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Post-mortem pulmonary arteriography with special reference to the study of pulmonary hypertension
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POST-MORTEM PULMONARY ARTERIOGRAPHY WITH SPECIAL REFERENCE TO THE STUDY OF PULMONARY H Y P E R T E N S I O N , BY D. S. SHORT, M.D., M.R.C.P. I N S T I T U T E OF C L I N I C A L RESEARCH AND EXPERIMENTAL MEDICINE~ T H E MIDDLESEX H O S P I T A L , A N D T H E CARDIAC D E P A R T M E N T OF T H E
LONDONaOSPITAL
THE existence of a state of high pressure in the pulmonary artery was suspected long before the introduction of cardiac catheterization made it possible to confirm the diagnosis. It is now recognized that pulmonary hypertension forms a serious complication of several common diseases, notably emphysema, mitral stenosis, and certain congenital heart defects which permit a left-to-right shunt (Bedford, i95i ). Each of these diseases generally runs its course without any serious rise of pressure in the pulmonary artery, but in an appreciable minority severe pulmonary hypertension develops and leads in turn to early right heart failure and death. Pulmonary hypertension also occurs apart from primary disease of the heart or lung parenchyma in a form corresponding to essential hypertension in the systemic circuit, and occasionally it is the result of recurrent pulmonary embolism. Once established, it is, as a rule, unresponsive to treatment, and death follows within two or three years of the onset of symptoms. This consistently bad prognosis has not been adequately explained. Irreversible changes in the pulmonary arteries have naturally been suspected, but these have not always been demonstrated at necropsy even when the greatest care has been taken (McKeown, 1952 ). The examination of scattered histological sections does not, however, provide an adequate picture of the arterial bed as a whole. For this reason, it was decided to study a series of lungs from patients with pulmonary hypertension by means of arteriography. Evans (i95 Q first emphasized the value of this procedure, and a reliable technique was developed by Dr. J. P. Shillingford at the London Hospital,
TECHNICAL CONSIDERATIONS The Radio-opaque Medium.--Barclay (I95I) found that if he used a medium such as thorotrast or colloidal silver iodide which fills the capillaries, the arterioles were inevitably obscured. This observation has since been confirmed by other workers. A radio-opaque medium which reaches the finest arterioles without entering the capillaries should therefore be selected. Schlesinger (1938) in his classical study of the coronary arteries used a lead-agar mass which penetrates to vessels with a diameter of 0.04 ram. This is not quite far enough. Indeed, the ideal medium has not yet been found. There are, however, two preparations which penetrate consistently as far as vessels of 0"03 mm. diameter. One is the bismuth oxyehloride suspension, prepared at the London Hospital by Mr. C. H. Sykes in collaboration with Dr. J. P. Shillingford, and used by Evans (i95i). The other is a suspension of finely divided barium sulphate (Micropaque, Damancy & Co.) used by Harrison and Asling (1955) in their investigations of the blood-supply of the adrenal gland. A 5° per cent suspension of Micropaque fills the smallest arterioles, but is scarcely radio-opaque enough. An 80 per cent suspension (with 3 per cent gelatin) gives a satisfactory image and penetrates to 0-03 mm. Micropaque has two advantages over bismuth oxychloride : first, its particles are finer and the filling of the small vessels is therefore more even, and secondly it is much simpler to prepare. The Mode of I n j e c t i o n . - - I n order that arteriograms may be strictly comparable, it is essential that all patent arteries should be fully distended. McWilliam and Mackie (i9o8) showed that the muscular arteries of both animals and man retain the power of contraction, a phenomenon which they carefully distinguished from rigor morris, for up to four days after death. They also demonstrated that this contraction could be overcome by various means, including freezing for a few hours, warming to 55 ° C., or the application of considerable tension. The pulmonary arteries are probably * Part of the work was done while holding a Leverhulme Scholarship.
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less resistant to distension than the stouter arteries of the systemic circulation, and experience has shown that if the radio-opaque medium is heated to a temperature of 8o ° C. and injected at a pressure of 5° to ioo ram. Hg, full distension is ensured. It is, however, essential that the success of the injection should be checked by histological examination. M a g n i f i c a t i o n o f t h e A r t e r i o g r a m . - - I n order to display the smallest arterioles adequately, arteriograms must be magnified by 15 to 3 ° diameters. T h e type of film used in routine medical radiography can be enlarged only three or four times owing to its relatively coarse grain, so that a special film is required. Barclay (i947) showed that by using Kodaline Standard film the desired magnification could be obtained with only slight modification of the usual radiographic technique.
MATERIAL Fifty-seven arteriograms have been made on lungs removed at necropsy : the diagnosis is shown in Table 1. Severe pulmonary hypertension, as judged by hypertrophy of the right ventricle to a thickness of at least 7 mm. (normal 3 to 4 mm.), in the absence of pulmonary valvular or sub-valvular stenosis, was present in 26 cases. T h e majority of these patients were investigated during life by cardiac catheterization, when pulmonary hypertension was confirmed, and all showed electrocardiographic evidence of right ventricular hypertrophy. Table / . - - C A S E S INVESTIGATED BY PULMONARY ARTERIOGRAPHY
Diagnosis
Mitral stenosis Congenital heart disease Other varieties of heart disease Emphysema and bronchitis Lone (or primary) pulmonary hypertension Recurrent pulmonary embolism Systemic hypertension Miscellaneous (including ur~emia, peritonitis, leuk~enaia, carcinoma of stomach (2), lupus erythematosus and accidental death) Totals
Number
Severe Pulmonary Hypertension
7
o
57
26
I7 4 7 ii 5 z 4
8 i 3 6 5 2 I
TECHNIQUE The Radio-opaque M e d i a . - - T h e majority of the lungs were injected with a bismuth oxychloride gelatin suspension which was prepared in three stages. First, a suspension of bismuth oxychloride was prepared by interaction of a solution of bismuth carbonate 515 g. in hydrochloric acid io5o ml. and water 2750 ml. when filtered into excess water. T h e precipitate was washed free from acid by decantation and allowed to settle to a volume of iooo ml. T h e supernatant water was then decanted. Next, a solution was prepared by heating powdered gelatin 75 ° g. and methyl hydroxybenzoate 3 g. in water 75 ° m l . Finally, the bismuth suspension was added to an equal volume of the gelatin solution, avoiding admixture of air, and this was strained through muslin into final containers. T h e ultimate suspension contained approximately 25 per cent bismuth oxychloride and 3 o per cent gelatin. Latterly, a number of lungs were injected with a barium sulphate suspension containing 80 per cent Micropaque and 3 per cent gelatin. The I n j e c t i o n . - - C a r e was taken to avoid puncturing the lung during its removal from the cadaver. Small lacerations could be closed with artery forceps, but larger ones leaked copiously during injection and spoilt the arteriogram. If there were dense adhesions, the parietal pleura was removed with the lung. It was found advisable to preserve as great a length of pulmonary artery as possible in order to have room to apply a ligature below the cannula at the conclusion of the
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injection. Special care was necessary when removing the right lung, as the first branch of the right pulmonary artery sometimes arises outside the lung. Sufficient extra-pulmonary bronchus was retained to permit the insertion of a cannula. Occasionally, the lung was preserved on ice or in a refrigerator for 48 hours. Prior to the injection, the lung was immersed in water at a temperature of 4 °0 C. for an hour. Meanwhile, the injection mass was heated to 80 ° C. This warming had the dual object of relaxing the arteries and ensuring that the gelatin did not set until the finest vessels had been filled. 5 A flanged cannula was tied firmly into the pulmonary artery and connected to the outlet tube of the flask containing the injection medium (Fig. 128). The flask was then connected to a cylinder of air, the outlet tube of which carried a pressure gauge. I n cases without pulmonary hypertension a pressure of 5 ° mm. Hg was employed, but where pulmonary hypertension was known to have been present the pressure was raised to 1oo ram. Hg. The aim was not to imitate physiological conditions, but to overcome post-mortem contraction and produce complete distension of the arteries and arterioles. Fig. I 2 8 . - - T h e injection apparatus : I, The lung ; 2, Flask containing radio-opaque meditun; 3, Cylinder of Perfusion of the arteries with water or saline prior air; 4, Gauge recording pressure in outlet tube; 5, Gauge to injection of the radio-opaque medium was disrecording pressure within the cylinder. continued after initial trials; it was found to be ineffective in removing thrombus and generally gave rise to pulmonary oedema. During the injection, the pleural surface was carefully watched. A few fine superficial vessels almost invariably became filled; indeed this came to be regarded as evidence of a satisfactory injection. The hilum and pulmonary ligaments were also carefully observed for reflux from the cut ends of the bronchial arteries. After the pressure had been maintained for IO to 15 minutes, the lung was immersed in cold water for 3 ° minutes. The pulmonary artery was clamped and ligated before reducing the pressure. Radiography and D i s s e c t i o n . - - P r i o r to radiography, a cannula was tied into the bronchus and connected to the cylinder of air. This arrangement, originally suggested by Howarth (1953) , ensured that the lung was maintained in full inflation even if small lacerations were present. The lung was X-rayed on ordinary non-screen X-ray film, a sheet of Stryafoil (BX Plastics Ltd.) I / I O O O in. thick intervening between the lung and the envelope containing the film. Stereoscopic lateral views were taken routinely and frequently an anteroposterior view was also taken. The X-ray set consisted of a standard four-valve transformer unit with a rotating anode tube and I mm. focus. At a focal-film distance of 220 cm. (7 ft. 3 in.), which was the maximum permitted by the stand, the exposure factors were 65 kV., 15o mA. and o. 4 sec. for the lateral, and 0"5 sec. for the anteroposterior view. The lung was fixed in formalin, preferably after prior distension with the fixative, and then carefully inspected. Pleural anastomoses were noted and the extra-pulmonary bronchial arteries dissected out and measured. T h e lung was then divided into lobes and each lobe cut into sections 5 mm. thick. W h e n pleural anastomoses were present, a thin slice including this area was also preserved. During the process of sectioning, reference was made to the arteriogram of the whole lung in order to determine the cause of any filling defects or abnormal shadows present. T h e sections were X-rayed on envelope-wrapped Kodaline Standard film. With focal-film distance of 60 cm. (24 in.), the exposure factors were 9 ° kV., ioo mA. and 2. 5 sec. Standard X-ray developer gave satisfactory results, provided it was reasonably fresh. When dry, the films were
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examined under the low power of the microscope and typical areas selected for enlargement up to t5 or 2o diameters. A magnification of 15 diameters was generally adequate for this investigation. Histological E x a m i n a t i o n . - - A t least three blocks from each lung were set aside for histological study in addition to any taken from sites of particular interest such as points of arterial
A
B
C
D E F Fig. I 2 9 . - - T h e lung arteries before and after injection. A, B, C, Uninjected lung ; D, E, F, Injected lung ; A, D, Segments of lobular arteries o-8 m m . diameter ; B, E, Arteries o.2 and o'4 rmn. diameter ; C, F, Arterioles o'o5 r a m . diameter. T h e injected arteries are distended, their walls are attenuated, and their elastic coats stretched. Sections f r o m a case of lone pulmonary hypertension stained w i t h Verhoff and V a n Gieson.
