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1.  Transcatheter Ventricular Septal Defect (VSD) Creation for Restrictive VSD in Double-Outlet Right Ventricle 
Pediatric Cardiology  2012;34(3):743-747.
Background
Double-outlet right ventricle (DORV) with a restrictive ventricular septum is a rare but highly morbid phenomenon that can be complicated by progressive left ventricular hypertrophy, arrhythmias, aneurysm formation, severe pulmonary hypertension, and death in the newborn. Surgical creation or enlargement of a ventricular septal defect (VSD) is palliative but may damage the conduction system or the atrioventricular valves in the newborn. This report presents a transcatheter approach to palliation for a newborn that had DORV with a restrictive ventricular septum.
Methods/Results
A full-term infant girl (2.9 kg) referred for hypoxia (80 % with room air) and murmur was found to have DORV, interrupted inferior vena cava, and restrictive VSD (95-mmHg gradient). Transhepatic access was performed, and an internal mammary (IM) catheter was advanced through the atrial septal defect and into the left ventricle. By transesophageal echocardiographic guidance, a Baylis radiofrequency perforation wire was used to cross the ventricular septum, and the defect was enlarged using a 4-mm cutting balloon. A bare metal stent then was deployed to maintain the newly created VSD. The patient did well after the procedure but required pulmonary artery banding 4 days later. She returned 5 months later with cyanosis and the development of obstructing right ventricle muscle bundles, requiring further surgical palliation.
Conclusions
This report describes the first transcatheter creation of VSD in DORV with a restrictive ventricular septum in a newborn infant. Use of the radiofrequency catheter in combination with cutting balloon dilation and stent implantation is an efficient method for creating a VSD in such a patient.
Electronic supplementary material
The online version of this article (doi:10.1007/s00246-012-0337-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s00246-012-0337-1
PMCID: PMC3586406  PMID: 22580772
Restrictive VSD; Transcatheter VSD creation; VSD stenting
2.  Combined obstructive hypertrophic cardiomyopathy and double outlet right ventricle in an infant with Down syndrome 
Patient: Male, 2
Final Diagnosis: Obstructive hypertrophic cardiomyopathy
Symptoms: Congestive heart failure
Medication: —
Clinical Procedure: Left ventricular septal myectomy • repair of congenital heart disease
Specialty: Cardiology
Objective:
Rare disease
Background:
Hypertrophic cardiomyopathy (HCM) is uncommon in Down syndrome (DS). When combined with congenital heart disease (CHD) both morbidity and mortality may be greater compared to CHD alone. Whether HCM in DS patients is related to having trisomy 21 versus a second site mutation is unknown.
Case Report:
We report a case of severe HCM in an infant with DS in combination with double outlet right ventricle (DORV) who required surgery for relive of sub-aortic obstruction and congestive heart failure. We predicted that this infant would have a second site mutation involving either a sarcomeric protein or metabolic disorder as a cause for his HCM. Using current genetic and metabolic testing as well as histologic assessment of excised cardiac tissue we sought to further characterize the nature of the HCM. A successful resection of sub-aortic stenosis and DORV repair was performed. Genetic and metabolic testing was negative for gene defects and/or syndromes commonly associated with familial HCM. Excised cardiac tissue from the ventricular septum exhibited myocyte hypertrophy and sub-endocardial fibrosis but no sarcomeric disarray, myocyte fibrosis or glycogen storage. Metabolic testing for common forms of mitochondrial disease was negative. Post-operative echocardiograms show persistent, non-obstructive septal hypertrophy.
Conclusions:
Unlike prior reports, this child required a surgical intervention to relieve his sub-aortic obstruction. Thus, HCM in this population can be more serious that previously suspected. Although testing did not reveal the cause of his HCM, we still suggest screening for known causes of HSC until the etiology of the HCM in DS is well understood.
doi:10.12659/AJCR.889581
PMCID: PMC3821707  PMID: 24222815
conal-truncal defect; hypertrophic cardiomyopathy; Down syndrome
3.  Single-centre experience of 101 paediatric and adult Ross procedures: mid-term results 
We aimed to determine outcomes for the Ross procedure in paediatric and adult patients, with particular emphasis on survival, complication and reintervention rates. A retrospective review of 101 patients who had the Ross procedure in a congenital cardiac surgical centre serving a population of approximately 2.5 million was performed. There were 69 adults and 32 children with a mean age of 24.8 ± 13.9 years. Indications for surgery were aortic stenosis (48), regurgitation (10), mixed disease (35) and complex left outflow tract obstruction (8). The mean follow-up duration was 4.7 ± 3.7 years. The mini-inclusion technique was used to incorporate the autograft, and in all cases, pulmonary homografts were placed in the right ventricular outflow tract. Sub-aortic resection was also performed in six and Ross–Konno operations in eight patients. There were no early deaths and there was one late death secondary to endocarditis. Freedom from reintervention was 92% at 5 years and 77% at 10 years. Children were significantly more likely to require reintervention (16%, 5 of 32 versus 4%, 3 of 69, P = 0.05). The Ross procedure carries low early and mid-term mortality, and reintervention rates appear acceptable. The Ross procedure should be considered a feasible alternative to prosthetic valves in patients who require aortic valve replacement.
doi:10.1093/icvts/ivr149
PMCID: PMC3329284  PMID: 22361123
Aortic valve; Mortality; Reoperation
4.  Surgical Management of Left Ventricular Outflow Tract Obstruction after Biventricular Repair of Double Outlet Right Ventricle 
Journal of Korean Medical Science  2010;25(3):374-379.
