Common genetic variants improve risk stratification after the atrial switch operation for transposition of the great arteries

Background: Clinical factors are used to estimate late complication risk in adults after atrial switch operation (AtrSO) for transposition of the great arteries (TGA), but heterogeneity in clinical course remains. We studied whether common genetic variants are associated with outcome and add value to a clinical risk score in TGA-AtrSO patients. Methods and results: This multicenter study followed 133 TGA-AtrSO patients (aged 28 [IQR 24–35] years) for 13 (IQR 9–16) years and examined the association of genome-wide single-nucleotide polymorphisms (SNPs) with a composite endpoint of symptomatic ventricular arrhythmia, heart failure hospitalization, ventricular assist device implantation, heart transplantation, or mortality. Thirty-two patients (24%) reached the endpoint. The genome-wide association study yielded one genome-wide significant (p 20%) risk. Stratified by the combined score, observed 5-year event-free survival was 100%, 79% and 31% for low, intermediate, and high-risk patients, respectively. Conclusions: Common genetic variants may explain some variation in the clinical course in TGA-AtrSO and improve risk stratification over clinical factors alone, especially in patients at intermediate clinical risk. These findings support the hypothesis that including genetic variants in risk assessment may be beneficial

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

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

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

A Rare Case of Primary Meningococcal Myopericarditis in a 71-Year-Old Male

We describe a case of primary meningococcal C pericarditis with myocardial involvement in a 71-year-old male that is thus far the oldest patient with isolated meningococcal pericardial disease and only the third patient with primary meningococcal myopericarditis described in English literature. Our patient was successfully treated by full sternotomy and surgical drainage combined with intravenous ceftriaxone. Mild symptoms unresponsive to anti-inflammatory treatment and leukocytosis may guide clinicians towards the correct diagnosis. It is important to recognize this cause of pericarditis as the relatively mild clinical presentation may rapidly progress into tamponade and right-sided heart failure

Origins and consequences of congenital heart defects affecting the right ventricle

Congenital heart disease is a major health issue, accounting for a third of all congenital defects. Improved early surgical management has led to a growing population of adults with congenital heart disease, including patients with defects affecting the right ventricle, which are often classified as severe. Defects affecting the right ventricle often cause right ventricular volume or pressure overload and affected patients are at high risk for complications such as heart failure and sudden death. Recent insights into the developmental mechanisms and distinct developmental origins of the left ventricle, right ventricle, and the outflow tract have shed light on the common features and distinct problems arising in specific defects. Here, we provide a comprehensive overview of the current knowledge on the development into the normal and congenitally malformed right heart and the clinical consequences of several congenital heart defects affecting the right ventricl

Clinical Course Long After Atrial Switch: A Novel Risk Score for Major Clinical Events

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22q11.2 deletion syndrome is associated with increased mortality in adults with tetralogy of Fallot and pulmonary atresia with ventricular septal defect

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

High burden of drug therapy in adult congenital heart disease: polypharmacy as marker of morbidity and mortality

Contains fulltext : 209444.pdf (publisher's version ) (Open Access