Double Outlet Right Ventricle Research Articles

OC134: Anatomy, association and outcome of prenatally detected double‐outlet right ventricle

OC134: Anatomy, association and outcome of prenatally detected double‐outlet right ventricle

Antenatal diagnosis of double outlet of right ventricle without extracardiac anomaly: A report of 4 cases

Four fetuses were diagnosed antenatally with double outlet of right ventricle (DORV) at 17, 20, 26, and 28 weeks' gestation, respectively, using 2-dimensional sonography. Chromosome study was normal in all 4 cases, and there were no extracardiac abnormalities. The sonographic diagnoses were based on the following findings: (1) arising of the 2 great vessels predominantly from the right ventricle; (2) the presence of bilateral coni; and (3) parallel direction of the 2 vessels rather than the normal perpendicular course. Two cases were terminated electively with postnatal autopsy confirmation; the other 2 cases were closely monitored throughout pregnancy and underwent normal vaginal delivery at term and subsequent surgical correction with good outcome. In conclusion, DORV can be readily diagnosed in utero by checking outflow tract even without 3-dimensional sonography and in the absence of obvious risk for congenital heart defects.

Accuracy of the Fetal Echocardiogram in Double-outlet Right Ventricle

Double-outlet right ventricle (DORV) is a complex congenital heart defect with heterogeneous anatomy. Patients require a variety of surgical interventions, and the long-term prognosis is variable. Therefore, accurate prenatal diagnosis is important in providing parents with appropriate counseling. Medical records were reviewed in patients with a diagnosis of DORV who had fetal echocardiography at our institution from 1998 to 2004. Pre- and postnatal diagnoses were compared, anticipated surgical procedure was compared with surgery performed, and neonatal outcome was assessed. The study group consisted of 49 fetal patients with 6 in utero deaths (including 4 terminations), 2 patients lost to follow-up, and 41 live births. Postnatal echocardiograms or autopsy results were available on 42 patients. The overall accuracy of fetal echocardiography in making a correct diagnosis of DORV was 76%. Accurate prenatal prediction of the type of cardiac surgery that would be performed was made in 91% of patients who had surgery. Among live births, survival to hospital discharge was 76%. Survival was 50% in patients with extracardiac or chromosomal anomalies, compared with 92% in infants without additional anomalies. In most cases, careful evaluation by fetal echocardiography can determine essential anatomic details in fetuses with DORV with enough accuracy to allow for accurate counseling regarding the type of surgery needed. Survival is better than previously reported but is poor in patients with extracardiac or chromosomal abnormalities.

Balloon pulmonary valvuloplasty for valvular pulmonary stenosis in double outlet right ventricle incriminating 46,X,der(X)t(X;3)(q28;q13.2)mat in an infant

Double outlet right ventricle (DORV) has never been logged on with the maternally inherited unbalanced translocation between chromosome X and chromosome 3; i.e., 46,X,der(X)t(X;3)(q28;q13.2)mat. We have recently encountered a 10.5-month-old female infant, who had been found to have intrauterine growth retardation at the 28th gestational weeks and was born with a low birth-weight (1395 g) at the 35th gestational week, presenting failure-tothrive in body weight and height, widened anterior fontanelle, facial dysmorphism, simian creases, cleft palate, and lip cyanosis (SpO2 of 72–78%) due to a constellation of DORV, subaortic ventricular septal defect, and severe valvular pulmonary stenosis (pressure gradients from 64 to 72 mmHg). Balloon pulmonary valvuloplasty was performed effectively to lessen the severity of the valvular pulmonary stenosis (pressure gradient dropped to 43 mmHg) and lip cyanosis (SpO2 elevated to 92–95%). Cytogenetic analysis of the proband's blood found a derivative chromosome X, and that of her parents' blood tracked down the gamete to be maternally inherited. To the best of our knowledge, DORV associated with 46,X,der(X)t(X;3)(q28;q13.2)

Invited commentary

Invited commentary

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.

