Atrioventricular Canal Defects

Etiology

There is a significant association between AVSDs and trisomy 21, with a 40% to 50% risk of trisomy 21 in fetuses diagnosed with AVSDs.[4] Nonsyndromic AVSDs are linked to rare genetic variants in multiple genes involved in cardiac development. Whole-exome sequencing has revealed a notable enrichment of these genetic variants in genes such as NIPBL, CHD7, CEP152, BMPR1A, ZFPM2, MDM4, and NR1D2. Some of these genes are known to be associated with syndromes, but can also contribute to isolated AVSDs even in the absence of syndromic features. Additionally, collagen genes and genes previously linked to other forms of congenital heart disease—eg, ZFPM2, NSD1, NOTCH1, VCAN, and MYH6—are also involved.[5][6]

Familial cases of AVSDs occur infrequently, typically exhibiting autosomal dominant inheritance and variable expression. Nonsyndromic AVSDs can also be found in conjunction with other cardiac abnormalities, including tetralogy of Fallot, coarctation of the aorta, and heterotaxy syndrome.[1] Other rare genetic syndromes that sometimes are associated with AVSDs include Ellis-van Creveld (EVC, EVC2), Holt-Oram (TBX5), CHARGE (CHD7), Ivemark and Kaufman-McKusick (MKKS), and Noonan (PTPN11, CBL, KRAS, RAF1, NRAS, MRAS, SPRED2, RRAS2).[7]

Epidemiology

The incidence of AVSDs ranges from 0.24 to 0.31 per 1000 live births.[8] AVSDs also account for 3% to 5% of all congenital heart defects.[9][10] No clear sex preponderance has been consistently demonstrated; however, some studies' results have reported a slight female predominance (female-to-male ratio, 1.3:1), particularly among cases associated with Down syndrome.[11] 

Pathophysiology

Forming a 4-chambered heart involves the coordinated fusion of several mesenchymal tissues. Mesenchymal tissue deposition on these endocardial cushions aids in the process of fusion, which in turn leads to the separation of the common AV canal. The AV canal has superior and inferior endocardial cushions that fuse around 4 to 5 weeks of gestation. The failure of fusion of this endocardial cushion at various levels leads to septal defects ranging from partial to complete AVSDs.[12] Abnormal fusion of the interatrial septum leads to communication in the inferior part of the septum, called an ostium primum defect.

AVSD is commonly classified into complete, partial, transitional, and intermediate forms. The primary distinction is based on the presence and extent of atrial and ventricular septal defects, as well as the anatomy of the AV valves.[13]

• Complete AVSD comprises a primum ASD, an inlet VSD, and a common AV valve with 4 to 5 leaflets, including superior and inferior bridging leaflets, all within a single annulus, which communicates all heart chambers. 
• Partial AVSD includes a primum ASD without a VSD. The right and left AV valves are separated by tissue, but they share a common junction. There are varying degrees of malformation in the left-sided component of the common AV valve, typically characterized by a cleft in the anterior leaflet. 
• Transitional and intermediate AVSDs are terms used interchangeably to describe a variant of complete AVSD that shares features of partial and complete forms. An interatrial communication above the AV valve and a restrictive interventricular communication below it characterize a transitional AVSD. This distinguishes it from complete AVSDs with large, unrestricted atrial and ventricular septal defects, and from partial AVSDs, which have a primum ASD with separate right and left AV valve orifices with a cleft in the left AV valve, and no VSD.[14]

Complete AVSDs may be further classified by AV valve morphology (Rastelli classification). The Rastelli classification is based on the insertion of the chordae and the morphology of the superior bridging leaflet.[15]

• Type A: This is the most common type associated with trisomy 21. The superior bridging leaflet is divided by attachments to the crest of the ventricular septum, with minimal bridging.
• Type B: This is the least common. The superior bridging leaflets by means of chordal insertion are extended onto the right ventricular papillar muscle, which is typically displaced onto the right side of the ventricular septum with moderate bridging.
• Type C: The superior bridging leaflet is free floating or undivided without attachments. This is associated with abnormalities, eg, tetralogy of Fallot and transposition of the great arteries.[16]

