scarce. In this study, our goals were to (i) measure vaccination coverage rates (VCR) for influenza in a large cohort of children, adolescents and adults with CHD, (ii) identity patient characteristics as predictors for vaccination, and (iii) investigate the impact of influenza vaccination on hospitalization.

Methods: A nationwide cohort study in Belgium included 16,778 patients, representing 134,782 vaccination years, from the BELgian COngenital heart disease Database combining Administrative and Clinical data (BELCODAC). Data over 9 vaccination years (2006-2015) were used, and patients were stratified into five age cohorts: 6 months-4 years; 5-17 years; 18-49 years; 50-64 years; and ≥65 years.

Results: In the respective age cohorts, the VCR was estimated to be 6.6%, 8.0%, 23.9%, 46.6%, and 72.8%. There was a steep increase in VCR as of the age of 40 years. Multivariable logistic regression showed that higher anatomical complexity of CHD, older age, presence of genetic syndromes, and prior cardiac interventions were associated with significantly higher VCRs. Among adults, men had lower and pregnant women had higher VCRs. The association between influenza vaccination and all-cause hospitalization was not significant in this study.

Conclusion: The influenza VCR in people with CHD is low, especially in children and adolescents. Older patients, particularly those with complex CHD, are well covered. Our findings should inform vaccination promotion strategies in populations with CHD.
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http://dx.doi.org/10.1016/j.cjca.2021.04.010DOI Listing
May 2021

QRS Duration During Follow-Up of Tetralogy of Fallot: How Valuable is it? Analysis of ECG Changes in Relation to Pulmonary Valve Implantation.

Pediatr Cardiol 2021 May 7. Epub 2021 May 7.

Department of Cardiac Surgery, Ghent University Hospital, Corneel Heymanslaan 10, 9000, Gent, Belgium.

Long-term results after tetralogy of Fallot (TOF) repair are determined by the extent of right ventricular remodeling to chronic pulmonary regurgitation entailing progressive RV dysfunction and a risk of developing ventricular arrhythmia. Pulmonary valve replacement (PVR) can alleviate this burden. As a predictor of ventricular arrhythmia, QRS duration remains a strong parameter in this decision. We performed a retrospective analysis of all PVR patients between 2005 and 2018, studying the time evolution of electrocardiographic parameters before and after PVR through linear mixed model analysis. 42 TOF patients underwent PVR. The median timespan between primary repair and PVR was 18 years (IQR 13-30). The indication for PVR was primarily based on the association of exercise intolerance (67%) and significant RV dilation on cMRI (median RVEDVi 161 ml/m IQR 133-181). Median QRS length was 155 ms (IQR 138-164), 4 (10%) patients had a QRS > 180 ms. QRS duration increased significantly before PVR, but barely showed regression after PVR. Changes of QRS duration after PVR were independent of RV dilation. In conclusion, when the decision for PVR in TOF patients is primarily based on RV volume and/or function threshold, QRS duration > 180 ms is rarely observed. In contrast with the significant increase of QRS duration before PVR, QRS length regression appears to be independent of the extent of RV dilation or QRS > 160 ms. Considering that the decision for PVR is based on mechanical RV characteristics, the utility of serial follow-up of QRS duration in contemporary operated TOF patients becomes questionable in absence of clinical arguments for ventricular arrhythmia.
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http://dx.doi.org/10.1007/s00246-021-02632-yDOI Listing
May 2021

Different levels of care for follow-up of adults with congenital heart disease: a cost analysis scrutinizing the impact on medical costs, hospitalizations, and emergency department visits.

Eur J Health Econ 2021 Apr 9. Epub 2021 Apr 9.

Department of Public Health and Primary Care, Ghent University, Corneel Heymanslaan 10, Entrance 42, Floor 4, 9000, Ghent, Belgium.

Aim: To scrutinize the economic impact of different care levels, such as shared care, in the follow-up of adult congenital heart disease (ACHD) patients.

Methods: The BELgian COngenital heart disease Database combining Administrative and Clinical data (BELCODAC) was analyzed. Patients (N = 6579) were categorized into five care levels based on their cardiac follow-up pattern between 2006 and 2010. Medical costs, hospitalizations, and emergency department visits were measured between 2011 and 2015.

Results: In patients with moderate lesions, highly specialized cardiac care (HSC; exclusive follow-up by ACHD specialists) and shared care with predominantly specialized cardiac care (SC+) were associated with significantly lower medical costs and resource use compared to shared care with predominantly general cardiac care (SC-) and general cardiac care (GCC). In the patient population with mild lesions, HSC was associated with better economic outcomes than SC- and GCC, but SC+ was not. HSC was associated with fewer hospitalizations (- 33%) and less pharmaceutical costs (- 46.3%) compared to SC+. Patients with mild and moderate lesions in the no cardiac care (NCC) group had better economic outcomes than those in the GCC and SC- groups, but post-hoc analysis revealed that they had a different patient profile than patients under cardiac care.

Conclusion: More specialized care levels are associated with better economic outcomes in patients with mild or moderate lesions in cardiac follow-up. Shared care with strong involvement of ACHD specialists might be a management option to consider. Characteristics of patients without cardiac follow-up but good medium-term economic prospects should be further scrutinized.
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http://dx.doi.org/10.1007/s10198-021-01300-5DOI Listing
April 2021

Needs and experiences of adolescents with congenital heart disease and parents in the transitional process: A qualitative study.

