• Almost always associated with a VSD which is usually a large malaligned outlet VSD.  Hence often referred to as Tetralogy of Fallot with absent pulmonary valve (TOF with APV).
• The pulmonary valve is rudimentary and usually both stenotic and regurgitant.
• The pulmonary arteries are aneurysmally dilated.
• Almost always associated with absence of PDA. In fact, this may be the cause of the syndrome.
• Commonly associated with airway abnormalities which may cause respiratory failure. Abnormally branching pulmonary arteries compress bronchi.
• Rarely, IVS may be intact.
• TOF with APV constitutes 2.5% of TOF.
• 75% of APV has 22q11 deletion. This is the commonest genetic association of APV.

Embryology

• Agenesis or early closure of the ductus plays an important role in the pathogenesis.
• APV syndrome is different from TOF in pathogenesis. Even though VSD and aortic override are present in APV also, obstruction is due to pulmonary annular hypoplasia, not infundibular narrowing.

Pathology

• Pulmonary valve tissue is rudimentary.
• Pulmonary annulus is hypoplastic.
• Proximal pulmonary arteries are aneurysmally dilated. These may compress major bronchi.
• Pulmonary segmental arterioles are replaced by tufts of vessels which compress bronchi.
• Non-restrictive malaligned VSD
• RVH
• Coronary anomalies may occur- single origin, aberrant course.
• MAPCAs may be present.

Clinical presentations

• Hydrops fetalis occurs in 20%.
• Neonatal presentation-
  • Cyanosis
  • Respiratory distress- sometimes needing mechanical ventilation
  • Harsh to-and-fro murmur, single S2, prominent right ventricular impulse, hepatomegaly due to RV failure.
  • Rhonchi due to bronchial narrowing.
  • VSD like- Presentation like a large VSD.

Diagnostic findings

• ECG shows RVH and wide QRS.
• Chest X-ray shows dilated pulmonary arteries with distal attenuation of pulmonary vasculature and cardiomegaly. Right aortic arch may be present.
• Echo makes the diagnosis.
• Cardiac catheterization may be needed for ruling out AP collaterals and for their preoperative coil embolization.
• PA and RV pressures equalize in diastole due to PR. During systole there is a gradient between RV and PA suggesting PS.

Medical management

• Respiratory distress may be lessened by placing the patient prone as this suspends the pulmonary artery off the airways.
• Cyanosis is due to right to left shunt due to pulmonary stenosis, pulmonary regurgitation and abnormal distal pulmonary arteriolar bed.
• Sometimes left to right shunt can occur leading to volume overload.

Surgery

1. VSD closure.
2. Transannular incision to relieve the annular obstruction.
3. Repair of pulmonary arteries- approaches include

• Anterior plication with or without translocation of MPA and RPA anterior to the aorta OR
• Homograft insertion with excision of aneurysmal pulmonary arteries.

• In longstanding unrepaired TOF, right ventricular hypertension induces fibrosis leading to RV systolic and diastolic dysfunctions and ventricular arrhythmias.
• Neonate with TOF should be carefully assessed by echo to see if the PS is so severe that ductal patency is needed. If this is the case, give PGE1 infusion and do early surgery.
• Cyanotic spells can occur in acyanotic TOF also.
• Treatment of cyanotic spells includes oxygen, volume expansion, sedation with morphine or ketamine and vasopressors like phenylephrine.
• Patients with relative anemia are at more risk of cerebrovascular accidents and hypercyanotic spells.

Interventional catheterization procedures

• Preoperative-

Palliation of cyanosis by RVOT stent placement or balloon valvuloplasty. This avoids need for BT shunt which may cause pulmonary artery distortion.
Coil embolization of aortopulmonary collaterals.

• Postoperative- For residual pulmonary artery obstruction- ballooning and stenting.

Primary repair

• This is done via median sternotomy.
• Approaches-
  • Atrial route- This is the preferred route. The VSD is closed by a Dacron patch. RVOT obstruction is resected. Atrial route was earlier done only for patients with coronaries crossing the RVOT. Now it is done for other patients also as it avoids the need for ventriculotomy.
  • Right ventriculotomy- A vertical incision is made over the infundibulum. RVOT obstruction is relieved. VSD is closed by a Dacron patch. RVOT is patched with pericardium. If the pulmonary annulus is hypoplastic (Z score preoperatively and visual impression of the surgeon intraoperatively), the initial incision is extended onto the pulmonary artery. A transannular patch is placed. A monocusp pericardial valve may be placed to avoid pulmonary regurgitation.
  • Combined atrial and transpulmonary approach- avoids need for ventriculotomy.
• AP collaterals- These are coiled prior to surgery to avoid steal phenomenon during cardiopulmonary bypass which causes neurologic sequelae. If it constitutes the sole blood supply to the lung, it should be incorporated into the final repair.

