Ventricular Septal Defect

Etiology

VSDs result from developmental abnormalities or disruptions in the formation of the interventricular septum during the complex process of embryological heart morphogenesis. Although VSDs often occur in isolation, they can be associated with other congenital heart defects, including atrial septal defects, patent ductus arteriosus, right aortic arch, and pulmonic stenosis. Additionally, VSDs may coexist with conditions such as aortic coarctation, subaortic stenosis, tetralogy of Fallot, and transposition of the great arteries, adding to the complexities of congenital heart disease.

Recent epidemiological studies have indicated that conditions such as maternal epilepsy (especially when treated with carbamazepine, as shown in animal studies), migraines, chronic hypertension, and paroxysmal supraventricular tachycardia may be associated with an elevated risk of VSDs. This association is supported by a study involving over 3000 live-born cases of congenital heart disease, which compared them to neonates born without congenital disabilities or with other isolated congenital abnormalities.[6][7][8]

Maternal infections (such as rubella, influenza, and febrile illness), maternal diabetes, and phenylketonuria have been associated with an increased risk of VSDs. Exposure to toxins such as alcohol, marijuana, cocaine, and certain medications, including metronidazole and ibuprofen, is also linked to VSDs. Williams et al found that moderate-to-high levels of alcohol consumption in expectant mothers were associated with isolated VSDs. Furthermore, mothers who used marijuana exhibited a 2-fold increase in the risk of isolated simple VSD. Recently, a stressful maternal lifestyle has also been correlated with a higher incidence of VSDs.[9][10][11][12]

A notable Italian study conducted in 2011 by Fesslova et al examined the recurrence of congenital heart disease in pregnant women with a familial predisposition. Among the 65 infants born with congenital heart disease, which represented 21.5% of the total cohort, 14 were diagnosed with VSD, indicating a significant genetic component.[13]

In women with congenital heart disease, the complications observed in their offspring are closely linked to the mother's cardiac function, particularly in cases of maternal cyanosis or reduced cardiac output. The recurrence rate of heart defects in the children of mothers with congenital heart disease is approximately 6%, with a similar 6% risk of VSD recurrence among these children.[14][15]

Several genetic factors contribute to VSDs, including chromosomal abnormalities, single-gene mutations, and polygenic inheritance. A recently discovered TBX5 mutation has been associated with septal defects in patients with Holt-Oram syndrome. Additionally, non-inherited risk factors also play a role in the development of VSDs.[16][17][18]

Epidemiology

Isolated VSD accounts for 37% of all congenital heart diseases in children, with an incidence of approximately 0.3% in newborns. The prevalence decreases significantly in adults due to spontaneous closure in up to 90% of cases. While VSDs show no gender predilection, some studies suggest that females are more likely to present with milder forms of the condition.[19][20]

Pathophysiology

The interventricular septum is an asymmetric, curved wall shaped by pressure differences between the ventricles. The septum consists of 2 distinct parts—the membranous and muscular portions. The membranous portion includes the atrioventricular segment, while the muscular portion comprises the trabecular, infundibular, and inlet segments.[21][22] 

VSD arises from the incomplete development or fusion of intraventricular septal components during embryonic cardiac morphogenesis. The different anatomical locations and histological variations of VSDs have led to several classification and nomenclature systems. A unified classification system has been introduced to simplify VSD descriptions and eliminate confusion from multiple synonyms. This system organizes VSDs into 4 significant groups, as mentioned below.[23] 

Infundibular (Outlet) Ventricular Septal Defect

• Location: This is positioned beneath the semilunar valves (aortic and pulmonary) within the outlet septum of the right ventricle, above the crista supraventricularis.

• Characteristics: Infundibular VSD, also referred to as supracristal, is a rare VSD type that accounts for only 6% of all cases but occurs in about 30% of the Asian population. Aortic valve prolapse and regurgitation frequently develop due to inadequate support for the right and noncoronary cusps of the aortic valve. Spontaneous closure of these defects is rare.

Perimembranous Ventricular Septal Defect

• Location: This is located in the membranous septum, below the crista supraventricularis.

