Tetralogy of Fallot

Template:Short description Template:Distinguish Template:Infobox medical condition (new) Tetralogy of Fallot (TOF), formerly known as Steno-Fallot tetralogy,<ref name="Diaz-Frias_2021">Template:Cite book</ref> is a congenital heart defect characterized by four specific cardiac defects.<ref name=NIH2011What>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Classically, the four defects are:<ref name="NIH2011What" />

• Pulmonary stenosis, which is narrowing of the exit from the right ventricle;
• A ventricular septal defect, which is a hole allowing blood to flow between the two ventricles;
• Right ventricular hypertrophy, which is thickening of the right ventricular muscle; and
• an overriding aorta, which is where the aorta expands to allow blood from both ventricles to enter.

At birth, children may be asymptomatic or present with many severe symptoms.<ref name="Curr2016">Template:Cite book</ref> Later in infancy, there are typically episodes of bluish colour to the skin due to a lack of sufficient oxygenation, known as cyanosis.<ref name="NIH2011Sym" /> 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.<ref name="NIH2011Sym" /> Other symptoms may include a heart murmur, finger clubbing, and easy tiring upon breastfeeding.<ref name="NIH2011Sym">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

The cause of tetralogy of Fallot is typically not known.<ref name="Roos-Hesselink_2017" /> Maternal risk factors include lifestyle-related habits (alcohol use during pregnancy, smoking, or recreational drugs), medical conditions (diabetes), infections during pregnancy (rubella), and advanced age of mother during pregnancy (35 years and older).<ref name="Roos-Hesselink_2017">Template:Cite book</ref>Template:Rp Babies with Down syndrome and other chromosomal defects that cause congenital heart defects may also be at risk of teratology of Fallot.<ref name="NIH2011Ca">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Teratology of fallot is typically treated by open heart surgery in the first year of life.<ref name=NIH2011Tx/> The timing of surgery depends on the baby's symptoms and size.<ref name=NIH2011Tx/> The procedure involves increasing the size of the pulmonary valve and pulmonary arteries and repairing the ventricular septal defect.<ref name=NIH2011Tx/> In babies who are too small, a temporary surgery may be done with plans for a second surgery when the baby is bigger.<ref name=NIH2011Tx>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> With proper care, most people who are affected live to be adults.<ref name=NIH2011What/> Long-term problems may include an irregular heart rate and pulmonary regurgitation.<ref name=War2005>Template:Cite journal</ref>

The prevalence is estimated to be anywhere from 0.02 to 0.04% in the general population.<ref name=NIH2011What/> Though males and females were initially thought to be affected equally, more recent studies have found males to be affected more than females.<ref name=NIH2011What/><ref name="NORD"/> It is the most common complex congenital heart defect, accounting for about 10 percent of cases.<ref>Template:Cite book</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It was initially described in 1671 by Niels Steensen.<ref name=Name2016>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=VanP2009>Template:Cite journal</ref> A further description was published in 1888 by the French physician Étienne-Louis Arthur Fallot, after whom it is named.<ref name=Name2016/><ref name=Fallot1888>Template:Cite book</ref> The first total surgical repair was carried out in 1954.<ref name=War2005/> Template:TOC limit

Signs and symptoms

File:CongenitalHeartCase-133.jpg

Digital clubbing with cyanotic nail beds in an adult with tetralogy of Fallot

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 (VSD) 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.<ref name="Abdulla_2011">Template:Cite book</ref>

Infants with TOF – a cyanotic heart disease – have low blood oxygen saturation.<ref name="Abdulla_2011" /> Blood oxygenation varies greatly from one patient to another depending on the severity of the anatomic defects.<ref name="Curr2016" /> Typical ranges vary from 60% to around 90%.<ref name="Abdulla_2011" /> Depending on the degree of obstruction, symptoms vary from no cyanosis or mild cyanosis to profound cyanosis at birth.<ref name="Curr2016" /> If the baby is not cyanotic, then it is sometimes referred to as a "pink tet".<ref name="urlTetralogy of Fallot: Overview - eMedicine">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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 (dyspnea) on exertion, clubbing of the fingers and toes, and polycythemia.<ref name="NIH2011Sym" /> The baby may turn blue with breastfeeding or crying.<ref name="NIH2011Sym" />

Those born with tetralogy of Fallot are more likely to experience psychiatric disorders such as attention deficit hyperactivity disorder (ADHD) in later life, potentially due to underlying genetic changes that predispose to both conditions.<ref>Template:Cite journal</ref>

Hypercyanotic "Tet" spells

Infants and children with unrepaired tetralogy of Fallot may develop hypercyanotic,<ref>Template:Cite journal</ref> or "tet," spells.<ref name="Abdulla_2011" /> 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.<ref name="Munoz_2010"/>Template:Rp This may be initiated by any event – such as anxiety, pain, dehydration, or fever<ref name="Munoz_2010">Template:Cite book</ref> – 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.<ref name="Abdulla_2011" /> The pathophysiology of these episodes is multifactorial; increased sympathetic activation (from pain, agitation, fever, etc.) leads to increased myocardial contractility, which worsens dynamic muscular obstruction of the right ventricular outflow tract, and increased heart rate (tachycardia), 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.<ref name="Munoz_2010" />Template:Rp

