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Whole exome sequencing with genomic triangulation implicates CDH2-encoded N-cadherin as a novel pathogenic substrate for arrhythmogenic cardiomyopathy.

Congenit Heart Dis. 2017 Mar;12(2):226-235

Authors: Turkowski KL, Tester DJ, Bos JM, Haugaa KH, Ackerman MJ

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is a heritable disease characterized by fibrofatty replacement of cardiomyocytes, has a prevalence of approximately 1 in 5000 individuals, and accounts for approximately 20% of sudden cardiac death in the young (≤35 years). ACM is most often inherited as an autosomal dominant trait with incomplete penetrance and variable expression. While mutations in several genes that encode key desmosomal proteins underlie about half of all ACM, the remainder is elusive genetically.
OBJECTIVE: Here, whole exome sequencing (WES) was performed with genomic triangulation in an effort to identify a novel explanation for a phenotype-positive, genotype-negative multi-generational pedigree with a presumed autosomal dominant, maternal inheritance of ACM.
METHODS: WES and genomic triangulation was performed on a symptomatic 14-year-old female proband, her affected mother and affected sister, and her unaffected father to elucidate a novel ACM-susceptibility gene for this pedigree. Following variant filtering using Ingenuity® Variant Analysis, gene priority ranking was performed on the candidate genes using ToppGene and Endeavour. The phylogenetic and physiochemical properties of candidate mutations were assessed further by 6 in silico prediction tools. Species alignment and amino acid conservation analysis was performed using the Uniprot Consortium. Tissue expression data was abstracted from Expression Atlas.
RESULTS: Following WES and genomic triangulation, CDH2 emerged as a novel, autosomal dominant, ACM-susceptibility gene. The CDH2-encoded N-cadherin is a cell-cell adhesion protein predominately expressed in the heart. Cardiac dysfunction has been demonstrated in prior CDH2 knockout and over-expression animal studies. Further in silico mutation prediction, species conservation, and protein expression analysis supported the ultra-rare (minor allele frequency <0.005%) p.Asp407Asn-CDH2 variant as a likely pathogenic variant.
CONCLUSIONS: Herein, it is demonstrated that genetic mutations in CDH2-encoded N-cadherin may represent a novel pathogenetic basis for ACM in humans. The prevalence of CDH2-mediated ACM in heretofore genetically elusive ACM remains to be determined.

PMID: 28326674 [PubMed - indexed for MEDLINE]

Cactus aorta.

Eur Heart J. 2017 Sep 12;:

Authors: Mahrouf A, Soulat G, Lebeaux D, Iserin L, Karsenty C

PMID: 29020389 [PubMed - as supplied by publisher]

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Limitations, depressive symptoms, and quality of life among a population-based sample of young adults with congenital heart defects.

Birth Defects Res A Clin Mol Teratol. 2016 Jul;106(7):580-6

Authors: Farr SL, Oster ME, Simeone RM, Gilboa SM, Honein MA

BACKGROUND: Little population-based data exist on limitations and health-related quality of life (HRQoL) in adults with congenital heart defects (CHD).
METHODS: We used 2004 to 2012 Medical Expenditure Panel Survey data to identify a population-based sample of young adults ages 18 to 40 years reporting health symptoms or healthcare encounters in the previous year. Comparing adults reporting CHD to others, we examined the prevalence of cognitive, physical, and activity limitations, depressive symptoms, and physical and mental HRQoL. We used chi square tests to examine differences in demographic characteristics, logistic regression to generate adjusted prevalence ratios (aPR), and linear regression to examine HRQoL. Multivariable associations were adjusted for sex, age, race/ethnicity, and smoking status. All analyses were conducted in SUDAAN using weights to account for clustering within sampling units and nonresponse.
RESULTS: Fifty-nine adults reported CHD (weighted prevalence = 0.1%; representing 700,000 U.S. adults from 2004 to 2012 or, on average, 80,000 per year) and 54,011 did not. No demographic characteristics differed significantly by CHD status except health insurance; 31.5% of adults with CHD, compared with 11.0% without, reported public insurance (p = 0.01). Compared with their counterparts, adults reporting CHD had a higher prevalence of cognitive (aPR = 2.7, 95% confidence interval (CI): 1.0, 7.2), physical (aPR = 4.0, 95% CI: 1.9, 8.2), and activity limitations (aPR = 4.8, 95% CI: 2.6, 9.1), and poorer physical HRQoL (p = 0.004). No differences were observed in depressive symptoms and mental HRQoL by CHD status.
CONCLUSION: Physical health and cognitive abilities of adults with CHD were compromised compared with adults without CHD. Birth Defects Research (Part A) 106:580-586, 2016. © 2016 Wiley Periodicals, Inc.

PMID: 26991777 [PubMed - indexed for MEDLINE]

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Thromboprophylaxis for atrial arrhythmias in congenital heart disease: A multicenter study.

