Genetic Risk Score Constructed from Polymorphisms in the VEGFA, TBX5, and SMAD7 Genes Provides Novel Insights into the Molecular Mechanisms of the Tetralogy of Fallot and Ventricular Septal Defect (Case-Control Study from the Pakistani Population).

Congenital heart defects are common and complex birth-defect malformations in developed and developing countries. It is a multifactorial disease that involves the interaction of either gene-gene or gene-environment. This comparative study was the first report on the genotypic-phenotypic correlation in the Pakistani population. The single nucleotide polymorphisms (SNPs) were further tested for association with maternal diabetes mellitus or hypertension. In addition, the cumulative genetic risk score (GRS) for low to moderately-associated SNPs was calculated for each study subject, which can ultimately guide us for better therapeutic options and prevention strategies. According to the predefined selection criteria, 376 subjects were recruited. The multiplex mini-sequencing genotyping technique opted for the cost-effective genotyping of selected loci. The association of variants with the disease was examined using logistic regression analysis. The statistical and graphical analysis was conducted using SPSS, Haploview, SNPStats, and GraphPad Prism. The results for all SNPs analysis suggested a nonsignificant association with overall congenital heart defect risk except rs3809923. However, interestingly on stratified analysis variants, rs3809923 and rs3809922 showed an association only with tetralogy of Fallot. The remaining risk factor analysis for maternal hypertension and diabetes mellitus association with SNPs were nonsignificant. The GRS was the first time constructed for this low to moderately-associated variants. Interestingly, the cumulative GRS was significantly different from the control group revealing the cumulative effect of these polymorphisms panel in patients. In conclusion, the use of GRS in the clinical setting can predict better risk association and patient outcomes.

Role of Vascular Endothelial Growth Factor as a Potential Biomarker in Congenital Heart Defects: A Systematic Review.

Background: Several studies have investigated the role of vascular endothelial growth factor (VEGF) variants, serum levels, and correlations with other extrinsic factors in congenital heart defects (CHDs); however, the findings need confirmation. The present systematic review evaluates the association between CHDs and genetic polymorphisms and serum expressions. Methods: Relevant literature was searched through electronic databases using keywords and MeSH terms. VEGF activity was comparatively assessed between cyanotic and acyanotic CHDs, and the association between different polymorphisms and heart defects was evaluated. Results: We ultimately evaluated 12 studies regarding the association between VEGF serum patterns and found that serum VEGF levels were upregulated or downregulated in correlation with hypoxia and hemoglobin levels and were significantly associated with cyanotic CHDs compared with acyanotic CHDs. Our results also showed a significant role for different single-nucleotide polymorphisms, including rs699947, rs2010963, and rs3025039. Conclusion: The findings of the current study suggested a significant association between CHDs and VEGF genetic polymorphisms or varied serum levels. Nevertheless, more comprehensive studies may provide conclusive results and valuable insights into the pathogenesis of CHDs and relevant treatment strategies.

Percutaneous closure of ventricular septal defect using LifeTechTM Konar-MF VSD Occluder: initial and short-term multi-institutional results.

BACKGROUND: Transcatheter ventricular septal defect closure remains a complex procedure with potential complications like complete heart block and aortic regurgitation. The ideal device design for such intervention is still evolving. AIM: To assess the safety, efficacy, and short-term outcome of ventricular septal defect closure using LifeTechTM multifunctional (KONAR-MFTM) VSD Occluder. PATIENTS AND METHODS: In a multicenre study, 44 patients with haemodynamically significant, restrictive ventricular septal defects underwent closure with the KONAR-MFTM device from April, 2019 to March, 2020. Clinical, echocardiographic, and angiographic data were collected and reviewed. Patients were followed up at 1, 3, 6, and 12 months. RESULTS: The median age and weight were 8 (1.7-36) years and 20 (11-79) kg. Of 44 patients, 8 (18%) had a high muscular and 36 (82%) had a perimembranous defect, of which 6 had mild prolapse of the right coronary cusp. The median ventricular septal defect size was 8.8 (3.9-13.4) mm. A retrograde approach was adopted in 39 (88.6%) patients. Nine patients (20.5%) had a small residual leak and there was a slight increase in aortic regurgitation in one patient. One device, which embolised to pulmonary artery was retrieved, and the defect was closed with a larger device. At a median follow-up of 13 (5-18) months, the residual leak persisted in 1 (2.3%) patient. Mild aortic regurgitation in one patient remained unchanged. There were no major complications. CONCLUSION: Percutaneous closure of ventricular septal defect using KONAR-MFTM device is safe and effective in short and midterm follow-up including selected patients with perimembranous defect and mild prolapse of the right coronary cusp.

