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Identification of candidate genes for congenital heart defects on proximal chromosome 8p.

Sci Rep. 2016 11 03;6:36133

Authors: Li T, Liu C, Xu Y, Guo Q, Chen S, Sun K, Xu R

Abstract
With the application of advanced molecular cytogenetic techniques, the number of patients identified as having abnormal chromosome 8p has increased progressively. Individuals with terminal 8p deletion have been extensively described in previous studies. The manifestations usually include cardiac anomalies, developmental delay/mental retardation, craniofacial abnormalities, and multiple other minor anomalies. However, some patients with proximal deletion also presented with similar phenotypic features. Here we describe a female child with an 18.5-Mb deletion at 8p11.23-p22 that include the cardiac-associated loci NKX2-6 and NRG1. Further mutation screening of these two candidate genes in 143 atrial septal defect patients, two heterozygous mutations NKX2-6 (c.1A > T) and NRG1 (c.1652G > A) were identified. The mutations were described for the first time in patients with congenital heart disease (CHD). The c.1A > T NKX2-6 generated a protein truncated by 45 amino acids with a decreased level of mRNA expression, whereas the NRG1 mutation had no significant effect on protein functions. Our findings suggest that 8p21-8p12 may be another critical region for 8p-associated CHD, and some cardiac malformations might be due to NKX2-6 haploinsufficiency. This study also links the NKX2-6 mutation to ASD for the first time, providing novel insight into the molecular underpinning of this common form of CHD.

PMID: 27808268 [PubMed - indexed for MEDLINE]

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Significance of right atrial tension for the development of complications in patients after atriopulmonary connection Fontan procedure: potential indicator for Fontan conversion.

Heart Vessels. 2017 Jul;32(7):850-855

Authors: Izumi G, Senzaki H, Takeda A, Yamazawa H, Takei K, Furukawa T, Inai K, Shinohara T, Nakanishi T

Abstract
Elevated right atrial (RA) pressure and progressive RA dilation are thought to play pivotal roles in the development of late complications after atriopulmonary connection (APC) Fontan surgery. However, no clear cut-off value for RA pressure or RA volume has been determined for stratifying the risk of developing Fontan complications. We hypothesized that RA tension, which incorporates information about both RA pressure and volume, might help predict the risk of developing complications. We retrospectively studied 51 consecutive APC Fontan patients (median postoperative period 14 years). RA tension was computed from the RA pressure and RA radius, which was calculated from RA volume measured by RA angiography. The correlation between the cardiac catheterization hemodynamic data and the complications of APC Fontan was investigated. Of the 51 patients, 28 had complications, including liver fibrosis (n = 28), arrhythmia (n = 8), protein-losing enteropathy (n = 1), and RA thrombosis (n = 1). Among the hemodynamic data, RA volume and RA tension, but not RA pressure, were significantly higher in patients with complications than in those without (P = 0.004 and P = 0.001, respectively). The cut-off level for RA tension to predict Fontan complications was 26,131 dyne/cm by receiver operating characteristic curve (area under the curve 0.79, sensitivity 71.4%, and specificity 73.9%). The present study demonstrated the significance of RA tension rather than high venous pressure for the development of Fontan complications. Amid the uncertainty about clinical outcomes, the present results, subject to further validation, may contribute to the indications for Fontan conversion.

PMID: 28064364 [PubMed - indexed for MEDLINE]

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Real-world, long-term survival of incident patients with pulmonary arterial hypertension.

