THE PULMONARY VESSELS IN MITRAL STENOSIS

DONALD HEATH* and WILLIAM WHITAKER From the Regional Cardiovascular Centre, City General Hospital, and

the University Department of Medicine, Royal Hospital, Shefield

(PLATE LXXIV)

ALTEOUGH it has long been recognised that the pulmonary vessels are abnormal in mitral stenosis, it is only since the introduction of a direct method of recording pulmonary-artery blood-pressure by cardiac catheterisation that it has been possible to correlate the anatomical changes with the degree of pulmonary hypertension. The present communication describes the changes in the pulmonary vessels in a group of cases of mitral stenosis where the pulmonary-artery blood- pressure was known or where the classical s i p of pulmonary hyper- tension were present. Our study indicates that some of the vascular changes are those which, being usually associated with pulmonary hypertension, seem to be caused by it, and some those which normally occur with increctsing age. None of the changes is thought to result from involvement of the vessels by acute rheumatism.

METHODS AND MATERIALS

"he resting pulmonary-artery blood-pressure was recorded by cardiac catheterisation in 19 patients with mitral stenosis. The existence of pulmonary hypertension was deduced from its claesical clinical signs in 12 other patients (Whitaker, 1954). These patients, of ages ranging from 23 to 85 years, were subsequently treated surgically and at the time of thoracotomy a biopsy was taken from the lingular lobe of the left lung. The large elastic arteries were further studied in 3 patients who came to autopsy. Sections were stained with Verhoeff's and Van Gieson's stains. Comparable control material wm obtained from 25 patients of ages ranging from 9 weeks to 79 years who died without evidence of cardiac or respiratory disease. Two of the 19 patients in whom the mean pulmonary-artery blood-pressure was directly m e w e d had mild pulmonary hypertension (16-40 111111. Hg.), 10 had moderate pulmonary hyper- tension (41-7Omm.Hg.) and 7 had severe pulmonary hypertension(>70mm. Hg.).

HISTOLOGICAL FINDINGS

Muscular arterim The muscular pulmonary arteries are characterised by the presence

of a muscular media lying between intima and adventitia. They range in diameter from 100 to 1000 p. Vessels of a smaller diameter

Leverhulme Research Scholar, Royal College of Physicians of London. J. PATH. BACT.-VOL. LXX (1966) 291 T 2

292 D. HEATH AND W . WHITAKER

than 100 p do not normally have a distinct media and are here termed arterioles, while vessels with a diameter greater than 1 O O O p have a larger amount of elastic tissue in the media and are classed as intra- pulmonary elastic arteries.

The media in the control cases is composed mainly of smooth-muscle cells and is bounded by internal and external elastic membranes which are distinct, single and thin. In all cases the thickness of the media is 5 per cent. or less of the external diameter of the vessels (fig. 1). In patients past middle age, fibrous tissue is intermingled with the smooth-muscle cells in the media, which is thinner than in the younger subjects and is associated with thin elastic membranes, often seen to be ruptured.

In most cases of mitral stenosis the media is thicker than normal, and in 20 of the 31 cases has a thickness amounting to 15 per cent. or more of the external diameter of the vessel (fig. 2 and table). In 3 cases the thickness of the media is more than 25 per cent. of the diameter, but the thickness is not in direct proportion to the pulmonary- artery blood-pressure. Thus in two cases where the pressures were 57 and 56 mm. Hg. the medial thickness is more than 25 per cent., while in 2 where the pressures were 94 and 87 mm. Hg., the medial thickness is only 15 per cent. There is, however, a close though indirect relationship between the thickness of the media and the pulmonary-artery blood-pressure, for, in all but one of the 11 cases of mitral stenosis where the media has a thickness of less than 15 per cent. of the external diameter of the vessel, the mean pulmonary- artery blood-pressure was below 70 mm. Hg. It is impossible to distinguish the muscular pulmonary arteries and arterioles of the low- pressure cases from those of the controls (fig. 2 ) . Where there is medial hypertrophy the internal and external elastic membranes are thickened and frequently show fragmentation, with fibrils entering the proliferated intimal fibrous tissue (fig. 3). The presence of fibrous tissue in the media is common. Even allowing for artifacts produced in cutting, the media sometimes appears to be of uneven thickness ; at certain points on the circumference it narrows so that the internal and external elastic membranes join as one lamina separating intima and adventitia.

