c.620C>T mutation in GATA4 is associated with congenital heart disease in South India.

BACKGROUND: Congenital heart diseases (CHDs) usually refer to abnormalities in the structure and/or function of the heart that arise before birth. GATA4 plays an important role in embryonic heart development, hence the aim of this study was to find the association of GATA4 mutations with CHD among the south Indian CHD patients. METHOD: GATA4 gene was sequenced in 100 CHD patients (ASD, VSD, TOF and SV) and 200 controls. Functional significance of the observed GATA4 mutations was analyzed using PolyPhen, SIFT, PMut, Plink, Haploview, ESE finder 3.0 and CONSITE. RESULTS: We observed a total of 19 mutations, of which, one was in 5' UTR, 10 in intronic regions, 3 in coding regions and 5 in 3' UTR. Of the above mutations, one was associated with Atrial Septal Defect (ASD), two were found to be associated with Tetralogy of Fallot (TOF) and three (rs804280, rs4841587 and rs4841588) were strongly associated with Ventricular Septal Defect (VSD). Interestingly, one promoter mutation (-490 to 100 bp) i.e., 620 C>T (rs61277615, p-value = 0.008514), one splice junction mutation (G>A rs73203482; p-value = 9.6e-3, OR = 6.508) and one intronic mutation rs4841587 (p-value = 4.6e-3, OR = 4.758) were the most significant findings of this study. In silico analysis also proves that some of the mutations reported above are pathogenic. CONCLUSION: The present study found that GATA4 genetic variations are associated with ASD, TOF and VSD in South Indian patients. In silico analysis provides further evidence that some of the observed mutations are pathogenic.

Indian Guidelines for Indications and Timing of Intervention for Common Congenital Heart Diseases: Revised and Updated Consensus Statement of the Working Group on Management of Congenital Heart Diseases. Abridged Secondary Publication.

JUSTIFICATION: A number of guidelines are available for management of congenital heart diseases from infancy to adult life. However, these guidelines are for patients living in high income countries. Separate guidelines, applicable to Indian children, are required when recommending an intervention for congenital heart diseases, as often these patients present late in the course of the disease and may have co-existing morbidities and malnutrition. PROCESS: Guidelines emerged following expert deliberations at the National Consensus Meeting on Management of Congenital Heart Diseases in India, held on 10th and 11th of August 2018 at the All India Institute of Medical Sciences, New Delhi. The meeting was supported by Children's HeartLink, a non-governmental organization based in Minnesota, USA. OBJECTIVES: To frame evidence based guidelines for (i) indications and optimal timing of intervention in common congenital heart diseases; (ii) follow-up protocols for patients who have undergone cardiac surgery/catheter interventions for congenital heart diseases. RECOMMENDATIONS: Evidence based recommendations are provided for indications and timing of intervention in common congenital heart diseases, including left-to-right shunts (atrial septal defect, ventricular septal defect, atrioventricular septal defect, patent ductus arteriosus and others), obstructive lesions (pulmonary stenosis, aortic stenosis and coarctation of aorta) and cyanotic congenital heart diseases (tetralogy of Fallot, transposition of great arteries, univentricular hearts, total anomalous pulmonary venous connection, Ebstein anomaly and others). In addition, protocols for follow-up of post surgical patients are also described, disease wise.

Guidelines for the management of common congenital heart diseases in India: A consensus statement on indications and timing of intervention.

INTRODUCTION: A number of guidelines are available for management of congenital heart diseases from infancy to adult life. However, these guidelines are for patients living in high-income countries. Separate guidelines, applicable to Indian children, are required when recommending an intervention for congenital heart diseases, as often these patients present late in the course of the disease and may have co-existing morbidities and malnutrition. PROCESS: Guidelines emerged following expert deliberations at the National Consensus Meeting on Management of Congenital Heart Diseases in India, held on the 10th and 11th of August, 2018 at the All India Institute of Medical Sciences. OBJECTIVES: The aim of the study was to frame evidence-based guidelines for (i) indications and optimal timing of intervention in common congenital heart diseases and (ii) follow-up protocols for patients who have undergone cardiac surgery/catheter interventions for congenital heart diseases. RECOMMENDATIONS: Evidence-based recommendations are provided for indications and timing of intervention in common congenital heart diseases, including left-to-right shunts, obstructive lesions, and cyanotic congenital heart diseases. In addition, protocols for follow-up of postsurgical patients are also described.

