Tetralogy of Fallot (TOF), formerly known as Steno-Fallot tetralogy, is a

congenital heart defect A congenital heart defect (CHD), also known as a congenital heart anomaly and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital heart defect is classed as a cardiovascular ...

characterized by four specific cardiac defects. Classically, the four defects are: *

pulmonary stenosis Pulmonic stenosis, is a dynamic or fixed obstruction of flow from the right ventricle of the heart to the pulmonary artery. It is usually first diagnosed in childhood. Signs and symptoms Cause Pulmonic stenosis is usually due to isolated valvula ...

, which is narrowing of the exit from the right ventricle; * a

ventricular septal defect A ventricular septal defect (VSD) is a defect in the ventricular septum, the wall dividing the left and right ventricles of the heart. The extent of the opening may vary from pin size to complete absence of the ventricular septum, creating one ...

, which is a hole allowing blood to flow between the two ventricles; *

right ventricular hypertrophy Right ventricular hypertrophy (RVH) is a condition defined by an abnormal enlargement of the cardiac muscle surrounding the right ventricle. The right ventricle is one of the four chambers of the heart. It is located towards the lower-end of the h ...

, which is thickening of the right ventricular muscle; and * an

overriding aorta An overriding aorta is a congenital heart defect where the aorta is positioned directly over a ventricular septal defect (VSD), instead of over the left ventricle. The result is that the aorta receives some blood from the right ventricle, causing ...

, which is where the

aorta The aorta ( ) is the main and largest artery in the human body, originating from the left ventricle of the heart and extending down to the abdomen, where it splits into two smaller arteries (the common iliac arteries). The aorta distributes ...

expands to allow blood from both ventricles to enter. 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 Cyanosis is the change of body tissue color to a bluish-purple hue as a result of having decreased amounts of oxygen bound to the hemoglobin in the red blood cells of the capillary bed. Body tissues that show cyanosis are usually in locations ...

. When affected babies cry or have a

bowel movement Defecation (or defaecation) follows digestion, and is a necessary process by which organisms eliminate a solid, semisolid, or liquid waste material known as feces from the digestive tract via the anus. The act has a variety of names ranging fro ...

, 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 Heart murmurs are unique heart sounds produced when blood flows across a heart valve or blood vessel. This occurs when turbulent blood flow creates a sound loud enough to hear with a stethoscope. Turbulent blood flow is not smooth. The sound di ...

, finger clubbing, and easy tiring upon

breastfeeding Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that br ...

. The cause of tetralogy of Fallot is typically not known. Risk factors include a mother who uses alcohol, has

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

, is over the age of 40, or gets

rubella Rubella, also known as German measles or three-day measles, is an infection caused by the rubella virus. This disease is often mild, with half of people not realizing that they are infected. A rash may start around two weeks after exposure and ...

during

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ca ...

. It may also be associated with

Down syndrome Down syndrome or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. It is usually associated with physical growth delays, mild to moderate intellectual dis ...

and other chromosomal defects that cause congenital heart defects. TOF is typically treated by

open heart surgery Cardiac surgery, or cardiovascular surgery, is surgery on the heart or great vessels performed by cardiac surgeons. It is often used to treat complications of ischemic heart disease (for example, with coronary artery bypass grafting); to c ...

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 The pulmonary valve (sometimes referred to as the pulmonic valve) is a valve of the heart that lies between the right ventricle and the pulmonary artery and has three cusps. It is one of the four valves of the heart and one of the two semilunar v ...

and

pulmonary arteries A pulmonary artery is an artery in the pulmonary circulation that carries deoxygenated blood from the right side of the heart to the lungs. The largest pulmonary artery is the ''main pulmonary artery'' or ''pulmonary trunk'' from the heart, and ...

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 Pulmonary (or pulmonic) insufficiency (or incompetence, or regurgitation) is a condition in which the pulmonary valve is incompetent and allows backflow from the pulmonary artery to the right ventricle of the heart during diastole. While a small ...