Regardless of the preoperative morphology and the type of operation, left ventricular outflow tract obstruction (LVOTO) after biventricular repair of double outlet right ventricle (DORV) may develop. This report presents our 10-yr experience with surgical management of LVOTO after biventricular repair of DORV. Between 1996 and 2006, 15 patients underwent reoperation for subaortic stenosis after biventricular repair of DORV. The mean age at biventricular repair was 23.3±18.3 months (1.1-64.2). Biventricular repairs included tunnel constructions from the left ventricle to the aorta in 14 cases and an arterial switch operation in one. The mean left ventricle-to-aorta peak pressure gradient was 54.0±37.7 mmHg (15-140) after a mean follow-up of 9.5±6.3 yr. We performed extended septoplasty in nine patients and fibromuscular resection in six. There were no early or late mortality. There was one heart block and one aortic valve injury after an extended septoplasty, and two and one after a fibromuscular resection. No patient required reoperation for recurrent subaortic stenosis. The mean pressure gradient was 11.2±11.4 mmHg (0-34) after a mean follow-up of 5.6±2.7 yr. Extended septoplasty is a safe and effective method for the treatment of subaortic stenosis, especially in cases with a long-tunnel shaped LVOTO.
doi:10.3346/jkms.2010.25.3.374
PMCID: PMC2826730  PMID: 20191035
DORV; Aortic Stenosis, Subvalvular
5.  Spectrum of congenital heart defects and extracardiac malformations associated with chromosomal abnormalities: results of a seven year necropsy study 
Heart  1999;82(1):34-39.
OBJECTIVE—To analyse the spectrum of congenital heart malformations, the frequency of extracardiac malformations, and the proportion of chromosome aberrations among fetuses sent for necropsy.
MATERIAL—Necropsies were performed on 815 fetuses—448 induced abortions (55%), 220 spontaneous abortions (27%), and 147 stillbirths (18%)—during a seven year period (1991-97) in the department of pathology of the Charité Medical Centre in Berlin. A congenital heart defect was identified in 129 cases (16%). For all 129 fetuses, karyotyping and an ultrasound examination had been performed.
RESULTS—Congenital heart defects were present in 22% of induced abortions (99 cases), 9% of spontaneous abortions (20 cases), and 7% of stillbirths (10 cases). The heart malformations were classified into 13 categories. A fetus with more than one defect was included only in the category of the most serious defect. The malformations in order of frequency were: ventricular septal defect (VSD) (28%), atrioventricular septal defect (AVSD) (16%), hypoplastic left heart (HLH) (16%), double outlet right ventricle (DORV) (12%), coarctation of the aorta (CoA) (6%), transposition of the great arteries (TGA) (4%), aortic valve stenosis (AoVS) (4%), tetralogy of Fallot (TOF) (3%), truncus arteriosus communis (TAC) (3%), pulmonary valve stenosis/pulmonary valve atresia (PaVS/PaVA) (3%), tricuspid atresia (TA) (3%), single ventricle (SV) (1.5%), and atrial septal defect (ASD) (0.5%). The most common congenital heart defects were VSD, AVSD, HLH, and DORV, which made up 72% of all the cases. In 11 cases the heart defect was isolated (no other cardiovascular or extracardiac malformations present), 85 cases (66%) were associated with additional cardiac malformations, 85 cases (66%) were associated with extracardiac malformations, and chromosome anomalies were detected in 43 cases (33%).
CONCLUSIONS—Fetal congenital heart malformations are common. These defects are often associated with other cardiovascular and extracardiac malformations, as well as with chromosome anomalies. Complex heart defects such as AVSD, HLH, and DORV are frequent in fetuses, as they often lead to spontaneous abortion or stillbirth or, after prenatal diagnosis, to deliberate termination of pregnancy.


Keywords: congenital heart defects; extracardiac malformations; chromosomal abnormalities; necropsy examination
PMCID: PMC1729082  PMID: 10377306
6.  Hybrid intraoperative pulmonary artery stenting in redo congenital cardiac surgeries 
Indian Heart Journal  2014;66(1):45-51.
Objective
Reconstruction of branch pulmonary arteries (PAs) can be challenging in redo congenital heart surgeries. Treatment options like percutaneous stent implantation and surgical patch angioplasty may yield suboptimal results. We present our experience with hybrid intraoperative stenting which may be an effective alternative option.
Methods
We retrospectively analyzed data of all patients with PA stenosis who underwent intraoperative PA branch stenting in our institution between January 2011 and December 2012.
