What is the pathophysiology of Tetralogy of Fallot (ToF)?

Pathophysiology of Tetralogy of Fallot (ToF)

Tetralogy of Fallot is fundamentally caused by anterosuperior deviation of the conal or outlet septum, resulting in four characteristic features: ventricular septal defect of the malalignment type, narrowing or atresia of the pulmonary outflow, biventricular origin of the aorta (aortic override), and right ventricular hypertrophy. 1, 2

Primary Anatomical Defect

The core pathophysiological mechanism in ToF involves:

• Anterosuperior deviation of the outlet septum - This is the primary embryological defect that leads to all other features 1, 2
• Malalignment ventricular septal defect (VSD) - Typically large and non-restrictive, located between or above the limbs of the septal band 1
• Right ventricular outflow tract (RVOT) obstruction - Can occur at multiple levels:
  • Infundibular/subvalvular stenosis (most common)
  • Pulmonary valve stenosis
  • Supravalvular stenosis
  • Branch pulmonary artery stenosis 1, 2
• Overriding aorta - The aortic valve has biventricular origin, straddling the malaligned ventricular septum 1, 3
• Right ventricular hypertrophy - Secondary to RVOT obstruction 3

Hemodynamic Consequences

The severity of clinical manifestations depends primarily on:

• Degree of RVOT obstruction - This is the principal determinant of pulmonary blood flow, not the VSD 3
• Right-to-left shunting - Occurs through the VSD due to RVOT obstruction, leading to:
  • Decreased pulmonary blood flow
  • Mixing of deoxygenated blood into the systemic circulation
  • Resulting hypoxemia and cyanosis 4

VSD Characteristics

The VSD in ToF has specific features:

• Type: Typically perimembranous in Western populations, but can also be subarterial/doubly committed subarterial or muscular outlet 2
• Size: Usually moderate to large and non-restrictive 1
• Location: Malalignment type that opens to the outlet of the right ventricle 1

Associated Vascular Anomalies

ToF may be associated with various vascular abnormalities:

• Pulmonary artery anomalies:
  • Branch pulmonary artery stenosis
  • Discontinuous pulmonary arteries
  • Pulmonary artery hypoplasia 5, 6
• Aortopulmonary collateral vessels - Develop to supply underperfused areas of the pulmonary bed, particularly in severe cases 5
• Coronary artery anomalies - May influence surgical approach 2, 6
• Right aortic arch - Present in approximately 25% of cases 6

Pathophysiology of "Tet Spells"

Hypercyanotic episodes ("Tet spells") occur due to:

• Increased infundibular contractility - Further narrows the RVOT
• Peripheral vasodilation - Decreases systemic vascular resistance
• Right ventricular mechanoreceptor stimulation - May trigger reflex responses
• These factors combine to increase right-to-left shunting, worsening hypoxemia and cyanosis 4

Long-term Pathophysiological Consequences

Without repair, or following repair with significant residual lesions:

• Progressive right ventricular dilation and dysfunction - Due to pulmonary regurgitation after repair 1
• Left ventricular dysfunction - From "ventricular-ventricular interaction" where the dilated RV impinges on LV geometry 1
• Myocardial fibrosis - Higher degree of RV and LV diffuse fibrosis compared to normal hearts 1
• Arrhythmias and conduction disturbances - Common long-term sequelae 1, 2

Genetic Associations

• 22q11.2 microdeletion - Present in a significant proportion of ToF patients, with implications for genetic counseling 2

Understanding the pathophysiology of ToF is crucial for appropriate surgical planning, anticipating potential complications, and managing long-term follow-up in these patients.