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Idiopathic pulmonary hypertension: Etiology, pathogenesis, diagnosis and treatment
Idiopathic Puhnonary Hypertension: Etiology, Pathogenesis, Diagnosis and Treatment By WILLIA.',t V~rlIITAKERAND DONALD HZA~rH INCE it became possible to record pulmonary artery blood pressures directly by cardiac catheterization, puhnonary arterial hypertension has been recognized as a complication of several diseases. It has been shown to occur in patients suffering from intrinsic heart disease, such as mitral stenosis or a congenital septal defect, with parenchymal lung disease such as emphysema, anthracosis or sarcoidosis, or with disease such as bilharzial endarteritis, lymphangitis, carcinomatosa or recurrent pulmonary embolism, which obstruct the pulmonary arterial bed. The occurrence of a primary pulmonary vascular disease had been suspected since 1891, when Romberg ~ reported a case in which hypertrophy of the right ventricle and pulmonary arterial sclerosis were found at autopsy in the absence of any apparent causal lesion, but the proof of the existence of this condition awaited cardiac catlleterization. In the last few years :there havebeen-several reports of series of patients with severe pulmonary arterial hypertension, who were not suffering from any of tile above recognizable predisposing diseases, and Dresdale, Schulz and Michtom "~ first pointed out that these patients presented a distinctive clinical syndrome which they termed "primary puhnonary hypertension." The existence of this condition is now firmly accepted, but it is a disease which is difficult to diagnose, since all patients with severe pulmonary arterial hypertension present a similar clinicopathologic picture, termed hypertensive pulmonary vascular disease by Heath and \Vhitaker, '~ which is dominated in life by the symptoms and signs of pulmonary hypertension and characterized at autopsy by specific changes in the small pulmonary blood vessels. Wood, 4 however, has recognized the condition 17 times and has decribed clinical features which he considers highly distinctive of the syndrome.
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CLINICAL FF~TUnF_S
Incidence.~It is difllcult to assess the incidence of idiopathic puhnonary hypertension from a survey of published cases, since it is obvious that, until recently, many patients with the disease were not recognized. An exhaustive analysis of the literature up to 1935, by Brenner, 5 produced only 16 cases which would have been acceptable as .suffering from idiopathic pulmonary hypertension while, in contrast, at least 34 new patients were described in 1957. G9 The best guide to the frequency of this disease has undoubtedly been given by Wood, 4 who found 17 examples in a consecutive clinical series of approximately 10,000 patients with cardiovascular disease personally examined by him. Tiffs is equivalent to an incidence of 0.17 per cent. In Brenner's 5 survey primary pulmonary vascular disease occurred mostly in childhood, adolescence and earl), adult life. Dresdale and his colleagues-~ recognized that idiopathic pulmonary hypertension might occur at any age but 380
IDIOPATIIIC
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described tlle syndrome as generally affecting young adults of either sex. However, subsequent series 4,G9 have shown a striking difference in the sex distribution of the disease, with an incidence in females of about 75 per cent. The majority of cases have appeared before tile age of 40, but the disease has been recognized in tile elderly,4 and recently Berthrong and Coehran 1~ reported a series of nine dlildren. Symptoms.--Breathlessness and fatigue with exertion, chest pain of anginal type, cough, blueness of the lips and nails, and abdominal distention and ankle swelling, due to congestive heart failure, arc common symptoms. Hemoptyses, hoarseness, syncopal attacks, palpitations and jaundice occnr ]ess frequently. Most of these symptoms also occur in other diseases where there is severe pulmonary hypertension,.~ so that they appear to be characteristic / of this complication and are probably related to anatomic abnormalities induced in the puhnonary blood vessels by the raised blood pressure. Breathlessness on exertion has been the dominant symptom in all reported series. Wade and Ball G comment on the striking difference between the distress on effort and well being at rest and state that none of their patients were orthopneie. In contrast Evans and his colleagues9 foundS'that sb: of their I i patients :developed ordmpnea and in five of these six the terminal stage was characterized by paroxysms of dyspnea with intense cyanosis, chest pain and occasionally repeated syncope. Pulmonary function has not been studied extensively in idiopathic pulmonary hypertension but the results -~ from the few patients whom tests have been carried out indicate that dyspnea is not due to impairment of ventilator), function. From a pathologic study of the pulmonary arteries in a child of 11 months with Eisenmenger's complex, Edwards L~ believed that the onset of dyspnea was related to the development in the pulmonary arteries of intimal changes caused by the pulmonary hypertension. It seems possible that the progressive dyspnea that occurs with other types of heart disease associated with pulmonary hypertension, including idiopathic pulmonary hypertension, is also due to anatomic changes which occur in the pulmonary vessels in all these patients. Like dyspnea, chest pain is a symptom common to all forms of heart disease associated with pulmonary hypertensiona and occurs in about 30 per cent of.patients with idiopathic pulmonary hypertension.4,C,",~3,~* All agree that the chest pain is of anginal type, and it has usually been reported as associated with effort. However, Evans and his associates9 observed that pain sometimes occurred at rest or at night and thought that its invariable association with dyspnea distinguished it from the usual form of coronary pain. Viar and Harrison 15 noted that nitroglycerine had no effect on chest pain associated with pulmonary hypertension and suggested that it was caused by distention of the main pulmonary arteries. However, most authors -",4,G consider that the chest pain is due to a funetio.nal coronary insufficiency, and Stuckey~ after investigating its pathogenesis concluded that it was essentially related to a severely restricted cardiac output and a high pulmonary vascular resistance with an inadequate
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XVILLIA.NI ~,VIIITAKEH AND DONALD IIEATII
coronary flow on effort. Similarly, effort syncope, which has occurred in about 20 pe r cent of patients reported with primary pulmonary hypertension, is caused by cerebral anemia consequent upon a low cardiac output. Howarth and Lowe~r have shown that in this type of patient exercise may produce a rise in pulmonary artery blood pressure which leads to acute right ventricular failure and a fall in cardiac output;/ Although hemoptysis has been described-~ it is rare in patients with idiopathic pulmonary hypertension. It is possible that tlle thin-walled pulmonary capillaries and veins are protected from the high puhnonary blood pressures by the anatomic changes that develop in the puhnonary arterioles and muscu!ar pulmonary arteries in this condition. In ourl experience a history of chronic cough and colds is very characteristic of patients With idiopathic pulmonary hypertension8 and commonly occnrs with other diseases associated with pulmonary hypertension. BrintonlSdescribed a patient with idiopathic ptfhnonary hypertension who had lost his. voice due to paralysis of the left vocal cord caused by pressure on tlm recurrent laryngeal nerve by the grossly dilated pulmonary arteries. This type of hoarseness also occurs in other patients with hypertensive pulmonary vascular disease, wjlo lmve extreme dilatation of the pulmonary arteries. Congestive failure is the usual terminal stage in idiopathic pulmonary hypertension and frequently produces symptoms as well as signs. Signs.~In idiopatlfic pulmonary hypertension the clinical picture is dominated by th e signs of right ventricular llypertrophy and pulmonary hypertension, and in the later stages of the disease there is invariably evidence of congestive heart failure, often accompanied by tricuspid incompetence. Tlm arterial pulse is small. The rhythm is usually regular, but terminally in chronic cases atrial flutter or fibrillation may occur.4 Cyanosis occurs commonly as a terminal feature and, unless there is a reversed shunt through a patent foramen ovale, is primarily peripheral in origin. Clubbing of the fingers is never conspicuous. Pulsation in the jugular veins is usually abnormal. ~Vood* has emphasized the importance of a giant "a" wave in the jugular venous pnlse of patients with idiopathic pulmonary hypertension, for lie believes that such waves deny the existence of an alternative ronte for blood ejected from the right ventricle and exclude patent ductus and ventrieular septal defect in diagnosis. Witil the development of heart failure the right atrium may also fail and the giant "a" wave may. disappear. Later when functional tricuspid incompetence appears, a single systolic wave dominates the venous pulse. This complication with the resultant hepatie distention and further lowering Of the eardiae output undoubtedly contributes in producing the terminal elinical picture with jaundice, facial pigmentation and cold, blue extremities. Palpation almost always provides evidence of right ventricular hypertrophy, for .a powerful heave can usually be felt between the left sternal border and the mid-clavicular line. In more than half the patients it will
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Fro. 1 . - - S y n c h r o n o u s recordings of jngular p h l e b o g r a m , electrocardiogram ( l e a d I I ) a n d p h o n o c a r d i o g r a m in tile p u h n o n a r y area. T h e phlebograna shows p r o m i n e n t presystolic 'a" waves. T h e p e a k e d P waves suggest right atrial h y p e r t r o p h y . Tile p h o n o c a r d i o g r a m shows a loud second s o u n d a n d a triple rhythm.