narrowing. Two sections were made from each block, one being stained with ha~matoxylin and eosin, and the other with Verhoff elastic stain combined with Van Gieson. Before any conclusions were drawn from the arteriogram, the histological sections were examined to confirm that the arteries were fully distended. In the uninjected lung, the elastic coats were invariably more or less deeply crenated, but after a satisfactory injection, the arterial wall was much thinner in relation to the size of the lumen and the elastic coat was quite smooth (Fig. 129).
THE NORMAL ARTERIOGRAM The arteriogram of the inflated lung, particularly when viewed stereoscopically, provided a clear picture of the entire pulmonary arterial bed (Fig. 13o). As Ewart (1889) showed, the arteries subdivide like the bronchi, and the two structures remain associated down to the smallest branches 8
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I32,
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~
Fig.
Fig.
i3I.
I33.
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Fig. I34.
ARTERIOGRAPHY
Fig. I35.
Fig. 13o.--Normal arteriogram of the right lung. Fig. I 3 I . - - R e c u r r e n t pulmonary embolism, pulmonary hypertension. Left pulmonary arteriogram. Filling defects, indicated by arrows, represent zones of isch~emia resulting from thrombotic occlusion of segmental arteries. T h e right pulmonary artery was occluded by organized thrombus, so that the total pulmonary arterial bed was greatly restricted. Fig. i 3 z . - - R e c u r r e n t pulmonary embolism, pulmonary hypertension. Left pulmonary arteriogram. I n addition to filling defects representing zones of ischmmia, there are clouds of radio-opaque medium marking sites of recent infarction. The right basal artery and a large artery to the right upper lobe were occluded; the total pulmonary arterial bed was therefore greatly reduced. See also Fig. I43. Fig. I 3 3 . - - L o n e pulmonary hypertension. R i g h t pulmonary arteriogram. There is generalized depletion of the finest branches due to widespread occlusion of lobular arteries (Figs. i4i and r44). T h e arteries in the left lung were similarly occluded, so that the total pulmonary arterial bed was greatly reduced. Fig. s34.--Lone pulmonary hypertension. Left pulmonary arteriogram. T h e segmental arteries, which are slightly narrower than normal, stand out unusually clearly because the finest vessels are contracted (Fig. I45). Neither the arteries nor the arterioles showed any abnormal intimal thickening; the photomicrographs in Fig. i29 were tsken from this case. Assuming that the arteriolar narrowing was also present in the uninjected lung, the total pulmonary arterial bed must have been considerably reduced. Fig, 135 - - M i t r a l stenosis, pulmonary hypertension. R i g h t pulmonary arteriogram. There is a generalized diminution of the finest branches owing to arteriolar obstruction (Fig. I46), and narrowing of the segmental arteries in the lower half of the lung. The histological appearance of the arteries and arterioles in the left lung was similar to that in the right, so that the total pulmonary arterial bed was considerably reduced. Fig. i 3 6 . - - E m p h y s e m a and bronchiectasis, pulmonary hypertension. Right pulmonary arteriogram. T h e peripheral arborization is deficient owing to loss of much of the arteriolar bed (Fig. 147). The left lung was not quite so extensively diseased as the right, but the reduction in the total pulmonary arterial bed must nevertheless have been considerable.
Fig. I36.
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visible to the naked eye. Because of this association, it is natural to name the larger arteries with reference to the accompanying bronchus. T h u s an artery which accompanies a segmental bronchus may appropriately be called a segmental artery. In the middle lobe of the right lung, the lingular portion of the left upper lobe, and both lower lobes, the pattern of the segmental arteries is almost identical with that of the bronchi (Table II). In the right upper lobe and the corresponding part of the left upper lobe, however, there are important differences. The right pulmonary artery often gives off its first branch before entering the lung, Table H.--THE SEGMENTALBRONCHIAND THE CORRESPONDINGARTERIES RIGHTLUNG LEFTLUNG
Bronchi Upper lobe Apical Posterior
Anterior
Arteries Apical Posterior superior Posterior inferior Anterior
Middle lobe Lateral Medial
Lateral Medial
Lower lobe Apical (Subapical)* Medial basal Anterior basal Lateral basal Posterior basal
Apical (Subapical)* Medial basal Anterior basal Lateral basal Posterior basal
Bronchi Upper lobe Apicoposterior
Arteries Apical Posterior
Anterior
Anterior lateral Anterior descending
Superior lingular Inferior lingular
Superior lingular Inferior lingular
Lower lobe Apical (Subapical) t (Medial basal):~ Anterior basal Lateral basal Posterior basal
Apical (Subapical)* (Medial basal)* Anterior basal Lateral basal Posterior basal
Notes from the Nomina Anatomica, International AnatomicalNomenclature Committee, I955. * Inconstant. Absent in 70 per cent as an independent entity. :~Rarely present. and this large vessel, named by Boyden (1955) the anterior trunk, carries the blood-supply to the greater part of the upper lobe. It quickly divides into anterior, apical, and posterior superior branches, to supply the anterior and apical bronchopulmonary segments and part of the posterior segment (Fig. 137 ) . T h e remainder of the posterior segment is supplied by the posterior inferior branch, which arises directly from the right pulmonary artery at a lower level. The arteries to the upper part of the left upper lobe usually arise directly from the left pulmonary artery, but there are separate apical and posterior arteries to the apicoposterior segment, and two branches to the anterior segment (Fig. I38 ). T h e arteries which are most prominent in a postero-anterior chest film are naturally those which supply the anterior parts of the lung. On the right side, where the lung is more accessible to inspection, these are (Fig. x39 ) the apical and anterior arteries and their branches in the upper lobe, the middle lobe artery and its lateral and medial branches, and the anterior and medial basal arteries and their branches in the lower lobe. On the left side, the most conspicuous arteries are the apical, the anterior lateral, the anterior descending, the superior and inferior lingular and their branches in the upper lobe ; and the anterior basal and its branches in the lower lobe. When arteriograms of normal lungs are compared with each other, the segmental arteries are seen to vary greatly both in their calibre and in their manner of branching. Indeed, so common are the variations that it is almost impossible to find an arteriogram which is ' typical ' in every respect.
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Segmental arteries often arise at a point either above or below their usual origin ; sometimes one bronchopulmonary segment and its artery are unusually small and the neighbouring segment unusually large ; or else, in a segment of normal size, the blood-supply consists of several small Posterior superior
. Apical
Posterior i n f e r i o r -
Anterior
Apical ( l o w e r lobe) _ Lateral (middle lobe) Basal portion of F-
right pulmonary artery
-
Lateral basal r -
Posterior basal
Medial (middle lobe
"" Medial basal
-''~
"" A n t e r i o r basal
f
J
Fig. I 3 7 . - - T h e branches of the r i g h t p u l m o n a r y artery as seen in the lateral projection. D r a w n f r o m Fig. 13o.
