Definition and Morphology
It was Etienne-Louis Arthur Fallot who, in a series of papers in 1888, separated the malformation we now describe with his name from other anatomic lesions responsible for the “maladie bleue.” Although autopsy cases had been recognized previously, he was the first to correlate clinical features with pathologic findings. In anatomic terms, the malformation is composed of four constant features, namely, subpulmonary infundibular stenosis, ventricular septal defect (VSD), rightward deviation of the aortic valve with biventricular origin of its leaflets, and right ventricular (RV) hypertrophy ( Fig. 47.1 ).
Nonetheless, the malformation represents a morphological spectrum. At one end it can be difficult to distinguish hearts with tetralogy of Fallot (TOF) from those with VSD and aortic overriding with minimal pulmonary stenosis. At the other extreme, the pulmonary obstruction is so severe as to represent the commonest variant of pulmonary atresia with VSD (which will be discussed in Chapter 48 ). One morphologic marker, however, usually unifies the overall entity. This is anterocephalad deviation of the outlet septum (the muscular structure that separates the subaortic from the subpulmonary outlets) in relationship to the rest of the muscular septum. However, something over and above septal deviation is needed to produce TOF. This is hypertrophy of the septoparietal trabeculations, a series of normally small trabeculations, extending from the anterior margin of the septomarginal trabeculations and encircling the parietal margin of the subpulmonary infundibulum. Together with the deviated outlet septum, this complex forms the narrowed path to the pulmonary valve (which itself is often small and bicuspid).
Ventricular Septal Defect
The VSD in tetralogy is usually single and almost always large and nonrestrictive, except in very rare cases where its right ventricular margin is shielded by accessory tricuspid valve tissue or where marked septal hypertrophy narrows the defect. In about 80% of cases the defect is perimembranous, the remainder having a muscular posteroinferior rim. Much less commonly, the defect can be doubly committed juxtaarterial, with its cephalad border being formed by the conjoined aortic and pulmonary valves. It is questionable if such a heart should be called TOF because the outlet septum is absent. But the anatomy otherwise is exactly that of tetralogy. Furthermore, the free wall of the subpulmonary infundibulum is present and can possess hypertrophied trabeculations that may be obstructive following closure of the defect.
Pulmonary Stenosis
There is infundibular stenosis in almost all cases, which commonly coexists with obstruction(s) at other sites. The crucial importance of anterocephalad deviation of the outlet septum and the hypertrophied septoparietal trabeculations has been described. Hypertrophy of the anterior limb of the septomarginal trabeculation may contribute to this, but a second level of “subinfundibular pulmonary” obstruction may be seen when there is hypertrophy of the moderator band and apical trabeculations, which produces more proximal stenosis and gives the appearance of a two-chambered RV (covered in Chapter 46 ). The pulmonary valve is abnormal in most cases, although rarely the major cause of obstruction. In young infants, however, valvar stenosis has been found at surgery to be the major obstructive lesion. Acquired atresia of the infundibulum or the valve can also occur. Stenoses within the pulmonary arteries themselves are of major surgical significance, usually occurring at branch points from the bifurcation onward. Hypoplasia of the pulmonary arteries has been reported to be as frequent as 50%. Lack of origin of one pulmonary artery (typically the left) from the pulmonary trunk is not infrequent. The nonconnected pulmonary artery is almost always present, usually being connected by the arterial duct to some part of the aortic arch. Rarely, it may arise directly from the ascending aorta, but it is more often the right pulmonary artery that is anomalously connected.
Aortic Overriding
The degree of aortic override can vary from 5% to 95% of the valve being connected to the RV. TOF therefore coexists with double outlet RV, when more than half of the aorta connects to the RV (see Chapter 54 ). This feature has surgical significance in that a much larger patch is required to connect the left ventricle (LV) to the aorta when it originates predominantly from the RV.
Associated Lesions
Patency of the oval fossa, atrial septal defect (ASD), a second muscular inlet VSD or an atrioventricular septal defect -usually in the setting of Down syndrome- can coexist with tetralogy. A right aortic arch is common. Coronary arterial abnormalities (see Chapter 58 ), the most common being a left anterior descending from the right coronary artery crossing the right ventricular outflow tract, occur in about 3% and may be of surgical importance, sometimes necessitating the use of a right ventricular-to-pulmonary artery conduit.