Int J Cardiol. 2016 Nov 15;223:729-735

Authors: Khairy P, Aboulhosn J, Broberg CS, Cohen S, Cook S, Dore A, Fernandes SM, Fournier A, Kay J, Levesque S, Macle L, Marcotte F, Mondésert B, Mongeon FP, Opotowsky AR, Proietti A, Rivard L, Ting J, Thibault B, Zaidi A, Hamilton R, Anticoagulation Therapy in Congenital Heart Disease (TACTIC) investigators and the Alliance for Adult Research in Congenital Cardiology (AARCC)

BACKGROUND: There is a paucity of data to guide decisions regarding thromboprophylaxis for atrial arrhythmias in congenital heart disease.
METHODS: A retrospective multicenter cohort study enrolled patients with documented sustained atrial arrhythmias and congenital heart disease from 12 North American centers to quantify thromboembolic and bleeding rates associated with antiplatelet and anticoagulation therapy, and explore associated factors. A blinded committee adjudicated all qualifying arrhythmias and outcomes.
RESULTS: A total of 482 patients, 45.2% female, age 32.0±18.0years, were followed for 11.3±9.4years since the qualifying arrhythmia. Antiplatelet therapy was administered to 37.8%, anticoagulation to 54.4%, and neither to 7.9%. Congenital heart disease complexity was simple, moderate, and severe in 18.5%, 34.4%, and 47.1%, respectively. Freedom from thromboembolic events was 84.7±2.7% at 15years, with no difference between anticoagulation versus antiplatelet therapy (P=0.97). Congenital heart disease complexity was independently associated with thromboembolic events, with rates of 0.00%, 0.93%, and 1.95%/year in those with simple, moderate, and severe forms (P<0.001). CHADS2 and CHA2DS2-VASc scores were not predictive of thromboembolic risk. Annualized bleeding rates with antiplatelet and anticoagulation therapy were 0.66% and 1.82% (P=0.039). In multivariable analyses, anticoagulation [hazard ratio (HR) 4.76, 95% CI (1.05-21.58), P=0.043] and HAS-BLED score [HR 3.15, 95% CI (1.02, 9.78), P=0.047] were independently associated with major bleeds.
CONCLUSION: Current management of atrial arrhythmias in congenital heart disease is associated with a modest rate of thromboembolic events, which is predicted by disease complexity but not CHADS2/CHA2DS2-VASc scores. HAS-BLED score is applicable to the congenital population in predicting major bleeds.

PMID: 27573597 [PubMed - indexed for MEDLINE]

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Magnetic resonance imaging 4-D flow-based analysis of aortic hemodynamics in Turner syndrome.

Pediatr Radiol. 2017 Apr;47(4):382-390

Authors: Arnold R, Neu M, Hirtler D, Gimpel C, Markl M, Geiger J

BACKGROUND: Cardiovascular surveillance is important in Turner syndrome because of the increased risk of aortic dilation and dissection with consecutively increased mortality.
OBJECTIVE: To compare 4-D flow MRI for the characterization of aortic 3-D flow patterns, dimensions and vessel wall parameters in pediatric patients with Turner syndrome and age-matched controls.
MATERIALS AND METHODS: We performed 4-D flow MRI measuring in vivo 3-D blood flow with coverage of the thoracic aorta in 25 patients with Turner syndrome and in 16 female healthy controls (age mean ± standard deviation were 16 ± 5 years and 17 ± 4 years, respectively). Blood flow was visualized by time-resolved 3-D path lines. Visual grading of aortic flow in terms of helices and vortices was performed by two independent observers. Quantitative analysis included measurement of aortic diameters, quantification of peak systolic wall shear stress, pulsatility index and oscillatory shear index at eight defined sites.
RESULTS: Patients with Turner syndrome had significantly larger aortic diameters normalized to BSA, increased vortices in the ascending aorta and elevated helix flow in the ascending and descending aorta compared to controls (all P<0.03). Patients with abnormal helical or vortical flow in the ascending aorta had significantly larger diameters of the ascending aorta (P<0.03). Peak systolic wall shear stress, pulsatility index and oscillatory shear index were significantly lower in Turner patients compared to controls (p=0.02, p=0.002 and p=0.01 respectively).
CONCLUSION: Four-dimensional flow MRI provides new insights into the altered aortic hemodynamics and wall shear stress that could have an impact on the development of aortic dissections.

PMID: 28184962 [PubMed - indexed for MEDLINE]

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Specific Etiologies Associated With the Multiple Organ Dysfunction Syndrome in Children: Part 1.

Pediatr Crit Care Med. 2017 Mar;18(3_suppl Suppl 1):S50-S57

Authors: Upperman JS, Lacroix J, Curley MA, Checchia PA, Lee DW, Cooke KR, Tamburro RF