Posterior
Apical
Apical ( l o w e r lobe)
Anterior descending
"
Basal portion of left pulmonary artery Superior lingular
Posterior basal I n f e r i o r lingular
Lateral basal A n t e r i o r basal
Fig. I 3 8 . - - T h e branches of the left pulmona r y artery as seen i n th e lateral projection.
arteries instead of one large one. It is important, as Lodge (i946) has stated, to bear this variability in mind when seeking to assess the arterial pattern in a chest radiograph. Examination of magnified arteriograms showed that the regularity of the arterial branching and the progressive decrease in calibre extends down to the finest arterioles (Fig. 142 ) . The smallest unit of lung tissue which can be recognized on the pleural surface is the secondary lobule. The artery supplying this unit, which may appropriately be called a lobular artery, varies in diameter between 0.6 and I'O mm. The lobular arteries and their branches are of the greatest importance in pulmonary hypertension, for it is in vessels of this size that the most significant abnormalities are found. Arterial A n a s t o m o s e s . - - I n the absence of pulmonary hypertension or parenchymal disease of the lung, there was no reflux from the bronchial arteries during the injection of the bismuth suspension. This implies that there are normally no patent bronchopulmonary anastomoses with a diameter greater than o'o 3 mm. A few fine vessels on the lung surface almost invariably became filled during the course of injection but they were never numerous nor did they exceed 0. 3 mm.
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in diameter. The fact that these vessels filled without any reflux appearing from the bronchial artery indicated that they were not bronchopulmonary anastomoses. Examination of magnified
Posterior superior
.
Apical "-
Posterior inferior
Basal p o r t i o n of right pulmonary artery -
J
.
_
.
L
.
t
~ Anterior
_ _
Lateral ( m i d d l e lobe)
....
M e d i a l ( m i d d l e lobe)
-
Lateral basal
P o s t e r i o r basal -
~ ~.
M e d i a l basal
\ Level o f d i a p h r a g m - -
Anterior
basal
Fig. I 3 9 . - - T h e branches of the right pulmonary artery as seen in the postero-anterior projection. Drawn from the same case as Fig. I3o. T h e stippling indicates those arteries which are most prominent in a routine chest radiograph.
P~'g. I 4 o . - - S u b p l e u r a l anastomosis i n pulmonary hypertension due to recurrent pulmonary embolism. T h e anastomotic vessel, whose diameter varies between o'5 and I'O mm., runs over an ischmmic zone and links two branches of the pulmonary artery. F r o m the arteriogram shown i n Fig. I3 I.
Fig. I 4 1 . - - S u b p l e u r a l anastomosis in lone pulmonary hypertension. T h e anastomotic vessel, I'o mm. i n diameter, links two branches of the pulmonary artery. F r o m the arteriogram shown in Fig. I33.
arteriograms showed that they were in fact communications between branches of the pulmonary artery. Reflux from the pulmonary veins was never observed in a technically satisfactory arteriogram.
T H E A R T E R I O G R A M IN P U L M O N A R Y H Y P E R T E N S I O N Pulmonary arteriography was proved to be of great value in the study of pulmonary hypertension, for it provided a far more accurate demonstration of the reduction in the pulmonary arterial bed than did the study of histological sections alone. When an artery is occluded for only a short
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distance, the existence of the obstruction may easily be missed on routine histological examination (Spencer, 195 o) but it is obvious on the arteriogram. Arteriography also brought to light a condition of diffuse arterial narrowing without mural thickening, demonstrated the presence of abnormal anastomoses, and aided the differentiation of arterioles from venules. The pulmonary arterial bed was considerably reduced in every case of severe pulmonary hypertension. Sometimes the reduction was focal, and caused by obstruction of a few large arteries ;
Fig. ~42.--Normal lung : magnified arteriogram. A lobular Fig. I43.--Recurrent pulmonary embolism, pulmonary hyperartery, 0.6 ram. diameter, enters at the left of the field. T h e tension: magnified arteriograra. I n many areas, such as that diameter of the smallest arterioles visible is o'o3 turn. shown here, the arteriolar pattern appeared normal. From the same ease as Fig. I32. Magnification as i n Fig. I42.
Fig. 144.--Lone pulmonary hypertension : magnified arteriogram. A lobular artery, 0"7 ram. diameter, is seen entering at the top of the field. T h e normal arteriolar pattern is replaced by tortuous anastomotic channels. T h i s is a typical field from the same case as Figs. I33 and I4I. Magnification as in Fig. I42.
Fig. I 4 5 . - - L o n e pulmonary hypertension : magnified arteriogram. T h e arterioles are considerably narrower than normal. T h i s is a typical field from the same case as Fig. I34. Magnification as in Fig. I4z.
more commonly it was diffuse and resulted from widespread narrowing or occlusion of arteries less than i.o mm. in diameter. The pattern varied with the underlying disease. The arteriograms of mitral stenosis, emphysema, and recurrent pulmonary embolism each showed distinctive features ; the pattern in lone (or primary) pulmonary hypertension, on the other hand, was less uniform. Abnormal bronchopulmonary and interpulmonary arterial anastomoses were found in the great majority of cases. Recurrent Pulmonary E m b o l i s m . - - T h e arteriogram in recurrent pulmonary embolism showed large filling defects because segmental arteries were occluded, and the opaque material was
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prevented from entering the territories beyond the obstructions (Fig. I3I ). In places of actual infarction, the injected material collected to form dense irregular blotches resembling birds' nests. (Fig. I32. ) Elsewhere, the arterial and even the arteriolar pattern was normal (Fig. I43 ). The bronchial arteries were prolific around occluded arteries; and abnormal subpleural anastomoses, linking the blood-supply of adjacent lobules or segments, were common over ischa~mic ZOnes (Fig. I4o ). Lone (or Primary) Pulmonary H y p e r t e n s i o n . - - T h e arteriographic pattern, like the histo. logical appearance of this condition, varied ; perhaps indicating that more than one disease is at present included under this diagnosis.
Fig. I 4 6 . - - M i t r a l stenosis, pulmonary hypertension: magnified arteriogram. A lobular artery, o'7 mm. diameter, enters at the left of the field. T h e arterioles are depleted. T h i s is a typical field from the same case as Fig. 135. Magnification as in Fig. 142.
Fig. I 4 7 . - - E m p h y s e m a and bronchiectasis, puhnonary hypertension : magnified arteriogram. T w o lobular arteries, 0"3 a n d 0 . 2 5 ram. diameter, are seen r u n n i n g ob]iquely across the field from left to right. Both are narrower than normal, and their arteriolar branches are depleted. A branch from the upper one is seen communicating with the bronchial artery which is r u n n i n g vertically on the right of the field. Magnification as in Fig. i42.
When the lobular arteries were chiefly affected, the arteriogram showed widespread loss of the normal peripheral arborization (Fig. 133 ). This appearance has been aptly likened to the denuded shrub of winter in contrast to the leafy bush of spring (Evans, I95I ). The magnified arteriogram showed that the majority of the lobular arteries ended blindly, and that the normal arteriolar pattern was virtually replaced by tortuous anastomotic channels (Figs. i41 , i44 ). This finding was of great help in interpreting the histological appearances. The segmental arteries were of normal size. There was one case of lone pulmonary hypertension in which careful histological examination revealed neither arterial occlusion nor even important mural thickening (Fig. I29). The media of the lobular arteries showed some hyalinization, but the arterioles appeared structurally normal. On naked-eye inspection of the arteriogram the segmental arteries, although slightly narrowed, seemed to stand out unusually clearly, suggesting a generalized reduction in the peripheral arborization (Fig. 134 ). This was confirmed when magnified arteriograms were scrutinized; for the diameters of the lobular arteries and their branches were reduced to half to two-thirds of those in the normal controls (Fig. i45 ). The arterioles appeared to be less numerous as well as narrower than normal, but this was probably because the smaller arterioles were too contracted to admit the opaque material. Abnormal subpleural anastomoses were seen, but these were few in number. In the three other cases of lone pulmonary hypertension, the state of the fine vasculature was more or less intermediate between the two examples which have been cited. In one, the main artery to the lung was grossly dilated and the segmental arteries were considerably enlarged, but in the remaining two cases the calibre of the segmental arteries was either normal or slightly reduced.
