Tetralogy of Fallot

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Fahimeh Shojaei, M.D., Priyamvada Singh, M.B.B.S. [2],Kristin Feeney, B.S. [3]

Tetralogy of Fallot was first discovered by Etienne Fallot, a French ohysician in 1888. Tetralogy of Fallot is a congenital heart defect which classically has four anatomical components: obstruction to right ventricular outflow, right ventricular hypertrophy, ventricular septal defect, and overriding of aorta. It accounts for approximately 10% of all forms of congenital heart disease. It is the most common cause of cyanosis in children over one year of age (blue baby syndrome). It is understood that tetralogy of fallot is the result of improper positioning of the outlet septum. In the normal heart, the outlet septum is an indistinguishable component of the crista supraventricularis that communicates with the septomarginal trabeculae to divide the right and left ventricular cavities. In Tetralogy of Fallot, proper ventricular septation is perturbed by anterocephalad displacement of the outlet septum relative to the septomarginal trabecula. These features include a ventricular septal defect, overriding aorta, pulmonary stenosis, and right ventricular hypertrophy. The obstruction of right ventricular outflow in tetralogy of Fallot causes blood to shunt or flow from the right to left side of heart through the ventricular septal defect. This causes right ventricular hypertrophy and eventual right sided heart failure. There is flow of deoxygenated venous blood from the right side of the heart to the systemic circulation resulting in cyanosis. Common causes of tetralogy of Fallot may include: Alcoholism in the mother, diabetes, pregnancy after the age of 40, rubella or other viral illnesses during pregnancy, phenylketonuria (PKU) in the mother, fetal hydantoin syndrome, and fetal carbamazepine syndrome. On the basis cyanosis, tetralogy of Fallot must be differentiated from total anomalous pulmonary venous connection, tricuspid atresia, transposition of the great vessels, and truncus arteriosus. Tetralogy of Fallot occurs in approximately 30 to 60 per 100,000 births. Tetralogy of Fallot represents 5-7% of congenital heart defects. The majority of cases are thought to be sporadic and are not familial. Tetralogy of Fallot occurs slightly more often in males than in females. Common risk factors in the development of tetralogy of Fallot include: Alcoholism in the mother, diabetes, and pregnancy after the age of 40. According to the Canadian Cardiovascular Society/Canadian Pediatric Cardiology Association, screening for tetralogy of Fallot by pulse oxymetry is recommended for all newborns. The prognosis of patients with repaired tetralogy of Fallot has improved over the years and these patients now have the potential to lead normal lives. As these patients grow, there may be leakage of the repaired pulmonic valve. There may be a persistent risk of sudden cardiac death. Echocardiography is the gold standard test for the diagnosis of tetralogy of fallot. Echocardiography establishes the initial diagnosis of tetralogy of Fallot, and is useful in evaluating the hemodynamic abnormalities that are present. Right-to-left shunting through the VSD can be visualized by color doppler imaging, and the severity of right ventricular outflow tract obstruction can be determined by spectral doppler measurements. Echocardiography may be helpful in the diagnosis of tetralogy of fallot. Findings on an echocardiography diagnostic of tetralogy of fallot include ventricular septal defect, right ventricular outflow tract obstruction, and overriding aorta. Repair of tetralogy of Fallot reduces mortality. we can either perform palliative surgery which involves forming an anastomosis between the subclavian artery and the pulmonary artery. 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 greatly relieving symptoms in patients or total surgical repair which involves making incisions into the heart muscle, relieving the right ventricular outflow tract stenosis by careful resection of muscle, repairing the VSD using a Gore-Tex or Dacron patch or a homograft. Additional reparative or reconstructive work may be done on patients as required by their particular anatomy.The repair could be done by either of the approaches i.e.transatrial or transpulmonary.

Tetralogy of Fallot was first discovered by Etienne Fallot, a French ohysician in 1888.

There is no established system for the classification of tetralogy of Fallot.

Tetralogy of Fallot is a congenital heart lesion characterized by a constellation of four morphologic abnormalities present in the newborn heart. It is understood that tetralogy of fallot is the result of improper positioning of the outlet septum. In the normal heart, the outlet septum is an indistinguishable component of the crista supraventricularis that communicates with the septomarginal trabeculae to divide the right and left ventricular cavities. In Tetralogy of Fallot, proper ventricular septation is perturbed by anterocephalad displacement of the outlet septum relative to the septomarginal trabecula. These features include a ventricular septal defect, overriding aorta, pulmonary stenosis, and right ventricular hypertrophy. The obstruction of right ventricular outflow in tetralogy of Fallot causes blood to shunt or flow from the right to left side of heart through the ventricular septal defect. This causes right ventricular hypertrophy and eventual right sided heart failure. There is flow of deoxygenated venous blood from the right side of the heart to the systemic circulation resulting in cyanosis.

Common causes of tetralogy of Fallot may include: Alcoholism in the mother, diabetes, pregnancy after the age of 40, rubella or other viral illnesses during pregnancy, phenylketonuria (PKU) in the mother, fetal hydantoin syndrome, and fetal carbamazepine syndrome.

On the basis cyanosis, tetralogy of Fallot must be differentiated from total anomalous pulmonary venous connection, tricuspid atresia, transposition of the great vessels, and truncus arteriosus.

Tetralogy of Fallot occurs in approximately 30 to 60 per 100,000 births. Tetralogy of Fallot represents 5-7% of congenital heart defects. The majority of cases are thought to be sporadic and are not familial. Tetralogy of Fallot occurs slightly more often in males than in females.

Common risk factors in the development of tetralogy of Fallot include: Alcoholism in the mother, diabetes, and pregnancy after the age of 40.