Rev Port Pneumol (2006). 2017 May - Jun;23(3):124-131

Authors: Marques-Alves P, Baptista R, Marinho da Silva A, Pêgo M, Castro G

Abstract
BACKGROUND: Pulmonary arterial hypertension (PAH) is a progressive, fatal disease. Long-term outcomes data are scarce in Portugal. We aimed to estimate survival of newly diagnosed PAH at a Portuguese referral center in the modern management era.
METHODS: Between January 2009 and November 2015 all incident PAH cases were consecutively enrolled in a prospective cohort study. Sixty-five patients were followed up for a median of 3.1 [interquartile range 1.7-5.4] years. Kaplan-Meier survival analysis was used to estimate 1-, 3-, and 5-year survival and to compare it with a historical PAH survival estimated from the NIH cohort.
RESULTS: Mean age was 48±19 years with female preponderance (68%). The most common PAH subgroup was congenital heart disease (PAH-CHD) (n=31; 48%), followed by connective tissue disease (PAH-CTD) (n=16; 25%), idiopathic (IPAH) (n=8; 12%) and hereditary (HPAP) (n=1; 1.5%). BNP values (hazard ratio [HR] 2.07; 95%CI 1.34-3.22; P=0.001) and male gender [HR 4.34 (1.44-13.09); P=0.009] were predictors of death. Survival rates at 1-, 3- and 5-years were 95%, 77% and 71%. Survival was not statistically different between PAH etiologies (Log-rank P=0.7). However, PAH-CHD was associated with a decreased risk of the combined endpoint of all-cause mortality and admission for decompensated heart failure [HR 0.36 (0.15-0.85); P=0.02]. We found a non-significant numerically higher survival of incident IPAH, HPAH and DPAH patients in comparison with the historical NIH cohort.
CONCLUSIONS: In this cohort of incident PAH patients, PAH-CHD patients had better overall prognosis. Higher BNP values and male gender were associated with higher mortality.

PMID: 28283462 [PubMed - indexed for MEDLINE]

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Evaluating the Performance of Ultrasound Screening for Congenital Heart Disease: A Descriptive Cohort Study.

Am J Perinatol. 2017 Jul;34(9):905-910

Authors: Froehlich RJ, Maggio L, Has P, Werner EF, Rouse DJ

Abstract
Objective The objective of this study was to evaluate the rate of abnormal fetal echocardiogram after normal detailed anatomy ultrasound when both are performed by maternal-fetal medicine specialists. Study Design Retrospective review of women who underwent detailed anatomy ultrasound and fetal echocardiography between 16 and 26 weeks' gestation at a single center. Women included had at least one indication for fetal echocardiography as recommended by the American Institute of Ultrasound in Medicine and normal cardiac anatomy on initial detailed anatomy ultrasound. Women with previous abnormal ultrasound, extracardiac anomalies, and abnormal or incomplete cardiac anatomy on initial examinations were excluded. The primary outcome was abnormal fetal echocardiogram, defined as a structural cardiac anomaly. Results A total of 1,000 women (1,052 fetuses) were included. The most common indication for echocardiography was family history of congenital heart disease. Five fetuses had an abnormal echocardiogram (0.5%, 95% confidence interval: 0.2-1.1%), only one of which altered care. The other four were suspected ventricular septal defects; of these, three were not seen on postnatal cardiac imaging. Conclusion The rate of abnormal fetal echocardiogram after a normal detailed anatomy ultrasound interpreted by maternal-fetal medicine specialists is low. Fetal echocardiography as a second screening test is of low clinical utility and unlikely to be cost-effective in this setting.

PMID: 28301892 [PubMed - indexed for MEDLINE]

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Pregnancy-Related Spontaneous Coronary Artery Dissection: A Case Series and Literature Review.

J Emerg Med. 2017 Jun;52(6):867-874

Authors: Rose E, Gedela M, Miller N, Carpenter PL

Abstract
BACKGROUND: Cardiac emergencies during pregnancy are rare but have significant associated morbidity and mortality when they do occur. The emergency physician must not only be aware of potentially life-threatening conditions in the pregnant woman, but also know the emergent management and treatment of these conditions to avoid worsening of the underlying condition. Pregnancy-related spontaneous coronary artery dissection has been described in the cardiology literature, but is not well-known in emergency medicine literature.
CASE SERIES: We present a case series of six previously healthy women ages 27 to 39 years who presented 1 to 75 days after delivery with spontaneous coronary artery dissection. The left main coronary was involved in 5 of 6 cases. One patient died, 5 survived. Two survivors maintained significant long-term disability. The patient that died had the diagnosis made on autopsy, the others were diagnosed with coronary angiography. Two patients were treated with stents, 2 with coronary artery bypass surgery, and 2 with medical management. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergent coronary catheterization is indicated if this diagnosis is suspected. However, emergency care teams must also understand how and why management including coronary artery catheterization can exacerbate the underlying condition. The role of coronary artery computed tomography remains unknown, although it exposes the fetus to significant radiation if the woman is still pregnant at presentation. Medical management is indicated with diffuse or distal disease as pregnancy-related coronary artery dissections often resolve with time. Localized discrete lesions may be stented. Coronary artery bypass graft surgery may be considered if the left main artery is involved or there are multiple proximal lesions. Cardiac transplantation is indicated rarely.