Older children will often squat instinctively during a hypercyanotic spell.<ref name="Abdulla_2011" /> 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.<ref name="Squatting: the hemodynamic change i">Template:Cite journal</ref><ref name="pmid5638470">Template:Cite journal</ref>

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.<ref name="Wang_2014">Template:Cite journal</ref> However, the other 80% of cases have little known about their cause.<ref name="Wang_2014"/>

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.<ref name="Francois_2016">Template:Cite bookTemplate:Page?</ref>

Specific genes associations with TOF include:

• JAG1 codes for ligands within the Notch family of proteins and is highly expressed in the developing heart.<ref name="pmid11152664">Template:Cite journal</ref> Mutations of the JAG1 gene can lead to abnormal heart development associated with TOF.<ref name="pmid11152664" />
• NKX2-5 codes for cardiac morphogenesis regulators to allow for proper heart development.<ref>Template:Cite journal</ref> Defects in this gene typically causes septal defects and has been associated with around 4% of all TOF cases.<ref name="pmid11714651">Template:Cite journal</ref>
• ZFPM2 is another cardiac regulator involved in regulation of GATA4.<ref name="pmid14517948">Template:Cite journal</ref> Mutations of the ZFPM2 gene lead to reduced GATA production and have been seen in some TOF cases.<ref name="pmid14517948" />
• VEGF a well-known endothelial growth factor involved in the vascularization of the heart.<ref name="pmid15937089">Template:Cite journal</ref> Decreased VEGF expression has been shown to be a modifier of TOF.<ref name="pmid15937089" />
• 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.<ref name="Page_2019">Template:Cite journal</ref>
• TBX1 expresses progenitors involved with the development of the right ventricle.<ref name="Griffin_2010">Template:Cite journal</ref> Chromosome 22q11 deletions also deleting TBX1 gene have been seen in 17% TOF cases.<ref name="Griffin_2010" />
• FLT4 gene expression leads to Vascular endothelial growth factor receptor 3 (VEGFR-3) which helps vascularization.<ref name="Page_2019"/> Mutations of this gene have been associated with TOF, accounting for 2.4% of all cases.<ref name="Page_2019" />
• FOXC2 is another gene involved in embryonic development of the cardiac system.<ref name="Morgenthau_2018">Template:Cite journal</ref> Mutations of this gene have been shown to result in dysfunctional lymphatic syndrome and TOF.<ref name="Morgenthau_2018" />
• GATA4 aids in cardiac development by helping increase the production of cardiomyocytes.<ref>Template:Cite journal</ref> Mutations of this gene have been seen in various familial TOF cases often lasting 2–3 generations.<ref name="Morgenthau_2018" />
• 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.<ref>Template:Cite journal</ref>

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.<ref name="Zhu_2015">Template:Cite journal</ref> Fetal body is unable to process alcohol as well as adults which can lead to improper development, including cardiogenesis.<ref name="Zhu_2015" /> 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.<ref name="Zhu_2015" />
• Maternal smoking: Maternal smoking has been associated with various fetal complications such as premature delivery and low birth weight which can lead to TOF.<ref name="Wang_2014"/> 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.<ref name="Wang_2014" />
• Maternal diabetes: Maternal diabetes, diabetes Mellitus, and gestational diabetes are well-known risk factors of fetal CHD, including TOF.<ref name="Priest_2015">Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> 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.<ref name="Priest_2015" /> Retrospective studies have shown that diabetic mothers with good glucose control still retained the elevated CHD risk.<ref name="Priest_2015" />
• Rubella: Rubella is characterized as mild, contagious viral disease with often unnoticed consequences.<ref name="Yazigi_2017">Template:Cite journal</ref> Infection with rubella during the first trimester has been seen to cause various fetal malformations, including TOF.<ref name="Yazigi_2017" />
• 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.<ref name="Hashim_2020">Template:Cite journal</ref> These risk factors can effect fetal development and lead to various fetal conditions such as CHD (including TOF), Down Syndrome and Autism.<ref name="Hashim_2020" />

Embryology studies show that anterior malalignment of the aorticopulmonary septum results in the clinical combination of a ventricular septal defect (VSD), pulmonary stenosis, and an overriding aorta.<ref name="Munoz_2010" />Template:Rp Right ventricular hypertrophy develops progressively from resistance to blood flow through the right ventricular outflow tract.<ref name="Curr2016" />

Pathophysiology

File:Tetralogy of fallot video.webm

Video explanation

In healthy individuals, the human heart develops around the 20th day of gestation, when the outer endocardial tubes merge into a single cardiac tube. Thereafter, the cardiac tube begins to fold, developing into the atrium and ventricle. The right ventricle is dominant prior to birth, receiving 65% of the venous return to the heart, and is the main contributor of blood flow to the lower part of the body, the placenta, and the lungs. Though the exact cause of TOF is unknown, an association that has been observed is an anterior deviation of the infundibular septum that results in a misaligned VSD, with an overriding aorta causing a subsequent right ventricular obstruction.<ref name="Diaz-Frias_2021" />

Different factors such as pulmonary stenosis can also contribute with the right ventricular outflow obstruction. During tet spells, a decrease in systemic vascular resistance or an increase in pulmonary resistance would be physiologically observed.

