**4. Pathophysiology**

The degree of shunting across the VSD is primarily dependent on the size of the defect. In large non-restrictive defects, the difference in the pulmonary vascular resistance (PVR) and systemic vascular resistance (SVR) determines the magnitude of the shunt. The degree of shunt is frequently described as the ratio of pulmonary blood flow (Qp) to systemic blood flow (Qs) and shunts with Qp:Qs ≥1.5 are typically considered hemodynamically significant.

In neonates, right after birth, there is significant drop in PVR as the gas exchange changes from placental circulation to the lung. Thereafter there is progressive rise in SVR, and decline of PVR, with consequent increase in pulmonary blood flow which continues over a period of the first 6–8 weeks of life. It is this rate of decline in PVR that determines the amount of left to right shunting in patients with VSDs.

In patients with small VSDs, the decrease in PVR does not influence pulmonary over circulation as the size of the defect intrinsically restricts flow. In comparison, in patients with large VSDs, the drop in PVR primarily determines the amount of pulmonary blood flow and direction of flow across the two ventricles. Once the pulmonary resistance decreases, blood flow from the left to the right ventricle causes over circulation to the lungs and increases preload to the left atrium and ventricle. Pulmonary mechanics are altered due to increased pulmonary blood flow including decreased lung compliance and tidal volume [12]. Another mechanism contributing to clinical symptoms of congestive heart failure is neurohormonal activation with increased levels of norepinephrine and renin – angiotensin seen in these infants [13]. In some patients, the medial muscle layer in the small pulmonary vessels does not regress as rapidly, in turn leading to slower decline of the PVR [14]. In such patients, there may be subsequent delay in development of symptoms.

Chronic exposure of volume and pressure overload due to large uncorrected VSDs leads to structural and functional changes of the pulmonary vascular bed. There is development of endothelial dysfunction, smooth muscle proliferation, vascular remodeling, and intravascular thrombosis. These changes lead to increase in pulmonary vascular resistance and pulmonary arterial hypertension (PAH) [15]. The definition of PAH includes a mean pulmonary arterial pressure ≥ 25 mmHg at rest, a left atrial pressure ≤ 15 mmHg, and normal resting cardiac output, suggesting a resting pulmonary vascular resistance of ≥3 Woods units (WU). Eisenmenger's syndrome (ES) is the most advanced stage of pulmonary arterial hypertension in patients with unrepaired shunts of congenital heart disease and often irreversible.