Computational modeling suggests impaired interactions between NKX2.5 and GATA4 in individuals carrying a novel pathogenic D16N NKX2.5 mutation.

NKX2.5, a homeobox containing gene, plays an important role in embryonic heart development and associated mutations are linked with various cardiac abnormalities. We sequenced the NKX2.5 gene in 100 congenital heart disease (CHD) patients and 200 controls. Our analysis revealed a total of 7 mutations, 3 in intronic region, 3 in coding region and 1 in 3' UTR. Of the above mutations, one mutation was found to be associated with tetralogy of fallot (TOF) and two (rs2277923 and a novel mutation, D16N) were strongly associated with VSD. A novel missense mutation, D16N (p-value =0.009744), located in the tinman (TN) region and associated with ventricular septal defect (VSD), is the most significant findings of this study. Computational analysis revealed that D16N mutation is pathogenic in nature. Through the molecular modeling, docking and molecular dynamics simulation studies, we have identified the location of mutant D16N in NKX2.5 and its interaction map with other partners at the atomic level. We found NKX2.5-GATA4 complex is stable, however, in case of mutant we observed significant conformational changes and loss of key polar interactions, which might be a cause of the pathogenic behavior. This study underscores the structural basis of D16N pathogenic mutation in the regulation of NKX2.5 and how this mutation renders the structural-functional divergence that possibly leading towards the diseased state.

Arterial switch operation with in situ coronary reallocation for transposition of great arteries with single coronary artery.

OBJECTIVES: Transposition of great arteries (TGA) with single coronary artery pattern is one of the high-risk groups for arterial switch operation (ASO). Any traction or kinking during coronary transfer can lead to a fatal outcome. With increase in experience, surgical results improved, but it did not completely eliminate the risks of coronary translocation. Many techniques have been described for transfer of single coronary and each one has its own merits and problems. We here in describe a new technique of in situ coronary reallocation during ASO for TGA with single coronary and also report the early and mid-term results with this new technique. METHODS: From September 1988 to June 2002, five consecutive cases of TGA with single coronary artery were operated employing this new technique. Their age ranged from 16 days to 9 months. ASO was done by transecting the great arteries just above the commissures. For coronary reallocation, hockey stick-shaped incisions were made in the facing sinuses of the proximal aorta and the pulmonary artery. These flaps were sutured in such a way that the coronary ostium was committed to the neo-aorta with the rest of surgical procedure done in the usual manner. RESULTS: All five patients had ASO. Additionally, four patients had closure of an associated ventricular septal defect and one patient had repair of the coarctation of the aorta. There was no in hospital mortality. All patients had follow-up echocardiograms at regular intervals, which showed no significant right or left ventricular outflow obstruction, no regional wall motion abnormalities and no neo-aortic or neo-pulmonary regurgitation. Three of five patients had cardiac catheterization and angiocardiography, which showed normal coronary arteries with no obstructive lesions and no neo-aortic regurgitation. Their follow up ranged from 5 to 50 months and there was no late mortality. CONCLUSIONS: This new coronary reallocation technique avoids problems related to coronary translocation such as traction and kinking. It spares the need for dissection of proximal coronary artery and its branches, and thereby eliminates the risk of development of fibrosis and stenosis. The same technique can be used regardless of the sinus of origin of the coronary artery. It is a reliable and a reproducible technique. The early and mid-term results appear excellent in this series.

Right pulmonary artery-to-left atrial fistula.

Right pulmonary artery-to-left atrial fistula is a rare congenital anomaly. Contrast echocardiography and cardiac catheterization diagnosed a right pulmonary artery-to-left atrial fistula in a 24-year-old female with a history of cyanosis since childhood, and recurrent thromboembolism. She underwent successful surgical closure of the fistula.

Arterial switch operation without coronary translocation: mid-term results.