Results
Ten patients [6 females, median age 10 (1.4 to 37) years], underwent hybrid stenting of the PA. Primary cardiac diagnoses were pulmonary atresia with ventricular septal defect (VSD) in three patients, pulmonary atresia with intact ventricular septum in two, Tetralogy of Fallot (TOF) in one, Double outlet right ventricle (DORV) with pulmonary stenosis (PS) in one, complex single ventricle in two and VSD with bilateral branch PA stenosis in one patient. Concomitant surgeries were revision/reconstruction of RV-PA conduit in 4, Fontan completion in 4, repair of TOF with conduit placement in 1 and VSD closure in 1 patient. The left PA was stented in 7, the right in 2 and both in 1, with a total of 11 stents. There were no complications related to stent implantation. Two early postoperative deaths were unrelated to stent implantation. At mean follow-up period of 14.8 (12–26) months, stent position and patency were satisfactory in all survivors. None of them needed repeat dilatation or surgical reintervention.
Conclusion
Hybrid stenting of branch PA is a safe and effective option for PA reconstruction in redo cardiac surgeries. With meticulous planning, it can be safely performed without fluoroscopy.
doi:10.1016/j.ihj.2013.12.018
PMCID: PMC3946464  PMID: 24581095
Pulmonary artery; Hybrid; Redo surgery; Stent
7.  One-stage neonatal repair of complex aortic arch obstruction or interruption. Recent experience at Texas Children's Hospital. 
Texas Heart Institute Journal  1997;24(4):317-321.
The optimal surgical approach for complex aortic coarctation or an interrupted aortic arch with associated intracardiac defects is not universally agreed upon. We reviewed our experience with 18 consecutive patients (10 with coarctation, 8 with interrupted aortic arch) undergoing a 1-stage repair through median sternotomy between September of 1995 and February of 1997. Age at operation ranged from 3 days to 3 months (mean 23 days) and weight ranged from 1,700 g to 5,100 g (mean 3,350 g). Under hypothermic circulatory arrest, the aortic arch was reconstructed using native tissue-tissue anastomoses, and coexisting intracardiac anomalies were repaired by standard techniques. All patients survived the procedure and were ultimately discharged from the hospital. There were 2 late deaths in the interrupted aortic arch group, 1 during reoperation for subaortic stenosis and the other from noncardiac causes 5 months after discharge. Another interrupted aortic arch patient required a Ross-Konno procedure 8 months later. There has been no recoarctation among the 16 survivors. Thus a 1-stage repair for complex aortic arch obstruction in neonates can be accomplished with low operative risk, although long-term outcome is strongly influenced by the presence of subaortic obstruction.
PMCID: PMC325474  PMID: 9456485
8.  Cardiac Teratogenicity in Mouse Maternal Phenylketonuria: Defining phenotype parameters and genetic background influences 
Molecular genetics and metabolism  2012;107(4):650-658.
Maternal phenylketonuria (MPKU) is a syndrome including cardiovascular malformations (CVMs), microcephaly, intellectual impairment, and small for gestational age, caused by in-utero exposure to elevated serum phenylalanine (Phe) due to PKU in the mother. It is becoming a public health concern as more women with PKU reach child bearing age. Although a mouse model of PKU, BTBR Pahenu2, has been available for 20 years, it has not been well utilized for studying MPKU. We used this model to delineate critical parameters in Phe cardiovascular teratogenicity and study the effect of genetic background. Dosing and timing experiments were performed with the BTBR Pahenu2 mouse. A dose response curve was noted, with CVM rates at maternal serum Phe levels <360 μM (control), 360 – 600 μM (low), 600 – 900 μM (mid), and >900μM (high) of 11.86%, 16.67%, 30.86%, and 46.67% respectively. A variety of CVMs were noted on the BTBR background, including double outlet right ventricle (DORV), aortic arch artery (AAA)abnormalities, and ventricular septal defects (VSDs). Timed exposure experiments identified a teratogenic window from embryonic day 8.5-13.5, with higher rates of conotruncal and valve defects occurring in early exposure time and persistent truncus arteriosus (PTA) and aortic arch branching abnormalities occurring with late exposure. Compared to the BTBR strain, N10+ Pahenu2 congenics on the C3H/HeJ background had higher rates of CVMs in general and propensity to left ventricular outflow tract (LVOT) malformations, while the C57B/L6 background had similar CVM rates but predominately AAA abnormalities. We have delineated key parameters of Phe cardiovascular teratogenicity, demonstrated the utility of this MPKU model on different mouse strains, and shown how genetic background profoundly affects the phenotype.
doi:10.1016/j.ymgme.2012.08.001
PMCID: PMC3504168  PMID: 22951387
9.  Ross-Konno Operation for Patients with Shone Complex 
Texas Heart Institute Journal  2010;37(2):240-241.
We report the cases of 2 pediatric patients who had Shone complex. Each child had severe left ventricular outflow tract obstruction and marginal mitral obstruction, and both underwent the Ross-Konno operation. The mitral valve was left alone. Both patients survived the operations, and serial follow-up echocardiography up to 4 years later showed a decreased or decreasing trend in the peak mitral diastolic velocity. The Ross-Konno procedure can be an acceptable approach for a subgroup of patients who have Shone complex.
PMCID: PMC2851429  PMID: 20401305
Aortic valve stenosis/congenital/surgery; cardiac surgical procedures/methods; child, preschool; heart defects, congenital/mortality/pathology/surgery; mitral valve/abnormalities/pathology/surgery; reoperation; risk assessment; treatment outcome; ventricular outflow obstruction/complications/congenital/surgery
10.  Double outlet right ventricle: clinical and anatomical spectrum. 
Thorax  1978;33(3):283-289.
