In the typical scenario of ASD, a left-to-right shunt develops because of the difference in pressure between the left and right atria. This shunting leads to increased blood flow to the pulmonary circulation, potentially causing pulmonary over-circulation, right atrial and ventricular dilation, and progressive right-sided heart failure. However, cyanosis in ASD patients with normal pulmonary artery pressure remains an uncommon clinical occurrence. The presence of a right-to-left shunt, despite normal pulmonary pressures, allows deoxygenated blood to bypass the lungs and enter systemic circulation, resulting in hypoxemia and cyanosis.

Various mechanisms underlie this phenomenon:

1. Abnormal Venous Drainage and Atypical Anatomical Variants

A primary mechanism for right-to-left shunting in ASD patients with normal PAP is abnormal venous drainage. In some cases, particularly those involving sinus venosus-type ASDs, the inferior vena cava (IVC) may drain directly into the left atrium, bypassing the pulmonary circulation entirely. This anatomical anomaly can result from a malposition of venous structures, such as the superior vena cava (SVC)/IVC straddling or anomalous blood flow patterns, like an enlarged Eustachian valve or tricuspid regurgitation [1-3]. Such abnormalities cause preferential streaming of deoxygenated blood into the left atrium and subsequently into systemic circulation.

The IVC blood flow can preferentially reach the left atrium by targeting the lower portion of the interatrial septum (IAS), contributing to the development of a right-to-left shunt. When additional hemodynamic factors such as increased right atrial pressure (due to conditions like right heart failure, tricuspid regurgitation, or increased intrathoracic pressure during the Valsalva manoeuvre) occur, these factors can further exacerbate the right-to-left shunting. In such cases, deoxygenated blood bypasses the lungs and enters the systemic circulation, leading to cyanosis.

Furthermore, anomalies like a persistent left superior vena cava (SVC) draining into the coronary sinus, which in turn drains into the left atrium through an unroofed coronary sinus, may also lead to significant cyanosis in these patients. These anatomical variations can be difficult to detect, often leading to misdiagnosis or delayed diagnosis.

2. Elevated Right Atrial Pressures

Another potential contributor to right-to-left shunting in ASD patients is elevated right atrial pressure (RAP). This condition can arise from a variety of pathologies, including right ventricular (RV) abnormalities such as RV infarction, RV diastolic dysfunction, or RV cardiomyopathy [4-7]. Additionally, conditions such as positive pressure ventilation (PPV) with high positive end-expiratory pressure (PEEP) or severe pulmonary stenosis can lead to increased RAP (8, 9). When RAP exceeds left atrial pressure, deoxygenated blood is directed through the ASD into the left atrium, bypassing the pulmonary circulation and leading to cyanosis.

The clinical presentation of elevated RAP often includes symptoms of right heart failure or systemic venous congestion. In such cases, right-to-left shunting is exacerbated by the high RAP, resulting in systemic desaturation even in the absence of pulmonary hypertension.

3. Inferiorly Positioned ASD and Abnormal Venous Return

The anatomical location of the ASD significantly influences the direction of the shunt. When the ASD is positioned in the inferior part of the atrial septum, venous return from the IVC can preferentially flow into the left atrium, particularly when the defect is large or multiple fenestrations exist [8]. This results in deoxygenated blood bypassing the lungs and entering the systemic circulation. This phenomenon is particularly pronounced when there is an abnormal venous return or when the ASD is sufficiently large to allow multiple pathways for blood to flow from the right atrium to the left.

In patients with inferiorly located ASDs, it is crucial to assess the size of the defect and the presence of any associated structural anomalies that might further influence blood flow dynamics and contribute to right-to-left shunting.

4. Platypnea-Orthodeoxia Syndrome (POS)

Platypnea-Orthodeoxia Syndrome (POS) is a rare but significant cause of cyanosis in patients with ASD. In POS, patients experience postural cyanosis, particularly in an upright position. This phenomenon results from the gravitational shift of blood flow from the right atrium to the left atrium through the ASD when the patient assumes an upright posture. This shift is accentuated when there are structural anomalies like aortic aneurysms, loculated pericardial effusions, or in patients who have undergone lobectomy [10-15]. The upright position exacerbates right-to-left shunting due to a decrease in venous return to the right atrium and a subsequent increase in the pressure gradient favouring right-to-left flow through the ASD. The mechanism is best understood as a pressure imbalance between the right and left atria that occurs due to the body’s position, resulting in systemic desaturation.

5. Eisenmenger Syndrome

Eisenmenger syndrome, which is typically associated with pulmonary hypertension, can also contribute to cyanosis in ASD patients. In cases where there is longstanding left-to-right shunting, pulmonary vascular resistance gradually increases, and the shunt direction can reverse to right-to-left. This condition, known as "Eisenmenger physiology," is usually accompanied by elevated PAP and the subsequent development of cyanosis [16]. However, in the case of ASD with normal PAP, this phenomenon is not the primary cause of cyanosis. It is important to distinguish Eisenmenger syndrome from other causes of right-to-left shunting in ASD patients with normal pulmonary pressures.