• Characteristics: Perimembranous VSD is the most common type, accounting for 80% of all VSDs. Perimembranous VSD may involve the muscular septum and can interchangeably be called membranous VSD. The septal leaflet of the tricuspid valve can form a pouch, which may reduce shunting, resulting in spontaneous closure.

Inlet or Atrioventricular Canal Ventricular Septal Defect

• Location: This is located just inferior to the inlet valves (tricuspid and mitral) within the inlet portion of the right ventricular septum.

• Characteristics: Inlet or atrioventricular canal VSD represents about 8% of all VSDs and is more frequently observed in patients with Trisomy 21.

Muscular (Trabecular) Ventricular Septal Defect

• Location: This is located in the muscular septum, usually in the apical, central, and outlet regions of the interventricular septum.

• Characteristics: Muscular VSD can occur as multiple defects, resembling a "Swiss cheese" appearance, and account for up to 20% of VSDs in infants. The incidence is lower in adults due to a tendency for spontaneous closure.

Gerbode Defects

In addition to the above 4 types of VSDs, the Gerbode defect is a distinct cardiac anomaly named after Frank Gerbode and colleagues from Stanford University School of Medicine, who first described it in 1958. This defect involves a direct connection between the left ventricle and the right atrium and is classified into 3 forms, as mentioned below (see Image. Gerbode Defects).

• Type 1: True Gerbode or supravalvular type is the rarest type, originating from a congenital deficiency in the atrioventricular component of the membranous septum.

• Type 2: Subvalvular type involves ventriculo-atrial shunting caused by a central VSD along with a deficiency in the septal leaflet of the tricuspid valve. 

• Type 3: This represents a combination of the characteristics observed in both types 1 and 2.[24][25][26]

The primary pathophysiological mechanism of VSD involves the creation of a shunt between the right and left ventricles. The hemodynamic significance of the VSD depends on the volume of blood shunted and the direction of that shunting. These factors are influenced by the size and location of the VSD, as well as the pulmonary vascular resistance.

In addition to classifying VSDs by location, they can also be categorized by size, which is determined in relation to the diameter of the aortic annulus. VSDs are considered small if their dimensions are equal to or less than 25% of the aortic annulus diameter, medium if they measure more than 25% but less than 75%, and large if they exceed 75% of the aortic annulus diameter.

In prolonged, large left-to-right shunts, the pulmonary vascular endothelium undergoes irreversible changes, resulting in persistent PAH. When the pressure within the pulmonary circulation exceeds that of the systemic circulation, the shunt direction reverses, leading to a right-to-left shunt. This condition is known as Eisenmenger syndrome and is observed in approximately 10% to 15% of individuals with VSD.

Conventional teaching has long stated that corrective surgery is contraindicated in established cases of Eisenmenger syndrome. However, advancements in surgical techniques and a better understanding of the syndrome's pathophysiology indicate that surgical intervention may now be a viable option in select cases.[27]

History and Physical

The clinical presentation of unrepaired VSDs primarily depends on the presence of a hemodynamically significant shunt, which directly correlates with the size of the defect. VSDs can be categorized as follows:

• Small VSDs: These defects cause minimal left-to-right shunting without leading to left ventricular fluid overload or PAH. Consequently, individuals with small VSDs are often asymptomatic, and the condition is frequently discovered incidentally during physical examinations.

• Medium VSDs: Individuals with medium-sized VSDs experience moderate left ventricular volume overload and may exhibit no or mild PAH. Symptoms typically present later in childhood and may be accompanied by mild congestive heart failure (CHF).

• Large VSDs: Individuals with significant defects often develop CHF early in childhood due to severe left ventricular overload and PAH.

The murmur associated with a VSD is typically pansystolic and best heard at the left lower sternal border. In small defects, the murmur is harsh and loud, whereas in larger defects, it tends to be softer and less intense. Handgrip exercises, which increase afterload, can intensify the murmur. Murmurs associated with infundibular defects are best heard in the pulmonic area. A diastolic decrescendo murmur, along with a wide pulse pressure, may indicate aortic regurgitation. Increased left ventricular flow can lead to a mid-diastolic rumble at the lower left sternal border. Additionally, a septal aneurysm may occasionally produce a systolic click, particularly in membranous defects.