Intimal thickening by fibrous tissue is present in every control case over the age of 40 years, but in only one case under this age. The thickened intima consists of fibrous tissue in the form of crescents or concentric rings. It is finely fibrillar and stains lightly, and elastic fibrils in the intima are rare.

Intimal proliferation of fibrous tissue is seen in every case of mitral stenosis (fig. 3). The endothelium can often be clearly distinguished internally to the proliferated tissue. The cells of this tissue are often arranged radially and, as in the case of the older controls, form crescents or concentric rings encroaching on the lumen of the vessel. A few fibrils of elastic tissue may intermingle with the fibrous tissue cells. These appearances are quite different from the intimal proliferation

Media.

Intimu.

PLaTB LXXIV FIQ. I.-Tmnweme section of 8 normal musculer pulmonary arterg of 150 p dhmeter

from a child a@ four months with no evidence of cardiac or Feepiratorg dinenee. There is a thin medie, bounded by thin, maplit elastic membranes and no intima1 prolifemtion of 5 b m t h a VerhoeFs and Van Gitmon’e stain. x 340.

FIQ. 2.--Trcureverse section of a muscular pulmonary artery of 300 1.1 diameter from a case of m i t d atmmsia with mild pulmonary hypertedon. Mean pulmonary artery blood-presaure 33 mm. Hg. There is 8 thin medie bounded by thin, uneplit elastic membranes There is minimnl subintimrrl proliferation of fibrous tissue and the adventitia is thin. The 8ppearance of the v-1 is n o d . Verhoeff’s and Van Uieeon’s etain. x 180.

RQ. 3.-Traneveree section of 8 muscular pulmonary artery of 160 p diemeter from 8 cam of d t rd etenosiS with severe pulmonary hypertension. Mean pulmonary- artmy blood-preeeure 74 mm. Hg. There is 8 hypea%rophied media. the elmtic membranes are thickened and subintimd proliferation of fibrous tissue has oacufied. VerhM’s and Ven Gieeon’s stain. x 340.

FIQ. 4.-Tr131wverse section of a pulmonary arteriole of 66 p diameter from a case of mitral atenosis with severe pulmonary hypertension. Mean pulmonary-arterg blood- preeaure 74 mm. Hg. A distinct media is present, and there is some mbintimd proliferation of fibmus t h e . Both thea featUree are abnormal. VerhoeR‘e and van Qiaeon’s etein. x 490.

mi- Btenoeie with eevere pulmonary hyPerteneion. Menu pulmonary-artmy blood-preewue 74 mm. Hg. A single elastic lemins in present between the adventitis and the prolifezated subintipal fibrous t h e . The appeanrnce of thie veeael is normal for th i~ age (25 yeam). Verhod‘s and Van (fieeon’s Stein. x 400.

FIQ. 6.-- ee0t ih Of 8 PUh- Vmde Of 70 p diemeter from 8 DBBB Of

J. PATH. HACT.-YOL. L S X PLATE LXXIV

PULMONARY VESSELS IN MITRAL STENOSIS

FIG. 3.

FIG. 1.

FIG. 4.

FIG. 2. FIG. 5.

PULMONARY VESSELS IA' MITRAL STENOSIS 293

Media of muscular pulmon-

a r ~ ~ e ~ ~ , l ~ ~ ~ ~ t . (meen) of vessel

~

Csse no.

that we have seen in cases of congenital heart disease with pulmonary hyperternion (Heath and Whitaker, 1955), where the proliferated fibrous tissue is coarser in structure and frequently leads to occlusion of the lumen of the vessel with later recanalisation and does not form crescents or rings. It is clear that intimal fibrosis in our cases of mitral shnosis is more like that seen in the control cases over the age of 40 than that in cases of congenital heart disease with pulmonary hypertension.

T-4BLE

The pulmnury-artery blood-pressure and the hktological featurea of pdmom.ry arteriecr and arterioles in nineteen cases of mitral stenoeis

Media in arteriole

- 30 - 33 I

- -

3 4 5 6 7 8 9

10 1 1 12

_ _ _ ~

13 14 15 16 17 18 19

42 41 45 48 51 56 57 60 65 68

I _~ Severe prllmonary hypertension ( >70 mm. Hg.)