also indicate the presence of pulmonary hypertension when there is a systolic thrust over the pulmonary artery and a diastolic shock is felt synchronous with pulmonary valve closure. On auscultation tile dominant sign is a loud second heart sound, which is closely split, with accentuation of the second pulmonary element. Loud pulmonary systolic eiection murmurs are rare but in about half the cases pulmonary early systolic eiection clicks have been present and a Graham Steell pulmonary incompetent diastolic murmur has been described iu about 30 per cent2 With tile development of tricuspid incompetence a pansystolic murnmr appears, and this is often heard well out to tile apex. A triple rhythm is a common feature and is probably a right atrial gallop, 4.s (fig. 1), although some observers have considered it usually due to a third heart sound. Although the above signs are characteristic of idiopathic puhnonary hypertension, they cannot be considered pathognomonic of this disease since few of us have the ability to recognize the slight distinctions which dif-
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ferentiate them from similar signs occurring in all patients with hypertensive pulmonary vascular disease. SPECIAL
INVESTIGATIONS
Electrocardiograt~hy.--The electrocardiogram in idiopathic pulmonary hypertension always presents unequivocal evidence of right ~;entrieular hypertrophy (fig. 2). There is often also a P pulmonale indicating right atrial hypertrophy. While these signs are characteristic of idiopathic pulmonary hypertension, they are not pathognomonie of it since, like many of the symptoms and signs, they occur with mitral stenosis and right to left shunts complicated by severe pulmonary hypertension. Radiology.--Radiologie examination of patients with idiopathic pulmonary hypertension shows dilatation of the pulmonary artery and its main branches, abnormally clear peripheral hmg fields and cardiac enlargement that is due to right ventrieular hypertrophy (fig. 3), but may suggest left ventrieular hypertrophy. These features are found in other forms of heart disease complicated by severe pulmonary arterial hypertension,~9-"-z and often mask other radiologie signs that occur with this disease, so that i t is impossible to differentiate idiopathic pulmonary hypertension from ventricular septal defect, atrial septal defect or patent ductus with pulmonary
IDIOPATtlIC PUL.~IONAHY tlYPERTENSION
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FIG. 3.--Postcroanterior tcleradiogram from a patient with idiopathic pulmonary hypertension, showing moderate over-all cardiac enlargement with prominence of the pulmonary trunk and its main branches. The peripheral hmg fields arc unusually clear. hypertension by examination of teleradiograms. Patients with mitral stenosis with severe puhnonary hypertension, who may show clinical and cardiographic featilres identical with those of idiopathic pulmonary hypertension can usually be distinguished on radiologic examination by the degree of left atrial enlargement, pulmonary hemosiderosis and horizontal lines at tile lung bases. 22 Angiocardiography.---As in all patients with severe pulmonary hypertension, angiocardiography demonstrates dilated main pulmonary arteries and a coppicing effect i n the peripheral lung fields. This method is not of diagnostic importance in idiopathic pulmonary hypertension unless there is central cyanosis when the demonstration of the absence of an abnormal shunt from the right chambers of the heart excludes conditions such as patent ductus, atrial septal defect and ventricnlar septal defect with reversal of flow. Cardiac catheterization.~By cardiac catheterization in patients with idio-
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pathie pulmonary hypertension it has been possible to demonstrate severe pulmonary arterial hypertension, normal pulmonary capillary blood pressure, abnormally high right atrial pulse pressures, normal or only slightly reduced arterial blood oxygen saturation and an abnormally low mixed venous blood oxygen saturation, indicating an increased arteriovenous oxygen difference and a low cardiac output. -~ When the pulmonary vascular resistance is calculated, it is abnormally high, being about eight times normal? The slight arterial oxygen unsaturation which is occasionally found in patients with idiopathic pulmonary hypertension has been discussed by Wade and Ball ~ and Evans and his colleagues, 9 who attribute it to venous admixture through arteriovenons shunts in tile lungs and not to an), diffusion defect. Cardiac catheterization is the most important method of special investigation, since it distinguishes patients with congenital cardiac anomalies such as patent ductus, atrial septal defect and ventricular septal defect with severe pulmonary arterial hypertension and balanced slmnts who are clinically indistinct from patients with idiopathic puhnonary hypertension. In the anomaly under discussion the blood samples show no evidence of an intracardiac slmnt while in these other congenital anomalies, even when the flows appear balanced from clinical examination, it is usual to detect some change in the oxygen saturation of samples from tile right side of the heart, and it is usually possible to direct the tip of the catheter through a ductus or a septal defect. Polycythemia may develop, but it is never very severe. Renal function has not been extensively studied, but Werkfi and Eliasch u and Heath and his associates s found a low glomerular filteration rate, a low renal plasma flow and a low renal blood flow in their cases. DIFFERENTIAL D~G,-,'osIs The differential diagnosis of idiopathic pulmonary hypertension is from other cyanotic and aeyanotie conditions associated with pulmonary hypertension. Cyanosis in idiopathic pulmonary hypertension is rarely so severe as in patients with septal defects, patent duetus or transposition, associated with pulmonary hypertension in whom the degree of polyeythemia may be so severe as to mimic polyeythemi_a rubra vera. a9 A long history of recurrent puhnonary infection and signs of pulmonary hypertension and eyanosis may suggest chronic pulmonary heart disease but the absence of carbon dioxide retention will exclude this diagnosis. -"4 Since the clinical, radiologie and electrocardiographic features of eases with left to right shunts and pulmonary hypertension may be indistinguishable from idiopathic pulmonary laypertension, these lesions are dit~eult to differentiate from it unless anglocardiography and cardiac catheterization are carried out. Angiocardiograms show no intracardiac shunt in idiopathic pulmonary hypertension but often demonstrate early filling of an overriding aorta in Eisenmenger's complex,-"~ early filling of the descending aorta from the pulmonary artery in patent ductus arteriosus, a~ early filling of the left atrium in atrial septal defect, ~'~ and early filling of the left ventricle in ventrieular septal defect, when
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IDIOPATIIIC PUL.XIONARY IIYPERTENSION