Conduction System
The atrioventricular node is normally located in patients with TOF. When the VSD is perimembranous, the His bundle penetrates at the posteroinferior rim of the defect in the area of tricuspid and mitral valve continuity. In most cases, the bundle and its left branch proceed on the left side of the defect, although occasionally they run directly on the crest of the septum. Nevertheless, most surgeons place their sutures along the right ventricular aspect of the defect, thus avoiding heart block. When the defect is muscular, that is, there is muscular interruption between the tricuspid and aortic valve fibrous continuity, the bundle runs along the anterosuperior aspect of the defect, and sutures can safely be placed on the lower rim of the VSD. Furthermore, the conduction tissue never runs along the outlet septum, the muscular structure separating the aortic from the pulmonary valve, which can be safely resected without risk of producing heart block.
Genetics and Epidemiology
TOF is the most common form of cyanotic congenital heart defect, accounting for approximately 10% of all congenital heart disease. There is a slight male-to-female predominance. Approximately 15% of patients with tetralogy have a deletion of chromosome 22q11. This occurs in 1 in 4000 births and is tested with the fluorescence in situ hybridization (FISH) test. The incidence of 22q11 deletion is especially high in TOF patients with right aortic arch, pulmonary atresia, and aortic-to-pulmonary collaterals. 22q11 deletion is also referred to as DiGeorge syndrome and was historically summarized in the so-called CATCH 22 acronym (Cardiac defect, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia [neonatal] and 22q11 deletion). Given that 22q11 deletion results in a spectrum of disease, it is therefore not always associated with cardiac abnormality but affected subjects have a 50% risk of transmission, hence the indication for family screening and genetic counseling. Deletion of 22q11 is usually sporadic. Patients with 22q11 deletion may be small for dates with respect to birthweight, have nasal speech, cleft palate, learning difficulties, and a propensity to early psychiatric disorder, most commonly depression or schizophrenia in adolescence or young adulthood. TOF also occurs in the context of Down (7%), Alagille, and CHARGE syndromes. A number of point mutations, such as NKX2.5, explain a small percentage (∼4%) of patients with isolated TOF and recent studies suggest that an excess of rare and de novo copy number variants are implicated in the etiology, but are not yet recommended for clinical screening. In those without 22q11 deletion, which is offered for clinical screening, there is a 3% risk of vertical transmission of congenital heart disease, which is greater for mothers with TOF than for fathers.
Early Presentation and Management
Patients with TOF invariably present with cyanosis. This is due to right-to-left shunting at the ventricular level through the large, nonrestrictive VSD. RV pressure is at systemic levels from birth. RV hypertrophy is rarely extreme and does not lead to cavity obliteration in the way seen in patients with critical pulmonary stenosis or atresia with an intact ventricular septum (see Chapter 45 , Chapter 50 ). Patients with tetralogy, therefore, always have an RV of adequate size, and from this perspective they are always suitable for biventricular repair. In contrast, extreme pulmonary artery hypoplasia, more common in patients with pulmonary atresia, may deem the occasional patient unsuitable for repair. The timing of presentation—with cyanosis—depends on the degree of right ventricular outflow tract (RVOT) obstruction. The latter can be labile, due to its infundibular component, leading to variable degrees of cyanosis for the individual patient. Although the severity of RVOT obstruction varies considerably, there always seems to be sufficient obstruction to protect the patient from developing pulmonary vascular disease. Patients with pulmonary atresia and multiple aortopulmonary collateral vessels represent an exemption to this, however, as parts of the lungs supplied by nonrestrictive collaterals may become hypertensive (see Chapter 48 ).
Most patients with TOF present in infancy. However, when the RVOT obstruction is mild, patients often have minimal cyanosis (so-called “pink tetralogy” or “acyanotic Fallot”) and may occasionally present in adulthood.
Most adults will have had surgery, either palliative or, more commonly, reparative by the time they present to the adult cardiologist. Rarely, adults present without previous surgery. For these patients, surgical repair is still recommended because the results are gratifying and the operative risk is comparable to pediatric series (provided there is no significant coexisting morbidity). However, late morbidity and mortality in patients undergoing late repair is higher compared to those who underwent repair in early childhood. This, in turn, is due to higher incidence of ventricular dysfunction, right heart failure, and sudden cardiac death.
Reparative surgery involves closing the VSD and relieving the RVOT obstruction. The latter may involve the following procedures.
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A pulmonary valvotomy may be needed because in most instances the pulmonary valve is involved, being “bicuspid” and dysplastic.
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Resection of the infundibular muscle, which represents the major site of RVOT obstruction.
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An RVOT patch is a patch across the RVOT that does not disrupt the integrity of the pulmonary valve annulus. The RVOT that may be combined with infundibular resection.
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A transannular patch is a patch across the pulmonary valve annulus that disrupts the integrity of the pulmonary valve annulus and creates the potential for free pulmonary regurgitation. A transannular patch is used when the pulmonary valve annulus is restrictive.
