Congenital A study before
of the pulmonary and
S. Fragoyannis, A. h7ardalinos, London,
he general interest in obstructive pulmonary hypertension, secondary to left-to-right shunt in congenital heart disease, began shortly after Gross’ treated patients who had patent ductus arteriosus by ligating the patent vessel. It was found later that patients with high pulmonaq pressure died during or soon after operation because of right ventricular failure2Jthe defect had been acting as a safety valve by which the right ventricle was protected from high pressure in the pulmonaqcirculation. The incidence of fatal pulmonary hypertension and the concomitant obstructive lesions in the pulmonary arteries, due to an artificial shunt between the systemic and pulmonary circulation, has been studied b, M’agenVoort and co-workers4 and Ross and associates.5 Pulmonary vascular changes analogous to those seen in congenital heart disease with left-to-right shunt have been produced experimentally by creating such an artificial shunt.6 Although considerable work has been done in this field, the exact mechanism responsible for the vascular changes is not known. It has been suggested that the structural changes of the intima of the small arteries and arterioles develop in ‘From the Hospital for Sick Children, London, Received for publication Sept. 18. 1961.
response to passive and hyperkinetic pulmonary hypertension, and gradually obliterate the pulmonary vascular b&d.7 Another view postulates a congenital deficiency of the media of the small pulmonary arteries, which results in intimal fibroelastic thickening as a protective reaction which finally obstructs the vascular lumen.* In an attempt to throw some light on the pathogenesis of the pulmonary vascular lesions in congenital heart disease, both in patients who have lung ischemia and in those who have had an artificial systemic pulmonary shunt, we have examined the histologic lesions in the vessels of infants and young children who suffer from the tetralogy of Fallot, tricuspid atresia, or pulmonary atresia. In evaluating the vnrious morphologic pictures we have considered the effect of age and have introduced new standards and values intended to put the work on a sound basis. Lye have also compared the histologic appearances of the vessels of the lung on the same side as the anastomosis with those of the opposite lung as well as with those of normal control subjects, and we have related the lesions to the age at operation and the duration of the shunt. England.
Ihble 1. Clinical
Cause of death
HNE PO HE PP?
On the operating table
data of patients studied
5 “lo. 5 mo.
S&ED) ESM, SSS
RVH RAH LVH RVH
On the operating table On the operating table
PVS stenosis PA, TA PVA agenesis
On the operating table
HE PP? HE PO
On the operating table Pneumonia
On the operating table
RVH P.PI. RVH
HNE PO HNE PO HE PO
HAV Dextrocardia RVH
After angiography HF
HNE PO HNE PO HNE PO
On the operating table
PVA ASD, PDA
On the operating table
ESM: Ejection systolic murmur SSS: Single second sound GM: Gibson’s murmur UND: Undetermined WSSS: Wide split second sound IDM : Immediate diastolic murmur Pr.M : Presystolic murmur CM: Continuous murmur RVH: Right ventricuIar hypertrophy LVH: Left ventricular hypertrophy RAH: Right atria1 hypertrophy IRBBB: Incomplete right bundle branch block P.Pl: P-pulmonale BVH: Biventricular hypertrophy HAV: Hypertrophy of anterior ventricle HNE: Heart not enlarged PO: Pulmonarv oligemia HE: Heart enlargement PP: Pulmonary plethora PA: Pulmonary atresia PDA: Patent ductus arteriosus SS: Second sound TA: Tricuspid atresia ASD: Atria1 septal defect VSD: Ventricular septal defect PVA: Pulmonary valve
agenesis HE PO HNE PO
The age of the patients ranged from 2 months to 8 years. Each had been investigated during his life and found to have congenital heart disease with oligemic lungs. Each had had a complete physical
TF: HF: Inf.:
Tetralogy of Fallot Heart failure Infundibular
examination with roentgenogram of the chest and heart, and electrocardiogram (Table I). A phonocardiogram was taken in 10 patients, but none had had a cardiac catheterization. In all but 10, heart failure was established as the cause of death. Of
the 10, one died of pneumonia, 7 died either on the operating table during an attempt to develop a systemic-pulmonary anastomosis or a few hours afterward, and one died after angiography. Seven patients underwent successful operations to create anastomoses, and had a postoperative survival time which varied from 3 days to 10 months (Table II). Postmortem examinations were performed on all, and the available data are summarized in Table III. Sections were taken from each lung, slightly below the level of the hilum, from
the apex of the lower lobe in a plane at right angles to the main vessels so that they included both large and small vessels. -411 the sections were from tissues which had been fixed for at least 3 days in a solution of 10 per cent formalin, and standard paraffin blocks were prepared. At least five serial sections at 25, intervals, to a total depth of approximately 300~, were cut from each block. Each section was stained with Weigert’s elastic stain, counterstained with van Gieson’s for collagen tissue, and neutral red for nuclei. The muscular arteries
Table Il. Data relating to operative procedure Anastomosis Case number
Age at first operation First
1. 3. 4. 5. 14. 16. 17.
