Browsing by Subject "congenital heart defects"
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Item Copy number variation as a genetic basis for heterotaxy and heterotaxy-spectrum congenital heart defects(Royal Society, 2016-12-19) Cowan, Jason R.; Tariq, Muhammad; Shaw, Chad; Rao, Mitchell; Belmont, John W.; Lalani, Seema R.; Smolarek, Teresa A.; Ware, Stephanie M.; Pediatrics, School of MedicineGenomic disorders and rare copy number abnormalities are identified in 15–25% of patients with syndromic conditions, but their prevalence in individuals with isolated birth defects is less clear. A spectrum of congenital heart defects (CHDs) is seen in heterotaxy, a highly heritable and genetically heterogeneous multiple congenital anomaly syndrome resulting from failure to properly establish left–right (L-R) organ asymmetry during early embryonic development. To identify novel genetic causes of heterotaxy, we analysed copy number variants (CNVs) in 225 patients with heterotaxy and heterotaxy-spectrum CHDs using array-based genotyping methods. Clinically relevant CNVs were identified in approximately 20% of patients and encompassed both known and putative heterotaxy genes. Patients were carefully phenotyped, revealing a significant association of abdominal situs inversus with pathogenic or likely pathogenic CNVs, while d-transposition of the great arteries was more frequently associated with common CNVs. Identified cytogenetic abnormalities ranged from large unbalanced translocations to smaller, kilobase-scale CNVs, including a rare, single exon deletion in ZIC3, a gene known to cause X-linked heterotaxy. Morpholino loss-of-function experiments in Xenopus support a role for one of these novel candidates, the platelet isoform of phosphofructokinase-1 (PFKP) in heterotaxy. Collectively, our results confirm a high CNV yield for array-based testing in patients with heterotaxy, and support use of CNV analysis for identification of novel biological processes relevant to human laterality., This article is part of the themed issue ‘Provocative questions in left–right asymmetry’.Item Dishevelled-associated activator of morphogenesis 1 (Daam1) is required for heart morphogenesis(2011-01) Li, Deqiang; Hallett, Mark A.; Zhu, Wuqiang; Rubart, Michael; Liu, Ying; Yang, Zhenyun; Chen, Hanying; Haneline, Laura S.; Chan, Rebecca J.; Schwartz, Robert J.; Field, Loren J.; Atkinson, Simon J.; Shou, WeinianDishevelled-associated activator of morphogenesis 1 (Daam1), a member of the formin protein family, plays an important role in regulating the actin cytoskeleton via mediation of linear actin assembly. Previous functional studies of Daam1 in lower species suggest its essential role in Drosophila trachea formation and Xenopus gastrulation. However, its in vivo physiological function in mammalian systems is largely unknown. We have generated Daam1-deficient mice via gene-trap technology and found that Daam1 is highly expressed in developing murine organs, including the heart. Daam1-deficient mice exhibit embryonic and neonatal lethality and suffer multiple cardiac defects, including ventricular noncompaction, double outlet right ventricles and ventricular septal defects. In vivo genetic rescue experiments further confirm that the lethality of Daam1-deficient mice results from the inherent cardiac abnormalities. In-depth analyses have revealed that Daam1 is important for regulating filamentous actin assembly and organization, and consequently for cytoskeletal function in cardiomyocytes, which contributes to proper heart morphogenesis. Daam1 is also found to be important for proper cytoskeletal architecture and functionalities in embryonic fibroblasts. Biochemical analyses indicate that Daam1 does not regulate cytoskeletal organization through RhoA, Rac1 or Cdc42. Our study highlights a crucial role for Daam1 in regulating the actin cytoskeleton and tissue morphogenesis.Item Extubation Failure after Neonatal Cardiac Surgery: A Multicenter Analysis(Elsevier, 2017-03) Mastropietro, Christopher W.; Cashen, Katherine; Grimaldi, Lisa M.; Narayana Gowda, Keshava Murty; Piggott, Kurt D.; Wilhelm, Michael; Gradidge, Eleanor; Moser, Elizabeth A. S.; Benneyworth, Brian D.; Costello, John M.; Department of Medicine, School of MedicineObjectives To describe the epidemiology of extubation failure and identify risk factors for its