The main anatomic defect in TOF is the anterior deviation of the pulmonary outflow septum.<ref name="Curr2016" /> This defect results in narrowing of the right ventricular outflow tract (RVOT), override of the aorta, and a VSD.<ref>Template:Cite bookTemplate:Page?</ref>

Four malformations

"Tetralogy" denotes four parts, here implying the syndrome's four anatomic defects.<ref name="NIH2011Sym" /> This is not to be confused with the similarly named teratology, a field of medicine concerned with abnormal development and congenital malformations (including tetralogy of Fallot). Below are the four heart malformations that present together in tetralogy of Fallot:

File:Heart tetralogy fallot.svg

Heart with tetralogy of fallot A: Pulmonary stenosis; B: Overriding aorta; C: Ventricular septal defect (VSD); D: Right ventricular hypertrophy

File:Heart normal.svg

Normal heart

Condition	Description
Pulmonary Infundibular Stenosis	A narrowing of the right ventricular outflow tract. It can occur at the pulmonary valve (valvular stenosis) or just below the pulmonary valve (infundibular stenosis).<ref name="NIH2011What" /> Infundibular pulmonic stenosis is mostly caused by the overgrowth of the heart muscle wall (hypertrophy of the septoparietal trabeculae),<ref name=gatzoulis/> however, the events leading to the formation of the overriding aorta are also believed to be a cause. The pulmonic stenosis is the major cause of the malformations, with the other associated malformations acting as compensatory mechanisms to the pulmonic stenosis.<ref>Template:Cite journal</ref> The degree of stenosis varies between individuals with TOF and is the primary determinant of symptoms and severity. This malformation is infrequently described as sub-pulmonary stenosis or subpulmonary obstruction.<ref>Template:Cite journal</ref>
Overriding aorta	An aortic valve with biventricular connection, that is, it is situated above the ventricular septal defect and connected to both the right and the left ventricle. The degree to which the aorta is attached to the right ventricle is referred to as its degree of "override." The aortic root can be displaced toward the front (anteriorly) or directly above the septal defect, but it is always abnormally located to the right of the root of the pulmonary artery. The degree of override is extremely variable, with 5–95% of the valve being connected to the right ventricle.<ref name=gatzoulis/>
Ventricular septal defect (VSD)	A hole between the two bottom chambers (ventricles) of the heart. The defect is centered around the most superior aspect of the ventricular septum (the outlet septum), and in the majority of cases is single and large. In some cases, thickening of the septum (septal hypertrophy) can narrow the margins of the defect.<ref name=gatzoulis>Gatzoulis MA, Webb GD, Daubeney PE. (2005) Diagnosis and Management of Adult Congenital Heart Disease. Churchill Livingstone, Philadelphia. Template:ISBN. Template:Page?</ref>
Right ventricular hypertrophy	The right ventricle is more muscular than normal, causing a characteristic boot-shaped (coeur-en-sabot) appearance as seen by chest X-ray. Due to the misarrangement of the external ventricular septum, the right ventricular wall increases in size to deal with the increased obstruction to the right outflow tract. This feature is now generally agreed to be a secondary anomaly, as the level of hypertrophy tends to increase with age.<ref>Template:Cite journal</ref>

File:PLC Fallots tetralogy.jpg

Fallot's tetralogy specimen, from the UCT Pathology Learning Centre

There is anatomic variation between the hearts of individuals with tetralogy of Fallot.<ref name="Curr2016" /> Primarily, the degree of right ventricular outflow tract obstruction varies between patients and generally determines clinical symptoms and disease progression.<ref name="Curr2016" />

Presumably, this arises from an unequal growth of the aorticopulmonary septum (aka pulmonary outflow septum).<ref name="Munoz_2010" />Template:Rp The aorta is too large, thus "overriding," and this "steals" from the pulmonary artery, which is therefore stenosed. This then prevents ventricular wall closure, therefore VSD, and this increases the pressures on the right side, and so the R ventricle becomes bigger to handle the work.<ref name="Munoz_2010" />Template:Rp

Additional anomalies

In addition, tetralogy of Fallot may present with other anatomical anomalies, including:<ref name="Francois_2016"/>Template:Rp<ref>Template:Cite journal</ref>

• stenosis of the left pulmonary artery, in 40%
• a bicuspid pulmonary valve, in 60%
• right-sided aortic arch, in 25%
• coronary artery anomalies, in 10%
• a patent foramen ovale or atrial septal defect, in which case the syndrome is sometimes called a pentalogy of Fallot<ref name="pmid7787464">Template:Cite journal</ref>
• an atrioventricular septal defect
• partially or totally anomalous pulmonary venous return

Tetralogy of Fallot with pulmonary atresia (pseudotruncus arteriosus) is a severe variant<ref name="pmid19079949">Template:Cite journal</ref> in which there is complete obstruction (atresia) of the right ventricular outflow tract, causing an absence of the pulmonary trunk during embryonic development.<ref name="Francois_2016"/>Template:Rp In these individuals, blood shunts completely from the right ventricle to the left where it is pumped only through the aorta. The lungs are perfused via extensive collaterals from the systemic arteries, and sometimes also via the ductus arteriosus.<ref name="Francois_2016"/>Template:Rp