8 10 4 3 3 16 38
wk. wk. wk. wk. mo. mo. mo.
Table III. Postmortem -
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.
Potts procedure, Blalock, left BIaIock, left Blalock, left Blalock, left Blalock, left Blalock, left
Age at second operation left
8 wk. 8 wk. 10 wk. 10 wk. 3 mo. 4 mo. 5 mo. 5 mo. 5 mo. 8 mo. 11 mo. 11 mo. 15 mo. 13 mo. 17 mo. 21 mo. 3% yr. 8 yr.
Key to abbreviations:
Not done Not done 10 wk. 3 mo. Not done 21 mo.; pulmonary Not done
8 12 10 3 13 21 42
wk. wk. wk. mo. mo. mo. mo.
3 14 6 10 10 5 4
days days wk. wk. mo. mo. mo.
data of the cases examined
Weight of heart (Gm.)
Age at death
28 40 54 42 54 N.A. 42 70 56 42 112 70 84 58 148 SE. 190 80
Weight Caliber of anastomosis
Right ventricle (cm.)
Left ventricle (cm.)
RigM lung (Gm.1
Left lutlg (GM.1
H 1.0 0.3 0.1 N.A. N.A. 1.5 1.5 0.8 H 0.8 0.7 1.0 1.1 N 0.8 1.0
N N 1.0 1.2 N.A. N.A. 1.5 N..?\. 0.8 N 0.8 1.0 0.5 1.1 H 1.0 1.0
40 26 28 44 46 N.A. 64 68 52 30 92 55 96 54 52 62 90 N.A.
40 26 36 40 44 N.A. 50 59 48 30 44 50 104 38 48 60 80 N.A.
3.0 mm. 3.0 mm. Thr. N.A. 0.3 cm. N.A. 0 3 cn,. N.A. 0.3
cm. N.A. 0.5 cm. N.A. enlarged.
Fig. 1. The mean transitional diameter (JITD) and mean medial value (MMTI) of pulmonary muscular arteries in 25 normal infants and children used as controls; plotted as a function of age. MT11 in microns. MMV as per cent of external diameter.
lyig. 2. The mean transitional diameter (MTD) and mean medial value (IMMII) of pulmonary muscular arteries in 18 patients who had congenital heart disease with ischemic lungs; plotted as a function of age. MTD in microns. MMV as per cent of external diameter.
were examined over an area of 2 square centimeters, and their external diameter and the ratio of the thickness of the medial coat to the external diameter were recorded. A mean value was extracted in each section for both external diameter (MTD) and medial value (MMV). The ten with the minimal values were considered to be reasonable representatives of the mean values at the terminal portion of the muscular segment, i.e., the transitional region. We did not adopt the method of naming an artery according to its diameter9 since we thought that it was unsatisfactory in a group of young patients, because of the considerable variance in the caliber of the
lumen with age. According to our classitication, an artery with more than two distinct, complete elastic laminae in its wall, regardless of its caliber, has been called “elastic.” The area of transition in which the elastic artery becomes muscular, wherein there are only two complete elastic laminae, together with a definite middle muscular layer, is not considered in this study. On the other hand, the transitional zone between a muscular artery and an arteriole, with its smaller diameter and thickness of the media, has been found to be particularly important. Although stable in pulmonary vessels of persons without congenital heart disease or pulmonary hypertension, it presents considerable variations in the various types of congenital heart disease associated with pulmollar> plethora or oligemia. The stillborn, full-term infant with no congenital heart disease has show11 an MTD that ranges from 23 to 27~ and an MM\’ of 22 to 26 per cent. Soon after respiration starts in the newborn infant the same area is dislocated centrally to an MTD of 40 to 45~, with an MMV of 15 to 20 per cent (Fig. 1). There is some thinIling of the wall, yet the total quantity of the muscle tissue is ilot decreased, but rather slightly increased. The arterioles, which in the fetus exhibit a considerable amount of muscle fibers but poor elastic tissue, expand as the muscular coat thins, so that there is a progressive development of the muscle and the elastic laminae. Thus, an arteriole which previously had 50 45 c
3 1 5 6 v/k.