Thirty-two patients with double outlet right ventricle (DORV) were studied between 1960 and 1976. Associated congenital defects frequently compounded the difficulty of clinical diagnosis. Cardiac catheterisation was performed in 27 patients, and the ventriculograms were studied with particular regard to the relative positions of the great vessels to each other and to the ventricular septal defect. These relationships determine which corrective operation is possible. Correction has been performed in 12 patients with a perioperative mortality of 25%. Although mitral-aortic discontinuity was demonstrated in all cases, consideration of the anatomical spectrum included in the term DORV suggests that discontinuity is not an essential feature. In common with other clinical data and in contrast with necropsy studies, none of our patients was found to show the normal relationship of the great vessels to each other, in which the aorta lies posterior and to the right of the pulmonary artery. The reason for this difference between the clinical and necropsy findings is not apparent. A similar disparity was shown with regard to pulmonary stenosis, which was demonstrated at catheterisation in 68% of the 27 patients (mean gradient 68 +/- 3 mmHg), in contrast with incidences of 18% and 25% in recent necropsy series. Patients in the necropsy studies were frequently neonates or infants, in whom death may have been the result of intractable cardiac failure secondary to excessive pulmonary blood flow. In older patients without pulmonary stenosis and with pulmonary hypertension, frequent observation is imperative so that surgical treatment can be instituted before the development of irreversible pulmonary vascular disease.
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PMCID: PMC470886  PMID: 684664
11.  SURGICAL CORRECTION OF COMBINED DOUBLE-OUTLET RIGHT VENTRICLE AND TAUSSIG-BING SYNDROME 
Cardiovascular Diseases  1979;6(1):12-25.
Total surgical correction of a Taussig-Bing type double outlet right ventricle (DORV) was successfully performed in a severely cyanotic 3-year-old girl. The malformation was associated with bilateral conus, d-transposition of the great arteries, d-loop, and a subpulmonary ventricular septal defect (VSD) without significant pulmonary stenosis in situs solitus. It was impossible to create a tunnel repair by resecting the markedly hypertrophied muscular conus that separated the aortic valve from the subpulmonary ventricular septal defect. Therefore, the VSD was repaired with a Dacron patch, transforming the double outlet right ventricle into a transposition, after which total correction was achieved by means of a Mustard procedure.
Images
PMCID: PMC287762  PMID: 15216021
12.  Targeted deletion of Hand2 in cardiac neural crest-derived cells influences cardiac gene expression and outflow tract development 
Developmental biology  2010;341(1):291-304.
The basic helix-loop-helix DNA binding protein Hand2 has critical functions in cardiac development both in neural crest-derived and mesoderm-derived structures. Targeted deletion of Hand2 in the neural crest has allowed us to genetically dissect Hand2-dependent defects specifically in outflow tract and cardiac cushion independent of Hand2 functions in mesoderm-derived structures. Targeted deletion of Hand2 in the neural crest results in misalignment of the aortic arch arteries and outflow tract, contributing to development of double outlet right ventricle (DORV) and ventricular septal defects (VSD). These neural crest-derived developmental anomalies are associated with altered expression of Hand2-target genes we have identified by gene profiling. A number of Hand2 direct target genes have been identified using ChIP and ChIP-on-chip analyses. We have identified and validated a number of genes related to cell migration, proliferation/cell cycle and intracellular signaling whose expression is affected by Hand2 deletion in the neural crest and which are associated with development of VSD and DORV. Our data suggest that Hand2 is a multifunctional DNA binding protein affecting expression of target genes associated with a number of functional interactions in neural crest-derived cells required for proper patterning of the outflow tract, generation of the appropriate number of neural crest-derived cells for elongation of the conotruncus and cardiac cushion organization. Our genetic model has made it possible to investigate the molecular genetics of neural crest contributions to outflow tract morphogenesis and cell differentiation.
doi:10.1016/j.ydbio.2010.02.001
PMCID: PMC2854279  PMID: 20144608
Hand2(dHand); neural crest; bHLH; heart; outflow tract; cardiac cushion; cell type-specific gene regulation; gene microarray
13.  Aortic Translocation with Autologous Tissue 
Texas Heart Institute Journal  2007;34(4):420-422.
Aortic translocation, although technically demanding, could be an excellent surgical option for d-transposition of the great vessels and left ventricular outflow tract obstruction. We report a modification of the aortic translocation technique that uses autologous tissue. The aortic root is mobilized from the right ventricle with an extension of infundibular free-wall muscle for use in closure of the ventricular septal defect, which is similar to the technique for harvesting pulmonary autograft in the Ross-Konno procedure. Our modification may offer an even better surgical outcome for aortic translocation.
PMCID: PMC2170485  PMID: 18172521
Abnormalities, multiple/surgery; aorta/surgery; cardiac surgical procedures; heart ventricles/surgery; transposition of great vessels/surgery
14.  Implication of anterior septal malalignment in isolated ventricular septal defect. 
British Heart Journal  1995;74(2):180-185.
