Complex Heart Disease Research Articles

Risk Factors for Cardiac Adverse Events in Infants and Children with Complex Heart Disease Scheduled for Bi-ventricular Repair: Prognostic Value of Pre-operative B-Type Natriuretic Peptide and High-Sensitivity Troponin T.

Few reports have described the prognostic value of measuring both B-type natriuretic peptides (BNP) and high-sensitivity troponin T (hs-TnT) in pediatric patients with complex congenital heart disease (CHD) undergoing surgery. We assessed demographic, hemodynamic, and laboratory data, including BNP and hs-TnT levels, for the prediction of cardiac adverse events in 85 patients. Cardiac adverse events were defined as death, cardiac arrest, worsening heart failure requiring inotropic agents and/or respiratory support, and unscheduled surgery/intervention either within or after 12months of surgery. There were 17 cardiac adverse events. Of the demographic variables, low birth weight (< 2500g: Odds ratio [OR], 5.97; 95% confidential interval [CI] 1.48-24.0; p = 0.001) and Ross/New York Heart Association [NYHA] class (≥ 2.0) (OR 12.7; 95% CI 3.08-52.7; p = 0.0004) were strongly association with cardiac adverse events. Among hemodynamic and laboratory variables, preoperative BNP (OR 14.04; 95% CI 2.15-91.7; p = 0.001) and hs-TnT levels (OR 16.66; 95% CI 2.27-122; p = 0.002) were found to be independent risk factors. Receiver operating characteristic analysis determined BNP and hs-TnT levels of 60.9pg/mL and 0.025ng/mL, respectively, to be markers of high risk. Kaplan-Meier analysis demonstrated significant differences in the freedom from cardiac adverse events between Group A (BNP or hs-TnT elevated, n = 26) and Group B (both biomarkers elevated, n = 19; log-rank, p < 0.001). In conclusion, low birth weight (< 2500g) and Ross/NYHA class ≥ 2.0 are strongly associated with cardiac adverse events. Preoperative BNP and hs-TnT also provide prognostic information in patients with complex CHD scheduled for surgery. Using both markers in combination predicts cardiac adverse events better than using either separately.