8 10 2 4 6 Mea.
8 10 11 12
Fig. 3. The mean transitional diameter (MTD) and mean medial value (MA&V) in pulmonary muscular arteries of 7 patients with congenital heart disease after a systemic-pulmonary anastomosis; plotted as a function of duration of shunt. MTD in microns. MMV as per cent of external diameter.
Congenital heart disease with pulmonary
Fig. 4. A, A pulmonary arteriole in a stillborn infant used as a control. There is a considerably thickened muscular wall of approximately 32 per cent of the external diameter (28~). B, From a 3-day-old infant, a pulmonar) arteriole of the same size with thinner muscular wall (24 per cent) and a wider lumen. Poor elastic tissue is present (28~). C, A terminal pulmonary artery from a S-month-old infant. Note the thin muscular layer of 16 per cent thickness and the well-developed elastic tissue (23~). D, Terminal pulmonary artery in a 2-year-old child used as a control. The muscle shows thinner layer (9 per cent) and it has been centrally dislocated (SO,). E, Normal terminal pulmonary artery in a 3-year-old child. Medial thickness of only 6 per cent (55~).
only one elastic ring may, in a few months, appear as a small but well-developed muscular arterv with two clearly differentiated elastic laminae and a well-defined muscular layer (Fig. 4). Results The available data on the 25 normal control subjects are summarized in Fig. 1. It is apparent that the medial thickness, which is considerable in the stillborn, full-term infant (MMV of 20 to 25 per cent), rapidly declines to 10 to 15 per cent within a few months; and this decline continues at a slower pace until the age of 4 years, when a slight rise appears. When we consider these values in the transitional zone of the muscular arteries, we find them in sharp contrast: the mean transitional diameter rises rapidly soon after the child begins to breathe (40 to SOP), with a short decline which lasts until the age of approximately 1 month, and a steady rise thereafter until it reaches between 60 and 80~. It is assumed, therefore, that a relative increase in the muscular tissue takes place during the first month of life. In early infancy, the ischemic lungs of the patients we studied showed no great difference in the over-all external diameter of the transitional pulmonary muscular vessels, but the medial coat was strikingI>, and consistently thin (MMV of 4 to 16 per cent). The small fluctuation in the values of medial thickness compares with the wide range of the transitional diameter (25 to 75~) (Fig. 2). Small muscular vessels (MTD of 2.5~) have appeared in onI?3 patients (Cases 2, 8, and lo), and their muscular thickness was almost comparable to that seen in patients who have congenital heart disease with plethoric lungsID The other patients have shown a minimal amount of middle muscular coat, that is to say, a relative loss of muscle tissue (Fig. 2), in striking contrast to the homolateral lungs of the surgically treated patients in whom the values tended to approach those of the normal controls (M&I\’ of 10 to 15 per cent and LlTD of 23 to 35~) (Fig. A), i.e., the medial transitional zone was dislocated distally and the thickness appeared to be greater, a relative gain of muscle tissue. There was no apparent correlation between the medial thickness and the size
of the anastomosis or the postoperative survival time. No obstructive changes were observed which could be attributed to the increased flow of blood. The MTD and MMV of the pulmonary arteries were found to be similar both in the lungs of the normal controls and in the lungs on the same side as the anastomosis. The slight degree of intimal proliferation found in the muscular pulmonary arteries (Cases 4, 5, 16, and 18) was not attributed to the shunt since it was found in both lungs (Figs. 6 and 8), but in Cases 3, 8, 9, 12, and 14 there were widespread thromboses of the bronchial arteries on both sides (Figs. 5 and 6). There were a few similar thrombi in Cases 8, 9, 12, md 14 which differed widely in the degree of organization (Figs. 6 and 7). N’e found a slight fibroelastic thickening of the