ORCID Profile
0000-0002-4595-5922
Current Organisations
University of Leuven
,
KU Leuven
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Publisher: Springer Science and Business Media LLC
Date: 26-05-2013
DOI: 10.1038/NG.2637
Publisher: Springer Science and Business Media LLC
Date: 08-2016
DOI: 10.1038/NG.3627
Publisher: Elsevier BV
Date: 12-2015
Publisher: Elsevier BV
Date: 09-2012
Publisher: Elsevier BV
Date: 04-1999
DOI: 10.1086/302330
Abstract: Deletions in the distal region of chromosome 8p (del8p) are associated with congenital heart malformations. Other major manifestations include microcephaly, intrauterine growth retardation, mental retardation, and a characteristic hyperactive, impulsive behavior. We studied genotype-phenotype correlations in nine unrelated patients with a de novo del8p, by using the combination of classic cytogenetics, FISH, and the analysis of polymorphic DNA markers. With the exception of one large terminal deletion, all deletions were interstitial. In five patients, a commonly deleted region of approximately 6 Mb was present, with breakpoints clustering in the same regions. One patient without a heart defect or microcephaly but with mild mental retardation and characteristic behavior had a smaller deletion within this commonly deleted region. Two patients without a heart defect had a more proximal interstitial deletion that did not overlap with the commonly deleted region. Taken together, these data allowed us to define the critical deletion regions for the major features of a del8p.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2013
DOI: 10.1161/CIRCGENETICS.113.000191
Abstract: Association between the C677T polymorphism of the methylene tetrahydrofolate reductase ( MTHFR ) gene and congenital heart disease (CHD) is contentious. We compared genotypes between CHD cases and controls and between mothers of CHD cases and controls. We placed our results in context by conducting meta-analyses of previously published studies. Among 5814 cases with primary genotype data and 10 056 controls, there was no evidence of association between MTHFR C677T genotype and CHD risk (odds ratio [OR], 0.96 [95% confidence interval, 0.87–1.07]). A random-effects meta-analysis of all studies (involving 7697 cases and 13 125 controls) suggested the presence of association (OR, 1.25 [95% confidence interval, 1.03–1.51] P =0.022) but with substantial heterogeneity among contributing studies (I 2 =64.4%) and evidence of publication bias. Meta-analysis of large studies only (defined by a variance of the log OR .05), which together contributed 83% of all cases, yielded no evidence of association (OR, 0.97 [95% confidence interval, 0.91–1.03]) without significant heterogeneity (I 2 =0). Moreover, meta-analysis of 1781 mothers of CHD cases (829 of whom were genotyped in this study) and 19 861 controls revealed no evidence of association between maternal C677T genotype and risk of CHD in offspring (OR, 1.13 [95% confidence interval, 0.87–1.47]). There was no significant association between MTHFR genotype and CHD risk in large studies from regions with different levels of dietary folate. The MTHFR C677T polymorphism, which directly influences plasma folate levels, is not associated with CHD risk. Publication biases appear to substantially contaminate the literature with regard to this genetic association.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-02-2019
DOI: 10.1161/CIRCRESAHA.118.313250
Abstract: 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. We used whole exome sequencing to assess the prevalence of unique, deleterious variants in the largest cohort of nonsyndromic TOF patients reported to date. 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 ×10 −8 ) 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 . 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.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-05-2019
Abstract: 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. 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 2 ). 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 2 were higher than in controls. The change in cardiac index relative to the change in VO 2 (∆cardiac index/∆ VO 2 ) was similar between groups, but Fontan patients had increased ∆ HR /∆ VO 2 and reduced ∆ stroke volume/∆ VO 2 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 . 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.
Publisher: Oxford University Press (OUP)
Date: 07-01-2013
DOI: 10.1093/HMG/DDS552
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-08-2019
DOI: 10.1161/CIR.0000000000000696
Abstract: 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 %. 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 in iduals.
