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Novel Variant in the ANK2 Membrane-Binding Domain Is Associated With Ankyrin-B Syndrome and Structural Heart Disease in a First Nations Population With a High Rate of Long QT Syndrome.

Circ Cardiovasc Genet. 2017 Jan;10(1):

Authors: Swayne LA, Murphy NP, Asuri S, Chen L, Xu X, McIntosh S, Wang C, Lancione PJ, Roberts JD, Kerr C, Sanatani S, Sherwin E, Kline CF, Zhang M, Mohler PJ, Arbour LT

BACKGROUND: Long QT syndrome confers susceptibility to ventricular arrhythmia, predisposing to syncope, seizures, and sudden death. While rare globally, long QT syndrome is ≈15× more common in First Nations of Northern British Columbia largely because of a known mutation in KCNQ1. However, 2 large multigenerational families were affected, but negative for the known mutation.
METHODS AND RESULTS: Long QT syndrome panel testing was carried out in the index case of each family, and clinical information was collected. Cascade genotyping was performed. Biochemical and myocyte-based assays were performed to evaluate the identified gene variant for loss-of-function activity. Index cases in these 2 families harbored a novel ANK2 c.1937C>T variant (p.S646F). An additional 16 carriers were identified, including 2 with structural heart disease: one with cardiomyopathy resulting in sudden death and the other with congenital heart disease. For all carriers of this variant, the average QTc was 475 ms (±40). Although ankyrin-B p.S646F is appropriately folded and expressed in bacteria, the mutant polypeptide displays reduced expression in cultured H9c2 cells and aberrant localization in primary cardiomyocytes. Furthermore, myocytes expressing ankyrin-B p.S646F lack normal membrane targeting of the ankyrin-binding partner, the Na/Ca exchanger. Thus, ankyrin-B p.S646F is a loss-of-function variant.
CONCLUSIONS: We identify the first disease-causing ANK2 variant localized to the membrane-binding domain resulting in reduced ankyrin-B expression and abnormal localization. Further study is warranted on the potential association of this variant with structural heart disease given the role of ANK2 in targeting and stabilization of key structural and signaling molecules in cardiac cells.

PMID: 28196901 [PubMed - indexed for MEDLINE]

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Noonan syndrome, PTPN11 mutations, and brain tumors. A clinical report and review of the literature.

Am J Med Genet A. 2017 Apr;173(4):1061-1065

Authors: Siegfried A, Cances C, Denuelle M, Loukh N, Tauber M, Cavé H, Delisle MB

Noonan syndrome (NS), an autosomal dominant disorder, is characterized by short stature, congenital heart defects, developmental delay, and facial dysmorphism. PTPN11 mutations are the most common cause of NS. PTPN11 encodes a non-receptor protein tyrosine phosphatase, SHP2. Hematopoietic malignancies and solid tumors are associated with NS. Among solid tumors, brain tumors have been described in children and young adults but remain rather rare. We report a 16-year-old boy with PTPN11-related NS who, at the age of 12, was incidentally found to have a left temporal lobe brain tumor and a cystic lesion in the right thalamus. He developed epilepsy 2 years later. The temporal tumor was surgically resected because of increasing crises and worsening radiological signs. Microscopy showed nodules with specific glioneuronal elements or glial nodules, leading to the diagnosis of dysembryoplastic neuroepithelial tumor (DNT). Immunohistochemistry revealed positive nuclear staining with Olig2 and pERK in small cells. SHP2 plays a key role in RAS/MAPK pathway signaling which controls several developmental cell processes and oncogenesis. An amino-acid substitution in the N-terminal SHP2 domain disrupts the self-locking conformation and leads to ERK activation. Glioneuronal tumors including DNTs and pilocytic astrocytomas have been described in NS. This report provides further support for the relation of DNTs with RASopathies and for the implication of RAS/MAPK pathways in sporadic low-grade glial tumors including DNTs. © 2017 Wiley Periodicals, Inc.

PMID: 28328117 [PubMed - indexed for MEDLINE]

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22q11.2 deletion syndrome in diverse populations.