OBJECTIVE: To describe a number of the conditions associated with multiple organ dysfunction syndrome presented as part of the Eunice Kennedy Shriver National Institute of Child Health and Human Development multiple organ dysfunction syndrome workshop (March 26-27, 2015).
DATA SOURCES: Literature review, research data, and expert opinion.
STUDY SELECTION: Not applicable.
DATA EXTRACTION: Moderated by an expert from the field, issues relevant to the association of multiple organ dysfunction syndrome with a variety of conditions were presented, discussed, and debated with a focus on identifying knowledge gaps and research priorities.
DATA SYNTHESIS: Summary of presentations and discussion supported and supplemented by the relevant literature.
CONCLUSIONS: There is a wide range of medical conditions associated with multiple organ dysfunction syndrome in children. Traditionally, sepsis and trauma are the two conditions most commonly associated with multiple organ dysfunction syndrome both in children and adults. However, there are a number of other pathophysiologic processes that may result in multiple organ dysfunction syndrome. In this article, we discuss conditions such as cancer, congenital heart disease, and acute respiratory distress syndrome. In addition, the relationship between multiple organ dysfunction syndrome and clinical therapies such as hematopoietic stem cell transplantation and cardiopulmonary bypass is also considered. The purpose of this article is to describe the association of multiple organ dysfunction syndrome with a variety of conditions in an attempt to identify similarities, differences, and opportunities for therapeutic intervention.

PMID: 28248834 [PubMed - indexed for MEDLINE]

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A Quarter-Century After Primary Direct Arterial Switch Operation: Four-D-Flow MRI Video Imaging of Blood Flow Dynamics Outcomes.

World J Pediatr Congenit Heart Surg. 2017 Sep;8(5):637-638

Authors: Sievers HH, Gabbert D, Rickers C

Four-dimensional (4-D) flow magnetic resonance imaging (MRI) examination was performed 25 years after a neonatal direct arterial switch operation for simple transposition of the great arteries. The 4-D flow MRI video shows physiological spiral anatomical configuration and laminar streamlines in the great arteries.

PMID: 28901233 [PubMed - indexed for MEDLINE]

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Esophageal Varix in an Adult Fontan Survivor.

Intern Med. 2017 Oct 11;:

Authors: Yamagata Y, Kawano H, Shibata H, Maemura K

PMID: 29021468 [PubMed - as supplied by publisher]

Plasma natriuretic peptide levels in fetuses with congenital heart defect and arrhythmia: a single-center prospective study.

Ultrasound Obstet Gynecol. 2017 Oct 11;:

Authors: Miyoshi T, Umekawa T, Hosoda H, Asada T, Fujiwara A, Kurosaki KI, Shiraishi I, Nakai M, Nishimura K, Miyazato M, Kangawa K, Ikeda T, Yoshimatsu J, Minamino N

OBJECTIVES: Diagnosing fetal heart failure remains challenging because it is difficult to know how well the fetal myocardium will perform as loading conditions change. In adult cardiology, natriuretic peptides (NPs) are established marker of heart failure. However, the number of studies investigating NP levels in fetuses is quite limited. The aim of this study was to evaluate the significance of plasma NP levels in the assessment of heart failure in fetuses with congenital heart defect (CHD) and arrhythmia.
METHODS: This was a prospective observational study at a tertiary pediatric cardiac center. A total of 129 singletons with CHD, arrhythmia, or both and 127 controls from 2012 to 2015 were analyzed. Umbilical cord plasma atrial NP, brain NP and N-terminal pro-brain NP levels at birth were compared with ultrasonography findings indicating fetal heart failure such as a cardiovascular profile (CVP) score and morphological characteristics.
RESULTS: Fetuses with CHD, arrhythmia, or both had higher NP levels than controls (P<0.01). NP levels of fetuses with CHD, arrhythmia, or both were inversely correlated with CVP score (P for trend <0.01). No differences were found in NP levels between fetuses with CHD or arrhythmia and a CVP score of ≥8 versus controls. Multivariate analysis showed that a CVP score of ≤5, tachy- or bradyarrhythmia at birth, preterm birth, and umbilical artery pH <7.15 are independently associated with high NP levels (P<0.01). Among fetuses with a CVP score of ≤7, abnormal venous Doppler sonography findings were significantly more common and more severe in fetuses with tachy- or bradyarrhythmia than those with CHDs, and fetuses with tachy- or bradyarrhythmia had higher NP levels than those with CHDs (P=0.01). Fetuses with right heart defect and moderate or severe tricuspid valve regurgitation had significantly higher NP levels than fetuses with other types of CHD (P<0.01).
CONCLUSIONS: Plasma NP levels in fetuses with CHD, arrhythmia, or both are correlated with the severity of fetal heart failure. Elevated NP levels are mainly attributed to increases in central venous pressure secondary to arrhythmia or atrioventricular valve regurgitation due to a CHD, rather than the morphological abnormality itself.

PMID: 29024133 [PubMed - as supplied by publisher]

Establishing a successful transition care plan for the adolescent with congenital heart disease.

Curr Opin Cardiol. 2017 Oct 11;:

Authors: Talluto C

PURPOSE OF REVIEW: In this review we explore the aspects needed to develop a successful transition program for adolescents with congenital heart disease and the barriers that exist to the development of such a program.
RECENT FINDINGS: We review the literature including more recent publications which support the development of a transition program in order to facilitate transfer from the pediatric to the adult healthcare system.
SUMMARY: With the development of a successful transition program patients will hopefully receive high-quality, continuous life-long care in the appropriate setting.

PMID: 29028634 [PubMed - as supplied by publisher]