Diagnosis

File:HeartTOP.jpg

A chest X-ray of a child with tetralogy of Fallot

There are three different useful diagnostic tests used for the diagnosis of tetralogy of Fallot.<ref name="Bailliard_2009">Template:Cite journal</ref> These include a chest radiograph, electrocardiogram, and echocardiogram.<ref name="Bailliard_2009" /> The echocardiography determines the final diagnosis and typically offers enough information for surgical treatment planning.<ref name="Bailliard_2009" /> About half of all patients are now diagnosed before they are born.<ref name="Bailliard_2009" /> Differential diagnosis is when physicians diagnose between two or more conditions for a person's symptoms and this can include primary pulmonary causes of cyanosis, cyanotic heart lesions, pulmonary stenosis and transposed arterial trunks.<ref name="Bailliard_2009" />

Chest radiograph

Before more sophisticated techniques became available, chest X-ray was the definitive method of diagnosis. The abnormal "coeur-en-sabot" (boot-like) appearance of a heart with tetralogy of Fallot is classically visible via chest X-ray, although most infants with tetralogy may not show this finding.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The boot like shape is due to the right ventricular hypertrophy present in TOF. Lung fields are often dark (absence of interstitial lung markings) due to decreased pulmonary blood flow.<ref name="Abdulla_20112">Template:Cite book</ref>Template:Rp

Electrocardiogram

An electrocardiogram (ECG) is one of the most basic procedures for assessing the heart.<ref name="Woods_1952">Template:Cite journal</ref> Tiny electrodes are applied to specific areas on the body, near the chest, arm, and neck. Lead cables connect the electrodes to an ECG machine. The heart's electrical activity is then measured.<ref name="Woods_1952" /> Natural electrical impulses help maintain blood flowing properly by coordinating contractions in different areas of the heart.<ref name="Woods_1952" /> These impulses are recorded by an ECG, which shows how fast, the rhythm, intensity and timing of the electrical impulses as they travel through the heart.<ref name="Woods_1952" />

Electrocardiography shows right ventricular hypertrophy (RVH), along with right axis deviation.<ref name="Francois_2016" /> RVH is noted on EKG as tall R-waves in lead V1 and deep S-waves in lead V5–V6.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Echocardiogram

Congenital heart defects are now diagnosed with echocardiography, which is quick, involves no radiation, is very specific, and can be done prenatally.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Echocardiography establishes the presence of TOF by demonstrating a VSD, RVH, and aortic override. Many patients are diagnosed prenatally. Color Doppler (type of echocardiography) measures the degree of pulmonary stenosis. Additionally, close monitoring of the ductus arteriosus is done in the neonatal period to ensure that there is adequate blood flow through the pulmonary valve.<ref name="Francois_2016" /><ref name="Abdulla_20112" />Template:Rp

In certain cases, coronary artery anatomy cannot be clearly viewed using echocardiogram. In this case, cardiac catheterization can be done.<ref name="Munoz_2010" />Template:Rp

Genetics

From a genetics perspective, it is important to screen for DiGeorge in all babies with TOF.<ref name="Munoz_2010" />Template:Rp

Treatment

Tet spells

Tet spells are defined as cyanotic spells occurring due to the obstruction right ventricular outflow.<ref>Template:Cite journal</ref> Tet spells can be triggered by various factors such as crying, progressive tachypnea, and deep breathing, with symptoms including but not limited to blue skin, nails and lips, profound crying and difficulty breathing.<ref>Template:Cite journal</ref>

Tet spells may be treated with beta-blockers such as propranolol, but acute episodes require rapid intervention with morphine or intranasal fentanyl<ref>Template:Cite journal</ref> to reduce ventilatory drive, a vasopressor such as phenylephrine, or norepinephrine to increase systemic vascular resistance, and IV fluids for volume expansion.<ref name="Munoz_2010" />Template:Rp

Oxygen (100%) may be effective in treating spells because it is a potent pulmonary vasodilator and systemic vasoconstrictor. This allows more blood flow to the lungs by decreasing shunting of deoxygenated blood from the right to left ventricle through the VSD. There are also simple procedures such as squatting and the knee chest position which increase systemic vascular resistance and decrease right-to-left shunting of deoxygenated blood into the systemic circulation.<ref name="Munoz_2010" />Template:Rp<ref name="Squatting: the hemodynamic change i"/>

If the spells are refractory to the above treatments, people are usually intubated and sedated. The treatment of last resort for tet spells is extracorporeal membrane oxygenation (ECMO) along with consideration of Blalock-Thomas-Taussig shunt (BTT shunt).<ref name="Munoz_2010" />Template:Rp

Total surgical repair

Total surgical repair of TOF is a curative surgery. Different techniques can be used in performing TOF repair. One method to permit pulmonary blood flow post-birth is the stenting of the ductus arterious (DA) through the inducement of a systemic-to-pulmonary shunt. This surgical approach has an 83% success rate. <ref>Template:Cite journal</ref> However, a transatrial, transpulmonary artery approach is used for most cases.<ref name = "Mavroudis_2015">Template:Cite book</ref>Template:Rp The repair consists of two main steps: closure of the VSD with a patch and reconstruction of the right ventricular outflow tract.<ref name="Corno_2009" />