. The prevalence of TOF is estimated to be anywhere from 0.02 to 0.04%. 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 Niels Steensen ( da, Niels Steensen; Latinized to ''Nicolaus Steno'' or ''Nicolaus Stenonius''; 1 January 1638 – 25 November 1686Étienne-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

(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 A right-to-left shunt is a cardiac shunt which allows blood to flow from the right heart to the left heart. This terminology is used both for the abnormal state in humans and for normal physiological shunts in reptiles. Clinical Significance A r ...

. 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

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 Polycythemia (also known as polycythaemia) is a laboratory finding in which the hematocrit (the volume percentage of red blood cells in the blood) and/or hemoglobin concentration are increased in the blood. Polycythemia is sometimes called eryth ...

. 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 Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inap ...

(ADHD) in later life, potentially due to underlying genetic changes that predispose to both conditions.

Tet spells

Infants and children with unrepaired tetralogy of Fallot may develop "tet spells". These are acute hypoxia spells, characterized by shortness of breath, cyanosis, agitation, and loss of consciousness. This may be initiated by any event – such as anxiety, pain, dehydration, or fever – leading to decreased oxygen saturation or that causes decreased systemic vascular resistance, which in turn leads to increased shunting through the ventricular septal defect. Typically, these spells decrease in frequency after the first four years of life. Clinically, tet spells are characterized by a sudden, marked increase in cyanosis followed by syncope. Older children will often squat instinctively during a tet 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, thus decreasing the amount of deoxygenated blood entering the systemic circulation.

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 CHD cases have been due to known causes such as genetic defects and

teratogens Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology. The related ...

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 DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a syndrome caused by a microdeletion on the long arm of chromosome 22. While the symptoms can vary, they often include congenital heart problems, specific facial features, frequent i ...

. Specific genes associations with TOF include: *

JAG1 Jagged1 (''JAG1'') is one of five cell surface proteins (ligands) that interact with four receptors in the mammalian Notch signaling pathway. The Notch Signaling Pathway is a highly conserved pathway that functions to establish and regulate cell fa ...

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 Homeobox protein Nkx-2.5 is a protein that in humans is encoded by the ''NKX2-5'' gene. Function Homeobox-containing genes play critical roles in regulating tissue-specific gene expression essential for tissue differentiation, as well as dete ...

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 Zinc finger protein ZFPM2, i.e. zinc finger protein, FOG family member 2, but also termed ''Friend of GATA2, Friend of GATA-2, FOG2'', or ''FOG-2'', is a protein that in humans is encoded by the ''ZFPM2'' and in mice by the ''Zfpm2'' gene. The zi ...

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 Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors ...

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 Neurogenic locus notch homolog protein 1 (Notch 1) is a protein encoded in humans by the ''NOTCH1'' gene. Notch 1 is a single-pass transmembrane receptor. Function This gene encodes a member of the Notch family. Members of this Type 1 transm ...

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 T-box transcription factor TBX1 also known as T-box protein 1 and testis-specific T-box protein is a protein that in humans is encoded by the TBX1 gene. Genes in the T-box family are transcription factors that play important roles in the formation ...

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 Fms-related tyrosine kinase 4, also known as FLT4, is a protein which in humans is encoded by the ''FLT4'' gene. This gene encodes a tyrosine kinase receptor for vascular endothelial growth factors C and D. The protein is thought to be involve ...

gene expression leads to Vascular endothelial growth factor receptor 3 (

VEGFR-3 VEGF receptors are receptors for vascular endothelial growth factor (VEGF). There are three main subtypes of VEGFR, numbered 1, 2 and 3. Also, they may be membrane-bound (mbVEGFR) or soluble (sVEGFR), depending on alternative splicing. Inhi ...

) which helps vascularization. Mutations of this gene have been associated with TOF, accounting for 2.4% of all cases. *

FOXC2 Forkhead box protein C2 (FOXC2) also known as forkhead-related protein FKHL14 (FKHL14), transcription factor FKH-14, or mesenchyme fork head protein 1 (MFH1) is a protein that in humans is encoded by the ''FOXC2'' gene. FOXC2 is a member of the ...

