Functional analysis of novel genetic variants of NKX2-5 associated with nonsyndromic congenital heart disease.

NKX2-5, a master cardiac regulatory transcription factor was the first known genetic cause of congenital heart diseases (CHDs). To further investigate its role in CHD pathogenesis, we performed mutational screening of 285 CHD probands and 200 healthy controls. Five coding sequence variants were identified in six CHD cases (2.1%), including three in the N-terminal region (p.A61G, p.R95L, and p.E131K) and one each in homeodomain (HD) (p.A148E) and tyrosine-rich domain (p.P247A). Variant-p.A148E showed tertiary structure changes and differential DNA binding affinity of mutant compared to wild type. Two N-terminal variants-p.A61G and p.E131K along with HD variant p.A148E demonstrated significantly reduced transcriptional activity of Nppa and Actc1 promoters in dual luciferase promoter assay supported by their reduced expression in qRT-PCR. Nonetheless, variant p.R95L affected the synergy of NKX2-5 with serum response factor and TBX5 leading to significantly decreased Actc1 promoter activity depicting a distinctive role of this region. The aberrant expression of other target genes-Irx4, Mef2c, Bmp10, Myh6, Myh7, and Myocd is also observed in response to NKX2-5 variants, possibly due to the defective gene regulatory network. Severely impaired downstream promoter activities and abnormal expression of target genes due to N-terminal variants supports the emerging role of this region during cardiac-developmental pathways.

Functionally significant, novel GATA4 variants are frequently associated with Tetralogy of Fallot.

Transcription factor GATA4 is known to play crucial role during heart development, regulating expression of several other key cardiogenic factors. Various GATA4 mutations are reported in familial as well as sporadic cases of congenital heart defects (CHDs). To estimate the prevalence and pathogenic potential of GATA4 variants in our CHD cohort, we have screened 285 CHD cases along with 200 controls by Sanger sequencing and identified 9 genetic variants (c.23C>A; p.Ala8Asp, c.25G>A; p.Ala9Thr, c.223G>T; p.Ala75Ser, c.383A>T; p.Glu128Val, c.397A>T; p.Ser133Cys, c.682T>A; p.Trp228Arg, c.1064C>G; p.Thr355Ser, c.1073G>C; p.Ser358Thr, and c.1220C>A; p.Pro407Gln) in 22 unrelated CHD probands (frequency:7.72%). Five of these are novel and located in the N-terminal transactivation domain (TAD) and first zinc finger domain. Majority C-terminal domain variants are polymorphic. Two of the TAD variants p.Glu128Val, p.Ser133Cys, and a first zinc finger variant p.Trp228Arg, impair combinatorial synergy of NKX2-5, SRF, and TBX5, suggesting potential role of these domains in GATA4 interactions with these factors. Decreased DNA-binding affinity with EMSA also supports this observation. Homology modeling and tertiary structure comparison show conformational changes in these variants. Interestingly, GATA4 variants are more frequently associated with ToF (45%; P = 0.0046) and PS (22.7%; P < 0.0001) in spite of abundance of septal defects in our study cohort.

Treatment of congenital non-ductal shunt lesions with the amplatzer duct occluder II.

Amplatzer Duct Occluder II (ADO II) is especially designed for closing long ducts in infants. The experience with off-label use of ADO II in non-ductal positions is limited. AIM: To evaluate feasibility of use of ADO II in non-ductal positions, incidence of complete heart block (CHB), advantages and disadvantages. MATERIAL AND RESULTS: Out of 79 defects closed with ADO II, 61 had perimembranous, 12 apical/mid-muscular ventricular septal defects (VSD), 4 Gerbode defects, one each of coronary arterio-venous fistula and aorto-right ventricular tunnel. Age ranged from 8 months to 21 years (mean 8.9 ± 4.02 years, median 9 years). The mean fluoroscopy time was 5.2 ± 1.1 min with range 4.2-9.2 min. Complete closure was achieved in all. Three cases developed transient junctional bradycardia, treated with steroids. One patient who developed CHB (1.3%) needed temporary pacing. DISCUSSION: ADO II is a low profile device. It can be easily delivered through a 5F guiding catheter and needs very short fluoroscopic time as arteriovenous loop is not needed. The cost is 1/3 of regular ventricular septal occluders. The CHB that is a major challenge for closure of VSDs is less common with soft, specially designed ADO II, which does not compress the conducting system. CONCLUSIONS: Use of the ADO II in non-ductal positions can be achieved with high success and low complication rates, especially CHB; its use is also associated with significantly reduced procedure time and device cost. Device size availability restricts use of the ADO II to defects up to 6 mm in diameter. © 2013 Wiley Periodicals, Inc.