Conjoined twins with a single heart with complex disease

Conjoined twins are a rare presentation with an estimated incidence of 1: 50000 pregnancies. They occur due to a random event, not related to heredity, maternal age or delivery conditions. This article is a case-report of a pair of female thoraco-omphalopagus conjoined twins, who were diagnosed during prenatal period through a morphological ultrasound. After a 24-week gestation period, the female newborns had a total weight of 1100g, and were born of a cesarean section. Both fetuses scored 3 in the Apgar scale in the first minute, getting down to a score of 1 in the fifth minute. Soon after birth, the newborns were referred to the Intensive Care Unit, where supportive measures were taken and transthoracic Doppler echocardiography was performed for diagnostic confirmation. The echocardiogram showed that there was only one heart for both newborns with a complex heart disease. In 75% of the cases of thoraco-omphalopagus conjoined twins, structural heart disfigurements are found in at least one of the fetuses. Besides, in approximately 80-90% of the cases, the cardiac abnormalities in the heart junction are far too complex, making it impossible to surgically separate the fetuses. This way, a structural and functional analysis of the heart is considerably more efficient post-birth, and it’s shown to be more accurately done through an echocardiography. This reveals that cardiac changes are a crucial factor in the fetal and postnatal evaluations of conjoined twins. Such procedures are a way of providing adequate medical recommendations, which may always be honest and based on scientific evidence.Descriptors: Diseases in Twins; Twins, Conjoined; Heart Diseases.ReferencesMcMahon CJ, Spencer R. Congenital heart defects in conjoined twins: outcome after surgical separation of thoracopagus. Pediatr Cardiol. 2006;27(1):1-12Rode H, Fieggen AG, Brown RA, Cywes S, Davies MRQ, Hewitson JP et al. Four decades of conjoined twins at Red Cross Children's Hospital--lessons learned. S Afr Med J. 2006; 96(9Pt2):931-40.Barth RA, Filly RA, Goldberg JD, Moore P, Silverman NH. Conjoined twins: prenatal diagnosis and assessment of associated malformations [published correction appears in Radiology 1991 Jan;178(1):287]. Radiology. 1990;177(1):201-7.Spencer R. Anatomic description of conjoined twins: a plea for standardized terminology. J Pediatr Surg. 1996;31(7):941-944.Andrews RE, Yates RW, Sullivan ID. The management of conjoined twins: Cardiology assessment. Semin Pediatr Surg. 2015;24(5):217-20.Andrews RE, McMahon CJ, Yates RW, et al. Echocardiographic assessment of conjoined twins. Heart. 2006;92(3):382-87.Lopes LM, Brizot ML, Schultz R, Liao AW, Krebs VLJ, Francisco RPV et al. Twenty-five years of fetal echocardiography in conjoined twins: lessons learned. J Am Soc Echocardiogr. 2013;26(5):530-538.Brooks R. Ian McEwan attacks church over right to die. Sunday may 18 2014. The Sunday Times https://www.thetimes.co.uk/article/mcewan-attacks-church-over-right-to-die-gq8nwtbhqjb.Sih DA, Bimerew M, Modeste RRM. Coping strategies of mothers with preterm babies admitted in a public hospital in Cape Town. Curationis. 2019;42(1):e1-8.Albuquerque S, Pereira M, Fonseca A, Canavarro MC. Impacto familiar e ajustamento de pais de crianças com diagnóstico de anomalia congênita: influência dos determinantes da criança. Rev psiquiatr clín. 2012;39(4):136-41.Pereira PK, Lima LA, Legay LF, Santos JFC, Lovisi GM. Congenital malformation of the baby and risk of maternal mental disorders during the pregnancy-puerperal period: a systematic review. Cad Saúde Colet (Rio de Janeiro). 2011;19(1):2-10.

Holt–Oram Syndrome Associated with Complex Congenital Heart Disease: A Rare Case Presentation and Literature Review

BACKGROUND: First described by Holt and Oram in 1960 in a four-generation family with atrial septal defects and thumb abnormalities, is an inherited disorder characterized by abnormalities of the upper limbs and heart. This syndrome is characterized by upper extremity malformations involving radial, thenar, or carpal bones. An abnormal carpal bone is present in all affected individuals and may be the only evidence of disease. About 75% of individuals with Holt–Oram syndrome (HOS) have a congenital heart malformation which may include an atrial or ventricular septal defect or heart block. In rare cases, the syndrome can affect other organs and systems which can be life threatening.&#x0D; CASE REPORT: Here, we present a newborn with clinical and radiologic features of HOS consisting of bilateral asymmetric hypoplastic thumbs, generalized brachydactyly, limited bilateral supination due to radioulnar synostosis, and associated with complex heart disease and hypoplastic tricuspid valve.&#x0D; CONCLUSION: In our case HOS is associated with complex congenital heart defects including atrial septal defect, ventricular septal defect with hypoplastic tricuspid valve. Based on the listed literature we didn’t find any other case where tricuspid valve was affected.

Comorbidity of congenital heart defects and holoprosencephaly is likely genetically driven and gene-specific.

