Atrioventricular Septal Defect

Etiology

In almost all patients, the atrioventricular septal defect is caused by genetic mutations, and most of the time, it is associated with syndromes. Every six patients with Down syndrome have associated atrioventricular septal defect, and Down syndrome cell adhesion molecule (DSCAM) gene has been described to be associated with an atrioventricular septal defect and other congenital heart diseases in these patients.[4][5] 

The other syndromes associated with the atrioventricular septal defect may include CHARGE, Ellis-van-Creveld, Smith-Lemli-Opitz, and 3p. Other than its association with syndromes, gene mutations associated with the atrioventricular septal defect can also be inherited as an autosomal dominant trait. Gestational diabetes and maternal obesity have also been reported to increase the risk of non-syndromic atrioventricular septal defects.[6]

Epidemiology

The incidence of an atrioventricular septal defect in the general population has been reported to be 0.24 to 0.31 per 1000 live births.[3] It accounts for 3% of all congenital cardiac malformations.[2] Although both male and female genders are affected equally, one of the studies suggests a female-to-male ratio of 1.3 to 1.0, especially in patients with Down syndrome.[7]According to the Society of Thoracic Surgeons congenital database, 4138 cases of complete AVSD were diagnosed between 2013 and 2017. Most of these cases were repaired surgically with low mortality, with or without valvuloplasty (2.6% to 2.9%). Repairs that were not amenable to valvular repair and were addressed with valvular replacement were associated with increased perioperative mortality (16.7%). Of the 2 cases where an attempt at valvuloplasty failed and an intraoperative decision of replacement was taken, the mortality rate was as high as 50% (see images). This demonstrates the importance of careful preoperative visualization & planning in the surgical decision of AVSD interventions.

Pathophysiology

Endocardial cushions are paired (superior and inferior) mesenchymal structures located in the common atrioventricular canal in the early embryonic period, and their growth is of prime importance in the development of atrioventricular septum and atrioventricular valves.[8] These endocardial cushions fuse at the end of 4 weeks of development and form two atria and two ventricles. Failure of fusion results in a variable degree of the atrioventricular septal defect.

The endocardial cushions, derived from the non-chamber myocardium of the atrioventricular canal (AVC), serve as foundational mesenchymal structures in the embryologic formation of cardiac valves and septa. Their morphogenesis relies heavily on signaling pathways driven by vascular endothelial growth factor (VEGF), and variants within genes regulating this pathway have been implicated in congenital malformations affecting the atrioventricular valves and septa.

The notably elevated incidence of AVC anomalies in individuals with trisomy 21 (Down syndrome) provides insight into the genetic underpinnings of endocardial cushion development. A longstanding hypothesis attributes this susceptibility to enhanced cellular adhesiveness observed in trisomy 21-derived cells. Experimental evidence supports this, as fetal fibroblasts from trisomy 21 endocardial-cushion regions exhibit increased in vitro adhesion compared to those from euploid counterparts. If endocardial cushion fusion is contingent on precise temporal and spatial parameters, then delayed cellular migration within the trisomic embryo may significantly disrupt this critical process.[9]

Collagen type VI, particularly its alpha-1 and alpha-2 chains encoded by the COL6A1/COL6A2 gene cluster located in the congenital heart disease–critical region of chromosome 21, is thought to contribute to this pathological mechanism. Fibroblasts from individuals with Down syndrome demonstrate altered adhesion properties to type VI collagen, further implicating matrix interactions in the etiology of these defects. Despite the presence of trisomy, only approximately 50% of individuals with Down syndrome manifest structural heart disease, prompting investigations into genetic modifiers both within and outside the trisomic chromosome that may influence the penetrance of AVC defects.[10][11]

Enrichment of pathogenic variants has been observed in multiple genes—VEGF-A, COL6A1, CRELD1, FBLN1, FRZB, GATA5, NOTCH4, and CEP290—among individuals with Down syndrome and AVC anomalies, suggesting a multifactorial and genetically heterogeneous basis for these defects.[12]

