be diagnosed, according to Brenner, when all the causes of secondary pulmonary hypertension can ... A married woman aged 38 was admitted to hospital complaining of severe ... The aorta showed early atheroma in the abdominal portion. ... with dyspnoea and she had had severe breathlessness for a fortnight. For several ...
fPRIMARY
PULMONARY
A Report
of
HYPERTENSIONt
Three Cases
By A. WHITLEY , BRANWOOD Departme7it of Pathology, University of Edinburgh
hypertension is known to occur in association with left failure, chronic pulmonary diseases such as bronchiectasis, lung abscess, extensive fibroid tuberculosis, silicosis, widespread carcinomatosis, emphysema and extensive pleural adhesions ; it is also encountered in certain types of congenital heart disease, especially in those with an increased pulmonary blood flow, in diffuse pulmonary embolism, in kyphoscoliotic heart disease and in primary pulmonary arteriosclerosis. This condition, primary pulmonary hypertension, may be diagnosed, according to Brenner, when all the causes of secondary pulmonary hypertension can be eliminated. In recent years with the advent of cardiac catheterisation, primary PULMONARY
heart
has been discovered in several instances associated with invariably right ventricular hypertrophy and many workers, including Dresdale et al., have stated that it is the cause of the so-called idiopathic, right ventricular hypertrophy. Prior to the introduction of cardiac catheterisation the disease was
pulmonary hypertension
considered rare. MacCallum reported one case in 1200 autopsies and in 1939 Killingsworth found one case in 2707 post mortems. Isolated cases have also been recorded from time to time by other authors. Cardiac catheterisation has enabled this disease, therefore, to be diagnosed more frequently than in the past. Nevertheless the disease is still uncommon and the cause of this
pulmonary hypertension and right ventricular hypertrophy has lead to much speculation as can be seen by the numerous descriptions given to this condition. Brenner, Brill and Cross called their cases primary pulmonary vascular sclerosis while De Navasquez et al. designated their series right ventricular hypertrophy of unknown origin ?so-called pulmonary hypertension. All these authors' cases showed marked right ventricular hypertrophy, but the nature, distribution and severity of the pulmonary vascular changes proximal to the capillaries showed considerable variation. The predominant changes were atheromatous lesions of the stem and larger elastic arteries, alone or in conjunction with fibrous intimal thickening and narrowing of the smaller arteries and arterioles. Medial hypertrophy was occasionally noted. In about half of the reported cases occlusive lesions of the smaller arteries and arterioles were described. Most of these changes have been ascribed to intimal sclerosis and some to thrombi in various stages of organisation.
PRIMARY PULMONARY HYPERTENSION
333
There is considerable difference of opinion as to whether this obliterative sclerosis or thrombosis is the cause or the effect of the pulmonary
hypertension. Dresdale et al. described three cases of primary pulmonary hypertension diagnosed during life by cardiac catheterisation and in whom there was post-mortem evidence of sclerosis of the pulmonary vessels in two of them. The third patient is still alive. These authors stress the similarity between primary pulmonary hypertension and essential
systemic hypertension such
as
of the
the elevated pressure, the hypertrophy of the affected circuit and the
corresponding ventricular muscle similar sclerotic changes in the arterioles
in the two circulatory systems. lends support to the similar theory of Brill et al. in 1941 and Raaschou and Samuelsson, who believe that the right ventricular hypertrophy and vascular changes in the pulmonary vessels
Their
statement
to pulmonary hypertension of unknown aetiology. al. by the use of priscoline, a sympatholytic and adrenolytic agent, found that the elevated pulmonary pressure was greatly reduced and there was a concomitant increase in blood flow through the lungs in these cases. They suggest that the autonomic nervous system may be a factor in the aetiology of primary pulmonary hypertension. are
secondary
Dresdale
et
Whatever the aetiology, however, the majority of these cases have The condition is common in relatively similar clinical picture. young females and attacks of syncope and angina are frequent. Cyanosis is variable. All cases show cyanosis on exertion and in the terminal stages of the disease ; it may be absent during rest. Dyspnoea a
and distress are very marked on effort but are absent at first during There is a normal systemic blood pressure and cardiac examination reveals invariably a greatly accentuated pulmonary second sound. rest.