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 Transcription factor GATA-4 is a protein that in humans is encoded by the ''GATA4'' gene. Function This gene encodes a member of the GATA family of zinc finger transcription factors. Members of this family recognize the GATA motif which is pr ...

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 Filamin A, alpha (FLNA) is a protein that in humans is encoded by the ''FLNA'' gene. Function Actin-binding protein, or filamin, is a 280-kD protein that crosslinks actin filaments into orthogonal networks in cortical cytoplasm and participate ...

is a protein coded by the gene of the same name that crosslinks actin filaments into networks in

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...

and helps anchor membrane proteins for the actin

cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...

. 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 An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sperm ...

, 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 Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

, and

gestational diabetes Gestational diabetes is a condition in which a woman without diabetes develops high blood sugar levels during pregnancy. Gestational diabetes generally results in few symptoms; however, it increases the risk of pre-eclampsia, depression, and of ...

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 (including TOF), Down Syndrome and Autism.

Embryology Embryology (from Greek ἔμβρυον, ''embryon'', "the unborn, embryo"; and -λογία, '' -logia'') is the branch of animal biology that studies the prenatal development of gametes (sex cells), fertilization, and development of embryos and ...

studies show that anterior malalignment of the aorticopulmonary septum results in the clinical combination of a

(VSD),

, and an

Right ventricular hypertrophy Right ventricular hypertrophy (RVH) is a condition defined by an abnormal enlargement of the cardiac muscle surrounding the right ventricle. The right ventricle is one of the four chambers of the heart. It is located towards the lower-end of the h ...

develops progressively from resistance to blood flow through the

right ventricular A ventricle is one of two large chambers toward the bottom of the heart that collect and expel blood towards the peripheral beds within the body and lungs. The blood pumped by a ventricle is supplied by an atrium, an adjacent chamber in the upper ...

outflow tract.

Pathophysiology

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. 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. This defect results in narrowing of the right ventricular outflow tract (RVOT), override of the aorta, and a VSD.

Four malformations

Tetralogy A tetralogy (from Greek τετρα- ''tetra-'', "four" and -λογία ''-logia'', "discourse") is a compound work that is made up of four distinct works. The name comes from the Attic theater, in which a tetralogy was a group of three tragedies ...

" denotes four parts, here implying the syndrome's four anatomic defects. This is not to be confused with the similarly named

teratology Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology. The relate ...

, a field of medicine concerned with abnormal development and congenital malformations (including tetralogy of Fallot). Below are the four

heart The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide t ...

malformations that present together in tetralogy of Fallot: PLC Fallots tetralogy

There is anatomic variation between the hearts of individuals with tetralogy of Fallot. Primarily, the degree of right ventricular outflow tract obstruction varies between patients and generally determines clinical symptoms and disease progression. Presumably, this arises from an unequal growth of the aorticopulmonary septum (aka pulmonary outflow septum). 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.

Additional anomalies

In addition, tetralogy of Fallot may present with other anatomical anomalies, including: * stenosis of the

left pulmonary artery A pulmonary artery is an artery in the pulmonary circulation that carries deoxygenated blood from the right side of the heart to the lungs. The largest pulmonary artery is the ''main pulmonary artery'' or ''pulmonary trunk'' from the heart, and ...

, in 40% * a bicuspid pulmonary valve, in 60% *

right-sided aortic arch Right-sided aortic arch is a rare anatomical variant in which the aortic arch is on the right side rather than on the left. During normal embryonic development, the aortic arch is formed by the left fourth aortic arch and the left dorsal aorta. I ...