Immediate And Midterm Results Of Balloon Aortic Valvuloplasty In Children With Aortic Valve Stenosis With Special Reference To Dysplastic Aortic Valve.

BACKGROUND: This study was conducted to determine the immediate and midterm outcome of balloon aortic valvuloplasty in children from age 1 month to 16 years, with special reference to mean balloon to aortic valve ratio along with dooming versus dysplastic valve. METHODS: This was a retrospective cohort study. Patients who underwent balloon aortic valvuloplasty in a single tertiary care hospital were reviewed regarding immediate outcome, morphology of aortic valve, mean balloon to aortic valve ratio and complications during procedure from January 2006 till December 2016. RESULTS: Of 171 patients, 80.11% had fall to good results while 73.1% had adequate outcome. Mean gradient fall of more than 50% or Peak systolic gradient decreased significantly post ballooning, which indicates good results. The age ranges from 1-92 months, 89.4% patients from age group less than1 year had adequate outcome, (p=0.017). In terms of morphology, 55.6% cases had doming while 44.4% cases had dysplastic aortic valve. There was no significant difference between dysplastic and doming valves in terms of outcome (p=0.224). Only 6 patients (3.5%) developed significant aortic regurgitation. Regarding short-term and intermediate outcome 92% of the patients were free from a second intervention and there was no significant difference between complications regarding balloon to aortic valve ratio also. CONCLUSIONS: Our 10-year experience showed that balloon aortic valvuloplasty is a safe and effective therapy, irrespective of age groups. The complications rate is low and good outcome is achieved by keeping balloon to aortic valve ratio of ±0.9 irrespective of morphology of valve..

Congenital heart disease and thyroid dysfunction in Down syndrome reported at Children`s Hospital, Lahore, Pakistan.

Yaqoob M, Manzoor J, Hyder SN, Sadiq M. Congenital heart disease and thyroid dysfunction in Down syndrome reported at Children`s Hospital, Lahore, Pakistan. Turk J Pediatr 2019; 61: 915-924. Down syndrome is one of the main causes of intellectual disability in children. It occurs in every community and ethnic group. Several co-morbid conditions are associated with this syndrome. The present study was conducted to determine the frequency of congenital heart disease and thyroid dysfunction in a group of children affected with this genetic disorder. It was a record based retrospective study. A child having specific clinical features and chromosomal analysis showing an extra chromosome 21 was diagnosed as having Down syndrome. Diagnosis of congenital heart disease was based upon results of echocardiography. Thyroid dysfunction was diagnosed when either or both tetraiodothyronine and thyroid-stimulating hormone serum levels were abnormal. Three hundred and fifty cases were enrolled in the study according to the preset criteria for Down syndrome. Two hundred and ten (60%) were males and 140 (40%) females showing male to female ratio as 1.5 to 1. Majority of the children (55.1%) presented between 7 months and 24 months of age. Congenital heart defects were found in 41.8% of the cases. Ventricular septal defect was the most common, 41%. Thyroid dysfunction was found in 22% (n=60) of the cases of which 5.9% (n=16) had hypothyroidism. In conclusion, the frequency of congenital heart disease and thyroid dysfunction in Down syndrome children is high. Early referral of these children to tertiary health care facilities is emphasized as timely detection and management of these comorbid conditions will help in reducing the morbidity and mortality in this group of children.

