Case 29 — Tetralogy of Fallot
Tetralogy of Fallot Chapter from “Small Animal Cardiovascular Medicine” On-Line
Text from “Small Animal Cardiovascular Medicine”
Introduction
Tetralogy of Fallot is a congenital cardiac abnormality characterized by the presence of a large ventricular septal defect, pulmonic stenosis, dextroposition of the aorta, and right ventricular hypertrophy. Blood shunts from the right ventricle to the left ventricle through the ventricular septal defect. The blood flows from the right side of the heart to the left side because the pulmonic stenosis increases resistance to blood flow out of the right ventricle to a point that it is greater than systemic vascular resistance. The delivery of deoxygenated blood to the systemic circulation results in systemic hypoxemia. The hypoxemia is often severe enough to cause cyanosis, either at rest or with exercise/stress.
Prevalence
Tetralogy of Fallot is an uncommon congenital cardiac defect in dogs and cats. While the overall prevalence of congenital heart disease in dogs has been estimated to be approximately 27/4,000, the prevalence of tetralogy of Fallot in dogs has been estimated to be 1/4,000. This is probably an underestimate because some severely affected dogs almost assuredly die at a young age before a veterinarian examines them. However, tetralogy of Fallot is the most common of the cyanotic congenital cardiac defects in the dog. We diagnosed tetralogy of Fallot in 19 dogs between 8/1/86 and 8/1/96. This is approximately 2 cases a year. The prevalence in our hospital patient population was also about 1 per 4000 (19/68,690). Tetralogy of Fallot comprised approximately 0.5% of our primary service caseload. Tetralogy of Fallot is an unusual, although reported, defect in the cat. We diagnosed tetralogy of Fallot in 4 cats in the same period. We also diagnosed a ventricular septal defect with mild to moderate pulmonic stenosis with or without dextroposition of the aorta in 3 cats within that time.
Without palliative surgery the prognosis for this abnormality is poor with most dogs dying within the first year of life from hypoxemia or complications from polycythemia. Other congenital defects may be identified in dogs with tetralogy of Fallot. These include tracheal hypoplasia, peritoneal pericardial diaphragmatic hernia, ventral abdominal wall hernia and sternal deformity, retinal dysplasia, and persistent pupillary membranes. Other congenital cardiac abnormalities may occasionally be noted in a patient with tetralogy of Fallot. They include but are not limited to patent ductus arteriosus (pentalogy of Fallot), atrial septal defect, and a persistent right aortic arch.
History
Nicholas Sten, a Danish scholar, provided the original description of this condition in children in 1673. Eduard Sandifort again described tetralogy of Fallot in 1777. In the mid-1800s, James Hope, Thomas Peacock, and Sir Thomas Watson provided descriptions of this abnormality. Etienne-Louis Arthur Fallot published his paper entitled “Contribution to the Pathologic Anatomy of Morbus Caeruleus” in 1888. In it he described what is now considered the classic description of the malady now known as tetralogy of Fallot. He described the following: (1) pulmonic stenosis; (2) interventricular communication; (3) deviation of the origin of the aorta to the right; (4) concentric right ventricular hypertrophy. The important features of this defect are the pulmonic stenosis and the large ventricular septal defect. The right ventricular hypertrophy is purely secondary to the right ventricular pressure overload. The overriding aorta is an important clue to the embryology of the defect and is an important consideration for surgical correction, but is not hemodynamically as important. With the large ventricular septal defect and pulmonic stenosis, blood shunts from the right ventricle through the ventricular septal defect and into the aorta and systemic circulation. This shunting of deoxygenated (venous) blood into the systemic circulation results in hypoxemia and, if the hypoxemia is severe enough, in cyanosis and polycythemia.
Embryology and Genetics
The name tetralogy of Fallot suggests that the patient has four separate congenital cardiac defects. It would be unusual for patients to have four cardiac defects simultaneously. That tetralogy of Fallot is common suggests that the abnormalities observed stem from one abnormality. The embryology and heritability of tetralogy of Fallot and related defects have been studied in keeshond dogs. The conotruncal (outlet or infundibular) septum is abnormal in keeshond dogs, and presumably is also abnormal in other patients with the disease. This abnormality is inherited as a simple autosomal recessive trait. The conotruncal septum forms the upper portion of the interventricular septum. In tetralogy of Fallot, this portion of the septum forms too far cranial. This results in malalignment with the lower portion of the interventricular septum and consequently a defect in the interventricular septum (a ventricular septal defect). The formation of the conotruncal septum in this position also results in a narrowed right ventricular outflow tract or abnormal pulmonic valve formation (pulmonic stenosis) and in dextroposition of the origin of the aorta. The right ventricular hypertrophy occurs secondary to the pulmonic stenosis.
