Clinical pathologic conference

Peter Harris, M.D., F.R.C.P.* Donald Heath, M.D., M.R.C.P., M.C. Puth. Paul Davison, M.D., F.R.C.P.

Birmingham, England

Clinical abstract DR. DAVISON: A young woman, 21 years of age,

was admitted to a hospital in Birmingham on April 19, 1967. She had been blue and breathless from birth. Up to the age of 7 years, she had been dys- pneic after walking only a few steps and, in 1953, she was admitted to the hospital for surgical treat- ment. Following this, her color improved and she was able to walk N mile, play games, and climb stairs without too much discomfort. She trained as a shorthand typist. In 1963, however, her excellent progress came to a halt when she required urgent treatment in a hospital in Shrewsbury, her home town. Following this, her breathlessness increased. In 1964, her ankles began to swell and this con- dition persisted. She began to cough up blood in November, 1966.

On examination, on her admission to a hospital in Birmingham, she had pronounced central cya- nosis, with gross clubbing of the fingers and toes. There was a report of “marked neck and supra- sternal pulsation.” Her systemic blood pressure was 120/70 mm. Hg. Her radial pulse rate was 80 per minute; the pulse was regular and of good volume. When sitting upright in bed, the jugular venous pressure was raised 4 cm. above the sternal notch. The apex beat was felt in the mid-clavicular line in the fifth left intercostal space. There was a parasternal impulse. The first sound was split in the apical region and the second sound was split at the base. There was a systolic murmur at the apex, but no thrills were present. An inconstant faint machinery murmur was audible in the second left interspace 1 inch from the sternal edge. The chest was resonant to percussion. There were no basal crepitations. There were no abnormal physical signs referable to the abdomen or to the central nervous system.

On April 26, cardiac catheterization was carried out. Following this investigation, she became very pale and breathless. After 5 minutes, she became unrousable and her pulse and systemic blood pres- sure were not recordable. She responded to treat- ment, and later that night her pulse rate was 120

per minute. Systolic blood pressure was 70 mm. Hg.

On the following day, she was given further treat- ment. Her systolic blood pressure had risen to 120 mm. Hg. She was drowsy, but there were no signs referable to the central nervous system.

On May I, she developed cramp-like pains in the left calf. She had pain in the chest and an irritating cough. The following day, the left lower leg became warm and swollen, and treatment for this was started. At 6:30 P.M. and at midnight, a few hours after starting treatment, she had large hemoptyses.

The following day, May 3, the left leg remained painful, and treatment was restarted. Further hemoptyses occurred.

On May 11, at IO:15 P.M., she coughed up more blood, became very dyspneic, and lost conscious- ness. Her pulse rate was 80 per minute. The systemic systolic blood pressure was recorded as 80 mm. Hg. She developed gallop rhythm. By lo:45 P.M., she was deeply unconscious. A lumbar puncture was performed. She died at 4:15 A.M. on May 12.

Irznvestigation~. On April 20, 1967, hemoglobin was 21.6 Gm. per cent; packed cell volume was 77 per cent; and mean corpuscular hemoglobin con- centration was 28 per cent. Erythrocyte sedimen- tation rate (Westergren) was 1 mm. per hour; and the white cells were normal in morphology and distribution.

Discussion

PROF. HARRIS: Perhaps I should say im- mediately, that I am not by training a “congenital cardiologist” because I am cer- tain from reading the clinical summary that we are dealing with a case of congenital heart disease. This girl was blue and breath- less from birth. If we exclude shunts in the lung, she must have had a shunt of blood from the right to the left side of the heart through a defect such as a patent ductus

From the Medical School, University of Birmingham, Birmingham, England. *Simon Marks Professor of Cardiology, Institute of Cardiology, University of London.

Vol. 77, No. 2, pfi. 267-273 February, 1969 American Heart Journal 267

268 Harris, H&h, and Davison .-1,,z. Heart 1. February, 1969

arteriosus, a ventricular septal defect, or an atria1 septal defect. Under normal cir- cumstances, the pressures in such defects are such that the blood flows from left to right so that we must postulate the exis- tence of an added factor to explain the flow of blood in the opposite direction.