We innovated a technique of arterial switch operation without coronary translocation in 1995, which avoids problems related to coronary artery translocation with good mid-term results. It is a better alternative for surgeons who are not well versed with coronary translocation of conventional arterial switch operation and with difficult coronary anatomy. This report deals with the mid-term results of our new technique.

One-stage repair of cardiac and arch anomalies without circulatory arrest.

Between 1999 and 2002, 23 patients underwent single-stage complete repair of cardiac anomalies and aortic arch obstruction, without circulatory arrest. Median age was 1.2 years. Intracardiac defects included ventricular septal defect in 9, double-outlet right ventricle in 6, d-transposition of the great arteries and ventricular septal defect in 2, subaortic obstruction in 3, and atrial septal defect in 3. Fourteen patients had coarctation of the aorta, 6 had coarctation with hypoplastic aortic arch, and 3 had interrupted aortic arch. Simple techniques were employed such as cannulation of the ascending aorta near the innominate artery and maintaining cerebral and myocardial perfusion. After correction of arch obstruction, intracardiac repair was undertaken. The mean cardiopulmonary bypass time was 169 min, aortic crossclamp time was 51 min, and arch repair took 16 min. There was no operative mortality or neurological deficit. In follow-up of 1-43 months, no patient had residual coarctation. This simplified technique avoids additional procedures, reduces ischemic time, and prevents problems related to circulatory arrest.

Total anomalous pulmonary venous connection beyond infancy.

Most patients with total anomalous pulmonary venous connection are operated on in infancy, with low mortality and morbidity, but in developing countries, we still encounter patients beyond infancy. We describe our experience in 26 patients aged 1-16 years (mean, 5.01 years), with total anomalous pulmonary venous connection, who underwent correction between June 2007 and December 2009. Eleven patients were >5-years old. Transthoracic echocardiography was diagnostic in all cases. Mean intensive care unit stay was 2.3 ± 0.87 days, and hospital stay was 9.23 ± 2.34 days. There were no early deaths and no major postoperative complications. Follow-up ranged from 10-40 months. Pulmonary artery pressure, as judged by echocardiography, reduced significantly in all patients. Repair of total anomalous pulmonary venous connection beyond infancy can be carried out safely with acceptable results.

Venoatrial shunt-assisted cavopulmonary anastomosis.

The bidirectional Glenn shunt operation is conventionally performed under cardiopulmonary bypass. Between June 2007 and September 2009, 218 consecutive patients underwent off-pump bidirectional Glenn shunt institution for single ventricle with pulmonary stenosis complex. Their mean age was 4.72 ± 1.80 years (range, 4 months to 6 years) and median weight was 10.12 kg (range, 4.1-19 kg). A temporary shunt was created between the innominate vein and the right atrium, with a 3-way connector for de-airing. Fifty-five patients had bilateral cavae. The mean internal jugular venous pressure on clamping the superior vena cava was 24.69 ± 1.81 mm Hg. Continuous end-tidal CO2 and O2 saturation were monitored. Adequate oxygen saturation and blood pressure were maintained by optimizing inotropics, volume, and inspired oxygen. The mean duration of ventilation was 10.17 ± 8.96 h (range, 1-73 h). There were no gross neurological complications. Postoperative pleural effusion developed in 6 (2.75%) patients, and 4 (1.83%) had nodal rhythm. Four (1.83%) patients died in the immediate postoperative period due to low cardiac output syndrome. Venoatrial shunt-assisted bidirectional Glenn shunt surgery can be performed safely by optimizing intraoperative management strategies. It is economical and avoids the deleterious effects cardiopulmonary bypass.

Sternotomy approach for modified Blalock-Taussig shunt: is it a safe option?