The trabecular septum forms the floor of the ventricular septal defect. The roof is formed by the aortic valve leaflets. The degree to which the aorta is shifted to the right is variable and has not been quantified in dogs. In man, the amount of override ranges from 15 to 95%.
Tetralogy of Fallot is not the only congenital cardiac abnormality identified when affected keeshond dogs are bred. Some dogs have subclinical defects in which the papillary muscle of the conus is absent and an aneurysm is present in the interventricular septum at the region of the membranous septum. Other dogs have just pulmonic stenosis or a ventricular septal defect. A few dogs have no formation of the conotruncal septum and so have truncus arteriosus where the aorta and pulmonary artery arise from the ventricles as one large great artery. A large ventricular septal defect is also present. These represent a spectrum of a genetic disease in which there are varying degrees of defective growth of the conotruncal cushions resulting in different degrees of embryologic abnormalities.
Pathophysiology
Tetralogy of Fallot is a shunting defect in which there is usually no resistance to flow between the left and right ventricles. Consequently, blood flows to the right and left circulations proportional to systemic and pulmonary resistances. The pulmonic stenosis in symptomatic tetralogy of Fallot is severe such that resistance to flow through the pulmonic valve is greater than systemic vascular resistance. Consequently a significant amount of blood flows from the right ventricle, through the VSD, and out the aorta. The amount of blood that flows from the right heart into the aorta depends on the relative resistances between the two circulations. For example, if the pulmonic stenosis increases resistance to flow out the right ventricle to twice that of systemic vascular resistance and if we give pulmonary blood flow an arbitrary value of 100 ml, 200 ml will flow through the systemic circulation (pulmonary blood flow must be one-half of the systemic blood flow if pulmonary resistance is twice that of systemic vascular resistance). The Qp/Qs is 0.5. Because the ventricular septal defect provides no resistance to flow, blood will flow wherever it can in proportion to the resistances. Systolic intraventricular pressures will be equal on both sides. Since the amount of blood pumped into the pulmonary circulation equals left heart venous return, left ventricular output must also be 100. Therefore, 100 ml of blood must also flow through the VSD and into the aorta (systemic flow = 200 ml; VSD flow = systemic flow − pulmonary flow). The amount of pulmonary blood flow is decreased from that seen in a normal animal in a patient with tetralogy of Fallot because of the pulmonic stenosis and an apparent lack of response by the body to this decrease in pulmonary blood volume. The decrease in pulmonary blood flow results in a decrease in venous return to the left ventricle with a resultant decrease in left ventricular size and stroke volume. The decrease in stroke volume results in a decrease in the amount of oxygenated blood that reaches the circulation.
The physiologic consequences of tetralogy of Fallot depend on two variables – the degree of pulmonic stenosis and systemic vascular resistance. The degree of aortic override is not hemodynamically very important. The same amount of shunting will occur in an animal with a comparably sized ventricular septal defect and comparably severe pulmonic stenosis. Exercise exacerbates the right-to-left shunting due to vasodilation in skeletal muscle beds and a decrease in systemic vascular resistance. Because of the pulmonic stenosis, pulmonary resistance is fixed and right-to-left shunting increases, producing more severe systemic hypoxemia and cyanosis.
When the right ventricular output of blood contributes to aortic flow, venous blood is pumped into the systemic circulation. Blood that has a low partial pressure of oxygen (venous) now mixes with blood with a high partial pressure of oxygen (arterial). The net results are decreases in oxygen tension and oxygen content of the systemic blood which result in cyanosis. The severity of the hypoxemia directly reflects the degree of shunting. It is a sensitive and specific means of evaluating the severity of a right-to-left shunt. Symptomatic patients typically have an arterial oxygen tension <40 mmHg at rest or with exercise.
Patients with tetralogy of Fallot do not necessarily have to be cyanotic although the vast majority are, either at rest or with exercise. A patient that has mild pulmonic stenosis (where pulmonary resistance is still less than the systemic vascular resistance) and a large ventricular septal defect can have a predominantly left-to-right shunt and have the same hemodynamics as a patient with a small, isolated ventricular septal defect. A patient with equal pulmonary and systemic resistances due to moderate pulmonic stenosis can be “balanced” so that very little net shunting occurs, in either direction. The latter type of patient would still be expected to develop more right-to-left shunting and arterial hypoxemia with exercise.
The pulmonic stenosis in tetralogy of Fallot does not necessarily have to be a fixed stenosis. Infundibular narrowing and hypertrophy can result in a stenosis that worsens when the contractility in this region increases (dynamic obstruction). This most commonly results in an increase in pulmonary resistance when the animal becomes excited or exercises. The fixed stenosis may be valvular, subvalvular, or infundibular (narrowing of the outflow tract).