occurrence in a multicenter population of neonates undergoing surgery for congenital heart disease. Study design We conducted a prospective observational study of neonates ≤30 days of age who underwent cardiac surgery at 7 centers within the US in 2015. Extubation failure was defined as reintubation within 72 hours of the first planned extubation. Risk factors were identified with the use of multivariable logistic regression analysis and reported as OR with 95% CIs. Multivariable logistic regression analysis was conducted to examine the relationship between extubation failure and worse clinical outcome, defined as hospital length of stay in the upper 25% or operative mortality. Results We enrolled 283 neonates, of whom 35 (12%) failed their first extubation at a median time of 7.5 hours (range 1-70 hours). In a multivariable model, use of uncuffed endotracheal tubes (OR 4.6; 95% CI 1.8-11.6) and open sternotomy of 4 days or more (OR 4.8; 95% CI 1.3-17.1) were associated independently with extubation failure. Accordingly, extubation failure was determined to be an independent risk factor for worse clinical outcome (OR 5.1; 95% CI 2-13). Conclusions In this multicenter cohort of neonates who underwent surgery for congenital heart disease, extubation failure occurred in 12% of cases and was associated independently with worse clinical outcome. Use of uncuffed endotracheal tubes and prolonged open sternotomy were identified as independent and potentially modifiable risk factors for the occurrence of this precarious complication.Item Genetics and Genetic Testing in Congenital Heart Disease(Elsevier, 2015-06) Cowan, Jason R.; Ware, Stephanie M.; Department of Pediatrics, IU School of MedicineCongenital heart defects (CHDs) are structural abnormalities of the heart and great vessels that are present from birth. The presence or absence of extra-cardiac anomalies has historically been used to identify patients with possible monogenic, chromosomal, or teratogenic CHD etiologies. These distinctions remain clinically relevant, particularly with regard to management; however, identification of genetic causes in patients with presumably non-syndromic CHD indicates that isolated CHD can also be genetic in origin. In recent years, the field of cardiac genetics has benefited from a growing understanding of the complex molecular mechanisms underpinning heart development, and the extreme genetic heterogeneity of CHD is increasingly appreciated. Progress has been largely supported by improvements in genetic testing technology derived from worldwide efforts to accurately and economically characterize the full breadth of human genomic variation. The last fifteen years in particular have witnessed emergence and refinement of novel cytogenetic and sequencing technologies, which have proven to be enormously effective tools for both diagnosis and identification of novel CHD-causing genes. These advancements have led to an increasing need for cardiac care providers to be well versed in the molecular genetic origins of CHD and to have working knowledge of the benefits and limitations of available testing methods. In this review, we provide a general overview of key morphologic, molecular, and signaling mechanisms relevant to heart development before summarizing overall progress in the molecular genetic analyses of CHDs and current recommendations for clinical application of genetic testing. Particular emphasis is placed on the utility and limitations of chromosomal microarray analyses (CMAs) and on emerging clinical roles for whole exome sequencing (WES) and other next-generation sequencing (NGS) technologies.Item Persistent left superior vena cava: an overlooked feature of CHARGE syndrome?