According to the Canadian Cardiovascular Society/Canadian Pediatric Cardiology Association, screening for tetralogy of Fallot by pulse oxymetry is recommended for all newborns.

The prognosis of patients with repaired tetralogy of Fallot has improved over the years and these patients now have the potential to lead normal lives. As these patients grow, there may be leakage of the repaired pulmonic valve. There may be a persistent risk of sudden cardiac death.

Echocardiography is the gold standard test for the diagnosis of tetralogy of fallot.

Patients with tetralogy of Fallot may have a positive history of alcoholism, diabetes, Poor nutrition in mother in mother. Common symptoms of tetralogy of Fallot include sudden, marked bluish skin (tet spell), dyspnea on exertion, difficulty in feeding, failure to gain weight, failure to thrive, retarded growth and physical development, and hemoptysis.

Patients with tetralogy of Fallot usually appear small due to a failure to thrive. Physical examination of patients with tetralogy of Fallot is usually remarkable for cyanosis, systolic thrill, systolic ejection murmur, and Clubbing.

Laboratory findings consistent with the diagnosis of tetralogy of fallot include diminished oxygen saturation, hematocrit between 65% to 70%, and low platelet count and coagulation factors.

An ECG may be helpful in the diagnosis of tetralogy of Fallot. Findings on an ECG suggestive of tetralogy of Fallot include right axis deviation, right ventricular hypertrophy, wide QRS, and right bundle branch block.

An x-ray may be helpful in the diagnosis of tetralogy of fallot. Findings on an x-ray diagnostic of tetralogy of fallot include normal or decreased pulmonary vascularity, concave pulmonary artery segment, “boot-like” heart, and right sided aortic arch.

Echocardiography establishes the initial diagnosis of tetralogy of Fallot, and is useful in evaluating the hemodynamic abnormalities that are present. Right-to-left shunting through the VSD can be visualized by color doppler imaging, and the severity of right ventricular outflow tract obstruction can be determined by spectral doppler measurements. Echocardiography may be helpful in the diagnosis of tetralogy of fallot. Findings on an echocardiography diagnostic of tetralogy of fallot include ventricular septal defect, right ventricular outflow tract obstruction, and overriding aorta.

Computed tomography can be helpful as a diagnostic tool in conditions where the echocardiographic findings are inconclusive.

Magnetic resonance imaging can be helpful as a diagnostic tool in patients in whom the echocardiographic findings are inconclusive.

There are no other imaging findings associated with tetralogy of fallot.

There are no other diagnostic studies associated with tetralogy of fallot.

Although operative repair of tetralogy of Fallot is definitive, medical therapy can be used to manage hypoxic or tet spells. Tet spells cause acute hypoxia and may be treated with beta blockers, morphine, phenylephrine, and oxygen.

Repair of tetralogy of Fallot reduces mortality. we can either perform palliative surgery which involves forming an anastomosis between the subclavian artery and the pulmonary artery. 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 greatly relieving symptoms in patients or total surgical repair which involves making incisions into the heart muscle, relieving the right ventricular outflow tract stenosis by careful resection of muscle, repairing the VSD using a Gore-Tex or Dacron patch or a homograft. Additional reparative or reconstructive work may be done on patients as required by their particular anatomy.The repair could be done by either of the approaches i.e.transatrial or transpulmonary.

There are no established measures for the primary prevention of Tetralogy of Fallot.

According to the Canadian Cardiovascular Society/Canadian Pediatric Cardiology Association, screening for tetralogy of Fallot by pulse oxymetry is recommended for all newborns.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Fahimeh Shojaei, M.D., Priyamvada Singh, M.B.B.S. [2], Assistant Editor-In-Chief: Kristin Feeney, B.S. [3]

Tetralogy of Fallot was first discovered by Etienne Fallot, a French ohysician in 1888.

• Tetralogy of Fallot was first discovered by Etienne Fallot, a French ohysician in 1888.^[1][2][3]
• Many physicians had described morphologic anomalies of heart related to tetralogy of fallot such as:
  • Niels Stensen (1671)
  • Eduard Sandifort (1777)
  • William Hunter (1784)
  • J. P. Farre (1814)
  • Thomas Bevill Peacock (1846)
  • Thomas Bevill Peacock’s (1866)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

There is no established system for the classification of tetralogy of Fallot.

There is no established system for the classification of tetralogy of Fallot.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Fahimeh Shojaei, M.D., Priyamvada Singh, M.B.B.S. [2], Keri Shafer, M.D. [3]; Omar Toubat; Assistant Editor-In-Chief: Kristin Feeney, B.S. [4]

Tetralogy of Fallot is a congenital heart lesion characterized by a constellation of four morphologic abnormalities present in the newborn heart. It is understood that tetralogy of fallot is the result of improper positioning of the outlet septum. In the normal heart, the outlet septum is an indistinguishable component of the crista supraventricularis that communicates with the septomarginal trabeculae to divide the right and left ventricular cavities. In Tetralogy of Fallot, proper ventricular septation is perturbed by anterocephalad displacement of the outlet septum relative to the septomarginal trabecula. These features include a ventricular septal defect, overriding aorta, pulmonary stenosis, and right ventricular hypertrophy. The obstruction of right ventricular outflow in tetralogy of Fallot causes blood to shunt or flow from the right to left side of heart through the ventricular septal defect. This causes right ventricular hypertrophy and eventual right sided heart failure. There is flow of deoxygenated venous blood from the right side of the heart to the systemic circulation resulting in cyanosis.