Beyond syndromic associations, familial clustering of AVC anomalies with an autosomal dominant inheritance pattern and incomplete penetrance has been documented, highlighting monogenic contributions. To date, five loci have been definitively associated with non-syndromic atrioventricular septal defects (AVSDs), designated AVSD1 through AVSD5:

• AVSD1 maps to chromosome 1p31-p21;

• AVSD2 is attributed to pathogenic mutations in CRELD1 on chromosome 3p25;

• AVSD3 involves GJA1, encoding connexin 43 (Cx43), on chromosome 6q22;

• AVSD4 is linked to GATA4 on chromosome 8p23.1;

• AVSD5 is associated with GATA6 mutations on chromosome 18q11.1.

The CRELD protein family, comprising matricellular proteins implicated in cell-cell interactions, plays a role in these pathologies. Among individuals with AVSDs unrelated to trisomy 21, approximately 6% harbor coding-region missense mutations in CRELD1. The GJA1 gene encodes connexin 43, a gap junction protein highly expressed in the ventricular myocardium, and cardiac neural crest derivatives; compound heterozygous mutations have been reported in AVSD cases.[13][14][13]

The GATA family of transcription factors—known for orchestrating lineage-specific gene expression—also contributes to cardiac morphogenesis. Neural crest-derived ectomesenchymal cells, which originate in the cranial neural folds, are crucial for outflow tract septation and the morphogenesis of branchial arch structures. These cells navigate through pharyngeal arches 3, 4, and 6 to participate in partitioning the conotruncus and aortic sac. Experimental ablation of preotic neural crest populations in animal studies has resulted in a range of conotruncal anomalies, including truncus arteriosus and subarterial ventricular septal defects, underscoring the indispensable role of these cells in cardiovascular development.[14]

Recent research has identified the SOX7 gene as a novel pathogenic candidate in the etiology of atrioventricular septal defects (AVSD). SOX7 appears to modulate the endothelial-to-mesenchymal transition (EndMT) crucial for atrioventricular cushion formation by influencing the WNT4–BMP2 signaling pathway. Specifically, SOX7 deficiency leads to downregulation of WNT4 expression in the endocardium, which in turn diminishes BMP2 expression in the adjacent myocardium. This disruption impairs the EndMT process, ultimately contributing to the pathogenesis of AVSD.[15]

Classification:

Atrioventricular septal defects (AVSDs) represent a spectrum of congenital anomalies characterized by varying degrees of atrial and ventricular septal involvement, as well as abnormalities of the atrioventricular (AV) valves.

Based on atrioventricular valve morphology and its development, atrioventricular septal defects are classified into partial, intermediate, and complete atrioventricular septal defects (AVSD).

These three anatomical variants—partial, intermediate, and complete—represent a phenotypic continuum resulting from a shared developmental defect at the level of the endocardial cushions, reflecting a common genetic and embryologic basis.[16] [17]

In the partial form of AVSD, also termed partial atrioventricular canal, the defining feature is an atrial septal defect located immediately adjacent to the AV valve plane. This defect typically appears as a crescent-shaped gap in the lower segment of the atrial septum and is associated with a morphologically trifoliate left AV valve, which frequently results in variable degrees of valvular regurgitation. Although historically referred to as an ostium primum atrial septal defect, this terminology is anatomically misleading, as the lesion does not originate from the septum primum.

The intermediate or transitional subtype of AVSD occupies a position between the partial and complete forms in terms of structural complexity. It is characterized by the presence of two distinct AV valve orifices—right and left—alongside a premum-type atrial septal defect and a ventricular septal defect situated beneath the AV valve plane. The ventricular component of the defect is typically localized to the inlet portion of the septum. Unlike in complete AVSD, there is no exposed or "bare" crest at the superior margin of the interventricular septum in these cases.

