tof

Tetralogy of Fallot

Tetralogy of Fallot (TOF), first described in 1888 and named after Louis Arthur Fallot, is the most commonly encountered of the cyanotic (bluish skin and mucous membranes due to insufficient oxygen supply to the tissues) congenital (present at birth) heart defects, affecting approximately 10% of all infants born with congenital heart diseases.1  TOF is comprised of four features:

• • Pulmonary valvular stenosis (narrowing of the valve opening) or atresia (complete absence of a developed valve)

  • Right ventricular hypertrophy (enlargement of the muscle mass within the right ventricle, primarily as a compensatory response to the added resistance from the restricted pulmonary valve and the added blood flow through the ventricular septal defect)

  • An over-riding aorta (in which the aortic valve opening points toward the septum of the heart rather than towards the left ventricular outflow tract)

  • Malalignment ventricular septal defect (large hole between the two ventricles, thus allowing mixing of oxygenated blood with poorly oxygenated blood)       

See a schematic representation of this condition from the US National Institutes of Health.

Causes

Despite this collection of abnormalities, it is commonly accepted that TOF arises from a single genetic defect involving the TBX1 gene, which encodes for a transcription factor integral to the development of the cardiac outflow tracts.2 This isolated genetic anomaly creates the various developmental derangement associated with TOF. There appears to be some maternal risk factors that could predispose to the development of Tetralogy of Fallot.3 Fetal alcohol syndrome has been implicated as one such potential cause.  Maternal use of anti-seizure medications, such as hydantoin and carbamazepine may also lead to this series of congenital defects.  Mothers with phenylketonuria (PKU; an abnormal presence of metabolic breakdown products of the essential amino acid phenylalanine) are also at risk for having children with TOF.

Prevalence

The prevalence of congenital heart defects within India is approximately 4 cases per 1,000 live births with TOF comprising 7 to 32% of these cases, making it among the most common congenital anomalies.4  There is also a 40% chance of patients having associated cardiac conditions, such as a right-sided aortic arch, anomalies of the coronary arteries, collateral vessels between the systemic and pulmonary vasculatures, patent ductus arteriosus, atrioventricular septal defect (also known as endocardial cushion defect; a failure of the atrial and ventricular septa to come together at the crux, or center, of the heart), and aortic valve problems including prolapsing of the leaflets and valvular regurgitation.5  Approximately 15% of patients also have some form of extracardiac conditions, such as Down syndrome (also associated with the aforementioned atrioventricular septal defect) and DiGeorge syndrome.  The latter of these syndromes is characterized by a distinct facial appearance, defects involving the pharynx, congenital absence of the parathyroid glands with resultant hypocalcemia (low calcium levels in blood), and defective immune T-cell function as a result of underdevelopment of the thymus gland.2  There is a slightly higher incidence of TOF occurring within males than in females.3

Diagnosis

The primary feature that leads to the diagnosis of TOF is persistent cyanosis that is present at the time of birth.3  Infants with TOF commonly exhibit poor feeding patterns with cyanosis occurring after eating, prolonged fussiness and agitation, and a tendency to have a rapid respiratory rate (tachypnea).  These symptoms, and the varying severity that can be noted, are a result of the hypertrophy of the right ventricular outflow tract, with the more pronounced the symptoms and the earlier their onset directly correlating to the severity of this obstruction.  The cyanosis can also become progressively worse with age as a result of increased pulmonary vascular resistance (resulting from chronic hypoxemia – low levels of oxygen in the blood – and impaired blood flow through the pulmonary vasculature).  This can necessitate surgical intervention (to be discussed later).

Children with TOF commonly display the action of squatting as a compensatory mechanism to the right-to-left shunting of blood and the resultant cyanosis that occurs during periods of exertion.3  Such periods of exertion, including immediately after feeding or when the child cries or is otherwise agitated is commonly associated with hyperpnea (rapid and deep breathing), cyanosis, and rarely syncope (passing out).6  Squatting, as an action that the child just inherently "learns" to perform in such settings, reduces the degree of right-to-left shunting and forces more blood through the pulmonary vasculature, allowing for better oxygenation.  The hypoxic "tet" spells that lead to the act of squatting can be potentially lethal, thought to result from irritation and spasming of the musculature around the right ventricular outflow tract leading to the pulmonary artery and vasculature.  These tet spells are not seen within the first couple of months of life, peaking in their incidence between the second and fourth months after birth.1  Such spells are not noted in adolescents or adults.7