Central aorta-pulmonary artery shunts have fallen into disfavor because of shunt thrombosis and congestive heart failure, and a modified Blalock-Taussig shunt via thoracotomy can lead to pulmonary artery hypoplasia and distortion. We reviewed the outcomes of a modified Blalock-Taussig shunt by a sternotomy approach in 20 infants from July 2007 to October 2009. Their mean age was 5.79 months, and median weight was 5.4 kg. A 4-mm graft was placed in 11 patients, a 5-mm graft in 8, and a 3.5-mm graft in 1. There was no incidence of sepsis, seroma, or phrenic nerve palsy. There was one hospital death. The mean hospital stay was 10.4 +/- 4.3 days (range, 8-15 days). The mean oxygen saturation at discharge was 89% (range, 81%-93%). The sternotomy approach is technically easier to perform, cosmetically preferable, and probably hemodynamically superior. Correction of branch pulmonary stenosis is easily incorporated into this procedure. The theoretical disadvantage of this method is a potential technical difficulty with sternal reentry for subsequent procedures.

Tricuspid valve repair with neopapillary muscle from right ventricular trabecula.

Congenital abnormalities of the tricuspid valve without downward displacement of the septal and posterior tricuspid leaflets are uncommon causes of tricuspid regurgitation. Progressive tricuspid regurgitation can lead to right heart dilatation, arrhythmia, and irreversible deterioration of right ventricular function. Tricuspid valve repair is an important method to stabilize symptomatic children because tricuspid valve replacement has a poor prognosis. We report the successful use of right ventricular trabecula as a "neopapillary muscle" for treating severe low-pressure tricuspid regurgitation in children.

Veno-venous shunt-assisted cavopulmonary anastomosis.

OBJECTIVE: The bidirectional Glenn shunt is commonly performed under cardiopulmonary bypass for conditions that lead to a single ventricle repair. We report our experience of bidirectional Glenn shunt done without cardiopulmonary bypass. METHODS: Between June 2007 and May 2009, 186 consecutive patients underwent off-pump bidirectional Glenn shunt for a variety of complex cyanotic congenital heart defects. Age ranged from four months to six years and the median weight was 11.17 kg (range 4.3 - 18). After systemic heparinization, the procedure was done by creating a temporary shunt between the innominate vein and the right atrium connected across a three way connector for de-airing. Fifty one patients had bilateral cavae. All cases underwent complete clinical neurological examination. RESULTS: No case required conversion onto cardiopulmonary bypass. Four patients (2.14%) died in the immediate postoperative period. The mean internal jugular venous pressure on clamping the decompressed superior vena cava was 24.69 +/- 1.81 mm Hg. There was no intra-operative hemodynamic instability and oxygen saturation was maintained at more than 70% throughout. Post Glenn shunt, the saturations improved to mid 80s. Seventy four cases had documented forward flow across the pulmonary valve. The mean duration of ventilation was 10.17 +/- 8.96 hours and there were no neurological complications. Six patients (3.22%) developed pleural effusions, 4 patients (2.15%) had nodal rhythm and 9 patients (4.83%) had superficial sternal wound infection. CONCLUSIONS: Our results show that off-pump bidirectional Glenn shunt can be done safely in patients not requiring associated intra-cardiac correction. It avoids cardiopulmonary bypass and its related complications, is economical and associated with excellent results. In our opinion, this is the largest series of off-pump bidirectional Glenn shunt in the literature.

Morphosurgical correlation of outcomes in complete double outlet right ventricle.

Even though surgical experience with wide spectrum of double outlet right ventricle (DORV) is available, the experience with extreme form of complete DORV where both great arteries completely arise from the right ventricle is limited. We present our experience with this unique subset where the systemic outflow is far removed from the interventricular foramen and hence, the systemic ventricle. In this situation, biventricular repair can be technically demanding and challenging. Between June 2002 and February 2006, 12 patients underwent biventricular repair of this subset. The VSD was subaortic in all; eight patients had infundibular and valvar obstruction. Aorta was anterior and to the right, with the pulmonary artery far posterior and to the left. The interventricular foramen was patched with a long Gore-Tex patch to route the LV flow to the aorta. Eight patients had infundibular resection and right ventricular outflow tract (RVOT) enlargement with an autologous monocusp pericardial patch. No patient required a valved conduit. There was no operative mortality. In one patient, there was a small residual VSD that was not of haemodynamic significance. There was no RVOT and left ventricular outflow tract obstruction and no RV inflow obstruction. The early and mid-term results are good.