The normal physiology of heart development can be understood as follows:

• Subsequent to the lateral folding and looping events that give rise to the primitive heart tube are a series of complex septation processes that will ultimately complete morphogenesis of the four chambered heart.
• The goals of cardiac septation are two-fold:
  • To create four distinct cardiac chambers
  • To correctly position the great vessels relative to these chambers

• It is understood that tetralogy of fallot is the result of improper positioning of the outlet septum.^[1][2][3]
• In the normal heart, the outlet septum is an indistinguishable component of the crista supraventricularis that communicates with the septomarginal trabeculae to divide the right and left ventricular cavities.
• In Tetralogy of Fallot, proper ventricular septation is perturbed by anterocephalad displacement of the outlet septum relative to the septomarginal trabecula.
• The direct consequence of this misalignment is an overriding aortic orifice and a ventricular septal defect, resulting in an intracardiac right to left shunt of blood.
• In addition, anterocephalad displacement of the outlet septum indirectly predisposes the pulmonary trunk to stenosis in the setting of septoparietal trabecular hypertrophy.
• Together, the displacement of the outlet septum coupled with the hypertrophic arrangement of the septoparietal trabeculae account for the three anatomical cardinal defects in Tetralogy of Fallot – aortic dextroposition, interventricular communication (VSD), and pulmonary stenosis.
• The fourth defect – right ventricular hypertrophy – is a hemodynamic consequence of these three morphologic changes, as the right ventricle physiologically adapts to the increased resistance of a stenotic pulmonary trunk.

This defect in outlet septum in turn leads to the four characteristic features: A: Pulmonic Stenosis Pulmonic stenosis is a right ventricular outflow tract obstruction A narrowing at (valvular stenosis, seen in approximately 20-25% case) or just below (infundibular stenosis, seen in around 50% of cases) the pulmonary valve. The stenosis is mostly the result of hypertrophy of the septoparietal trabeculae,[4] however the deviated outlet septum is believed to play a role. The stenosis is the major cause of the malformations, with the other associated malformations acting as compensatory mechanisms to the pulmonic stenosis.[5] 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.[6] Tetralogy of Fallot with pulmonary atresia or pseudotruncus arteriosus is a severe variant in which there is complete obstruction of the right ventricular outflow tract and absence of the pulmonary trunk. In these individuals, there is complete right-to-left shunting of blood. The lungs are perfused via extensive collaterals from the systemic arteries. B: Overriding Aorta Overriding aorta is defined as when the aortic valve is not restricted to the left ventricle, thus having biventricular connections. The aortic root can be moved anteriorly or override the septal defect, but it is still to the right of the root of the pulmonary artery. The degree of override is quite variable, with 5-95% of the valve being connected to the right ventricle.[4] C: Ventricular Septal Defect Ventricular septal defect is a hole between the two bottom chambers (ventricles) of the heart. The defect is centered around the outlet septum, the most superior aspect of the septum, and in the majority of cases is single and large. In some cases septal hypertrophy can narrow the margins of the defect.[4] D: Right Ventricular Hypertrophy The right ventricle is more muscular than normal, causing a characteristic coeur-en-sabot (boot-shaped) appearance as seen by chest x-ray. Due to the misarrangement of the external ventricular septum, the right ventricular wall increase 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 generally increases with age.[7] There is anatomic variation between the hearts of individuals with tetralogy of Fallot. The degree of right ventricular outflow tract obstruction varies between patients and is generally determines clinical symptoms and disease progression. {{#ev:youtube|ACRfFkxow7w}}

• Embryologic studies show that tetralogy of Fallot is a result of anterior misalignment of the conal septum, resulting in the clinical combination of a ventricular septal defect (VSD), pulmonary stenosis, and an overriding aorta.
• Right ventricular hypertrophy is secondary to this combination of abnormalities, which causes resistance to blood flow from the right ventricle.
• Tetralogy of Fallot results in cyanosis, (hypoxia or low oxygenation) of the blood due to mixing of deoxygenated venous blood from the right ventricle with oxygenated blood in the left ventricle through the ventricular septal defect and preferential flow of both oxygenated and deoxygenated blood from the ventricles through the aorta because of obstruction to flow through the pulmonary valve.
• This is known as a right-to-left shunt.
• If pulmonary blood flow is dramatically reduced, pulmonary blood flow may depend on a patent ductus arteriosus (PDA) or bronchial collaterals.
• If obstruction of the right ventricular outflow tract is minimal, the intracardiac shunt may be mostly from left to right, and this may result in what is termed a pink tet or pink tetralogy.
• Although cyanosis is absent on clinical exam, laboratory testing will often show systemic oxygen desaturation.
• Children with tetralogy of Fallot may develop acute severe cyanosis or hypoxic tet spells.
• The mechanism underlying these episodes is not entirely clear, but may be due to spasm of the infundibular septum and the right ventricular outflow tract.
• Whatever the mechanism, there is an increase in resistance to blood flow to the lungs with increased preferential flow of desaturated blood to the systemic circulation.
• The child will often squat during a tet spell to improve venous return to the right side of the heart.
• Squatting increases the systemic vascular resistance and thereby shunts flow to pulmonary circuit.
• These spells can be fatal, and can occur in patients who are not cyanotic.