This open-heart surgery is designed to relieve the right ventricular outflow tract stenosis by careful resection of muscle and to repair the VSD.<ref name = "Mavroudis_2015" />Template:RpThe right ventricle outflow tract can be reconstructed using mainly 2 procedures: a transannular patch (TAP) or a pulmonary valve-sparing procedure (PVS). The decision on the type of the procedure depends on individual anatomy (especially the size of the pulmonary valve). PVS showed better overall survival, event-free survival and less pulmonary regurgitation at 10, 20 and 30 years after the operation.  PVS  can be performed with or without ventriculotomy. A study found similar overall and event-free survival and pulmonary regurgitation rate between patients who underwent PVS with ventriculotomy and the ones who did not.<ref>Template:Cite journal</ref>

Additional reparative or reconstructive surgery may be done on patients as required by their particular cardiac anatomy.<ref name="Mavroudis_2015" />Template:Rp

Timing of surgery in asymptomatic patients is usually between the ages of two months to one year.<ref name="Munoz_2010" />Template:Rp However, in symptomatic patients showing worsening blood oxygen levels, severe tet-spells (cyanotic spells), or dependence on prostaglandins from early neonatal period (to keep the ductus arteriosus open) need to be planned fairly urgently<ref name="Munoz_2010" />Template:Rp

Potential surgical repair complications include residual ventricular septal defect, residual outflow tract obstruction, complete atrioventricular block, arrhythmias, aneurysm of right ventricular outflow patch, and pulmonary valve insufficiency.<ref name="Corno_2009" />Template:Rp Long-term complications most commonly include pulmonary valve regurgitation, and arrhythmias.<ref name="Chessa_2012" /> Adults with repaired TOF require lifelong surveillance to monitor for such complications, with frequency of monitoring varying according to age, diagnostic methods, and the severity of the condition. <ref>Template:Cite journal</ref>

Total repair of tetralogy of Fallot initially carried a high mortality risk, but this risk has gone down steadily over the years. Surgery is now often carried out in infants one year of age or younger with less than 5% perioperative mortality.<ref name="Munoz_2010" />Template:Rp Post surgery, most patients enjoy an active life free of symptoms.<ref name="Munoz_2010" />Template:Rp Currently, long-term survival is close to 90%.<ref name="Munoz_2010" />Template:Rp Today the adult TOF population continues to grow and is one of the most common congenital heart defects seen in adult outpatient clinics.<ref name="Roos-Hesselink_2017" />Template:Rp

Palliative surgery

Initially surgery involved forming a side to end anastomosis between the subclavian artery and the pulmonary artery -i.e. a systemic to pulmonary arterial shunt.<ref name="Corno_2009">Template:Cite book</ref>Template:Rp This redirected a large portion of the partially oxygenated blood leaving the heart for the body into the lungs, increasing flow through the pulmonary circuit, and relieving symptoms. The first Blalock–Thomas–Taussig shunt surgery was performed on 15-month-old Eileen Saxon on November 29, 1944 with the surgery ending in momentary success. Months later Saxon experienced more symptoms, and was operated on again, shortly before her 2nd birthday. She soon after died.<ref name="JHMI">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

The Potts shunt<ref name="pmid15619282">Template:Cite journal</ref> and the Waterston–Cooley shunt<ref name="pmid15854971">Template:Cite journal</ref><ref name="urlSystemic to Pulmonary Artery Shunting for Palliation: - eMedicine">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> are other shunt procedures which were developed for the same purpose. These are no longer used.

Currently, palliative surgery is not normally performed on infants with TOF except for extreme cases.<ref name="Abdulla_2011" />Template:Rp For example, in symptomatic infants, a two-stage repair (initial systemic to arterial shunt placement followed by total surgical repair) may be done.<ref>Template:Cite book</ref> Potential complications include inadequate pulmonary blood flow, pulmonary artery distortion, inadequate growth of the pulmonary arteries, and acquired pulmonary atresia.<ref name="Corno_2009" />Template:Rp

Approaches to surgical repair

After years of tetralogy of Fallot surgical repair expertise, the attention shifted to the emerging evidence that long-term pulmonary insufficiency is detrimental to right ventricular function and clinical prognosis.<ref name="Bové_2017">Template:Cite journal</ref><ref name="van_der_Ven_2019">Template:Cite journal</ref> As a result, the hunt for surgical procedures to relieve right ventricular outflow tract obstruction while minimizing pulmonary regurgitation has intensified.<ref name="Bové_2017" /><ref name="van_der_Ven_2019" />

A constrained right ventricular outflow tract reconstruction with a Dacron patch matched to a nominal pulmonary annulus expansion or an annulus-sparing approach yielded primary complete repair outcomes in 94 TOF infants.<ref name="Bové_2017" /><ref name="van_der_Ven_2019" /> The pulmonary annulus size was larger in babies treated with the latter technique, as predicted.<ref name="Bové_2017" /><ref name="van_der_Ven_2019" /> After an average follow-up of around eight years, the first group had a higher than moderate PR, yet there was no significant difference in independence from severe PR after ten years.<ref name="Bové_2017" /><ref name="van_der_Ven_2019" />

