Gross Description

The Big Heart Disease Lie

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The body measured 160 cm and weighed 55 kg. The external exam was significant for clubbing of fingers and toes. There was no evidence of past thoracic surgery.

The heart weighed 460 g and had right ventricular prominence with a double apex. The pericardium was smooth and glistening. There was a moderate amount of subepicardial fat. The right atrium was hypertrophied, but the left was normal in size and free of thrombi. The foramen ovale was closed. The right and left ventricular wall thickness was 1.1 and 1.5 cm, respectively. Both ventricles were hypertrophied and the right ventricle was dilated as well. The membranous interventricular septum was absent, and thus there was a large high ventricular septal defect measuring 2 x 1.5 cm (Figure 38). The aortic valve, which had three normal cusps, was shifted to the right and opened over the right ventricle, with a small area overriding the ventricular septal defect. Therefore, the left ventricular outflow was through the ventricular septal defect and into the aorta. The ductus arteriosus was closed. The pulmonary artery trunk and left and right pulmonary artery branches were atrophic and fibrotic with no identifiable lumen (Figure 39). There was no associated identifiable pulmonary valve. The lungs received their arterial supply from two large bronchial arteries arising from the descending aorta. These arteries arose at the level of the aortic valve. The lungs drained via four normal pulmonary veins into the left atrium (two from each lung). The valve leaflets were delicate and pliable except for mild myxomatous change of the mitral valve. The chordae tendineae were slender. The endocardium was thin and glistening. The myocardium was brown-red of average consistency. The coronary arteries were of normal caliber and distribution with right dominance. There were no occlusions. The superior and inferior caval veins were unremarkable. The aorta showed extensive fatty streaking, especially in the abdominal portion. A non-adherent thrombus was present in the right carotid artery.

The lungs weighed 1360 g combined. The visceral and parietal pleural surfaces were adherent. Dilated pleural lymphatic vessels were seen. On section, the parenchyma showed confluent areas of firmness in the upper lobes, apices of the lower lobes and to a lesser extent in the lung bases. Within the upper lobes there were foci of necrosis.

The brain weighed 1120 g. The calvarium was unremarkable. The dural sinuses were free of thrombi. The leptomeninges over the base of the brain were focally opaque and contained exudate consistent with basal meningitis. The cerebral hemispheres were asymmetrical. The right frontal lobe was soft and replaced by an abscess (Figure 40). There was evidence of cerebral herniation with bilateral uncal grooving and necrotic tonsils. The pons was soft. The spinal cord was grossly normal.

Microscopic Description

Sections of the heart showed bilateral myocyte hypertrophy. The aorta had focal fibrous plaque and subendothelial degeneration with increased basophilic ground substance. All lobes of the lungs showed extensive bronchopneumonia with hemorrhage and associated bronchiolitis. Fungal stain revealed pseudohyphal forms in the upper lobes consistent with Candida species. The most significant finding was present in the pulmonary arteries. The small pulmonary arteries showed variable degrees of intimal hyperplasia with thickening of the media. Some vessels had evidence of complete luminal occlusion with recanalization (Figure 41). Many vessels had reduplication of their elastic lamellae making it very difficult to distinguish bronchial and pulmonary arteries. No bronchopulmonary anastomoses were identified on the sections examined.

The brain abscess showed necrotic tissue surrounded by mild gliosis. No capsule was present. Within the areas of necrosis, many gram positive cocci, some in chains, were seen associated with neutrophils and macrophages. The hippocampus had many hypoxic-ischemic neurons. In the area of the temporal horn, there was focal ventriculitis. In addition, the choroid plexus was denuded of epithelium and revealed numerous bacterial colonies as well as focal necrosis.

Case Analysis

In 1888, Professor Etienne-Louis Arthur Fallot authored a paper entitled, "Contribution 'a L'Anatomic Pathologique de la Maladie Bleue (Cyanose Cardiaque)". It is the blue sickness, or cyanotic heart disease, that is the crux of this case; the particular entity known as Tetralogy of Fallot (TOF), which represents the most common of the cyanotic congenital heart diseases. Although Fallot's paper followed prior descriptions of the syndrome by more than 200 years, it is his name that has been associated with the condition. One does not always have to be first to win the battle of the eponyms! It helps to write well and to provide a detailed report; it also helps to have your predecessors forgotten in obscurity.