these anomalies are associated with pulmonary hypertension of s u c h a degree as to cause reversal of the flow. After studying patients with congenital septal defects complicated by severe pulmonary hypertension, who o,l clinical, radiologic and cardiographic examination had appeared indistinguishable from patients with idiopathic pulmonary hypertension, tile present authors thought that tile latter diagnosis could be sustained only when autopsy proof was available. 19 However, it now seems that cardiac catheterization usually reveals underlying congenital cardiac anomalies, when they are present, and that, if at this investigation it has not bee,a possible to pass the catheter through a ductus or ~, septal defect to demonstrate an intracardiae shunt from an examination of tile oxygen saturation of tile blood samples from the heart, idiopathic pulRaonary hypertension may generally be diagnosed. Shepherd and his associates r have demonstrated t h a t indicator-dilution methods are useful for detecting a shunt. Mitral stenosis, which is the commonest lesion found with severe pulmonary hypertension, presents tile same clinical syndrome as idiopathic pulmonary hypertension and may be difficult to recognize if tile classic signs are masked by the large right ventricle. Tile diagnosis may be suggested by a history of dleumatie fever and it is usual to be able to detect an opening snap or a diastolic murmur on auscultation. Radiologic examination will help by demonstrating left atrial enlargement, pulmonary hemosiderosis, horizontal lines at the lung bases -"-~or mitral valve calcification, a If doubt persists after clinical and radiologie examination, mitral stenosis can always be differentiated from idiopathic pulmonary hypertension by recording the left atrial pressure, bronchoscopically or by suprasternal puncture, since it is difficult to obtain satisfactory wedge pressures With severe pulmonary hypertension, and demonstrating the abnormally high pressures behind the stenosed valve. Pulmonary hypertension and right heart failure due to recurrent pulmonary embolism may be impossible to distinguish from idiopathic pulmonary hypertension, but in general, embolic or thrombotic pulmonary hypertension occurs at an older age and from the history it may be possible to recognize episodes of peripheral venous thrombosis and pulmonary infarction. Systemic sclerosis, periarteritis nodosa, disseminated lupus and schistosomiasis must all be considered as causes of puhnonary hypertension and eliminated by negative clinical and laboratory investigations. COURSE AND
TREAT~tENT
Although patients with idiopathic puhnonary hypertension may have symptoms of breathlessness for many years and have survived up to 10 years after the onset of symptoms, the average duration of life after tile condition has been recognized is about three years. 4 After tile onset of congestive heart failure tile disease runs a nmlignant course to death within two years. There is no treatment which has any significant influence on the course of idiopathic puhnonary hypertension. Although XVood4 found that Pris-
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~VILLIAXI ~VIIITAKER AND DONALD IIEATtI
eoline, aeetylcholine and aminophylline all lowered the pulmonary artery blood pressure when he injected them into the pulmonary artery, maintenance therapy with these and other hypotensive drugs has not had the slightest effect on the course of the disease. -",4"e' Furthermore, hypotensive dru~s lowering the systemic blood pressure are potentially dangerous, for they are liable to cause a lethal d~'op in coronary artery blood flow. There is no strong case for sympathectomy in idiopatlfic pulmonary hypertension and where tried tim operation appears to lmve been a dangerous venture.-~ Prolonged anticoagulant therapy, a steroids 4,G and decompression of the pulmonary circulation by a subclavian-pulmonary artery anastomosis a have all been reported without any beneficial effect on the progress of the disease. In t h e management of idiopathic pulmonary hypertension one can either adopt an attitude of therapeutic nihilism to the primary disease and concentrate on the prevention and treatment of heart failure by usual methods, or advise restriction of activities, mild hypotensive drugs, prolonged anticoagulant therapy and steroids whida will probably not heneficially inlluence the course of the r PATIIOLOGY
The struetural changes in the pulmonary arteries in idiopathic puhnonary hypertension are closely related both to the hemodynamie conditions in the lesser circulation and to the time of onset of the raised pulmonary artery blood pressure3 ~ (figs. 4-8). They are of little hel P, however, in elucidating the etiology of the disease. In the following account the nature and significance of the structural changes occurring in each class of pulmonary artery will be considered.
Elastic Pulmonary Arteries The pulmonary trunk and the large puhnonary afleries exceeding about lmm. in external diameter are classified as "elastic" arteries. The media of this type of vessel consists of smooth muscle fibers, elastic fibrils, collagen and ground substance, generally considered to be an acid mucopolysaccharide related to chondroitins B and C. Three of these four elements show changes, either qualitative or quantitative in nature, in association with pulmonary arterial hypertension. The intima of the elastic pulmonary artery consisting of an endothelial lining, with an underlying subintima of collagen in tim pulmonary trunk and the large vessels, also changes in reaction to increased blood pressure. There are no significant alterations ha tim adventitia of this class of vessel in response to pulmonary hypertension. Muscle fibers.~In pulmonary hypertension there is muscular hypertrophy in tim media of elastic arteries just as there is in the wall of the right ventricle or the snmll muscular pulmonary arteries in the lung substance. As a result of this the elastic arteries increase in thickness. Normally the ratio of the thickness of the media of the pulmonary trunk to tlmt of the aorta is in the range ~ of 0.4 to 0.7. In patients with idiopathic pulmonary hypertension, or any form of heart disease with severe elevation of pulmonary artery blood
IDIOPATIIIC PUL.'klONARY ttYPERTENSION
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Fxa. 4.--a. (at left) Part of transverse section of nor,hal aorta stained to demonstrate elastic tissue by the Lawson modification of the Weigert-Sheridan method. The elastic fibrils are long, uniform and parallel; they do not branch. In the fetus and the newborn the configuration of the elastic tissue rcsem~cs this aortic pattern very closely (x 150). b. (middle) Part of transverse section of norma'~ pulmonary trunk also stained to show the elastic tissue. The elastic tissue configuration consists of a loosely arranged network of fragmented elastic fibrils, which are branched and in some cases show clublike terminal expansions. This adult pattern arises after a transitional period in infancy when the long elastic fibrils of the fetal pulmonary trunk break into stick-like fragments. c. (at right) Part of transverse section of the pulmonary trunk in a woman with idiopathic pulmonary hypertension. The elastic tissue configuration resembles that of the nor,nal adult pulmonary trunk. This demonstrates that the puhnonary hypertension in this case was acquired after the normal transition, in infancy, of the elastic tissue configuration in the puhnonary trunk from tbe fetal to the adnh pattern. If pulmonary hypertension is present from birth, as in a large ventricular septal defect or widely patent ductus arteriosus, the fetal, aortic-like configuration of elastic tissue is retained. (x 100). pressure, this ratio approaches or exceeds unity. -"GAs tile elastic arteries thicken they also dilate, demonstrating that true muscular h y p e r t r o p h y with tile formation of new muscle does occur as a response to p u l m o n a r y hypertension. Some authors have been reluctant to a c c e p t this fact and have considered constriction to account for the increase i n - m e d i a l thickness in pulm o n a r y arteries exposed to hypertension. It would a p p e a r that in idiopathic p u l m o n a r y hypertension both constriction and true medial h y p e r t r o p h y m a y occur in the small muscular pulmonary arteries. Elastic 15brils.NThe cases of idiopathic p u l m o n a r y hypertension in which we have had an opportunity to study tile configuration of tile elastic tissue of tile p u l m o n a r y trunk have all been adult, and tlle pattern has been that seen in the normal adult p u l m o n a r y artery. This is of significance in indicating that in these cases the pulmonary hypertension was acquired after the transition from the fetal a r r a n g e m e n t of elastic tissue in the p u l m o n a r y trunk to the adult form had occurred. Hence the idiopathic p u l m o n a r y hypertension in these cases was not present from birth but an acquired phenomenon.