Furthermore, there was no significant difference in right ventricular dilation between the two techniques.<ref name="Bové_2017" /><ref name="van_der_Ven_2019" /> Finally, they found that reconstructing the pulmonary annulus in TOF with only a tiny transannular incision and a stiff Dacron patch to inhibit pulmonary annulus extension throughout the normal growing phase produces the same long-term benefits as preserving the full pulmonary annulus integrity.<ref name="Bové_2017" /><ref name="van_der_Ven_2019" />

Complications

Short-term

Residual ventricular septal defects and persistent right ventricular outflow blockage are common problems in the immediate postoperative period. Arrhythmias such as ventricular tachycardia, atrial fibrillation/flutter, and intra-atrial re-entrant tachycardia can occur after tetralogy repair.<ref name="Diaz-Frias_2021" /> With broad complex tachycardia, the ECG will likely show a right bundle branch block or left bundle branch block patterns. Patients who have had their hearts repaired may experience sudden cardiac death. Risk factors for abnormal heart rhythms include:

• Age (at repair)<ref name="Diaz-Frias_2021" />
• Male gender<ref name="Diaz-Frias_2021" />
• Transient complete heart block beyond post operative day three<ref name="Diaz-Frias_2021" />
• QRS duration greater than 180 milliseconds<ref name="Diaz-Frias_2021" />

Long-term

Adult patients with congenital cardiac disease are on the rise at a rate of about 5% per year, outpacing the pediatric population.<ref name="Diaz-Frias_2021" /> Right ventricular volume overload form pulmonary insufficiency, right ventricular aneurysm from outflow patch or ventriculotomy, distal pulmonary artery obstruction, ventricular hypertrophy, chamber enlargement, biventricular dysfunction, and aortic root dilation and insufficient are all long-term complications seen in these patients.<ref name="Diaz-Frias_2021" /> Arrhythmia, heart failure, and complications from reoperations are the three primary causes of death in individuals with corrected tetralogy of Fallot. QRS duration greater than 180 milliseconds, older age at repair (greater than three years), significant pulmonary valve or tricuspid valve regurgitation, history of syncope, multifocal premature ventricular contractions, and ventricular tachycardia are some of the factors associated with sudden death after 30 years of procedure.<ref name="Singab_2021">Template:Cite journal</ref> Pulmonary insufficiency is the most common reason for reoperation, and pulmonary valve replacement criteria have traditionally been based on the severity of the regurgitant fraction on a magnetic resonance or CT scan. Right and left ventricular end-systolic and end-diastolic volume indices, ejection fractions, and the existence of aneurysm generating obstructive outflow are all parameters seen in this research. Exercise intolerance, heart failure signs and symptoms, syncope, and prolonged ventricular tachycardia are all possible symptoms. A transcatheter pulmonary valve method can also be used to replace a pulmonary valve.<ref name="Singab_2021" />

Pregnancy

In comparison to the general obstetric population, women who had their tetralogy of Fallot repaired completely have similar outcomes.<ref name="Singh_2021">Template:Cite journal</ref> The degree of pulmonary regurgitation with right or left ventricular dysfunction, as well as the level of pulmonary hypertension, are linked to an increased risk of pregnancy complications.<ref name="Singh_2021" /> Fetal death is more likely in women who have moderate right ventricular hypertension or who have undergone a palliative shunt. In comparison to 0.8% of the general population, offspring of women with tetralogy have a 3–5% chance of developing congenital cardiac disease. If the 22q11 deletion is present, there is a 50% chance of transferring the damaged chromosome, with a high risk of a congenital cardiac abnormality.<ref name="Singh_2021" />

Prognosis

Untreated, tetralogy of Fallot rapidly results in progressive right ventricular hypertrophy due to the increased resistance caused by narrowing of the pulmonary trunk.<ref name="Munoz_2010" />Template:Rp This progresses to heart failure which begins in the right ventricle and often leads to left heart failure and dilated cardiomyopathy. Mortality rate depends on the severity of the tetralogy of Fallot. If left untreated, TOF carries a 35% mortality rate in the first year of life, and a 50% mortality rate in the first three years of life.<ref name="Chessa_2012"/> Patients with untreated TOF rarely progress to adulthood.<ref name="Chessa_2012">Template:Cite book</ref>

Patients who have undergone total surgical repair of tetralogy of Fallot have improved hemodynamics and often have good to excellent cardiac function after the operation with some to no exercise intolerance (New York Heart Association Class I-II).<ref name="Cobanoglu_2002">Template:Cite journal</ref> Long-term outcome is usually excellent for most patients, however residual post-surgical defects such as pulmonary regurgitation, pulmonary artery stenosis, residual VSD, right ventricular dysfunction, right ventricular outflow tract obstruction may affect life expectancy and increase the need for reoperation.<ref name="Munoz_2010" />Template:Rp

Cardiovascular and cerebrovascular complications in patients with repaired CHD such as TOF occur earlier in life compared to healthy subjects.<ref>Template:Cite journal</ref> Chronic pulmonary regurgitation and right ventricular dilation and dysfunction is also common.<ref>Template:Cite journal</ref>