Fallot detailed all of the characteristics of the syndrome at a period in medical history when interest in heart disease was attaining a new level of sophistication. He described four components (hence, tetralogy): 1.

pulmonary outflow tract obstruction; 2. ventricular septal defect; 3. dextroposition of the aorta (or aorta over-riding the ventricular septal defect); and, 4. right ventricular hypertrophy. The TOF has far more complex features than indicated by a simple listing. It also is a syndrome that is virtually never encountered today in adults, except in Third World countries that do not have easy access to open heart surgery. Early surgical repair is common and has a high level of success. Despite the rarity of the disease in adults, a case such as this is instructive at many levels. The following discussion will address many of the embryological, pathophysiological, pathological and clinical issues.

TOF is the most common of the cyanotic congenital heart diseases. This may be in part because it does not lead to intra-uterine fetal demise. There are no significant hemodynamic effects to the fetus, and the disease only becomes manifest after birth. The reasons for this will become obvious as we discuss the pathology and pathophysiology. The primary abnormality in TOF is obstruction to pulmonary outflow. The lungs are essentially nonfunctional in utero. There is high pulmonary vascular resistance with shunting of oxygenated blood returning from the placenta through the patent foramen ovale and patent ductus arteriosus into the systemic circulation. Thus, obstruction to right ventricular outflow has no effect. It is only after birth, with a fall in pulmonary vascular resistance and closure of the foramen ovale and the ductus arteriosus that symptoms may develop. Their severity and rapidity of onset depend on several factors to be described. Before we address them, however, we should discuss the embryology to better understand why the tetralogy has four components.

TOF develops as a result of a defective bulbus cordis, which is the most cranial portion of the primitive cardiac tube. It participates in separation of the aorta and pulmonary arteries, the formation of the ventricular septum, and the organization of the right ventricular outflow tract. An abnormal bulbus cordis at 5-7 weeks of fetal development leads to inappropriate septation of the truncus arteriosus, the common artery leading from the cardiac tube. If the spiral septum in the truncus is shifted toward the right, the pulmonary artery may be hypoplastic (if the shift is partial) or atretic (if the shift is complete). At the same time, since the bulbus is involved with the development of the membranous septum, its failure leads to a high ventricular septal defect. With the aorta now shifted rightward, it results in the dextroposition of the aorta over the interventricular septum immediately superior to the membranous septal defect, with blood from both right and left ventricular chambers mixing and entering the aorta. Thus, after birth, there is a venous-arterial shunt with oxygen de-saturated blood mixing with oxygenated blood. If the pulmonary artery is atretic, then the only exodus for right ventricular blood is through the ventricular septum. The bulbus also affects the development of the infundibulum (the region below the pulmonic valve), and the pulmonary valve itself. Accordingly, defects associated with tetralogy may include infundibular stenosis, valvular stenosis or atresia, pulmonary artery hypoplasia or atresia, or combinations. In the case being discussed, there was pulmonic valve and pulmonary artery atresia. Finally, the fourth component of the tetralogy is right ventricular hypertrophy. This results from increased right ventricular work secondary to increased resistance at the level of the outflow tract (if it is stenotic), and pumping against systemic pressure in the left ventricle. Characteristically, since the left ventricular volume is decreased due to less blood returning from the lungs (see below), the left ventricle is generally not hypertrophied. The total mass of the lungs may be normal, or at most moderately increased; however, most of the increase is from the right ventricle.

The question arises as to how blood reaches the lungs post-natally? If there is stenosis and/or hypoplasia of the infundibulum, valve, or artery, a decreased volume of blood will be ejected into the pulmonary artery. With time, the stenosis may remain static, or as the heart grows disproportionately to the stenotic outflow tract, it may increase in relative severity. A progressive, but slower course of obstruction may permit collateral circulation to develop to partially compensate for the decreasing flow of blood through the outflow tract. If the ductus arteriosus remains patent, this serves as a conduit. In most cases, however, the ductus closes over weeks to months after birth. If that occurs, then flow to the lungs is entirely dependent on collateral supply. The bronchial arteries arising in the aorta rapidly enlarge. The bronchial vessels in the pulmonary parenchyma anastomose with the pulmonary vessels, thus permitting some flow to reach the lungs for oxygenation. Other collaterals may also participate, including intercostal arteries and the internal mammary arteries. If the ductus arteriosus closes rapidly after birth in the setting of complete outflow tract obstruction, then either collaterals open rapidly, or death occurs. In this patient, since the ductus was closed and with complete valvular and pulmonary artery atresia, all blood supply to the lungs was through large bronchial arteries from the descending aorta. In some cases, because pressure in the right atrium may be higher than that in the left atrium, the foramen ovale remains open, thereby providing another pathway for de-oxygenated blood to reach the systemic circulation. If there is either a true atrial septal defect due to a defective formation of the atrial septum, or an acquired type of defect through a patent foramen ovale, the addition of an atrial septal defect to the four components of the tetralogy has been called Pentalogy of Fallot.