1

76 81 81 87 90 94

108

+ I - &

j I

, T ...

I + 1

. .. . . ._

Arterioles

In the control cases, arterioles of less than 100 p in diameter show no distinct media. In 17 out of 31 cases of mitral stenosis a definite media exists, bounded by two distinct elastic membranes (fig. 4). Where the pulmonary-artery blood-pressure had been measured directly, it was observed that patients showing arterioles with no niedia had a mean pulmonary-artery blood-pressure of 51 mm. Hg. or less, with but two exceptions (table). Intimal thickening by fine,

294 D. HEATH AND W. WHITAKER

faintly-staining fibrous tissue occurs commonly in the control cases (17 out of 26) and is also found in 25 of the 31 cases of mitral stenosis.

Veins These vessels have a diameter of 100 p or more and possess a

media which has a thickness of 1-5 per cent. of the external diameter of the vessel, the media and adventitia tending to merge with one another. Some fibrosis of the intima of the veins is seen in every w e in the control series with the exception of a child aged 9 months, and in every case of mitral stenosis.

Venules These vessels have a diameter of less than 100 p and consist of a

single elastic lamina lying between the endothelium and a thin adventitia. In the control cases it is impossible to distinguish between arterioles and venules. Only in patients with pulmonary hypertension and arteriolar hypertrophy is it possible to distinguish between a venule and an arteriole (fig. 5 ) . Fibrous tissue in the intima can be distinguished in most of the control cases (23 out of 25) and in all the cases of mitral stenosis (fig. 5 ) .

Elastic arteries Atheroma was found in the intima of the intrapulmonary elastic

arteries (> 1000 p ) in one of the 3 necropsy cases, aged 55, where the mean pulmonary-artery blood-pressure was 94 mm. Hg. No medial necrosis was observed. Elastic arteries were not included in the biopsy tissues taken at operation.

DISCUSSION The most consistent finding in the small

pulmonary vessels in mitral stenosis is medial hypertrophy in the muscular pulmonary arteries and the development of a distinct media in the arterioles. Lmrabee et al. (1949) found that the cab re of the arterioles was reduced in 15 of 20 cases of mitral stenosis, and in 10 of these considered that this was due to intimal fibrosis and medial hypertrophy. Henry (1952) studied the arteriolar changes in relation to the degree of mitral stenosis and, although there waa a higher incidence of abnormal arterioles in patients with severe mitral stenosis, his results did not suggest that there was any direct correlation between these two conditions. However, in the patients with mitral stenosis in our series where the pulmonary-artery blood-pressure was directly measured, medial hypertrophy of the muscular pulmonary arteries and the development of a distinct media in the arterioles were present in all but one of the cases with severe pulmonary hypertension ( > 7 0 mm. Hg,), absent in all cases with mild hypertension ( <40 mm. Hg.) and also absent in the 5 patients with moderate pulmonary

Medial hypertrophy.

PULMONARY VESSELS I N MITRAL STENOSIS 295

hypertension (41-70 mm. Hg.) in whom the pulmonary-artery blood- pressure was 51 mm. Hg. or less. These results indicate that the medial hypertrophy of the muscular pulmonary arteries and the development of a media in the arterioles observed in the present series and noted by previous authors are most probably manifestations of pulmonary hypertension. Similarly in a series of patients with patent ductus arteriosus studied by Heath and Whitaker there was a close correlation between pulmonary-artery blood-pressure and the appear- ance of the media of the pulmonary vessels. Patients with normal pulmonary-artery blood-pressure had normal arterioles. Patients with severe pulmonary hypertension, where the pulmonary-artery blood- pressure wa8 higher than the systemic pressure, had grossly abnormal arterioles, with a thick media lying between thick internal and external elastic laminae and occlusion of the lumen by intimal fibrous tissue. The patients with a pulmonary-artery blood-pressure lying between the two extremes had a media in the arterioles which was bounded by two thin but distinct elastic membranes, but there were no other abnormalities. These results suggest that the development of an abnormal media is related to pulmonary hypertension. Such changes are characteristic of the pulmonary vessels in patients with mitral stenosis but they are not pathognomonic of this condition, since they occur with congenital heart disease where there is associated pulmonary hypertension, as in Eisenmenger’s complex (Brown et al., 1955), patent ductus arteriosus with severe pulmonary hypertension (Whitaker et al., 1955) and ventricular septd defect with severe pulmonary hypertension (Heath et al., 1956). A distinct media in the pulmonary arterioles in patients with acquired or congenital heart disease is always associated with pulmonary hypertension.