Balanced vs Unbalanced AVSDs

Unbalanced AVSDs account for approximately 10% to 15% of all AVSD cases, although the exact percentage can vary based on the definition used and the population studied. In these lesions, the AV valve is more committed to one ventricle. Thus, an unbalanced AVSD can be either right- or left-dominant. RV dominance is more common and is associated with left ventricular hypoplasia. The degree of AV valve commitment is the primary determinant of candidacy for full biventricular surgical repair versus single ventricle palliation.[17] 

History and Physical

The hemodynamic consequences of AVSDs vary with the anatomic subtypes; they depend on the degree of shunting across the atrial and ventricular communications and the severity of AV valve regurgitation. In complete AVSDs, there is typically a large left-to-right shunt in early infancy. Individuals with complete AVSDs usually start to exhibit congestive heart failure (CHF) symptoms at 4 to 6 weeks of life as the pulmonary vascular resistance (PVR) drops to its nadir.

CHF symptoms are primarily secondary to pulmonary overcirculation, and the severity of symptoms depends on the ratio of PVR to systemic vascular resistance. Tachypnea and difficulty gaining weight are the first signs noticeable in patients with AV canal defects. The occurrence and severity of symptoms depend on the degree of AV valve regurgitation and other associated CHD.

In patients with a partial AVSD, symptoms might not be detected in the first few years of life and might manifest later in childhood. Of note, patients who have ostium primum atrial septal defect (ASD), seen in AVSDs, present at an earlier age than those with ostium secundum ASD. The most common presentation is evaluation of a murmur, secondary to increased flow across the pulmonary valve, best heard at the upper left sternal border. Symptoms of CHF include increased work of breathing, sweating while feeding, poor feeding, lethargy, or increased sleepiness. Signs of CHF include tachypnea, tachycardia, failure to thrive (fall across 2 major centiles on the growth chart), wheezing or rales on lung auscultation, S3 gallop rhythm, apical displacement of the apical impulse, hepatomegaly, or increased jugular venous pressure.

A careful and complete cardiac exam should be done to look for:

• Wide and fixed split S2 heard due to left-to-right shunting across the ASD, causing increased blood flow in the right side of the heart, irrespective of the phase of respiration.
• S3 due to the increased flow of blood splashing across the LV walls, which are still compliant.
• Additional murmurs such as:
  • A holosystolic murmur secondary to left AV valve regurgitation is best heard at the apex.
  • Mid-diastolic murmur (rumble) if the shunt is large or if there is increased flow across the left AV valve due to "relative" left AV valve stenosis.

Some patients can become symptomatic earlier at birth if there are associated cardiac lesions such as coarctation of the aorta and LV outflow obstruction. 

Physical Exam

Dysmorphic features, such as flat facies, upslanting palpebral fissures, and a single palmar crease, characteristic of patients with Down syndrome, should be evaluated for AVSD, as 40% to 45% of patients with Down syndrome have an AVSD. Because AVSD often co-occurs with other systemic abnormalities and genetic syndromes, a survey for congenital anomalies, such as cleft lip/palate and musculoskeletal issues, is strongly recommended for patients with AVSD.[18]

Evaluation

Prenatal Diagnosis

Ultrasound remains the diagnostic method of choice for prenatal diagnosis of AVCDs. The inclusion of a 4-chamber view is a routine part of the obstetric ultrasound examination and has improved prenatal detection of AVSDs. When an AVSD is suspected during an obstetric ultrasound, referral to fetal cardiology for a comprehensive fetal echocardiogram is recommended for a detailed assessment of the AV valve morphology and commitment, and associated cardiac lesions. Genetic testing should be offered to all families, given the higher incidence of genetic syndromes associated with this CHD. 

Postnatal Diagnosis 

Echocardiogram

The echocardiogram remains the cornerstone of diagnosis for AVSDs and should be performed before hospital discharge after birth. A detailed assessment of cardiac structures should be conducted.

Elements listed below should be evaluated in detail and given priority:

• The ventricular and atrial components of the AVSD from long and short axis, apical 4-chamber, and subcostal views.
• AV valve morphology and attachment, especially in subcostal sweeps.
• AV valve commitment from the apical 4-chamber and oblique subcostal views.
• Subvalvar apparatus with special attention to papillary muscle anatomy to confirm or rule out a single left ventricle papillary muscle, a parachaute deformity, a cleft, or a double orifice left AV valve.
• Evaluate the degree of AV valve regurgitation. 
• Assessment of any left ventricular outflow obstruction.
• Assessment of the aortic arch to rule out obstruction, especially in RV-dominant AVSDs.
• Assessment of the right ventricular outflow tract to rule out any levels of obstruction.[14]