• Genes involved in the pathogenesis of tetralogy of fallot include:^{[8][9][10][11][12][13][14]}
  • The cellular processes that underlie cardiogenesis are extensively regulated in the developing heart.
  • Proper cardiac development requires the complex orchestration of cardiac transcription factors and signaling pathways in a spatiotemporal specific manner.
  • Previous genetic studies demonstrated that mutations in numerous genes encoding cardiac transcription factors and cell signaling proteins have a role in the development of Tetralogy of Fallot.
  • Specifically, heterozygous mutations in NKX2-5, HAND1, TBX5, and GATA4 have been reported in familial forms of disease.
  • Many of these single gene mutations result in haploinsufficiency and suggest a dose dependent relationship between genetic expression and disease.
  • While the mechanistic basis of this relationship is currently poorly understood, it is hypothesized that disruption of the direct protein–protein interactions that allow these transcription factors to work synergistically impedes the activation of downstream targets and signaling pathways central to cardiac morphogenesis.
  • In addition, recent whole-exome sequencing investigations have introduced a novel role for epigenetic dysregulation in the pathogenesis of Tetralogy of Fallot.
  • Aberrant epigenetic modifications are thought to provide an alternative mechanism to perturb normal spatiotemporal expression of these essential developmental genes.

• Conditions associated with tetralogy of fallot include:^{[15][16][17][18]}
  • Left superior vena cava
  • Anomalies of the mitral valve
  • Anomalies of the tricuspid valve
  • Stenosis of the left pulmonary artery, in 40% of patients
  • A bicuspid pulmonary valve, in 40% of patients
  • Right sided aortic arch, in 25% of patients
  • Coronary artery anomalies, in 10% of patients
  • An atrial septal defect, in which case the syndrome is sometimes called a pentalogy of Fallot.
  • An atrioventricular septal defect
  • Partially or totally anomalous pulmonary venous return
  • Forked ribs and scoliosis
  • Associated abnormalities include cleft lip, cleft palate, hypospadias, skeletal and craniofacial abnormalities.

• On gross pathology characteristic features findings of tetralogy of fallot include:
  • Right ventricular hypertrophy
  • VSD
  • Overriding aorta
  • Subpulmonic stenosis

There is no characteristic findings of tetralogy of fallot on microscopic histopathological analysis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Fahimeh Shojaei, M.D., Priyamvada Singh, M.B.B.S. [2], Keri Shafer, M.D. [3]; Assistant Editor-In-Chief: Kristin Feeney, B.S. [4]

Common causes of tetralogy of Fallot may include: Alcoholism in the mother, diabetes, pregnancy after the age of 40, rubella or other viral illnesses during pregnancy, phenylketonuria (PKU) in the mother, fetal hydantoin syndrome, and fetal carbamazepine syndrome.

Common causes of tetralogy of Fallot may include:

• Alcoholism in the mother
• Diabetes
• Pregnancy after the age of 40
• Rubella or other viral illnesses during pregnancy
• Phenylketonuria (PKU) in the mother
• Fetal hydantoin syndrome
• Fetal carbamazepine syndrome

Less common causes of tetralogy of Fallot may include:

• Clomifene
• Poor nutrition during pregnancy

Genetic causes of tetralogy of Fallot may include:

• There is a high incidence of chromosomal disorders in children with tetralogy of Fallot.^[1][2]
• Tetralogy of Fallot is associated with:

• Down syndrome
• DiGeorge syndrome (a 22q11.2 deletion, a condition associated with heart defects, hypocalcemia, and immune deficiency) A gene polymorphism at the methylenetetrahydrofolate reductase (MTHFR) region has been associated with tetralogy of Fallot.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Eiman Ghaffarpasand, M.D. [2], Fahimeh Shojaei, M.D., Priyamvada Singh, M.B.B.S. [3], Keri Shafer, M.D. [4]; Assistant Editor-In-Chief: Kristin Feeney, B.S. [5]

On the basis cyanosis, tetralogy of Fallot must be differentiated from total anomalous pulmonary venous connection, tricuspid atresia, transposition of the great vessels, truncus arteriosus.

Tetralogy of Fallot must be differentiated from other diseases that cause cyanosis:

Diseases			Cyanosis		Clinical manifestations						Para-clinical findings							Gold standard	Additional findings
					Symptoms			Physical examination
											Lab Findings				Imaging
			Peripheral	Central	Dyspnea	Fever	Chest pain	Clubbing	Peripheral edema	Auscultation	CBC	ABG	Electrolytes	Other	X-ray	CT scan	Other
Pulmonary diseases	Airway disorder	Severe croup[1]	+	–	+	+/-	–	–	–	Stridor	Lymphocytosis	Normal	Normal	–	Steeple sign	Normal	Distended hypopharynx during inspiration	Clinical findings	Intercostal and subcostal retraction, Barking cough
		Epiglottitis[2]	+	–	+	+	–	–	–	Stridor	Leukocytosis with neutrophilia	Normal	Normal	–	Thumb sign	Normal	–	Laryngoscopy	Muffled voice, Drooling
		Foreign body aspiration[3]	+	–	+	–	+/-	–	–	Decreased breath sounds, Wheezing	Normal	Normal	Normal	–	Hyperinflation, Atelectasis, Objects	Foreign body entrapment with edema or granulation tissue	–	Bronchoscopy	Mediastinitis
		Bacterial tracheitis[4]	+	–	+	+	+	–	–	Inspiratory stridor	Leukocytosis	Normal	Normal	Blood culture, Gram stain	Irregular tracheal margin	Normal	Steeple sign (confusing)	Laryngotracheobronchoscopy	Brassy cough, Hoarseness
		Sleep apnea[5]	–	+	+	–	–	–	–	Normal	Polycythemia	↓O2, ↑CO2	Normal	–	Normal	Normal	Polysomnography	Polysomnography	Nightmares, Snoring
		Chronic bronchitis[6]	–	+	+	+/-	+/-	+	–	Rales, crackles, Wheeze	Leukocytosis	↓O2, ↑CO2, Respiratory acidosis	Hypokalemia, Hypernatremia	Gram stain of sputum	Elongated heart, Flattened diaphragms, Prominent hilar vasculature	Bronchial wall thickening with increased bronchovascular markings	–	HRCT	Productive cough, Chest tightness
		Atelectasis[7]	–	+	+	–	+	–	–	Localized diminished breath sounds, Wheeze	Leukocytosis	↓O2, ↑CO2, Respiratory acidosis	Normal	–	Localized increased opacity, Deviation toward the atelectasis	Local crowding of pulmonary vessels and bronchi	MRI for distinguishing obstructive from non-obstructive	HRCT	Cough, Shallow breathing
	Parenchymal disorder	Alveolitis[8]	+/-	+	+	+	+	+/-	–	Wheeze, Crackles	Leukocytosis, Eosinophilia	↓O2, ↑CO2	Normal	↑ESR, ↑CRP	Scattered opacities, Fine reticulation	Homogeneous ground-glass opacity	–	HRCT PLUS Clinical findings	Malaise, Chills, Headache
		Pneumonia[9]	–	+	+	+	+	+/-	–	Rales, Crackles, Wheeze, Pleural friction rub	Leukocytosis with neutrophilia	Normal	Hyponatremia	–	Entire lobe consolidated, Air bronchograms	Focal ground-glass opacity	–	HRCT	Tachycardia, Bradycardia (Legionella)
		Asthma (Late)[10]	–	+	+	–	+/-	+/-	–	End expiratory wheeze	Eosinophilia	↓O2, ↑CO2	Normal	↑ IgE	Atelectasis	Allergic bronchopulmonary aspergillosis, Bronchiectasis	–	Spirometry before and after bronchodilator	Triad of asthma, nasal polyps, and rash is indicative of aspirin sensitivity.
		Cystic fibrosis[11]	+	–		+/-	+/-	+	–	Wheeze, Crackles	Normal	↓O2, ↑CO2	Increased sweat chloride	Sweat chloride test	Hyperinflation, Nodules	Peribronchial thickening, Bronchiectasis	–	Sweat chloride test	Absent vas deferens
		COPD (Severe emphysema)[12]	+	–	+	+/-	+	+/-	+/-	Reduced breath sounds, Wheeze, Inspiratory crackles	Polycythemia	↓O2, ↑CO2	Normal	Alpha 1-antitrypsin test	Elongated heart, Flattened diaphragms, Prominent hilar vasculature	Bullae	–	HRCT	Pulmonary hypertension, Right heart failure
		Tuberculosis[13]	–	+	+	+	+	+/-	–	Reduced breath sounds, Wheeze, Inspiratory crackles	Leukocytosis, ↑Lymphocyte	↓O2, ↑CO2	Hyponatremia, Hyperkalemia, Hypochloremia	PPD, interferon-gamma release assay (IGRA)	Dense, homogeneous parenchymal consolidation	Nodules with low-density centers and rim enhancement	Fluorodeoxyglucose positron emission tomography/CT (FDG PET/CT)	Sputum culture, QuantiFERON-TB Gold (QFT)	Loss of appetite, Night sweats
		Pulmonary fibrosis[14]	–	+	+	–	+	+	–	Inspiratory crackles	Anemia	↓O2, ↑CO2	Normal	Matrix metalloproteinases (MMPs)	Honeycombing	Traction bronchiectasis, Interlobular septal thickening	HRCT	HRCT	Fatigue, Weight loss
		Pneumoconiosis[15]	–	+	+	–	+/-	+/-	–	End expiratory wheeze	Leukocytosis, Anemia	↓O2, ↑CO2, Respiratory acidosis	Hyper/Hypocalcemia, Hypermagnesemia	–	Small to large round nodular opacities	Diffuse distribution of small nodules	MRI and PET-CT scan	CT/HRCT scan	Tightness in the chest
		Lung cancer[16]	–	+	+	–	+/-	+	–	Absence of breath sounds, Stridor, Wheezing	Leukocytosis, Anemia	↓O2, ↑CO2	Hyponatremia	↑CRP, ↑ESR	Pulmonary nodule or mass, Mediastinal widening Hilar lymphadenopathy	Massive lymphadenopathy, Direct mediastinal invasion	MRI, PET-CT scan, Bronchoscopy	Low dose computed tomography scan (LDCT)	Weight loss, Loss of appetite
		Acute respiratory distress syndrome[17]	–	+	+	+/-	+	–	–	Inspiratory crackles	Leukopenia/Leukocytosis	↓O2, ↓CO2, Respiratory alkalosis	Hyponatremia, Hyperkalemia	↑BNP, ↑Von Willebrand factor (VWF)	Bilateral pulmonary infiltrates (patchy to diffuse)	Emphysema, Pneumothorax and pneumomediastinum, Mediastinal lymphadenopathy	Invasive Hemodynamic Monitoring (PCWP), Bronchoscopy	Chest CT scan	Tachypnea, Muscle weakness