Am J Med Genet A. 2017 Apr;173(4):879-888

Authors: Kruszka P, Addissie YA, McGinn DE, Porras AR, Biggs E, Share M, Crowley TB, Chung BH, Mok GT, Mak CC, Muthukumarasamy P, Thong MK, Sirisena ND, Dissanayake VH, Paththinige CS, Prabodha LB, Mishra R, Shotelersuk V, Ekure EN, Sokunbi OJ, Kalu N, Ferreira CR, Duncan JM, Patil SJ, Jones KL, Kaplan JD, Abdul-Rahman OA, Uwineza A, Mutesa L, Moresco A, Obregon MG, Richieri-Costa A, Gil-da-Silva-Lopes VL, Adeyemo AA, Summar M, Zackai EH, McDonald-McGinn DM, Linguraru MG, Muenke M

22q11.2 deletion syndrome (22q11.2 DS) is the most common microdeletion syndrome and is underdiagnosed in diverse populations. This syndrome has a variable phenotype and affects multiple systems, making early recognition imperative. In this study, individuals from diverse populations with 22q11.2 DS were evaluated clinically and by facial analysis technology. Clinical information from 106 individuals and images from 101 were collected from individuals with 22q11.2 DS from 11 countries; average age was 11.7 and 47% were male. Individuals were grouped into categories of African descent (African), Asian, and Latin American. We found that the phenotype of 22q11.2 DS varied across population groups. Only two findings, congenital heart disease and learning problems, were found in greater than 50% of participants. When comparing the clinical features of 22q11.2 DS in each population, the proportion of individuals within each clinical category was statistically different except for learning problems and ear anomalies (P < 0.05). However, when Africans were removed from analysis, six additional clinical features were found to be independent of ethnicity (P ≥ 0.05). Using facial analysis technology, we compared 156 Caucasians, Africans, Asians, and Latin American individuals with 22q11.2 DS with 156 age and gender matched controls and found that sensitivity and specificity were greater than 96% for all populations. In summary, we present the varied findings from global populations with 22q11.2 DS and demonstrate how facial analysis technology can assist clinicians in making accurate 22q11.2 DS diagnoses. This work will assist in earlier detection and in increasing recognition of 22q11.2 DS throughout the world.

PMID: 28328118 [PubMed - indexed for MEDLINE]

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Interstage Home Monitoring After Newborn First-Stage Palliation for Hypoplastic Left Heart Syndrome: Family Education Strategies.

Crit Care Nurse. 2017 Apr;37(2):72-88

Authors: Nieves JA, Uzark K, Rudd NA, Strawn J, Schmelzer A, Dobrolet N

Children born with hypoplastic left heart syndrome are at high risk for serious morbidity, growth failure, and mortality during the interstage period, which is the time from discharge home after first-stage hypoplastic left heart syndrome palliation until the second-stage surgical intervention. The single-ventricle circulatory physiology is complex, fragile, and potentially unstable. Multicenter initiatives have been successfully implemented to improve outcomes and optimize growth and survival during the interstage period. A crucial focus of care is the comprehensive family training in the use of home surveillance monitoring of oxygen saturation, enteral intake, weight, and the early recognition of "red flag" symptoms indicating potential cardiopulmonary or nutritional decompensation. Beginning with admission to the intensive care unit of the newborn with hypoplastic left heart syndrome, nurses provide critical care and education to prepare the family for interstage home care. This article presents detailed nursing guidelines for educating families on the home care of their medically fragile infant with single-ventricle circulation.

PMID: 28365652 [PubMed - indexed for MEDLINE]

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Tissue-engineered vascular grafts for congenital cardiac disease: Clinical experience and current status.

Trends Cardiovasc Med. 2017 Nov;27(8):521-531

Authors: Drews JD, Miyachi H, Shinoka T

Congenital heart disease is a leading cause of death in the newborn period, and man-made grafts currently used for reconstruction are associated with multiple complications. Tissue engineering can provide an alternative source of vascular tissue in congenital cardiac surgery. Clinical trials have been successful overall, but the most frequent complication is graft stenosis. Recent studies in animal models have indicated the important role of the recipient׳s immune response in neotissue formation, and that modulating the immune response can reduce the incidence of stenosis.

PMID: 28754230 [PubMed - indexed for MEDLINE]

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Internal mammary artery-to-pulmonary vasculature fistula: Systematic review of case reports.

Vasc Med. 2017 Oct;22(5):426-431

Authors: Abdul Jabbar A, Patel A, Marzlin N, Altabaqchali S, Hasan M, Al-Zubaidi M, Agarwal A

The formation of a fistula between the internal mammary artery and the pulmonary vasculature (IMA-to-PV) is a rare anomaly. The etiology can be congenital; however, most recent cases have been associated with coronary artery bypass grafting, trauma, inflammatory conditions, chronic infections, or neoplasia. The knowledge base on the formation of these fistulas is derived primarily from case reports. To our knowledge, no systematic reviews or guidelines are available that provide information on how to manage these cases, and the treatment of an IMA-to-PV fistula is controversial. To our knowledge, this report is the first to review 80 cases of IMA-to-PV fistulas reported in the literature. We describe the etiologies, clinical presentation, and management of these fistulas.