J Pediatr Nurs 2021 Mar 31;61:90-95. Epub 2021 Mar 31.

Ghent University - Faculty of Medicine and Health Sciences -Department of Public Health and Primary Care - University Center for Nursing and Midwifery - Corneel Heymanslaan 10 - B-9000, Ghent, Belgium; Ghent University Hospital - Staff nursing department - Corneel Heymanslaan 10 - B-9000, Ghent, Belgium. Electronic address:

Purpose: Most patients with congenital heart disease (CHD) need lifelong cardiac follow-up. Transitioning to adulthood and transferring to adult-focused care are often challenging. We explored the experiences and needs of adolescents with CHD and parents during the entire transitional process, including the post-transfer period.

Design And Methods: We performed a qualitative study according to the phenomenological approach, focusing on adolescents with CHD and parents. Semi-structured interviews were carried out with patients (n = 9) and parents (n = 12) after being transferred to adult care facilities. Data were analyzed with inductive thematic analysis. Data collection and -analysis of both samples were done separately in a first step, after which results were merged to discover common themes.

Results: Five common themes were identified: 1) Having mixed feelings about leaving pediatric care; 2) Being prepared and informed; 3) Shifting responsibilities and roles; 4) Being accompanied during consultations; and 5) Gaining trust in new healthcare providers.

Conclusion: Adolescents with CHD and parents express a need for adequate preparation and personalized guidance to reduce anxiety and uncertainty during transition. The process may benefit from focusing on improving the adolescents´ transitional skills and disease-related knowledge, which may, in turn, facilitate handing over responsibilities and adapting to new roles by the parents. Adolescents appreciate the presence of parents during the consultation, albeit with reduced input. Finally, a transition coordinator and a joint transfer consultation involving the pediatric cardiologist seem paramount for a fluent transitional process, especially in establishing new treatment relationships.
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http://dx.doi.org/10.1016/j.pedn.2021.03.016DOI Listing
March 2021

Hereditary thoracic aortic disease: How to save lives.

J Thorac Cardiovasc Surg 2021 Feb 2. Epub 2021 Feb 2.

Department of Cardiology and Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.

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http://dx.doi.org/10.1016/j.jtcvs.2021.01.075DOI Listing
February 2021

Pregnancy outcome in thoracic aortic disease data from the Registry Of Pregnancy And Cardiac disease.

Heart 2021 Jan 19. Epub 2021 Jan 19.

Cardiology Department, Erasmus Medical Center, Rotterdam, Netherlands

Background: Cardiovascular disease is the leading cause of death during pregnancy with thoracic aortic dissection being one of the main causes. Thoracic aortic disease is commonly related to hereditary disorders and congenital heart malformations such as bicuspid aortic valve (BAV). Pregnancy is considered a high risk period in women with underlying aortopathy.

Methods: The ESC EORP Registry Of Pregnancy And Cardiac disease (ROPAC) is a prospective global registry that enrolled 5739 women with pre-existing cardiac disease. With this analysis, we aim to study the maternal and fetal outcome of pregnancy in women with thoracic aortic disease.

Results: Thoracic aortic disease was reported in 189 women (3.3%). Half of them were patients with Marfan syndrome (MFS), 26% had a BAV, 8% Turner syndrome, 2% vascular Ehlers-Danlos syndrome and 11% had no underlying genetic defect or associated congenital heart defect. Aortic dilatation was reported in 58% of patients and 6% had a history of aortic dissection. Four patients, of whom three were patients with MFS, had an acute aortic dissection (three type A and one type B aortic dissection) without maternal or fetal mortality. No complications occurred in women with a history of aortic dissection. There was no significant difference in median fetal birth weight if treated with a beta-blocker or not (2960 g (2358-3390 g) vs 3270 g (2750-3570 g), p value 0.25).

Conclusion: This ancillary analysis provides the largest prospective data review on pregnancy risk for patients with thoracic aortic disease. Overall pregnancy outcomes in women with thoracic aortic disease followed according to current guidelines are good.
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http://dx.doi.org/10.1136/heartjnl-2020-318183DOI Listing
January 2021

Transfer and transition practices in 96 European adult congenital heart disease centres.

Int J Cardiol 2021 Apr 1;328:89-95. Epub 2020 Dec 1.

Department of Public Health and Primary Care, KU Leuven, University of Leuven, Leuven, Belgium; Institute of Health and Care Science, University of Gothenburg, Gothenburg, Sweden; Department of Paediatrics and Child Health, University of Cape Town, Cape Town, South Africa.

Background: Irrespective of initial treatment for congenital heart disease (CHD) in childhood, CHD is a lifelong condition, leaving patients at risk for complications. To support uninterrupted, age- and development-based care for young persons with CHD, guidelines and consensus papers emphasise the need for formal transition programmes, including transfer to adult CHD (ACHD) clinics. Here, we surveyed existing transfer and transition programmes in European ACHD centres. Our aims were to provide a contemporary view of transitional care for patients with CHD and to evaluate progress over the last decade.

Methods: We conducted a descriptive, cross-sectional survey in 96 ACHD centres in Europe. A specific survey form was developed that sampled the practices of transfer and/or transition. We used a transfer-transition index to quantify adherence to quality indicators of successful transfer and transition.