The first surgery performed for the palliation of TOF in 1945, the Blalock-Taussig operation, was an attempt to artificially create a collateral blood supply to the lungs by anastomosing the left subclavian artery to the pulmonary artery. Another early collateralization approach was the Potts anastomosis, with a surgical window between the aorta and pulmonary artery.

Until the advent of open heart surgery in the 1950's, these procedures permitted prolonged survival until the 3rd and 4th decades. These operations are still employed as temporizing measures until the baby reaches a sufficient size to allow for definitive surgical repair without significant increasing operative mortality. Alternatively, in cases where there is only partial outflow tract obstruction, immediate definitive repair can be undertaken.

The signs and symptoms of TOF are dependent on the severity of the anatomical outflow tract obstruction. There are 3 groups of patients:

1. Babies who are cyanotic at birth, usually associated with the most severe obstruction of the right ventricular outflow. Because there is generally complete atresia or marked hypoplasia of the valve and/or artery, there is no systolic murmur, or if there is one, it is of low intensity. These babies suffer anoxic spells, and they die within a short time, unless the ductus arteriosus remains open and/or collateral circulation develops rapidly, or there is surgical intervention. As collateral flow increases, there may be a continuous murmur auscultated over the left chest.

2. The most common type of TOF is the one in which cyanosis develops after one month of age, and increases in intensity during the first year of life. These babies generally have outflow tract stenosis. Accordingly, they have a loud systolic murmur, and they may not have continuous murmur of collateral flow. Anoxic spells may not occur until months after birth. Other signs and symptoms develop as they begin to ambulate. Without surgery, these infants survived until the 2nd or 3rd decades, and their death was usually secondary to stroke or congestive heart failure. Today, the natural history has been markedly improved with surgical intervention. However, with increasing numbers of adults living into their 4th and 5 th decades and beyond, after TOF surgical repair in infancy or childhood; there have been reports of significant late cardiac dysfunction secondary to a cardiomyopathy. The cardiomyopathy may even occur at an early age. Late deaths and cardiac transplantations for ventricular failure have occurred.

3. The 3rd type of tetralogy generally does not become cyanotic until after one year of age. These have been referred to as 'acyanotic or pink TOF'. They have less severe stenosis of the outflow tract, and with reduced pulmonary vascular resistance the pulmonary blood flow is adequate to prevent immediate cyanosis. They may not have anoxic episodes. Symptoms, however, do increase with age, and particularly with exercise. At rest they may not be dyspneic, but with exercise they may develop shortness of breath and cyanosis. This may also be exacerbated with cold weather. They do not have significant polycythemia. Without surgery they may survive until the

2nd to the 4 decade of life.

The general signs and symptoms include paroxysmal episodes of dyspnea on exertion, and syncope particularly associated with exercise. The infants and children have central cyanosis. They characteristically often squat, following minimal exercise. This posture is spontaneous; and it is thought to result from an attempt to maximize central blood flow to the lungs by decreasing blood flow to the legs and increasing venous return to the heart. With age and more severe cyanosis, the red blood cell mass increases, leading to secondary polycythemia. Hematocrits of 65 to 70 vol.% or higher are possible, although there are consequences to this compensatory mechanism (discussed below). Also secondary to the oxygen de-saturation (and possibly the intra-pulmonary collateral circulation) is the development of clubbing. Clubbing is a growth of connective tissue and thickening of periosteal bone at the junction between the nail and soft tissue of the fingers and toes. It is not unique to TOF, but occurs in other cyanotic heart diseases, as well as in association with lung disease (particularly carcinoma) and cirrhosis. Although hormonal stimulation and blood flow phenomena have been implicated, the etiology remains unknown.