PMID: 28990495 [PubMed - indexed for MEDLINE]

Device closure for patent foramen ovale following cryptogenic stroke: a survey of current practice in the UK.

Open Heart. 2017;4(2):e000636

Authors: Von Klemperer K, Kempny A, Pavitt CW, Janssen JC, Uebing A, Nicol E

Patent foramen ovale (PFO) closure for cryptogenic stroke remains controversial due to a lack of conclusive randomised controlled data. Many experts feel PFO closure is indicated in selected cases; however, national and international guideline recommendations differ. We surveyed the UK cardiologists, stroke physicians and neurologists, seeking to determine specialist interpretation of the evidence base, and to gain an insight into the current UK practice. The British Cardiac Society and British Society of Stroke physicians distributed our survey which was performed using an online platform. 120 physicians (70 stroke physicians, 23 neurologists, 27 cardiologists) completed the survey. Most (89%) felt PFO closure should be considered in selected patients. Atrial fibrillation (86.6%), significant carotid stenosis (86.6%), diabetes (38.4%) and hypertension (36.6%) were considered exclusion criteria for cryptogenic stroke diagnosis. More stroke physicians than cardiologists considered an age cut-off when considering PFO as the stroke aetiology (70.4%vs 54.5%p=0.04). Anatomical features felt to support PFO closure were aneurysmal septum (89.6%), shunt size (73.6%), prominent Eustachian valve (16%). 60% discuss patients in multidisciplinary meetings prior to PFO closure, with more cardiologists than stroke physicians/neurologists favouring this approach (76.9% vs 54.8%; p=0.05). After PFO closure, patients receive Clopidogrel (72.3%), aspirin (50%) or anticoagulants (17%). 63.2% continue therapy for a limited period after PFO closure, while 34% prefer life-long therapy (14.8% cardiologists vs 40.5% non-cardiologists; p=0.02). While experts support selective PFO closure in cryptogenic stroke, current practice remains variable with significant differences in perceptions of cardiologists and neurologists/stroke physicians.

PMID: 29081978 [PubMed]

Related Articles

Healthcare needs of adolescents with congenital heart disease transitioning into adulthood: a Delphi survey of patients, parents, and healthcare providers.

Eur J Cardiovasc Nurs. 2017 Feb;16(2):125-135

Authors: Chen CW, Su WJ, Chiang YT, Shu YM, Moons P

BACKGROUND: The increasing survival of children with congenital heart disease (CHD) challenges healthcare systems regarding how to manage the many health needs of patients undergoing transitional care. A comprehensive understanding of the perspectives of patients, parents, and healthcare providers is required.
OBJECTIVE: This study systematically identified the healthcare needs of adolescents with CHD transitioning into young adults by collecting the perspectives of patients, parents, and healthcare providers.
METHODS: A sample of CHD patients ( n = 29), parents of children with CHD ( n = 29), and healthcare providers ( n = 16) completed the two-round Delphi study, and 64 healthcare needs were identified. The central tendency and the level of dispersion were computed in order to establish a consensus.
RESULTS: A consensus was reached on 25 healthcare needs including health, family, individual, interpersonal interaction, and policy dimensions, which were classified as important with a moderate to high level of agreement by all three groups. The three groups were strongly agreed that "encouraging the patient to learn health self-management" and "cultivating a positive attitude toward the illness" were very important. The opinions of the three groups differed significantly on 12 needs ( p < 0.05) related to health, family, and policy dimensions.
CONCLUSION: A consensus was reached on the needs that were identified as being potentially valid measures of the healthcare needs of adolescents with CHD transitioning into young adults. The identified needs can serve as the basis for establishing a transitional health passport and developing a clinical intervention for adolescents with CHD transitioning into young adults.

PMID: 27045011 [PubMed - indexed for MEDLINE]

Extracorporeal membrane oxygenation in adult congenital heart disease: a case series and literature review.