Results: Of the 96 ACHD centres, 40 (41.7%) offered a formal transition, and 85 (88.5%) had structured transfer from paediatric to ACHD care. Although 31% of the centres performed at a 'good' level on the transfer-transition index, only 4 (4.2%) satisfied all criteria. Most centres with a transition programme offered education and support through a dedicated transition specialist, who was a master's-prepared nurse in most centres. A minority of the ACHD centres offered a flexible transition process, starting at least two years before transfer.

Conclusions: Nearly half of the included ACHD centres offered a formal transition programme, and almost 90% offered structured transfer. Despite some improvements since 2009, most of the programmes lacked an age- and development-based approach.
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http://dx.doi.org/10.1016/j.ijcard.2020.11.031DOI Listing
April 2021

The Dynamic and Multifaceted Nature of Cardiovascular Disease and Using Genetic Testing to Inform Clinical Care: An International Perspective.

Clin Chem 2021 Jan;67(1):33-40

Department of Clinical Biochemistry, Section for Molecular Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

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http://dx.doi.org/10.1093/clinchem/hvaa251DOI Listing
January 2021

The 'Ten Commandments' in Adult Congenital Heart Disease Guidelines.

Eur Heart J 2020 11;41(43):4155

Chair of ESC Taskforce.

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http://dx.doi.org/10.1093/eurheartj/ehaa702DOI Listing
November 2020

Myocardial disease and ventricular arrhythmia in Marfan syndrome: a prospective study.

Orphanet J Rare Dis 2020 10 23;15(1):300. Epub 2020 Oct 23.

Centre for Medical Genetics, Ghent University Hospital, Ghent, Belgium.

Background: Aortic root dilatation and-dissection and mitral valve prolapse are established cardiovascular manifestations in Marfan syndrome (MFS). Heart failure and arrhythmic sudden cardiac death have emerged as additional causes of morbidity and mortality.

Methods: To characterize myocardial dysfunction and arrhythmia in MFS we conducted a prospective longitudinal case-control study including 86 patients with MFS (55.8% women, mean age 36.3 yr-range 13-70 yr-) and 40 age-and sex-matched healthy controls. Cardiac ultrasound, resting and ambulatory ECG (AECG) and NT-proBNP measurements were performed in all subjects at baseline. Additionally, patients with MFS underwent 2 extra evaluations during 30 ± 7 months follow-up. To study primary versus secondary myocardial involvement, patients with MFS were divided in 2 groups: without previous surgery and normal/mild valvular function (MFS-1; N = 55) and with previous surgery or valvular dysfunction (MFS-2; N = 31).

Results: Compared to controls, patients in MFS-1 showed mild myocardial disease reflected in a larger left ventricular end-diastolic diameter (LVEDD), lower TAPSE and higher amount of (supra) ventricular extrasystoles [(S)VES]. Patients in MFS-2 were more severely affected. Seven patients (five in MFS-2) presented decreased LV ejection fraction. Twenty patients (twelve in MFS-2) had non-sustained ventricular tachycardia (NSVT) in at least one AECG. Larger LVEDD and higher amount of VES were independently associated with NSVT.

Conclusion: Our study shows mild but significant myocardial involvement in patients with MFS. Patients with previous surgery or valvular dysfunction are more severely affected. Evaluation of myocardial function with echocardiography and AECG should be considered in all patients with MFS, especially in those with valvular disease and a history of cardiac surgery.
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http://dx.doi.org/10.1186/s13023-020-01581-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585308PMC
October 2020

Effects of fibrillin mutations on the behavior of heart muscle cells in Marfan syndrome.

Sci Rep 2020 10 7;10(1):16756. Epub 2020 Oct 7.

Medical Cell Biology Research Group, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Corneel Heymanslaan 10, Building B, Entrance 36, 9000, Ghent, Belgium.

Marfan syndrome (MFS) is a systemic disorder of connective tissue caused by pathogenic variants in the fibrillin-1 (FBN1) gene. Myocardial dysfunction has been demonstrated in MFS patients and mouse models, but little is known about the intrinsic effect on the cardiomyocytes (CMs). In this study, both induced pluripotent stem cells derived from a MFS-patient and the line with the corrected FBN1 mutation were differentiated to CMs. Several functional analyses are performed on this model to study MFS related cardiomyopathy. Atomic force microscopy revealed that MFS CMs are stiffer compared to corrected CMs. The contraction amplitude of MFS CMs is decreased compared to corrected CMs. Under normal culture conditions, MFS CMs show a lower beat-to-beat variability compared to corrected CMs using multi electrode array. Isoproterenol-induced stress or cyclic strain demonstrates lack of support from the matrix in MFS CMs. This study reports the first cardiac cell culture model for MFS, revealing abnormalities in the behavior of MFS CMs that are related to matrix defects. Based on these results, we postulate that impaired support from the extracellular environment plays a key role in the improper functioning of CMs in MFS.
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http://dx.doi.org/10.1038/s41598-020-73802-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542175PMC
October 2020

Myocardial Function, Heart Failure and Arrhythmia in Marfan Syndrome: A Systematic Literature Review.

Diagnostics (Basel) 2020 Sep 25;10(10). Epub 2020 Sep 25.

Centre for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.