The electrocardiograph shows right ventricular hypertrophy which is confirmed
radiologically.
pulmonary
The additional
X-ray findings
are a
prominent diminished intra-pulmonary vascular markings. artery segment,
The three
logical
bulging
hilar vessels and normal
cases described below illustrate the clinical and features of this disease.
or
patho-
Case I A married of
severe
woman
aged 38
breathlessness.
A
was admitted to hospital complaining satisfactory history was unobtainable
due to her poor general condition. She did state, however, that she had always been breathless on exertion but this had become much Worse during the past two months. She had been troubled with her heart since she was young and had had numerous fainting attacks. She had never had rheumatic fever. On
examination she was cyanosed, oedematous and obviously The pulse was regular in time and force and the blood pressure was no mm. systolic and 70 mm. diastolic. The apex beat
orthopnceic.
A. WHITLEY BRANWOOD
334
in the 5th left intercostal space within the midclavicular line and gave a distinct tap rather than a thrust to the palpating hand. A soft systolic murmur was audible at the mitral area and the pulmonary second sound was markedly accentuated. Intravenous digoxin was
was
administered but the patient died two hours after admission. Electrocardiograph and X-ray examination were not carried out. At post-mortem examination the body was seen to be that of a
moderately well-nourished adult female showing oedema legs and thighs. The pericardial sac contained a few c.c. of serous fluid. sacs
contained about
fluid
was
200
c.c.
of
serous
of the feet, The
fluid and about 400
pleural c.c.
of
present in the peritoneal cavity. It was Cardiovascular System.?The heart weighed 500 gm. increased in size and was globular in shape. No abnormalities were detected in the pericardium. The right auricle was considerably dilated and its wall was hypertrophied. The tricuspid ring was dilated but the valve cusps were healthy. The right ventricle was greatly dilated and the
ring
was
myocardium grossly
thickened.
dilated but the cusps showed
no
The
pulmonary
abnormalities.
valve
The left
auricle and left ventricle were normal but the interventricular septum hypertrophied and bulged slightly into the left ventricle. The mitral and aortic valves were healthy. The aorta showed early atheroma in the abdominal portion. The pulmonary artery and its main branches were dilated and this dilatation was seen to extend into the secondary and even the tertiary branches of the artery. There was marked atheroma in the main
was
trunk and even
seen
branches of the pulmonary artery and this was in the very small branches of the pulmonary artery in the
principal
lung. Respiratory System.?The
mucous
membrane of the
larynx,
trachea
and main bronchi was congested. There The left lung weighed 470 gm. and the right lung 650 gm. was some atelectasis at the bases of both organs, presumably due to the pleural effusions. The pleural surfaces were smooth and glistening and apart from this atelectasis no abnormalities were detected in the
lungs. Other
organs
no
Organs.?Apart other lesions
from chronic
were
venous
congestion
in all the
present.
Histological
Examination
Lungs.?The pleura showed no abnormalities. The majority of the alveoli were healthy. A little oedema fluid was seen in an occasional alveolus but there was no evidence in the sections examined of chronic venous congestion. The bronchi, bronchioles and interstitial fibrous tissue were healthy. Pulmonary Vessels.?The main trunk and major branches of the
PRIMARY PULMONARY
HYPERTENSION
335
The media artery showed marked intimal thickening. and adventitia of these vessels showed no abnormalities. The smaller branches of the pulmonary artery also showed marked thickening of the intima and many atheromatous plaques, in many instances showing fat spaces, were present in these vessels. The adventitia of these smaller
pulmonary
vessels in all the sections examined was healthy although the media, in several sections, showed atrophy, especially in relationship to the plaques of atheroma. The arterioles showed the most striking changes (Figs. 1, 2, 3, 4). Although in some cases the vessels were of normal
appearance the majority showed intimal thickening. This thickening brought about by fibrous proliferation and in some sections the arterioles were narrowed to a mere slit by the proliferated fibrous tissue in the intima. In these latter cases small round cells were also
was
present among the fibrous tissue. Fragmentation of the internal elastic lamina was a notable feature in most cases. The media was often atrophied beneath the mass of intimal fibrosis. The adventitia was healthy in every case. In one vessel recanalisation of an old thrombus The alveolar capillaries were slightly engorged but was present. showed no pathological changes. Other Organs.?There was chronic venous congestion in the other organs. No signs of vascular sclerosis were present apart from minimal atheroma of the abdominal
aorta.