Balloon valvuloplasty in dysplastic pulmonary valve stenosis: immediate and intermediate outcomes.

OBJECTIVE: To determine the immediate and intermediate outcome in dysplastic and doming pulmonary valve stenosis in children and to determine various factors associated with unsuccessful outcome. STUDY DESIGN: An interventional study. PLACE AND DURATION OF STUDY: The Children's Hospital, Lahore, Pakistan, from June 2006 to December 2012. METHODOLOGY: All patients presenting with severe pulmonary valve stenosis were enrolled in the study. Balloon valvuloplasty was performed on all patients. Successful outcome (residual gradient < 36 mmHg) was compared with matched doming pulmonary valve stenosis control group valvuloplasty. Difference in various quantitative variables was calculated using independent t-test and Mann Whitney U test. Categorical variables were compared using Chi square and Kruskal-Wallis test. Multivariate analysis was performed to determine various factors associated with outcome. Kaplan- Meier survival table was used to determine freedom from re-intervention proportions. RESULTS: One hundred and fifty two patients (Dysplastic group A, n=73; Doming group B, n=79) with median age of 24 months (range 3 - 192 months) and M:F; 2:1 were included in the study. Mean gradient decreased from 96 ± 33 mmHg to 29 ± 20 mmHg. Group A had significantly higher number of patients with unsuccessful outcome (9.6%, p=0.02). Preprocedure gradient > 75 mmHg was the most significant factor associated with unsuccessful outcome (p < 0.001). Median follow-up duration was 3 years (range 1 - 6 years). Freedom from re-intervention proportion at 1, 3 and 6 years was 91.3%, 86.7% and 78.9% respectively in group A compared to 100%, 96.5% and 96.5% respectively in group B. Immediate postprocedure gradient > 60 mmHg was the only significant factor associated with re-intervention in group A (p=0.001). CONCLUSION: The results from balloon valvuloplasty in dysplastic pulmonary valve were suboptimal when compared to doming valves. However, it provides a high freedom from re-intervention rate in intermediate follow-up. Intervention at moderate severity can result in better outcome.

Optimal dose of adenosine effective for supraventricular tachycardia in children.

OBJECTIVE: To determine the optimal adenosine dose effective in supraventricular tachycardia (SVT) and underlying conditions affecting the effective dose in children. STUDY DESIGN: Experimental study. PLACE AND DURATION OF STUDY: Department of Cardiology, The Children's Hospital and Institute of Child Health, Lahore, from July 2008 to June 2011. METHODOLOGY: All children presenting with SVT were administered adenosine in rapid boluses according to PALS guidelines using incremental doses of 100, 200 and 300 µg/kg. The response was recorded on 12 lead ECG. Preexcitation was documented and echocardiography performed on all children after attaining sinus rhythm. Mann Whitney test and Kruskal-Wallis test were used as a test of significance to determine any difference in effective adenosine dose between normal heart and various underlying conditions, taking p < 0.05 as significant. RESULTS: Eighty five patients were treated for 110 episodes of SVT with adenosine. M:F ratio was 2.2:1. Their age ranged from 6 days to 14 years with mean age of 27.9 months. Adenosine was effective in reverting 97 episodes of SVT to sinus rhythm (88.2%). A dose of upto 100 µg/kg was only effective in 36.4% episodes of SVT. Two hundred µg/kg was effective in 44.3% of those not responding to 100 µg/kg dose (n = 31/70, cumulative 64.5%). A dose of 300 µg/kg was effective in further 25 patients not responding to lower doses (n = 25/38, 65.8%; cumulative 88.2%). Mean effective dose of adenosine was 185.3 + 81.0 µg/kg with median effective dose of 200 µg/kg. Significantly higher dose of adenosine was required in children with underlying pre-excitation, n = 18/97 (220.8 + 67.6 µg/kg vs. 177.2 + 81.9 µg/kg, p = 0.039). CONCLUSION: Adenosine is an effective medicine in treating SVT in children. A higher dose of 200 µg/kg may be used as first bolus particularly in children with pre-excitation.