One determining factor is the relative resistances of the systemic and pulmonary circulations. Thus, if the pulmonary vascu- lar resistance becomes raised, the flow will be reversed from pulmonary artery to aorta. This is associated with structural changes in the small puhnonary arteries which progress from medial hypertrophy, through obstructive intimal lesions, to bizarre “dila- tation lesions.” Such hypertensive pulmo- nary vascular disease takes time to develop, however, and even a large patent ductus arteriosus or ventricular septal defect does not cause reversed flow of blood from birth. Hence, I believe that we can exclude the possibility of a congenital cardiac shunt with pulmonary hypertension and a re- versed shunt in this case. We may, never- theless, need to return to these hypertensive vascular lesions later on to explain the clinical features of this case.

A second factor to explain the reversal of blood flow may be a mechanical obstruc- tion, say in the form of pulmonary stenosis, which will lead to preferential flow into the aorta. The combination of pulmonary ste- nosis at the valvular or subvalvular level with a septal defect is not uncommon. The commonest lesion here is Fallot’s tetrad. Another possibility is tricuspid atresia where blood flows from right to left through an atria1 septal defect to the left atrium and left ventricle; usually, there is associated pulmonary stenosis. A combination of atria1 septal defect and pulmonary stenosis is quite common, but again, cyanosis usually occurs later in life. Mixing of streams of blood with the flow of deoxygenated blood into the aorta also occurs in persistent truncus arteriosus or t.ransposition of the great vessels. It seems likely, even in per- sistent truncus, that there must be some diminution of blood flow to the lungs to produce cyanosis, say with a sole bronchial arterial supply to the lung. Even in trans- position, the great flow prevents all but minimal cyanosis, unless there is associated pulmonary stenosis. There are many rare

forms of cyanotic congenital heart disease, but we have considered the most likely ones.

In 1953, she had surgical treatment. In general, such treatment for congenital heart disease may be either palliative or correc- tive. At that time, the surgical treatment most likely to have been carried out was palliative to increase the flow of blood to the lungs. This would have been done by the creation of a systemic-pulmonary anas- tomosis such as by the Blalock-Taussig or Pott’s operations. The impact that this type of surgery had on cyanotic congenital heart disease is well demonstrated in this case, for her life was changed into an active one for 10 years, and she was able to train as a shorthand typist.

Then, in 1963, her excellent progress came to a halt and she needed urgent treat- ment. If she had Fallot’s tetrad, she might have developed a paradoxical embolus or, even more likely, a brain abscess.

Her breathlessness increased, and her ankles began to swell, presumably because she developed congestive cardiac failure. She also coughed up blood. Why should she do this with diminished pulmonary blood flow? Had she developed significant pulmo- nary hypertension as a result of the crea- tion of too large a systemic-pulmonary anastomosis with a pathological increase of pulmonary flow? If pulmonary vascular resistance increased, the initial left-to-right flow through the anastomosis might be diminished and then even reversed.

As to the physical signs, her increased neck pulsation with a systemic blood pres- sure of 120/70 mm. Hg leads me to believe it was venous rather than arterial in nature. This might be due to a raised pressure in the right atrium and neck veins with ac- centuated normal “a” and “v” waves. There might be obstruction of blood flow

out of the right atrium making the “a” waves abnormally high. Finally, she may have developed dilatation of the tricuspid ring due to right ventricular hypertrophy and dilatation leading to tricuspid incom- petence. The jugular venous pressure was raised so she was in congestive cardiac failure.

The left parasternal impulse implies right ventricular hypertrophy. I note, that the first cardiac sound was split. Normally this

sound does have 2 components. An alterna- tive explanation is that after the first sound, there was an extra clicking noise due to an impact of blood coming from a hyper- trophied ventricle into a dilated aorta as in Fallot’s tetrad or a persistent truncus.

