Tetralogy of Fallot
Tetralogy of Fallot (TOF), formerly known as Steno-Fallot tetralogy,[9] is a congenital heart defect characterized by four specific cardiac defects.[4] Classically, the four defects are:[4]
Not to be confused with Teratology.Tetralogy of Fallot
Fallot’s syndrome, Fallot’s tetrad, Steno-Fallot tetralogy[1]
Episodes of bluish color to the skin, difficulty breathing, heart murmur, finger clubbing[2]
From birth[4]
Unknown[5]
Based on symptoms, echocardiogram[6]
1 in 2,000 babies[4]
At birth, children may be asymptomatic or present with many severe symptoms.[10] Later in infancy, there are typically episodes of bluish colour to the skin due to a lack of sufficient oxygenation, known as cyanosis.[2] When affected babies cry or have a bowel movement, they may undergo a "tet spell" where they turn cyanotic, have difficulty breathing, become limp, and occasionally lose consciousness.[2] Other symptoms may include a heart murmur, finger clubbing, and easy tiring upon breastfeeding.[2]
The cause of tetralogy of Fallot is typically not known.[5] Risk factors include a mother who uses alcohol, has diabetes, is over the age of 40, or gets rubella during pregnancy.[5]: 62 It may also be associated with Down syndrome and other chromosomal defects that cause congenital heart defects.[11]
TOF is typically treated by open heart surgery in the first year of life.[8] The timing of surgery depends on the baby's symptoms and size.[8] The procedure involves increasing the size of the pulmonary valve and pulmonary arteries and repairing the ventricular septal defect.[8] In babies who are too small, a temporary surgery may be done with plans for a second surgery when the baby is bigger.[8] With proper care, most people who are affected live to be adults.[4] Long-term problems may include an irregular heart rate and pulmonary regurgitation.[3]
The prevalence of TOF is estimated to be anywhere from 0.02 to 0.04%.[4] Though males and females were initially thought to be affected equally, more recent studies have found males to be affected more than females.[4][12] It is the most common complex congenital heart defect, accounting for about 10 percent of cases.[13][14] It was initially described in 1671 by Niels Steensen.[1][15] A further description was published in 1888 by the French physician Étienne-Louis Arthur Fallot, after whom it is named.[1][16] The first total surgical repair was carried out in 1954.[3]
While the specific causes of TOF have not been fully identified, there are various environmental or genetic factors that have been associated with TOF. So far, around 20% of overall congenital heart defect cases have been due to known causes such as genetic defects and teratogens which are various factors causing embryo development abnormalities or birth defects.[23] However, the other 80% of cases have little known about their cause.[23]
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.[24]
Specific genes associations with TOF include:
The Environmental Factors that have been studied to potentially be associated with TOF include:
Embryology studies show that anterior malalignment of the aorticopulmonary septum results in the clinical combination of a ventricular septal defect (VSD), pulmonary stenosis, and an overriding aorta.[20]: 200 Right ventricular hypertrophy develops progressively from resistance to blood flow through the right ventricular outflow tract.[10]
Treatment[edit]
Tet spells[edit]
Tet spells are defined as cyanotic spells occurring due to the obstruction right ventricular outflow.[54] 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.[55]
Tet spells may be treated with beta-blockers such as propranolol, but acute episodes require rapid intervention with morphine or intranasal fentanyl[56] to reduce ventilatory drive, a vasopressor such as phenylephrine, or norepinephrine to increase systemic vascular resistance, and IV fluids for volume expansion.[20]: 18, 201
Oxygen (100%) may be effective in treating spells because it is a potent pulmonary vasodilator and systemic vasoconstrictor. This allows more blood flow to the lungs by decreasing shunting of deoxygenated blood from the right to left ventricle through the VSD. There are also simple procedures such as squatting and the knee chest position which increase systemic vascular resistance and decrease right-to-left shunting of deoxygenated blood into the systemic circulation.[20]: 18, 201 [21]
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).[20]: 18, 201
Total surgical repair[edit]
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.[57]: 153 The repair consists of two main steps: closure of the VSD with a patch and reconstruction of the right ventricular outflow tract.[58]
This open-heart surgery is designed to relieve the right ventricular outflow tract stenosis by careful resection of muscle and to repair the VSD.[57]: 154 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.[59]
Additional reparative or reconstructive surgery may be done on patients as required by their particular cardiac anatomy.[57]: 153
Timing of surgery in asymptomatic patients is usually between the ages of two months to one year.[20]: 201–2 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[20]: 201–2
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.[58]: 59 Long-term complications most commonly include pulmonary valve regurgitation, and arrhythmias.[60]
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.[20]: 205 Post surgery, most patients enjoy an active life free of symptoms.[20]: 205 Currently, long-term survival is close to 90%.[20]: 167 Today the adult TOF population continues to grow and is one of the most common congenital heart defects seen in adult outpatient clinics.[5]: 100–101
Palliative surgery[edit]
Initially surgery involved forming a side to end anastomosis between the subclavian artery and the pulmonary artery -i.e. a systemic to pulmonary arterial shunt.[58]: 57 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.[61]