Case II
patient was a married woman aged 37 who had complained precordial pain on exertion for six months. This was associated with dyspnoea and she had had severe breathlessness for a fortnight. For several years prior to this she had noticed undue fatigue and The
of
She on exertion and she had fainted on several occasions. had noticed oedema of the feet and legs for the past month. On examination the patient was cyanosed, oedematous, orthopnoeic and had pulsating neck veins. The pulse was 100 per min., regular in time and force with a blood pressure of 100 mm. systolic and 78 mm. diastolic. The apex beat was in the 6th left intercostal space, about half an inch outside the midclavicular line and gave a distinct tap to the palpating hand. Auscultation revealed a markedly accentuated sound. Fluid was present at the bases of both second pulmonary
dyspnoea
but there were no moist sounds in the chest. The liver was enlarged and free fluid was elicited on the abdomen. The patient suddenly collapsed and died the night after her admission.
lungs
Post-Mortem Examination was that of a rather thin adult female. Pitting oedema limits. in lower the present Serous Sacs.?'The pericardial sac contained the normal quantity of serous fluid. Both pleural sacs contained about 150 c.c. of clear
The
was
body
A. WHITLEY BRANWOOL)
336 The fluid. of ascitic fluid.
peritoneal
serous
sac
contained
approximately
500
c.c.
Cardiovascular enlarged and was
System.?The heart weighed 640 gm. It was globular in shape. The pericardial surface was smooth and glistening. The right auricle was considerably dilated and its wall showed a moderate degree of hypertrophy. The tricuspid valve ring was dilated but the cusps showed no abnormalities. The right ventricle was also dilated and the myocardium was markedly thickened. The pulmonary valve ring was also dilated but the cusps The left auricle and left ventricle were slightly dilated were healthy. but the myocardium was of the normal thickness. The mitral valve ring was slightly dilated. The mitral and aortic valve cusps were healthy. The aorta showed no abnormalities. The pulmonary artery and its main branches were definitely dilated. This dilatation extended into the smaller branches of the pulmonary artery as far as could be seen with the naked eye. Atheromatous
plaques were present in all these vessels. Respiratory System.?There was congestion of the mucous membrane of the larynx, trachea and bronchi. Lungs.?Both lungs weighed 500 gm. each. Both organs were of the usual shape although each showed a moderate degree of atelectasis at the base. The pleural surfaces were uniformly smooth and glistening and the parenchyma of each lung, apart from the basal atelectasis
showed
emphysema,
no
fibrosis
or
There was abnormalities. lesion other capable of any
no
evidence
of
producing right
ventricular hypertrophy. Other Organs.?Apart from chronic venous congestion and a few calcified tuberculous glands in the ileo-caecal region, no other abnormalities were detected.
Histological
Lungs.?The pleura containing
carbon
showed
no
venous
abnormalities.
Several
histiocytes
present in the alveolar spaces but abnormalities were present in the alveoli, bronchi,
pigment
were
apart from this no bronchioles and interstitial fibrous of chronic
Examination
stroma.
There
was
no
evidence
congestion.
Pulmonary Vessels.?The main trunk of the pulmonary artery and its main branches showed the typical intimal thickening of atheroma. The adventitia and media were normal apart from localised areas of atrophy of the media beneath the atheromatous plaques. The majority of the arterioles were narrowed, indeed in some vessels there was The intima in all these vessels obliteration of the lumen.
complete
grossly thickened by fibrous tissue and the internal elastic lamina reduplicated and split in practically all the sections examined. Some of the arterioles which had been occluded showed commencing
was
was
^ IG*??Case ?Case I.
fibrosis.