In cases of Eisenmenger syndrome, clinical manifestations include cyanosis, desaturation, dyspnea, syncope, secondary erythrocytosis, and clubbing. The typical murmur associated with VSD may be absent, and an accentuated pulmonic component of the second heart sound may be present.[28]

Evaluation

Color Doppler transthoracic echocardiography (TTE) is the most valuable diagnostic tool for VSDs due to its high sensitivity, detecting up to 95% of cases, particularly for nonapical lesions larger than 5 mm. This imaging technique provides crucial morphological information, including the size, location, and number of defects, along with hemodynamic data, such as jet size, severity, and estimates of pulmonary artery pressure.

Additionally, TTE is useful for identifying associated conditions, such as aortic insufficiency and other congenital heart defects, while also assessing right and left ventricular chamber size and function. However, TTE has limitations, including operator dependence and difficulties posed by poor acoustic windows. When conventional TTE results are inconclusive, transesophageal echocardiography is recommended for further evaluation.[29][30]

Electrocardiography (ECG) results are normal in about half of patients with VSD. The ECG may reveal left ventricular hypertrophy in individuals with large shunts when abnormalities are present. In patients with PAH, the ECG may demonstrate right bundle branch block, right axis deviation, and signs of right ventricular hypertrophy and strain.

Chest radiography usually appears normal in individuals with minor defects. However, larger defects may show an enlarged cardiac silhouette, along with increased left ventricular size. In patients with PAH, signs of right ventricular enlargement and increased pulmonary artery diameter may also be evident. 

Cardiac magnetic resonance imaging (MRI) and computed tomography (CT) are beneficial for evaluating complex anatomy, such as VSDs associated with other congenital heart anomalies or defects located in unusual areas that are difficult to visualize with conventional TTE.

Cardiac catheterization is a vital diagnostic tool that provides accurate hemodynamic information, particularly regarding pulmonary vascular resistance and the response to vasodilators. This information is valuable for individuals being evaluated for surgical closure of VSDs. Furthermore, cardiac catheterization offers detailed insights into coexisting conditions, such as aortic regurgitation, and is beneficial in cases involving multiple VSDs or when coronary artery disease is suspected.

Treatment / Management

Approximately 85% to 90% of small isolated VSDs undergo spontaneous closure within the first year of life. Patients with small, asymptomatic VSDs, in the absence of PAH, typically have an excellent prognosis without intervention. However, if intervention becomes necessary, the management approach involves VSD closure.[31]

Management of Eisenmenger syndrome is typically performed at specialized centers due to the complexity of these cases. Historically, surgical intervention was the primary option, with heart-lung transplantation considered the ultimate solution. However, recent advancements in interventional techniques have demonstrated promising results.

Routine antibiotic prophylaxis for infective endocarditis in patients with unrepaired VSDs is no longer recommended.[32] Endocarditis prophylaxis is primarily indicated for individuals with cyanotic congenital heart disease, a history of previous endocarditis episodes, those with prosthetic heart valves, or individuals who have undergone repair with prosthetic material.

VSD closure is generally indicated for medium-to-large defects causing significant hemodynamic compromise, especially in symptomatic cases with left ventricular dysfunction. Intervention may also be warranted in instances of progressive aortic insufficiency or following an episode of endocarditis. The 2008 guidelines from the American College of Cardiology and the American Heart Association outline the following indications for surgical closure of VSDs:

• History of endocarditis.
• Pulmonary to systemic blood flow (Qp:Qs) ratio of greater than or equal to 2 with clinical evidence of left ventricular fluid overload.

Surgical intervention may also be considered for milder shunts (Qp:Qs >1.5) if there is evidence of left ventricular systolic or diastolic dysfunction. Additionally, surgical closure is recommended when the pulmonary artery pressure and pulmonary vascular resistance are less than two-thirds of systemic pressure and systemic vascular resistance, respectively.