The Potts shunt[62] and the Waterston–Cooley shunt[63][64] 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.[17]: 173 For example, in symptomatic infants, a two-stage repair (initial systemic to arterial shunt placement followed by total surgical repair) may be done.[65] Potential complications include inadequate pulmonary blood flow, pulmonary artery distortion, inadequate growth of the pulmonary arteries, and acquired pulmonary atresia.[58]: 59
Approaches to surgical repair[edit]
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.[66][67] As a result, the hunt for surgical procedures to relieve right ventricular outflow tract obstruction while minimizing pulmonary regurgitation has intensified.[66][67]
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.[66][67] The pulmonary annulus size was larger in babies treated with the latter technique, as predicted.[66][67] 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.[66][67]
Furthermore, there was no significant difference in right ventricular dilation between the two techniques.[66][67] 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.[66][67]
Complications[edit]
Short-term[edit]
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.[9] 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:
Prognosis[edit]
Untreated, tetralogy of Fallot rapidly results in progressive right ventricular hypertrophy due to the increased resistance caused by narrowing of the pulmonary trunk.[20]: 199 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.[60] Patients with untreated TOF rarely progress to adulthood.[60]
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).[70] 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.[20]: 205
Cardiovascular and cerebrovascular complications in patients with repaired CHD such as TOF occur earlier in life compared to healthy subjects.[71] Chronic pulmonary regurgitation and right ventricular dilation and dysfunction is also common.[72]
Within 30 years after correction, 50% of patients will require reoperation.[60] The most common cause of reoperation is a leaky pulmonary valve (pulmonary valve insufficiency).[60] This is usually corrected with a procedure called pulmonary valve replacement.[24]: 136
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.[73][74]
Comorbidities[edit]
There are many comorbid conditions that can occur with TOF that may exacerbate the condition. Often, TOF can present with low birth weight and prematurity. In both of these cases, mortality and morbidity were both seen to increase.[75] 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.[76] 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.[77]
Danon disease, which is a rare genetic disorder, was also observed to complicate TOF. In particular, elongation of the QRS complex and a shortened PR interval. Genetic abnormalities found in TOF may lead to the earlier diagnosis of Danon disease, helping to improve prognostic outcomes.[78]
Epidemiology[edit]
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.[79][12] It accounts for 7–10% of all congenital heart abnormalities, making it the most common cyanotic heart defect.[5]: 100–101 Although males and females were initially believed to be affected equally, more recent studies have shown TOF affects males more than females.[80][12] About 1 in 100 newborns is diagnosed with a congential heart defect, of which 10% are diagnosed with TOF.[12] Genetically, it is most commonly associated with Down syndrome and DiGeorge syndrome.[5][24] Down syndrome and other chromosomal disorders are known to occur alongside congential heart defects such as TOF.[12]
History[edit]
Tetralogy of Fallot was initially described in 1671 by the Danish researcher Niels Steensen.[1][15] Also referenced as Nicolaus Steno in Latin, Stensen was a pioneer in anatomy and geology, his work making significant specific contribution to the fields of cardiac anatomy and pathology.[9] A further description was published in 1888 by the French physician Étienne-Louis Arthur Fallot, after whom it was ultimately named.[1][16] In 1924, Maude Elizabeth Seymour Abbott, a pediatric cardiologist from Montreal, Canada, named it tetralogy of Fallot.[81]
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.[9] Over a hundred years later in 1777, Dutch physician Eduard Sandifort reported what he referred to as "the blue boy" patient. This patient, who was 16 months old, was initially thought to have asthma, though an autopsy postmortem revealed a cardiac malformation with no ductus arteriosus or ligamentum arteriosum, indicating that the child may have died from TOF.[9] 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.[9]
Other cases, such as those presented by Pulteney (1785), Abernethy (1793), Bell (1797), Dorsey (1812), and Farre (1814) also contributed to modern understandings of TOF. The first reported case of TOF was in America at the University of Pennsylvania in 1816, with more cases being reported by Peacock (1858 and 1869), Widman (1881), and finally Fallot (1888), after whom the condition is named.[9] Fallot was the first to elegantly describe the four key features that differentiate it from other cyanotic cardiac conditions, and was prominent in the disqualification of a patent foramen ovale as a fifth feature. Fallot initially referred to it as "La maladie bleue", which is French for "the blue disease" or "cyanose cardiaque", translating to "cardiac cyanosis".[9]
The first surgical repair was carried out in 1944 at Johns Hopkins.[82] The procedure was conducted by surgeon Alfred Blalock and cardiologist Helen B. Taussig, with Vivien Thomas also providing substantial contributions and listed as an assistant.[3] This first surgery was depicted in the film Something the Lord Made.[61] 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.[61] Furthermore, the Blalock-Thomas-Taussig procedure, initially the only surgical treatment available for tetralogy of Fallot, was palliative but not curative. The first total repair of tetralogy of Fallot was done by a team led by C. Walton Lillehei at the University of Minnesota in 1954 on an 11-year-old boy.[83] Total repair on infants has had success from 1981, with research indicating that it has a comparatively low mortality rate.[70] Today the adult TOF population continues to grow and is one of the most common congenital heart defect seen in adult outpatient clinics.[5]: 100–101