Comorbidity of holoprosencephaly (HPE) and congenital heart disease (CHD) in individuals with genetic variants in known HPE-related genes has been recurrently observed. Morphogenesis of the brain and heart from very early stages are regulated by several biological pathways, some of them involved in both heart and brain development as evidenced by genetic studies on model organisms. For instance, downregulation of Hedgehog or Nodal signaling pathways, both known as major triggers of HPE, has been shown to play a role in the pathogenesis of CHD, including structural defects and left-right asymmetry defects. In this study, individuals with various types of HPE were investigated clinically and by genomic sequencing. Cardiac phenotypes were assessed in 434 individuals with HPE who underwent targeted sequencing. CHDs were identified in 8% (n = 33) of individuals, including 10 (30%) cases of complex heart disease. Only four individuals (4/33) had damaging variants in the known HPE genes STAG2, SIX3, and SHH. Interestingly, no CHD was identified in the 37 individuals of our cohort with pathogenic variants in ZIC2. These findings suggest that CHD occurs more frequently in HPE-affected individuals with or without identifiable genetic variants, and this co-occurrence may be genetically driven and gene-specific.

Comparison of Different Machine Learning Algorithms for the Prediction of Coronary Artery Disease

Coronary Artery Disease (CAD) is the leading cause of mortality worldwide. It is a complex heart disease that is associated with numerous risk factors and a variety of Symptoms. During the past decade, Coronary Artery Disease (CAD) has undergone a remarkable evolution. The purpose of this research is to build a prototype system using different Machine Learning Algorithms (models) and compare their performance to identify a suitable model. This paper explores three most commonly used Machine Learning Algorithms named as Logistic Regression, Support Vector Machine and Artificial Neural Network. To conduct this research, a clinical dataset has been used. To evaluate the performance, different evaluation methods have been used such as Confusion Matrix, Stratified K-fold Cross Validation, Accuracy, AUC and ROC. To validate the results, the accuracy and AUC scores have been validated using the K-Fold Cross-validation technique. The dataset contains class imbalance, so the SMOTE Algorithm has been used to balance the dataset and the performance analysis has been carried out on both sets of data. The results show that accuracy scores of all the models have been increased while training the balanced dataset. Overall, Artificial Neural Network has the highest accuracy whereas Logistic Regression has the least accurate among the trained Algorithms.

Early Diagnosis of Congenital Heart Disease Improves Outcome

Congenital heart disease has an overall incidence of 8-10/1000 live births and is similar across the globe. The incidence may be higher in countries where consanguinity is high, suggesting an autosomal recessive gene as a risk factor. Advances in surgical expertise has improved outcome of simple and complex heart diseases. Early diagnosis and referral to centers caring for such babies is an important contributory factor to a better outcome. This review focuses on early diagnosis of congenital heart disease in neonates and children by Health Care Physicians (General and Family Physicians) and Pediatricians. Careful neonatal and pediatric cardiovascular examination, screening pulse oximetry on all newborns before hospital discharge and an early post natal follow up are important to diagnose CHD.

Systemic Sirolimus to Prevent In-Stent Stenosis in Pediatric Pulmonary Vein Stenosis.

Evaluate the efficacy of systemic sirolimus (rapamycin) in preventing in-stent stenosis (ISS) in pediatric intraluminal pulmonary vein stenosis (PVS). Report the adverse events related to sirolimus therapy. There is a high incidence of ISS following stent implantation in PVS. The use of sirolimus in preventing ISS has not been reported. Retrospective review of all patients who received sirolimus (8week course) for treatment of ISS for PVS between January 2013 and June 2018. Forty stents (37 bare metal, 3 drug-eluting) in 20 patients were treated with sirolimus; 20 at the time of implantation (primary prevention [1P]) and 20 following documented ISS requiring transcatheter reintervention (secondary prevention [2P]). Treated patients were young (median 2 y/o [0.7-5.7]) and most had PVS associated with congenital heart disease (75%, 15/20; 4/15 with TAPVC). In the 1P group, 85% (17/20) of stents were without significant (< 50%) ISS at median of 102days (range 56-527); the growth rate of ISS in this group was 7.5 ± 7.1%/month. In the 2P group, most stents had a slower growth rate of ISS after sirolimus therapy compared to pre-treatment (median 3.7 [- 0.2 to 13.1] vs. 10.4 [1.3 to 19.5] %/month; p < 0.001). One patient developed pneumonia on drug while concurrently taking another immunosuppressive agent. No other serious adverse events were related to sirolimus therapy. Systemic sirolimus slows the growth rate of ISS following stent implantation in PVS compared to pre-treatment rates and was administered safely in a small number of pediatric patients with complex heart disease.