Socioeconomic status and impact of treatment on families of children with congenital heart disease.

OBJECTIVE: To assess the socioeconomic status, treatment being offered and the impact of congenital heart disease treatment on families. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: The Children's Hospital / Institute of Child Health, Lahore, from 1st March to 31st August 2010. METHODOLOGY: All patients undergoing a cardiac surgical or angiographic intervention were enrolled. Socioeconomic status was assessed by Kuppuswamy socioeconomic status scale with income group modification. The impact was measured by the source of financing, effect on family financing source and schooling and health of siblings. RESULTS: Of 211 patients undergoing treatment in the study period, surgery was the definitive treatment in 164 (77.7%) and angiographic intervention in 47 (22.3%) patients. Male to female ratio was 1.5:1. The mean age of the patient was 39.1 + 3.2 months (range 01 day to 15 years). Majority of families belonged to middle (66.4%, n=140) and lower (27%, n=57) socioeconomic class. The mean cost of medicines and disposables was PKR 78378.2 ± 8845.9 (US$ 933.1 ± 105.3) in open heart surgery, PKR 12581 ± 7010.8 (US$ 149.8 ± 83.5) in closed heart surgery and PKR 69091 + 60906 in angiographic interventions. In 63.1% patients, families contributed towards these costs either completely (12.3%) or partly (50.8%) with significant contribution from the hospital. Adverse effect on families ranged from leave without pay to losing jobs or business (46%), and selling their assets (11.3%). It also affected schooling and health of siblings (22.7% and 26.1% respectively). CONCLUSION: Majority of children with congenital heart disease belonged to middle and lower socioeconomic status in this study. Main definitive treatment was surgery. The cost of health care facilities posed a marked socioeconomic burden on those families.

Pattern of ventricular septal defects and associated complications.

OBJECTIVE: To determine the frequency of various types of Ventricular Septal Defect (VSD) in local population and their complications. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: The Paediatric Cardiac Unit of the Children Hospital and Institute of Child Health, Lahore, from January 2006 to December 2007. METHODOLOGY: All patients aged between one day to 18 years presenting to the unit with isolated VSD during the study period were evaluated using 2-D, continuous wave Doppler and colour Doppler techniques on transthoracic echocardiography. Where necessary, transesophageal echocardiography and/or angiography data was used to further clarify the anatomy. RESULTS: Of the 854 patients with isolated VSD, 710 were of perimembranous type (83.1%), 100 were muscular type (11.7%), 25 were doubly committed subarterial (DCSA) type (2.9%) and 19 patients were having inlet VSD (2.2%). The mean age was 2.1+3 years. Females were 332 (38.8%) and males were 522 (61.1%). Aortic Valve Prolapse (AVP) was seen in 77 patients (10.8%). The mean age for this subgroup was 5.8+4 years with 54 (70.1%) males and 23 (29.9%) females. Of those, 36 (47.3%) had various degree of aortic regurgitation. Right ventricular outflow tract obstruction of variable severity was found in 4 patients. Two of these patients had echocardiographic evidence of subacute bacterial endocarditis. CONCLUSION: Perimembranous (PM) VSD is the commonest type of ventricular septal defect presenting to a tertiary care hospital. The incidence of AVP and AR is high (10.8%) and was found almost entirely in perimembranous outlet VSDs rather than DCSA. This observation has special implication in Pakistan where pool of unoperated VSDs is large.

Anatomical variations of pulmonary artery and associated cardiac defects in Tetralogy of Fallot.