Marfan syndrome (MFS) is a heritable systemic connective tissue disease with important cardiovascular involvement, including aortic root dilatation and mitral valve prolapse. Life expectancy in patients with MFS is mainly determined by cardiovascular complications, among which aortic dissection or rupture are most dreaded. In recent years, heart failure and ventricular arrhythmia have drawn attention as extra-aortic cardiovascular manifestations and as additional reported causes of death. Imaging studies have provided data supporting a primary myocardial impairment in the absence of valvular disease or cardiovascular surgery, while studies using ambulatory ECG have demonstrated an increased susceptibility to ventricular arrhythmia. In this paper, current literature was reviewed in order to provide insights in characteristics, pathophysiology and evolution of myocardial function, heart failure and ventricular arrhythmia in MFS.
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http://dx.doi.org/10.3390/diagnostics10100751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599866PMC
September 2020

A genotype-first approach to exploring Mendelian cardiovascular traits with clear external manifestations.

Genet Med 2021 Jan 29;23(1):94-102. Epub 2020 Sep 29.

Mindich Child Health and Development Institute, Icahn School of Medicine, New York, NY, USA.

Purpose: The purpose of this study is to use a genotype-first approach to explore highly penetrant, autosomal dominant cardiovascular diseases with external features, the RASopathies and Marfan syndrome (MFS), using biobank data.

Methods: This study uses exome sequencing and corresponding phenotypic data from Mount Sinai's BioMe (n = 32,344) and the United Kingdom Biobank (UKBB; n = 49,960). Variant curation identified pathogenic/likely pathogenic (P/LP) variants in RASopathy genes and FBN1.

Results: Twenty-one subjects harbored P/LP RASopathy variants; three (14%) were diagnosed, and another 46% had ≥1 classic Noonan syndrome (NS) feature. Major NS features (short stature [9.5% p = 7e-5] and heart anomalies [19%, p < 1e-5]) were less frequent than expected. Prevalence of hypothyroidism/autoimmune disorders was enriched compared with biobank populations (p = 0.007). For subjects with FBN1 P/LP variants, 14/41 (34%) had a MFS diagnosis or highly suggestive features. Five of 15 participants (33%) with echocardiographic data had aortic dilation, fewer than expected (p = 8e-6). Ectopia lentis affected only 15% (p < 1e-5).

Conclusions: Substantial fractions of individuals harboring P/LP variants with partial or full phenotypic matches to a RASopathy or MFS remain undiagnosed, some not meeting diagnostic criteria. Routine population genotyping would enable multidisciplinary care and avoid life-threatening events.
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http://dx.doi.org/10.1038/s41436-020-00973-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796917PMC
January 2021

Spontaneous Right Ventricular Pseudoaneurysms and Increased Arrhythmogenicity in a Mouse Model of Marfan Syndrome.

Int J Mol Sci 2020 Sep 24;21(19). Epub 2020 Sep 24.

Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium.

Patients with Marfan syndrome (MFS), a connective tissue disorder caused by pathogenic variants in the gene encoding the extracellular matrix protein fibrillin-1, have an increased prevalence of primary cardiomyopathy, arrhythmias, and sudden cardiac death. We have performed an in-depth in vivo and ex vivo study of the cardiac phenotype of mice, an established mouse model of MFS with a severely reduced expression of fibrillin-1. Using ultrasound measurements, we confirmed the presence of aortic dilatation and observed cardiac diastolic dysfunction in male mice. Upon post-mortem examination, we discovered that the mutant mice consistently presented myocardial lesions at the level of the right ventricular free wall, which we characterized as spontaneous pseudoaneurysms. Histological investigation demonstrated a decrease in myocardial compaction in the MFS mouse model. Furthermore, continuous 24 h electrocardiographic analysis showed a decreased heart rate variability and an increased prevalence of extrasystolic arrhythmic events in mice compared to wild-type littermates. Taken together, in this paper we document a previously unreported cardiac phenotype in the MFS mouse model and provide a detailed characterization of the cardiac dysfunction and rhythm disorders which are caused by fibrillin-1 deficiency. These findings highlight the wide spectrum of cardiac manifestations of MFS, which might have implications for patient care.
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http://dx.doi.org/10.3390/ijms21197024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582482PMC
September 2020

MEK1/2 Inhibition in Murine Heart and Aorta After Oral Administration of Refametinib Supplemented Drinking Water.

Front Pharmacol 2020 28;11:1336. Epub 2020 Aug 28.

Center for Medical Genetics, Ghent University, Ghent, Belgium.