OBJECTIVE--The aim was to define the long term prognosis of isolated ventricular septal defect (VSD) with anteriorly malaligned outlet septum. DESIGN--Cohort study. SETTING--University hospital, tertiary medical care centre. PATIENTS--Between July 1986 and June 1993, 63 patients were studied with an isolated VSD and anteriorly malaligned outlet septum (59 perimembranous; 4 muscular outlet). MAIN OUTCOME MEASURES--The diagnosis of septal malalignment, aneurysmal transformation, right ventricular obstruction, subaortic ridge, and aortic valve prolapse was based on echocardiographic criteria, then confirmed by angiography in 33 patients and by surgery in 28. An actuarial curve for each event was obtained by Kaplan-Meier non-parametric analysis and the significance was examined by log-rank test. RESULTS--Aneurysmal transformation decreased the size of the VSD in 52% of the patients, but was also associated with the appearance of subaortic ridge (p < 0.05). Progressive obstruction in the right ventricle was observed in 51%, more often in those without aneurysmal transformation (p < 0.05). Aortic valve prolapse was quite common whether or not aneurysmal transformation occurred (33% and 23%, respectively). This was attributed to the location of the VSD and the anterior malalignment of the outlet septum. Surgery was performed in 28 patients at a median age of 50 months because of significant left to right shunt (n = 5), or the development of obstruction in right ventricle (n = 9), aortic valve prolapse (n = 3), or combinations (n = 11). The presence of subaortic ridge per se was not considered to be a surgical indication. CONCLUSIONS--Anteriorly malaligned VSDs have variable presentation. Careful echocardiographic evaluation is needed to identify various combinations of progressive right ventricular obstruction, aneurysmal transformation, subaortic ridge, or aortic valve prolapse. In extreme cases a patient may have a pathology complex comprising right ventricular outflow obstruction, subaortic ridge, aortic valve prolapse, and anteriorly malaligned VSD.
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PMCID: PMC483996  PMID: 7546999
15.  Loss of miRNAs in neural crest leads to cardiovascular syndromes resembling human congenital heart defects 
Rationale
Congenital heart defects (CHD) represent the most common human birth defects. Even though the genetic cause for these syndromes has been linked to respective candidate genes, the underlying molecular mechanisms are still largely unknown. Disturbance of neural crest cell (NCC) migration into the derivatives of the pharyngeal arches and pouches can account for many of the developmental defects.
Objective
To investigate the function of miRNA in NCCs and cardiovascular system.
Methods and Results
we deleted Dicer from neural crest cell (NCC) lineage and showed that Dicer conditional mutants exhibit severe defects in multiple craniofacial and cardiovascular structures, many of them are observed in human NCCS patients. We found that cranial NCCs require Dicer for their survival and deletion of Dicer led to massive cell death and complete loss of NCC-derived craniofacial structures. In contrast, Dicer and miRNAs were not essential for the survival of cardiac NCCs. However, the migration and patterning of these cells were impaired in Dicer knockout mice, resulting in a spectrum of cardiovascular abnormalities, including Type B Interrupted Aortic Arch (IAA-B), Double Outlet Right Ventricle (DORV) and Ventricular Septal Defect (VSD). We show that Dicer loss-of-function was, at least in part, mediated by miR-21 and miR-181a, which in turn, repressed the protein level of Sprouty 2, an inhibitor of Erk1/2 signaling.
Conclusion
Our results uncovered a central role for Dicer and miRNAs in neural crest cells survival, migration and patterning in craniofacial and cardiovascular development which, when mutated, lead to congenital neuro-craniofacial-cardiac defects.
doi:10.1161/ATVBAHA.110.213306
PMCID: PMC2988089  PMID: 20884876
microRNAs; neural crest cells; Dicer; cardiovascular development
16.  Morphology of left ventricular outflow tract structures in patients with subaortic stenosis and a ventricular septal defect. 
British Heart Journal  1994;72(3):251-260.
OBJECTIVE--To compare the incidence and prognosis of subaortic stenosis associated with a ventricular septal defect and to define the morphological basis of subaortic stenosis. DESIGN--Presentation and follow up data on 202 patients with subaortic stenosis seen at the Royal Liverpool Children's Hospital between 1 January 1960 and 31 December 1991 were reviewed. Survivors were traced to assess their current clinical state. Necropsy specimens of 291 patients with lesions associated with subaortic stenosis were also examined. RESULTS--In the clinical study; 65 (32.1%) of the 202 patients with subaortic stenosis had a ventricular septal defect (excluding an atrioventricular septal defect). 32 of these patients had a short segment (fibromuscular) subaortic stenosis. 33 had subaortic stenosis produced by deviation of muscular components of the outflow tracts. In 17 patients (51.5%) this was caused by posterior deviation or extension of structures into the left ventricular outflow tract, resulting in obstruction above the ventricular septal defect. In the other 16 patients (48.5%) there was over-riding of the aorta with concordant ventriculoarterial connections, (without compromise to right ventricular outflow) producing subaortic stenosis below the ventricular septal defect. Additional fibrous obstruction occurred in 39% of the patients with deviated structures. The age at presentation was lower (P < 0.01) in patients with deviated structures (median (range) 0.4 (0 to 9.2) months) than in those with short segment obstruction (median (range) 4.2 (0 to 84.9) months). The incidence of aortic arch obstruction was higher (P < 0.002) in patients with deviated structures than in those with short segment obstruction (38%). In the morphological study 35 pathological specimens showed obstructive muscular structures in the left ventricular outflow tract either above or below the ventricular septal defect. 