What is the natural history of Tetralogy of Fallot (TOF)?

Natural History of Tetralogy of Fallot (TOF)

Without surgical intervention, Tetralogy of Fallot has a poor prognosis with more than 95% of patients dying before age 40, making early surgical correction essential for survival. 1

Pathophysiology and Anatomical Features

Tetralogy of Fallot is the most common cyanotic congenital heart disease after 1 year of age, representing approximately 10% of all congenital heart diseases. The fundamental defect involves:

• Anatomical components:

  • Non-restrictive ventricular septal defect (malalignment type)
  • Overriding aorta (<50%)
  • Right ventricular outflow tract obstruction (RVOTO)
  • Right ventricular hypertrophy 1, 2

• Pathological basis: Anterocephalad deviation of the outlet septum, causing the constellation of defects 1

• Associated anomalies (may be present):

  • Atrial septal defect
  • Additional muscular VSDs
  • Right aortic arch
  • Anomalous left anterior descending coronary artery (3%)
  • Complete atrioventricular septal defect (rare, often with Down syndrome) 1

• Genetic associations: Approximately 15% of TOF patients have deletion of chromosome 22q11 (previously called DiGeorge syndrome) 1

Natural History Without Intervention

1. Early presentation:

   • Heart murmur in infancy
   • Progressive cyanosis due to right-to-left shunting at ventricular level secondary to RVOTO 1

2. Survival rates:

   • Without surgical correction, >95% of patients die before age 40 1
   • Only about 3% of untreated patients survive beyond age 40 2

3. Disease progression:

   • Increasing cyanosis as pulmonary stenosis worsens
   • Development of right ventricular hypertrophy
   • Progressive exercise intolerance
   • Hypoxic spells ("tet spells") - acute episodes of increased cyanosis 1

4. Late manifestations in untreated adults:

   • Severe cyanosis
   • Polycythemia (elevated hematocrit, averaging 53.6% in untreated adults) 3
   • Right ventricular pressure overload (gradient across RVOT averaging 93.9 mmHg in untreated adults) 3
   • Functional impairment (38.5% of untreated adults in NYHA class III or IV) 3
   • Complications from chronic hypoxia including arrhythmias and ventricular dysfunction 3

Surgical Interventions and Modified Natural History

1. Historical palliative procedures:

   • Blalock-Taussig shunt (subclavian artery to PA)
   • Waterston shunt (ascending aorta to right PA)
   • Potts shunt (descending aorta to left PA) 1

2. Complete repair:

   • VSD closure
   • Relief of RVOTO (infundibular resection and pulmonary valvotomy)
   • Often requires RVOT or transannular patch 1
   • Currently performed between 6-18 months of age with perioperative mortality of ~1% 1

3. Post-repair survival:

   • Excellent long-term survival with 35-year survival of 85% 1
   • Actuarial survival rates for adult repairs: 91.2% at 3 years, 85.5% at 7 years, and 68.4% at 15 years 3

Common Complications After Repair

1. Pulmonary regurgitation (PR):

   • Almost universal following transannular patch repair
   • Initially well-tolerated but eventually leads to RV dilation and dysfunction 1
   • Many adolescents and young adults have regurgitant fractions exceeding 40-50% 1

2. Residual RVOTO:

   • Can occur at infundibulum, pulmonary valve, main pulmonary trunk, or branch PAs 1

3. RV dilation and dysfunction:

   • Due to longstanding PR and/or RVOTO
   • Can lead to tricuspid regurgitation 1
   • RV end-diastolic volumes often exceed 150 ml/m² (normal: 75 ml/m²) 1
   • RV ejection fraction may fall below 0.40 1

4. Residual VSD:

   • Due to partial patch dehiscence or incomplete closure 1

5. Arrhythmias:

   • Ventricular tachycardia (4.2% in long-term follow-up) 1
   • Atrial flutter/fibrillation (3.7% in long-term follow-up) 1
   • QRS prolongation >180 ms predicts malignant ventricular arrhythmias and sudden death 1

6. Sudden cardiac death:

   • Risk of 0.2-0.3% per year after repair 1
   • Risk factors include older age at surgery, residual hemodynamic lesions, right heart failure, complex ventricular ectopy, and QRS prolongation 1

7. Aortic root dilation and aortic regurgitation:

   • Seen in approximately 15% of adults after repair 1

Risk Factors for Poor Outcomes

1. Surgical factors:

   • Older age at time of repair 1
   • Absence of previous palliation before complete repair 1
   • Higher preoperative NYHA status 1

2. Electrocardiographic factors:

   • QRS duration (prolongation associated with increased risk) 1

3. Hemodynamic factors:

   • Residual RVOTO
   • Severe pulmonary regurgitation
   • RV dysfunction 1

Modern Management Considerations

1. Imaging surveillance:

   • Cardiac MRI is crucial for evaluating RV volumes, function, and pulmonary regurgitant fraction 1, 4
   • Echocardiography for routine follow-up 1

2. Pulmonary valve replacement:

   • Indicated for severe PR with RV dilation/dysfunction
   • Can stabilize QRS duration and reduce risk of arrhythmias 1
   • Emerging percutaneous options in select cases 5

3. Long-term follow-up:

   • Regular assessment of ventricular function
   • Monitoring for arrhythmias
   • Exercise capacity evaluation 1

Pitfalls and Caveats

1. Timing of pulmonary valve replacement: Waiting too long may result in irreversible RV dysfunction, but intervening too early subjects patients to multiple reoperations over their lifetime.

2. QRS duration monitoring: QRS prolongation >180 ms is a significant risk factor for sudden cardiac death and should prompt thorough evaluation.

3. Adult survivors: Require specialized adult congenital heart disease care as they face unique challenges different from pediatric patients or adults with acquired heart disease.

4. Arrhythmia surveillance: Patients with symptoms suspicious of rhythm disturbances should undergo thorough evaluation, as arrhythmias occur in approximately 39% of these patients 3.

5. Pregnancy considerations: Women with repaired TOF generally tolerate pregnancy well, but those with significant residual lesions require careful monitoring.