Electrocardiogram 

The characteristic electrocardiogram in AVSDs has a leftward counterclockwise superior axis between -150 and -90 degrees in the frontal plane. This finding results from abnormal ventricular activation caused by the conduction system coursing along the inferior ridge of the inlet VSD. The next most common finding is the presence of rsR’ or rR’ in the right precordial leads, caused by the volume/pressure overload. The other findings include a prolonged PR interval and right ventricular enlargement.[19][20]

Chest x-ray

In partial AVSD, the chest x-ray shows right heart enlargement with increased pulmonary vasculature. While the intermediate and complete forms show more diffuse enlargement of all chambers, left atrial involvement is unusual; left ventricle enlargement is not very obvious due to masking by the enlarged right ventricles.[21]

Cardiac catheterization 

Cardiac catheterization is not a part of routine preoperative evaluation for uncomplicated AVSDs who undergo surgical repair at the appropriate timing based on the AVSD subtype. Cardiac catheterization can be beneficial to evaluate pulmonary vascular resistance in untreated older patients with complete AVSD or complex infants with associated comorbidities, such as airway/lung anomalies, who do not exhibit CHF symptoms.

Cross-sectional imaging 

Cross-sectional imaging, including cardiac computed tomography and cardiac magnetic resonance imaging, is usually not required in uncomplicated AVSDs; however, it can be beneficial in a subset of patients, such as those with unbalanced AVSDs, to assess ventricular volumes and guide decision-making. In addition, this test can be important in complex lesions such as heterotaxy to evaluate vascular anatomy for initial palliation in patients with inadequate pulmonary blood flow.[22]

Treatment / Management

AVSD Management

The definitive management of a complete AVSD is surgical correction. However, overall management can be divided into 3 parts: initial medical management, surgical correction, and long-term follow-up care.[23]

Surgical Management

Surgical management of AVSD depends on various factors, including the type of defect, valve morphology, associated valvular and conduction abnormalities, the presence of a shunt, and other vascular anomalies.[24] Surgical repair of complete AVSD is typically performed between 3 and 6 months of age to prevent irreversible pulmonary vascular disease and to achieve excellent long-term outcomes. If complete AVSD is not repaired early in life (usually by 6 months), irreversible pulmonary vascular disease can develop, leading to Eisenmenger physiology, which makes complete repair impossible.[1](A1)

Early surgical intervention

In cases where infants experience severe heart failure or failure to thrive, earlier repair before 3 months of age is performed. This early intervention can be done safely and has outcomes comparable to those of later repairs. Moreover, it is associated with better survival rates than staged repair following pulmonary artery banding (94.2% vs 58.4% at 20 years). Repair is also deemed safe for infants weighing 3.5 kg or less, with similar overall survival rates (83.8% vs 90.4%) and comparable freedom from left AV valve reoperation (73.6% vs 74.5%) compared with infants weighing more than 3.5 kg.[25] However, procedures performed more than 3 months ago are associated with longer intensive care unit stays, greater need for mechanical ventilation, and longer postoperative hospital stays than repairs performed at 3 to 6 months.[26]

Surgical techniques

There are 2 primary surgical techniques used to repair AVSDs: the 2-patch technique and the modified single-patch technique, with variations in valve management and patch configuration. 

• The 2-patch technique uses patch material to divide the common atrioventricular valve into right and left components, allowing the atrial and ventricular defects to be closed independently. The mitral cleft is also sutured.[27] 
• The modified single-patch technique involves suturing of the common AV valve leaflets to the crest of the ventricular septum without using ventricular septal patch material.[28]

Nutrition

Nutritional optimization and calorie fortification play an important role in allowing more somatic growth before surgical repair. The medical management is generally directed towards improving myocardial function by reducing preload and afterload with diuretics and angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. To improve contractility, inotropic agents such as digoxin are used.[8] 

Long-Term Follow-Up Care

The American College of Cardiology and American Heart Association recommend long-term follow-up of patients with AVSD. The frequency of surveillance should be tailored to the complexity of the AVSD. More symptomatic individuals should be monitored every 3 to 6 months, while those who are asymptomatic can be evaluated every 24 to 36 months.[1](A1)