intima of the large elastic arteries in Cases 5, 6, 15, and 16, and a moderate degree in Case 18 (Fig. 6). There was some venous thrombosis in Cases 4, 12, and 18 (Figs. 5 and 8). Furthermore, Cases 8 and 18 exhibited multiple defects of the media of the middlesized arteries, but the fibroelastic proliferation seemed to be entirely independent of these defects (Fig. 8). Discussion The relative increase in the middle coat of the small pulmonary arteries on the same side as the anastomosis, as indicated by the low transitional zone of 23 to 35~ and high medial thickness of 10 to 15 per cent (Fig. 3), is probablv the result of a stimulus exerted by the jncreased flow of blood. The size of the anastomosis was such as to suggest that the reduced circulation in the corresponding lung was corrected without excessive inflow of blood, and the roentgenographic appearances c-onfirmed the fact that the systemic pulmonary anastomosis was working efficiently. That all patients who had a postoperative period which ranged from 3 da)-s to 10 months were without obstructive lesions, such as are usually attributed to a shullt, is an optimistic finding which indicates the importance of the size of an anastomosis capable of allowing a normal or neari\, normal puln~onary flow. Although a large shunt usually guarantees a dramatic improvement in the condition of the pa-
Congenital heart disease with pulmonary
tient, it is apt to initiate a secondary obstructive hypertension, which eventually proves fata1.4v5 The relative loss of arterial muscle tissue in the opposite lung and in the lungs of patients not treated by operation,
and the fact that patients with successful anastomoses between the two circulatory systems tend to restore the media of the small pulmonary arteries to normal (Fig. 3) are strong indications of the importance of
Fig. 5. .-I, Case 3; right lung. ;\ large bronchial artery markedly dilated and thrombosed; half of the lumen is still patent (X370). B, Case 3; left lung. A distal pulmonary muscular artery with an external diameter of 30~ and medial thickness of 15 per cent (X370). C, Case 4. Pulmonary artery showing intimal fibroelastic thickening (X370). D, Case 4. The transitional zone from a pulmonary muscular artery to an arteriole, with an external diameter of 30~. E, Case 4. Wall of a vein with fibroelastic thickening projecting into the lumen (X370). F, Case 4. Prominent venous tree compared with an elastic artery giving rise to a muscular branch (X38).
Fig. 6. A, Case 5; left lung. Terminal pulmonary artery of 40,~ external diameter and 12 per cent medial thickness. B, Case 5; right lung. In the opposite lung of the same patient as in A, a distal artery of 80~ diameter and 12 per cent medial thickness, showing slight but diffuse intimal proliferation. C, Case 8. Note the prominent bronchial arteriai tree, and one small muscular artery branching off an arteriole (X 100). D, Case 9. Large thrombus in a bronchial artery leaving a narrow crescent-shaped lumen (X370). E, Case 10. Prominent pulmonar) arterial tree with thick media (X 100). F, Case 12. Two bronchial arteries with organized and recanalized thrombi (X58). (For Fig. 6,G, see top of opposite page.)
Fig. B,G. Case 12. A very elastic artery (X38).
Fig. 7. A, Case 14; right lung. Bronchial artery showing an organized thrombus (X370). R, Case 14; left lung. Pulmonary artery with an external diameter of 40~ and 14 per cent medial thickness. C, Case 16; left lung. Elastic artery showing intimal fibroelastic thickening (X38). D, Case 16: left lung. Pulmonary arteries of 38~ diameter and 12 per cent medial thickness.
Am Heart J. March, 1962
Fig. 8. A, Case 18; right lung. Pulmonary artery showing defects of the media1 layer and ring-like intimal thickening which considerably reduces the lumen (X370). B, Case 18; left lung. A middle-sized muscular artery with intimal thickening on the right side, and considerable thinning of the opposite wall, probably representing defective development (X370). C, C ase 18. Marked intimal proliferation and partial occlusion of the lumen in a small vein (X370).