Because of the profound hypoxemia in patients with symptomatic tetralogy of Fallot, polycythemia is a common sequela. The polycythemia occurs when receptors in the kidney, and to a lesser extent in the liver, are stimulated by hypoxemia to release erythropoietin. Erythropoietin is a glycoprotein that has an oxygen sensing site that probably contains heme. Erythropoietin is produced in a subset of peritubular cells that lie along the capillary lumen and outside the tubular basement membrane in the inner renal cortex. Serum erythropoietin concentration is increased in patients with chronic hypoxemia. Erythropoietin stimulates red cell production. Erythropoietin binds to receptors on erythroid cells in bone marrow and stimulates cell growth via a tyrosine protein kinase. The protein kinases probably stimulate biological activation of erythroid cells by phosphorylating nuclear proteins. The resultant increase in hematocrit increases the oxygen carrying capacity of the blood. This is beneficial to a hypoxemic patient if the hematocrit is in the 55–70% range. Blood viscosity increases exponentially with increases in hematocrit and at hematocrits exceeding 70% blood viscosity increases dramatically. The increase in blood viscosity increases resistance to flow, decreasing cardiac output and so decreasing tissue oxygen delivery. Consequently, severe polycythemia is often detrimental. The hematocrit at which blood viscosity increases to the point of being detrimental varies tremendously from patient to patient. It should be noted that not all animals with tetralogy of Fallot have an increase in serum erythropoietin concentration.
Signalment and Medical History
Most dogs are presented to a veterinarian when they are young, most commonly between two and eight months of age. Most dogs are purebred dogs. Many breeds have been identified with this defect. Tetralogy of Fallot has been diagnosed in 19 dogs at our hospital (the UCD VMTH) in the past 10 years. Seventeen of these dogs were purebred dogs. Numerous breeds were represented with three keeshonds and two wire-haired fox terriers identified.
The history obtained from the client can be quite varied. An animal may show no clinical signs, may be dyspneic, may have exercise intolerance, or may be less active than previously or less active than a littermate. The puppy or kitten may grow slower than litter mates. The owner may have noted cyanosis that may be continuous or occur in episodes, especially with exercise. The patient may be dyspneic or become dyspneic with stress or exercise. Cyanotic episodes may culminate in syncope, especially with exercise. There may be other central nervous system signs, including seizures, due to polycythemia. Right heart failure is rare.
Physical Examination
The patient may be smaller than normal. Cyanosis varies from absent to severe. When cyanosis is absent, exercise may produce cyanosis. When cyanosis is present at rest, exercise often makes it worse. The cyanosis is symmetrically distributed and is best appreciated by examining the mucous membranes (oral, penile, vulvar, anal) and the sclera. In animals with black oral mucous membrane color, cyanosis is difficult to impossible to appreciate in this region.
A cardiac murmur is commonly, but not always, present. The murmur is most commonly due to the pulmonic stenosis and is usually loudest at the left heart base. The ventricular septal defect in tetralogy of Fallot is large. Consequently flow velocity is low and flow through the VSD is laminar. In dogs with right-to-left shunting, pulmonary blood flow decreases as the pulmonic stenosis increases in severity. Consequently, the murmur intensity varies inversely with the severity of the stenosis. Occasionally a dog with tetralogy of Fallot does not have a murmur.
Femoral artery pulse pressure is usually normal. In dogs with decreased pulmonary blood flow, left heart venous return is decreased resulting in a decreased left heart size. However, the combination of the decreased left ventricular stroke volume and shunt stroke volume combine to produce a normal amount of blood pumped into the aorta with each beat.
Diagnostic Tests
Radiography
The chest radiographic findings are variable, depending on the severity of the abnormalities, the chest configuration, etc. The chest radiographs are almost always abnormal. The classic findings in tetralogy of Fallot include evidence of right ventricular enlargement and decreased pulmonary vascular markings. The right ventricular enlargement is due to concentric right ventricular hypertrophy. The decrease in pulmonary vascular markings is consistent in dogs with severe tetralogy of Fallot but may not be present in dogs with less severe disease.
Electrocardiography
The electrocardiogram is usually consistent with right ventricular enlargement. Right axis deviation in the frontal plane, terminal orientation of the QRS complex toward the right ventricle, and a deep S wave in a left chest lead are all common in patients with severe right ventricular concentric hypertrophy. Arrhythmias can occur but are uncommon.
Echocardiography
A definitive diagnosis of tetralogy of Fallot can usually be made using two-dimensional and color flow Doppler echocardiography. From a right parasternal long-axis view in which the aorta is seen, the large ventricular septal defect and overriding aorta can be visualized. Color flow Doppler imaging from this site may provide evidence for laminar blood flow from the right ventricle into the aorta. The right ventricular free wall is thickened, usually to the same degree as or to a greater degree than the left ventricular free wall. Contrast echocardiography is helpful and more reliable than color Doppler echocardiography in identifying the intracardiac right-to-left shunt.