Although patients with mitral stenosis and severe pulmonary hypertension have organic changes in their pulmonary arteries and arterioles, such patients are not necessarily suffering from irreversible pulmonary hypertension. Baker et al. (1952) showed that the pulmonary-artery blood-pressure fell after mitral valvotomy, but did not reach normal levels in any of their patients. Larrabee et al. thought that the abnormal muscular component in the small pulmonary vessels would disappear after surgical tseatment of mitral stenosis, but did not believe that the intimal proliferation of fibrous tissue would revert to normal. There is, ;18 yet, no evidence that reversal of organic changes in the pulmonary vessels occurs after mitrd valvotomy and that such a change is responsible for the fall in pulmonary-artery blood-pressure observed. The fall in pressure may equally well be due to the removal of vaso-constrictor impulses produced by an abnormally high left-auricular blood-pressure.

Inti& thickening. Fibrous thickening of the intima of the small pulmonary vessels is a characteristic normal age change and is un- related to the pulmonary-artery blood-pressure. In the present series this change occurred extensively in arteries, arterioles and veins in

296 D . HEATH A N D W . WHITAKER

all but the very young control cases. It was not present in two children aged 9 weeks and 4 months respectively, but slight changes had occurred in a man aged 19 years. In all the older control patients intimal thickening was obvious. Brenner (1935) was aware of this widespread change in the pulmonary vessels in patients over the age of 10 years. All the patients with mitral stenosis in the present series had obvious intimal thickening of the small pulmonary vessels but, in view of similar findings in normal patients of the same age group, this can be of no significance. Henry thought that stagnation of blood in patients with mitral stenosis caused proliferation of fibro- elastic tissue and accentuation of the subintimal thickening. However, since it is not established that intimal changes are any more obvious in patients with mitral stenosis than in normal controls, it is un- necessary to postulate any specific factor operating in mitral stenosis to explain intimal thickening. Barnard (1954) concluded from the results of animal experiments that characteristic intimal lesions occurred as the result of pulmonary hypertension induced by repeated intravenous injections of minute autogenous blood clots. Denst et al. (1954) thought it unlikely that the changes in the pulmonary vessels of patients with mitral stenosis indicated precocious ageing of the pulmonary vascular tree. We agree with this view, since the age changes in the media of the control patients in the present series were those of thinning and rupture of both media and elastic membranes and in no way resembled the abnormalities seen in the media of the pulmonary vessels of patients with mitral stenosis.

Atherma. Atheroma was noted in the elastic arteries of the 3 patients in the present series who were examined at autopsy: all had severe pulmonary hypertension. Atheroma was also present in patients with mitral stenosis described by Elkeles and Glynn (1946) and Hicks (1953) and in a patient with mitral incompetence of non- rheumatic origin described by Becker et al. (1951). In all these cases there was presumptive evidence of severe pulmonary hypertension. This suggests that pulmonary atheroma is a product of severe pul- monary hypertension, and such a concept is supported by the occurrence of atheroma in the pulmonary arteries in Eisenmenger’s complex (Brown et al.), in patients with patent ductus arteriosus com- plicated by severe hypertension (Whitaker et al.) and in a patient with a muscular ventricular septa1 defect associated with severe pulmonary hypertension (Heath et al.).

No patient in this series showed acute necrosis of the pulmonary vessels, but such changes were described by Hicks in a patient with long-standing mitral stenosis who, from the evidence of right ventricular hypertrophy, ‘. hyperplastic sclerosis ” and atheroma of the larger branches of the pulmonary artery, undoubtedly had severe pulmonary hypertension. Similar arterial necrosis has been noted in other patients with pulmonary hypertension. Old and Russell (1950) described it in a patient with Eisenmenger’s complex,

Arterial necrosis.