The Konno Operation Is a Durable Option for Relief of Aortic Stenosis in Patients With Complex Left Ventricular Outflow Tract Obstruction-A Single-Center 20-Year Experience.

A Konno operation with a mechanical prosthesis may be applied in patients with complex left ventricular outflow tract obstruction to avoid further operations. We reviewed our 20-year experience with the Konno operation. All patients who underwent the Konno operation between 1996 and 2015 were evaluated. Study end points were survival and reoperations. Twenty-one consecutive patients were included. The median age at operation was 12 years (5 months to 34 years). Twenty (95%) patients had prior interventions for left-sided heart lesions. Additional mitral valve disease was present in 17 (81%) patients. The preoperative mean pressure gradient over the left ventricular outflow tract was 50 ± 25 mm Hg. The median size of implanted valve prostheses was 21 mm (16-25 mm). Concomitant procedures for left-sided heart lesions were performed in six patients, including two mitral valve replacements. There were two hospital mortalities (9.5%) and four late mortalities (19%). Overall survival was 85% ± 7.8% and 72% ± 11% at 5 and 10 years, respectively. In two patients, mitral valve replacement was performed during the same hospital admission. During a mean follow-up time of 7.6 ± 4.8 years, two patients required late reoperations, one for mitral valve replacement and one for heart transplantation. Freedom from late reoperation at 10 years was 89% ± 7.4%. The Konno operation can be considered as a definitive option with a low probability of reoperation on the left ventricular outflow tract in patients with complex left ventricular heart disease. Subsequent operations focus on the treatment of additional mitral valve disease, which remains the cause of mortality and morbidity.

Tensor-based mathematical framework and new centralities for temporal multilayer networks

Although networks provide a powerful methodology to study a variety of real-world and engineered systems, their current formulation does not typically account for multiple interaction types that vary in space and time, or address interconnected systems such as networks of networks. Unavoidably, ignoring time-dependence and multiple interactions of topological structures might lead to important temporal and structural information loss and may obscure the actual organization. To achieve a deep understanding of the time-varying and interconnected complex networked systems, in this paper, we develop a more general mathematical model, referred to as a temporal multilayer network, which explicitly incorporates time-dependence and multiple relationships of topological structures into a system, and provides a natural and reasonable description for real-world complex systems. Furthermore, using a fifth-order tensorial framework to represent temporal multilayer networks, we generalize four important topological metrics, including overlapping degree, entropy, degree correlation and link overlap, to quantitatively evaluate the temporal multilayer networks. In particular, based on the tensorial framework, we propose two iterative refinement centralities for temporal multilayer networks, referred to as TM-eigenvector and TM-PageRank centralities, which are used to quantitatively evaluate the importance of nodes in real-world complex systems. Moreover, we use the theory of multilinear algebra and matrix analysis to strictly prove the convergence of these iterative algorithms. The proposed mathematical frameworks are validated using two real-world temporal multilayer networked systems related to complex diseases, i.e., influenza and heart diseases.

DOES A HEART TEAM ACTUALLY IMPROVE CLINICAL OUTCOMES?