Unusual cases of right-sided and left-sided May-Thurner syndrome.

May-Thurner syndrome is a rare clinical entity involving venous obstruction of the left lower extremity. The May-Thurner syndrome is a phenomenon commonly described as an acquired stenosis of the left common iliac vein secondary to compression of the left common iliac vein between the right common iliac artery and the underlying vertebral body. We report one case of May-Thurner syndrome, and another rare case of reverse May-Thurner syndrome, incidently detected during intervention, in a case of aortic stenosis and mitral stenosis with dextrocardia and situs inversus.

Percutaneous device closure of patent ductus arteriosus with pulmonary artery hypertension: long-term results.

UNLABELLED: Device closure of patent ductus arteriosus (PDA) is treatment of choice. But device closure in presence of pulmonary artery hypertension (PAH) remains a challenge. Data on patient selection, technical considerations, and complications are limited. AIM: To know the challenges and efficacy of device closure of PDA with PAH. MATERIALS AND RESULTS: Out of 1,325 cases of device closure of PDA, 246 (18.6%) with PAH formed the study material. To test the feasibility, chosen device is used to occlude PDA for ten minutes without oxygen inhalation. The device is released only if PAH reduced. PAH decreased in all except in 1 patient after closure with muscular ventricular septal occluder (MVSDO), pulmonary artery pressure (PAP) transiently increased (became supra-systemic), without significant reduction in aortic pressure. Device embolized in 8 patients (3.3%). Percutaneous retrieval was done in 4 (by snare in 2 and by fixing the cable to device in 2) and replaced with bigger devices. The surgical removal of the embolized MVSDO and ligation was done in 4 cases. All patients were on oral sildenafil and bosentan until PAP regressed to normal. Follow up was from 6 months to 9 years. No residual shunt in any patient on follow-up. The PAP regressed to normal in all except 5 cases (2.03%) of Down's syndrome with systemic PAP. CONCLUSIONS: Device closure of PDA with PAH is feasible, safe in all age groups. Temporary PDA occlusion with device is effective and time saving for evaluating pulmonary vascular reactivity. Device embolization in aorta is higher with severe PAH. Novel method of retrieval is effective.

Multiple intracardiac tumors secondary to non-Hodgkin lymphoma.

Primary tumors of the heart are rare and are usually benign. Disseminated malignancies and lymphomas rarely involve the heart. Non-Hodgkin lymphomas (NHL) are one of the common hematological malignancies that can affect the heart usually in the form of pericardial effusion. Involvement as intracardiac masses in NHL is extremely rare and usually described in autopsy series. We report a case of NHL and massive intracardiac involvement diagnosed on echocardiographic assessment. Primary cardiac NHL is extremely rare and accounts for 1-2 % of primary cardiac tumors involving the right versus left atrium at a ratio of about 8:1 (Ceresoli et al., Cancer 80:1497-1506, 1997; Delmas-Marsalet et al., Nouv Rev Fr Hematol 37:223-230, 1995). The intracardiac secondaries in NHL are extremely rare. They are usually described in autopsy series. We report the detection of secondaries in the cardiac chambers, on interatrial septum and in atrioventricular groove, diagnosed by transthoracic echocardiography.

Transposition of great arteries with natural partial Senning: A rare case report.

The association of transposition of the great arteries (TGA) and anomalous pulmonary venous connection is extremely rare. Children with transposition of the great arteries improved dramatically with the advent of the atrial repair. In this report, we describe a 40-day old male infant with TGA and associated anomalous pulmonary venous connection who presented with the history of cyanosis and hurried breathing. This patient underwent successful balloon atrial septostomy and discharged with uneventful recovery.