	Pulmonary vascular disorders	Massive pulmonary embolism[18]	+	–	+	+/-	+	–	+/-	Reduced breath sounds, Crackles, Loud P2	Leukocytosis	↓O2, ↑CO2, Respiratory acidosis	Normal	D-dimer, BNP	Fleischner sign, Hampton hump, Westermark sign, Pleural effusion	Filling defects in the pulmonary vasculature	Spiral CT pulmonary angiogram	Spiral CT pulmonary angiogram	Tachycardia, Shock, Pulmonary hypertension
		Pulmonary arterio-venous malformation[19][20][21]	–	+	+	–	+	+	–	Pulmonary bruit	Normal	↓O2, ↑CO2, Respiratory acidosis	Normal	–	One or more rounded or multilobular opacities	Connecting vessel in hilum	Magnetic resonance angiography, Echocardiography	Contrast enhanced magnetic resonance angiography	Cerebral arteriovenous malformation
		Pulmonary hypertension[22]	–	+	+	–	+/-	+/-	–	Tricuspid regurgitation murmur, Pulmonic insufficiency murmur	Mild anemia	↓O2, ↑CO2	Hypernatremia	↑BNP, ↑ANP	Right deviated cardiac apex, Prominent pulmonary artery	Ill-defined nodules, Interlobular septal thickening	CT pulmonary angiography (CTPA), MRA	Cardiac catheterization (PCWP)	Fatigue, Inability to exercise
Chest wall disorders		Flail chest[23]	+	–	+	–	+	–	–	Normal	Normal	↓O2, ↑CO2	Normal	–	≥3 adjacent ribs with segmental fractures, >5 adjacent rib fractures	Normal	–	CXR	Bruises over chest
		Pneumothorax[24]	+	–	+	–	+	–	–	Diminished breath sounds	Normal	↓O2, ↑CO2	Normal	–	No lung marking on one side, Collapsed lung	Loculated air in thoracic cavity	M-mode ultrasonography	Chest CT scan	Tachypnea
Disease			Peripheral	Central	Dyspnea	Fever	Chest pain	Clubbing	Peripheral edema	Auscultation	CBC	ABG	Electrolytes	Other	X-ray	CT scan	Other	Gold standard	Additional findings
Cardiac diseases	Congenital disorders	Atrioventricular canal defect[25]	+/-	+	+	–	+/-	+/-	–	Wheezing,Holosystolic or systolic ejection murmur	Normal	Normal	Normal	Pulse oximetry	Cardiomegaly, Increased pulmonary vascular markings	Normal	Echocardiography, MRI	Echocardiography	Tachypnea, Lack of appetite, Pale skin color, Excessive sweating
		Ebstein anomaly[26]	–	+	+/-	–	+/-	–	–	Loud S1	Normal	Normal	Normal	Pulse oximetry	Cardiomegaly, “Box shape” heart	Apical displacement of the septal and posterior leaflets of the tricuspid valve	“Atrialisation” of the right ventricle in MRI, Tricuspid regurgitation in echocardiography	Echocardiography	Fatigue, Palpitations
		Tetralogy of Fallot[27]	–	+	+/-	–	+/-	–	–	Harsh systolic murmur	Normal	Normal	Normal	Pulse oximetry	“Boot-shaped” heart with an upturned cardiac apex	Aortopulmonary collateral vessels	Peripheral pulmonary stenosis and atresia in echocardiography	Echocardiography	Fainting, Palpitation
		Pulmonic stenosis[28]	–	+	+	–	+	+/-	–	Crescendo-decrescendo ejection murmur	Schistocyte	↓O2	Normal	Pulse oximetry	Right ventricular hypertrophy, Dilated main pulmonary artery	Stenotic segment, Post stenotic dilatation	Severity of the stenosis by velocity encoded phase contrast (VEC) cine sequences	Echocardiography	Fainting, Palpitation
		Total anomalous pulmonary venous connection[29]	–	+	+	–	+/-	+/-	–	Systolic murmur over the pulmonary area	Normal	↓O2	Normal	Pulse oximetry	Snowman sign	Anomalous venous return	Blind ended left atrium with no connecting veins in echocardiography	Echocardiography	Pounding heart, Weak pulse, Extreme sleepiness
		Transposition of the great vessels[30]	–	+	+	–	+/-	+/-	–	Diastolic and Systolic murmur	Normal	↓O2	Normal	Pulse oximetry	Cardiomegaly with narrow superior mediastinum (egg on a string sign)	Abnormal great vessel anatomy	Flow dynamics on Steady-state free precession (SSFP) MRI	Echocardiography	Lack of appetite, Poor weight gain
		Truncus arteriosus[31]	–	+	+/-	–	+/-	+/-	–	Holosystolic or ejection type murmur	Normal	↓O2	Normal	Pulse oximetry	Moderate cardiomegaly, pulmonary plethora, Widened mediastinum	Single cardiac trunk	Anomalous anatomy in MRI	Echocardiography	Fatigue, Sweating, Pale or cool skin
		Patent ductus arteriosus[32]	–	+	+/-	–	+/-	+/-	–	Continuous machinery murmur	Normal	↓O2, ↑CO2	Normal	Pulse oximetry	Cardiomegaly, Aortopulmonary window obsecuration	Tortuous morphology of ductus (Krichenko classification)	Spiral CT pulmonary angiogram	Echocardiography	Failure to thrive, Respiratory distress
	Acquired disorders	Heart failure[33]	+	–	+	+/-	+	–	+	Coarse crackles, S3	Anemia	↓O2, ↑CO2	Hyponatremia, Hypokalemia, Hypomagnesemia	Elevated BNP	Pleural effusion, Cardiomegaly Kerley B lines	Normal	Radioisotope scan	Echocardiography	Generalized edema, Hepatomegaly
		Valvular heart disease[34]	+	–	+	–	–	–	+	Murmurs	Schistocyte	Normal	Normal	Hyperthyroidism	Valve calcification	Normal	Valvular dysfunction in echocardiography	Echocardiography	Syncope, Palpitation
		Myocardial infarction[35]	–	+	+	+/-	+	–	–	S3 and S4	Normal	Normal	Hyponatremia, Hypokalemia	Elevated troponin I and CKMB	Rolling out other causes	Coronary luminal narrowing in CT perfusion scan	Wall motion abnormality in echocardiography	Cardiac troponin I	Dizziness, Fatigue, Lightheadedness, Cold sweat