16 had either posterior deviation of the outlet septum or extension of the right ventriculoinfundibular fold, or both of these together into the left ventricle. 19 had anterior deviation of the outlet septum into the right ventricle with overriding of the aorta (without compromise to right ventricular outflow). The earliest age at which additional fibrous obstruction was seen was 9 months. The aortic valve circumference was small in 18% of specimens. FOLLOW UP--The median (range) duration of follow up in survivors from the clinical study was 6.6 (1 to 25.7) years. 16 patients with deviated musculature (49%) and 16 with short segment fibromuscular stenosis (50%) underwent operation for subaortic stenosis. Patients with deviated structures were younger at operation than those with short segment stenosis (P < 0.005). Patients with posterior deviation or extension of structures into the left ventricular outflow tract underwent operation for subaortic stenosis more frequently (P < 0.05) than those with anterior deviation of the outlet septum and aortic override. The ventricular septal defect required surgical closure more frequently (P < 0.005) in patients with deviation (93.9%) than in those with short segment obstruction (21.9%). There was no significant difference in the mortality between patients with deviation (27%) and those with short segment obstruction (12%). CONCLUSIONS--32% of patients in the clinical study with subaortic stenosis had a ventricular septal defect. Only 51% of these had obstructive and deviated muscular structures in the left ventricular outflow tract. These patients had a significantly higher incidence of aortic arch obstruction and required surgery for subaortic stenosis at a younger age than those with short segment obstruction. The ventricular septal defect also required surgical closure more frequently in those patients with deviation. The morphological study defined the two sites of obstruction. The presence or absence and type of deviation should be clearly defined in all patients with a ventricular septal defect,
Images
PMCID: PMC1025511  PMID: 7946776
17.  Myocardial deletion of Smad4 using a novel α skeletal muscle actin Cre recombinase transgenic mouse causes misalignment of the cardiac outflow tract 
SMAD4 acts as the converging point for TGFβ and BMP signaling in heart development. Here, we investigated the role of SMAD4 in heart development using a novel α skeletal muscle actin Cre recombinase (MuCre) transgenic mouse strain. Lineage tracing using MuCre/ROSA26LacZ reporter mice indicated strong Cre-recombinase expression in developing and adult heart and skeletal muscles. In heart development, significant MuCre expression was noted at E11.5 in the atrial, ventricular, outflow tract and atrioventricular canal myocardium, but not in the endocardial cushions. MuCre-driven conditional deletion of Smad4 in mice caused double outlet right ventricle (DORV), ventricular septal defect (VSD), impaired trabeculation and thinning of ventricular myocardium, and mid-gestational embryonic lethality. In conclusion, MuCre mice effectively delete genes in both heart and skeletal muscles, thus enabling the discovery that myocardial Smad4 deletion causes misalignment of the outflow tract and DORV.
PMCID: PMC2945925  PMID: 20877696
heart; myogenesis; transforming growth factor beta; SMAD; Marfan syndrome.
18.  Transatrial repair of double-outlet right ventricle in infants. 
Thorax  1982;37(5):371-375.
In three infant cases of double outlet right ventricle (DORV), two with normally related great arteries (NGA) and one with side-by-side great arteries, a transatrial repair was carried out. In all three cases, the results were excellent. It is concluded that in the small baby with DORV with NGA and in DORV with side-by-side great arteries with a hypoplastic crista, a transatrial repair should be successful. This is dependent on the VSD being in the perimembranous (and, therefore, subaortic) location and on the absence of infundibular pulmonary stenosis. In all other varieties of DORV the repair should probably be done through the ventricle.
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PMCID: PMC459319  PMID: 7112474
19.  Ross-Konno and Endocardial Fibroelastosis Resection After Hybrid Stage I Palliation in Infancy: Successful Staged Left-Ventricular Rehabilitation and Conversion to Biventricular Circulation After Fetal Diagnosis of Aortic Stenosis 
Pediatric Cardiology  2010;32(2):211-214.
We report a patient who presented during fetal life with severe aortic stenosis, left-ventricular dysfunction, and endocardial fibroelastosis (evolving hypoplastic left heart syndrome). Management involved in utero and postnatal balloon aortic valvuloplasty for partial relief of obstruction and early postnatal hybrid stage I palliation until recovery of left-ventricular systolic function had occurred. The infant subsequently had successful conversion to a biventricular circulation by combining resection of endocardial fibroelastosis with single-stage Ross-Konno, aortic arch reconstruction, hybrid takedown, and pulmonary artery reconstruction.
doi:10.1007/s00246-010-9841-3
PMCID: PMC3033510  PMID: 21107553
Aortic stenosis; Fetal balloon aortic valvuloplasty; Fetal intervention; Hypoplastic left heart syndrome; Resection of endocardial fibroelastosis; Stage 1 hybrid
20.  The Phenotypic Spectrum of ZIC3 Mutations Includes Isolated d-Transposition of the Great Arteries and Double Outlet Right Ventricle 
Disease causing mutations for heterotaxy syndrome were first identified in the X-linked laterality gene, ZIC3. Mutations typically result in males with situs ambiguus and complex congenital heart disease; however affected females and one male with isolated d-transposition of the great arteries (d-TGA) have been reported. We hypothesized that a subset of patients with heart defects common to heterotaxy but without laterality defects would have ZIC3 mutations. We also sought to estimate the prevalence of ZIC3 mutations in sporadic heterotaxy.