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Mitral S t e n o s i s . - - I n mitral stenosis, the segmental arteries to the.upper lobe were occasionally dilated, but those to the middle lobe (or lingula) and to the basal segments of the lower lobe were usually contracted (Fig. i35), and often strikingly so. When the outline of these contracted arteries was regular, histological examination showed no intimal or medial thickening ; indeed apart from their size these vessels appeared normal. Sometimes the lumen was irregular and then superimposed intimal thickening was found. The most important narrowing was found in the arterioles, for the magnified arteriogram showed a considerable reduction of the arteriolar bed throughout the lung (Fig. 146). Interpulmonary arterial anastomoses were inconspicuous unless the disease had been complicated by pulmonary embolism. E m p h y s e m a . - - I n emphysema, the segmental arteries in the upper half of the lung were sometimes dilated (Fig. i36), but those in the lower half were generally normal. The main abnormality was to be found in the small arteries and arterioles, for magnified arteriograms showed long straggling lobular arteries almost devoid of arteriolar branches (Fig. I47 ). Interpulmonary arterial anastomoses were infrequent, but abnormal bronchopulmonary communications were abundant. Congenital Heart Disease.--Only one case of congenital heart disease with pulmonary hypertension was investigated. In this, a case of atrial septal defect, the arteriogram showed gross dilatation of the segmental arteries, with widespread loss of the peripheral arborization due to obstruction of lobular arteries. A r t e r i a l Anastomoses.--Bronchial artery reflux was a frequent finding in pulmonary hypertension, but it was never copious. The opaque medium flowed from all the bronchial arteries, both at the hilum and in the pulmonary ligament. It usually appeared about a minute after the start of the injection at the same time as the filling of the pleural vessels. This delay suggests that the abnormal bronchopulmonary anastomoses involved small peripheral arteries rather than large ones near the hilum, and this was confirmed on the few occasions when it was possible to demonstrate the communications on a magnified arteriogram (Fig. i47 ). In pulmonary hypertension, the extrapulmonary bronchial arteries were never significantly enlarged, in contrast to Fallot's tetrad and bronchiectasis where they were considerably dilated and the reflux was profuse. It seems improbable, therefore, that pulmonary-bronchial anastomoses are the cause of pulmonary hypertension as some have suggested (Froment, Galy, Tolot, Cahen, Gardere, and Ugnat, i954) and more likely that they are a result of arterial obstruction. Abnormally large subpleural arteries (o. 5 to i.o mm. diameter) were common, and were particularly prominent over the territories of occluded pulmonary arteries. They appeared to be anastomoses between branches of the pulmonary artery, serving as an alternative blood-supply to ischa~mic areas (Figs. 14o and I4I ).
THE SIGNIFICANCE OF THE ARTERIOGRAM IN PULMONARY HYPERTENSION The pulmonary arterial bed was shown to be considerably reduced in each of the 26 cases of pulmonary hypertension investigated. This reduction could generally be correlated with histological abnormalities and especially with thrombosis or intimal thickening, but sometimes it could not be accounted for on histological grounds. Thus, diffuse narrowing of the segmental arteries ill the lower half of the lung, without corresponding intimal or medial thickening, was demonstrated in several cases of mitral stenosis, while a similar condition of the lobular arteries and the arterioles was the sole abnormality in one case of lone pulmonary hypertension. The diameter of the contracted vessels was one-half to two-thirds of the normal. This appearance was not an artefact, nor was it due to ' spasm ', for the arteries were shown to be fully distended by the opaque medium, the elastic coats having lost all their crenation.
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The effect of this lack of distensibility on the resistance to blood-flow cannot be accurately assessed since the precise relationship between calibre and pressure in the pulmonary arteries is not yet established. Poiseuille's law states that in a system where the tubes are rigid and the flow non-turbulent, the resistance varies inversely with the fourth power of the radius ; so that under these conditions, and provided the flow is kept constant, reducing the diameter by one-third is sufficient to raise the pressure five-fold. Thus the narrowing which was observed in these arteries might have been responsible for considerable pulmonary hypertension. It must be remembered moreover that the difference in calibre which was observed in the arteriogram applies to the fully distended state. During life, these arteries and arterioles were doubtless subject to at least a normal degree of vasoconstriction so that their relative narrowing may have been even greater. This observation carries important implications. It shows that organic arterial narrowing cannot be excluded solely on the ground of the absence of intimal thickening or medial hypertrophy. In any future study of the arterial bed whether in pulmonary or systemic hypertension, arteriography must be regarded as complementary to histology. It also explains why the arterial narrowing which is seen in the chest radiograph in cases of mitral stenosis with pulmonary hypertension (Davies, Goodwin, Steiner, and Van Leuven, i953 ; Short, i955) often persists after successful valvotomy (Goodwin, Hunter, Cleland, Davies, and Steiner, i955). The structural changes in the arterial bed in puhnonary hypertension are much more severe than is generally recognized. There can be little doubt that they account for the uniformly serious prognosis of this condition, and the failure of antispasmodic drugs and nerve-section operations. In our present ignorance of pulmonary h~emodynamics, it is impossible to say whether organic arterial disease was wholly responsible for the pulmonary hypertension which was present during life, or whether another ' functional ' factor must be postulated. In some cases the arterial obstruction was so great as to leave no doubt that it was the major if not the sole mechanical cause of the hypertension. This appeared to be so in some of the cases of so-called primary pulmonary hypertension. If in this group the hypertension is sometimes secondary to arterial disease, the term ' p r i m a r y ' is clearly inappropriate; it is for this reason that the designation ' l o n e ' has been preferred. SUMMARY AND CONCLUSIONS A method of arteriography is described by means of which the puhnonary arterial and arteriolar bed may be portrayed in full distension. Following injection of a radio-opaque medium the lung is inflated and radiographed. After fixation, thin sections are cut; these are then radiographed on Kodaline Standard film and the resulting radiographs enlarged up to 25 times. Fifty-seven lungs have been investigated by this technique, 26 being from cases of severe pulmonary hypertension, and including instances of mitral stenosis, emphysema, recurrent pulmonary embolism and lone (or primary) pulmonary hypertension. The arteriogram of the inflated lung, particularly when viewed stereoscopically, provides a clear demonstration of the anatomy of the pulmonary arterial system. In pulmonary hypertension, the arteriogram was always grossly abnormal. It showed two main differences from the pattern found in health ; first the arterial bed was considerably reduced, and secondly new anastomoses were present. In recurrent pulmonary embolism, the main obstruction lay in the large arteries, whereas in mitrat stenosis and emphysema it lay in the arterioles. In lone pulmonary hypertension, the changes were found either in the small arteries or in the arterioles. In most instances, the reduction in the arterial bed could be readily correlated with histological abnormalities, and especially with thrombosis or intimal thickening, but narrowing was sometimes demonstrated in arteries which showed no mural thickening on histological examination. Pulmonary
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arteriography is therefore essential to a thorough post-mortem investigation of pulmonary hypertensi °n. The structural changes in the arteries in pulmonary hypertension have been underestimated in the past. There can be little doubt that they account for the uniformly serious prognosis of this condition and its resistance to treatment. In some cases, the arterial obstruction was so great and widespread that it appeared to be entirely responsible for the pulmonary hypertension. Subpleural anastomoses between peripheral branches of the pulmonary artery were found in apparently normal lungs. In pulmonary hypertension, these anastomoses were often extraordinarily large and numerous, particularly over zones of isch~emia. The injection medium never passed into the bronchial arteries in apparently healthy lungs, but it did so in the majority of cases of pulmonary hypertension; the reflux from the extrapulmonary bronchial arteries was, however, rarely copious and the arteries themselves were scarcely enlarged. Reflux from the pulmonary veins was never seen. A c k n o w l e d g e m e n t s . - - I t is a pleasure to acknowledge the help of many departments both in the London and the Middlesex Hospitals. I am particularly grateful to Professor Dorothy Russell and to Professor Scarff for facilities in the respective Departments of Pathology ; to Miss F. M. King of the L o n d o n Hospital, and to Miss Franks and Mrs. Fife of the Middlesex Hospital, for radiographic assistance ; to the Chief Pharmacists, Mr. C. H. Sykes and Mr. G. Bryan, for advice and help with the injection media ; and to Mr. Turney of the Middlesex Hospital Photographic Department for the enlargements and reproductions. Above all, I am indebted to Dr. William Evans and Dr. Evan Bedford for their encouragement and stimulating criticism, and to Dr. Peter Kerley for his constant advice and inspiration. REFERENCES BARCLAY,A. E. (I947), Brit. J. Radiol., 2o, 394-- - - (I95I), Microarteriography, 87. Oxford : Blackwell Scientific Publications Ltd. BEDFORD,D. E. (I95I), Proc. R. Soc. Med., 44, 597. BOYDEN,E. A. (I955) , Segmental Anatomy of the Lungs: a Study of the Patterns of the Segmental Bronchi and Related Pulmonary Vessels. New York : McGraw-Hill Book Company Inc. DAVIES,L. G., CooDWIN, J. F., STEINER,R. E., and VAN LEUVEN,B. D. (I953), Brit. HeartJ., I5, 393. EVANS,W. (I95I), Proc. R. Soc. Med., 44, 6oo. EWART, C. (I889) , The Bronchi and Pulmonary Vessels. London : Bailli~re, Tindall, & Cox. FROMENT,R., GALY, P., TOLOT, F., CAHEN,P., GARDERE,J., and UGNAT, V. A. (I954), Rev. Lyon, 3, 255. GOODWIN,J. F., HUNTER,J. D., CLELAND,W. 1J., DAVIES,L. G., and STEINER,R. E. (I955) , Brit. med.J., 2, 573. HARRISON, R. G., and ASLING, C. W. (I955),J. Anat., 89, IO6. HOWARTH,E. H. (I953) , personal communication. LODCE,T. (I946), Brit. J. Radiol., 19, i. McKEOWN, F. (I952), Brit. Heart J., 14, 25. McWILLIAM, J. A., and MACKIE,A. H. (I9O8), Brit. med. J., 2, 1477. SCHLESlNC-ER,M. J. (i938), Amer. HeartJ., 15, 52.8. SHORT,D. S. (I955), Brit. HeartJ., I7, 33. SPENCER,H. (I95O), J. Path. Bact., 62, 75-
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POST-MORTEM PULMONARY ARTERIOGRAPHY WITH SPECIAL REFERENCE TO THE STUDY OF PULMONARY H Y P E R T E N S I O N , BY D. S. SHORT, M.D., M.R.C.P. I N S T I T U T E OF C L I N I C A L RESEARCH AND EXPERIMENTAL MEDICINE~ T H E MIDDLESEX H O S P I T A L , A N D T H E CARDIAC D E P A R T M E N T OF T H E
LONDONaOSPITAL