Upregulation of the RAS-RAF-MEK-ERK-MAPK pathway is involved in the development of several human tumors, aortic aneurysms, atherosclerosis, and cardiomyopathy. Refametinib, a highly selective MEK-inhibitor, has already shown antineoplastic activity in phase II trials. Furthermore, it showed potency to attenuate aortic root growth in murine models. Current formulations of this drug however necessitate oral gavage as a delivery method for long-term studies, which is labor-intensive and induces stress and occasional injury, potentially confounding results. Therefore, we developed a novel oral administration method for refametinib. A 2-hydroxypropyl-beta-cyclodextrin (HPBCD) based drinking water preparation of refametinib was formulated, for which a selective, analytical UHPLC-UV method was developed to assess the in-use stability. Next, 16 week old male wild-type C57Bl/6J mice received either a daily dose of 50 or 75 mg/kg/day refametinib or were given regular drinking water during 7 days. In both dosage groups the refametinib plasma levels were measured (n = 10 or 7, respectively). Furthermore, pERK/total ERK protein levels were calculated in the myocardial and aortic tissue of mice receiving a daily dose of 50 mg/kg/day refametinib and untreated mice (n = 4/group). After 7 days no significant degradation of refametinib was observed when dissolved in drinking water provided that drinking bottles were protected from UV/visible light. Furthermore, a dose-dependent increase in refametinib plasma levels was found whereby active plasma levels (> 1.2 µg/mL) were obtained even in the lowest dose-group of 50 mg/kg/day. A significant reduction of pERK/total ERK protein levels compared to untreated mice was observed in aortic and myocardial tissue of mice receiving a daily dose of 50 mg/kg/day refametinib. Importantly, a relatively high mortality rate was noted in the highest dose group (n = 5). This approach provides a valid alternative oral administration method for refametinib with a reduced risk of complications due to animal manipulation and without loss of functionality, which can be implemented in future research regarding the malignant upregulation of the RAS-RAF-MEK-ERK-MAPK pathway. However, care must be taken not to exceed the toxic dose.
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http://dx.doi.org/10.3389/fphar.2020.01336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483920PMC
August 2020

Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm.

Genet Med 2021 Jan 28;23(1):111-122. Epub 2020 Aug 28.

Laboratory for Vascular Translational Science, INSERM U1148, Université de Paris, Centre Hospitalo-Universitaire Xavier Bichat, APHP, Paris, France.

Purpose: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD.

Methods: We analyzed exome sequencing data from 35 French TAAD families and performed next-generation sequencing capture panel of genes in 1114 unrelated TAAD patients. Functional effects of pathogenic variants identified were validated in cell, tissue, and mouse models.

Results: We identified five functional variants in THSD4 of which two heterozygous variants lead to a premature termination codon. THSD4 encodes ADAMTSL6 (member of the ADAMTS/L superfamily), a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4 mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4 mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix.

Conclusion: These findings highlight the role of ADAMTSL6 in aortic physiology and TAAD pathogenesis. They will improve TAAD management and help develop new targeted therapies.
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http://dx.doi.org/10.1038/s41436-020-00947-4DOI Listing
January 2021

Ambulatory Electrocardiographic Monitoring and Ectopic Beat Detection in Conscious Mice.

Sensors (Basel) 2020 Jul 10;20(14). Epub 2020 Jul 10.

Center for Medical Genetics, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium.

Ambulatory electrocardiography (AECG) is a primary diagnostic tool in patients with potential arrhythmic disorders. To study the pathophysiological mechanisms of arrhythmic disorders, mouse models are widely implemented. The use of a technique similar to AECG for mice is thus of great relevance. We have optimized a protocol which allows qualitative, long-term ECG data recording in conscious, freely moving mice. Automated algorithms were developed to efficiently process the large amount of data and calculate the average heart rate (HR), the mean peak-to-peak interval and heart rate variability (HRV) based on peak detection. Ectopic beats are automatically detected based on aberrant peak intervals. As we have incorporated a multiple lead configuration in our ECG set-up, the nature and origin of the suggested ectopic beats can be analyzed in detail. The protocol and analysis tools presented here are promising tools for studies which require detailed, long-term ECG characterization in mouse models with potential arrhythmic disorders.
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http://dx.doi.org/10.3390/s20143867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412233PMC
July 2020

Genetics in congenital heart disease. Are we ready for it?

Rev Esp Cardiol (Engl Ed) 2020 Jul 6. Epub 2020 Jul 6.

Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium; Division of Pediatric Cardiology, Department of Pediatrics, Ghent University Hospital, Ghent, Belgium.

Genetics has rightly acquired an important place in almost all medical disciplines in recent years and this is certainly the case in the field of congenital cardiology. Not only has this led to greater insight into the pathophysiology of congenital heart defects but it also has a beneficial impact on patient management. Integration of clinical genetics in multidisciplinary centers of expertise for CHD is therefore a clear recommendation. Adult and pediatric cardiologists play a crucial role in the process of genetic evaluation of patients and families and should have be familiar with red flags for referral for further clinical genetic elaboration, counseling, and eventual testing. Some basic knowledge is also important for the correct interpretation of genetic testing results. In this review article, we provide a practical overview of what genetic evaluation entails, which type of genetic tests are possible today, and how this can be used in practice for the individual patient.
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http://dx.doi.org/10.1016/j.rec.2020.05.019DOI Listing
July 2020

A new dimension in patent foramen ovale size estimation.

Echocardiography 2020 07 7;37(7):1049-1055. Epub 2020 Jul 7.

Department of Pediatric Cardiology, Ghent University Hospital, Ghent, Belgium.

Background: Detailed multidimensional assessment of patent foramen ovale (PFO) size with transesophageal echocardiography (TOE) may help to determine PFO pathogenicity in cryptogenic stroke patients. We explored the potential additive value of Live xPlane and three-dimensional (3D) TOE anatomical PFO sizing techniques.