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~VILLIA.~,[ ~VIIITAKER AND DONALD IIEATIt
FiG. 5.--a. (at left) Transverse section of a muscular pulmonary artery from a boy, aged 14 years, with idiopatlfic pulmonary hypertension. There is medial hypertrophy and increase in thickness of the inteLnal elastic lamina (x 230). b. (at right) Transverse suction of a pulmonary arterial vessel of arteriolar dimensions from the same case. There is a thick muscular media with internal and external elastic laminae. The wall of a pulmenary arteriole norlnally consists of a single elastic lamina (x 560). (In both cases the stain employed was Elastic/Van Gieson) In the fetus tile elastic tissue of tile media of tile puhnonary trunk is very similar to that seen in the fetal aorta. In both, the elastic fibrils are long, uniform, non-branched and parallel to one another. In infancy these long fibrils fragment into stick-like rods3 G This transitional configuration soon merges into tlle adult configuration of elastic tissue in the pulmonary trunk which consists of a loosely arranged network of branched, fragmented elastic fibrils which often show club-like terminal expansions. This disorderly, non-parallel arrangement of the elastica of tile normal pulmonary trunk allows a transverse section of this vessel to be immediately distinguished from one of the normal aorta (fig: 4). This transition does not occur in those forms of heart disease associated with arterial p u l m o n a r y hypertension from birth, such as a large communication between tile ventricles or between tile aorta and the pulmonary trunk, so that tile elastie configuration of the pulmonary trunk in such cas.es is like that of the aorta3 ~' When pulmonary hypertension is acquired in adult life, as in the secundum type of atrial septal defect or rheumatic mitral stenosis, the transition to tile adult pulmonary configuration of elastic tissue in the pulmonary trunk has already occurred. -~ Hence the association of pulmonary hypertension with a normal configuration of elastic tissue in the media of the pulmonary trunk, as in the cases of idiopathic pulmonary hypertension referred to, implies that the raised pulmonary artery blood pressure was acquired. Since we Imve made this observation on only a small group of adult cases it would not be jus-
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stress of severely increased vascular resistance distally this artery has become dilated. Contrast this appearance with the medial hypertrophy shown in figure 5a. The media is necrotic, and holes can be seen in this layer. To the left of the
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derived from the media and thrombns !~'r are present in the lmnen (x 100). (Stain: Elastic/Van Gieson)
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illustrated in figure 5. In addition to the abuormal mnscnlar media sandwiched between '.'nternal and external elastic laminae is severe intimal fibrosis which almost totally occludes the vessel (x 560). (Stain: Elastic/Van Gicson) Fro. 8 (bottom, right).--Transverse section of a muscular puhnonary artery from a girl, aged 12 years, with idiopathic pulnmnary hypertension. The healing stage of arterial necrosis is present. Tim arcs of media destroyed by acatte necrotizing arteritis have been replaced by fibrous tissue which also forms masses in the adventitia and the lumen of the vessel9 (Stain: Elastic/Van Gieson)
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assume tliat all forms of idiopathic pulmonary hypertension are A study of the configuration of elastic tissue in the pulmonary aorta from a large series of cases is clearly desirable to settle this subslance.~Ground substance, which stains metaehromatically
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with tolnidine blue and which is considered to be acid mucopolysaeeharide related to chondroitins B and C, is found in the normal aorta and pulmonary trunk in young and aged persons. While it is found universally in the pulmonary trunk in diseases associated with pulmonary arterial hypertension, it is also present in the pulmonary trunk of cases of Fallot's tetralogy and pulmonary stenosis. Hence the presence of this metachromic material in the media of the elastic pulmonary artery in idiopathic pulmonary hyperteosion is of doubtful significance. It is however, well known that areas of media filled with this mucopolysaccharide tend to become cystic by the very nature of the mucoid material. While such a cystic change is found to a minimal degree in normal elastic arteries, it appears to become much accentuated in the presence of pulmonary hypertension.G,19 Hence the presence of "cystic medial necrosis" in tlle pulmonary trunk is of importance, first, because it is suggestive of increased pulmonary artery blood pressure and, secondly, because its existence in the media weakens this structure at tile very time that it is exposed to increased intravascular tension, and it is not surprising that rupture of the pulmonary trunk occurs under such circumstances, as Intimal reaction.~Iu .idiopathic pulmonary hypertension the intima of the elastic pulmonary arteries becomes the site for the development of atheromatous plaques. -0,27,-0s This is not specific for this disease since pulmonary athcroma is characteristic of all conditions associated with pulmonary arterial hypertension, even including young children with Fallot's tetralogy associated with a raised pulmonary artery blood pressure. -"9 Atheroma in the lesser circulation is not even specific for pulmonary hypertension since it is commonly found in the middle-aged and elderly who die from diseases unassociated with hemodynamie abnormalities in the lesser circulation. Intimal fibrosis in tile large elastic arteries is uncommon in idiopathic pulmonary hypertension, as in other forms of h)q~ertensive puhnonary vascular disease.
Mzlscular P,Imonary Arteries and Arterioles Medial hyperlrolJhy.--In idiopathic pu!monary hypertension many of tile muscular pulmonary arteries,6,2s (arterial vessels defined as exceeding 100 t~. in diameter) and pulmonary arterioles (arterial vessels less than 100 /~. in diameter) have a thick muscular media bounded by internal and external elastic laminae which may be equivalent in thickness to 30 per cent of the external diameter of the vesseF. (fig. 5). This represents a severe increase in medial thickness in these vessels, for tile normal muscular pulmonary artery under 300 It. in external diameter has a medial thickness less than 5 per cent of the external diameter of the vessel and tlle normal arteriole has no recognizable muscular media at all. 5 Available evidence suggests that both constriction and tile medial hypertrophy, including tile development of longitudinal and spiral smooth muscle,6 are concerned in bringing about this increase in medial thickness. Whatever the etiology of tile increase in the thickness of the media, the presence of vessels less than 100 ~.
393
IDIOPATIIIC PUL.~,IONARY tIYPERTENSION
in diameter with a thick muscular media between well defined internal and external elastic laminae is pathognomonic of severe pulmonary hypertension, though not necessarily, of course, of the idiopathic variety (fig. 7). Generalized vasCtdar dilatation.win all forms of hypertensive pulmonary vascular_disease, and especially in the case of idiopathic pulmonary hypertension where the rise in pulmonary arteriolar resistance is rapid, generalized dilatation occurs throughout the pulmonary vascular bed s (fig. 6). This is usually subsequent to the development of the thick media and since at first only some of the arterial vessels show dilatation, one sees hypertrophied and widely dilated muscular pulmonary arteries and pulmonary arterioles existing side by side in the same section of lung. For this reason it is clear that in idiopathic pulmonary hypertension as in all diseases associated with severely raised pulmonary artery blood pressure, the measurement of lumen-to-wall ratios, a technic widely used by many authors, is valueless and misleading. Intimal changes.--Intimal reaction is very commonly found in the small arteries and arterioles of the lung in idiopatlfic pulmonary hypertension. It is usually fibrous in nature (fig. 7), 2,r'8 either cellular or acellular, and very severe so that total occlusion of many small arteries throughout the lung occurs. This fibrous occlusion appears to be the cause for the very high total pulmonary and pulmonary arteriolar resistance in this disease. Tim fibrotic occlusion is clmracteristically focaF so that pulmonary arteries in lung biopsies may show only hypertrophy, or only dilatation, and this proves a trap for the unwary in the assessment of vascular changes in such material. Muscular intimal proliferation in arteries 100 ft. or less in diameter has been reported. 6 Localized "dilatation leslons."---As well as generalized arterial dilatation seen in this disease, localized, highly complex forms of dilatation may occur, giving rise to bizarre "dilatation lesions. These are essentially excessive dilatation of a segment of the pulmonary arterial tree usually at the site of origin of a small pulmonary arterial branch; They are found either proximal in the pulmonary vascular bed as a side branch of a medium-sized muscular pulmonary artery or distally as a terminal branch of a small muscular artery. Inside these distended sacs, endothelial cellular proliferation occurs. Four main types of "dilatation lesion" occur. They are (a) the plexiform lesion, so called because of the plexiform pattern of the proliferated endothelium in the distended sac, (b) the vein-like branch of an occluded muscular artery arising proximal to a focus of fibrotic occlusion and passing to the lung substance to form a collateral pulmonary blood flow, (c) the cavernous lesion and (d) the angiomatoid lesion. In the latter forms the designations are descriptive of the form of the dilated sacs in the lung substance. " Physiologic associations.--The association of medial hypertrophy in some pulmonary arteries with generalized and localized forms of dilatation in others, and the existence of widespread focal occlusio~ of muscular pulmonary arteries and arterioles forms a distinctive histologic picture that characterizes tile more severe forms of hypertensive pulmonary vascular disease. The association of 9
"
"30
394
WILLIA~Xt WtlITAKEH AND DONALD IIEA'I"}|
these features is of special importance in idiopathic pulmonary hypertension, for examples of this disease coming to autopsy rarely show earlier forms of structural change as is common in congenital heart disease. This combination of medial hypertrophy, vascular dilatation and widespreadocclusion of arteries by fibrous tissue has been known to have a precise physiologic connotation, always being associated with a very high total pulmonary and pulmonary arteriolar resistance, a high pulmonary artery blood pressure, a diminished pulmonary blood flow, usually 31 less than 2.5 L./M 2. Corresponding vascular changes found in association with congenital septal defects in the heart have been demonstrated to be associated with puhnonary hypertension which is either irreversible or only partially reversible, with a residual elevation of pulmonary artery blood pressure after surgical closure of the defect. 3z To summarize our description so far, tile structural changes in the pulmonary arteries in a case of idiopathic pulmonary hypertension are those of severe hypertensive pulmonary vascular disease of an aquired type such as might be found in a case of atrial septal defect with severe pulmonary hypertension. They are merely the structural changes brought about by the effects of acquired pulmonary hypertension and are in no sense specific for idiopathic pulmonary-hypertension. Necrolizing arterilis.--The high incidence of neerotizing arteritis in idiopathic pulmonary hypertension 6,2s tends to single this condition out from other forms of hypertensive pulmonary vascular disease, although again it must be stated,that medial necrosis is also found in the pulmonary arteries in pulmonary hypertension complicating congenital defects. In short, necrotizing arteritis is characteristic but not pathognomonic of idiopathic pulmonary hypertension (figs. 6 and 8). The reason for the relative frequency of necrosis of the muscle of the media in this disease appears to be that the pulmonary hypertension is of sudden onset and is rapidly exaggerated to extreme heights. This appears t o be the real significance of medial necrosis and since this hemodynamic situation is most commonly found in idiopathic pulmonary laypertension, so is the corresponding structural change in the pulmonary arteries. Both the acute stage, characterized by fibrinoid necrosis of tile medial muscle with a surrounding inflammatory response of polymorphonuclears, eosinophils and giant cells, and a subacute stateare found r (figs. 6 and 8). The latter is typified by masses of young basophilie granulation tissue in the media, forming dumb-bell shaped masses in the intima and adventitia.r,s Thrombi and emboli.mThrombi commonly, if not always, form over necrotic areas of media, and many of these are carried in the blood stream from the site of formation to plug the arterioles and smallest muscular arteries in the lung. 7 These thrombi then become organized 6 and form foci of fibrous tissue indistinguishable from those apparently formed directly as an effect of the pulmonary arterial hypertension on t h e intima of tile smallest pulmonary arteries. Thrombi- not formed near necrotic muscle also occur in idiopathic pulmonary.]~ypertension.-o,9,'-'T It is conceivable that emboli may initiate the vicious Circle of hypertension and fibrous occlusion in the pulmonary arteries, but it will be appreciated that it is impossible to differentiate cause from
IDIOPATIIIC PUL.X.fONAllYIIYPEHTENSION
effect by histologic means. in offering suggestions as histologic changes which with being the effect of arteries.