Within 30 years after correction, 50% of patients will require reoperation.<ref name="Chessa_2012" /> The most common cause of reoperation is a leaky pulmonary valve (pulmonary valve insufficiency).<ref name="Chessa_2012" /> This is usually corrected with a procedure called pulmonary valve replacement.<ref name="Francois_2016" />Template:Rp

One common prognostic factor with TOF is the development of ischemia reperfusion injury. Insufficient myocardial protection is considered one of the main causes of death in the correction of TOF.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Comorbidities

There are many comorbid conditions that can occur with TOF that may exacerbate the condition. Often, TOF can present with low birth weight and prematurity. In both of these cases, mortality and morbidity were both seen to increase.<ref>Template:Cite thesis</ref> Differences in right atrial and ventricular mechanics and liver stiffness was also observed in adults with repaired TOF, as well as pulmonary atresia and persistent pulmonary stenosis.<ref>Template:Cite journal</ref> In patients with pulmonary atresia, there is complete failure of forward flow from the right ventricle to the pulmonary arterial vasculature. As such, pulmonary blood flow is entirely dependent on shunting from the systemic circulation, typically through a patent ductus arteriosus. The pathophysiology of TOF together with pulmonary arteriosus is uniquely attributable to defects of the pulmonary arteries. Even after operative care, these patients remain at higher risk for pulmonary arterial stenoses and pulmonary hypertension.<ref>Template:Cite journal</ref>

Danon disease, which is a rare genetic disorder, was also observed to complicate TOF. In particular, elongation of the QRS complex and a shortened PR interval. Genetic abnormalities found in TOF may lead to the earlier diagnosis of Danon disease, helping to improve prognostic outcomes.<ref>Template:Cite journal</ref>

Epidemiology

The prevalence of tetralogy of Fallot is estimated to be 0.02–0.04%, which corresponds to approximately 200 to 400 cases per million live births.<ref name="pmid152344302">Template:Cite journal</ref><ref name="NORD">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It accounts for 7–10% of all congenital heart abnormalities, making it the most common cyanotic heart defect.<ref name="Roos-Hesselink_2017" />Template:Rp Although males and females were initially believed to be affected equally, more recent studies have shown TOF affects males more than females.<ref name="NIH2011What2">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="NORD" /> About 1 in 100 newborns is diagnosed with a congential heart defect, of which 10% are diagnosed with TOF.<ref name="NORD" /> Genetically, it is most commonly associated with Down syndrome and DiGeorge syndrome.<ref name="Roos-Hesselink_2017" /><ref name="Francois_2016"/> Down syndrome and other chromosomal disorders are known to occur alongside congential heart defects such as TOF.<ref name="NORD" />

History

Tetralogy of Fallot was initially described in 1671 by the Danish researcher Niels Steensen.<ref name=Name2016/><ref name=VanP2009/> Also referenced as Nicolaus Steno in Latin, Steensen was a pioneer in anatomy and geology, his work making significant specific contribution to the fields of cardiac anatomy and pathology.<ref name="Diaz-Frias_2021" /> A further description was published in 1888 by the French physician Étienne-Louis Arthur Fallot, after whom it was ultimately named.<ref name=Name2016/><ref name=Fallot1888/> In 1924, Maude Elizabeth Seymour Abbott, a pediatric cardiologist from Montreal, Canada, named it tetralogy of Fallot.<ref>Template:Cite journal</ref>

The short paper "Dissection of a Monstrous Foetus in Paris" in 1671 first described the conditions that would later together be known as TOF. In particular, it highlighted the unusual formation of arteries, the stenosing of the pulmonary artery, the absence of the ductus arteriosus, an overriding aorta, and fetal cardiac circulation where blood was redirected to the aorta from the pulmonary artery.<ref name="Diaz-Frias_2021" /> Over a hundred years later in 1777, Dutch physician Eduard Sandifort reported what he referred to as "the blue boy" patient. This patient, who was 16 months old, was initially thought to have asthma, though an autopsy postmortem revealed a cardiac malformation with no ductus arteriosus or ligamentum arteriosum, indicating that the child may have died from TOF.<ref name="Diaz-Frias_2021" /> Another 13-year-old patient was reported by Scottish physician William Hunter in 1782. Hunter described the patient, along with three others, as suffering from cyanosis after a posthumous examination in 1774.<ref name="Diaz-Frias_2021" />

Other cases, such as those presented by Pulteney (1785), Abernethy (1793), Bell (1797), Dorsey (1812), and Farre (1814) also contributed to modern understandings of TOF. The first reported case of TOF was in America at the University of Pennsylvania in 1816, with more cases being reported by Peacock (1858 and 1869), Widman (1881), and finally Fallot (1888), after whom the condition is named.<ref name="Diaz-Frias_2021" /> Fallot was the first to elegantly describe the four key features that differentiate it from other cyanotic cardiac conditions, and was prominent in the disqualification of a patent foramen ovale as a fifth feature. Fallot initially referred to it as "La maladie bleue", which is French for "the blue disease" or "cyanose cardiaque", translating to "cardiac cyanosis".<ref name="Diaz-Frias_2021" />

