Tetralogy of Fallot


Tetralogy of Fallot, formerly known as Steno-Fallot tetralogy, is a congenital heart defect characterized by four specific cardiac defects. Classically, the four defects are:
At birth, children may be asymptomatic or present with many severe symptoms. Later in infancy, there are typically episodes of bluish colour to the skin due to a lack of sufficient oxygenation, known as cyanosis. When affected babies cry or have a bowel movement, they may undergo a "tet spell" where they turn cyanotic, have difficulty breathing, become limp, and occasionally lose consciousness. Other symptoms may include a heart murmur, finger clubbing, and easy tiring upon breastfeeding.
The cause of tetralogy of Fallot is typically not known. Maternal risk factors include lifestyle-related habits, medical conditions, infections during pregnancy, and advanced age of mother during pregnancy. Babies with Down syndrome and other chromosomal defects that cause congenital heart defects may also be at risk of tetralogy of Fallot.
Tetralogy of Fallot is typically treated by open heart surgery in the first year of life. The timing of surgery depends on the baby's symptoms and size. The procedure involves increasing the size of the pulmonary valve and pulmonary arteries and repairing the ventricular septal defect. In babies who are too small, a temporary surgery may be done with plans for a second surgery when the baby is bigger. With proper care, most people who are affected live to be adults. Long-term problems may include an irregular heart rate and pulmonary regurgitation.
The prevalence is estimated to be anywhere from 0.02 to 0.04% in the general population. Though males and females were initially thought to be affected equally, more recent studies have found males to be affected more than females. It is the most common complex congenital heart defect, accounting for about 10 percent of cases. It was initially described in 1671 by Niels Steensen. A further description was published in 1888 by the French physician Étienne-Louis Arthur Fallot, after whom it is named. The first total surgical repair was carried out in 1954.

Signs and symptoms

Tetralogy of Fallot results in low oxygenation of blood. This is due to a mixing of oxygenated and deoxygenated blood in the left ventricle via the ventricular septal defect and preferential flow of the mixed blood from both ventricles through the aorta because of the obstruction to flow through the pulmonary valve. The latter is known as a right-to-left shunt.
Infants with TOF – a cyanotic heart disease – have low blood oxygen saturation. Blood oxygenation varies greatly from one patient to another depending on the severity of the anatomic defects. Typical ranges vary from 60% to around 90%. Depending on the degree of obstruction, symptoms vary from no cyanosis or mild cyanosis to profound cyanosis at birth. If the baby is not cyanotic, then it is sometimes referred to as a "pink tet". Other symptoms include a heart murmur which may range from almost imperceptible to very loud, difficulty in feeding, failure to gain weight, retarded growth and physical development, labored breathing on exertion, clubbing of the fingers and toes, and polycythemia. The baby may turn blue with breastfeeding or crying.
Those born with tetralogy of Fallot are more likely to experience psychiatric disorders such as attention deficit hyperactivity disorder in later life, potentially due to underlying genetic changes that predispose to both conditions.

Hypercyanotic "Tet" spells

Infants and children with unrepaired tetralogy of Fallot may develop hypercyanotic, or "tet," spells. Patients with prominent subvalvar muscle bundles and/or conal tissue in the right ventricular outflow tract are thought to be at higher risk for hypercyanotic spells. These are acute spells characterized by profound cyanosis, often in the setting of agitation or tachycardia, that may progress to loss of consciousness or cardiac arrest if not aborted. This may be initiated by any event – such as anxiety, pain, dehydration, or fever – that leads to an increase in dynamic muscular obstruction of the right ventricular outflow tract. This in turn leads to decreased blood flow through the right ventricular outflow tract to the lungs and increased shunt of deoxygenated blood from the right ventricle to the left ventricle and, subsequently, to the systemic circulation. The pathophysiology of these episodes is multifactorial; increased sympathetic activation leads to increased myocardial contractility, which worsens dynamic muscular obstruction of the right ventricular outflow tract, and increased heart rate, which allows less time for right ventricular diastolic filling. Right ventricular outflow tract obstruction is more likely to occur in a relatively underfilled ventricle with increased contractility of the outflow tract myocardium. A relative decrease in systemic vascular resistance, as may be observed in distributive or neurogenic shock, may also precipitate hypercyanotic spells by increasing shunt from the right ventricle to the left ventricle.
Clinically, hypercyanotic spells are characterized by a sudden, marked increase in cyanosis and may progress to syncope.
Older children will often squat instinctively during a hypercyanotic spell. This increases systemic vascular resistance and allows for a temporary reversal of the shunt. It increases pressure on the left side of the heart, decreasing the right to left shunt. The decreased shunt volume results in a decrease in deoxygenated blood flow entering the systemic circulation and an increase in deoxygenated blood flow antegrade through the obstructed right ventricular outflow tract.