Palliative procedures

• Initial palliative BT shunt is not preferred due to PA distortion, ventricular volume loading and the surgical risks of an additional thoracotomy. Primary repair is directly done. But palliation may need to be done in severe PA hypoplasia and aberrant LAD form RCA.
• Blalock Thomas Taussig shunt and central shunt are used now. Waterston shunt and Potts shunt are not used now. Modified BTT shunt is the most commonly used one. It is done opposite to the side of the aortic arch. Shunt size in newborn is usually 3.5 to 4 mm.

Surgical results-

• Early primary repair is not associated with higher incidence of early complications or late reintervention compared to late repair. Also, primary repair is not associated with more reintervention for residual obstruction  compared to staged repair. Hence, early primary repair is preferred though repair in first 3 months of life increases intensive care morbidity.
• Hospital survival for repair is 100% even for early surgery. 20 year survival after primary repair is 98% for TOF with PS and slightly lower for TOF with primary atresia.
• In TOF with PS, after primary repair, at 2 years 25% needed reoperation usually for residual obstruction in RV or PA. The indication for reoperation in older patients is different and is residual VSD.

Long-term follow-up

• Early repair may be associated with less long term incidence of arrhythmias, ventricular dysfunction and cognitive dysfunction.

Sudden death and arrhythmias

• Incidence of sudden death is 1.2% at 10 years, 2.2% at 20 years, 4% at 25 years and 6% at 30 years.
• Sudden death is not more in patients who underwent surgery before 80s.
• Ventricular arrhythmias are more in patients who undergo surgery at older age. These patients are predisposed to ventricular arrhythmias before surgery itself due to their older age and surgery does not decrease the chance of ventricular arrhythmias.
• Ventricular arrhythmias are more in patients with PR and in those with RV dilation.
• EP studies are not clearly shown to predict sudden death in patients with ventricular arrhythmias.
• Other predictors of sudden death are significant PR, sustained ventricular arrhythmias, QRS duration more than 180 msec and LV dysfunction.
• Other arrhythmias noted in the long term are sinus dysfunction, atrial flutter , atrial fibrillation and supraventricular tachycardia. The incidence of supraventricular tachycardia is 10% at 12 years after repair.

Residual defects and hemodynamic abnormalities

• Branch PA stenosis
  • After shunt procedures.
  • After RVOT patch, due to compression by the redundant patch.
  • Treated by ballooning or stenting- the complications include aneurysms, stent migration and stent thrombosis.
  • Redundant RVOT patch should be surgically revised.
• Membranous subaortic stenosis- uncommon late complication.
• Coronary to RV fistula
• Pulmonary regurgitation
  • All patients have PR by echo.
  • Some have audible PR.
  • Pan-diastolic PR with end-diastolic velocity of 1 m/s indicates mild PR and good pulmonary valve anatomy.
  • PR signal ending before the end of diastole indicates that pulmonary valve function is poor and that the RV is stiff. This occurs due to equalization of PA diastolic pressure and RV diastolic pressure in diastole itself.
  • PR may occur due to increased pulmonary arterial impedance which is due to either stenosis of main or branch pulmonary arteries or elevated LA pressure due to causes like LV dysfunction. If branch PA stenosis is the cause of PR, it may be treated by interventional catheterization. If LV dysfunction is the cause of PR, it may decrease with treatment of the LV dysfunction.
  • For significant PR, pulmonary valve replacement (homograft) will be needed.
• Tricuspid regurgitation
  • Present in many.
  • Not audible unless RV pressure is elevated.
  • May need repair.
• Aortic dilation
  • Aorta is dilated in TOF patients after repair. This dilation may progress.
  • Avoid isometric exercise and high blood pressure.
  • Serial monitoring for enlargement and development of AR is needed.

Exercise testing

• Reduced exercise capacity is present in patients with PA stenosis, PR or RV dysfunction.

Bacterial endocarditis

• Prophylaxis is needed in unoperated patients, palliated patients, in repaired patients for 6 months and in repaired patients with prosthetic valves.