Pulmonary
arteriole X IiSo, So,
showing
gross
narrowing
of the lumen
by
the intimal intimal
p IG- 2 ?Case i. Pulmonary arterioleX400, showing reduplication and splitting of the internal elastic lamina and almost almost complete occlusion of the lumen. j, p IG3--?Case 1.?Pulmonary arteriole X 300. There is splitting of the elastic lamina and fibrous 3-;?Case with round cell infiltration in the intima. j, P IG4-?Case 1. Pulmonary arteriole X 300, showing marked splitting of the internal elastic lamina and intimal fibrosis. p IG" P IG- 5-"?Case 2. There is commencing recanalisation of the occluded 400. Pulmonary arteriole X 400. lumen and well-marked reduplication of the internal elastic lamina. p IG. j, 6.-?Case 2. Pulmonary arteriole X 300, showing the changes in the elastic lamina as above 6.?Case and occlusion of the lumen by intimal fibrosis and thrombus.
thickening
*mss2nmm"
k
Pulmonary arterioles X 300, showing well-marked reduplication and splitting of the internal elastic lamina. Medium-sized pulmonary arteries X 40, showing well-marked atheroma. Fig. 9.?Case 3. intimal fibrous thickening Fig. 10 X 180; Fig. ii X300.?Case 3. Pulmonary arterioles showing gross intimal with almost complete occlusion of the lumen. FlG. 12.?Case 3. Pulmonary arteriole X 300. There is thickening and splitting of the internal elastic lamina with gross intimal fibrosis with almost complete occlusion of the lumen.
Figs. 7 and
8.?Case
2.
PRIMARY PULMONARY HYPERTENSION
337
recanalisation while in the others collections of small round cells were The adventitia in all these vessels was present in the fibrous intima.
healthy
the
and the media showed only pressure atrophy in areas beneath grossly thickened intima (Figs. 5, 6, 7, 8). The alveolar capillaries
were
healthy. Organs.?Well-marked signs
Other
present in the other organs. sclerosis elsewhere in the body.
were
of chronic venous congestion There was no evidence of arterio-
Case III
patient was a married woman aged 22 years. She was admitted hospital complaining of breathlessness of two years' duration. This had become much worse during the last six months. She had also noticed swelling of the feet and legs for the past three weeks and at The
to
this time her breathlessness became much she had been or
cyanosed.
There
disease. On examination the
patient
was
no
worse.
previous
For the past week history of rheumatic
respiratory
cyanosed and orthopnoeic. Gross rib 9th posteriorly. There was marked present up venous engorgement of the neck veins. The pulse was 112 per min. and the in time force blood and regular pressure 110 mm. systolic and 65 mm. diastolic. The apex beat was in the 5th left intercostal space well outside the midclavicular line and was tapping in character. A soft, systolic murmur was audible at the apex of the heart and the anasarca
was
to
was
the
second sound was markedly accentuated. The liver was grossly enlarged, free fluid was elicited on the abdomen and thoracic cavity but no accompaniments were audible in the chest. An electrocardiogram showed tachycardia with marked right axis deviation. The patient died suddenly three hours after admission.
pulmonary
Post-Mortem Examination The
body was that of a well-developed adult female showing gross oedema from the feet to the mid thorax. Serotis Sacs.?The pericardial sac contained about 40 c.c. of serous fluid. Each pleural sac contained about 300 c.c. of serous fluid and the peritoneal sac contained about a litre of serous fluid.
pitting
Cardiovascular System.?The heart weighed 400 gm. It was firm in consistence and was globular in shape. The pericardial surface was smooth and glistening. The right auricle was
enlarged,
dilated and the myocardium definitely
hypertrophied. The tricuspid dilated and the cusps were healthy. The right ventricle was dilated and its wall markedly hypertrophied, being as thick as the muscle of the left ventricle. The left auricle and left ventricle were slightly dilated but the muscle was of the normal thickness. The valve
ring
was
mitral valve ring was dilated but the cusps valves were healthy. vol. lxi. no. 10.
were
healthy.
The aortic z
A. WHITLEY BRANWOOD
338 The aorta showed
early
atheromatous
deposits
in the abdominal
portion. Pulmonary Artery.?The main pulmonary artery and its major and minor branches were obviously dilated. Atheromatous plaques were
present in all these vessels and many of them
were
of considerable
size.