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Pulmonary valve implantation (human homograft valve or porcine bioprosthesis) is “routinely” performed in adolescents and adults undergoing late repair, because these patients usually do not tolerate pulmonary regurgitation well, hence the need for a competent RVOT and bioprosthetic valve implantation.
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An extracardiac conduit is placed between the RV and pulmonary artery (in patients with pulmonary atresia, congenital or acquired).
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Angioplasty/patch augmentation of central pulmonary arteries is done in patients with hypoplastic main pulmonary trunk and/or stenoses of the central pulmonary arteries.
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A patent foramen ovale or secundum ASD is closed, if present.
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Additional treatable lesions such as aortic regurgitation or muscular VSDs may also need to be addressed.
The nature of the surgical approach to repair of tetralogy has evolved over the years. Early cohorts underwent repair through a right ventriculotomy. Furthermore, complete relief of RVOT obstruction often necessitated the use of a transannular patch, which creates the potential for free pulmonary regurgitation. Recent data, however, have shown detrimental long-term effects of right ventriculotomy and chronic pulmonary regurgitation on RV function, and a propensity to clinical arrhythmia and sudden cardiac death. This has led to a modified approach of repairing the lesion with a combined transatrial/transpulmonary approach involving closure of the VSD and relief of the RVOT obstruction through the right atrium and the pulmonary artery. A limited RV incision is often required for patch augmentation of the RVOT and/or the pulmonary valve annulus. Routine and generous transannular patching has been abandoned. In summary, every effort is now made to maintain the integrity and competence of the pulmonary valve even where this implies insertion of a bioprosthetic valve. It is of note that residual RVOT pressure gradients present in the immediate postoperative period, previously thought to carry a poor long-term prognosis, often regress within days. Furthermore, mild to moderate residual RVOT obstruction in isolation is well tolerated in the long term. Avoidance of free pulmonary regurgitation, at the expense of residual mild to moderate pulmonary stenosis, is well within the current therapeutic goal of reparative surgery.
The timing of surgical repair has also changed. Contemporary patients often undergo primary repair at presentation or when they become symptomatic. This approach may convey long-term benefits because it abolishes cyanosis early and—by normalizing pulmonary blood flow—promotes pulmonary artery growth. Many contemporary adult patients with repaired tetralogy, however, had one or more palliative procedures prior to undergoing repair.
There are occasional patients who reach adulthood with a palliative procedure only. The types of different palliative procedures, augmenting pulmonary blood flow in the setting of tetralogy, are shown in Table 47.1 .
| Blalock-Taussig shunt (classic) | Subclavian artery-to-pulmonary artery anastomosis (end-to-side). Infrequently, this may lead to pulmonary hypertension. |
| Blalock-Taussig shunt (modified) | Interposition graft between subclavian artery and ipsilateral pulmonary artery. Controlled augmentation of pulmonary blood flow. Usually a 4-mm Gore-Tex shunt is required early in infancy. Larger shunts would be required for older patients, although the possibility of repair should always be explored first. |
| Waterston shunt | Ascending aorta-to-main or right pulmonary artery (side-by-side). No artificial material used; shunt grows with the patient. May lead to pulmonary hypertension. Problems have also been encountered with pulmonary artery disruption, requiring extensive arterioplasty. |
| Potts shunt | Descending aorta-to-left pulmonary artery (side-by-side). Frequent complication of narrowing and kinking of the left pulmonary artery at the site of the anastomosis. The latter necessitates reconstructive surgery during repair, occasionally through an additional thoracotomy, which made this shunt unpopular. |
| Central interposition tube graft | A Gore-Tex graft is often used for patients not suitable for early repair. |
| Infundibular resection (Brock procedure) or closed pulmonary valvotomy | Often effective palliative procedure from an earlier surgical era. |
| Relief of RVOT obstruction without VSD closure or with fenestrated VSD closure | Used in patients with multiple pulmonary artery stenoses or hypoplasia. |
Late Outcomes
Survival and Functional Status
Repaired Patients
The overall survival of patients who have had operative repair is excellent, provided the VSD has been closed, the RVOT obstruction relieved satisfactorily, and there is no severe pulmonary regurgitation which may lead to RV dilatation and RV dysfunction. A 32- to 36-year survival of 86% and 85% have been reported, respectively. Older age at repair is consistently associated with decreased late survival. Death usually occurs suddenly or due to congestive heart failure. The reported incidence of sudden death, presumably arrhythmic, in late follow-up series varies between 0.5% and 6% and accounts for approximately one-third to one-half of late deaths. In a recent study the risk of sudden death increased incrementally after the first 20 years from repair of tetralogy (1.2% and 2.2% at 10 and 20 years, respectively, increased to 4% and 6% at 25 and 35 years). With increasing age, acquired heart disease may contribute to late mortality for these patients and should not be overlooked.