Patients with TGA (n=169), double outlet right ventricle (DORV) (n=89), common atrioventricular canal (CAVC) (n= 41) and heterotaxy (n=54) underwent sequencing of ZIC3 exons. We tested 90 patients with tetralogy of Fallot (TOF) to correlate genotype with phenotype. Three potentially disease-related missense mutations were detected: c.49G>T (Gly17Cys) in a female with isolated DORV, c.98C>T (Ala33Val) in a male with isolated d-TGA, and c.841C>T (His281Tyr) in a female with sporadic heterotaxy. We also identified a novel insertion (CPFP333ins) in a family with heterotaxy. All were absent in 200 control patients and the 1000 Genomes Project (n = 629). No significant mutations were found in patients with TOF. Functional studies demonstrated reduced transcriptional activity of the ZIC3 His281Tyr mutant protein.
ZIC3 mutations were rarely identified in isolated DORV and d-TGA suggesting that a subset of DORV and d-TGA may fall within the spectrum of laterality defects. ZIC3 mutations were found in 3.7% of patients with sporadic heterotaxy; therefore testing should be considered in patients with heterotaxy.
doi:10.1002/ajmg.a.35849
PMCID: PMC3707401  PMID: 23427188
Heterotaxy; Situs; Transposition of the great arteries; Double outlet right ventricle; ZIC3
21.  Microdeletion and Microduplication Analysis of Chinese Conotruncal Defects Patients with Targeted Array Comparative Genomic Hybridization 
PLoS ONE  2013;8(10):e76314.
Objective
The current study aimed to develop a reliable targeted array comparative genomic hybridization (aCGH) to detect microdeletions and microduplications in congenital conotruncal defects (CTDs), especially on 22q11.2 region, and for some other chromosomal aberrations, such as 5p15-5p, 7q11.23 and 4p16.3.
Methods
Twenty-seven patients with CTDs, including 12 pulmonary atresia (PA), 10 double-outlet right ventricle (DORV), 3 transposition of great arteries (TGA), 1 tetralogy of Fallot (TOF) and one ventricular septal defect (VSD), were enrolled in this study and screened for pathogenic copy number variations (CNVs), using Agilent 8 x 15K targeted aCGH. Real-time quantitative polymerase chain reaction (qPCR) was performed to test the molecular results of targeted aCGH.
Results
Four of 27 patients (14.8%) had 22q11.2 CNVs, 1 microdeletion and 3 microduplications. qPCR test confirmed the microdeletion and microduplication detected by the targeted aCGH.
Conclusion
Chromosomal abnormalities were a well-known cause of multiple congenital anomalies (MCA). This aCGH using arrays with high-density coverage in the targeted regions can detect genomic imbalances including 22q11.2 and other 10 kinds CNVs effectively and quickly. This approach has the potential to be applied to detect aneuploidy and common microdeletion/microduplication syndromes on a single microarray.
doi:10.1371/journal.pone.0076314
PMCID: PMC3788710  PMID: 24098474
22.  Outcomes of the Infant Ross Procedure for Congenital Aortic Stenosis Followed into Adolescence 
Objectives
The Ross procedure is used to treat aortic valve disease in children. Advantages include autograft growth, long-term durability, and avoidance of anticoagulation. Long-term follow-up of the Ross procedure in infancy is limited. We sought to characterize the long-term outcomes of infants undergoing the Ross procedure.
Methods
We performed a retrospective review of all patients who underwent a Ross operation at 18 months of age or less at New-York Presbyterian and Cardiothoracic Center of Monaco between 1991 and 2010. Clinical, catheterization, and surgical records were reviewed. The most recent follow-up information, including echocardiogram and electrocardiogram, was obtained and analyzed.
Results
34 patients underwent a Ross at a median age of 6 months (4 d–18.4 yrs). All had congenital aortic stenosis. All but 1 patient had prior surgical or catheter based interventions. Median follow-up was 10.6 yrs (1.4-20.4 yrs). There were 4 early deaths and 1 late transplant. Freedom from right ventricular outflow tract (RVOT) reintervention was 85% at 5 yrs and 64% at 10 yrs. Freedom from autograft reintervention was 95.5% at 10 yrs. In 20 subjects, late follow-up echocardiograms showed a significant difference between mean early and late Z scores of autograft annulus (0.8 vs 2.4, p=.03), sinus (0.8 vs 2.8, p=.002) and sino-tubular junction (1.2 vs 2.7, p=.04). Mild or less aortic insufficiency occurred in 17 subjects. None had significant aortic stenosis.
Conclusions
Long-term outcomes of the Ross procedure in infants and toddlers are favorable despite moderate dilatation of the autograft. Reintervention at the RVOT is common.
doi:10.1016/j.jtcvs.2012.09.004
PMCID: PMC3657341  PMID: 23062969
23.  N-Acetylcysteine prevents congenital heart defects induced by pregestational diabetes 
Background
Pregestational diabetes is a major risk factor of congenital heart defects (CHDs). Glutathione is depleted and reactive oxygen species (ROS) production is elevated in diabetes. In the present study, we aimed to examine whether treatment with N-acetylcysteine (NAC), which increases glutathione synthesis and inhibits ROS production, prevents CHDs induced by pregestational diabetes.