Consultation by a “Heart Team” has become a level I recommendation by multiple cardiovascular societies in the management of patients with complex cardiac disease. The “Heart Team” consultation typically takes place in the form of multidisciplinary “Complex Case” rounds attended by cardiologists, interventionalists, surgeons, intensivists and anesthesiologists to develop a care plan. Despite the Level I recommendation, there is no strong evidence to support the role of a “Heart Team”. This study was performed to determine whether “Heart Team” consultation resulted in improved outcomes. We performed a mixed retrospective and prospective analysis of our cohort that underwent consultation by the “Heart Team” for primarily complex coronary artery disease (CAD) or vascular heart disease (VHD). Patient characteristics and key outcomes including death, myocardial infarction (MI), emergency room (ER) visits and unanticipated hospital admissions have been entered into the Complex Care Database and were evaluated at six-months from the time of case discussion. Endpoints including death, major adverse cardiovascular events, emergency room visits and hospital admissions were analyzed using a multivariate logistic regression. Results: In total 253 unique patients were reviewed. The median age was 67 +/- 13.7 years (73% (185) male) and an average EuroSCORE II score of 7.2%. CAD composed the majority of consultations with 158 (62.5%) cases, VHD composed 79 (31.2%) and other the remaining 16 (6.3%) cases. A unanimous decision was made in 76% of cases and majority decision in 18%. Recommendations by the Heart Team were followed in 209 cases (82.6%) and not followed in 44 cases (17.4%). The presence of chronic lung disease was a predictor of the “Heart Team” recommendation not being followed (p ≤ 0.01). When recommendations were followed there was a significant reduction in cardiac death (4.1% vs. 15.9% p=0.009), composite cardiac outcome (including death, stroke, dialysis, MI, hospitalization) (12.4% vs 38.6% p ≤ 0.001) as well as hospital admissions (23.2% vs 52.3% p ≤ 0.001). Reasons for why recommendations were not followed included: the attending physician decided for medical therapy instead of the recommended intervention (25.0%), the attending physician decided on an intervention instead of medical therapy (20.5%), the patient declined the recommendation (15.9%) or the recommended investigations were not completed (11.4%). These results are the first available showing both a mortality and morbidity benefit when recommendations by a “Heart Team” are followed.

What are the important morbidities associated with paediatric cardiac surgery? A mixed methods study

ObjectivesGiven the current excellent early mortality rates for paediatric cardiac surgery, stakeholders believe that this important safety outcome should be supplemented by a wider range of measures. Our objectives were...

Cardiovascular interventions planning through a three-dimensional printing patient-specific approach

: In recent years, three-dimensional modelling and printing techniques have improved diagnosis and preprocedural planning during percutaneous interventions or surgery in cardiovascular disease. The raw data for the whole process are obtained through medical imaging, where regions of interest, that is heart chambers, valves, aorta, coronary vessels etc., are segmented and converted into three-dimensional digital models, which are then reproduced in physical replica by a three-dimensional printer. In the current article, a freeware patient-specific three-dimensional modelling and printing step-by-step procedure for preprocedural planning for complex heart diseases is presented and applied on four patients. Finally, a general discussion on the potential and future developments of personalized three-dimensional modelling and rapid prototyping for preprocedural planning is also presented.

Incidence and risk factors for important early morbidities associated with pediatric cardiac surgery in a UK population

ObjectiveGiven excellent 30-day survival for pediatric cardiac surgery, other outcome measures are important. We aimed to study important early postoperative morbidities selected by stakeholders following a rigorous and evidenced-based process, with a view to identifying potential risk factors. MethodsThe incidence of selected morbidities was prospectively measured for 3090 consecutive pediatric cardiac surgical admissions in 5 UK centers between October 2015 and June 2017. The relationship between the candidate risk factors and the incidence of morbidities was explored using multiple regressions. Patient survival, a secondary outcome, was checked at 6 months. ResultsA total of 675 (21.8%) procedure episodes led to at least 1 of the following: acute neurologic event, unplanned reoperation, feeding problems, renal replacement therapy, major adverse events, extracorporeal life support, necrotizing enterocolitis, surgical infection, or prolonged pleural effusion. The highest adjusted odds ratio of morbidity was in neonates compared with children, 5.26 (95% confidence interval, 3.90-7.06), and complex heart diseases (eg, hypoplastic left heart), 2.14 (95% confidence interval, 1.41-3.24) compared with low complexity (eg, atrial septal defect, P < .001 for all). Patients with any selected morbidity had a 6-month survival of 88.2% (95% confidence interval, 85.4-90.6) compared with 99.3% (95% confidence interval, 98.9-99.6) with no defined morbidity (P < .001). ConclusionsEvaluation of postoperative morbidity provides important information over and above 30-day survival and should become a focus for audit and quality improvement. Our results have been used to initiate UK-based audit for 5 of these 9 morbidities, co-develop software for local monitoring of these morbidities, and parent information about these morbidities.