, in 25% *

coronary artery The coronary arteries are the arterial blood vessels of coronary circulation, which transport oxygenated blood to the heart muscle. The heart requires a continuous supply of oxygen to function and survive, much like any other tissue or organ ...

anomalies, in 10% * a patent foramen ovale or

atrial septal defect Atrial septal defect (ASD) is a congenital heart defect in which blood flows between the atria (upper chambers) of the heart. Some flow is a normal condition both pre-birth and immediately post-birth via the foramen ovale; however, when this d ...

, in which case the syndrome is sometimes called a pentalogy of Fallot * an

atrioventricular septal defect Atrioventricular septal defect (AVSD) or atrioventricular canal defect (AVCD), also known as "common atrioventricular canal" (CAVC) or "endocardial cushion defect" (ECD), is characterized by a deficiency of the atrioventricular septum of the heart ...

* partially or totally anomalous pulmonary venous return Tetralogy of Fallot with

pulmonary atresia Pulmonary atresia is a congenital malformation of the pulmonary valve in which the valve orifice fails to develop. The valve is completely closed thereby obstructing the outflow of blood from the heart to the lungs. The pulmonary valve is located ...

(''pseudotruncus arteriosus'') is a severe variant in which there is complete obstruction (atresia) of the right ventricular outflow tract, causing an absence of the pulmonary trunk during embryonic development. 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.

Diagnosis

There are three different useful diagnostic tests used for the diagnosis of tetralogy of Fallot. These include a chest radiograph, electrocardiogram, and echocardiogram. The echocardiography determines the final diagnosis and typically offers enough information for surgical treatment planning. About half of all patients are now diagnosed before they are born. 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.

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. 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.

Electrocardiogram

An electrocardiogram (ECG) is one of the most basic procedures for assessing the heart. 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. Natural electrical impulses help maintain blood flowing properly by coordinating contractions in different areas of the heart. 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. Electrocardiography shows right ventricular hypertrophy (RVH), along with right axis deviation. RVH is noted on EKG as tall R-waves in lead V1 and deep S-waves in lead V5-V6.

Echocardiogram

Congenital heart defects are now diagnosed with

echocardiography An echocardiography, echocardiogram, cardiac echo or simply an echo, is an ultrasound of the heart. It is a type of medical imaging of the heart, using standard ultrasound or Doppler ultrasound. Echocardiography has become routinely used in t ...

, which is quick, involves no radiation, is very specific, and can be done prenatally.

Echocardiography An echocardiography, echocardiogram, cardiac echo or simply an echo, is an ultrasound of the heart. It is a type of medical imaging of the heart, using standard ultrasound or Doppler ultrasound. Echocardiography has become routinely used in t ...

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. In certain cases, coronary artery anatomy cannot be clearly viewed using echocardiogram. In this case, cardiac catheterization can be done.

Genetics

From a genetics perspective, it is important to screen for DiGeorge in all babies with TOF.

Treatment

Tet spells

Tet spells are defined as cyanotic spells occurring due to the obstruction right ventricular outflow. 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. Tet spells may be treated with beta-blockers such as

propranolol Propranolol, sold under the brand name Inderal among others, is a medication of the beta blocker class. It is used to treat high blood pressure, a number of types of irregular heart rate, thyrotoxicosis, capillary hemangiomas, performance an ...

, but acute episodes require rapid intervention with

morphine Morphine is a strong opiate that is found naturally in opium, a dark brown resin in poppies (''Papaver somniferum''). It is mainly used as a analgesic, pain medication, and is also commonly used recreational drug, recreationally, or to make ...

or intranasal

fentanyl Fentanyl, also spelled fentanil, is a very potent synthetic opioid used as a pain medication. Together with other drugs, fentanyl is used for anesthesia. It is also used illicitly as a recreational drug, sometimes mixed with heroin, cocain ...

to reduce ventilatory drive, a vasopressor such as

phenylephrine Phenylephrine is a medication primarily used as a decongestant, to dilate the pupil, to increase blood pressure, and to relieve hemorrhoids. In the United States, it was previously used orally as an over-the-counter decongestant to relieve nas ...