395
Herein lies the extreme difficulty for the pathologist to the etiology of pulmonary hypertension, for all have been described in this article are compatible severe pulmonary hypertension on the pulmonary ETIOLOGIC FACTORS
Numerous etiologic factors lmve been suggested. The predominance of the disease in the female. 7-9 has led some authors r to postulate nonfatal amniotic pulmonary embolism as a cause. The same authors r believe that in some cases the basis for the disease lies in the conditions set up by the menstrual cycle stimulating thrombosis in the puhnonary arteries or in the uterine vessels, which in turn leads to small and recurring pulmonary emboli. Recurring pulmonary thrombi or emboli, not related to the menstrual cycle, are commonly held to be an important etiological factor, r,33,3~ Increased tonus of the small pulmonary arteries with contraction of the terminal arterial segments is an important possibility. -~ Other factors which have been suggested are multiple loci of medial aplasia w i t h reactive intimal fibrosis over them, ~ syphilitic arteritis, and the excessive entry of blood-into the lesser circulation from the bronchial arteriesY It m a y well be, as suggested by Wade and Ball, G that this disease is not homogeneous clinically or pathologically. They favor the coexistence of functional contraction of muscular pulmonary arteries and abnormal bronchopulmonary anastomotie channels to bring about the pulmonary hypertension, but believe pulmonary arteritis may characterize a third group. From an examination of the configuration of the elastic tissue of the pulmonary trunk it should be possible to say at least whether cases of idiopathic pulmonary hypertension are all presen t from birth, all acquired or a heterogeneous group. REFERENCES 1. Romberg, E.: Ucber Sklerose der Lungenarterie. Deutsches Arch.klin.Med. 48:197, 1891. 2. Dresdale, D. T., Schultz, M. and Michtom, R. J.: Primary pulmonary hypertcnsion. Am.J.Med. 11:686, 1951. 3. Heath, D. and Whitaker, W.: tlypertensive pulmonary vascular disease. Circulation.14:323, 1956. 4. Wood, P.: Diseases of the Heart and Circulation. London, Eyre and Spottiswoode, 1956. 5. Brenner, O.: Pathology of the vessels of tile pulmonary circulation. Arch. Int.Med. 56:211, 1935. 6. Wade, G. and Ball, J.: Unexplained pulmonary hypertension. QuartJ.Med. 26:83, 1957. 7. Shepherd, J. T., Edwards, J. E., Bur-
8. 9. 10.
11.
chell, H. B., Swan, tt. J. C. and Wood, E. tI.: Clinical, physiological and pathological considerations in patients with idiopathic puhnonary hypertension. Brit. Heart J. 19:70, 1957. Heath, D., Whitaker, W. and Brown, J. W.: Idiopathic pulmonary hypertension. Brit. Heart J. 19:83, 1957. Evans, W., Short, D. S. and Bedford, D. E.: Solitary puhnonary hypertension. Brit. Heart J. 19:93, 1957. Berthrong, M. and Cochran, T. H.: Pathological findings in nine children with "primary" pulmonary hypertension. Johns Hopkins Ilosp.Bull. 97:69, 1955. WerkS, L. and Eliasch, H.: Circulatory studies in a case of primary pulmonary hypertension. Cardiologica
39~
21:403, 1952. 12. Edwards, J. E., In Gould, S. G., Ed.: Pathology of the Heart. Springfield, I11., C. C Thomas, 1953. 13. Gilmour, J. R. and Evans, W.: Primary pulmonary hypertension. J.Path.et. Bact. 58:687, 1946. 14. Branwood, A. W.: Primary pulmonary hypertension. Edinburgh MJ. 61:332, 1954. 15. Viar, W. N. and Harrison, T. R.: Chest pain in association with puhnonary hypertension. Circulation 5:1, 1952. 16. Stuckcy, D.: Cardiac pain in association with mitral stenosis and congenital heart disease. Brit. Heart J. 17:397, 1955. 17. Howarth, S. and Lowe, J. B.: The mechanism of effort syncope in primary pulmonary hypertension and cyanotic congenital heart disease. Brit. Heart J. 15.-47, 1953. 18. Brinton, W. D.: Primary'puhnonary hypertension. Brit. I/cart J. 12:305, 1950. 19. Whitakcr, W., Iteath, D. and Brown, J. W.: Patent ductus arteriosus with pulmonary hypertension. Brit. Heart J. 17:121, 1955. 20. Brown, J. W., Iteath, D. and Whitaker, W.: Eisenmenger's complex. Brit. Heart J. 17:273, 1955. 21. Heath, D., Brown, J. W. and Whitaker, W.: Mnscular defects in the ventricular septum. Brit. Heart J. 18:1, 1956. 22. Whitakcr, W., and Lodge, T.: Radiological~ manifestations of puhnonary hypertension in patients with mitral stenosis. J.Fac.Radiologists. 5:182, 1954. 23: Howarth, S., McMichael, J. and SharpeySchafcr, E. P.: Cardiac catheterization in cases of patent interauricular septmn, primary pulmonary hypertension, Fallot's tetralogy and pulmonary stenosis. Brit. Heart J. 9:292, 1947. 24. Platts, M. and Whitaker, W.: The diagnostic importance of the blood carbon dioxide content of patients with central cyanosis. Am. Ileart J. 48:77, 1954. 25. Inklcy, S. R., Gillespie, L. and Funkhouser, R. K.: Two cases of primary
WILLIA.~t ~VtIITAKER AND DONALD tIEATII pulmonary hypertension with sudden death associated with the administration of barbiturates. Ann.Int. Med. 43:396, 1955. 26. Heath, D., Wood, E. H. Dnshane, J. W. and Edwards, J. E.: The structure of the pulmonary trunk at different ages and in cases of pulmonary hypertension and pulmonary stenosis. J. Path.Bact. 77, April, 1959. 27. Brinton, W. D.: Primary pulmonary hypertension. Brit. Heart J. 12:305, 1950. 28. Aitchison, J. D. and Richmond, H. G.: Pulmonary hypertension associated with necrotizing pulmonary arteritis. Brit. Heart J. 17:312, 1955. 29.. tteath, D., Wood, E. H., Dushane, J. W. and Edwards, J. E.: The relation of age and blood pressure to atheroma in the pulmonary arteries and thoracic aorta in congenital heart disease. Lab.Invest. In press. 30. - and Edwards, J. E.: The pathology of hypertensive pulmonary vascular disease; a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation 18:533, 1958. 31.--, Helmholz, H. F., Jr., Burchell, H. B., Dushane, J. W. and Edwards, J. E.: Graded pulmonary vascular changes and haemodynamie findings in atrial and vcntricular septal defect and patent ductus arteriosus. Circulation 18:1155, 1958. 32.--, Hohnolz, H. F., Jr., Burchell, It. B., Dushane, J. '~V., Kirklin, J. W. and Edwards, J. E.: Relation between structural changes in the small pulmonary arteries and the immediate reversibility of pulmonary hypertension following closure of ventricular and atrial septal defects. Circulation 18:1167, 1958. 33. Barnard, P. J.: Thrombo-embolie primary pulmonary arteriosclerosis. Brit. tteart J. 16:93, 1954. 34. Castleman, B. and Bland, E. T.: Organised emboli of the tertiary pulmonary arteries. An unusual cause of cor pulmonale. Arch.Path. 42:581, 1946.
