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    Drugs & Diseases>Cardiology

    Atrial Septal Defect

    Updated: Sep 12, 2024
    • Author: David H Adler, MD, FACC, FSCAI; Chief Editor: Yasmine S Ali, MD, MSCI, FACC, FACP  more...
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    Overview

    Background

    An atrial septal defect (ASD) is one of the more commonly recognized congenital cardiac anomalies presenting in adults. It is characterized by an abnormal connection between the upper chambers of the heart, allowing for mixing of oxygenated and deoxygenated blood—thus, a defect or hole in the interatrial septum allows pulmonary venous return (oxygenated blood) from the left atrium to pass directly to the right atrium (left-to-right shunt). While often diagnosed in childhood, the clinical presentation of some ASDs may be subtle, thus delaying diagnosis until adulthood.

    Other times, deoxygenated blood from the right atrium can traverse the defect and enter the systemic circulation (right-to-left shunt). Depending on the size and site of the defect, compliance/pressures of the atria and ventricles, and associated anomalies, this can result in a spectrum of disease ranging from no significant cardiac sequelae to major conditions as a result of right-sided volume overload. Small ASDs may not produce any noticeable signs or symptoms, whereas large defects may lead to significant issues with right ventricular enlargement and resultant heart failure and poor growth in childhood or pulmonary arterial hypertension and atrial arrhythmias in adulthood.

    With the routine use of echocardiography, the detection and, therefore, the incidence of ASD is increased compared to earlier incidence studies using catheterization, surgery, or autopsy for diagnosis. [1, 2] For some ASDs, the subtle physical examination findings and often minimal symptoms during the first 1-3 decades of life may contribute to a delay in diagnosis until adulthood. However, the majority of ASDs (>70%) are detected by the fifth decade of life. If an ASD is hemodynamically significant, earlier intervention is recommended.

    Next: Pathophysiology

    Pathophysiology

    The magnitude of the left-to-right shunt across the atrial septal defect (ASD) depends on the defect size, the relative compliance of the ventricles (ie, determinates of left atrial [LA] and right atrial [RA] pressures), and the relative resistance of the ventricles (ie, in both the pulmonary and systemic circulation. With a small ASD, the LA pressure may exceed the RA pressure by several millimeters of mercury (mm Hg), whereas with a large ASD, mean atrial pressures are nearly identical. Shunting across the interatrial septum is usually left-to-right and occurs predominantly in late ventricular systole and early diastole/atrial systole. Some additional augmentation likely occurs during atrial systole; however, a transient and small right-to-left shunt can occur, especially during respiratory periods of decreasing intrathoracic pressure, even in the absence of pulmonary arterial hypertension.

    The chronic left-to-right shunt results in diastolic volume loading of the right ventricle (RV) and increased pulmonary blood flow. Over time, this chronically increased blood flow will affect the pulmonary vascular resistance (PVR) and filling/geometry of the RV and interventricular septum (IVS). Often through early childhood, the volume load is usually well tolerated even though pulmonary blood flow may be more than double the systemic blood flow (Qp:Qs >2) and the PVR remains normal. However, altered ventricular compliance with age can result in an increased left-to-right shunt, contributing to higher pulmonary blood flow and symptoms of pulmonary overcirculation (eg, increased respiratory effort, fatigue, decreased exercise tolerance, poor growth). RV enlargement shifts the interventricular septum toward the left ventricle (LV) during diastole, which will then decrease LV filling and may raise LV end-diastolic pressure, causing lower cardiac output and increased left-to-right shunting. [3]

    A chronic, significant left-to-right shunt can permanently alter the PVR, leading to pulmonary arterial hypertension and, eventually, reversal of shunt (now becoming right to left), also known as Eisenmenger syndrome.

    Owing to an increase in plasma volume during pregnancy, shunt volume can increase, also leading to symptoms. However, pulmonary artery pressures usually remain normal.

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    Next: Pathophysiology

    Etiology

    Atrial septal defects (ASDs) are a congenital cardiac disorder caused by the spontaneous malformation of the interatrial septum. Embryologically, there are three tissue planes that eventually fuse to septate the atria: the septum primum, the septum secundum, and the atrioventricular (AV) canal septum (ie, the endocardial cushions that separate the atria and the ventricles). Initially, there is a common atrium, and the septum primum arises from the superior surface and grows inferiorly toward the AV canal septum. The fusion between these two structures closes the orifice (ostium primum), separating the right and left atria. In addition, the septum secundum forms, arising as an invagination from the rightward aspect of the atrial wall. Defects in the atrial septum result from abnormalities of this process.

    Note the following types of ASD:

    • Patent foramen ovale: This type of ASD results from a residual flap connection between the septum primum and the septum secundum. The septum secundum grows leftward until the seventh week of gestation and then stops before completely fusing with the septum primum, leaving a posterior and inferior gap known as the fossa ovalis. This connection is normal in all fetuses, allowing oxygenated umbilical venous blood to traverse the atrial septum into the left side of the heart for ejection to the systemic circulation. After birth, left atrial pressures increase due to the expansion of the lungs and higher systemic vascular resistance. This pushes the flap closed and many seal shut. However, approximately 25% of foramen ovales remain patent into adulthood. [4]

    • Ostium secundum ASD: Before the septum primum can completely fuse with the AV canal septum, small perforations develop and coalesce in the superior portion of the septum primum, leading to a secundum ASD. The combination of excessive resorption of the septum primum from apoptosis and incomplete development of the septum secundum produce a large ostium secundum ASD.