Cardiovascular anomalies in patients with chromosome 22q11.2 deletion: A Korean multicenter study

The 22q11.2 deletion syndrome is reported with increasing frequency worldwide, and its clinical manifestations, including cardiovascular anomalies, appear to be more diverse than previously reported. The aim of this study was to determine the incidence and the pattern of cardiovascular anomalies in Korean patients with 22q11 deletion. This study involved six Korean institutions. We reviewed the clinical records of patients and confirmed the presence of 22q11.2 deletion by fluorescent in situ hybridization (FISH). A total of 222 patients were examined and 190 (85.6%) patients had the cardiovascular abnormalities: 63.2% tetralogy of Fallot (TOF), 20.5% isolated ventricular septal defects (VSDs), 5.3% interrupted aortic arch type B (IAA B), 3.6% double outlet right ventricle (DORV), 3.6% atrial septal defects (ASDs) and 1.7% truncus arteriosus (TA). Of 168 patients with VSD, 69.6% had the perimembranous type, 11.9% the total conal defect type, 6.5% the subarterial type, 4.2% the muscular type and 1.2% the mixed type. A right aortic arch was observed in 50% of patients, and an aberrant subclavian artery was significantly more common with a right (30.9%) than a left (18.3%) aortic arch (p<0.05). A wide variety of cardiovascular anomalies were present in Korean patients with the 22q11.2 deletion.

Borderline left ventricles in prenatally diagnosed atrioventricular septal defect or double outlet right ventricle: Echocardiographic predictors of biventricular repair

Atrioventricular septal defect (AVSD) and double outlet right ventricle (DORV) with normally related great arteries and normal ventricular sizes are associated with a good long-term prognosis after biventricular (BV) repair. The outcome of cases with a borderline small left ventricle (bLV) is unclear. The purpose of the study was to retrospectively determine echocardiographic predictors of successful BV repair in fetuses with AVSD or DORV with a bLV. From 1991 to 2004, 24 fetuses with AVSD plus bLV and 24 with DORV plus bLV were identified. Fetal echocardiographic parameters comparing BV repair versus single ventricle (SV) palliation were obtained, including the presence or absence of an apex-forming bLV was recorded. A bLV was defined as a right ventricular/left ventricular end-diastolic dimension ratio between 2 and 4 SDs for gestational age. The overall survival from fetal diagnosis was 21% (5/24) for AVSD/bLV and 13% (3/24) for DORV/bLV. Of 11 liveborns with AVSD/bLV and 8 liveborns with DORV/bLV, 6 underwent BV repair (5 survivors), 7 SV palliation (3 survivors), and 1 cardiac transplant. Five infants receiving compassionate care only were excluded from the analysis. Parameters such as ratio of valve annuli, ventricular end-diastolic dimensions, degree of valve regurgitation, and the presence of endocardial fibroelastosis were not too predictive of outcome. The presence of an apex-forming bLV was the only predictor of BV repair (6/6 BV repair vs 2/8 SV palliation, P < .05). Prenatally diagnosed AVSD or DORV with bLV has a very poor prognosis. An apex-forming bLV predicts successful BV repair and is an important prognostic indicator.

Diagnosis and prognosis of fetuses with double outlet right ventricle

To examine the echocardiographic features, associated anomalies, and outcomes of fetuses diagnosed with double outlet right ventricle (DORV). Fetuses with DORV were identified from 987 fetal echocardiograms performed from August 1, 2002 to August 1, 2004. The medical records of 19 fetuses with DORV were reviewed. Nineteen fetuses were diagnosed with DORV. The pregnancy was terminated in 15.8% (3/19) of cases. Postnatal assessment was not obtained in 26.3% (5/19) cases. Accurate prenatal diagnosis of the relationship of the ventricular septal defect (VSD) with the great arteries was achieved in 14 of 14 cases (100%). Chromosomal abnormalities (21.4%), abnormalities of body situs (35.7%), and other extracardiac abnormalities were diagnosed in association. Only 4 of 13 (30.8%) infants with confirmed DORV survived beyond 28 days. DORV is found in fetuses with a large spectrum of associated cardiac and extracardiac lesions. The overall prognosis for fetuses with DORV is poor throughout the spectrum of these lesions, not only related to the primary lesion but also depending on the associated intra- and extracardiac abnormalities. While the complexity of the heart disease in fetuses with DORV makes detailed fetal diagnosis challenging, it can be accomplished with a high degree of accuracy.