MicroRNA expression in the hippocampal CA1 region under deep hypothermic circulatory arrest.

Using deep hypothermic circulatory arrest, thoracic aorta diseases and complex heart diseases can be subjected to corrective procedures. However, mechanisms underlying brain protection during deep hypothermic circulatory arrest are unclear. After piglet models underwent 60 minutes of deep hypothermic circulatory arrest at 14°C, expression of microRNAs (miRNAs) was analyzed in the hippocampus by microarray. Subsequently, TargetScan 6.2, RNA22 v2.0, miRWalk 2.0, and miRanda were used to predict potential targets, and gene ontology enrichment analysis was carried out to identify functional pathways involved. Quantitative reverse transcription-polymerase chain reaction was conducted to verify miRNA changes. Deep hypothermic circulatory arrest altered the expression of 35 miRNAs. Twenty-two miRNAs were significantly downregulated and thirteen miRNAs were significantly upregulated in the hippocampus after deep hypothermic circulatory arrest. Six out of eight targets among the differentially expressed miRNAs were enriched for neuronal projection (cyclin dependent kinase, CDK16 and SLC1A2), central nervous system development (FOXO3, TYRO3, and SLC1A2), ion transmembrane transporter activity (ATP2B2 and SLC1A2), and interleukin-6 receptor binding (IL6R) - these are the key functional pathways involved in cerebral protection during deep hypothermic circulatory arrest. Quantitative reverse transcription-polymerase chain reaction confirmed the results of microarray analysis. Our experimental results illustrate a new role for transcriptional regulation in deep hypothermic circulatory arrest, and provide significant insight for the development of miRNAs to treat brain injuries. All procedures were approved by the Animal Care Committee of Xuanwu Hospital, Capital Medical University, China on March 1, 2017 (approval No. XW-INI-AD2017-0112).

Neonatal gastric necrosis and perforation associated with impacted medication

Abstract Introduction Gastric perforation is a serious life-threatening condition in newborns. Its etiologies include idiopathy, distal obstruction, high acidity with local ischemia, and iatrogenesis. Moreover, there have been some reports of Kalimate (a potassium-lowering agent) possibly being irritated, obstructed, and necrotized the gastric mucosa. This article reports on the risk of gastric necrosis and perforation while using this potassium-lowering agent, as well as management of this complication. Methodology Case report. Patient information A female infant was born at 38 weeks gestation, weighting 3180 g. She had undergone a central shunt on the 13th day of life due to complex heart disease. The first day after the operation, the infant was found to have an acute kidney injury and hyperkalemia. After successful resuscitation from cardiac arrest, she was administered intravenous calcium gluconate, sodium bicarbonate, and oral calcium polystyrene sulfonate (Kalimate®). The infant's abdomen became distended and abdominal radiography showed pneumoperitoneum and an opaque particle at the upper-left quadrant of the abdomen. The patient was then referred to our hospital, where an exploratory laparotomy was immediately performed. We found a large area of necrosis and a rupture along the greater curvature of the stomach that extended to the fundus with impaction of the medical bezoars inside and generalized contamination of the abdominal cavity. After the operation, the infant clinically improved. Conclusion These findings suggest that physicians should be aware of potentially serious complications while using this potassium-lowering agent and point to the importance of early surgical intervention in cases of neonatal gastric perforation.