    • Ostium primum ASD: These defects are caused by incomplete fusion of septum primum with the endocardial cushion. The defect lies immediately adjacent to the AV valves, either of which may be deformed and incompetent. In most cases, only the anterior or septal leaflet of the mitral valve is displaced, and it is commonly cleft. The tricuspid valve is usually not involved.

    The remaining two defects do not actually involve a true defect in the interatrial septum but physiologically behave similarly, allowing for atrial mixing of blood:

    • Sinus venosus ASD: Abnormal fusion between the embryologic sinus venosus and the atrium causes these defects. In most cases, the defect lies superior in the atrial septum near the entry of superior vena cava. Often there is associated anomalous drainage of the right superior pulmonary vein. The relatively uncommon inferior type is associated with partial anomalous drainage of the right inferior pulmonary vein. Anomalous drainage can be into the right atrium, the superior vena cava, or the inferior vena cava.

    • Coronary sinus ASD: The coronary sinus defect is characterized by unroofed coronary sinus and persistent left superior vena cava that drains into the left atrium. A dilated coronary sinus often suggests this defect. This can result in desaturation due to right-to-left shunt into the left atrium. The diagnosis can be made by injecting a contrast agent into the left upper extremity; coronary sinus opacification precedes right atrial opacification.

    Genetics

    ASD may occur on a familial basis. Holt-Oram syndrome, characterized by an autosomal dominant pattern of inheritance and deformities of the upper limbs (most often, absent or hypoplastic radii), has been attributed to a single gene defect in TBX5. [5]  The penetrance is nearly 100% for Holt-Oram syndrome. Approximately 40% of Holt-Oram cases are due to new mutations. An estimated 58% of individuals with Holt-Oram syndrome have ASD. [2]

    Ellis van Creveld syndrome is an autosomal recessive disorder associated with skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails and teeth, and a common atrium, occurring in 60% of affected individuals. [6]

    Mutations in the cardiac transcription factor NKX2.5 have been attributed to the syndrome familial ASD associated with progressive atrioventricular block. [7, 8, 9] This syndrome is an autosomal dominant trait with a high degree of penetrance but no associated skeletal abnormalities.

    Variants in the GATA4 gene have also been implicated in ASD. [8, 10] Relatively recently, a novel mutation at the methylation position of GATA4 (c.A899C, p.K300T) was reported in association with ASD. [10]

    Wang et al reported that downregulation of the following genes in ASD may affect heart atrial septum formation, cardiomyocyte proliferation, and cardiac muscle development [8] :

    • Cardiac specific transcriptional factors GATA4 and NKX2-5
    • Extracellular signal molecules VEGFA and BMP10
    • Cardiac sarcomeric proteins MYL2, MYL3, MYH7, TNNT1, and TNNT3

    The investigators noted that dysregulation of these genes during heart septum morphogenesis may lead to cell cycle as the dominant pathway among downregulated genes, with the potential for the decreased expression of the proteins included in the cell cycle then disturbing cardiomyocyte growth and differentiation during atrial septum formation. [8]

    Previous
    Next: Pathophysiology

    Epidemiology

    In the last half century, there has been an increasing prevalence of congenital heart disease and atrial septal defects (ASDs), with the former diagnosed in an estimated 9 per 1000 live births and the latter in 1.6 per 1000 live births. [2]  

    The three major types of ASD account for 10% of all congenital heart disease and as much as 25-30% of congenital heart disease presenting in adulthood. [11] The most common types of ASD include the following:

    • Ostium secundum: The most common type of ASD accounting for 80% of all ASD cases, [11, 12] representing approximately 7% of all congenital cardiac defects and 30-40% of all congenital heart disease in patients older than 40 years.

    • Ostium primum: The second most common type of ASD accounts for 15-20% of all ASDs. [11, 12] Primum ASD is a form of atrioventricular septal defect and is commonly associated with mitral valve abnormalities.

    • Sinus venosus: The least common of the three, sinus venosus (SV) ASD is seen in 5-6% of all ASDs. [11, 12]  The defect is located along the superior aspect of the atrial septum. Anomalous connection of the right-sided pulmonary veins is common and should be expected. Alternate imaging is generally required.

    Sex- and age-related demographics

    ASD occurs in about 25% of children. [2] There is a female-to-male ratio of approximately 2:1. The recurrence rate of ASD in the offspring of women with ASD is 4-6%; in males with ASD, it is 1.5-3.5%. [12]

    Patients with ASD can be asymptomatic through infancy and childhood, although the timing of clinical presentation depends on the degree of left-to-right shunt. Symptoms become more common with advancing age. By age 40 years, 9 in 10 untreated patients exhibit exertional dyspnea, fatigue, palpitations, sustained arrhythmia, or indications of heart failure. [13]

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