P4-113: Two ventricular tachycardias which showed the opposite axis shared the critical isthmus in a patient with double outlet right ventricle after Rastelli procedure

A 33-year-old male, s/p Rastelli procedure at the age of 9 y/o for double outlet right ventricle (DORV) was admitted to our hospital due to ventricular tachycardia (VT). The morphology of clinical VT was LBBB, superior axis (CL 410 ms). During the EP study, 2 types of VTs including the clinical VT were induced. VT2 had LBBB with inferior axis (CL 440 ms). Activation mapping was performed both in VT1 and VT2, early-diastolic potential during VT1 and mid-diastolic potential during VT2 were recorded at the same channel in LVOT.

Biventricular repair in double outlet right ventricle: surgical results based on the STS-EACTS International Nomenclature classification☆

The STS-EACTS International Nomenclature for Congenital Heart Surgery (CHS) defines four anatomic subtypes of double outlet right ventricle (DORV) based on the relationship of the ventricular septal defect (VSD) with the great vessels and the presence of right ventricular outflow tract obstruction (RVOTO). We reviewed our experience with DORV patients and two ventricles that underwent repair, applying this nomenclature. Between January 2000 and January 2005, 50 patients with DORV and two viable ventricles underwent surgical intervention: 44 patients had biventricular repair, 3 had 1.5 ventricular repair, 2 underwent a Fontan, and 1 died prior to corrective surgery. Median age at repair was 9.1 months (range: 4D-4Y). Eighteen patients (36%) were DORV-Fallot (including 5 with AVSD and heterotaxy), 9 (18%) were DORV-TGA (Taussig-Bing), 12 (24%) were DORV-VSD, and 11 (22%) were DORV non-committed VSD. Corrective surgery included 35 repairs with a VSD-aorta baffle+/-RVOTO procedure and 12 arterial switches with a VSD-PA baffle (9 Taussig-Bing and 3 DORV-ncVSD). Associated procedures included 13 VSD enlargements, 8 subaortic resections, 9 arch repairs, 5 AVSD repairs, and 7 others. There were three deaths in the 50 patients studied (overall mortality of 6%). Excluding one patient that died prior to corrective surgery and the two patients palliated with a Fontan procedure, the actual surgical mortality for a corrective repair was 4.3% (2/47 patients). Two surgical deaths occurred following, respectively, one repair of a Taussig-Bing with an interrupted arch and a Swiss cheese VSD and one repair of ncVSD-type with pulmonary atresia that had undergone a previous cavo-pulmonary anastamosis. No late deaths occurred. Two late reoperations included a heart transplant in a DORV-Fallot patient with Swiss cheese VSD and subaortic resection in a DORV-ncVSD patient. Angioplasties were needed for PA stenosis (n=2) and aortic arch obstruction (n=2). Four patients had LV to aorta baffle gradients between 10 and 20 mmHg. All patients were of NYHA class I/II. The STS-EACTS International Nomenclature provides more uniform analysis of outcomes with respect to acceptable surgical risk and mortality. Biventricular repair can be safely achieved on selected DORV, including DORV-ncVSD and DORV with AVSD and heterotaxy lesions traditionally indicated for a single ventricle palliative approach.

Rotation of the Myocardial Wall of the Outflow Tract Is Implicated in the Normal Positioning of the Great Arteries

Congenital heart defects frequently involve a failure of outflow tract (OFT) formation during development. We analyzed the remodeling of the OFT, using the y96-Myf5-nlacZ-16 transgene, which marks a subpopulation of myocardial cells of the pulmonary trunk. Expression analyses of reporter transcript and protein suggest that the myocardial wall of the OFT rotates before and during the formation of the great arteries. Rotational movement was confirmed by Di-I injection experiments with cultured embryos. We subsequently examined the expression of the transgene in mouse models for OFT defects. In hearts with persistent truncus arteriosus (PTA), double outlet right ventricle (DORV), or transposition of the great arteries, rotation of the myocardial wall of the OFT is arrested or fails to initiate. This is observed in Splotch (Pax3) mutants with PTA or DORV and may be a result of defects in neural crest migration, known to affect OFT septation. However, in Pitx2deltac mutant embryos, where cardiac neural crest cells are present in the heart, PTA and DORV are again associated with a rotation defect. This is also seen in Pitx2deltac mutants, which have transposition of the great arteries. Because Pitx2c is involved in left-right signaling, these results suggest that embryonic laterality affects rotation of the myocardial wall during OFT maturation. We propose that failure of normal rotation of OFT myocardium may underlie major forms of congenital heart disease.