(PAGEpress, 2015-12-19) Goldenberg, Paula; Shikany, Amy; Parrott, Ashley; Ware, Stephanie M.; Hinton, Robert B.; Medical and Molecular Genetics, School of MedicineCHARGE is a well-characterized syndrome (OMIM 2148400) associated with multiple congenital anomalies including cardiovascular malformations. Mutations in CHD7 are the most common cause of CHARGE syndrome. Persistent left superior vena cava (LSVC) has been described in patients with CHARGE syndrome in one study of LSVC associations. A retrospective chart review was conducted for all patients with CHARGE syndrome, diagnosed by Blake criterion features and/or the presence of a pathogenic CHD7 mutation. Echocardio - grams were performed on a clinical basis for all patients and were systematically reviewed and classified. Persistent LSVC was present in 50% of patients with CHARGE syndrome (4/8) and was seen in 3 out of 33 patients seen by cardiovascular genetics with 22q11.2 deletion syndrome. Persistent LSVC is a common finding in patients with CHARGE syndrome and its presence may increase the index of suspicion in patients with other characteristic congenital anomalies.Item Prevalence and Risk Factors for Upper Airway Obstruction after Pediatric Cardiac Surgery(Elsevier, 2015-02) Green, Jack; Walters, Henry L. III; Delius, Ralph E.; Sarnaik, Ajit; Mastropietro, Christopher W.; Department of Pediatrics, Indiana University School of MedicineObjective To determine the prevalence of and risk factors for extrathoracic upper-airway obstruction after pediatric cardiac surgery. Study design A retrospective chart review was performed on 213 patients younger than 18 years of age who recovered from cardiac surgery in our multidisciplinary intensive care unit in 2012. Clinically significant upper-airway obstruction was defined as postextubation stridor with at least one of the following: receiving more than 2 corticosteroid doses, receiving helium-oxygen therapy, or reintubation. Multivariate logistic regression analysis was performed to determine independent risk factors for this complication. Results Thirty-five patients (16%) with extrathoracic upper-airway obstruction were identified. On bivariate analysis, patients with upper-airway obstruction had greater surgical complexity, greater vasoactive medication requirements, and longer postoperative durations of endotracheal intubation. They also were more difficult to calm while on mechanical ventilation, as indicated by greater infusion doses of narcotics and greater likelihood to receive dexmedetomidine or vecuronium. On multivariable analysis, adjunctive use of dexmedetomedine or vecuronium (OR 3.4, 95% CI 1.4-8) remained independently associated with upper-airway obstruction. Conclusion Extrathoracic upper-airway obstruction is relatively common after pediatric cardiac surgery, especially in children who are difficult to calm during endotracheal intubation. Postoperative upper-airway obstruction could be an important outcome measure in future studies of sedation practices in this patient population.Item Use of a novel vasoactive-ventilation-renal score to predict outcomes after paediatric cardiac surgery(Oxford, 2014-12) Miletic, Kyle G.; Spiering, Tyler J.; Delius, Ralph E.; Walters, Henry L. III; Mastropietro, Christopher W.; Department of Pediatrics, Indiana University School of MedicineOBJECTIVES Prior studies have established peak postoperative lactate and the vasoactive-inotrope score (VIS) as modest predictors of outcome following paediatric cardiac surgery. We developed a novel vasoactive-ventilation-renal (VVR) score and aimed to determine if this index, which incorporates postoperative respiratory, cardiovascular and renal function, would more consistently predict outcome in this patient population. METHODS We performed an Institutional Review Board-approved retrospective analysis of 222 infants at our institution less than 365 days old who underwent surgery for congenital heart disease at our centre from January 2009 to April 2013. The VVR score was calculated as follows: vasoactive-inotrope score + ventilation index + (change in serum creatinine from baseline × 10). For all patients, peak lactate and admission, peak, and 48 h VIS and VVR were recorded. RESULTS For all outcome measures, areas under the curve for 48-h VVR were greater than its corresponding admission and peak values, VIS alone at all three time points and peak lactate. On multivariate regression, 48-h VVR was strongly associated with prolonged intubation [odds ratio (OR): 39.13, P <0.0001], significantly more so than 48-h VIS (odds ratio: 6.18, P <0.0001) and peak lactate (odds ratio: 2.52, P = 0.017). The 48-h VVR was also more significantly associated with prolonged use of vasoactive infusions, chest tube drainage and ICU and hospital stay when compared with VIS alone and peak lactate. CONCLUSIONS The novel 48-h VVR was a robust predictor of outcome following paediatric cardiac surgery and outperformed the VIS and peak postoperative lactate.