Palliated Patients
Palliation with arterial shunts and relief of severe cyanosis has dramatically improved the early and midterm outcome for patients with TOF. Recognized complications following palliative procedures for tetralogy comprise pulmonary arterial distortion and pulmonary hypertension. Pulmonary arterial distortion has been described with any type of previous arterial shunts, although more commonly seen after a Potts or Waterston shunt. Pulmonary hypertension due to a large left-to-right shunt with volume and pressure pulmonary artery overload, is more common after a Waterston anastomosis. Despite early dramatic relief of symptoms, very long-term outcome for patients who underwent only palliative procedures for tetralogy is limited, compared with those who ultimately underwent repair. This is because in patients with palliative procedures only, residual cyanosis, volume overload of the LV, and pressure overload of the RV (with RV pressures at systemic pressures due to the large VSD) persist. With time, biventricular dysfunction ensues and ultimately patients die prematurely, usually from heart failure or sudden cardiac death.
Unoperated Patients
Twenty-five percent of patients die in the first year of life, if not surgically treated. Forty percent die before 3 years of age, 70% before 10 years, and 95% before 40 years of age. Morbidity in adult survivors of tetralogy without surgery is high and relates to progressive cyanosis, exercise intolerance, arrhythmia, tendency to thrombosis, and cerebral abscess. In those few naturally surviving into the fourth and fifth decades of life, death usually occurs due to chronic congestive heart failure, secondary to long-standing right ventricular hypertension or suddenly, presumably arrhythmic.
Outpatient Assessment
Repaired Patients
Most adults with previous repair of TOF lead unrestricted lives. Late symptoms can comprise exertional dyspnea, palpitations, syncope, or sudden cardiac death. The latter can indeed be the first presentation in patients previously free of overt symptoms. Investigations are directed toward late complications (see Complications after Repair, Box 47.1 ) and preservation of biventricular function. Investigations may vary according to the type of operation performed, the locally available facilities, and the status of the patient.
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Endocarditis
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Aortic regurgitation with or without aortic root dilation: due to damage to the aortic valve during VSD closure or secondary to intrinsic aortic root abnormality (common in patients with pulmonary atresia and systemic to pulmonary artery collateral vessels)
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LV dysfunction: secondary to inadequate myocardial protection during previous repair, chronic LV volume overload due to long-standing palliative arterial shunts and/or residual VSD, injury to anomalous coronary artery (uncommon)
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Residual RVOT obstruction: infundibular, at the level of the pulmonary valve and main pulmonary trunk, and distally, beyond the bifurcation and occasionally into the branches of the left and right pulmonary arteries
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Residual pulmonary regurgitation: usually well tolerated if mild to moderate. Severe chronic pulmonary regurgitation, however, may lead to symptomatic RV dysfunction. Severity of pulmonary regurgitation and its deleterious long-term effects are exacerbated by coexisting proximal or distal pulmonary artery stenosis.
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RV dysfunction: usually due to residual RVOT lesions and can also be due to inadequate myocardial protection during initial repair
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Exercise intolerance: often due to pulmonary regurgitation and RV dysfunction
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Heart block, late postoperative (uncommon)
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Atrial tachyarrhythmia: atrial flutter and or atrial fibrillation
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Sustained ventricular tachycardia
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Sudden cardiac death
LV, Left ventricular; RV, right ventricular; RVOT, right ventricular outflow tract; VSD, ventricular septal defect.
All patients should periodically have a minimum of the following:
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A thorough clinical examination ( Box 47.2 )
BOX 47.2
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Patients with repaired TOF should have normal oxygen saturation.
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A right ventricular heave is common.
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Signs of right-sided heart failure (edema, elevated jugular veins, and hepatomegaly) are uncommon. The presence of any of these signs may suggest neglected underlying right-sided hemodynamic lesions. Patients need to be investigated thoroughly and the option of re-intervention explored.
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A single S2 sound is common because only the aortic component can be heard.
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A to-and-fro murmur in the pulmonary area is very common. The degree of pulmonary regurgitation can be difficult to ascertain on clinical grounds only.
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Diastolic murmurs may be due to pulmonary regurgitation (common) or aortic regurgitation (less common, but with increasing frequency observed with longer follow-up).