, or

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...

to increase systemic vascular resistance, and IV fluids for volume expansion. 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 Squatting is the action of occupying an abandoned or unoccupied area of land or a building, usually residential, that the squatter does not own, rent or otherwise have lawful permission to use. The United Nations estimated in 2003 that there ...

and the knee chest position which increase systemic vascular resistance and decrease right-to-left shunting of deoxygenated blood into the systemic circulation. 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 Taussig shunt (BT shunt).

Total surgical repair

Total surgical repair of TOF is a curative surgery. Different techniques can be used in performing TOF repair. However, a transatrial, transpulmonary artery approach is used for most cases. The repair consists of two main steps: closure of the VSD with a patch and reconstruction of the right ventricular outflow tract. This open-heart surgery is designed to relieve the right ventricular outflow tract stenosis by careful resection of muscle and to repair the VSD.The 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. Additional reparative or reconstructive surgery may be done on patients as required by their particular cardiac anatomy. Timing of surgery in asymptomatic patients is usually between the ages of two months to one year. 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 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. Long-term complications most commonly include pulmonary valve regurgitation, and arrhythmias. 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. Post surgery, most patients enjoy an active life free of symptoms. Currently, long-term survival is close to 90%. Today the adult TOF population continues to grow and is one of the most common congenital heart defects seen in adult outpatient clinics.

Palliative surgery

Initially surgery involved forming a side to end

anastomosis An anastomosis (, plural anastomoses) is a connection or opening between two things (especially cavities or passages) that are normally diverging or branching, such as between blood vessels, leaf#Veins, leaf veins, or streams. Such a connection m ...

between the subclavian artery and the

pulmonary artery A pulmonary artery is an artery in the pulmonary circulation that carries deoxygenated blood from the right side of the heart to the lungs. The largest pulmonary artery is the ''main pulmonary artery'' or ''pulmonary trunk'' from the heart, and ...

-i.e. a systemic to pulmonary arterial shunt. 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 dramatic results. The Potts shunt and the Waterston-Cooley shunt 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. For example, in symptomatic infants, a two-stage repair (initial systemic to arterial shunt placement followed by total surgical repair) may be done. Potential complications include inadequate pulmonary blood flow, pulmonary artery distortion, inadequate growth of the pulmonary arteries, and acquired pulmonary atresia.

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. As a result, the hunt for surgical procedures to relieve right ventricular outflow tract obstruction while minimizing pulmonary regurgitation has intensified. 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. The pulmonary annulus size was larger in babies treated with the latter technique, as predicted. 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. Furthermore, there was no significant difference in right ventricular dilation between the two techniques. 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.

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. 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) * Male gender * Transient complete heart block beyond post operative day three * QRS duration greater than 180 milliseconds

Long-term

Adult patients with congenital cardiac disease are on the rise at a rate of about 5% per year, outpacing the pediatric population. 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. 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. 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.

Pregnancy

In comparison to the general obstetric population, women who had their tetralogy of Fallot repaired completely have similar outcomes. 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. 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.

Prognosis

Untreated, tetralogy of Fallot rapidly results in progressive right ventricular hypertrophy due to the increased resistance caused by narrowing of the pulmonary trunk. 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. Patients with untreated TOF rarely progress to adulthood. 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). 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. Cardiovascular and cerebrovascular complications in patients with repaired CHD such as TOF occur earlier in life compared to healthy subjects. Chronic pulmonary regurgitation and right ventricular dilation and dysfunction is also common. Within 30 years after correction, 50% of patients will require reoperation. The most common cause of reoperation is a leaky pulmonary valve ( pulmonary valve insufficiency). This is usually corrected with a procedure called

pulmonary valve replacement The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side of t ...

. 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.

Comorbidities

There are many

comorbid In medicine, comorbidity - from Latin morbus ("sickness"), co ("together"), -ity (as if - several sicknesses together) - is the presence of one or more additional conditions often co-occurring (that is, concomitant or concurrent) with a primary ...

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. 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. 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.