the blood flow as the essential stimulus for the maintenance of the muscular tissue and its normal functions. The importance of evaluating the flow immediately after operation cannot be overstressed. The mild obstructive lesions in the pulmonary arteries and veins of 7 of the 18 patients had no apparent association with the anastomosis; these lesions were also equally obvious in the patients with ischemic lungs. It has been suggested that a progressive thrombosis of the pulmonary arteries follows the increased viscosity which results from secondary polycythemia and reduction of the blood flow.” A direct relationship between the obstructive lesions and the age of the patient has also been postulated.r2 The prominent bronchial arterial tree noted in 12 of the 18 patients, with throm-
botic lesions in Cases 3, 8, 9, 12, and 14 (Figs. 5 and 6)) has been regarded as a compensatory mechanism to facilitate the flow of blood into the oligemic lungs. The thrombotic lesions in the bronchial arteries are probably due to the combination of at least two factors, both of which result in sluggishness of the circulating blood: one is the already recognized secondary polycythemia which accompanies thrombosis of the pulmonary artery; and the other is the abnormal dilatation of the vessels, which are unable to accommodate such an increased collateral circulation. Although one would expect an increased rate of flow in these vessels because of the difference in pressures between the two circulations, the anomalous dilation of the vessel walls does constitute an important predisposing factor to the development of the thromboses.
In 18 infants and young children with congenital heart disease associated with pulmonary oligemia the condition of the middle muscular layer of the small pulmonary arteries has been evaluated and compared with that in the lungs of 2.5 normal control subjects and that in the lungs, homolateral to a systemic-pulmonary anastomosis, of 7 surgically treated patients. Age, duration of shunt, and size of anastomosis were taken into consideration in the evaluation of the results. In order to standardize the results, the mean values of external diameter and medial thickness were calculated at the zone of transition between the arteries and the arterioles. It was observed that the muscular tissue tended to revert to normal after a welljudged systemic-pulmonary anastomosis. The possibility was suggested that the flow of blood is the important factor in maintaining the normal quantity and function of the muscular tissue. A relative loss of muscle in the arteries of the oligemic lungs was also observed, and slight intimal thickening unrelated to the anastomosis. A possible cause of the prominent bronchial arterial tree with a high incidence of thrombosis is also suggested. We wish to thank Dr. Martin Bodian and Dr. B;u-bara Ockenden for permission to use their material in this work and for providing the necessary laboratory facilities. We also wish to thank Mr. L. Spain for his technical assistance. REFERENCES 1. Gross, ductus gically
heart disease with pulmonary
R. E.: Surgical management of patent arteriosus, with summary of four surtreated cases, Ann. Surg. 110:321, 1939.
Johnson, E. R., Wermer,I’., Kuhner, M., and Cournand, A.: Intermittent reversal flow in a case of patent ductus arteriosus. A physiologic study with autopsy findings, Circulation 1:1293, 1950. Swan, H., Trapneil, J. M., and Denst, J.: Congenital mitral stenosis and systemic right ventricle with associated pulmonary vascular changes frustrating surgical repair of patent ductus arteriosus and coarctation of aorta, AM. HEART J. 38:914, 1949. WagenVoort, C. A., DuShane, ;. W., and Edwards, J. E.: Cardiac Clinics No. 151; hypertensive pulmonary arterial lesions as a late result of anastomosis of systemic and pulmonary circulations, Proc. Staff Meet. Mayo Clin. 35:186, 1960. Ross, R. S., Taussig, H. B., and Evans, M. H.: Late hemodynamic complications of anastomotic surgery for treatment of tetralogy of Fallot, Circulation 18553, 1958. Heath, D., Donald, D. E., and Edwards, J. E.: Pulmonary vascular changes in a dog after aorto-pulmonary anastomosis for four years, Brit. Heart J. 21:187, 1959. Q’ood, P.: Diseases of the heart and circulation, London, 1956, Eyre S: Spottiswoode, p. 838. Evans, W. : Congenital pulmonary hypertention, Proc. Roy. Sot. Med. 44:600, 1951. Brenner, 0. : Classification of pulmonary arteries, Arch. Int. Med. 56:211, 457, 724, 97.5, and 1189, 1935. WagenVoort, C. A., Neufeld, H. N., DuShane, J. W., and Edwards, J. E.: The pulmonary arterial tree in ventricular septal defect, Circulation 23:740, 1961. Rich, A. R.: A hitherto unrecognized tendency to the development of widespread pulmonary vascular obstruction in patients with congenital pulmonary stenosis (tetralogy of Fallot), Bull. Johns Hopkins Hosp. 82:389, 1948. Heath, D., DuShane, J. \V., \Vood, E. H., and Edwards, J. E.: The etiology of pulmonary thrombosis in cyanotic congenital heart disease with pulmonary stenoses, Thorax 13:213, 1958.