PULMONARY VESSELS IN MITRAL STENOSIS 297

and McKeown (1952) noted it in four patients with right-sided heart failure of uncertain setiology. Welch and Knney (1948) considered that acute necrosis in the small pulmonary arteries was a manifestation of extreme pulmonary hypertension similar to the necrotising arterio- litis seen in the systemic blood vessels in patients with malignant hypertension. The possibility of a rheumatic setiology for pulmonary arterial necrosis was considered by Hicks, who concluded that there was no evidence for this. The pulmonary vascular changes, including fibrinoid medial necrosis with destruction of the elastica, described by Elkeles and Glynn in a patient with mitral stenosis associated with pulmonary ossification, were considered by those authors to be characteristic of rheumatic arteritis. From the description given of their patient it is obvious that a severe degree of pulmonary hyper- tension was present and the vascular changes are more probably a manifestation of this condition.

Rheumatic arteritis. Both Hicks and Denst et al. considered the possibility that the histological changes in the small pulmonary TTessels were in part due to their direct involvement by acute rheumatism. Denst el al. noted that " non-distinctive " cerebral lesions occurred in rheumatic fever and believed that, since the variety of reactions of the pulmonary vessels to any noxious stimulus is limited, a similar sh t e of affairs might exist in the lungs. Becker et al. described two cases of mitral incompetence where the pulmonary vascular changes were identical with those occurring in mitral stenosis. In one of these w e s , where there was no clinical or pathological evidence of acute rheumatism, the incompetence followed spontaneous rupture of the chordse tendinere. Both cases had right ventricular hypertrophy, which is presumptive evidence that they also had pulmonary hypertension.

There is complete lack of evidence of rheumatic involvement of the pulmonary vasculature in our patients, and our data indicate that the typical changes in the pulmonary vessels in mitral-valve disease are dependent upon the associated pulmonary hypertension but are not otherwise directly related to the degree of valvular stenosis or incompetence.

SUMMARY

A description is given of the histological changes in the pulmonary vessels in 19 cases of mitral stenosis where the pulmonary-artery blood-pressure was known and in a further 12 cases where the classical clinical signs of pulmonary hypertension were present. The age range in these patients was 23-55 years. These changes are contrasted with those found in the pulmonary vessels of 25 patients, free of cardiac or respiratory disease, whose ages ranged from 9 weeks to 79 years.

The most consistent abnormal finding in the small pulmonary vessels in mitral stenosis is medial hypertrophy in the muscular pulmonary arteries and the development of a distinct media in the

298 D. HEATH AND W . WHITAKER

arterioles. These changes were present in all but one of the patients with pulmonary-artery blood-pressure greater than 70 mm. Hg. and in many patients with a lower pressure. There was a close relationship between pulmonary-artery blood-pressure and the presence and degree of these histological changes in individual cases.

Intimal proliferation of fibrous tissue was present in nearly all the cases of mitral stenosis and also in the controls. This change occurred extensively in all types of pulmonary vessel. It is character- istically associated with increasing age and is unrelated to pulmonary- artery blood-pressure. There was no evidence that acute rheumatic involvement of pulmonary vessels accounted for any of the structural changes observed.

We wish to thank Mr 6. T. Chesterman, who provided us with some of the lung biopsies, Dr A. Cumming, who generously allowed us access to data and biopsy material from patients under his care, and Dr J. W. Brown for his constant advice and encouragement. We also wish to thank Mr C. Lambourne for his invaluable help with the sections.

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WHITAKER, W. DENS?, J., EDWARDS, A., NEU-

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ELKELES, A., AND GLYNX, L. E. . HEATH, D., BROWN, J. W., AND

HEATH, D., AND WEITAKER, W. . HICKS. J. D. . . . . . . LARRABEE, W. F., PARKER, R. L.,

MCKEOWN,F’LORENCE. . . . OLD, J. W., AND RUSSELL, W. 0. WELCH, K. J., AND KINNEY, T. D. WHITHER, W. . . . . . . WHITAKER. W., HEATH. D., AND

BELL, M., AND WOOD, P.

AND EDWARDS, J. E.

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This Journal, Ixx, 285. Brit. Heart J . , xiv, 406. This Journal, lxv, 333. Proc. Staff. Meet. Mayo Clinic, xxiv,

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316.