Respiratory System.?There was congestion of the mucous memlarynx, trachea and bronchi. The left lung weighed 260 gm. and the right weighed 400 gm. Both lungs were of moderate size and were normal in shape, apart The pleural from basal atelectasis caused by the pleural effusions. surface was smooth and glistening and the lung parenchyma appeared normal. There was no evidence of fibrosis or any lesion capable of producing right ventricular hypertrophy. Other Organs.?Apart from chronic venous congestion no other brane of the
abnormalities
were
detected.
Histological
Examination
Lungs.?The pleura showed no abnormalities. There was an occasional dust laden macrophage in the alveoli but there were no signs of chronic venous congestion and the alveoli, bronchi and bronchioles and interstitial stroma were normal. Pulmonary Vessels.?The main trunk of the pulmonary artery and its branches showed atheroma of the intima with no changes either in the media, other than slight pressure atrophy, or in the adventitia. The arterioles showed gross intimal fibrous thickening reducing the lumen in many cases to a mere slit. Small round cells were again present in this fibrous tissue in many of the vessels. The internal elastic lamina, as in the previous two cases, showed splitting and reduplication. The adventitia was healthy but the media again showed
atrophy in areas deep to the greatly thickened intima (Figs. 9, 12). The alveolar capillaries showed no abnormalities. Other Organs.?There was chronic venous congestion in all the
pressure 10, 11,
No evidence of arterial disease was present in the other organs. small vessels elsewhere. These three cases illustrate the clinical and pathological features of this disease. Clinical Features.?Most authors have found primary pulmonary hypertension to occur in the age groups between 20 and 40 although Cross et al. described the disease in a patient only 20 months old, and MacCallum found the condition present in a patient aged 74 years. The ages of the three cases in this series were 38, 37 and 22 years. Sixty per cent, of all the cases described in the literature, in whom the
sex
were
all
was
stated,
were
females.
The three
cases
described above
women.
The duration of the symptoms varies from
a
few months
to
years.
PRIMARY PULMONARY HYPERTENSION
339
MacCallum reported a patient who lived fifteen years after the onset Brenner, in a review of this subject, stated that the disease ran a course of from five months to five years.
of symptoms.
In this series only one patient had symptoms of some definite duration, Case III, who had complained for two years. The other two individuals stated they had had heart trouble " for years ". Once symptoms develop, however, the disease runs a progressive course and as described by Hart, Brenner, Killingsworth, and Evans usually ends in sudden death as was the Gilmour Brill, case in the three patients described above. Sudden death appears to be a feature of right ventricular hypertrophy and failure, for very
downhill
congenital heart disease with right ventricular hypertrophy right-sided failure die suddenly. It is interesting to note that intravenous digitalis, which usually has a good effect in congestive cardiac failure, had no effect at all in the one case in this series, where it was administered, indeed death occurred very shortly afterwards. Dresdale et al. have also noted this fact and conclude that the heart failure in these cases is not favourably influenced by digitalis.
many
cases
of
and
The main
clinical features in 39 cases in the literature, from Monckeberg's description in 1907 to the cases described by Jernell in 1950, were dyspnoea on exertion, weakness, substernal anginal pain, syncope and cyanosis. All these symptoms were present in at least of the patients in this series. (Edema appears to be a late feature of the disease. There is usually regular rhythm and the pulmonary second sound is invariably accentuated on auscultation of the heart. Distended neck veins, hepatomegaly and ascites are present. The
one
absence of moist sounds in the chest was a notable feature in these three patients and is in keeping with the findings in the cases in the literature. Haemodynamic studies by cardiac catheterisation, in the three cases described by Dresdale et al. showed greatly elevated
elevated right ventricular diastolic pressures and diminished cardiac output. There was an increased difference between the arterial and venous oxygen content and a normal arterial blood oxygen saturation. The dyspnoea and the cyanosis, both
pulmonary artery pressures,
thus be explained. somewhat puzzling. It is well known, however, that the coronary blood flow is greatest during diastole and it is possible that the marked rise in the right ventricular diastolic pressure may impede the coronary circulation. This could account for the anginal symptoms and could precipitate
symptoms being greatly exaggerated by effort, The angina and syncopal attacks in these cases
can
are
cardiac arrest with resultant syncope. Support is given to this suggestion by one of the cases described by Dresdale. One patient in his series developed severe chest pains and then fainted during an exercise
tolerance test, and for the
a half minutes no heart sounds also stated that relative coronary have Krygier chest both of the was the cause pain and of the sudden insufficiency death in their cases. It is interesting to note, however, that angina
Were audible.