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.IJCARD.2018.03.029
Abstract: To evaluate the relationship between right ventricular (RV) systolic dysfunction at rest and reduced exercise capacity in patients with a systemic RV (sRV). All patients with congenitally corrected transposition of the great arteries (ccTGA) or complete TGA after atrial switch (TGA-Mustard/Senning) followed in our institution between July 2011 and September 2017 who underwent cardiac imaging within a six-month time period of cardiopulmonary exercise testing (CPET) were analyzed. We assessed sRV systolic function with TAPSE and fractional area change on echocardiogram and, if possible, with ejection fraction, global longitudinal and circumferential strain on cardiac magnetic resonance (CMR) imaging. We studied 105 patients with an sRV (median age 34 [IQR 28-42] years, 29% ccTGA and 71% TGA-Mustard/Senning) of which 39% had either a pacemaker (n = 17), Eisenmenger physiology (n = 6), severe systemic atrioventricular valve regurgitation (n = 14), or peak exercise arterial oxygen saturation < 92% (n = 17). Most patients were asymptomatic or mildly symptomatic (NYHA class I/II/III in 71/23/6%). Sixty-four percent had evidence of moderate or severe sRV dysfunction on cardiac imaging. Mean peak oxygen uptake (pVO2) was 24.1 ± 7.4 mL/kg/min, corresponding to a percentage of predicted pVO2 (%ppVO2) of 69 ± 17%. No parameter of sRV systolic function as evaluated on echocardiography (n = 105) or CMR (n = 46) was correlated with the %ppVO2, even after adjusting for associated cardiac defects or pacemakers. In adults with an sRV, there is no relation between echocardiographic or CMR-derived sRV systolic function parameters at rest and peak oxygen uptake. Exercise imaging may be superior to evaluate whether sRV contractility limits exercise capacity.
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.CJCA.2019.04.018
Abstract: 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. 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. 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). 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.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-01-2022
DOI: 10.1161/CIRCRESAHA.120.317107
Abstract: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in in idual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10 -10 , OR=0.69 per C allele). SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10 -5 ). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A , which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A . Genomic and functional data support a causal role of WNT5A at the locus.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2013
DOI: 10.1161/CIRCIMAGING.112.980037
Abstract: Accurate measures are critical when attempting to distinguish normal from pathological changes in cardiac function during exercise, yet imaging modalities have seldom been assessed against invasive exercise standards. We sought to validate a novel method of biventricular volume quantification by cardiac MRI (CMR) during maximal exercise. CMR was performed on 34 subjects during exercise and free-breathing with the use of an ungated real-time (RT-ungated) CMR sequence. ECG and respiratory movements were retrospectively synchronized, enabling compensation for cardiac cycle and respiratory phase. Feasibility of RT-ungated imaging was compared with standard exercise CMR imaging with ECG gating (gated) accuracy of RT-ungated CMR was assessed against an invasive standard (direct Fick) and reproducibility was determined after a second bout of maximal exercise. Ventricular volumes were analyzed more frequently during high-intensity exercise with RT-ungated compared with gated CMR (100% versus 47% P .0001) and with better interobserver variability for RT-ungated (coefficient of variation=1.9% and 2.0% for left and right ventricular stroke volumes, respectively) than gated (coefficient of variation=15.2% and 13.6% P .01). Cardiac output determined by RT-ungated CMR proved accurate against the direct Fick method with excellent agreement (intraclass correlation coefficient, R =0.96), which was highly reproducible during a second bout of maximal exercise ( R =0.98). When RT-ungated CMR is combined with post hoc analysis incorporating compensation for respiratory motion, highly reproducible and accurate biventricular volumes can be measured during maximal exercise.