In complete AVSD, also referred to as complete atrioventricular canal defects, the malformation comprises both an interatrial and interventricular communication beneath a single, undivided common AV valve. This valve bridges the ventricular septum, incorporating both superior (anterior) and inferior (posterior) bridging leaflets. A characteristic feature of this form is the presence of an uncovered or "bare" zone at the crest of the ventricular septum, representing the common atrioventricular junction. 

In the complete form of the atrioventricular septal defect, a common atrioventricular valve has five leaflets, including superior bridging, inferior bridging, left mural, right mural, and anterosuperior. Rastelli divided complete atrioventricular septal defect into three anatomical subgroups, based solely on the degree of attachment and bridging of the superior leaflet to the ventricular septum.[18]

In type A, the superior bridging leaflet of the common atrioventricular valve is equally divided but firmly attached to the crest of the interventricular septum with the help of chordae (incidence 69%). (See image)

In type B, an aberrant insertion of a papillary muscle originates from the right aspect of the interventricular septum and extends to the left portion of the shared anterior bridging leaflet (incidence 9%). (See image)

In type C, the superior bridging leaflet is not divided and does not have an attachment to the interventricular septum, thus providing a large unrestricted atrioventricular septal defect (incidence 22%). (See image)

Rastelli type A is associated with left-sided obstruction, type C is associated with tetralogy of Fallot and other complex congenital heart diseases, and type B is the least common form of the complete atrioventricular septal defect.[19]

The Concept of Balance in Atrioventricular Septal Defects

Approximately one-tenth of atrioventricular canal defects (AVCDs) exhibit disproportionate commitment of the common atrioventricular valve (AVV) to one ventricle, resulting in what is termed an unbalanced AVCD. In these cases, the AVV preferentially directs inflow toward either the right or the left ventricle, giving rise to right-dominant or left-dominant anatomical configurations, respectively. This imbalance is closely associated with underlying disparities in ventricular size and development, with unequal AVV inflow serving as a cardinal diagnostic feature.

Right ventricular (RV) dominance is observed approximately twice as often as left ventricular (LV) dominance. It frequently presents alongside hypoplasia of the left ventricle, a parachute-like configuration of the left AV valve, closely approximated LV papillary muscles with a diminutive or absent mural leaflet, and may coexist with other structural anomalies such as a bicuspid aortic valve or coarctation of the aorta. In contrast, AV canal defects with left ventricular dominance are typically accompanied by right ventricular hypoplasia and obstructive lesions of the right ventricular outflow tract, including pulmonary stenosis or pulmonary atresia.

Efforts to objectively assess the degree of AVV and ventricular imbalance have led to the development of various echocardiographic indices aimed at stratifying patients for biventricular versus univentricular surgical strategies. Among these tools is the atrioventricular valve index (AVVI)—which quantifies the relative area of the AVV committed to each ventricle—as well as assessments of the angular alignment of AVV inflows and measurements relating valve inflow dimensions to the size of the ventricular septal defect. Despite their theoretical utility, these metrics often suffer from limited reproducibility and have not gained widespread clinical adoption.

In recent years, advanced imaging modalities such as cardiac magnetic resonance (CMR) and ECG-gated cine computed tomography (CT) have emerged as valuable adjuncts for detailed anatomical assessment. These techniques offer superior spatial resolution and enhanced accuracy in quantifying ventricular volumes and AVV geometry, thus playing an increasingly critical role in preoperative planning for patients with unbalanced AV canal anatomy.[20]

History and Physical

Clinical presentation of atrioventricular septal defects is influenced by the type of atrioventricular septal defect, the magnitude of the intracardiac shunt, and other associated cardiac malformations.[3] In patients with complete atrioventricular septal defect, signs of pulmonary congestion, and right heart failure develop in early infancy due to significant left to right shunt as pulmonary vascular resistance drops after birth. Heart failure and Eisenminger may develop even earlier if these patients have associated atrioventricular valve regurgitation, ventricular imbalance, or coarctation of the aorta.[21] 

Patients with the partial atrioventricular septal defect without other complex congenital cardiac malformations and minimal atrioventricular valve regurgitation, usually remain asymptomatic in infancy and early childhood. They are diagnosed on the bases of incidental findings, including pulmonary or tricuspid flow murmur and a fixed splitting due to atrial septal defect.