S
CLINICAL FF~TUnF_S
Incidence.~It is difllcult to assess the incidence of idiopathic puhnonary hypertension from a survey of published cases, since it is obvious that, until recently, many patients with the disease were not recognized. An exhaustive analysis of the literature up to 1935, by Brenner, 5 produced only 16 cases which would have been acceptable as .suffering from idiopathic pulmonary hypertension while, in contrast, at least 34 new patients were described in 1957. G9 The best guide to the frequency of this disease has undoubtedly been given by Wood, 4 who found 17 examples in a consecutive clinical series of approximately 10,000 patients with cardiovascular disease personally examined by him. Tiffs is equivalent to an incidence of 0.17 per cent. In Brenner's 5 survey primary pulmonary vascular disease occurred mostly in childhood, adolescence and earl), adult life. Dresdale and his colleagues-~ recognized that idiopathic pulmonary hypertension might occur at any age but 380
IDIOPATIIIC
PUL.-~IONARY ttYPERTENSION
381
described tlle syndrome as generally affecting young adults of either sex. However, subsequent series 4,G9 have shown a striking difference in the sex distribution of the disease, with an incidence in females of about 75 per cent. The majority of cases have appeared before tile age of 40, but the disease has been recognized in tile elderly,4 and recently Berthrong and Coehran 1~ reported a series of nine dlildren. Symptoms.--Breathlessness and fatigue with exertion, chest pain of anginal type, cough, blueness of the lips and nails, and abdominal distention and ankle swelling, due to congestive heart failure, arc common symptoms. Hemoptyses, hoarseness, syncopal attacks, palpitations and jaundice occnr ]ess frequently. Most of these symptoms also occur in other diseases where there is severe pulmonary hypertension,.~ so that they appear to be characteristic / of this complication and are probably related to anatomic abnormalities induced in the puhnonary blood vessels by the raised blood pressure. Breathlessness on exertion has been the dominant symptom in all reported series. Wade and Ball G comment on the striking difference between the distress on effort and well being at rest and state that none of their patients were orthopneie. In contrast Evans and his colleagues9 foundS'that sb: of their I i patients :developed ordmpnea and in five of these six the terminal stage was characterized by paroxysms of dyspnea with intense cyanosis, chest pain and occasionally repeated syncope. Pulmonary function has not been studied extensively in idiopathic pulmonary hypertension but the results -~ from the few patients whom tests have been carried out indicate that dyspnea is not due to impairment of ventilator), function. From a pathologic study of the pulmonary arteries in a child of 11 months with Eisenmenger's complex, Edwards L~ believed that the onset of dyspnea was related to the development in the pulmonary arteries of intimal changes caused by the pulmonary hypertension. It seems possible that the progressive dyspnea that occurs with other types of heart disease associated with pulmonary hypertension, including idiopathic pulmonary hypertension, is also due to anatomic changes which occur in the pulmonary vessels in all these patients. Like dyspnea, chest pain is a symptom common to all forms of heart disease associated with pulmonary hypertensiona and occurs in about 30 per cent of.patients with idiopathic pulmonary hypertension.4,C,",~3,~* All agree that the chest pain is of anginal type, and it has usually been reported as associated with effort. However, Evans and his associates9 observed that pain sometimes occurred at rest or at night and thought that its invariable association with dyspnea distinguished it from the usual form of coronary pain. Viar and Harrison 15 noted that nitroglycerine had no effect on chest pain associated with pulmonary hypertension and suggested that it was caused by distention of the main pulmonary arteries. However, most authors -",4,G consider that the chest pain is due to a funetio.nal coronary insufficiency, and Stuckey~ after investigating its pathogenesis concluded that it was essentially related to a severely restricted cardiac output and a high pulmonary vascular resistance with an inadequate
38~
XVILLIA.NI ~,VIIITAKEH AND DONALD IIEATII
coronary flow on effort. Similarly, effort syncope, which has occurred in about 20 pe r cent of patients reported with primary pulmonary hypertension, is caused by cerebral anemia consequent upon a low cardiac output. Howarth and Lowe~r have shown that in this type of patient exercise may produce a rise in pulmonary artery blood pressure which leads to acute right ventricular failure and a fall in cardiac output;/ Although hemoptysis has been described-~ it is rare in patients with idiopathic pulmonary hypertension. It is possible that tlle thin-walled pulmonary capillaries and veins are protected from the high puhnonary blood pressures by the anatomic changes that develop in the puhnonary arterioles and muscu!ar pulmonary arteries in this condition. In ourl experience a history of chronic cough and colds is very characteristic of patients With idiopathic pulmonary hypertension8 and commonly occnrs with other diseases associated with pulmonary hypertension. BrintonlSdescribed a patient with idiopathic ptfhnonary hypertension who had lost his. voice due to paralysis of the left vocal cord caused by pressure on tlm recurrent laryngeal nerve by the grossly dilated pulmonary arteries. This type of hoarseness also occurs in other patients with hypertensive pulmonary vascular disease, wjlo lmve extreme dilatation of the pulmonary arteries. Congestive failure is the usual terminal stage in idiopathic pulmonary hypertension and frequently produces symptoms as well as signs. Signs.~In idiopatlfic pulmonary hypertension the clinical picture is dominated by th e signs of right ventricular llypertrophy and pulmonary hypertension, and in the later stages of the disease there is invariably evidence of congestive heart failure, often accompanied by tricuspid incompetence. Tlm arterial pulse is small. The rhythm is usually regular, but terminally in chronic cases atrial flutter or fibrillation may occur.4 Cyanosis occurs commonly as a terminal feature and, unless there is a reversed shunt through a patent foramen ovale, is primarily peripheral in origin. Clubbing of the fingers is never conspicuous. Pulsation in the jugular veins is usually abnormal. ~Vood* has emphasized the importance of a giant "a" wave in the jugular venous pnlse of patients with idiopathic pulmonary hypertension, for lie believes that such waves deny the existence of an alternative ronte for blood ejected from the right ventricle and exclude patent ductus and ventrieular septal defect in diagnosis. Witil the development of heart failure the right atrium may also fail and the giant "a" wave may. disappear. Later when functional tricuspid incompetence appears, a single systolic wave dominates the venous pulse. This complication with the resultant hepatie distention and further lowering Of the eardiae output undoubtedly contributes in producing the terminal elinical picture with jaundice, facial pigmentation and cold, blue extremities. Palpation almost always provides evidence of right ventricular hypertrophy, for .a powerful heave can usually be felt between the left sternal border and the mid-clavicular line. In more than half the patients it will
383
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also indicate the presence of pulmonary hypertension when there is a systolic thrust over the pulmonary artery and a diastolic shock is felt synchronous with pulmonary valve closure. On auscultation tile dominant sign is a loud second heart sound, which is closely split, with accentuation of the second pulmonary element. Loud pulmonary systolic eiection murmurs are rare but in about half the cases pulmonary early systolic eiection clicks have been present and a Graham Steell pulmonary incompetent diastolic murmur has been described iu about 30 per cent2 With tile development of tricuspid incompetence a pansystolic murnmr appears, and this is often heard well out to tile apex. A triple rhythm is a common feature and is probably a right atrial gallop, 4.s (fig. 1), although some observers have considered it usually due to a third heart sound. Although the above signs are characteristic of idiopathic puhnonary hypertension, they cannot be considered pathognomonic of this disease since few of us have the ability to recognize the slight distinctions which dif-
384
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ferentiate them from similar signs occurring in all patients with hypertensive pulmonary vascular disease. SPECIAL
INVESTIGATIONS
Electrocardiograt~hy.--The electrocardiogram in idiopathic pulmonary hypertension always presents unequivocal evidence of right ~;entrieular hypertrophy (fig. 2). There is often also a P pulmonale indicating right atrial hypertrophy. While these signs are characteristic of idiopathic pulmonary hypertension, they are not pathognomonie of it since, like many of the symptoms and signs, they occur with mitral stenosis and right to left shunts complicated by severe pulmonary hypertension. Radiology.--Radiologie examination of patients with idiopathic pulmonary hypertension shows dilatation of the pulmonary artery and its main branches, abnormally clear peripheral hmg fields and cardiac enlargement that is due to right ventrieular hypertrophy (fig. 3), but may suggest left ventrieular hypertrophy. These features are found in other forms of heart disease complicated by severe pulmonary arterial hypertension,~9-"-z and often mask other radiologie signs that occur with this disease, so that i t is impossible to differentiate idiopathic pulmonary hypertension from ventricular septal defect, atrial septal defect or patent ductus with pulmonary