1996–2017: A humanitarian action for 3000 children with congenital heart diseases from developing countries

Mécénat-Chirurgie Cardiaque is a humanitarian association whose mission is to enable children suffering from cardiac malformations to come to France to access the care that is not available in their native countries. The purpose of this study is to analyse the follow-up of the children managed since the creation of MCC. We reviewed all patients, and analysed long-term survival. Since 1996, 3000 children were entrusted, from 66 different countries, mainly from sub-Saharan Africa (68%). Mean age at venue was 7 years old. Main diagnosis were tetralogy of Fallot 25%, VSD 16%, acquired valvular diseases 16%, complex congenital heart disease: single ventricle, pulmonary atresia with VSD, DORV, D-TGV 5% each, truncus arteriosus 2%. In total, 2728 children came to France once, 119 twice, and 11 three times or more. Seven children died before surgery. Among the children, 228 were withdrawn for surgery, mainly because of pulmonary hypertension or overly complex heart disease, or because of venial disease. Among the children, 2765 underwent surgery or intervention. Postoperative mortality has been 2.2%. After a mean follow-up of 4.4 years, 401 children were lost to follow-up (13.4%). At last follow-up, 291 children were dead at a mean age of 10.5. Mean delay until death was 2.3 years. Survival rate at 5 and 10 years was 89% and 84% in operated children, and 74% and 62% in non-operated children respectively, in Fallot 95.4%–94.9%; VSD 94.9%–91.1%; acquired valvular diseases 77.9%–68.5%; single ventricle 78.2%–71.7%. With low operative mortality for often very severe heart disease, and good long-term follow-up, the management of children from countries without cardiac surgery is justified by survival similar to that of Western cohorts - except for acquired valvulopathies, presumably because of the difficulty of anticoagulant treatment. Thus our humanitarian action must continue, and improve for an optimal management of the disinherited populations.

New conception of interventional therapy for congenital heart disease in neonates

The main clinical manifestations of neonatal critical and complex congenital heart disease (CHD) are cardiac insufficiency and severe hypoxemia.Because of the rapid development of the CHD, most children will die early.Through the analysis of the successful interventional treatment of some severe CHDs in the neonatal, the indivi-dualized interventional treatment can be used according to different congenital malformations, and the interventional materials, which are different from the pediatric cardiology, are used reasonably.So many interventional therapies before or after surgery were used, and even, replace traditional surgical treatment to cure or palliate the CHD in neonates. Key words: Congenital heart disease; Interventional therapy; Infant, newborn

Signed Differential Co‐Expression Network Analysis Suggests Differential Regulation of SP/KLF Family of Transcription Factors in Dilated Cardiomyopathy