Double outlet right ventricle: Opinions regarding management

In the current era of superb surgical results for congenital heart disease, several management options are available for patients born with double outlet right ventricle (DORV). The surgical repair of DORV is tailored to address the variety of abnormalities associated with this lesion. The treatment strategies are dependent upon the anatomy and relationship of the ventricular septal defect (VSD) and the great arteries. For patients with subaortic or doubly committed VSDs, without right ventricular outflow tract obstruction, the usual repair is an intraventricular tunnel from the VSD to the aorta. If right ventricular outflow tract obstruction exists, then augmentation of the right ventricular outflow tract or conduit placement from the right ventricle to the pulmonary artery is necessary. For the "Taussig-Bing anomaly" (subpulmonary VSD) an arterial switch operation is indicated with tunneling of the VSD to the neoaorta. For patients with a remote VSD, complex atrioventricular valve abnormalities, or unbalanced ventricles, a staged palliative approach is warranted. This approach will result in the patient having "single ventricle" physiology, and "Fontan anatomy" after the staging surgeries. Outcomes are determined by the surgery performed. Patients who require conduit placement from right ventricle to pulmonary artery will need subsequent surgery for replacement of the conduit. Complex intraventricular tunnels are at risk for developing subaortic obstruction. Patients who had arterial switch operations have thus far had excellent results. However, these patients may be at risk for development of neoaortic valve regurgitation requiring subsequent reoperation. Complex biventricular intracardiac repairs have been associated with a higher risk of reoperation. In the past 10 to 15 years, patients undergoing Fontan operations have had improved early and late survival. However, long-term problems after the Fontan operation include arrhythmia and development of protein-losing enteropathy.

59 A Clinical and Genetic Study of Newborns with Conotruncal Heart Diseases and Del22Q11.2 Syndrome

Background/aims Congenital heart diseases (CHD) occur in 8 per 1000 births. ConoTruncal Heart Defects (CTHD) account for 50% of CHD. 22q11 deletion prevalence is high in patients with CTHD (16%). The most common CTHDs in del22q11 patients are Tetralogy of Fallot (ToF), Pulmonary Atresia + Ventricular Septal Defect (PA+VSD), Aortic Arch Interruption (AAI), Truncus arteriosus (TA).Patients and methods in 1999 a study to determine the prevalence of del22q11 in patients with CTHD, to describe the phenotypic variability and to analyse the familial occurrence of deletion, was designed. The parents of deleted probands were studied too. Caryotype from peripheral blood lymphocytes by fluorescent in situ hybridisation (FISH) using specific probe D22S75 was performed.Results Over a period of 5 years, 135 patients (M: 70, F: 65) with CTHD were enrolled.: 47 (35%) ToF, 39 (29%) Transposition of Great Arteries (TGA), 23 (17%) PA+VSD, 10 (7,5%) Double Outlet Right Ventricle (DORV), 7 (5%) TA, 3 (2%) AAI, 6 (4,4%) other CHDs. 27 (M: 12, F: 15) showed del22q11.2: 14 (30%) ToF, 8 (35%) PA+VSD, 1 (33%) AAI, 1 (14%) TA and 3 other types of CHD. In the familial cases with del22q11.2, we found: An affected father of a child without CTHD, a mother and her daughter with the same CHD, 2 unaffected mothers of affected probands. 26 deleted patients showed dysmorphic facial features (elongated face, micrognatia, hypertelorism, bulbous nose), 1 cleft-palate, 4 velopharyngeal insufficiency, 2 thymic hypo-/aplasia, 2 hypocalcemia, 1 reduced cell CD3+, 9 developmental and speech delay/behavioural problems.Conclusions Del22q11 frequency in patients with CTHD is high (20%) and higher in patients with CTHD and clinical features of del22q11 syndrome. The analysis of del22q11 should not be excluded: In patients with CTHD, including the newborns, and without characteristic fenotype; in parents of deleted children.