THE existence of a state of high pressure in the pulmonary artery was suspected long before the introduction of cardiac catheterization made it possible to confirm the diagnosis. It is now recognized that pulmonary hypertension forms a serious complication of several common diseases, notably emphysema, mitral stenosis, and certain congenital heart defects which permit a left-to-right shunt (Bedford, i95i ). Each of these diseases generally runs its course without any serious rise of pressure in the pulmonary artery, but in an appreciable minority severe pulmonary hypertension develops and leads in turn to early right heart failure and death. Pulmonary hypertension also occurs apart from primary disease of the heart or lung parenchyma in a form corresponding to essential hypertension in the systemic circuit, and occasionally it is the result of recurrent pulmonary embolism. Once established, it is, as a rule, unresponsive to treatment, and death follows within two or three years of the onset of symptoms. This consistently bad prognosis has not been adequately explained. Irreversible changes in the pulmonary arteries have naturally been suspected, but these have not always been demonstrated at necropsy even when the greatest care has been taken (McKeown, 1952 ). The examination of scattered histological sections does not, however, provide an adequate picture of the arterial bed as a whole. For this reason, it was decided to study a series of lungs from patients with pulmonary hypertension by means of arteriography. Evans (i95 Q first emphasized the value of this procedure, and a reliable technique was developed by Dr. J. P. Shillingford at the London Hospital,
TECHNICAL CONSIDERATIONS The Radio-opaque Medium.--Barclay (I95I) found that if he used a medium such as thorotrast or colloidal silver iodide which fills the capillaries, the arterioles were inevitably obscured. This observation has since been confirmed by other workers. A radio-opaque medium which reaches the finest arterioles without entering the capillaries should therefore be selected. Schlesinger (1938) in his classical study of the coronary arteries used a lead-agar mass which penetrates to vessels with a diameter of 0.04 ram. This is not quite far enough. Indeed, the ideal medium has not yet been found. There are, however, two preparations which penetrate consistently as far as vessels of 0"03 mm. diameter. One is the bismuth oxyehloride suspension, prepared at the London Hospital by Mr. C. H. Sykes in collaboration with Dr. J. P. Shillingford, and used by Evans (i95i). The other is a suspension of finely divided barium sulphate (Micropaque, Damancy & Co.) used by Harrison and Asling (1955) in their investigations of the blood-supply of the adrenal gland. A 5° per cent suspension of Micropaque fills the smallest arterioles, but is scarcely radio-opaque enough. An 80 per cent suspension (with 3 per cent gelatin) gives a satisfactory image and penetrates to 0-03 mm. Micropaque has two advantages over bismuth oxychloride : first, its particles are finer and the filling of the small vessels is therefore more even, and secondly it is much simpler to prepare. The Mode of I n j e c t i o n . - - I n order that arteriograms may be strictly comparable, it is essential that all patent arteries should be fully distended. McWilliam and Mackie (i9o8) showed that the muscular arteries of both animals and man retain the power of contraction, a phenomenon which they carefully distinguished from rigor morris, for up to four days after death. They also demonstrated that this contraction could be overcome by various means, including freezing for a few hours, warming to 55 ° C., or the application of considerable tension. The pulmonary arteries are probably * Part of the work was done while holding a Leverhulme Scholarship.
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less resistant to distension than the stouter arteries of the systemic circulation, and experience has shown that if the radio-opaque medium is heated to a temperature of 8o ° C. and injected at a pressure of 5° to ioo ram. Hg, full distension is ensured. It is, however, essential that the success of the injection should be checked by histological examination. M a g n i f i c a t i o n o f t h e A r t e r i o g r a m . - - I n order to display the smallest arterioles adequately, arteriograms must be magnified by 15 to 3 ° diameters. T h e type of film used in routine medical radiography can be enlarged only three or four times owing to its relatively coarse grain, so that a special film is required. Barclay (i947) showed that by using Kodaline Standard film the desired magnification could be obtained with only slight modification of the usual radiographic technique.
MATERIAL Fifty-seven arteriograms have been made on lungs removed at necropsy : the diagnosis is shown in Table 1. Severe pulmonary hypertension, as judged by hypertrophy of the right ventricle to a thickness of at least 7 mm. (normal 3 to 4 mm.), in the absence of pulmonary valvular or sub-valvular stenosis, was present in 26 cases. T h e majority of these patients were investigated during life by cardiac catheterization, when pulmonary hypertension was confirmed, and all showed electrocardiographic evidence of right ventricular hypertrophy. Table / . - - C A S E S INVESTIGATED BY PULMONARY ARTERIOGRAPHY
Diagnosis
Mitral stenosis Congenital heart disease Other varieties of heart disease Emphysema and bronchitis Lone (or primary) pulmonary hypertension Recurrent pulmonary embolism Systemic hypertension Miscellaneous (including ur~emia, peritonitis, leuk~enaia, carcinoma of stomach (2), lupus erythematosus and accidental death) Totals
Number
Severe Pulmonary Hypertension
7
o
57
26
I7 4 7 ii 5 z 4
8 i 3 6 5 2 I
TECHNIQUE The Radio-opaque M e d i a . - - T h e majority of the lungs were injected with a bismuth oxychloride gelatin suspension which was prepared in three stages. First, a suspension of bismuth oxychloride was prepared by interaction of a solution of bismuth carbonate 515 g. in hydrochloric acid io5o ml. and water 2750 ml. when filtered into excess water. T h e precipitate was washed free from acid by decantation and allowed to settle to a volume of iooo ml. T h e supernatant water was then decanted. Next, a solution was prepared by heating powdered gelatin 75 ° g. and methyl hydroxybenzoate 3 g. in water 75 ° m l . Finally, the bismuth suspension was added to an equal volume of the gelatin solution, avoiding admixture of air, and this was strained through muslin into final containers. T h e ultimate suspension contained approximately 25 per cent bismuth oxychloride and 3 o per cent gelatin. Latterly, a number of lungs were injected with a barium sulphate suspension containing 80 per cent Micropaque and 3 per cent gelatin. The I n j e c t i o n . - - C a r e was taken to avoid puncturing the lung during its removal from the cadaver. Small lacerations could be closed with artery forceps, but larger ones leaked copiously during injection and spoilt the arteriogram. If there were dense adhesions, the parietal pleura was removed with the lung. It was found advisable to preserve as great a length of pulmonary artery as possible in order to have room to apply a ligature below the cannula at the conclusion of the
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injection. Special care was necessary when removing the right lung, as the first branch of the right pulmonary artery sometimes arises outside the lung. Sufficient extra-pulmonary bronchus was retained to permit the insertion of a cannula. Occasionally, the lung was preserved on ice or in a refrigerator for 48 hours. Prior to the injection, the lung was immersed in water at a temperature of 4 °0 C. for an hour. Meanwhile, the injection mass was heated to 80 ° C. This warming had the dual object of relaxing the arteries and ensuring that the gelatin did not set until the finest vessels had been filled. 5 A flanged cannula was tied firmly into the pulmonary artery and connected to the outlet tube of the flask containing the injection medium (Fig. 128). The flask was then connected to a cylinder of air, the outlet tube of which carried a pressure gauge. I n cases without pulmonary hypertension a pressure of 5 ° mm. Hg was employed, but where pulmonary hypertension was known to have been present the pressure was raised to 1oo ram. Hg. The aim was not to imitate physiological conditions, but to overcome post-mortem contraction and produce complete distension of the arteries and arterioles. Fig. I 2 8 . - - T h e injection apparatus : I, The lung ; 2, Flask containing radio-opaque meditun; 3, Cylinder of Perfusion of the arteries with water or saline prior air; 4, Gauge recording pressure in outlet tube; 5, Gauge to injection of the radio-opaque medium was disrecording pressure within the cylinder. continued after initial trials; it was found to be ineffective in removing thrombus and generally gave rise to pulmonary oedema. During the injection, the pleural surface was carefully watched. A few fine superficial vessels almost invariably became filled; indeed this came to be regarded as evidence of a satisfactory injection. The hilum and pulmonary ligaments were also carefully observed for reflux from the cut ends of the bronchial arteries. After the pressure had been maintained for IO to 15 minutes, the lung was immersed in cold water for 3 ° minutes. The pulmonary artery was clamped and ligated before reducing the pressure. Radiography and D i s s e c t i o n . - - P r i o r to radiography, a cannula was tied into the bronchus and connected to the cylinder of air. This arrangement, originally suggested by Howarth (1953) , ensured that the lung was maintained in full inflation even if small lacerations were present. The lung was X-rayed on ordinary non-screen X-ray film, a sheet of Stryafoil (BX Plastics Ltd.) I / I O O O in. thick intervening between the lung and the envelope containing the film. Stereoscopic lateral views were taken routinely and frequently an anteroposterior view was also taken. The X-ray set consisted of a standard four-valve transformer unit with a rotating anode tube and I mm. focus. At a focal-film distance of 220 cm. (7 ft. 3 in.), which was the maximum permitted by the stand, the exposure factors were 65 kV., 15o mA. and o. 4 sec. for the lateral, and 0"5 sec. for the anteroposterior view. The lung was fixed in formalin, preferably after prior distension with the fixative, and then carefully inspected. Pleural anastomoses were noted and the extra-pulmonary bronchial arteries dissected out and measured. T h e lung was then divided into lobes and each lobe cut into sections 5 mm. thick. W h e n pleural anastomoses were present, a thin slice including this area was also preserved. During the process of sectioning, reference was made to the arteriogram of the whole lung in order to determine the cause of any filling defects or abnormal shadows present. T h e sections were X-rayed on envelope-wrapped Kodaline Standard film. With focal-film distance of 60 cm. (24 in.), the exposure factors were 9 ° kV., ioo mA. and 2. 5 sec. Standard X-ray developer gave satisfactory results, provided it was reasonably fresh. When dry, the films were
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examined under the low power of the microscope and typical areas selected for enlargement up to t5 or 2o diameters. A magnification of 15 diameters was generally adequate for this investigation. Histological E x a m i n a t i o n . - - A t least three blocks from each lung were set aside for histological study in addition to any taken from sites of particular interest such as points of arterial
A
B
C
D E F Fig. I 2 9 . - - T h e lung arteries before and after injection. A, B, C, Uninjected lung ; D, E, F, Injected lung ; A, D, Segments of lobular arteries o-8 m m . diameter ; B, E, Arteries o.2 and o'4 rmn. diameter ; C, F, Arterioles o'o5 r a m . diameter. T h e injected arteries are distended, their walls are attenuated, and their elastic coats stretched. Sections f r o m a case of lone pulmonary hypertension stained w i t h Verhoff and V a n Gieson.