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• Some patients may have left to right shunt will full arterial oxygen saturation.
• PA pressure is normal or low, never is it high.
• All patients have subpulmonic obstruction.
• VSD is non-restrictive usually. So, RVH is in proportion to the LV mass.
• Rarely, VSD is restrictive. Then RVH will be severe due to suprasystemic RV pressure.
• Exercise produces cyanosis due to decrease in systemic vascular resistance leading to increased right to left shunting.
• Hypercyanotic episode is due to acute increase in infundibular obstruction.

Clinical features

• Fetal diagnosis is possible by echo.
• Newborn with severe RVOT obstruction may have only mild cyanosis till ductus closes.
• Hypercyanotic spells or tetralogy spells-
  • More common in patients with iron deficiency anemia.
  • Mechanisms-
    • Acute increase in subpulmonic obstruction due to contraction due to catecholamines or due to hypovolemia.
    • Decreased systemic vascular resistance
• Severe cyanosis.
• Hyperpnea due to hypoxia and metabolic acidosis.
• Can be lethal.
• Murmur intensity is markedly decreased.
• Squatting-
  • Usually after exercise.
  • Instinctive- to increase arterial saturation.
  • Increased systemic vascular resistance decreases shunting.
• Left parasternal impulse is present.
• S2 is single in almost all patients.
• S2 is often loud due to anterior aorta.
• No S3 or S4.
• Wide pulse pressure if
  • PDA
  • AP collaterals or
  • Palliative shunt.
• Mid-systolic murmur
  • Site – inferior to the site of valvular PS murmur
  • Crescendo-decrescendo or plateau shaped
  • Harsh
  • Intensity is inversely proportional to RVOT obstruction
  • Decreases during hypercyanotic spell
  • Absent in TOF with PA
• EDM
  • AR
  • PR
    • In TOF with PA
    • Harsh sawing to and fro murmur
    • Pathognomonic
• AES (aortic ejection sound) – in older patients.
• Continuous murmur-
  • PDA
  • AP collaterals (murmur in back)
• Postoperative-
  • S2 is single (only A2).
  • MSM of PS is often heart due to some degree of residual PS.
  • Low frequency EDM of PR is heart in many.
  • PSM if residual VSD.

Diagnostic studies

• ECG-
  • RVH is evident beyond 3 months when neonatal RVH should have resolved.
  • Right axis deviation is present.
  • In older untreated patients, RV fibrosis may cause ventricular ectopy or arrhythmias.
• Chest X-ray-
  • No cardiomegaly.
  • Upturned apex- boot-shaped heart or coeur en sabot.
  • Concavity of left heart border due to RV infundibular hypoplasia and MPA hypoplasia.
  • Decreased pulmonary vascularity.
  • Right aortic arch in 25%.
• Blood investigations-
  • Hematocrit more than 65% will cause hyperviscosity syndrome.
  • Microcytosis due to iron deficiency can cause cerebrovascular events and should be avoided.
• Echocardiography-
  • With more than 50% override, look for bilateral conus to rule out DORV.
  • TR will not occur despite RV hypertension.
  • In the first few days of life, PS severity is underestimated due to elevated PVR and due to PDA.
  • The VSD is just below the RCC, at 10’O clock position.
• Cardiac catheterization-
  • Stenting for PS has been done along with surgery.
  • AP collaterals can be closed with coils.
  • RV hypertension is equal to LV hypertension.
  • PA anatomy and coronary anatomy clarifications are the usual indications for cath study.
  • PA pressure is normal or low. Elevation suggests diffuse distal pulmonary arterial stenosis.
  • With AP collaterals, calculation of right to left ventricular shunt gives a falsely low value.
  • Pulmonary artery anatomy delineation is especially important in patients who have undergone palliative aortopulmonary shunts.
  • AP collaterals usually originate from the descending aorta. Occasionally they originate from the brachicephalic vessels as in pulmonary atresia.

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The hallmark of tetralogy of Fallot is anterior and cephalad deviation of the conotruncal septum.

Pulmonic stenosis – is always significant and hence pulmonary artery pressure is normal or low, never high as in pure VSD. The obstruction is subpulmonic. If this is severe, distal obstructions are more commonly present. Usually pulmonary arteries are of adequate size to permit surgical repair. In pulmonary atresia, pulmonary artery size may be too less for repair.

Subpulmonic obstruction is due to both antero-cephalad deviation of the conotruncal septum and muscular hypertrophy of the deviated septum and the right ventricular free wall. In addition, there may be intracavitary obstruction due to hypertrophied muscle bundles.