IDIOPATtlIC PUL.~IONAHY tlYPERTENSION
385
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FIG. 3.--Postcroanterior tcleradiogram from a patient with idiopathic pulmonary hypertension, showing moderate over-all cardiac enlargement with prominence of the pulmonary trunk and its main branches. The peripheral hmg fields arc unusually clear. hypertension by examination of teleradiograms. Patients with mitral stenosis with severe puhnonary hypertension, who may show clinical and cardiographic featilres identical with those of idiopathic pulmonary hypertension can usually be distinguished on radiologic examination by the degree of left atrial enlargement, pulmonary hemosiderosis and horizontal lines at tile lung bases. 22 Angiocardiography.---As in all patients with severe pulmonary hypertension, angiocardiography demonstrates dilated main pulmonary arteries and a coppicing effect i n the peripheral lung fields. This method is not of diagnostic importance in idiopathic pulmonary hypertension unless there is central cyanosis when the demonstration of the absence of an abnormal shunt from the right chambers of the heart excludes conditions such as patent ductus, atrial septal defect and ventricnlar septal defect with reversal of flow. Cardiac catheterization.~By cardiac catheterization in patients with idio-
386
V,'ILLIA3[ ~VInTAKER AND DONALD IIEATII
pathie pulmonary hypertension it has been possible to demonstrate severe pulmonary arterial hypertension, normal pulmonary capillary blood pressure, abnormally high right atrial pulse pressures, normal or only slightly reduced arterial blood oxygen saturation and an abnormally low mixed venous blood oxygen saturation, indicating an increased arteriovenous oxygen difference and a low cardiac output. -~ When the pulmonary vascular resistance is calculated, it is abnormally high, being about eight times normal? The slight arterial oxygen unsaturation which is occasionally found in patients with idiopathic pulmonary hypertension has been discussed by Wade and Ball ~ and Evans and his colleagues, 9 who attribute it to venous admixture through arteriovenons shunts in tile lungs and not to an), diffusion defect. Cardiac catheterization is the most important method of special investigation, since it distinguishes patients with congenital cardiac anomalies such as patent ductus, atrial septal defect and ventricular septal defect with severe pulmonary arterial hypertension and balanced slmnts who are clinically indistinct from patients with idiopathic puhnonary hypertension. In the anomaly under discussion the blood samples show no evidence of an intracardiac slmnt while in these other congenital anomalies, even when the flows appear balanced from clinical examination, it is usual to detect some change in the oxygen saturation of samples from tile right side of the heart, and it is usually possible to direct the tip of the catheter through a ductus or a septal defect. Polycythemia may develop, but it is never very severe. Renal function has not been extensively studied, but Werkfi and Eliasch u and Heath and his associates s found a low glomerular filteration rate, a low renal plasma flow and a low renal blood flow in their cases. DIFFERENTIAL D~G,-,'osIs The differential diagnosis of idiopathic pulmonary hypertension is from other cyanotic and aeyanotie conditions associated with pulmonary hypertension. Cyanosis in idiopathic pulmonary hypertension is rarely so severe as in patients with septal defects, patent duetus or transposition, associated with pulmonary hypertension in whom the degree of polyeythemia may be so severe as to mimic polyeythemi_a rubra vera. a9 A long history of recurrent puhnonary infection and signs of pulmonary hypertension and eyanosis may suggest chronic pulmonary heart disease but the absence of carbon dioxide retention will exclude this diagnosis. -"4 Since the clinical, radiologie and electrocardiographic features of eases with left to right shunts and pulmonary hypertension may be indistinguishable from idiopathic pulmonary laypertension, these lesions are dit~eult to differentiate from it unless anglocardiography and cardiac catheterization are carried out. Angiocardiograms show no intracardiac shunt in idiopathic pulmonary hypertension but often demonstrate early filling of an overriding aorta in Eisenmenger's complex,-"~ early filling of the descending aorta from the pulmonary artery in patent ductus arteriosus, a~ early filling of the left atrium in atrial septal defect, ~'~ and early filling of the left ventricle in ventrieular septal defect, when
387
IDIOPATIIIC PUL.XIONARY IIYPERTENSION
these anomalies are associated with pulmonary hypertension of s u c h a degree as to cause reversal of the flow. After studying patients with congenital septal defects complicated by severe pulmonary hypertension, who o,l clinical, radiologic and cardiographic examination had appeared indistinguishable from patients with idiopathic pulmonary hypertension, tile present authors thought that tile latter diagnosis could be sustained only when autopsy proof was available. 19 However, it now seems that cardiac catheterization usually reveals underlying congenital cardiac anomalies, when they are present, and that, if at this investigation it has not bee,a possible to pass the catheter through a ductus or ~, septal defect to demonstrate an intracardiae shunt from an examination of tile oxygen saturation of tile blood samples from the heart, idiopathic pulRaonary hypertension may generally be diagnosed. Shepherd and his associates r have demonstrated t h a t indicator-dilution methods are useful for detecting a shunt. Mitral stenosis, which is the commonest lesion found with severe pulmonary hypertension, presents tile same clinical syndrome as idiopathic pulmonary hypertension and may be difficult to recognize if tile classic signs are masked by the large right ventricle. Tile diagnosis may be suggested by a history of dleumatie fever and it is usual to be able to detect an opening snap or a diastolic murmur on auscultation. Radiologic examination will help by demonstrating left atrial enlargement, pulmonary hemosiderosis, horizontal lines at the lung bases -"-~or mitral valve calcification, a If doubt persists after clinical and radiologie examination, mitral stenosis can always be differentiated from idiopathic pulmonary hypertension by recording the left atrial pressure, bronchoscopically or by suprasternal puncture, since it is difficult to obtain satisfactory wedge pressures With severe pulmonary hypertension, and demonstrating the abnormally high pressures behind the stenosed valve. Pulmonary hypertension and right heart failure due to recurrent pulmonary embolism may be impossible to distinguish from idiopathic pulmonary hypertension, but in general, embolic or thrombotic pulmonary hypertension occurs at an older age and from the history it may be possible to recognize episodes of peripheral venous thrombosis and pulmonary infarction. Systemic sclerosis, periarteritis nodosa, disseminated lupus and schistosomiasis must all be considered as causes of puhnonary hypertension and eliminated by negative clinical and laboratory investigations. COURSE AND
TREAT~tENT
Although patients with idiopathic puhnonary hypertension may have symptoms of breathlessness for many years and have survived up to 10 years after the onset of symptoms, the average duration of life after tile condition has been recognized is about three years. 4 After tile onset of congestive heart failure tile disease runs a nmlignant course to death within two years. There is no treatment which has any significant influence on the course of idiopathic puhnonary hypertension. Although XVood4 found that Pris-
388
~VILLIAXI ~VIIITAKER AND DONALD IIEATtI
eoline, aeetylcholine and aminophylline all lowered the pulmonary artery blood pressure when he injected them into the pulmonary artery, maintenance therapy with these and other hypotensive drugs has not had the slightest effect on the course of the disease. -",4"e' Furthermore, hypotensive dru~s lowering the systemic blood pressure are potentially dangerous, for they are liable to cause a lethal d~'op in coronary artery blood flow. There is no strong case for sympathectomy in idiopatlfic pulmonary hypertension and where tried tim operation appears to lmve been a dangerous venture.-~ Prolonged anticoagulant therapy, a steroids 4,G and decompression of the pulmonary circulation by a subclavian-pulmonary artery anastomosis a have all been reported without any beneficial effect on the progress of the disease. In t h e management of idiopathic pulmonary hypertension one can either adopt an attitude of therapeutic nihilism to the primary disease and concentrate on the prevention and treatment of heart failure by usual methods, or advise restriction of activities, mild hypotensive drugs, prolonged anticoagulant therapy and steroids whida will probably not heneficially inlluence the course of the r PATIIOLOGY
The struetural changes in the pulmonary arteries in idiopathic puhnonary hypertension are closely related both to the hemodynamie conditions in the lesser circulation and to the time of onset of the raised pulmonary artery blood pressure3 ~ (figs. 4-8). They are of little hel P, however, in elucidating the etiology of the disease. In the following account the nature and significance of the structural changes occurring in each class of pulmonary artery will be considered.