Crit Care Resusc. 2017 Oct;19(Suppl 1):15-20

Authors: Maybauer MO, Vohra A, O'Keeffe NJ, Prodromou OE, Maher W, Haravi H, Mountney K, Hoschtitzky JA

OBJECTIVE: Extracorporeal membrane oxygenation (ECMO) can be used as rescue intervention for cardiac and/or respiratory failure. High-risk adult patients with adult congenital heart disease (ACHD) may require pre- and post-operative ECMO support.
DESIGN, SETTING AND PARTICIPANTS: Retrospective data collection within a five-year time period from 2011 to 2016, at a single-centre study at a tertiary university hospital and regional unit for ACHD. Patients with ACHD in cardiogenic shock or failure to be separated from cardio-pulmonary bypass (CPB) were included.
RESULTS: Three patients had Ebstein anomaly and one patient had a double-outlet right ventricle transposition type and severe atrioventricular valve insufficiency. Three male patients and one female patient were aged ranging from 19 to 52 years. All received VA ECMO, two each with central or peripheral cannulation. The mean duration of ECMO support was 7 days (range, 3-13 days) and bleeding complications were the main complications observed, with a range of 12 to 104 blood products used. One patient required renal replacement therapy for acute kidney injury and also had leg ischaemia.
MAIN OUTCOME MEASURES: Two of four patients (50%) were successfully weaned off ECMO and survived to hospital discharge in this high-risk group of patients in severe heart failure. The patients are currently at 3 and 4 years follow-up, with improved mobility and exercise tolerance compared with pre-operatively.
CONCLUSION: ECMO is a promising temporary rescue intervention for patients with ACHD and cardiogenic shock. The extracorporeal cardiac support is a useful bridge to recovery.

PMID: 29084497 [PubMed - in process]

Immediate and Midterm Cardiac Remodeling After Surgical Pulmonary Valve Replacement in Adults With Repaired Tetralogy of Fallot: A Prospective Cardiovascular Magnetic Resonance and Clinical Study.

Circulation. 2017 Oct 31;136(18):1703-1713

Authors: Heng EL, Gatzoulis MA, Uebing A, Sethia B, Uemura H, Smith GC, Diller GP, McCarthy KP, Ho SY, Li W, Wright P, Spadotto V, Kilner PJ, Oldershaw P, Pennell DJ, Shore DF, Babu-Narayan SV

BACKGROUND: Pulmonary valve replacement (PVR) in patients with repaired tetralogy of Fallot provides symptomatic benefit and right ventricular (RV) volume reduction. However, data on the rate of ventricular structural and functional adaptation are scarce. We aimed to assess immediate and midterm post-PVR changes and predictors of reverse remoeling.
METHODS: Fifty-seven patients with repaired tetralogy of Fallot (age ≥16 y; mean age, 35.8±10.1 y; 38 male) undergoing PVR were prospectively recruited for cardiovascular magnetic resonance performed before PVR (pPVR), immediately after PVR (median, 6 d), and midterm after PVR (mPVR; median, 3 y).
RESULTS: There were immediate and midterm reductions in indexed RV end-diastolic volumes and RV end-systolic volumes (RVESVi) (indexed RV end-diastolic volume pPVR versus immediately after PVR versus mPVR, 156.1±41.9 versus 104.9±28.4 versus 104.2±34.4 mL/m(2); RVESVi pPVR versus immediately after PVR versus mPVR, 74.9±26.2 versus 57.4±22.7 versus 50.5±21.7 mL/m(2); P<0.01). Normal postoperative diastolic and systolic RV volumes (the primary end point) achieved in 70% of patients were predicted by a preoperative indexed RV end-diastolic volume ≤158 mL/m(2) and RVESVi ≤82 mL/m(2). RVESVi showed a progressive decrease from baseline to immediate to midterm follow-up, indicating ongoing intrinsic RV functional improvement after PVR. Left ventricular ejection fraction improved (pPVR versus mPVR, 59.4±7.6% versus 61.9±6.8%; P<0.01), and right atrial reverse remodeling occurred (pPVR versus mPVR, 15.2±3.4 versus 13.8±3.6 cm(2)/m(2); P<0.01). Larger preoperative RV outflow tract scar was associated with a smaller improvement in post-PVR RV/left ventricular ejection fraction. RV ejection fraction and peak oxygen uptake predicted mortality (P=0.03) over a median of 9.5 years of follow-up.
CONCLUSIONS: Significant right heart structural reverse remodeling takes place immediately after PVR, followed by a continuing process of further biological remodeling manifested by further reduction in RVESVi. PVR before RVESVi reaches 82 mL/m(2) confers optimal chances of normalization of RV function.

PMID: 29084778 [PubMed - in process]