Purulent pericarditis with quadruple valve endocarditis.

BACKGROUND: Infective endocarditis (IE) is a disease with a highly varied clinical picture. Spread of the infection to the pericardium from the infective endocardium is uncommon and IE involving all 4 cardiac valves is also a very rare occurrence, being more common in intravenous drug users (IVDU). CASE REPORT: A 7-year-old boy had purulent pericarditis with infective endocarditis (IE) on all 4 cardiac valves and vegetation in the left ventricular and right atrial cavity. Culture of the pericardial fluid grew methicillin-resistant staphylococcus aureus (MRSA) sensitive to tigecycline. The child made a dramatic improvement with tigecycline treatment. CONCLUSIONS: Aggressive management with pericardiocentesis and appropriate antibiotics can show remarkable clinical improvement. Tigecycline can be used safely and effectively as a life-saving drug in children.

Echocardiography in the diagnosis of apical non-compaction associated with congenital heart diseases.

BACKGROUND: Isolated left ventricular non-compaction has been reported extensively. However, apical non-compaction of both ventricles and the interventricular septum (IVS) is not often reported in the literature. The objective of our study is to evolve the echocardiographic diagnostic criteria and to assess the types and impact of the associated lesions in "apical non-compaction". METHODS AND RESULTS: Seventy consecutive cases that fulfilled standard echocardiographic criteria for non-compaction of the left ventricle and, in addition, N/C ratio of >3 for the right ventricle and apical IVS formed the material. The age of patients ranged from 3 days to 35 years, with 37 males and 33 females. The associated lesions were present in all 70 cases: 62 had acyanotic (88.6 %) and 8 had cyanotic congenital heart diseases (11.4 %). Of the 70 cases, 18 had pump failure (25.7 %): 8 cases had left ventricular dysfunction, 7 had right ventricular dysfunction, and 3 had biventricular dysfunction; 33 (47.1 %) had pulmonary hypertension, 2 (2.9 %) had thrombus, and 1 (1.4 %) had tachyarrhythmia. Pump failure was worsened by volume overload in 33.9 % and by pressure overload in 8.1 % of cases. Some very rare lesions were detected. All 70 cases had Swiss cheese appearance of the apical half of the IVS, looking like the delta of a river. CONCLUSION: All of the apical non-compaction syndrome cases had associated lesions, mostly acyanotic congenital heart disease with volume overload, rather than obstructive lesions. Transthoracic echocardiography plays an important role in the diagnosis of apical non-compaction syndrome and associated lesions that worsen the pump failure.

Percutaneous closure of pseudoaneurysm of common iliac artery with amplatzer duct occluder II.

Seven-year-old boy presented with pain in right lower limb and abdomen after a fall from a bullock cart. He was referred for management of pseudoaneurysm of the right common iliac artery. After CT angiogram, the vascular surgeon opined that child was not suitable for surgical patch or graft or endovascular stenting as there was no landing zone for the stent. Hence the child was treated with transcatheter closure with two Amplatzer duct occluder II (ADO II). On follow-up the symptoms and bruit disappeared. To the best of our knowledge this is the first case of pseudoaneurysm, treated with ADO II.

Closure of aorto-right ventricular tunnel with Amplatzer duct occluder II.

Aorto-right ventricular tunnel (ARVT) is a very rare, congenital, abnormal extracardiac channel that connects the ascending aorta at or above the sinotubular junction to the cavity of the right ventricle. Only 16 cases have been reported thus far in the English literature. We report the first transcatheter closure of ARVT with the Amplatzer duct occluder II in an infant, with both coronary arteries arising from the left coronary sinus and with biventricular apical non-compaction.

Transcatheter closure of left coronary cameral fistula with Amplatzer duct occluder II.

The surgical and transcatheter coil closure of coronary arterial fistulas are described in the literature. We report our experience with the successful transcatheter closure of a coronary arterial fistula, arising from the left coronary artery and draining into the right ventricle, with the new Amplatzer duct occluder II device.