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A new pansystolic heart murmur in the left lower sternal edge, varying with respiration, would often indicate new-onset tricuspid regurgitation. This, in turn, may be the result of further RV dilation secondary to pulmonary regurgitation and may necessitate pulmonary valve implantation with or without tricuspid valve annuloplasty.
RV, Right ventricular; TOF, tetralogy of Fallot.
Assessment
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A 12-lead electrocardiogram (EKG) to assess for sinus rhythm, PR interval, QRS duration ( Fig. 47.2 ), QRS prolongation over time, and finally, QT dispersion (for high-risk patients). The last three variables have been shown to relate to propensity to sustained ventricular tachycardia and risk of sudden death (see Arrhythmia and Sudden Cardiac Death ).
Figure 47.2
QRS duration predicts sustained ventricular tachycardia and sudden cardiac death. A, Standard 12-lead surface electrocardiogram from a patient presenting with sustained monomorphic ventricular tachycardia 20 years after tetralogy of Fallot (TOF) repair. Maximum QRS duration in V 1 ( inset ) occupies a large square (200 ms). B, Plot of maximum QRS duration in eight patients with repaired TOF. Those with syncope due to sustained monomorphic ventricular tachycardia (nine patients, squares ), atrial flutter (one patient, asterisk ), and sudden cardiac death (four patients, triangles ) are plotted separately on the right column. P < .0001 signifies statistical difference in mean QRS duration between patients without syncope and those with syncope or sudden death.
(After Gatzoulis MA, Till JA, Somerville J, et al. Mechanoelectrical interaction in tetralogy of Fallot: QRS prolongation relates to right ventricular size and predicts malignant ventricular arrhythmias and sudden death. Circulation . 1995;92:231-237, with permission.)
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Chest X-ray. The cardiothoracic ratio on the posteroanterior view, presence of a left or right aortic arch, dilatation or not of the ascending aorta and central pulmonary arteries, presence of retrosternal filling on the lateral view suggestive of RV dilatation, and features of a calcified RV-to-PA conduit should be noted.
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Echocardiographic examination ( Fig. 47.3 , Box 47.3 ; echocardiography)
Figure 47.3
Echocardiographic assessment after repair of tetralogy of Fallot (TOF). A, Color Doppler interrogation of the right ventricular outflow tract (RVOT) in the parasternal short-axis view: patient with free pulmonary regurgitation after previous TOF repair with a transannular patch. Laminar (broad jet) retrograde flow in red from the pulmonary artery in the RV outflow. Note RVOT aneurysm. B, Pulsed-wave Doppler image from the same patient. Note early termination of pulmonary regurgitation (flow above the curve returning to equilibrium by mid-diastole) indicative of severe pulmonary regurgitation. Forward blood velocity is not increased, suggesting the absence of pulmonary stenosis. C, Continuous wave Doppler interrogation of the tricuspid valve from the same patient. Maximum pressure drop across the tricuspid valve is 36 mm Hg, excluding severe proximal or distal pulmonary stenosis. D, Pulsed wave Doppler interrogation of the RVOT in the parasternal short-axis view in a patient with free pulmonary regurgitation (PR) after repair of TOF. As in B , the systolic forward flow (SFF) trace does not demonstrate evidence of pulmonary stenosis and early termination of the diastolic reverse flow (DRF) suggests severe pulmonary regurgitation. There is the additional finding of antegrade flow in late diastole (a wave, arrow ) present throughout the respiratory cycle and suggesting so-called RV restrictive physiology.
(Courtesy Dr. Wei Li.)
BOX 47.3
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Measure RV size and assess RV function; changes with time may guide optimal timing for reintervention.
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Assess septal motion (indirect sign of RV dilation) and RV hypertrophy.
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Interrogate the RVOT with 2D, Doppler, and color flow mapping for residual pulmonary stenosis and regurgitation (see Fig. 43.3A–C ). Measure maximum continuous wave Doppler velocities. Assess for features of RV restrictive physiology including searching for anterograde flow in the pulmonary artery in late diastole throughout the respiratory cycle (see Fig. 43.3D ).
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Detect and quantify tricuspid regurgitation.
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Estimate RV systolic pressure (from tricuspid regurgitation). This may disclose proximal and or peripheral pulmonary artery stenosis; the latter can be difficult to image.
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Exclude residual VSD. If it is present, assess Doppler gradient across the VSD.
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Assess LV size and function.
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Exclude intraatrial communications.
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Document left and right atrial size.
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Measure aortic root size and interrogate for aortic regurgitation.
LV, Left ventricular; RV, right ventricular; RVOT, right ventricular outflow tract; 2D, two-dimensional; VSD, ventricular septal defect.
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