PMID: 28396082 [PubMed - indexed for MEDLINE]

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MESP1 loss‑of‑function mutation contributes to double outlet right ventricle.

Mol Med Rep. 2017 Sep;16(3):2747-2754

Authors: Zhang M, Li FX, Liu XY, Huang RT, Xue S, Yang XX, Li YJ, Liu H, Shi HY, Pan X, Qiu XB, Yang YQ

Abstract
Congenital heart disease (CHD) is the most common form of birth defect in humans, and remains a leading non‑infectious cause of infant mortality worldwide. An increasing number of studies have demonstrated that genetic defects serve a pivotal role in the pathogenesis of CHD, and mutations in >60 genes have been causally associated with CHD. CHD is a heterogeneous disease and the genetic basis of CHD in the majority of patients remains poorly understood. In the present study, the coding exons and flanking introns of the mesoderm posterior 1 (MESP1) gene, which encodes a basic helix‑loop‑helix transcription factor required for normal cardiovascular development, were sequenced in 178 unrelated patients with CHD. The available relatives of the index patient carrying an identified mutation and 200 unrelated, ethnically‑matched healthy individuals, who were used as controls, were genotyped for MESP1. The functional characteristics of the MESP1 mutation were determined using a dual‑luciferase reporter assay system. As a result, a novel de novo heterozygous MESP1 mutation, p.Q118X, was identified in an index patient with double outlet right ventricle (DORV) and a ventricular septal defect. The nonsense mutation was absent in the 400 reference chromosomes and the altered amino acid was completely conserved evolutionarily across species. Functional assays indicated that the mutant MESP1 protein had no transcriptional activity when compared with its wild‑type counterpart. The present study firstly provided experimental evidence supporting the concept that a MESP1 loss‑of‑function mutation may contribute to the development of DORV in humans, which presents a significant insight into the molecular pathogenesis of CHD. The results highlight the potential implications for the genetic counseling and personalized treatment of patients with CHD.

PMID: 28677747 [PubMed - indexed for MEDLINE]

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Does Pharmacological Therapy Still Play a Role in Preventing Sudden Death in Surgically Treated Tetralogy of Fallot?

Mini Rev Med Chem. 2018;18(6):490-494

Authors: Gabriele B, Maurizio B, Marco B

Abstract
Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease, with a familial recurrence risk of 3%. Despite performing an optimal surgical repair, TOF patients may feature a poor medium and long-term survival rate: atrial re-entrant tachycardia will develop in more than 30% of patients and high-grade ventricular arrhythmias will be seen in about 10% of patients. These life-threatening arrhythmias and consequent sudden death continue to represent serious complications following TOF repair. Radiofrequency ablation and implantable cardioverter defibrillator are today the most effective therapeutic tools in these subjects, while the administration of antiarrhythmic drugs (Ib agents, beta blockers, and amiodarone), widely prescribed in the past, is now limited to few conditions. However pharmacological therapy still plays a role in the management of those patients who are resistant to the above stated invasive electrophysiological treatments.

PMID: 28685697 [PubMed - indexed for MEDLINE]

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Survival, by Birth Weight and Gestational Age, in Individuals With Congenital Heart Disease: A Population-Based Study.