Methods: Imaging data of 45 patients who underwent a 3D TOE-assisted percutaneous PFO closure were studied. The two-dimensional (2D) PFO separation distance and right-to-left (RL) contrast shunt magnitude were assessed on preprocedural TOE recordings. Peri-procedural measurements of the triangular anatomical PFO opening (base, height, and area) were performed after positioning of a stiff guidewire (SW) through the PFO, using Live xPlane imaging and 3D Zoom mode.

Results: The PFO SW base appeared on average 5 times larger than the preprocedural 2D PFO separation (median difference [IQR] = 13[5] mm; P < .001). For a same PFO separation, the width of the PFO base may vary significantly. The PFO SW base was significantly larger in patients with a large versus a small-to-moderate PFO RL contrast shunt (18 vs 15 mm; P = .007) and in those with a spontaneous versus a provoked shunt (18 vs 14 mm; P = .003).

Conclusion: Live xPlane and 3D Zoom TOE allow peri-procedural measurement of the largest dimension of a PFO, which is the PFO base. Patients with a large or spontaneous RL contrast shunt appear to have a larger PFO base. The anatomical PFO base dimension may be taken into account for optimization of device and patient selection strategies.
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http://dx.doi.org/10.1111/echo.14696DOI Listing
July 2020

Creating the BELgian COngenital heart disease database combining administrative and clinical data (BELCODAC): Rationale, design and methodology.

Int J Cardiol 2020 10 27;316:72-78. Epub 2020 May 27.

KU Leuven Department of Public Health and Primary Care, Academic Center for Nursing and Midwifery, 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: Congenital heart disease (CHD) entails a broad spectrum of malformations with various degrees of severity and prognosis. Consequently, new and specific healthcare needs are emerging, requiring responsive healthcare provision. Research on this matter is predominantly performed on population-based databases, to inform clinicians, researchers and policy-makers on health outcomes and economic burden of CHD. Most databases contain data either from administrative sources or from clinical systems. We describe the methodological design of the BELgian COngenital Heart Disease Database combining Administrative and Clinical data (BELCODAC), to investigate patients with CHD.

Methods: Data on clinical characteristics from three university hospitals in Belgium (Leuven, Ghent and Brussels) were merged with mortality and socio-economic data from the official Belgian statistical office (StatBel), and with healthcare use data from the InterMutualistic Agency, an overarching national organization that collects data from the seven sickness funds for all Belgian citizens. Over 60 variables with multiple entries over time are included in the database.

Results: BELCODAC contains data on 18,510 patients, of which 8926 patients (48%) have a mild, 7490 (41%) a moderately complex and 2094 (11%) a complex anatomical heart defect. The most prevalent diagnosis is Ventricular Septal Defect in 3879 patients (21%), followed by Atrial Septal Defect in 2565 patients (14%).

Conclusions: BELCODAC comprises longitudinal data on patients with CHD in Belgium. This will help build evidence-based provision of care to the changing CHD population.
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http://dx.doi.org/10.1016/j.ijcard.2020.05.059DOI Listing
October 2020

Corrosion casting of the cardiovascular structure in adult zebrafish for analysis by scanning electron microscopy and X-ray microtomography.

Anat Histol Embryol 2020 Sep 29;49(5):635-642. Epub 2020 Jan 29.

Center for Medical Genetics Ghent, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.

Zebrafish have come to the forefront as a flexible, relevant animal model to study human disease, including cardiovascular disorders. Zebrafish are optically transparent during early developmental stages, enabling unparalleled imaging modalities to examine cardiovascular structure and function in vivo and ex vivo. At later stages, however, the options for systematic cardiovascular phenotyping are more limited. To visualise the complete vascular tree of adult zebrafish, we have optimised a vascular corrosion casting method. We present several improvements to the technique leading to increased reproducibility and accuracy. We designed a customised support system and used a combination of the commercially available Mercox II methyl methacrylate with the Batson's catalyst for optimal vascular corrosion casting of zebrafish. We also highlight different imaging approaches, with a focus on scanning electron microscopy (SEM) and X-ray microtomography (micro-CT) to obtain highly detailed, faithful three-dimensional reconstructed images of the zebrafish cardiovascular structure. This procedure can be of great value to a wide range of research lines related to cardiovascular biology in small specimens.
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http://dx.doi.org/10.1111/ahe.12535DOI Listing
September 2020

Angiotensin-II receptor blockade in Marfan syndrome.

Lancet 2019 12 10;394(10216):2206-2207. Epub 2019 Dec 10.

Centre for Medical Genetics, Ghent University Hospital, Ghent 9000, Belgium; Department of Cardiology, Ghent University Hospital, Ghent 9000, Belgium.

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http://dx.doi.org/10.1016/S0140-6736(19)32536-XDOI Listing
December 2019

Features of Marfan syndrome not listed in the Ghent nosology - the dark side of the disease.

Expert Rev Cardiovasc Ther 2019 Dec;17(12):883-915

Center for Medical Genetics and Department of Cardiology, Ghent University Hospital, VASCERN HTAD European Reference Centre, Ghent, Belgium.