Surgical Repair

Surgical repair of VSDs offers several benefits, including a reduced risk of endocarditis, potential improvement in PAH, and enhanced overall survival. In the absence of PAH, the operative mortality rate is approximately 1%. However, surgical intervention may present potential complications.

Complications of VSD surgical repair include:

• Residual or recurrent VSD.
• Valvular incompetence: This includes tricuspid regurgitation and aortic insufficiency.
• Arrhythmias: Common postoperative arrhythmias may include atrial fibrillation, complete heart block, and ventricular tachycardia.
• Left ventricular dysfunction.
• Progression of PAH.

The primary contraindication for surgical VSD closure is the presence of irreversible PAH, as this significantly increases the risk of perioperative mortality and complications. In these cases, alternative management strategies are explored to address the underlying condition while minimizing risk.[33](A1)

Percutaneous Closure

Indications for transcatheter closure: Transcatheter closure is increasingly recognized as an effective intervention for various types of VSDs, with specific indications guiding its use based on the defect's characteristics and the patient's clinical condition.

• Muscular VSDs: Transcatheter closure is primarily recommended for muscular VSDs, particularly those located in the mid-muscular or apical regions, as these defects are often difficult to access surgically.

• Perimembranous VSDs: Selected cases of perimembranous VSDs may be appropriate for transcatheter closure, depending on factors such as the defect's size and location, its proximity to the aortic valve, and the associated risk of complications such as heart block.

• Hemodynamically significant VSDs: Patients exhibiting significant left-to-right shunts that result in left heart volume overload, heart failure symptoms, or growth failure despite optimal medical management may be considered for intervention.

• Residual VSDs postoperative: Residual defects following surgical repair of a VSD may be appropriate for transcatheter closure, particularly if they are hemodynamically significant or symptomatic.

Contraindications: Certain clinical scenarios may preclude the use of transcatheter closure for VSDs.

• Large defects: VSDs that are too large to be effectively closed with commercially available devices.

• Proximity to vital structures: VSDs located near vital structures, such as the aortic valve, tricuspid valve, or conduction tissue (eg, the Bundle of His), where there is a high risk of damaging the valves or causing heart block.

• Infective endocarditis: Active infection or a history of infective endocarditis associated with the defect.

• Pulmonary hypertension with shunt reversal (Eisenmenger syndrome): Patients with irreversible pulmonary vascular disease are not candidates for closure.

Closure of Gerbode Defects

This intervention is typically recommended to prevent the progression of tricuspid regurgitation and the potential development of infective endocarditis. Although spontaneous closure of Gerbode defects is rare, effective treatment options are available.

• Surgical closure is the most common and widely used treatment for Gerbode defects, offering well-established and favorable outcomes.

• Transcatheter device closure serves as an effective alternative treatment. Although less common, successful cases of transcatheter closure have been reported for both congenital and acquired Gerbode defects. Key considerations during the procedure include achieving proper device alignment, mitigating potential conduction disturbances, and minimizing the risk of exacerbating tricuspid regurgitation.

In summary, VSD is the most common congenital anomaly identified at birth. While small defects often close spontaneously within the first year of life, larger defects can lead to significant complications. Surgical closure and transcatheter device closure are the primary interventions for managing larger defects effectively.[19][34][35](B3)

Differential Diagnosis

Although VSD is a distinct condition, several cardiac and non-cardiac disorders can present with similar symptoms. The differential diagnosis for VSD includes:

• Atrioventricular septal defect
• Atrial septal defect
• Patent ductus arteriosus
• Pulmonary stenosis
• Tetralogy of Fallot
• Mitral valve prolapse
• Tricuspid regurgitation
• Eisenmenger syndrome
• Infective endocarditis
• Myocarditis

Prognosis

Patients who have undergone VSD repair generally have a favorable prognosis. However, they have an elevated long-term risk of arrhythmia, endocarditis, and heart failure compared to the general population.[36]

Complications

Complications of VSD may include:

• Eisenmenger syndrome
• Aortic insufficiency from aortic valve leaflet prolapse
• Endocarditis
• Embolization
• Heart failure
• Pulmonary hypertension
• Arrythmias [37]