Double-Outlet Right Ventricle in an Angus Calf

Double-outlet right ventricle (DORV) is a conotruncal malformation where both great arteries arise from the right ventricle. Anatomic variations of DORV are classified according to the position of the great arteries in relation to each other, the relationship between a ventricular septal defect (VSD) and the great arteries, and the presence and degree of pulmonary stenosis. The prevalence of congenital cardiac defects in bovine fetuses has been reported at approximately 0.7 %, with VSDs representing the most common congenital cardiac defect. DORV has been described in veterinary literature in few cats and dogs, a foal, and 2 calves with variable clinical and pathologic documentation. In this report, we describe the angiographic, echocardiographic, and postmortem examination findings in a calf with a DORV with concurrent pulmonary stenosis, subaortic VSD, patent ductus arteriosus (PDA), aberrant left subclavian artery, and a tracheal malformation.

Double-Outlet Right Ventricle in an Angus Calf

Double-outlet right ventricle (DORV) is a conotruncal malformation where both great arteries arise from the right ventricle. Anatomic variations of DORV are classified according to the position of the great arteries in relation to each other, the relationship between a ventricular septal defect (VSD) and the great arteries, and the presence and degree of pulmonary stenosis. The prevalence of congenital cardiac defects in bovine fetuses has been reported at approximately 0.7 %, with VSDs representing the most common congenital cardiac defect. DORV has been described in veterinary literature in few cats and dogs, a foal, and 2 calves with variable clinical and pathologic documentation. In this report, we describe the angiographic, echocardiographic, and postmortem examination findings in a calf with a DORV with concurrent pulmonary stenosis, subaortic VSD, patent ductus arteriosus (PDA), aberrant left subclavian artery, and a tracheal malformation.

Prenatal diagnosis of transposition-like double-outlet right ventricle with mitral valve atresia in heterotaxy syndrome

We present a case of heterotaxy syndrome with right isomerism detected in a twin fetus, with the sonographic findings that established this diagnosis. At 24 weeks' menstrual age, ultrasound detected anomalies in the heart suggestive of heterotaxy syndrome. Intrauterine fetal echocardiography demonstrated that the heart of the affected twin was located on the left side with a normal cardiac axis. The right ventricle was much larger than the left ventricle. The appearance of the mitral valve was dysplastic with restricted motion. The ascending aorta exited from the right ventricle, anterior to, right to, and parallel to the smaller pulmonary trunk, which also arose from the right ventricle. Double-outlet right ventricle (DORV) was clearly demonstrated. Cesarean section was performed at 38 weeks' menstrual age. Both twins were healthy and survived. Postnatal echocardiography and MRI confirmed the prenatal findings. At the age of 4 months, the affected infant had no evidence of cardiac decompensation. This report shows that conventional ultrasound can be used to detect heterotaxy syndrome and that intrauterine fetal echocardiography can delineate the cardiac complex in heterotaxy syndrome. Postnatal surgery with complex Fontan procedures was planned for the affected twin.

Long-Term Predictors of Aortic Root Dilation and Aortic Regurgitation After Arterial Switch Operation

Neo-aortic root dilation (ARD) and neo-aortic regurgitation (AR) may be progressive after arterial switch operation (ASO) for d-loop transposition of the great arteries (dTGA). We sought to identify predictors of ARD and AR after ASO. 335 patients were identified who underwent ASO for dTGA with intact ventricular septum or ventricular septal defect (VSD), including double-outlet right ventricle (DORV), before 2001 with at least 1 postoperative echocardiogram at our institution, at least 1 year after ASO, and no previous atrial switch procedure (median follow-up of 5.0 years). Probability of freedom from ARD was 97%, 92%, 82%, and 51%, from at least moderate AR was 98%, 97%, 96%, and 93%, and from neo-aortic valve or root surgery was 100%, 100%, 99%, and 95%, at 1, 2, 5, and 10 years, respectively. For patients in whom ARD developed, progressive dilation was not observed during late follow-up. By Kaplan-Meier method, independent predictors of ARD, with neo-aortic root z-score of > or =3.0, were previous pulmonary artery band (PAB) (P=0.002, hazard ratio [HR]=2.4) and later time period when ASO was performed (P<0.002, HR=19.0). Risk factor for at least moderate AR was age > or =1 year at ASO (P=0.002, HR=5.8), which was closely related to VSD repair at ASO (P<0.001) and previous PAB. Significant ARD and AR continue to develop over time after ASO, but ARD does not tend to be progressive during late follow-up. Previous PAB was a significant risk factor for ARD. Older age at time of ASO, presence of VSD, and previous PAB were risk factors for AR.