Physical examination in the child with TOF reveals evidence of prolonged cyanosis, including clubbing of the terminal digits.5 Palpation of the precordium may reveal medial displacement of the apical impulse as a result of right ventricular enlargement.  There might also be a systolic thrill (palpable vibration felt over the heart as a result of underlying turbulent blood flow).  Cardiac auscultation may reveal an systolic ejection murmur best heard along the left sternal border (pulmonic valve region), the intensity of which varies inversely with the severity of the obstruction within the right ventricular outflow tract.7  The second heart sound frequently is heard as a single heart sound; vice the normal splitting found with the physiologic closure of the aortic valve a few milliseconds before the pulmonic valve, as a result of pulmonic valvular compromise or even absence (pulmonic atresia).3 Contrary to other patients with ventricular septal defects, a murmur is commonly not heard in patients with TOF due to the enormity of the defect and the relative lack of turbulent flow.

Chest radiography is frequently used to evaluate patients with TOF.  Although the heart size is commonly normal, there are characteristic changes in the shape of the heart.1 The main segment of the pulmonary artery is commonly concave with the heart taking on an upturned apex as a result of the right ventricular hypertrophy.  This gives the heart an appearance that is typically referred to as "boot shaped."  The pulmonary vascular markings are commonly decreased as a result of the diminished blood flow through the lungs, making the lungs appear darker than normal.  However, if the degree of right ventricular outflow tract obstruction or pulmonic valve stenosis is relatively mild, the vascularity will actually be increased.

Imaging studies such as echocardiography, computed tomography (CT), and magnetic resonance imaging (MRI) scanning, and cardiac catheterization are commonly used to help identify the four lesions associated with TOF, as well as the make out any of the aforementioned anomalies that can accompany TOF.  These studies can also be useful in assessing the degree of severity of the condition.

Clinical Management

Due to the congenital nature of TOF, life-long clinical supportive management is the main alternate to surgical correction.  Though of limited efficacy, supplemental oxygen is commonly administered to compensate for restricted pulmonary blood flow.3  The use of narcotic analgesics (such as morphine sulfate) might be of benefit by decreasing the ventilatory drive as well as producing a sedative effect that provides comfort and diminishes anxiety for the patient.  In newborns with severe cyanosis, intravenous administration of prostaglandins and aggressive management of airway, breathing, and circulation is followed.8 Congestive heart failure resulting from pulmonary congestion is normally managed with digoxin and diuretics.  Right ventricular filling can be optimized by using intravenous beta-adrenergic antagonists (commonly referred to as "beta-blockers") and intramuscular morphine (which has the added benefit of opening the vessels within the lungs and reducing pulmonary congestion from elevated heart pressures).

Acute episodes of hypoxic "tet" spells can be managed through a series of strategies.6 Infant can be placed in a knee-to-chest position if possible, thereby increasing right-heart pressures to enhance perfusion to the pulmonary blood vessels.  Morphine sulfate can be administered in order to reduce the resistance within this vascular bed, further enhancing perfusion and oxygen delivery at the alveoli-capillary bed. The tranquilizer drug ketamine, can also be used in selected patients in an effort to increase systemic blood pressure, thus forcing additional blood flow to the lungs; the alpha-agonist phenylephrine can also be used to accomplish this increase in systemic vascular resistance.9 Correction of acidosis is imperative and usually can be accomplished by maximizing perfusion to the lungs in order to "off-load" carbon dioxide (the body's primary acid and the culprit responsible for respiratory acidosis) into the alveoli.  In severe cases, such as those in which there is severe cyanosis or fixed obstructions that prevent perfusion to the lungs should be managed aggressively with pharmacologic sedation and paralysis prior to endotracheal intubation (the placement of breathing tube into the windpipe to allow for mechanical ventilation in the setting of severe respiratory failure and impairment in pulmonary perfusion).

Surgical management is a major intervention to manage TOF.  However, complications are relatively common even despite surgical intervention.  There are two broad types of surgical interventions:  palliative and corrective.  Use of shunts to accommodate additional blood flow around the outflow obstruction and into the pulmonary vasculature falls under palliative care.10  Corrective surgical intervention involves closure of the ventricular septal defect utilizing a patch.5  The infundibular obstruction can be surgically resected, with the excessive tissue being sliced away to reduce the amount of restriction.  

References and Further Reading

A schematic representation of TOF is available at the US National Institutes of Health.

 Contributors:

Sean M. Hancock, RDCS (AE), RCS, RCSA, RCIS, CCT

Staff Cardiovascular Technician & Clinical Educator

Naval Hospital Bremerton, Washington, USA

and

Pochi R. Subbarayan PhD

University of Miami, FL, USA

June 2011