narrowing. Two sections were made from each block, one being stained with ha~matoxylin and eosin, and the other with Verhoff elastic stain combined with Van Gieson. Before any conclusions were drawn from the arteriogram, the histological sections were examined to confirm that the arteries were fully distended. In the uninjected lung, the elastic coats were invariably more or less deeply crenated, but after a satisfactory injection, the arterial wall was much thinner in relation to the size of the lumen and the elastic coat was quite smooth (Fig. 129).
THE NORMAL ARTERIOGRAM The arteriogram of the inflated lung, particularly when viewed stereoscopically, provided a clear picture of the entire pulmonary arterial bed (Fig. 13o). As Ewart (1889) showed, the arteries subdivide like the bronchi, and the two structures remain associated down to the smallest branches 8
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~
Fig.
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I33.
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Fig. I34.
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Fig. I35.
Fig. 13o.--Normal arteriogram of the right lung. Fig. I 3 I . - - R e c u r r e n t pulmonary embolism, pulmonary hypertension. Left pulmonary arteriogram. Filling defects, indicated by arrows, represent zones of isch~emia resulting from thrombotic occlusion of segmental arteries. T h e right pulmonary artery was occluded by organized thrombus, so that the total pulmonary arterial bed was greatly restricted. Fig. i 3 z . - - R e c u r r e n t pulmonary embolism, pulmonary hypertension. Left pulmonary arteriogram. I n addition to filling defects representing zones of ischmmia, there are clouds of radio-opaque medium marking sites of recent infarction. The right basal artery and a large artery to the right upper lobe were occluded; the total pulmonary arterial bed was therefore greatly reduced. See also Fig. I43. Fig. I 3 3 . - - L o n e pulmonary hypertension. R i g h t pulmonary arteriogram. There is generalized depletion of the finest branches due to widespread occlusion of lobular arteries (Figs. i4i and r44). T h e arteries in the left lung were similarly occluded, so that the total pulmonary arterial bed was greatly reduced. Fig. s34.--Lone pulmonary hypertension. Left pulmonary arteriogram. T h e segmental arteries, which are slightly narrower than normal, stand out unusually clearly because the finest vessels are contracted (Fig. I45). Neither the arteries nor the arterioles showed any abnormal intimal thickening; the photomicrographs in Fig. i29 were tsken from this case. Assuming that the arteriolar narrowing was also present in the uninjected lung, the total pulmonary arterial bed must have been considerably reduced. Fig, 135 - - M i t r a l stenosis, pulmonary hypertension. R i g h t pulmonary arteriogram. There is a generalized diminution of the finest branches owing to arteriolar obstruction (Fig. I46), and narrowing of the segmental arteries in the lower half of the lung. The histological appearance of the arteries and arterioles in the left lung was similar to that in the right, so that the total pulmonary arterial bed was considerably reduced. Fig. i 3 6 . - - E m p h y s e m a and bronchiectasis, pulmonary hypertension. Right pulmonary arteriogram. T h e peripheral arborization is deficient owing to loss of much of the arteriolar bed (Fig. 147). The left lung was not quite so extensively diseased as the right, but the reduction in the total pulmonary arterial bed must nevertheless have been considerable.
Fig. I36.
~z3
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visible to the naked eye. Because of this association, it is natural to name the larger arteries with reference to the accompanying bronchus. T h u s an artery which accompanies a segmental bronchus may appropriately be called a segmental artery. In the middle lobe of the right lung, the lingular portion of the left upper lobe, and both lower lobes, the pattern of the segmental arteries is almost identical with that of the bronchi (Table II). In the right upper lobe and the corresponding part of the left upper lobe, however, there are important differences. The right pulmonary artery often gives off its first branch before entering the lung, Table H.--THE SEGMENTALBRONCHIAND THE CORRESPONDINGARTERIES RIGHTLUNG LEFTLUNG
Bronchi Upper lobe Apical Posterior
Anterior
Arteries Apical Posterior superior Posterior inferior Anterior
Middle lobe Lateral Medial
Lateral Medial
Lower lobe Apical (Subapical)* Medial basal Anterior basal Lateral basal Posterior basal
Apical (Subapical)* Medial basal Anterior basal Lateral basal Posterior basal
Bronchi Upper lobe Apicoposterior
Arteries Apical Posterior
Anterior
Anterior lateral Anterior descending
Superior lingular Inferior lingular
Superior lingular Inferior lingular
Lower lobe Apical (Subapical) t (Medial basal):~ Anterior basal Lateral basal Posterior basal
Apical (Subapical)* (Medial basal)* Anterior basal Lateral basal Posterior basal
Notes from the Nomina Anatomica, International AnatomicalNomenclature Committee, I955. * Inconstant. Absent in 70 per cent as an independent entity. :~Rarely present. and this large vessel, named by Boyden (1955) the anterior trunk, carries the blood-supply to the greater part of the upper lobe. It quickly divides into anterior, apical, and posterior superior branches, to supply the anterior and apical bronchopulmonary segments and part of the posterior segment (Fig. 137 ) . T h e remainder of the posterior segment is supplied by the posterior inferior branch, which arises directly from the right pulmonary artery at a lower level. The arteries to the upper part of the left upper lobe usually arise directly from the left pulmonary artery, but there are separate apical and posterior arteries to the apicoposterior segment, and two branches to the anterior segment (Fig. I38 ). T h e arteries which are most prominent in a postero-anterior chest film are naturally those which supply the anterior parts of the lung. On the right side, where the lung is more accessible to inspection, these are (Fig. x39 ) the apical and anterior arteries and their branches in the upper lobe, the middle lobe artery and its lateral and medial branches, and the anterior and medial basal arteries and their branches in the lower lobe. On the left side, the most conspicuous arteries are the apical, the anterior lateral, the anterior descending, the superior and inferior lingular and their branches in the upper lobe ; and the anterior basal and its branches in the lower lobe. When arteriograms of normal lungs are compared with each other, the segmental arteries are seen to vary greatly both in their calibre and in their manner of branching. Indeed, so common are the variations that it is almost impossible to find an arteriogram which is ' typical ' in every respect.
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Segmental arteries often arise at a point either above or below their usual origin ; sometimes one bronchopulmonary segment and its artery are unusually small and the neighbouring segment unusually large ; or else, in a segment of normal size, the blood-supply consists of several small Posterior superior
. Apical
Posterior i n f e r i o r -
Anterior
Apical ( l o w e r lobe) _ Lateral (middle lobe) Basal portion of F-
right pulmonary artery
-
Lateral basal r -
Posterior basal
Medial (middle lobe
"" Medial basal
-''~
"" A n t e r i o r basal
f
J
Fig. I 3 7 . - - T h e branches of the r i g h t p u l m o n a r y artery as seen in the lateral projection. D r a w n f r o m Fig. 13o.