Cause

While the specific causes of TOF have not been fully identified, there are various environmental or genetic factors that have been associated with TOF. So far, around 20% of overall congenital heart defect cases have been due to known causes such as genetic defects and teratogens which are various factors causing embryo development abnormalities or birth defects. However, the other 80% of cases have little known about their cause.
Genetic factors linked to TOF include various gene mutations or deletions. Gene deletions associated with TOF include chromosome 22 deletion as well as DiGeorge syndrome.
Specific genes associations with TOF include:
  • JAG1 codes for ligands within the Notch family of proteins and is highly expressed in the developing heart. Mutations of the JAG1 gene can lead to abnormal heart development associated with TOF.
  • NKX2-5 codes for cardiac morphogenesis regulators to allow for proper heart development. Defects in this gene typically causes septal defects and has been associated with around 4% of all TOF cases.
  • ZFPM2 is another cardiac regulator involved in regulation of GATA4. Mutations of the ZFPM2 gene lead to reduced GATA production and have been seen in some TOF cases.
  • VEGF a well-known endothelial growth factor involved in the vascularization of the heart. Decreased VEGF expression has been shown to be a modifier of TOF.
  • NOTCH1 is involved in the vascularization of tissues and is the most common site of genetic variations involved with TOF, accounting for 7% of all TOF cases.
  • TBX1 expresses progenitors involved with the development of the right ventricle. Chromosome 22q11 deletions also deleting TBX1 gene have been seen in 17% TOF cases.
  • FLT4 gene expression leads to Vascular endothelial growth factor receptor 3 which helps vascularization. Mutations of this gene have been associated with TOF, accounting for 2.4% of all cases.
  • FOXC2 is another gene involved in embryonic development of the cardiac system. Mutations of this gene have been shown to result in dysfunctional lymphatic syndrome and TOF.
  • GATA4 aids in cardiac development by helping increase the production of cardiomyocytes. Mutations of this gene have been seen in various familial TOF cases often lasting 2–3 generations.
  • FLNA is a protein coded by the gene of the same name that crosslinks actin filaments into networks in cytoplasm and helps anchor membrane proteins for the actin cytoskeleton. Mutations of this gene were seen to cause TOF in some patients.
The Environmental Factors that have been studied to potentially be associated with TOF include:
  • Maternal Alcohol consumption: During embryonic development, many of the body's processing and filtration systems are not fully developed. Fetal body is unable to process alcohol as well as adults which can lead to improper development, including cardiogenesis. While no conclusive evidence has been found between effects of alcohol consumption and TOF, maternal alcohol consumption has been seen in various patients with TOF.
  • Maternal smoking: Maternal smoking has been associated with various fetal complications such as premature delivery and low birth weight which can lead to TOF. In the famous Baltimore-Washington Study, it was reported that smoking more than one pack per day while pregnant was associated with two specific cardiac deflects, both part of TOF: pulmonary stenosis and transposition with VSD.
  • Maternal diabetes: Maternal diabetes, diabetes Mellitus, and gestational diabetes are well-known risk factors of fetal CHD, including TOF. Maternal diabetes has been shown to increase the risk of cardiovascular deformations, namely the transposition of great arteries, one of the four deformations in TOF. Studies have also looked at whether diabetes increases the risk of malformation or poor sugar regulation and have found that sugar regulation does not significantly affect cardiac malformations. Retrospective studies have shown that diabetic mothers with good glucose control still retained the elevated CHD risk.
  • Rubella: Rubella is characterized as mild, contagious viral disease with often unnoticed consequences. Infection with rubella during the first trimester has been seen to cause various fetal malformations, including TOF.
  • Maternal Age: Older maternal age, especially after 35 can have various pregnancy risks due to existing co-morbidities such as hypertension, diabetes, hypothyroidism, and consanguinity. These risk factors can effect fetal development and lead to various fetal conditions such as CHD, Down Syndrome and Autism.
Embryology studies show that anterior malalignment of the aorticopulmonary septum results in the clinical combination of a ventricular septal defect, pulmonary stenosis, and an overriding aorta. Right ventricular hypertrophy develops progressively from resistance to blood flow through the right ventricular outflow tract.