Methods
Female mice were treated with streptozotocin (STZ) to induce pregestational diabetes prior to breeding with normal males to produce offspring. Some diabetic mice were treated with N-acetylcysteine (NAC) in drinking water from E0.5 to the end of gestation or harvesting of the embryos. CHDs were identified by histology. ROS levels, cell proliferation and gene expression in the fetal heart were analyzed.
Results
Our data show that pregestational diabetes resulted in CHDs in 58% of the offspring, including ventricular septal defect (VSD), atrial septal defect (ASD), atrioventricular septal defects (AVSD), transposition of great arteries (TGA), double outlet right ventricle (DORV) and tetralogy of Fallot (TOF). Treatment with NAC in drinking water in pregestational diabetic mice completely eliminated the incidence of AVSD, TGA, TOF and significantly diminished the incidence of ASD and VSD. Furthermore, pregestational diabetes increased ROS, impaired cell proliferation, and altered Gata4, Gata5 and Vegf-a expression in the fetal heart of diabetic offspring, which were all prevented by NAC treatment.
Conclusions
Treatment with NAC increases GSH levels, decreases ROS levels in the fetal heart and prevents the development of CHDs in the offspring of pregestational diabetes. Our study suggests that NAC may have therapeutic potential in the prevention of CHDs induced by pregestational diabetes.
doi:10.1186/1475-2840-13-46
PMCID: PMC3942143  PMID: 24533448
Pregestational diabetes; Congenital heart defects; N-acetylcysteine; Glutathione; Reactive oxygen species
24.  Novel Missense Variants of ZFPM2/FOG2 Identified in Conotruncal Heart Defect Patients Do Not Impair Interaction with GATA4 
PLoS ONE  2014;9(7):e102379.
Conotruncal heart defect (CTD) is a complex form of congenital heart disease and usually has a poor prognosis. ZFPM2/FOG2 encodes a transcription cofactor that interacts with GATA4 to regulate cardiac development. This regulation has been established in knockout mouse models that display a range of heart malformations, especially CTD. Although previous studies have identified several missense variants in ZFPM2/FOG2 that may cause CTD, it remains unclear whether they are involved in CTD pathogenesis because the study populations were limited and the functional status was unknown. In this report, we screened a larger CTD population, which comprised 145 tetralogy of Fallot (TOF), 37 double-outlet ventricle outflow (DORV), and 18 transposition of the great artery (TGA), to investigate exon mutations as well as copy number variations in ZFPM2/FOG2. Four variants (p.V339I in one DORV, p.A426T in one DORV, p.M703L in three TOF, p.T843M in one TOF) were found in six patients, of which two are reported here for the first time. No copy number variations of the gene were detected. GST pull-down assays demonstrated that all potentially deleterious variants, including those previously reported, did not impair the interaction with GATA4, except for variant p.M544I and p.K737E, which subtly impaired the binding. Thus, these missense variants may be involved in other mechanisms underlying CTD or may be unrelated to CTD occurrence.
doi:10.1371/journal.pone.0102379
PMCID: PMC4099368  PMID: 25025186
25.  Heart failure with preserved left ventricular systolic function: a hospital cohort study 
Heart  2005;91(7):907-913.
Objective: To investigate how patients with heart failure with preserved left ventricular systolic function (LVSF) compare with patients with reduced LVSF.
Design: Cohort study.
Setting: Urban university hospital.
Patients: 528 index emergency admissions with heart failure during the year 2000. Information on LVSF and follow up was available for 445 (84%) of these patients.
Results: 130 (29%) patients had preserved LVSF (defined as an ejection fraction > 40%). The median follow up was 814 days (range 632–978 days). The average (SD) age was 72 (13) years. Women accounted for 62% and 45% of patients with preserved and reduced LVSF, respectively (p  =  0.001). Patients with preserved LVSF (compared with those with reduced LVSF) had a higher prevalence of left ventricular hypertrophy (56% v 29%) and aortic valve disease (mean gradient > 20 mm Hg; 31% v 9%). Fewer patients with preserved LVSF received an angiotensin converting enzyme inhibitor (65% v 78%, p  =  0.008) or spironolactone (12% v 21%, p  =  0.027). Anaemia tended to occur more often in patients with preserved LVSF than in those with reduced LVSF (43% v 33% for women, p  =  0.12; 59% v 49% for men, p  =  0.22). There was a similarly high prevalence of significant renal dysfunction in both groups (estimated glomerular filtration rate < 60 ml/min/1.73 m2 in 68% with preserved and 64% with reduced LVSF, p  =  0.40). Mortality was similar in both groups (preserved versus reduced 51 (39%) v 132 (42%), p  =  0.51). Compared with patients with reduced LVSF, patients with preserved LVSF tended to have a lower risk of death or hospital admission for heart failure (56 (42%) v 165 (53%), p  =  0.072) but a similar rate of death or readmission for any reason.
Conclusion: Patients with preserved LVSF had more co-morbid problems than those with reduced LVSF; however, prognosis was similar for both groups.
doi:10.1136/hrt.2004.041996
PMCID: PMC1769014  PMID: 15958359
heart failure; hospitalisation; preserved systolic function; reduced systolic function

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