Posterior
Apical
Apical ( l o w e r lobe)
Anterior descending
"
Basal portion of left pulmonary artery Superior lingular
Posterior basal I n f e r i o r lingular
Lateral basal A n t e r i o r basal
Fig. I 3 8 . - - T h e branches of the left pulmona r y artery as seen i n th e lateral projection.
arteries instead of one large one. It is important, as Lodge (i946) has stated, to bear this variability in mind when seeking to assess the arterial pattern in a chest radiograph. Examination of magnified arteriograms showed that the regularity of the arterial branching and the progressive decrease in calibre extends down to the finest arterioles (Fig. 142 ) . The smallest unit of lung tissue which can be recognized on the pleural surface is the secondary lobule. The artery supplying this unit, which may appropriately be called a lobular artery, varies in diameter between 0.6 and I'O mm. The lobular arteries and their branches are of the greatest importance in pulmonary hypertension, for it is in vessels of this size that the most significant abnormalities are found. Arterial A n a s t o m o s e s . - - I n the absence of pulmonary hypertension or parenchymal disease of the lung, there was no reflux from the bronchial arteries during the injection of the bismuth suspension. This implies that there are normally no patent bronchopulmonary anastomoses with a diameter greater than o'o 3 mm. A few fine vessels on the lung surface almost invariably became filled during the course of injection but they were never numerous nor did they exceed 0. 3 mm.
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in diameter. The fact that these vessels filled without any reflux appearing from the bronchial artery indicated that they were not bronchopulmonary anastomoses. Examination of magnified
Posterior superior
.
Apical "-
Posterior inferior
Basal p o r t i o n of right pulmonary artery -
J
.
_
.
L
.
t
~ Anterior
_ _
Lateral ( m i d d l e lobe)
....
M e d i a l ( m i d d l e lobe)
-
Lateral basal
P o s t e r i o r basal -
~ ~.
M e d i a l basal
\ Level o f d i a p h r a g m - -
Anterior
basal
Fig. I 3 9 . - - T h e branches of the right pulmonary artery as seen in the postero-anterior projection. Drawn from the same case as Fig. I3o. T h e stippling indicates those arteries which are most prominent in a routine chest radiograph.
P~'g. I 4 o . - - S u b p l e u r a l anastomosis i n pulmonary hypertension due to recurrent pulmonary embolism. T h e anastomotic vessel, whose diameter varies between o'5 and I'O mm., runs over an ischmmic zone and links two branches of the pulmonary artery. F r o m the arteriogram shown i n Fig. I3 I.
Fig. I 4 1 . - - S u b p l e u r a l anastomosis in lone pulmonary hypertension. T h e anastomotic vessel, I'o mm. i n diameter, links two branches of the pulmonary artery. F r o m the arteriogram shown in Fig. I33.
arteriograms showed that they were in fact communications between branches of the pulmonary artery. Reflux from the pulmonary veins was never observed in a technically satisfactory arteriogram.
T H E A R T E R I O G R A M IN P U L M O N A R Y H Y P E R T E N S I O N Pulmonary arteriography was proved to be of great value in the study of pulmonary hypertension, for it provided a far more accurate demonstration of the reduction in the pulmonary arterial bed than did the study of histological sections alone. When an artery is occluded for only a short
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distance, the existence of the obstruction may easily be missed on routine histological examination (Spencer, 195 o) but it is obvious on the arteriogram. Arteriography also brought to light a condition of diffuse arterial narrowing without mural thickening, demonstrated the presence of abnormal anastomoses, and aided the differentiation of arterioles from venules. The pulmonary arterial bed was considerably reduced in every case of severe pulmonary hypertension. Sometimes the reduction was focal, and caused by obstruction of a few large arteries ;
Fig. ~42.--Normal lung : magnified arteriogram. A lobular Fig. I43.--Recurrent pulmonary embolism, pulmonary hyperartery, 0.6 ram. diameter, enters at the left of the field. T h e tension: magnified arteriograra. I n many areas, such as that diameter of the smallest arterioles visible is o'o3 turn. shown here, the arteriolar pattern appeared normal. From the same ease as Fig. I32. Magnification as i n Fig. I42.
Fig. 144.--Lone pulmonary hypertension : magnified arteriogram. A lobular artery, 0"7 ram. diameter, is seen entering at the top of the field. T h e normal arteriolar pattern is replaced by tortuous anastomotic channels. T h i s is a typical field from the same case as Figs. I33 and I4I. Magnification as in Fig. I42.
Fig. I 4 5 . - - L o n e pulmonary hypertension : magnified arteriogram. T h e arterioles are considerably narrower than normal. T h i s is a typical field from the same case as Fig. I34. Magnification as in Fig. I4z.
more commonly it was diffuse and resulted from widespread narrowing or occlusion of arteries less than i.o mm. in diameter. The pattern varied with the underlying disease. The arteriograms of mitral stenosis, emphysema, and recurrent pulmonary embolism each showed distinctive features ; the pattern in lone (or primary) pulmonary hypertension, on the other hand, was less uniform. Abnormal bronchopulmonary and interpulmonary arterial anastomoses were found in the great majority of cases. Recurrent Pulmonary E m b o l i s m . - - T h e arteriogram in recurrent pulmonary embolism showed large filling defects because segmental arteries were occluded, and the opaque material was
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prevented from entering the territories beyond the obstructions (Fig. I3I ). In places of actual infarction, the injected material collected to form dense irregular blotches resembling birds' nests. (Fig. I32. ) Elsewhere, the arterial and even the arteriolar pattern was normal (Fig. I43 ). The bronchial arteries were prolific around occluded arteries; and abnormal subpleural anastomoses, linking the blood-supply of adjacent lobules or segments, were common over ischa~mic ZOnes (Fig. I4o ). Lone (or Primary) Pulmonary H y p e r t e n s i o n . - - T h e arteriographic pattern, like the histo. logical appearance of this condition, varied ; perhaps indicating that more than one disease is at present included under this diagnosis.
Fig. I 4 6 . - - M i t r a l stenosis, pulmonary hypertension: magnified arteriogram. A lobular artery, o'7 mm. diameter, enters at the left of the field. T h e arterioles are depleted. T h i s is a typical field from the same case as Fig. 135. Magnification as in Fig. 142.
Fig. I 4 7 . - - E m p h y s e m a and bronchiectasis, puhnonary hypertension : magnified arteriogram. T w o lobular arteries, 0"3 a n d 0 . 2 5 ram. diameter, are seen r u n n i n g ob]iquely across the field from left to right. Both are narrower than normal, and their arteriolar branches are depleted. A branch from the upper one is seen communicating with the bronchial artery which is r u n n i n g vertically on the right of the field. Magnification as in Fig. i42.
When the lobular arteries were chiefly affected, the arteriogram showed widespread loss of the normal peripheral arborization (Fig. 133 ). This appearance has been aptly likened to the denuded shrub of winter in contrast to the leafy bush of spring (Evans, I95I ). The magnified arteriogram showed that the majority of the lobular arteries ended blindly, and that the normal arteriolar pattern was virtually replaced by tortuous anastomotic channels (Figs. i41 , i44 ). This finding was of great help in interpreting the histological appearances. The segmental arteries were of normal size. There was one case of lone pulmonary hypertension in which careful histological examination revealed neither arterial occlusion nor even important mural thickening (Fig. I29). The media of the lobular arteries showed some hyalinization, but the arterioles appeared structurally normal. On naked-eye inspection of the arteriogram the segmental arteries, although slightly narrowed, seemed to stand out unusually clearly, suggesting a generalized reduction in the peripheral arborization (Fig. 134 ). This was confirmed when magnified arteriograms were scrutinized; for the diameters of the lobular arteries and their branches were reduced to half to two-thirds of those in the normal controls (Fig. i45 ). The arterioles appeared to be less numerous as well as narrower than normal, but this was probably because the smaller arterioles were too contracted to admit the opaque material. Abnormal subpleural anastomoses were seen, but these were few in number. In the three other cases of lone pulmonary hypertension, the state of the fine vasculature was more or less intermediate between the two examples which have been cited. In one, the main artery to the lung was grossly dilated and the segmental arteries were considerably enlarged, but in the remaining two cases the calibre of the segmental arteries was either normal or slightly reduced.
