78 research outputs found
Fetal heart and increased nuchal translucency: anatomical, pathophysiological, diagnostic and clinical aspects
Intrapericardial Extralobar Pulmonary Sequestration Presenting as a Prenatal Intrathoracic Mass
An intrathoracic mass, which persisted during the remaining pregnancy, was first seen during routine ultrasound examination performed at 20 weeks gestation. After birth, the child was asymptomatic. Echocardiography showed the mass to be located intrapericardially. The mass was electively resected via sternotomy 3 weeks after the birth. Microscopic examination showed normal lung tissue surrounded by pleura corresponding to the diagnosis of extralobar pulmonary sequestration. To the authorsā knowledge, this is the earliest described detection of such a lesion. Furthermore, this article reports the unique finding of a feeding vessel from the right pulmonary artery
Psychological Functioning and Disease-Related Quality of Life in Pediatric Patients With an Implantable Cardioverter Defibrillator
The objective of this multicenter study was to evaluate psychological functioning and disease-related quality of life (DRQoL) in pediatric patients with an implantable cardioverter defibrillator (ICD) in The Netherlands. Thirty patients were investigated; the mean age was 16.3Ā years, and the mean duration of implantation was 3.6Ā years. To assess psychological problems, three domains of the Symptom Checklist (SCL-90-R) were administered to the 25 patientsĀ >13Ā years old. DRQoL was assessed with a disease-specific pediatric questionnaire, the short-form 11-item Worries About (WA)ICDs Scale. PatientsĀ ā„13Ā years old scored significantly higher than the reference group on the domains of anxiety, depression, and sleeping problems of the SCL-90-R (TĀ =Ā 7.5, pĀ <Ā 0.001; TĀ =Ā 5.4, pĀ <Ā 0.001; and TĀ =Ā 7.8, pĀ <Ā 0.001, respectively). Patients who had received an (in)appropriate shock reported more depressive symptoms (TĀ =Ā 2.1, pĀ <Ā 0.03). Patients withĀ >2Ā years implant duration (NĀ =Ā 19) or who had received an (in)appropriate shock (NĀ =Ā 13) showed lower DRQoL scores on the modified WAICD (TĀ =Ā 2.1, pĀ <Ā 0.04; TĀ =Ā 2.1, pĀ <Ā 0.5, respectively). Age at implantation or underlying disease did not influence psychological problems or DRQoL. Young ICD patients showed more anxiety, depression, and sleeping disorders. Worries were increased among patients with ICD shocks and in those who had their ICD implanted forĀ >2Ā years. To determine psychological problems and help children to learn to cope with shocks, proper guidance and monitoring of young ICD patients are recommended
Heart Rate Recovery After Exercise Is Associated With Arrhythmic Events in Patients With Catecholaminergic Polymorphic Ventricular Tachycardia
BACKGROUND: Risk stratification in catecholaminergic polymorphic ventricular tachycardia remains ill defined. Heart rate recovery (HRR) immediately after exercise is regulated by autonomic reflexes, particularly vagal tone, and may be associated with symptoms and ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. Our objective was to evaluate whether HRR after maximal exercise on the exercise stress test (EST) is associated with symptoms and ventricular arrhythmias. METHODS: In this retrospective observational study, we included patients ā¤65 years of age with an EST without antiarrhythmic drugs who attained at least 80% of their age- and sex-predicted maximal HR. HRR in the recovery phase was calculated as the difference in heart rate (HR) at maximal exercise and at 1 minute in the recovery phase (ĪHRR1'). RESULTS: We included 187 patients (median age, 36 years; 68 [36%] symptomatic before diagnosis). Pre-EST HR and maximal HR were equal among symptomatic and asymptomatic patients. Patients who were symptomatic before diagnosis had a greater ĪHRR1' after maximal exercise (43 [interquartile range, 25-58] versus 25 [interquartile range, 19-34] beats/min; P<0.001). Corrected for age, sex, and relatedness, patients in the upper tertile for ĪHRR1' had an odds ratio of 3.4 (95% CI, 1.6-7.4) of being symptomatic before diagnosis (P<0.001). In addition, ĪHRR1' was higher in patients with complex ventricular arrhythmias at EST off antiarrhythmic drugs (33 [interquartile range, 22-48] versus 27 [interquartile range, 20-36] beats/min; P=0.01). After diagnosis, patients with a ĪHRR1' in the upper tertile of its distribution had significantly more arrhythmic events as compared with patients in the other tertiles (P=0.045). CONCLUSIONS: Catecholaminergic polymorphic ventricular tachycardia patients with a larger HRR following exercise are more likely to be symptomatic and have complex ventricular arrhythmias during the first EST off antiarrhythmic drug
Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries.
RATIONALE: 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 individual 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.
OBJECTIVE: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA.
METHODS AND RESULTS: 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
CONCLUSIONS: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 nea
Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot
Purpose Rare genetic variants in KDR, encoding the vascular endothelial growth factor receptor 2 (VEGFR2), have been reported in patients with tetralogy of Fallot (TOF). However, their role in disease causality and pathogenesis remains unclear. Methods We conducted exome sequencing in a familial case of TOF and large-scale genetic studies, including burden testing, in >1,500 patients with TOF. We studied gene-targeted mice and conducted cell-based assays to explore the role of KDR genetic variation in the etiology of TOF. Results Exome sequencing in a family with two siblings affected by TOF revealed biallelic missense variants in KDR. Studies in knock-in mice and in HEK 293T cells identified embryonic lethality for one variant when occurring in the homozygous state, and a significantly reduced VEGFR2 phosphorylation for both variants. Rare variant burden analysis conducted in a set of 1,569 patients of European descent with TOF identified a 46-fold enrichment of protein-truncating variants (PTVs) in TOF cases compared to controls (P = 7 x 10(-11)). Conclusion Rare KDR variants, in particular PTVs, strongly associate with TOF, likely in the setting of different inheritance patterns. Supported by genetic and in vivo and in vitro functional analysis, we propose loss-of-function of VEGFR2 as one of the mechanisms involved in the pathogenesis of TOF.Developmen
Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy
Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.1668F is a founder variant among Ashkenazi Jews (allele frequency of -.2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function.Genetics of disease, diagnosis and treatmen
Common genetic variants contribute to risk of transposition of the great arteries
Rationale:
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 individual 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.
Objective:
We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA.
Methods and Results:
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.
Conclusions:
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
Fetal heart and increased nuchal translucency: anatomical, pathophysiological, diagnostic and clinical aspects
The nuchal translucency and the fetal heart: a literature review
In this overview the current knowledge of the relationship between an increased nuchal translucency (NT) measurement and fetal heart structure and function in chromosomally normal fetuses is reviewed. Relevant pathophysiological theories behind the increased NT are discussed. Fetuses with an increased NT have an increased risk for congenital heart disease (CHD) with no particular bias for one form of CHD over another. This risk increases with increasing NT measurement. Although the NT measurement is only a modestly effective screening tool for all CHD when used alone, it may indeed be effective in identifying specific CHD "likely to benefit" from prenatal diagnosis. The combination of an increased NT, tricuspid regurgitation and an abnormal ductus venosus (DV) Doppler flow profile, is a strong marker for CHD. A fetal echocardiogram should be performed at 20 weeks' gestation in fetuses with an NT > or = 95th percentile but or = 99th percentile, or when tricuspid regurgitation and/or an abnormal DV flow pattern is found along with the increased NT, an earlier echocardiogram is indicated, followed by a repeat scan at around 20 weeks' gestation. The resultant increased demand for early fetal echocardiography and sonographers with this special expertise needs to be planned and provided fo
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