Continuous wave Doppler is not a good measure of the severity of the stenosis in patients with tetralogy of Fallot and decreased pulmonary blood flow. The pressure gradient across a valve is related to the resistance to flow (determined by the size of the orifice) and blood flow (pressure gradient = flow × resistance). In a circulation with a large ventricular septal defect imposed, the right ventricular pressure will also be maintained at 100–150 mmHg since maintenance of systemic pressure is highly regulated. Since this pressure is now regulated on both sides of the circulation, pulmonary flow and resistance will change in direct proportion to each other. Consequently, pressure gradient, and so flow velocity, are always the same (around 100 mmHg and 5 m/sec respectively).
Laboratory Evaluation
Many dogs and cats with tetralogy of Fallot have polycythemia. However, younger animals may be extremely hypoxemic and not have severe polycythemia. An arterial blood gas analysis is useful for determining the severity of the disease, especially in animals that are not polycythemic. Arterial oxygen tension has been reported to range between 39 and 64 mmHg (normal is approximately 90–110 mmHg depending on elevation) in dogs with tetralogy of Fallot.
Differential Diagnoses
Differential diagnoses include other congenital cardiac abnormalities that produce cyanosis. A right-to-left shunting patent ductus arteriosus most commonly results in differential cyanosis with the caudal regions of the body being cyanotic and the cranial regions spared. However, generalized cyanosis can occur. Examples of other congenital cardiac abnormalities that produce cyanosis include Eisenmenger’s complex, pulmonic stenosis with an atrial septal defect, double outlet right ventricle with pulmonic stenosis, transposition of the great arteries, pulmonary atresia with intact ventricular septum, truncus arteriosus, and pseudotruncus arteriosus.
Treatment
Medical Management
Phlebotomy: Medical management of tetralogy of Fallot is primarily aimed at alleviating clinical signs referable to polycythemia. Phlebotomy is the procedure of choice for the symptomatic patient with tetralogy of Fallot. Mild decreases in hematocrit can produce significant clinical benefit while overzealous phlebotomy decreases tissue oxygen delivery to the point that the patient becomes more symptomatic. The goal should be to restore the hematocrit to between 60 and 65%. Blood should be removed through a large bore catheter. The blood removed must be replaced with intravenous fluid (1 to 2 times the blood volume removed) when the blood is withdrawn.
Hydroxyurea: Hydroxyurea can be tried in cases that require frequent phlebotomies. Hydroxyurea is a myelosuppressive agent that produces reversible bone marrow suppression. It is administered initially as a loading dose of 30 mg/kg/day for 7–10 days followed by 15 mg/kg/day. Complete blood counts and platelet counts must be determined every 1–2 weeks. The side effects of hydroxyurea in the dog include anorexia, vomiting, bone marrow hypoplasia, and sloughing of the nails.
Beta Blockers: Beta adrenergic blocking drugs may be beneficial in relieving hypoxemic episodes. Propranolol appears to be the beta blocker of choice. It can be used for acute termination of a hypoxemic episode or can be used chronically to prevent hypoxemic episodes from occurring. Presumably the patients that respond to beta blockade are having hypoxemic episodes because of adrenergic drive to hypertrophied myocardium in the right ventricular outflow tract causing dynamic infundibular narrowing.
Interventional Therapy
Balloon valvuloplasty of the pulmonic valve can be attempted in dogs with tetralogy of Fallot. Although results at the UC-Davis Veterinary Medical Teaching Hospital have been varied, successful outcomes have been identified. These patients have had apparent increases in pulmonary blood flow and decreases in right-to-left shunting as evidenced by increased arterial oxygen tensions after valvuloplasty and improved clinical status. It should be noted that an improvement in the pulmonic stenosis cannot be verified using flow velocity or pressure gradient measurements.
Surgical Management
Palliative surgery can be performed in dogs with tetralogy of Fallot. The primary goal of any palliative treatment for this disease is to increase the oxygen tension in the systemic blood. Corrective surgery using cardiopulmonary bypass and open-heart surgery is commonplace in human medicine and is aimed at relieving the pulmonic stenosis and patching the VSD.
Palliative surgery consists of producing systemic to pulmonary anastomoses. The most common is an anastomosis of the left subclavian artery to a pulmonary artery. This type of shunt was first described by Helen Taussig and A. Blalock in 1945 and so carries their names. A Blalock-Taussig shunt creates an artificial patent ductus arteriosus by connecting the left subclavian artery to a pulmonary artery using an end-to-side anastomosis.
Successful palliative surgery will increase systemic oxygen tension. This increase is not generally into the normal range. The decrease in polycythemia after surgery is generally a good marker of the success of the procedure.