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Mitral S t e n o s i s . - - I n mitral stenosis, the segmental arteries to the.upper lobe were occasionally dilated, but those to the middle lobe (or lingula) and to the basal segments of the lower lobe were usually contracted (Fig. i35), and often strikingly so. When the outline of these contracted arteries was regular, histological examination showed no intimal or medial thickening ; indeed apart from their size these vessels appeared normal. Sometimes the lumen was irregular and then superimposed intimal thickening was found. The most important narrowing was found in the arterioles, for the magnified arteriogram showed a considerable reduction of the arteriolar bed throughout the lung (Fig. 146). Interpulmonary arterial anastomoses were inconspicuous unless the disease had been complicated by pulmonary embolism. E m p h y s e m a . - - I n emphysema, the segmental arteries in the upper half of the lung were sometimes dilated (Fig. i36), but those in the lower half were generally normal. The main abnormality was to be found in the small arteries and arterioles, for magnified arteriograms showed long straggling lobular arteries almost devoid of arteriolar branches (Fig. I47 ). Interpulmonary arterial anastomoses were infrequent, but abnormal bronchopulmonary communications were abundant. Congenital Heart Disease.--Only one case of congenital heart disease with pulmonary hypertension was investigated. In this, a case of atrial septal defect, the arteriogram showed gross dilatation of the segmental arteries, with widespread loss of the peripheral arborization due to obstruction of lobular arteries. A r t e r i a l Anastomoses.--Bronchial artery reflux was a frequent finding in pulmonary hypertension, but it was never copious. The opaque medium flowed from all the bronchial arteries, both at the hilum and in the pulmonary ligament. It usually appeared about a minute after the start of the injection at the same time as the filling of the pleural vessels. This delay suggests that the abnormal bronchopulmonary anastomoses involved small peripheral arteries rather than large ones near the hilum, and this was confirmed on the few occasions when it was possible to demonstrate the communications on a magnified arteriogram (Fig. i47 ). In pulmonary hypertension, the extrapulmonary bronchial arteries were never significantly enlarged, in contrast to Fallot's tetrad and bronchiectasis where they were considerably dilated and the reflux was profuse. It seems improbable, therefore, that pulmonary-bronchial anastomoses are the cause of pulmonary hypertension as some have suggested (Froment, Galy, Tolot, Cahen, Gardere, and Ugnat, i954) and more likely that they are a result of arterial obstruction. Abnormally large subpleural arteries (o. 5 to i.o mm. diameter) were common, and were particularly prominent over the territories of occluded pulmonary arteries. They appeared to be anastomoses between branches of the pulmonary artery, serving as an alternative blood-supply to ischa~mic areas (Figs. 14o and I4I ).
THE SIGNIFICANCE OF THE ARTERIOGRAM IN PULMONARY HYPERTENSION The pulmonary arterial bed was shown to be considerably reduced in each of the 26 cases of pulmonary hypertension investigated. This reduction could generally be correlated with histological abnormalities and especially with thrombosis or intimal thickening, but sometimes it could not be accounted for on histological grounds. Thus, diffuse narrowing of the segmental arteries ill the lower half of the lung, without corresponding intimal or medial thickening, was demonstrated in several cases of mitral stenosis, while a similar condition of the lobular arteries and the arterioles was the sole abnormality in one case of lone pulmonary hypertension. The diameter of the contracted vessels was one-half to two-thirds of the normal. This appearance was not an artefact, nor was it due to ' spasm ', for the arteries were shown to be fully distended by the opaque medium, the elastic coats having lost all their crenation.
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The effect of this lack of distensibility on the resistance to blood-flow cannot be accurately assessed since the precise relationship between calibre and pressure in the pulmonary arteries is not yet established. Poiseuille's law states that in a system where the tubes are rigid and the flow non-turbulent, the resistance varies inversely with the fourth power of the radius ; so that under these conditions, and provided the flow is kept constant, reducing the diameter by one-third is sufficient to raise the pressure five-fold. Thus the narrowing which was observed in these arteries might have been responsible for considerable pulmonary hypertension. It must be remembered moreover that the difference in calibre which was observed in the arteriogram applies to the fully distended state. During life, these arteries and arterioles were doubtless subject to at least a normal degree of vasoconstriction so that their relative narrowing may have been even greater. This observation carries important implications. It shows that organic arterial narrowing cannot be excluded solely on the ground of the absence of intimal thickening or medial hypertrophy. In any future study of the arterial bed whether in pulmonary or systemic hypertension, arteriography must be regarded as complementary to histology. It also explains why the arterial narrowing which is seen in the chest radiograph in cases of mitral stenosis with pulmonary hypertension (Davies, Goodwin, Steiner, and Van Leuven, i953 ; Short, i955) often persists after successful valvotomy (Goodwin, Hunter, Cleland, Davies, and Steiner, i955). The structural changes in the arterial bed in puhnonary hypertension are much more severe than is generally recognized. There can be little doubt that they account for the uniformly serious prognosis of this condition, and the failure of antispasmodic drugs and nerve-section operations. In our present ignorance of pulmonary h~emodynamics, it is impossible to say whether organic arterial disease was wholly responsible for the pulmonary hypertension which was present during life, or whether another ' functional ' factor must be postulated. In some cases the arterial obstruction was so great as to leave no doubt that it was the major if not the sole mechanical cause of the hypertension. This appeared to be so in some of the cases of so-called primary pulmonary hypertension. If in this group the hypertension is sometimes secondary to arterial disease, the term ' p r i m a r y ' is clearly inappropriate; it is for this reason that the designation ' l o n e ' has been preferred. SUMMARY AND CONCLUSIONS A method of arteriography is described by means of which the puhnonary arterial and arteriolar bed may be portrayed in full distension. Following injection of a radio-opaque medium the lung is inflated and radiographed. After fixation, thin sections are cut; these are then radiographed on Kodaline Standard film and the resulting radiographs enlarged up to 25 times. Fifty-seven lungs have been investigated by this technique, 26 being from cases of severe pulmonary hypertension, and including instances of mitral stenosis, emphysema, recurrent pulmonary embolism and lone (or primary) pulmonary hypertension. The arteriogram of the inflated lung, particularly when viewed stereoscopically, provides a clear demonstration of the anatomy of the pulmonary arterial system. In pulmonary hypertension, the arteriogram was always grossly abnormal. It showed two main differences from the pattern found in health ; first the arterial bed was considerably reduced, and secondly new anastomoses were present. In recurrent pulmonary embolism, the main obstruction lay in the large arteries, whereas in mitrat stenosis and emphysema it lay in the arterioles. In lone pulmonary hypertension, the changes were found either in the small arteries or in the arterioles. In most instances, the reduction in the arterial bed could be readily correlated with histological abnormalities, and especially with thrombosis or intimal thickening, but narrowing was sometimes demonstrated in arteries which showed no mural thickening on histological examination. Pulmonary
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arteriography is therefore essential to a thorough post-mortem investigation of pulmonary hypertensi °n. The structural changes in the arteries in pulmonary hypertension have been underestimated in the past. There can be little doubt that they account for the uniformly serious prognosis of this condition and its resistance to treatment. In some cases, the arterial obstruction was so great and widespread that it appeared to be entirely responsible for the pulmonary hypertension. Subpleural anastomoses between peripheral branches of the pulmonary artery were found in apparently normal lungs. In pulmonary hypertension, these anastomoses were often extraordinarily large and numerous, particularly over zones of isch~emia. The injection medium never passed into the bronchial arteries in apparently healthy lungs, but it did so in the majority of cases of pulmonary hypertension; the reflux from the extrapulmonary bronchial arteries was, however, rarely copious and the arteries themselves were scarcely enlarged. Reflux from the pulmonary veins was never seen. A c k n o w l e d g e m e n t s . - - I t is a pleasure to acknowledge the help of many departments both in the London and the Middlesex Hospitals. I am particularly grateful to Professor Dorothy Russell and to Professor Scarff for facilities in the respective Departments of Pathology ; to Miss F. M. King of the L o n d o n Hospital, and to Miss Franks and Mrs. Fife of the Middlesex Hospital, for radiographic assistance ; to the Chief Pharmacists, Mr. C. H. Sykes and Mr. G. Bryan, for advice and help with the injection media ; and to Mr. Turney of the Middlesex Hospital Photographic Department for the enlargements and reproductions. Above all, I am indebted to Dr. William Evans and Dr. Evan Bedford for their encouragement and stimulating criticism, and to Dr. Peter Kerley for his constant advice and inspiration. REFERENCES BARCLAY,A. E. (I947), Brit. J. Radiol., 2o, 394-- - - (I95I), Microarteriography, 87. Oxford : Blackwell Scientific Publications Ltd. BEDFORD,D. E. (I95I), Proc. R. Soc. Med., 44, 597. BOYDEN,E. A. (I955) , Segmental Anatomy of the Lungs: a Study of the Patterns of the Segmental Bronchi and Related Pulmonary Vessels. New York : McGraw-Hill Book Company Inc. DAVIES,L. G., CooDWIN, J. F., STEINER,R. E., and VAN LEUVEN,B. D. (I953), Brit. HeartJ., I5, 393. EVANS,W. (I95I), Proc. R. Soc. Med., 44, 6oo. EWART, C. (I889) , The Bronchi and Pulmonary Vessels. London : Bailli~re, Tindall, & Cox. FROMENT,R., GALY, P., TOLOT, F., CAHEN,P., GARDERE,J., and UGNAT, V. A. (I954), Rev. Lyon, 3, 255. GOODWIN,J. F., HUNTER,J. D., CLELAND,W. 1J., DAVIES,L. G., and STEINER,R. E. (I955) , Brit. med.J., 2, 573. HARRISON, R. G., and ASLING, C. W. (I955),J. Anat., 89, IO6. HOWARTH,E. H. (I953) , personal communication. LODCE,T. (I946), Brit. J. Radiol., 19, i. McKEOWN, F. (I952), Brit. Heart J., 14, 25. McWILLIAM, J. A., and MACKIE,A. H. (I9O8), Brit. med. J., 2, 1477. SCHLESlNC-ER,M. J. (i938), Amer. HeartJ., 15, 52.8. SHORT,D. S. (I955), Brit. HeartJ., I7, 33. SPENCER,H. (I95O), J. Path. Bact., 62, 75-