Symptoms of heart failure in infants may include difficulty in feeding, sleepiness, lethargy, and failure to thrive, while children may have a complaint of dyspnea.

Signs of heart failure include:

• Tachypnea, tachycardia
• S3 gallop
• Rales on chest auscultation
• Raised jugular venous pressure
• Tender hepatomegaly
• Wide fixed splitting due to atrial septal defect
• Pansystolic murmur due to atrioventricular valve regurgitation
• Pulmonary flow murmur due to increased flow through the pulmonary valve
• Mid diastolic flow murmur due to increased flow through the tricuspid valve

General physical examination may reveal cyanosis when there is a reversal of shunt (Eisenmenger syndrome) and dysmorphic features in case of associated syndromes.

Evaluation

Antenatal Evaluation

Antenatal ultrasonography with a four-chamber view is the commonly used diagnostic test for the atrioventricular septal defect. The most common findings include a common atrioventricular valve and a defect in the atrial or ventricular septum. However, the sensitivity of antenatal ultrasound for the atrioventricular septal defect is very low.[22]

Postnatal Evaluation

Chest Radiograph: It demonstrates cardiomegaly and pulmonary plethora, especially in those cases with associated atrioventricular valve regurgitation.

Electrocardiogram: The characteristic electrocardiographic findings include a superior axis in the frontal plan, right ventricular hypertrophy, and atrioventricular block. Other findings may include superior p wave axis and partial right bundle branch block.

Echocardiogram: Echocardiographic findings include:[23]

• Abnormal configuration of atrioventricular valve
• Loss of normal offset of atrioventricular valve
• Abnormal position of papillary muscles
• Disproportion in left ventricular inlet and outlet
• Ostium primum atrial septal defect
• Ventricular septal defect of inlet type
• And other associated cardiac malformations.

Cardiac Magnetic Resonance Imaging: Magnetic resonance imaging reveals findings similar to an echocardiogram. It is more accurate in measuring the size of defects and regurgitation fraction through the atrioventricular valve.

Treatment / Management

The management of atrioventricular septal defects can be divided into medical and surgical treatment.[24]

Medical Treatment

It includes diuretics and vasodilators to reduce the preload and afterload to relieve the symptoms associated with pulmonary congestion and heart failure. Associated feeding problems and failure to thrive are managed by tube feeding and providing extra calories. In atrioventricular septal defects, medical treatment is usually directed at optimizing the condition of the patient for surgery.[3] 

Surgical Treatment

Surgical correction is the ultimate treatment of atrioventricular septal defect. Atrioventricular septal repair is a complex surgical procedure and carries operative mortality of more than 3% even in the contemporary era of advanced surgical techniques.[25] It also carries significant postoperative mortality and morbidity due to residual intracardiac shunts, atrioventricular valve regurgitation, left ventricular outflow tract obstruction, and arrhythmias.[26]

The assessment of pre-operative imaging and hemodynamic data is essential for the optimal selection of surgical procedures to reduce the need for recurrent surgery and postoperative complications.[27] In previous studies, the requirement of the recurrent procedure is reported as high as 18.2% at 15 years after surgical correction, and left atrioventricular valve dysplasia, absence of cleft closure, and associated cardiac malformations are found to increase the rate of recurrent procedures.[28](B2)

Surgical Approaches for Repairing Complete Atrioventricular Septal Defects

The operative correction of complete atrioventricular septal defects (AVSDs) may be undertaken using one of several established techniques, each aimed at reconstructing the atrioventricular septum while preserving valvular function and minimizing postoperative complications.