OBJECTIVE: To determine pulmonary artery variations and other associated cardiac defects in patients with Tetralogy of Fallot (TOF). STUDY DESIGN: Cross-sectional, descriptive study. PLACE AND DURATION OF STUDY: The Children's Hospital and the Institute of Child Health, Lahore, from April 2006 to October 2007. METHODOLOGY: All patients with TOF, who underwent cardiac catheterization during this period, were included. Standard cine-angiograms were recorded and pulmonary artery sizing was done using z-scoring. RESULTS: A total of 216 patients with TOF were catheterized. Pulmonary Artery (PA) abnormalities were present in 84 (38.9%) patients. The commonest abnormality was isolated Left Pulmonary Artery (LPA) stenosis (n=27, 32.14%) followed by isolated hypoplasia of Main Pulmonary Artery (MPA) (n=18, 21.43%) and supra-valvular stenosis in (n=11, 13.1%) patients. LPA was absent in one patient, while 2 patients had both absent right and left PA with segmental branch pulmonary arteries originating directly from MPA. Associated cardiac lesions included right aortic arch in 34 (15%), additional muscular VSD vary in 13 (5.5%), Patent Ductus Arteriosus (PDA) in 11 (6%) and Major Aortopulmonary Collateral Arteries (MAPCA) in 2 (1.9%) patients. Significant coronary artery abnormality was present in 10 (4.6%) children. CONCLUSION: Pulmonary artery abnormalities were present in 38.9% of patients with TOF. Isolated LPA origin stenosis and MPA hypoplasia were the most common abnormalities. Significant associated cardiac lesions were present in one-third of the patients and included PDA, additional muscular VSD, coronary artery abnormalities and MAPCA.

Evidence of abnormal left ventricular function in patients with thalassaemia major: an echocardiography based study.

BACKGROUND: Thalassaemia represent one of the most common single gene disorder causing a major public health problem in Pakistan. Nearly 100,000 people are born worldwide with this severe blood disorder every year. Over the last 3 decades, the development of regular transfusion therapy and iron chelation has dramatically improved the quality of life and transformed thalassaemia from a rapidly fatal disease to a chronic disease compatible with prolonged survival. Objective of this observational cross sectional study was to determine the effects of chronic anaemia and transfusional iron overload on the left ventricular function using Doppler echocardiography. METHODS: This study was conducted in the Department of Paediatric Cardiology, The Children's Hospital & Institute of Child Health, Lahore, Pakistan from 1st April 2006 to 30th September 2007. The study comprised of 50 consecutive cases of beta-Thalassaemia major and 30 controls with normal haemoglobin and electrophoresis pattern. Beta-Thalassaemia major patients were diagnosed on the basis of haemoglobin electrophoresis. Patients with any congenital or acquired heart disease, concurrent infective disorder and with history of cardiac surgery were excluded from the study. 2-D, M-mode and Doppler echocardiography was performed in all the study cases and controls. Statistical comparison of study cases and controls was conducted by using unpaired t-test. RESULTS: The age of the patients ranged from 2 years to 25 years with mean age of 9.65 years. Males were 34 (68%) and females were 16 (32%). None of the study cases was on regular chelation programme while 31 (62%) patients were on irregular chelation with single dose of intravenous desferrioxamine only at the time of blood transfusion. 19 (38%) of the patients had LV dysfunction in the form of isolated systolic dysfunction in 2 (4%), isolated diastolic dysfunction in 15 (30%) while global dysfunction in 2 (4%) of the patients. Left ventricular dimensions, stroke volume and E/A ratio were found considerably high in the study group. CONCLUSION: A very high percentage of Thalassaemia patients have cardiac involvement as LV dysfunction. This is mainly due to chronic anaemia, poor compliance with chelation therapy and non-availability of proper cardiac monitoring. Regular assessment of cardiac function may help a lot to improve the quality of life of these patients and may reduce the morbidity and mortality to a great extent.