: The revised Ghent nosology presents the classical features of Marfan syndrome. However, behind its familiar face, Marfan syndrome hides less well-known features.: The German Marfan Organization listed unusual symptoms and clinical experts reviewed the literature on clinical features of Marfan syndrome not listed in the Ghent nosology. Thereby we identified the following features: (1) bicuspid aortic valve, mitral valve prolapse, pulmonary valve prolapse, tricuspid valve prolapse, (2) heart failure and cardiomyopathy, (3) supraventricular arrhythmia, ventricular arrhythmia, and abnormal repolarization, (4) spontaneous coronary artery dissection, anomalous coronary arteries, and atherosclerotic coronary artery disease, tortuosity-, aneurysm-, and dissection of large and medium-sized arteries, (5) restrictive lung disease, parenchymal lung disease, and airway disorders, (6) obstructive- and central sleep apnea, (7) liver and kidney cysts, biliary tract disease, diaphragmatic hernia, and adiposity, (8) premature labor, and urinary incontinence, (9) myopathy, reduced bone mineral density, and craniofacial manifestations, (10) atrophic scars, (11) caries, and craniomandibular dysfunction, (12) headache from migraine and spontaneous cerebrospinal fluid leakage, (13) cognitive dysfunction, schizophrenia, depression, fatigue, and pain, (14) and activated fibrinolysis, thrombin, platelets, acquired von Willebrand disease, and platelet dysfunction.: Future research, nosologies, and guidelines may consider less well-known features of Marfan syndrome.
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http://dx.doi.org/10.1080/14779072.2019.1704625DOI Listing
December 2019

Case-matched Comparison of Cardiovascular Outcome in Loeys-Dietz Syndrome versus Marfan Syndrome.

J Clin Med 2019 Nov 29;8(12). Epub 2019 Nov 29.

Department of Congenital Heart Disease and Pediatric Cardiology, Deutsches Herzzentrum München, Technical University München, 80636 Munich, Germany.

Pathogenic variants in , and genes cause Loeys-Dietz syndrome, and pathogenic variants in cause Marfan syndrome. Despite their similar phenotypes, both syndromes may have different cardiovascular outcomes. Three expert centers performed a case-matched comparison of cardiovascular outcomes. The Loeys-Dietz group comprised 43 men and 40 women with a mean age of 34 ± 18 years. Twenty-six individuals had pathogenic variants in , 40 in , and 17 in . For case-matched comparison we used 83 age and sex-frequency matched individuals with Marfan syndrome. In Loeys-Dietz compared to Marfan syndrome, a patent ductus arteriosus ( = 0.014) was more prevalent, the craniofacial score was higher ( < 0.001), the systemic score lower ( < 0.001), and mitral valve prolapse less frequent ( = 0.003). Mean survival for Loeys-Dietz and Marfan syndrome was similar (75 ± 3 versus 73 ± 2 years; = 0.811). Cardiovascular outcome was comparable between Loeys-Dietz and Marfan syndrome, including mean freedom from proximal aortic surgery (53 ± 4 versus 48 ± 3 years; = 0.589), distal aortic repair (72 ± 3 versus 67 ± 2 years; = 0.777), mitral valve surgery (75 ± 4 versus 65 ± 3 years; = 0.108), and reintervention (20 ± 3 versus 14 ± 2 years; = 0.112). In Loeys-Dietz syndrome, lower age at initial presentation predicted proximal aortic surgery (HR = 0.748; < 0.001), where receiver operating characteristic analysis identified ≤33.5 years with increased risk. In addition, increased aortic sinus diameters (HR = 6.502; = 0.001), and higher systemic score points at least marginally (HR = 1.175; = 0.065) related to proximal aortic surgery in Loeys-Dietz syndrome. Cardiovascular outcome of Loeys-Dietz syndrome was comparable to Marfan syndrome, but the severity of systemic manifestations was a predictor of proximal aortic surgery.
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http://dx.doi.org/10.3390/jcm8122079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947024PMC
November 2019

Development of a transition program for adolescents with congenital heart disease.

Eur J Pediatr 2020 Feb 22;179(2):339-348. Epub 2019 Nov 22.

Research Foundation Flanders (FWO), Brussels, Belgium.

Thanks to advances in care, most children with congenital heart disease nowadays survive into adulthood. The majority of patients remain at high risk for future complications. Hence, life-long follow-up is mandatory. Care needs of patients evolve, especially when reaching adulthood. A structured transition period to adult care is advocated. Currently, a fully detailed and structured transition program is not available for patients with congenital heart disease. The aim is to describe the development and design of a multicomponent transition program for adolescents with congenital heart disease, called "Transition with a heart." Transition with a heart was developed based on the Dutch program "On your own feet," starting at the age of 12 years and continuing after transfer. The most vital core components include a general and individualized flowchart, adolescent-centered communication, a joined transfer consultation, and an appointed transition coordinator. Adolescents are gradually informed about their condition and potential late consequences in adult life and stimulated to take medical care in their own hands.Conclusion: Transition with a heart is a practical, multicomponent, comprehensive transition program developed to cover the essential aspects of transitional care for adolescents with congenital heart disease (i.e., continuity of care, disease knowledge, and self-management skills). Interventions were selected from the highest sources of scientific evidence currently available.Clinical trial registration: Not applicableWhat is Known:• Transition towards adult life and health care is a complex process, requiring careful patients' guidance. Various task forces have described the need and potential benefits of transition programs in young people with chronic conditions. Details about the practical development and content of such programs in congenital heart disease are, however, currently lacking.What is New:• This method paper presents the development and design of a person-centered multicomponent transition program for adolescents with congenital heart disease comprising interventional components covering the most important aspects of transitional care: promoting autonomy, disease knowledge, and continuity of care.
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http://dx.doi.org/10.1007/s00431-019-03515-4DOI Listing
February 2020

European reference network for rare vascular diseases (VASCERN) consensus statement for the screening and management of patients with pathogenic ACTA2 variants.