There are signs of the condition that may be evident. Today, the diagnosis is easily made with echocardiogram. In the past, clinicians depended on chest X-ray, electrocardiogram, and ultimately ventricular angiography. The chest X-ray typically demonstrates hypoperfused lung fields. The heart may not be enlarged, but if so it is the right ventricle that increases the cardiac silhouette. The pulmonary artery segment, below the aortic knob, is either absent or decreased in prominence; depending on whether the artery is hypoplastic or atretic. The result of a prominent right ventricle and an absent pulmonary artery segment gives rise to a boot-shaped heart, or coeur en sabot. The ECG shows right axis deviation, and enlarged R waves in the right precordial leads. The degree of right ventricular hypertrophy is dependent on the degree of stenosis. On auscultation, in addition to the murmurs described above, there is a decreased second heart sound without splitting.

An unusual physical finding, virtually never seen any more because of surgical intervention, is the development of hemi-atrophy of the body. The atrophy occurs opposite the side in which the aorta arches. In other words, the normal side would be the left, if there were a normal left-sided aortic arch. Since another associated finding seen in TOF, which we have not discussed, is the presence of a right aortic arch (up to 30% of cases), the hemi-atrophy would be on the left side, with the right side normal. The condition can be diagnosed clinically with this finding alone. Obviously, on chest X-ray or echocardiography the anomaly can be confirmed. The etiology is not understood.

The complications of tetralogy have been altered by surgical intervention, but now include the late-onset cardiomyopathy and heart failure as described above. Complications include sudden death secondary to prolonged anoxic spells. Other complications are directly related to the flow across the ventricular septal defect, and flow across a stenotic pulmonary outflow tract. Thus, endocarditis may occur, particularly in regions of turbulent high velocity flow. A particular complication associated with right to left shunt, characteristic of tetralogy but not unique, is the development of cerebral abscess. This was the cause of death in our patient. Cerebral abscess is a result of flow from the right-sided circulation with organisms from the intestinal tract and elsewhere, which cross the membranous septum and gain access to the systemic circulation. It has been suggested that the decreased filtering of organisms by the hypoperfused lungs contributes to this complication. It is also possible that infected emboli may pass paradoxically across the septum and directly travel to the brain. Cerebral infection may also occur as a result of secondary bacterial seeding of bland cerebral thrombi.

Cerebral and other organ thrombi are common in tetralogy as a result of the polycythemia. Thus, thrombotic, non-infectious strokes may occur. The increased red blood cell mass enhances thrombogenesis, particularly when the hematocrit is greater than 70 vol.%. At this level, there is sludging of flow, and also decreased capillary flow with secondary local tissue ischemia. It is also important to recognize that there may be relative anemia in these children, even with hematocrits of 40 vol.%, and hemoglobin of 1013 g/dL. These levels, though normal for children without cyanotic heart disease, are distinctly abnormal for children with TOF. Iron deficiency may be an important contributing factor.

As discussed earlier, this case is extremely unusual in this era of aggressive surgical intervention. It is unknown why she was not surgically repaired, although there was speculation that it had to do with her mental retardation and placement in foster homes. She had severe pulmonary outflow tract obstruction with atresia of the valve and the artery. The ductus arteriosus was closed. Thus, the only blood supply to her lungs was through the very large bronchial arteries that extended to both sides. She did not have a murmur upon admission, although admittedly since she was in a terminal state secondary to her cerebral infection and septicemia, the cardiac contraction may not have been sufficient to generate one. She had no splitting of the second heart sound. She had clubbing, cyanosis, and polycythemia. There was moderate cardiac hypertrophy, with both right ventricular hypertrophy and mild dilatation. She died secondary to a cerebral abscess, with changes that were subacute consistent with a duration of days to several weeks. The abscess demonstrated gram-positive cocci that eventually grew gamma-hemolytic streptococcus. In addition, she had ventriculitis and meningitis, and the extensive cerebral infection led to cerebral edema and herniation. She also had bronchopneumonia. The lungs demonstrated multiple thrombi, with organization and recanalization. The latter, is another common finding in tetralogy that may contribute to late deterioration of right ventricular function due to increasing pulmonary vascular resistance, even in those patients without severe obstruction. Her survival to age 28 is fairly characteristic of TOF as an overall group (without surgery), but distinctly rare with the type of complete outflow obstruction she had. The survival can only be attributed to the large size of the bronchial collateral vessels that produced a spontaneous shunt comparable to a Blalock-Taussig anastomosis.

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