next one and
Brill and
vol. lxi. no. 10.
z 2
A. WHITLEY BRANWOOD
340
syncopal attacks are pulmonary hypertension.
and
not
important symptoms
in
secondary
The absence of moist sounds in the chest in the cases in this series and also noted in the literature is not surprising in view of the main pathological changes being proximal to the alveolar capillaries and the absence histologically of any congestive changes in the lungs. Pathological Features
findings in these three cases were (a) right ventricular hypertrophy, (b) dilatation of the main pulmonary vessels, (c) atheroma of these vessels, and (d) arteriolosclerosis of the pulmonary arterioles. The above changes are identical with those seen in the systemic It is tempting to note the circulation in essential hypertension. between essential similarity hypertension and primary pulmonary which was hypertension previously pointed out by Brill et al. in 1941 and Raaschou and Samuelsson in 1946. In both diseases the aetiology is, as yet, unknown. The elevated pressure in essential hypertension is thought to be caused by increased tonus of the arterioles. In primary pulmonary hypertension also there would appear to be an increased tonus of the pulmonary arterioles for Dresdale et al. have demonstrated a fall in the pulmonary vascular resistance following the administration of priscolene. The right ventricular hypertrophy and the dilatation of the main pulmonary artery seen in the cases described above, and in the literature, would appear to be due to the elevated pulmonary pressure, analogous to the left ventricular hypertrophy and aortic dilatation which is encountered in hypertension involving the systemic circulation. Another feature in common between systemic hypertension and primary pulmonary hypertension are the identical changes in the respective vascular beds. These changes, in both instances, The main
may range from normal vessels to obliterative arteriolosclerosis.
It is
generally accepted that the hall mark of prolonged systemic hypertension is found in the arterioles, the changes in the pulmonary arterioles would therefore indicate pulmonary hypertension as the cause of the vascular sclerosis in these
cases.
Summary Three cases of primary pulmonary hypertension are described. The clinical and pathological features of this condition are briefly The author is in agreement with Dresdale and other discussed. believe that the cause of this condition is a primary who workers elevation of the pulmonary pressure brought about by increased tone of the pulmonary vessels and there is evidence to suggest that the autonomic
nervous
system may be
a
factor in this disease.
I wish to thank Professor A. M. Drennan for his help and advice and I would like to acknowledge the co-operation of the late Dr W. Forbes in the compilation of this paper. I am indebted to Mr T. C. Dodds for the micro-photographs.
PRIMARY
PULMONARY
HYPERTENSION
341
REFERENCES
Brenner, O. (1935), Med., 56, 211. Brill, I. C. et al. (1941), Arch. Int. Med., 68, 560. Cross, K. R. et al. (1947), Amer. Journ. Clin. Path., 17, 155. De Navasquez, S. et al. (1940), Brit. Heart Journ., 2, 177. Dresdale, D. T. et al. (1951), Amer. Journ. Med., 11, 686. GlLMOUR, J. R., and Evans, W. (1946), Journ. Path, and Bad., 58, 687. Hart, C. (1916), Berl. Klin. Wchnschr., 53, 304. Jernell, O. (1950), Acta Med. Scandinav., 138, 430. KlLLlNGSWORTH, W. P. et al. (1939), Amer. Journ. Dis. Child., 57, 1099. Arch. Int.
MacCallum, W. G. (1931), Bull. Johns Hopkins Hosp., 49, 37. Monckeberg, J. G. (1907), Deutsche Med. Wchnschr., 33, 1243. Raaschou, F., and SAMUELSSON, S. (1946), Acta Med. Scandinav. Suppl., 206,
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