Publisher: Springer Science and Business Media LLC
Date: 07-09-2023
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2014
DOI: 10.1161/CIRCIMAGING.113.001243
Abstract: Patients with Fontan circulation have reduced exercise capacity. The absence of a presystemic pump may limit flow through the pulmonary circulation, restricting ventricular filling and cardiac output. We evaluated exercise hemodynamics and the effect of sildenafil on exercise hemodynamics in Fontan patients. Ten Fontan patients (6 men, 20±4 years) underwent cardiac magnetic resonance imaging at rest and during supine bicycle exercise before and after sildenafil. Systemic ventricular volumes were obtained at rest and during low- (34±15 W), moderate- (69±29 W), and high-intensity (97±36 W) exercise using an ungated, free-breathing cardiac magnetic resonance sequence and analyzed correcting for cardiac phase and respiratory translation. Radial and pulmonary artery pressures and cGMP were measured. Before sildenafil, cardiac index increased throughout exercise (4.0±0.9, 5.9±1.1, 7.0±1.6, 7.4±1.7 L/(min·m 2 ) P .0001) with 106±49% increase in heart rate. Stroke volume index ( P =0.015) and end-diastolic volume index ( P =0.001) decreased during exercise. End-systolic volume index remained unchanged ( P =0.8). Total pulmonary resistance index ( P =0.005) increased, whereas systemic vascular resistance index decreased during exercise ( P .0001). Sildenafil increased cardiac index ( P .0001) and stroke volume index ( P =0.003), especially at high-intensity exercise (interaction P =0.004 and P =0.003, respectively). Systemic vascular resistance index was reduced ( P .0001–interaction P =0.1), whereas total pulmonary resistance index was reduced at rest and reduced further during exercise ( P =0.008–interaction P =0.029). cGMP remained unchanged before sildenafil ( P =0.9), whereas it increased significantly after sildenafil ( P =0.019). In Fontan patients, sildenafil improved cardiac index during exercise with a decrease in total pulmonary resistance index and an increase in stroke volume index. This implies that pulmonary vasculature represents a physiological limitation, which can be attenuated by sildenafil, the clinical significance of which warrants further study.
Publisher: BMJ
Date: 17-12-2010
Abstract: m.14487T>C, a missense mutation (p.M63V) affecting the ND6 subunit of complex I of the mitochondrial respiratory chain, has been reported in isolated childhood cases with Leigh syndrome (LS) and progressive dystonia. Adult-onset phenotypes have not been reported. To determine the clinical-neurological spectrum and associated mutation loads in an extended m.14487T>C family. A genotype-phenotype correlation study of a Belgian five-generation family with 12 affected family members segregating m.14487T>C was carried out. Clinical and mutation load data were available for nine family members. Biochemical analysis of the respiratory chain was performed in three muscle biopsies. Heteroplasmic m.14487T>C levels (36-52% in leucocytes, 97-99% in muscle) were found in patients with progressive myoclonic epilepsy (PME) and dystonia or progressive hypokinetic-rigid syndrome. Patients with infantile LS were homoplasmic (99-100% in leucocytes, 100% in muscle). We found lower mutation loads (between 8 and 35% in blood) in adult patients with clinical features including migraine with aura, Leber hereditary optic neuropathy, sensorineural hearing loss and diabetes mellitus type 2. Despite homoplasmic mutation loads, complex I catalytic activity was only moderately decreased in muscle tissue. m.14487T>C resulted in a broad spectrum of phenotypes in our family. Depending on the mutation load, it caused severe encephalopathies ranging from infantile LS to adult-onset PME with dystonia. This is the first report of PME as an important neurological manifestation of an isolated mitochondrial complex I defect.
Publisher: Oxford University Press (OUP)
Date: 03-2010
DOI: 10.1510/ICVTS.2009.218594
Abstract: In a Fontan circuit the mechanisms involved in control of cardiac output at rest and during exercise differ significantly from normal. The classical model presumes an unlimited preload which is not available in the Fontan circuit. This review critically analyses the role of contractility, heart rate, and afterload and highlights the importance of pulmonary vascular resistance (PVR) in determining adequate preload and, therefore, cardiac output in these patients. A conceptual model of the determinants of cardiac output in Fontan patients is presented.
No related grants have been discovered for Marc Gewillig.