Danon disease Danon disease (or glycogen storage disease Type IIb) is a metabolic disorder. Danon disease is an X-linked lysosomal and glycogen storage disorder associated with hypertrophic cardiomyopathy, skeletal muscle weakness, and intellectual disability. I ...

, which is a rare genetic disorder, was also observed to complicate TOF. In particular, elongation of the

QRS complex The QRS complex is the combination of three of the graphical deflections seen on a typical electrocardiogram (ECG or EKG). It is usually the central and most visually obvious part of the tracing. It corresponds to the depolarization of the ri ...

and a shortened

PR interval In electrocardiography, the PR interval is the period, measured in milliseconds, that extends from the beginning of the P wave (the onset of atrial depolarization) until the beginning of the QRS complex (the onset of ventricular depolarization ...

. Genetic abnormalities found in TOF may lead to the earlier diagnosis of Danon disease, helping to improve prognostic outcomes.

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. It accounts for 7–10% of all congenital heart abnormalities, making it the most common cyanotic heart defect. Although males and females were initially believed to be affected equally, more recent studies have shown TOF affects males more than females. About 1 in 100 newborns is diagnosed with a congential heart defect, of which 10% are diagnosed with TOF. Genetically, it is most commonly associated with Down syndrome and DiGeorge syndrome. Down syndrome and other chromosomal disorders are known to occur alongside congential heart defects such as TOF.

History

Tetralogy of Fallot was initially described in 1671 by the Danish researcher

Niels Steensen Niels Steensen ( da, Niels Steensen; Latinized to ''Nicolaus Steno'' or ''Nicolaus Stenonius''; 1 January 1638 – 25 November 1686 A further description was published in 1888 by the French physician Étienne-Louis Arthur Fallot, after whom it was ultimately named. In 1924, Maude Elizabeth Seymour Abbott, a pediatric cardiologist from Montreal, Canada, named it tetralogy of Fallot. 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. 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 Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...

, though an autopsy postmortem revealed a cardiac malformation with no ductus arteriosus or ligamentum arteriosum, indicating that the child may have died from TOF. 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. 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 The University of Pennsylvania (also known as Penn or UPenn) is a private research university in Philadelphia. It is the fourth-oldest institution of higher education in the United States and is ranked among the highest-regarded universitie ...

in 1816, with more cases being reported by Peacock (1858 and 1869), Widman (1881), and finally Fallot (1888), after whom the condition is named. 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 Atrial septal defect (ASD) is a congenital heart defect in which blood flows between the atria (upper chambers) of the heart. Some flow is a normal condition both pre-birth and immediately post-birth via the foramen ovale; however, when this d ...

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". The first surgical repair was carried out in 1944 at Johns Hopkins. The procedure was conducted by surgeon

Alfred Blalock Alfred Blalock (April 5, 1899 – September 15, 1964) was an American surgeon most noted for his work on the medical condition of shock as well as Tetralogy of Fallot— commonly known as Blue baby syndrome. He created, with assistance from h ...

and cardiologist Helen B. Taussig, with

Vivien Thomas Vivien Theodore Thomas (August 29, 1910 – November 26, 1985) was an American laboratory supervisor who developed a procedure used to treat blue baby syndrome (now known as cyanotic heart disease) in the 1940s. He was the assistant to surgeon ...

also providing substantial contributions and listed as an assistant. This first surgery was depicted in the film ''

Something the Lord Made ''Something the Lord Made'' is a 2004 American television film, made-for-television biographical film, biographical drama (film and television), drama film about the black cardiac pioneer Vivien Thomas (1910–1985) and his complex and volatile pa ...