		Cardiogenic shock[36]	+/-	+	+	–	–	–	+	Muffled heart sound	Anemia	↓O2, ↑CO2	Hyperkalemia	↓PaO2 in pulse oximetry	Normal	Normal	Echocardiography	Clinical findings	Tachypnea, Palpitation, Hypotension, Weak pulse
		Cardiomyopathy[37]	–	+	+	–	+	+	+	S3 and S4	Lymphocytosis	↓O2, ↑CO2	Normal	↓PaO2 in pulse oximetry	Enlarged left ventricle and atria, Pulmonary edema	Normal	MRI	Endomyocardial biopsy	Arrhythmia, Bloating
		Heart tumors[38]	–	+	+	–	+/-	+/-	+/-	Early diastolic tumor plop	Normal	Normal	Normal	Mild ↓PaO2 in pulse oximetry	Calcification in lateral view	Intracardiac mass	Echocardiography	Histologic diagnosis (biopsy)	Syncope, Weight loss
		Mitral Stenosis[39]	–	+	+	–	+/-	+/-	+/-	Diastolic murmur	Normal	Normal	Normal	Mild ↓PaO2 in pulse oximetry	Left atrial enlargement, Mitral annular calcification	Secondary pulmonary hemosiderosis	Velocity-encoded cine-magnetic resonance imaging (VEC-MRI)	Echocardiography	Dizziness, Hemoptysis
Vascular disease	Arterial disorders	Acrocyanosis[40]	+	–	+/-	–	–	+	–	Normal	Anemia, Leukocytosis	↓O2, ↑CO2	Hypercalcemia	↓PaO2 in pulse oximetry	Normal	Normal	–	Clinical findings	Brittle nails, Telangiectasia
		Arterial embolism[41]	+	–	+	–	+	+/-	–	Normal	Normal	Normal	Hyperkalemia	↓PaO2 in pulse oximetry	Normal	Normal	Transesophageal echocardiography (TEE)	Clinical findings	Headache, Decreased sensation
		Raynaud’s Phenomenon[42]	+	–	–	–	–	+	–	Normal	Polycythemia	↓O2	Normal	Mild ↓PaO2 in pulse oximetry	Normal	Normal	–	Clinical findings	Sensitivity to cold, Decreased sensation
	Venous disorders	Superior vena cava obstruction[43]	+	–	+/-	–	+/-	+/-	+	Normal	Polycythemia	↓O2	Normal	↓PaO2 in pulse oximetry	Superior mediastinal widening, Right hilar prominence	Thrombosis, Mediastinal mass or lymphadenopathy, Associated lung mass	–	Chest CT scan	Headache, Facial swelling
		Venous stasis[44]	+	–	–	–	–	+/-	+	Normal	Polycythemia	↓O2	Hypercalcemia	Normal	Normal	Normal	Color-flow duplex ultrasound	Color-flow duplex ultrasound	Leg swelling, Pain during walking, Leg ulcers
Disease			Peripheral	Central	Dyspnea	Fever	Chest pain	Clubbing	Peripheral edema	Auscultation	CBC	ABG	Electrolytes	Other	X-ray	CT scan	Other	Gold standard	Additional findings
Hematologic diseases		Methemoglobinemia[45]	–	+	+	+/-	+	–	–	Wheezing	Anemia, Methemoglobinemia	Normal PaO2, ↑SaO2, “Saturation gap”	Normal	↓SaO2 in pulse oximetry	Normal	Normal	Echocardiography for ruling out other causes	Co-oximetry, ABG paired with pulse oximetry. Serum methemoglobin levels	Headache, Altered mental status, Delirium, Seizure, Coma
		Polycythemia[46]	+	+	+	+/-	+/-	+	–	Normal	↑RBC, ↑WBC, ↑HGB, ↑Plt	↓O2	Hyperkalemia	↑Leukocyte alkaline phosphatase, ↑Ferritin, ↑Erythropoietin	AVM, COPD, pulmonary hypertension	Normal	Abdominal ultrasound or renal vascular studies for ruling out renal artery stenosis	RBC mass (RCM) and plasma volume measurement	Itchiness, Headache. Dizziness. Blurred vision
Neurological disease		Breath-holding spells[47]	–	+	+	–	+/-	–	–	Wheezing	Hypochromic microcytic anemia	↓O2	Hypocalcemia, Hypokalemia	Iron deficiency	Ruling out foreign body aspiration	Normal	EEG monitoring	Clinical findings	Fainting, Twitching muscles, Seizure
		Seizure[48]	–	+	+	+/-	–	–	–	Normal	Normal	↓O2, ↑CO2	Hyponatremia, Hypo/Hypercalcemia	↑CPK, ↑LDH,	Normal	Normal	EEG	EEG	Fainting, Tonic-clonic movements
		Coma[49]	–	+	–	–	–	–	+/-	Wheezing	Normal	↓O2, ↑CO2	Normal	–	Underlying disease	Underlying disease	–	Glasgow Coma Scale (GCS)	Depressed brainstem reflexes, Agonal breathing
		Head trauma[50]	–	+	+	–	–	–	–	Normal	Normal	↓O2, ↑CO2	Normal	–	Skull fracture	Intracranial hemorrhage	MRI	CT scan	Nausea, Hypertension, Bradycardia,Tachypnea
Miscellaneous		High altitude exposure[51]	+/-	+	+	–	+/-	+	–	Wheezing	Polycythemia	↓O2, ↓CO2, Respiratory alkalosis	Hyperphosphatemia, Hypercalcemia, Hyponatremia, Hypokalemia, Hypomagnesemia	Decreased bicarbonate	Central interstitial edema	Pulmonary consolidation	–	Hypoxic challenge test	Dizziness, Coma, Death
		Septic shock[52]	+	–	+	+	+/-	–	–	Rales, crackles, Wheeze, Pleural friction rub	Leukocytosis with neutrophilia	↓O2, ↑CO2, Metabolic acidosis	Hyperkalemia	↑ESR, ↑CRP	Consolidation	Pulmonary infiltration	Echocardiography	Blood culture	Chills, Hypothermia, Loss of consciousness
		Smoke inhalation[53]	+/-	+	+	–	+	–	–	Wheezing	Anemia, Carboxyhemoglobin	↓O2, ↑CO2, Respiratory acidosis	Normal	CO-oximetry	Diffuse opacities	Pulmonary infiltration	Pulmonary function testing	Bronchoscopy	Cough, Hoarseness, Hemoptysis, Headache, Fainting
		Cold exposure[54]	+	–	+/-	–	–	–	–	Normal	Leukopenia, ↑RBC	↓O2, ↑CO2, Metabolic acidosis	Hypokalemia, Hypocalcemia	Hyperglycemia, ↑CK	Normal	Normal	–	Clinical findings	Confusion, Tachycardia/Bradycardia, Coma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Priyamvada Singh, M.B.B.S. [2], Keri Shafer, M.D. [3]; Assistant Editor-In-Chief: Kristin Feeney, B.S. [4]