The first surgical palliation was carried out in 1944 at Johns Hopkins.<ref>Template:Cite journal</ref> The procedure was conducted by surgeon Alfred Blalock and cardiologist Helen B. Taussig, with Vivien Thomas also providing substantial contributions and listed as an assistant.<ref name=War2005/> This first surgery was depicted in the film Something the Lord Made.<ref name="JHMI" /> It was actually Helen Taussig who convinced Alfred Blalock that the shunt was going to work. 15-month-old Eileen Saxon was the first person to receive a Blalock–Thomas–Taussig shunt.<ref name="JHMI" /> Furthermore, the Blalock-Thomas-Taussig procedure, initially the only surgical treatment available for tetralogy of Fallot, was palliative but not curative. The first total repair of tetralogy of Fallot was done by a team led by C. Walton Lillehei at the University of Minnesota in 1954 on an 11-year-old boy.<ref name="PMC1465089">Template:Cite journal</ref> Total repair on infants has had success from 1981, with research indicating that it has a comparatively low mortality rate.<ref name="Cobanoglu_2002" /> Today the adult TOF population continues to grow and is one of the most common congenital heart defects seen in adult outpatient clinics.<ref name="Roos-Hesselink_2017" />Template:Rp

Related disorders

The following illnesses have symptoms that are comparable to tetralogy of Fallot. For a differential diagnosis, comparisons between these disorders provides valuable knowledge.

Atrial septal defects

Atrial septal defects (ASDs) are a kind of congenital heart abnormality in which a tiny opening exists between the two atria of the heart.<ref name="Thorne_2011">Template:Cite journal</ref><ref name="NORD" /> The burden on the right side of the heart is increased as a result of these abnormalities, as is the blood flow to the lungs.<ref name="Thorne_2011" /><ref name="NORD" /> This leads to excessive blood flow to the lungs and an increased workload on the right side of the heart.<ref name="Thorne_2011" /><ref name="NORD" /> Another common finding associated with ASDs is right ventricular hypertrophy, also known as enlargement of the right ventricle.<ref name="NORD" />

Ventricular septal defects

Ventricular septal defects (VSDs) are a kind of congenital heart abnormality in which one of the ventricles is missing.<ref name="Dakkak_2021">Template:Cite book</ref><ref name="NORD" /> Two atria and one big ventricle are common in infants with congenital abnormalities.<ref name="Dakkak_2021" /><ref name="NORD" /> Symptoms of these diseases include an unusually high rate of breathing (tachypnea), a blue hue to the skin (cyanosis), wheezing, a rapid heartbeat (tachycardia), and/or an abnormally enlarged liver, which are similar to those of other congenital heart problems (hepatomegaly).<ref name="Dakkak_2021" /><ref name="NORD" /> VSDs can also lead to a build-up of fluid around the heart, which can lead to congestive heart failure.<ref name="Dakkak_2021" /><ref name="NORD" />

Atrioventricular septal defect

Atrioventricular septal defect (AVSD) is an uncommon congenital heart condition characterized by faulty development of the heart's septa and valves.<ref name="Ahmed_2021">Template:Cite book</ref><ref name="NORD" /> Congestive heart failure is common in infants with the entire version of the condition.<ref name="Ahmed_2021" /><ref name="NORD" /> Fluid builds up in other parts of the body, particularly the lungs.<ref name="Ahmed_2021" /><ref name="NORD" /> Breathing difficulties may result from pulmonary congestion (dyspnea).<ref name="Ahmed_2021" /><ref name="NORD" />

Mitral valve stenosis

Mitral valve stenosis is an uncommon cardiac abnormality that can occur at birth (congenital) or develop later in life (acquired).<ref name="Shah_2021">Template:Cite book</ref><ref name="NORD" /> The aberrant narrowing of the mitral valve's opening characterizes this condition.<ref name="Shah_2021" /><ref name="NORD" /> There are two versions of this condition known as congenital and acquired characterized by different symptoms.<ref name="NORD" /> Congenital Mitral valve stenosis symptoms include a wide array such as respiratory infections, breathing difficulties, heart palpitations and coughing.<ref name="NORD" /> Acquired mitral valve stenosis symptoms also include a wide array such as consciousness losses, angina, general weakness and abdominal discomfort.<ref name="NORD" />

Notable cases

• Shaun White,<ref name="Yen_2003">Template:Cite news</ref> American professional snowboarder and skateboarder
• Beau Casson,<ref name="smh.com.au">Template:Cite news</ref> Australian cricketer
• Dennis McEldowney,<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref> New Zealand author and publisher

• Max Page, Volkswagen's "Little Darth Vader" from the 2011 Super Bowl commercial<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• Billy Kimmel, the son of talk show host Jimmy Kimmel; Billy's diagnosis led Kimmel to discuss access to health care on his show Jimmy Kimmel Live!<ref>Template:Cite magazine</ref>

See also

• Trilogy of Fallot
• Congenital rubella syndrome

External links

• What Is Tetralogy of Fallot? at the National Institutes of Health
• Understanding your child's heart: Tetralogy of Fallot by the British Heart Foundation