1. Single-Patch Repair:This method involves the use of a single patch to simultaneously close both the atrial and ventricular septal components of the defect. Following the division of the common atrioventricular valve (AVV), the right and left valve components are reattached to the newly created septal structure. Closure of the left AVV cleft is routinely performed as part of this reconstruction. Untreated autologous pericardium is commonly utilized as the patch material. Careful attention is given to anchoring the AVV tissue close to the crest of the ventricular septum, which facilitates optimal leaflet coaptation and function.

2. Two-Patch Technique:This approach employs separate patches to address the atrial and ventricular septal defects individually. Typically, a Dacron patch is used to close the ventricular component, while the atrial septum is reconstructed with a patch fashioned from autologous pericardium. As with the single-patch technique, the cleft in the left AV valve is closed primarily. It is critical to undersize the ventricular patch in the anteroposterior axis and maintain a low patch profile to prevent excessive displacement of valve tissue into the atrial chamber, which has been correlated with an increased risk of postoperative left AVV regurgitation.

3. Modified Single-Patch ("Australian") Technique:In this variation, the ventricular component is eliminated by directly suturing the common AVV leaflets to the crest of the ventricular septum. A separate pericardial patch is then used to close the primum atrial septal defect. Closure of the left AVV cleft is carried out similarly to the aforementioned techniques.

All three strategies have demonstrated favorable early outcomes; however, none entirely eliminates the possibility of late reoperation, particularly in the context of residual or recurrent left AVV regurgitation. The likelihood of requiring reintervention appears to be higher in patients presenting with significant preoperative valve insufficiency. Accordingly, comprehensive echocardiographic assessment is imperative before hospital discharge and throughout long-term follow-up.[29][30][31]

In complete AVSD, surgical closure should be performed in early infancy to reduce the pulmonary vascular disease, whereas, in incomplete atrioventricular septal defect, a repair can be slightly delayed if the patient is not symptomatic. For partial AVSD, the primary repair is preferred with patch closure and atrioventricular valvuloplasty.

For balanced complete AVSD, early primary repair with two patch closure techniques is preferred over one patch closure, as one patch closure is associated with an increased rate of recurrent procedures due to patch dehiscence and residual shunt. Pulmonary artery banding is no longer used as a routine procedure in complete AVSD repair. For unbalanced complete AVSD, the repair technique may include single ventricle palliation with the staged biventricular repair or primary biventricular repair.[26]

Differential Diagnosis

Common differential diagnoses of AVSD include ostium secondum atrial septal defect, isolated ventricular septal defect and tetralogy of Fallot. The symptoms of heart failure and enlargement of cardiac chambers are common in these malformations, and echocardiogram plays a major role in differentiating AVSD from the aforementioned conditions.

Prognosis

The prognosis of untreated atrioventricular septal defect is dismal. Around 50% of the patients die during infancy, either due to heart failure or pulmonary infections.[2] Those who survive beyond one year, they develop the irreversible pulmonary vascular disease and later on the reversal of the shunt.

Patients undergoing surgical repair have 15 years of survival of around 90%, and 9% to 10% of those require reoperation within 15 years.[32]

Complications

Most of the complications of AVSD are related to intracardiac shunts or atrioventricular valve regurgitation. In complete AVSD, shunting of blood from left to right leads to right-sided overload and signs of heart failure and pulmonary congestion at a very early age, which contributes to significant mortality during infancy. If the shunt is not corrected, it causes an irreversible pulmonary vascular disease that leads to pulmonary hypertension and Eisenmenger syndrome.

Regurgitation of blood from the ventricle to atria through the atrioventricular valve leads to pulmonary congestion and enlargement of the atrium. Enlargement of the atrium can lead to supraventricular arrhythmias. Other complications are related to poor feeding, which may include malnutrition and failure to thrive.