It is difficult to explain why the second sound at the base was split. All the abnor- malities I have considered have one thing in common, that the second sound at the base is single. A phonocardiogram in Fal- lot’s tetrad may show splitting of the second sound with an asynchronous closure of the aortic and pulmonary valves because the right ventricle empties more slowly than normal and the closure of the pulmonary valve is delay-ed. Normally, this is not suf- ficiently loud enough to be heard. If she had developed pulmonary hypertension, this might give rise to an audible pulmonary component of the second sound. There was a systolic murmur at the apex and I think it likely that this was due to a tricuspid leak. If pulmonary stenosis was present, one would have expected the murmur in the pulmonary area.

An inconstant faint machinery murmur was audible in the second left interspace. This implies a systemic-pulmonary shunt which could be due to either the artificial shunt or an abnormal bronchial circulation. One would have expected the murtnur to be loud and consistent if it had been due to the surgical shunt, but it may have been modified by the development of pulmonary hypertension.

Finally, she had a cardiac catheterization on April 26. Following it, she became pale and breathless and her pulse and blood pressure were unrecordable. I think it most likely that this girl was critically ill with congestive cardiac failure and had a simple vasovagal attack. This led to a critical lessening of pulmonary blood flow and, hence, to serious cerebral hypoxia. Para- doxical thromboembolism is a less likely alternative. She responded readily to treat- ment, and there were no signs in the central nervous system to indicate the presence of an embolus.

Then, on May 1, she developed cramp- like pains in the calf, pain in the chest, and an irregular cough. It is evident that she had a venous thrombosis and I am sure that her doctors felt that they had to treat

this with anticoagulants. A few hours later, she had a large hemoptysis and presented the clinicians with a terrible dilemma. If the hemoptysis was due to embolism, the cor- rect treatment was anticoagulation. If the hetnoptysis was due to local pulmottary arterial disease, the correct treatment would be not to give anticoagulants. Also, these patients with polycythemia may have an abnormally low platelet count so that

Fig. 1. Radiograph of chest taken on April 20, 1967, showing “coeur en sabot,” dextroaorta, pulmonary oligemia, and evidence of a previous left-sided thoracotomy.

Fig. 2. Angiocardiogram taken on April 26, 1967. ‘There is an over-riding aorta with dextroaorta. A large tortuous left internal mammary artery is anastomosed to the left pulmonary artery. There is no sign of a pulmonary trunk, the pulmonary arteries are small, and the lungs are oligemic.

270 Harris, Heath, and L3uvison AWL Heart 2. February, 1969

they have prolonged clotting and bleeding time making the use of anticoagulation difficult. More hemoptyses occurred and she became unconscious and died. In conclu- sion, from the clinical history, I believe she had Fallot’s tetrad with an artificial sys- temic-pulmonary anastomosis which had led to pulmonary hypertension.

May I now see some radiographs of the chest? Well, the radiograph taken on April 20 (Fig. 1) shows right ventricular hyper- trophy, and there is no shadow of a pulmo- nary trunk. These are the appearances of so called “coeur en sabot.” The lung fields are oligemic. There is also radiographic evidence of the previous left thoracotomy. These features are consistent with Fallot’s tetrad with a right sided aortic arch. The pulmonary oligemia suggests that my con- jecture that she had pulmonary hyper- tension due to an abnormally high flow through the anastomosis was wrong. Per- haps this had become blocked by thrombus.

DR. DAVISON: Here is the electrocardio- gram (ECG) taken on the same day.

PROF. HARRIS: This shows sinus rhythm and right axis deviation and confirms the presence of right atria1 and right ventricu- lar hypertrophy.

DR. DAVISON: Here are some angiocardio- grams in sequence taken during cardiac catheterization (Fig. 2).

PROF. HARRIS: These are of interest. So far as the aorta and its branches are con- cerned, the angiocardiogram shows an over- riding aorta, dextroaorta, and a dilated tortuous artery arising from the aorta and clearly passing to the left lung, presumably to be anastomosed to the left pulmonary artery.

DR. DAVISON: The surgeon described the vessel as an aberrant left internal mam- mary artery.

PROF. HARRIS : The angiocardiogram shows no sign of a pulmonary trunk. The pulmo- nary arteries appear to be very small and the lungs are oligemic. I am wondering if she had developed some lesion like wide- spread thrombosis in the small pulmonary arteries preventing blood getting to the lungs.