''. 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. 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 Clarence Walton Lillehei (October 23, 1918 – July 5, 1999), was an American surgeon who pioneered open-heart surgery, as well as numerous techniques, equipment and prostheses for cardiothoracic surgery. Background Clarence (often called "W ...

at the

University of Minnesota The University of Minnesota, formally the University of Minnesota, Twin Cities, (UMN Twin Cities, the U of M, or Minnesota) is a public university, public Land-grant university, land-grant research university in the Minneapolis–Saint Paul, Tw ...

in 1954 on an 11-year-old boy. Total repair on infants has had success from 1981, with research indicating that it has a comparatively low mortality rate. Today the adult TOF population continues to grow and is one of the most common congenital heart defect seen in adult outpatient clinics.

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. 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. This leads to excessive blood flow to the lungs and an increased workload on the right side of the heart. Another common finding associated with ASDs is right ventricular hypertrophy, also known as enlargement of the right ventricle.

Ventricular septal defects

Ventricular septal defects (VSDs) are a kind of congenital heart abnormality in which one of the ventricles is missing. Two atria and one big ventricle are common in infants with congenital abnormalities. 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). VSDs can also lead to a build-up of fluid around the heart, which can lead to congestive heart failure.

Atrioventricular septal defect

Atrioventricular septal defect (AVSD) is an uncommon congenital heart condition characterized by faulty development of the heart's septa and valves. Congestive heart failure is common in infants with the entire version of the condition. Fluid builds up in other parts of the body, particularly the lungs. Breathing difficulties may result from pulmonary congestion (dyspnea).

Mitral valve stenosis

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

Notable cases

Shaun White Shaun Roger White (born September 3, 1986) is an American former professional snowboarder and skateboarder. He is a five-time Olympian and a three-time Olympic gold medalist in half-pipe snowboarding. He holds the world record for the most X G ...

, American professional snowboarder and skateboarder *

Beau Casson Beau Casson (born 7 December 1982) is a former Australian cricketer who played for Western Australia cricket team, Western Australia and New South Wales cricket team, New South Wales from 2002 to 2011, and represented Australia national cricket ...

, Australian cricketer *

Dennis McEldowney Richard Dennis McEldowney (29 January 1926 – 23 September 2003) was a New Zealand author and publisher. His best known work was ''The World Regained.'' Auto-biographical in nature, it described how he dealt with being an invalid due to having ...

, New Zealand author and publisher * Max Page, Volkswagen's "Little Darth Vader" from the 2011 Super Bowl commercial * Billy Kimmel, the son of talk show host

Jimmy Kimmel James Christian Kimmel (born November 13, 1967) is an American television host, comedian, writer, and producer. He is the host and executive producer of ''Jimmy Kimmel Live!'', a late-night talk show that premiered on ABC on January 26, 2003, ...

; Billy's diagnosis led Kimmel to discuss access to health care on his show ''

Jimmy Kimmel Live! ''Jimmy Kimmel Live!'' is an American late-night talk show, created and hosted by Jimmy Kimmel, broadcast on American Broadcasting Company, ABC. The nightly hour-long show debuted on January 26, 2003, at Hollywood Masonic Temple in Hollywood, Los ...

References

External links

What Is Tetralogy of Fallot?
at the

National Institutes of Health The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...

Understanding your child's heart: Tetralogy of Fallot
by the

British Heart Foundation The British Heart Foundation (BHF) is a cardiovascular research charity in the United Kingdom. It funds medical research related to heart and circulatory diseases and their risk factors, and runs influencing work aimed at shaping public policy ...

{{DEFAULTSORT:Tetralogy Of Fallot Congenital heart defects Medical pentads Wikipedia medicine articles ready to translate Fallot, Tetralogy of

Signs and symptoms

Tet spells

Cause

Pathophysiology

Four malformations

Additional anomalies

Diagnosis

Chest radiograph

Electrocardiogram

Echocardiogram

Genetics

Treatment

Tet spells

Total surgical repair

Palliative surgery

Approaches to surgical repair

Complications

Short-term

Long-term

Pregnancy

Prognosis

Comorbidities

Epidemiology

History

Related disorders

Atrial septal defects

Ventricular septal defects

Atrioventricular septal defect

Mitral valve stenosis

Notable cases

See also

References

External links