The pulmonary valve is commonly small and stenotic and is usually unicuspid or bicuspid. Supravalvular discrete stenosis may occur. Branch ostial stenosis may occur, especially on the left. In pulmonary atresia, the pulmonary arteries are very small and are feeded by aortopulmonary collaterals.

Ventricular septal defect- This has fibrous continuity between tricuspid and aortic valve and hence is a true perimembranous defect, even though it lies in a subarterial location. It is non-restrictive by definition, though some defects may be restrictive due to tricuspid valve tissue.

Aortic override- This may vary from 15% to 95%. Override of more than 50% does not mean double outlet right ventricle- this needs presence of both subaortic conus (absent aorto-mitral continuity) and subpulmonary conus. Aortic override is not only due to the malalignment. It is also due to aortic dilation due to malseptation of the conotruncus and due to rotation of the aorta so that the right aortic sinus becomes more anterior (and left).

Coronary arteries-

1. 15% have a large conal branch or accessory left anterior descending artery.
2. 5% have origin of left anterior descending artery from right coronary artery. This then crosses the right ventricular outflow tract- this is important surgically as the surgeon cannot approach through this area for repair.
3. 4% have single origin of coronaries.

Coronary artery origin has to be found by echocardiography, angiography or MRI before surgery.

Aortic arch anomalies – These are more common if there is Catch 22. Right aortic arch is present in 25%. Aberrant origin of ipsilateral subclavian artery and origin of left subclavian artery from pulmonary artery are sometimes seen.

Aortopulmonary collaterals- Rabinovich type 1 (bronchial artery collaterals) collaterals are uncommonly present in Tetralogy of Fallot with pulmonic stenosis. Collaterals are much more common in Tetralogy of Fallot with pulmonary atresia.

Other anomalies- ASD is present in 83%. Left superior vena cava is found in 11%. Atrioventricular septal defect may be associated, especially in Down’s syndrome. Left sided anomalies are rare.

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First described by Niels Stensen in 1672.

First correlation between pathology and clinical features by Fallot in 1888.

First aortopulmonary shunt by Blalock, Taussig and Thomas in 1945.

First intracardiac repair by Lillihei.

Prevalence

Tetralogy of Fallot is one of the most common cyanotic congenital heart diseases, by some series it is the commonest eg the BWIS study.

The prevalence of tetralogy of Fallot is 0.33 per 1000 live births.

Some studies have shown slight male preponderance in TOF eg BWIS study.

Recurrence

The sibling recurrence rate is 3%.

The chance of getting tetralogy of Fallot if a parent has tetralogy of Fallot is higher and is in the range of 1 to 8%. The chance may be higher if the affected parent is the mother.

Environmental factors

These include maternal diabetes, maternal phenylketonuria and maternal intake of retinoic acid, trimethadione or paramethadione.

Chromosomal anomalies

Some form of extracardiac anomaly is present in one-third of tetralogy of Fallot.

The most important syndromes associated with tetralogy of Fallot are Catch 22 and Alagille syndrome.

Catch 22 syndrome is characterized also by truncus arteriosus and interrupted aortic arch type B. The extracardiac anomalies are distinct facies, palatal anomalies, speech defects, learning defects, psychiatric defects, hypocalcemia and immunodeficiency. Earlier terms used for the syndrome were DiGeorge syndrome and velocardiofacial or Shprintzen syndrome. It is due to 22q11 deletion.

Alagille syndrome is characterized also by peripheral pulmonic stenoses. The extracardiac features are typical facies, ocular defects, skeletal defects and bile duct paucity. The defective gene is Jagged 1. The defect is inherited as autosomal dominant.

Development

The conotruncus refers to the bulbus cordis and the truncus arteriosus together. It gives rise to the ventricular outflow tracts and the great arteries. It is divided into two by ingrowth of the truncal-bulbar ridges. It also undergoes a rotation. The conotruncal septum joins with the trabecular ventricular septum. There is a defect between these two that is closed by the membranous septum.

Tetralogy of Fallot is caused by malrotation of the truncal-bulbar ridges. This causes malalignment between the conotrunal septum and the trabecular septum.

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1. Diabetes in mother- This increases the chance of tetralogy of Fallot (TOF) three times.

2. Retinoic acids- If taken during the first trimester, there is increased chance of tetralogy of Fallot (TOF) along with nervous system and facial anomalies.

3. Phenylketonuria in the mother- tetralogy of Fallot (TOF) is especially likely to occur if the mother did not control intake of phenylalanine during pregnancy.

4. Trimethadione or paramethadione treatment during pregnancy.