PROF. D'ABKELJ: Was a blood culture done at any time?

DR. DAVISON: No. She was never febrile. PROF. BREWER: What blood pressures

were recorded at the cardiac catheteriza- tion?

DR. DAVISON: The pressure in the right atrium (mean) was 5 mm. Hg and in the aorta was 125/75 mm. Hg. We found that the catheter passed easily from the right ventricle into the aorta but despite re- peated attempts we could not enter the pulmonary trunk from the right ventricle. The oxygen saturation in the right atrium was 43 per cent and in the aorta 59 per cent.

MR. MAYOU: What did the cerebrospinal fluid show?

DR. DAVISON: It was a clear colorless fluid with one white cell per cubic millimeter. There was 156 mg. of glucose per 100 ml., 20 mg. of protein per 100 ml., and 736 mg. of chloride per 100 ml. Do you think that the worsening of cyanosis was associated with puberty and increased oxygen de- mand?

PROF. HARRIS: It might well have been since the valve orifice grows as a function of the square of the radius, whereas body oxygen requirements grow as a function of the cube of the bodily dimensions.

DR. ALLISON: Is it not possible that the recurrent hemoptyses were due to multiple pulmonary thromboses rather than pulmo- nary hypertension? Diminished pulmonary flow and associated polycythemia could certainly account for such widespread pul- monary thrombosis.

PROF. HARRIS: Certainly, pulmonary thrombosis is common in Fallot’s tetrad and increases with age. I don’t know, how- ever, if they give rise to hemoptysis. How- ever, it is certainly true that the throm- botic lesions do not give rise to pulmonary hypertension. We must remember that hemoptysis can occur in Fallot’s tetrad without pulmonary hypertension.

DR. DAVISON: Perhaps we can now ask Dr. Heath to tell us what he found at the post mortem.

DR. HEATH: The body was that of a slightly built girl showing cyanosis of the mucous membranes and clubbing of the finger and toenails. The heart was consider- ably enlarged. The right atrium was dilated. The tricuspid valve was normal in struc- ture, but the valve orifice was dilated. The right ventricle was dilated and hypertro- phied, its thickness being 13 mm. There was a large membranous ventricular septal de-

Volrwm 77 Number 2 Clinical pathologic conference 271

Fig. 3. The heart has been opened through the hypertrophied right ventricle and over-riding ascending aorta to show the large membranous ventricular septal defect.

B

Fig. 4. A, Dissected great vessels. To the left is the thick-walled aorta. To the right is the thin-walled pulmo- nary trunk showing the features of “coarctation of the pulmonary artery.” At the origin of this is the atretic pulmonary valve. B, The atretic pulmonary valve with a hypoplastic pulmonary trunk arising above it.

Fig. 5. The systemic-pulmonary anastomosis. The aberrant left internal mammary artery is shown to the left. The thin-walled pulmonary artery is shown to the right. TWO pins have been inserted slightly to the left of the site of anastomosis.

272 Harris, Heath, and Davison

B

Fig. 6. Transverse sections of the 2 great vessels stained to show their elastic tissue pattern. (Both Elastic/Van Gieson, X100). A, Aorta. There is a dense network of parallel long elastic fibrils. B, Pulmonary trunk. There is a sparse network of short clumped elastic fibrils.

Fig. 7. Transverse section of left internal mammary artery used in the systemic-pulmonary anasto- mosis. The internal elastic lamina is disrupted due to organization of superimposed thrombus. The media is of typical systemic structure. (Elastic/Van Gieson, X 50).

feet allowing free communication between the 2 ventricles (Fig. 3). The pulmonary valve was minute and atretic (Fig. 4). Arising above this was a small, thin-walled pulmonary trunk showing the features of the so-called coarctation of the pulmonary trunk (Fig. 4). This passed upward and to the left of the aorta and then divided into

two. The hypoplastic right pulmonary artery passed behind the ascending aorta to the right lung. The hypoplastic left pul- monary artery passed to the left lung. It had been anastomosed to an aberrant left internal mammary artery (Fig. 5). Distal to the site of the systemic-pulmonary anas- tomosis, the left pulmonary artery was dilated but still thin-walled. The venae cavae and the pulmonary veins were nor- mal. The left atrium was of normal size. The mitral valve was normal in structure and circumference. The left ventricle was normal in thickness. The aorta was over- riding. The aortic valve was normal in structure but was dilated. Both ventricles communicated with the aorta, and with one another through the ventricular septal defect.