The primary reason for re-intervention in these patients is typically AV valve regurgitation. However, other complications can also arise, including left ventricular outflow tract obstruction due to abnormal left ventricular outflow tract shape, bradyarrhythmias, tachyarrhythmias, late-onset heart block, and residual shunts. Cardiac catheterization may be helpful if there is a suspicion of pulmonary hypertension.[14]

Independent risk factors for reoperation include the presence of associated cardiovascular defects, left AV valve dysplasia, and inadequate cleft closure. Choosing primary cleft closure instead of patch augmentation can also increase risk.[29] Additional factors that contribute to the likelihood of reoperation include undergoing an initial complete repair of AVSD, having an unbalanced AVSD that required a single-ventricle approach, having concurrent ventricular septal defects or aortic coarctation, having a persistent left superior vena cava, and having genetic syndromes other than trisomy 21.[30]

Differential Diagnosis

The differential diagnosis includes conditions that may mimic AVSD on imaging or present with similar anatomical features:

• A primum ASD does not have the ventricular septal component or the common AV valve observed in complete AVSDs.
• An isolated cleft of the mitral valve, especially if it leads to moderate or severe mitral regurgitation, requires detailed imaging. This type of cleft typically occurs in the anterior leaflet (mid-A1 or mid-A3 scallops), similar to those seen in partial AVSDs.
• Inlet VSDs are located in the posterior septum beneath the atrioventricular valves and can be mistaken for the ventricular component of AVSD.
• A common atrium may also be confused with AVSD; however, it lacks the characteristic abnormalities of the atrioventricular valves and the primum defect.
• Importantly, a double-outlet right ventricle defect can present with either an inlet VSD or an AVSD.
• Moreover, AVSD can occur concurrently with conditions such as tetralogy of Fallot, heterotaxy syndrome, and truncus arteriosus.[1] 

Prognosis

Postoperative mortality rates for AVSD repair have significantly improved over time. Contemporary studies report perioperative mortality rates of 0.9% to 2% for isolated AVSDs and 4% for complex cases, including unbalanced AVSD, and associated defects, including tetralogy of Fallot, double outlet right ventricle, aortic arch anomalies, and total anomalous pulmonary venous connection. The overall 10-year survival rate is 92%, while the incidence of any reoperation is about 11%. Complex anatomy does not appear to increase the risk of mortality but is associated with a higher likelihood of reoperation. 

Other risk factors for reoperation of the left atrioventricular valve include having a second bypass run and preoperative moderate or worse regurgitation.[31] Long-term survival following AVSD surgery is excellent, with 10-year overall survival rates of 85% to 92% and 20-year rates of 82% to 91%. Risk factors for mortality include the earlier surgical era, prior pulmonary artery banding, preoperative severe pulmonary hypertension, complex anatomy, being less than 3 months old, and having needed reoperation.[30]

Complications

Unrepaired AVSDs

CHF results from significant communication between the atria and ventricles, leading to volume overload in both the right atrium and the right ventricle. The large left-to-right shunt causes excessive blood flow to the lungs, resulting in increased pulmonary artery pressures. Pulmonary hypertension develops early and can progress rapidly, typically within the first 6 to 12 months of life if surgical intervention is not performed. If this condition advances to Eisenmenger physiology, it complicates the possibility of complete repair and is associated with very high morbidity and mortality if surgery is attempted after this stage has been reached.[1]

Postsurgical Complications

Complications that may arise after the repair of AVSDs include dysfunction of the left AV valve, left ventricular outflow tract obstruction (LVOTO), arrhythmias, residual shunts, and heart block. Among these, left AV valve complications are the most common, occurring in 5% to 10% of patients and often necessitating reoperation: both regurgitation and stenosis can develop in the left AV valve, with regurgitation being significantly more frequent than stenosis. Additionally, LVOTO occurs in approximately 3.5% to 5% of patients, primarily due to the abnormal LVOT shape associated with AVSD anatomy. Furthermore, moderate to large residual shunts can lead to clinical deterioration over time.[1]

Supraventricular tachycardias have been reported in about 8% of patients early after AVSD surgery and in 3.6% of patients later on after the repair. In AVSD, the atrioventricular node is often displaced inferiorly, leading to conduction abnormalities. Thus, complete heart block, which requires permanent pacemaker implantation, occurs in approximately 3.6% of patients. Nonsyndromic AVSDs (AVSD without Down syndrome) and partial AVSDs constitute independent risk factors for the need for a pacemaker.[32]