Tetralogy of Fallot occurs in approximately 30 to 60 per 100,000 births. Tetralogy of Fallot represents 5-7% of congenital heart defects. The majority of cases are thought to be sporadic and are not familial. Tetralogy of Fallot occurs slightly more often in males than in females.

• Tetralogy of Fallot occurs in approximately 30 to 60 per 100,000 births.^[1]
• It represents 5-7% of congenital heart defects.

• The majority of cases are thought to be sporadic and are not familial.
• The incidence in siblings is 1% to 5%.

• Tetralogy of Fallot occurs slightly more often in males than in females.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

Common risk factors in the development of tetralogy of Fallot include: Alcoholism in the mother, diabetes, and pregnancy after the age of 40.

• Common risk factors in the development of tetralogy of Fallot include:Patients with tetralogy of Fallot may have a positive history of:^[1][2]
  • Alcoholism in the mother
  • Diabetes in mother
  • Pregnancy after the age of 40

• Less common risk factors in the development of tetralogy of Fallot include:
  • Poor nutrition during pregnancy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

According to the Canadian Cardiovascular Society/Canadian Pediatric Cardiology Association, screening for tetralogy of Fallot by pulse oxymetry is recommended for all newborns.

According to the Canadian Cardiovascular Society/Canadian Pediatric Cardiology Association, screening for tetralogy of Fallot by pulse oxymetry is recommended for all newborns:^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-In-Chief: Fahimeh Shojaei, M.D., Priyamvada Singh, M.B.B.S. [2]; Kristin Feeney, B.S. [3]

The prognosis of patients with repaired tetralogy of Fallot has improved over the years and these patients now have the potential to lead normal lives. As these patients grow, there may be leakage of the repaired pulmonic valve. There may be a persistent risk of sudden cardiac death.

• If left untreated, the natural history of tetralogy of Fallot results in progressive right ventricular hypertrophy and right ventricular dilatation due to the increased resistance to flow into the pulmonary circuit.
• The dilated cardiomyopathy progresses to right heart failure, usually with accompanying left heart failure.

Common complications of tetralogy of fallot include:^[1][2]

• Delayed growth and development
• Irregular heart rhythms (arrhythmias)
• Seizures as a result of hypoxia
• Stroke and embolic complications such as a brain abscess
• Pulmonary embolism
• Sudden cardiac death: The worse the right ventricle dysfunction, the worse the risk for ventricular tachycardia and sudden death.
• Bacterial endocarditis
• Reoperation for pulmonary stenosis

The survival for unrepaired tetralogy of Fallot is as follows:^[3]

• 75% at one year
• 70% at two years
• 60% at four years
• 50% at six years
• 30% at ten years
• 10% at twenty years
• 5% at forty years

• If pulmonary atresia is present as well, survival is even poorer with only 50% of patients surviving to one year, and only 8% of patients surviving to 10 years.

• Patients with repaired tetralogy of Fallot now have the potential to lead normal lives with continued excellent cardiac function.
• Most survivors are in NYHA Class I heart failure.
• Some patients have more pronounced symptoms with exertion.^[4][5]
• Current techniques for total surgical repair greatly improve the hemodynamic function of the heart with tetralogy of Fallot but do not provide a lifetime correction of the defect.
• Ninety percent of patients with total repair as infants develop a progressively leaky pulmonary valve (pulmonic insufficiency as the heart grows to its adult size. Patients also may have some degree of residual right ventricular outflow obstruction and damage to the conduction system of the heart from surgical corrections, causing conduction abnormalities on the EKG and/or arrhythmias.
• Tetralogy of Fallot patients are at risk for development of heart failure. Therefore, lifetime follow-up care by an adult congenital cardiologist is recommended to assess and monitor these risks and to recommend treatment, such as interventional procedures or re-operation, if it becomes necessary.
• Tetralogy of Fallot patients are at risk for sudden cardiac death with a 1% to 5% lifetime incidence. Risk factors for sudden cardiac death include:

• Older age at repair
• Male sex
• Advanced NY heart association class
• Repair via atriotomy
• Two major electrocardiographic risk factors include complete heart block beyond the third post operative day and QRS duration > 18 milliseconds, and rapid development of QRS prolongation in the first 6 months after repair.

• There is limited data regarding the benefit of automatic implantable cardiac defibrillator (AICD) implantation in these patients.
• Antibiotic prophylaxis is indicated during dental treatment in order to prevent infective endocarditis.

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