The lungs were congested and there were large hemorrhages into the parenchyma consistent with having followed anticoagu- lant therapy. The brain was deeply con- gested. So too were all the abdominal viscera, including the spleen and kidneys. The liver showed the “nutmeg pattern” of chronic passive venous congestion and the fatty element of this was more pronounced than usual.

It is of some interest to consider the structure of some of the arteries concerned in this case.

The thick-walled aorta showed a normal dense network of elastic tissue in its media composed of roughly parallel long elastic fibers (Fig. 6, left). The hypoplastic pulmo- nary trunk showed a characteristic “hypo- tensive configuration” generally associated with states of diminished pulmonary arte- rial pressure and flow (Fig. 6, right).’ The elastic tissue was sparse and clumped to- gether. The left internal mammary artery showed the characteristic structure of a muscular systemic artery, with a well- defined muscular media with 2 distinct elastic laminae. There was heaped up in- timal fibrosis in this vessel which was found to be due to organization of thrombus with disruption of the underlying internal elastic lamina (Fig. 7). The small pulmonary ar- teries were very thin-walled and contained eccentric nodules of organized thrombus (Fig. 8). This histological picture is highly characteristic of diminished pulmonary arterial pressure and flow with associated

Clinictrl pathologic conference 273

A

Fig. 8. Sections of 2 small pulmonary arteries. (Both stained by Elastic/Van Gieson, X 130). A, Longitudinal section of artery showing recanalized thrombus. B, Transverse section of artery showing eccentric nodules of organized thrombus.

polycythemia. 2-3 The small bronchial ar- teries, easily recognized by their thick band of intimal longitudinal muscle, were un- usually prominent in sections of the lung suggesting the development of a collateral bronchial circulation.

Sections of the lung were solid with blood due to the hemorrhage into the paren- chyma. The liver showed pronounced fatty change as was evident from its macroscopic appearance. Finally, sections of the myo- cardium showed considerable areas of fibro- sis possibly related to patchy coronary arterial ischemia brought about by small thromboses in the radicles of the coronary arterial tree due to polycythemia.

In summary, the appearances were those of pulmonary atresia with so-called coarcta- tion of the pulmonary trunk. The associated diminution in pulmonary arterial pressure and flow had led to atrophic changes in the pulmonary trunk and widespread throm- bosis in the pulmonary arteries. The inade- quate blood supply to the lung had been alleviated by the previous performance of a systemic-pulmonary anastomosis and this had resulted in prolonged survival. There

was also evidence of a collateral bronchial circulation. Death appears to have resulted from severe hemorrhage into the lungs. Patchy myocardial fibrosis appears to have followed focal coronary thrombosis, also related to the polycythemia.

Diagnosis

Pulmonary atresia with coarctation of the pulmonary trunk. Widespread pulmo- nary arterial thrombosis. Surgical systemic- pulmonary anastomosis and bronchial col- lateral circulation. Pulmonary hemorrhage.

REFERENCES

1. Heath, D., DuShane, J. W., Wood, E. H., and Edwards, J. E.: The structure of the pulmonary trunk at different ages and in cases of pul- monary hypertension and pulmonary stenosis, J. Path. Bact. 77:443, 1959.

2. Best, P. V., and Heath, D.: Pulmonary throm- bosis in cyanotic congenital heart disease with- out pulmonary hypertension, J. Path. Bact. 75:281, 1958.

3. Heath, D., DuShane, J. W., Wood, E. H., and Edwards, J. E.: The aetiology of pulmonary thrombosis in cyanotic congenital heart disease with pulmonary stenosis, Thorax 13:213, 1958.