INTRODUCTIONCo‐expression analyses utilize correlation to identify co‐regulated gene groups. Differential co‐expression (DC) networks asses the differential co‐regulation of genes across conditions. Differences in properties of networks with unsigned and signed (with a sign on the magnitude) edges have been previously documented (e.g. in social networks). However, research in biological DC networks, have rarely focused on the influence of signed edges prior to network clustering and their biological interpretation. To address this, we developed an approach to DC network analysis from signed, weighted co‐expression data and apply it to understand dilated cardiomyopathy.METHODSA signed scalar matrix of difference (δ) was first calculated using absolute Fisher r to z‐scores of correlations from each condition (1 and 2). Taking a difference in absolutes allowed us to capture the change in magnitudes of correlations between conditions 1 and 2. For e.g., positive δ indicated higher magnitudes of correlation in condition 1. Adjacency matrix was then calculated from δ and hierarchically clustered. Cut height was dynamically determined to identify differentially co‐expressed modules (M). We defined signed node connectivity to measure “hubness” of a gene as conn+ (u)‐ conn− (u); where, conn+/− (u) is the sum of all +/− edge weights incident at node u from all nodes in M respectively.RESULTSWe used the above approach to understand mechanisms underlying ischemic (ICM) and idiopathic dilated (IDCM) cardiomyopathy‐ two progressive, largely irreversible complex heart diseases. We obtained publicly available cardiac muscle expression data (from Gene Expression Omnibus), for ICM and IDCM. Using our approach on a list of 4363 genes across 166 ICM and 149 IDCM samples, we identified 11/28 modules as significantly differentially co‐expressed (p&lt;0.05, via permutation testing). Functional analysis corresponded well with current understanding of aberrant processes underlying dilated cardiomyopathy (Tbl. 1). Interestingly, all 11 modules were significantly associated with protein‐protein interactions (p&lt;0.05, extracted from STRING database) (Tbl. 1). 152 hub genes were identified in the 11 significant modules with 100/152 in top 5 modules (identified via module ranking metrics). Topological assessment of 100 hubs exhibited strong associations with known markers of ICM and IDCM, such as BMP6, ACVRL1, VCAM1 and IRS2. Hubs were also enriched for variants in cis‐eQTL within heart left ventricle (p&lt;0.05, from the GTeX consortium's cis‐eQTL data within the heart left ventricle) (Tbl. 2). SP/KLF family of transcriptional factors and its targets (Fig. 2) were over‐represented in significantly differentially co‐regulated modules, suggesting their differential role in ICM and IDCM.CONCLUSIONWe provide a scalable and unsupervised approach to identifying signed DC from two condition studies. Our results not only corroborate the extant knowledge on dilated cardiomyopathy but provide novel insights for further scientific research in identifying mechanistic differences between ICM and IDCM.Support or Funding InformationSupported by NIH Grants R01 HL108735, R01 HL106579, U01 CA200147, U01 CA198941, and NSF Grant CCF‐0939370.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Primigravida with trilogy of Fallot (severe pulmonary stenosis, right ventricular hypertrophy and huge atrial septal defect) for emergency lower segment caesarean section

Trilogy of Fallot; a triad of pulmonary stenosis, right ventricular hypertrophy and atrial septal defect is an uncommon acyanotic congenital heart disease. We present a severe case of trilogy of Fallot diagnosed for the first time in pregnancy. The patient was otherwise in a compensated state and had become symptomatic due to physiological changes in pregnancy. The anaesthetic goals therefore included maintaining the existing physiology and preventing decompensation thereby avoiding Eisenmengerisation. The anaesthetic management of the severe and complex heart disease keeping patient safety at the core is discussed. Keywords: Caesarean section, congenital heart disease, trilogy of Fallot.

Classification of New Biomarkers of Dilated Cardiomyopathy Based on Pathogenesis—An Update

Dilated Cardiomyopathy (DCM) is a complex heart disease affecting the heart musculature and vasculature, involving one or several underlying pathophysiological mechanisms. Identifying potential biomarkers for dilated cardiomyopathy is a challenge owing to various aetiologies involved. Studying the biomarkers involved in DCM will ultimately give a better insight about which pathophysiological pathways are involved in the onset of the disease. Owing to its multifactorial aetiologies, response to treatment is usually poor. If we can find the exact underlying causes, a better treatment approach could be implemented. One way to obtain better insight of DCM is to study the biomarkers released. Through biomarkers, we can know which underlying mechanisms are involved. Biomarkers can provide us with clinical information such as diagnostic, prognostic, risk stratification as well as response to treatment. Underlying mechanisms such as inflammation, stress/strain, myocyte injury, matrix remodelling, oxidative stress, neurohormones involvement, among others, can contribute to the onset of DCM. Different mechanisms will yield different biomarkers. So it would be wise to classify those biomarkers involving in DCM based on their respective pathogenesis. Moreover, most importantly is to be able to make use of the information that biomarker pertains. However, specificity of those biomarkers poses a problem. One way of making these biomarkers clinically useful is to make use of a biomarker modelling score system.