Orphanet J Rare Dis 2019 11 21;14(1):264. Epub 2019 Nov 21.

VASCERN HTAD European Reference Centre, Ghent, Belgium.

The ACTA2 gene encodes for smooth muscle specific α-actin, a critical component of the contractile apparatus of the vascular smooth muscle cell. Pathogenic variants in the ACTA2 gene are the most frequently encountered genetic cause of non-syndromic hereditary thoracic aortic disease (HTAD). Although thoracic aortic aneurysm and/or dissection is the main clinical manifestation, a variety of occlusive vascular disease and extravascular manifestations occur in ACTA2-related vasculopathy. Current data suggest possible mutation-specific manifestations of vascular and extra-aortic traits.Despite its relatively high prevalence, comprehensive recommendations on the care of patients and families with pathogenic variants in ACTA2 have not yet been established. We aimed to develop a consensus document to provide medical guidance for health care professionals involved in the diagnosis and treatment of patients and relatives with pathogenic variants in ACTA2.The HTAD Working Group of the European Reference Network for Rare Vascular Diseases (VASCERN) convened to review current literature and discuss expert opinions on clinical management of ACTA2 related vasculopathy. This consensus statement summarizes our recommendations on diagnosis, monitoring, treatment, pregnancy, genetic counselling and testing in patients with ACTA2-related vasculopathy. However, there is a clear need for additional prospective multicenter studies to further define proper guidelines.
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http://dx.doi.org/10.1186/s13023-019-1186-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868850PMC
November 2019

Opinions of general and adult congenital heart disease cardiologists on care for adults with congenital heart disease in Belgium: a qualitative study.

Cardiol Young 2019 Nov 6;29(11):1368-1374. Epub 2019 Sep 6.

Department of Public Health and Primary Care, Ghent University, Ghent, Belgium.

Background: The growing adult congenital heart disease (CHD) population requires efficient healthcare organisation. It has been suggested that clinically appropriate care be provided for individual patients on the least complex level possible, in order to alleviate saturation of special care programmes.

Methods: Semi-structured interviews with 10 general and 10 adult CHD cardiologists were conducted to elucidate opinions on healthcare organisation in Belgium. A particular focus was placed on the potential role of general cardiologists. The software program NVivo 12 facilitated thematic analysis.

Results: A discrepancy existed between how general cardiologists thought about congenital care and what adult CHD cardiologists considered the minimum knowledge required to adequately treat patients. Qualitative data were categorised under the following themes: knowledge dissemination, certification, (de)centralisation of care, the role of adult CHD cardiologists, the role of dedicated nurse specialists, and patient referral. It appeared to be pivotal to organise care in such a way that providing basic care locally does not impede the generation of sufficient patient volume, and to continue improving communications between different care levels when there is no referral back. Moreover, practical knowledge is best disseminated locally. Cardiologists' opinions on certification and on the role of dedicated nurse specialists were mixed.

Conclusion: On the basis of the results, we propose five recommendations for improving the provision of care to adults with CHD. A multidimensional approach to defining the role of different healthcare professionals, to improving communication channels, and to effectively sensitising healthcare professionals is needed to improve the organisation of care.
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http://dx.doi.org/10.1017/S1047951119002245DOI Listing
November 2019

Genetic testing for aortopathies: primer for the nongeneticist.

Curr Opin Cardiol 2019 11;34(6):585-593

VASCERN HTAD European Reference Centre, Centre National Maladies Rares pour le Syndrome de Marfan et apparente[Combining Acute Accent]s.

Purpose Of Review: Although the majority of thoracic aortic aneurysms and dissections (TAD) in the overall population are mainly related to arterial hypertension and atherosclerosis, Heritable Thoracic Aortic Disease (HTAD) are increasingly recognized, especially in younger individuals. As fatal events in the setting of HTAD are preventable with timely detection and appropriate management, this review aims to provide an overview of the genetic basis of HTAD and practical recommendations for genetic evaluation in this setting.

Recent Findings: Thanks in part to a number of important efforts to set up (inter)national networks and consortia for collecting clinical and genetic data from patients with these rare disorders, significant progress has been made in understanding the natural evolution of these disorders. These insights are now starting to enable the development of recommendations for the management of these patients.In addition, pathogenic variants in a number of new genes have been identified in HTAD patients. On the basis of more extensive genetic screening in cohorts of patients with TAD, it is becoming clear that there is no strict boundary between syndromal and nonsyndromal HTAD entities. It is, therefore, important to at least consider genetic evaluation, not only for patients presenting with syndromic forms but also for more isolated TAD.Finally, there are indications that we will -- up to a certain point -- soon be able to draw up a more precise policy for individual patients, based on the underlying genetic defects SUMMARY: Genetic evaluation in (young) patients with both syndromic and nonsyndromic forms of HTAD should be considered and is helpful for the development of more precise medicine.
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http://dx.doi.org/10.1097/HCO.0000000000000669DOI Listing
November 2019