J Am Heart Assoc. 2017 Jul 21;6(7):

Authors: Best KE, Tennant PWG, Rankin J

Abstract
BACKGROUND: Congenital heart disease (CHD) survival estimates are important to understand prognosis and evaluate health and social care needs. Few studies have reported CHD survival estimates according to maternal and fetal characteristics. This study aimed to identify predictors of CHD survival and report conditional survival estimates.
METHODS AND RESULTS: Cases of CHD (n=5070) born during 1985-2003 and notified to the Northern Congenital Abnormality Survey (NorCAS) were matched to national mortality information in 2008. Royston-Parmar regression was performed to identify predictors of survival. Five-year survival estimates conditional on gestational age at delivery, birth weight, and year of birth were produced for isolated CHD (ie, CHD without extracardiac anomalies). Year of birth, gestational age, birth weight, and extracardiac anomalies were independently associated with mortality (all P≤0.001). Five-year survival for children born at term (37-41 weeks) in 2003 with average birth weight (within 1 SD of the mean) was 96.3% (95% CI, 95.6-97.0). Survival was most optimistic for high-birth-weight children (>1 SD from the mean) born post-term (≥42 weeks; 97.9%; 95% CI, 96.8-99.1%) and least optimistic for very preterm (<32 weeks) low-birth-weight (<1 SD from mean) children (78.8%; 95% CI, 72.8-99.1).
CONCLUSIONS: Five-year CHD survival is highly influenced by gestational age and birth weight. For prenatal counseling, conditional survival estimates provide best- and worst-case scenarios, depending on final gestational age and birth weight. For postnatal diagnoses, they can provide parents with more-accurate predictions based on their baby's birth weight and gestational age.

PMID: 28733436 [PubMed - indexed for MEDLINE]

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Percutaneous valve in valve in the tricuspid position in a patient with Tetralogy of Fallot.

BMJ Case Rep. 2017 Aug 02;2017:

Authors: Challa A, Markham R, Walters D

Abstract
Here, we describe a case of a successful percutaneous insertion of a transcatheter 29 mm Edwards Sapien XT valve into a tricuspid valve in a patient with repaired tetralogy of fallot.Similar procedures have been performed with the Edwards Sapien valve and Melody valves; however, this is the first case described in the literature of an Edwards Sapien valve used in a patient with Tetralogy of Fallot.With procedural safety being demonstrated, this case illustrates an important alternative treatment option for patients with congenital heart disease. Although long-term data is required to compare its efficacy with surgically replaced valves, percutaneous procedures can serve as a delay to surgical valve replacement which over a patients' lifetime with congenital heart disease, can minimise the amount of invasive surgeries and potential complications.

PMID: 28768675 [PubMed - indexed for MEDLINE]

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Administrative health databases for addressing emerging issues in adults with CHD: a systematic review.

Cardiol Young. 2018 Apr 29;:1-11

Authors: Cohen S, Gilutz H, Marelli AJ, Iserin L, Benis A, Bonnet D, Burgun A

Abstract
The need for population-based studies of adults with CHD has motivated the growing use of secondary analyses of administrative health data in a variety of jurisdictions worldwide. We aimed at systematically reviewing all studies using administrative health data sources for adult CHD research from 2006 to 2016. Using PubMed and Embase (1 January, 2006 to 1 January, 2016), we identified 2217 abstracts, from which 59 studies were included in this review. These comprised 12 different data sources from six countries. Of these, 55% originated in the United States of America, 28% in Canada, and 17% in Europe and Asia. No study was published before 2007, after which the number of publications grew exponentially. In all, 41% of the studies were cross-sectional and 25% were retrospective cohort studies with a wide variation in the availability of patient-level compared with hospitalisation-level episodes of care; 58% of studies from eight different data sources linked administrative data at a patient level; and 37% of studies reported validation procedures. Assessing resource utilisation and temporal trends of relevant epidemiological and outcome end points were the most reported objectives. The median impact factor of publication journals was 4.04, with an interquartile range of 3.15, 7.44. Although not designed for research purposes, administrative health databases have become powerful data sources for studying adult CHD populations because of their large sample sizes, comprehensive records, and long observation periods, providing a useful tool to further develop quality of care improvement programmes. Data linkage with electronic records will become important in obtaining more granular life-long adult CHD data. The health services nature of the data optimises the impact on policy and public health.

PMID: 29704902 [PubMed - as supplied by publisher]

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