GATA4 is a dosage-sensitive regulator of cardiac morphogenesis

Normal heart development is orchestrated by a set of highly conserved transcription factors that includes GATA4, Nkx2-5, and Tbx5. Heterozygous mutation of each of these genes causes congenital heart disease in humans. In mouse models, haploinsufficiency for Nkx2-5 or Tbx5 resulted in an increased incidence of structural heart disease, confirming that normal heart development is sensitive to small changes in expression levels of Nkx2-5 and Tbx5. However, mice haploinsufficient for GATA4 have not been reported to have cardiac abnormalities. We generated two new GATA4 alleles, GATA4 H and GATA4 flox . GATA4 flox/flox embryos expressed 50% less GATA4 protein in the heart and survived normally. In contrast, GATA4 H/H embryos expressed 70% less GATA4 protein in the heart and died between days 13.5 and 16.5 of gestation. These embryos had common atrioventricular canal (CAVC), double outlet right ventricle (DORV), hypoplastic ventricular myocardium, and normal coronary vasculature. Myocardial hypoplasia was associated with diminished cardiomyocyte proliferation. Hemodynamic measurements demonstrated that these embryos had normal systolic function, severe diastolic dysfunction, and atrioventricular regurgitation. Surprisingly, expression levels of the putative GATA4 target genes ANF, BNP, MEF2C, Nkx2-5, cyclin D2, and BMP4 were unchanged in mutant hearts, suggesting that GATA4 is not a dose-limiting regulator of the expression of these genes during later stages of embryonic cardiac development. These data demonstrate that multiple aspects of embryonic cardiac morphogenesis and function are exquisitely sensitive to small changes in GATA4 expression levels.

Hypoxia-responsive signaling regulates the apoptosis-dependent remodeling of the embryonic avian cardiac outflow tract

We proposed a model in which myocardial hypoxia triggers the apoptosis-dependent remodeling of the avian outflow tract (OFT) in the transition of the embryo to a dual circulation. In this study, we examined hypoxia-dependent signaling in cardiomyocyte apoptosis and outflow tract remodeling. The hypoxia-inducible transcription factor HIF-1α was specifically present in the nuclei of OFT cardiomyocytes from stages 25–32, the period of hypoxia-dependent OFT remodeling. HIF-1α expression was sensitive to changes in ambient oxygen concentrations, while its dimerization partner HIF-1β was constitutively expressed. There was not a simple relationship between HIF-1α expression and apoptosis. Apoptotic cardiomyocytes were detected in HIF-1α-positive and -negative regions, and a hypoxic stimulus sufficient to induce nuclear accumulation of HIF-1α did not induce cardiomyocyte apoptosis. The hypoxia-dependent expression of the vascular endothelial growth factor receptor (VEGFR2) in the distal OFT myocardium may be protective as cardiomyocyte apoptosis in the early stages (25–30) of OFT remodeling was absent from this region. Furthermore, recombinant adenoviral-mediated expression of dominant negative Akt, an inhibitor of tyrosine kinase receptor signaling, augmented cardiomyocyte apoptosis in the OFT and constitutively active Akt suppressed it. Adenovirus-mediated forced expression of VEGF165 induced conotruncal malformation such as double outlet right ventricle (DORV) and ventricular septal defect (VSD), similar to defects observed when apoptosis-dependent remodeling of the OFT was specifically targeted. We conclude that normal developmental remodeling of the embryonic avian cardiac OFT involves hypoxia/HIF-1-dependent signaling and cardiomyocyte apoptosis. Autocrine signaling through VEGF/VEGFR2 and Akt provides survival signals for the hypoxic OFT cardiomyocytes, and regulated VEGF signaling is required for the normal development of the OFT.