Elastic Pulmonary Arteries The pulmonary trunk and the large puhnonary afleries exceeding about lmm. in external diameter are classified as "elastic" arteries. The media of this type of vessel consists of smooth muscle fibers, elastic fibrils, collagen and ground substance, generally considered to be an acid mucopolysaccharide related to chondroitins B and C. Three of these four elements show changes, either qualitative or quantitative in nature, in association with pulmonary arterial hypertension. The intima of the elastic pulmonary artery consisting of an endothelial lining, with an underlying subintima of collagen in tim pulmonary trunk and the large vessels, also changes in reaction to increased blood pressure. There are no significant alterations ha tim adventitia of this class of vessel in response to pulmonary hypertension. Muscle fibers.~In pulmonary hypertension there is muscular hypertrophy in tim media of elastic arteries just as there is in the wall of the right ventricle or the snmll muscular pulmonary arteries in the lung substance. As a result of this the elastic arteries increase in thickness. Normally the ratio of the thickness of the media of the pulmonary trunk to tlmt of the aorta is in the range ~ of 0.4 to 0.7. In patients with idiopathic pulmonary hypertension, or any form of heart disease with severe elevation of pulmonary artery blood
IDIOPATIIIC PUL.'klONARY ttYPERTENSION
389
Fxa. 4.--a. (at left) Part of transverse section of nor,hal aorta stained to demonstrate elastic tissue by the Lawson modification of the Weigert-Sheridan method. The elastic fibrils are long, uniform and parallel; they do not branch. In the fetus and the newborn the configuration of the elastic tissue rcsem~cs this aortic pattern very closely (x 150). b. (middle) Part of transverse section of norma'~ pulmonary trunk also stained to show the elastic tissue. The elastic tissue configuration consists of a loosely arranged network of fragmented elastic fibrils, which are branched and in some cases show clublike terminal expansions. This adult pattern arises after a transitional period in infancy when the long elastic fibrils of the fetal pulmonary trunk break into stick-like fragments. c. (at right) Part of transverse section of the pulmonary trunk in a woman with idiopathic pulmonary hypertension. The elastic tissue configuration resembles that of the nor,nal adult pulmonary trunk. This demonstrates that the puhnonary hypertension in this case was acquired after the normal transition, in infancy, of the elastic tissue configuration in the puhnonary trunk from tbe fetal to the adnh pattern. If pulmonary hypertension is present from birth, as in a large ventricular septal defect or widely patent ductus arteriosus, the fetal, aortic-like configuration of elastic tissue is retained. (x 100). pressure, this ratio approaches or exceeds unity. -"GAs tile elastic arteries thicken they also dilate, demonstrating that true muscular h y p e r t r o p h y with tile formation of new muscle does occur as a response to p u l m o n a r y hypertension. Some authors have been reluctant to a c c e p t this fact and have considered constriction to account for the increase i n - m e d i a l thickness in pulm o n a r y arteries exposed to hypertension. It would a p p e a r that in idiopathic p u l m o n a r y hypertension both constriction and true medial h y p e r t r o p h y m a y occur in the small muscular pulmonary arteries. Elastic 15brils.NThe cases of idiopathic p u l m o n a r y hypertension in which we have had an opportunity to study tile configuration of tile elastic tissue of tile p u l m o n a r y trunk have all been adult, and tlle pattern has been that seen in the normal adult p u l m o n a r y artery. This is of significance in indicating that in these cases the pulmonary hypertension was acquired after the transition from the fetal a r r a n g e m e n t of elastic tissue in the p u l m o n a r y trunk to the adult form had occurred. Hence the idiopathic p u l m o n a r y hypertension in these cases was not present from birth but an acquired phenomenon.
390
~VILLIA.~,[ ~VIIITAKER AND DONALD IIEATIt
FiG. 5.--a. (at left) Transverse section of a muscular pulmonary artery from a boy, aged 14 years, with idiopatlfic pulmonary hypertension. There is medial hypertrophy and increase in thickness of the inteLnal elastic lamina (x 230). b. (at right) Transverse suction of a pulmonary arterial vessel of arteriolar dimensions from the same case. There is a thick muscular media with internal and external elastic laminae. The wall of a pulmenary arteriole norlnally consists of a single elastic lamina (x 560). (In both cases the stain employed was Elastic/Van Gieson) In the fetus tile elastic tissue of tile media of tile puhnonary trunk is very similar to that seen in the fetal aorta. In both, the elastic fibrils are long, uniform, non-branched and parallel to one another. In infancy these long fibrils fragment into stick-like rods3 G This transitional configuration soon merges into tlle adult configuration of elastic tissue in the pulmonary trunk which consists of a loosely arranged network of branched, fragmented elastic fibrils which often show club-like terminal expansions. This disorderly, non-parallel arrangement of the elastica of tile normal pulmonary trunk allows a transverse section of this vessel to be immediately distinguished from one of the normal aorta (fig: 4). This transition does not occur in those forms of heart disease associated with arterial p u l m o n a r y hypertension from birth, such as a large communication between tile ventricles or between tile aorta and the pulmonary trunk, so that tile elastie configuration of the pulmonary trunk in such cas.es is like that of the aorta3 ~' When pulmonary hypertension is acquired in adult life, as in the secundum type of atrial septal defect or rheumatic mitral stenosis, the transition to tile adult pulmonary configuration of elastic tissue in the pulmonary trunk has already occurred. -~ Hence the association of pulmonary hypertension with a normal configuration of elastic tissue in the media of the pulmonary trunk, as in the cases of idiopathic pulmonary hypertension referred to, implies that the raised pulmonary artery blood pressure was acquired. Since we Imve made this observation on only a small group of adult cases it would not be jus-
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stress of severely increased vascular resistance distally this artery has become dilated. Contrast this appearance with the medial hypertrophy shown in figure 5a. The media is necrotic, and holes can be seen in this layer. To the left of the
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illustrated in figure 5. In addition to the abuormal mnscnlar media sandwiched between '.'nternal and external elastic laminae is severe intimal fibrosis which almost totally occludes the vessel (x 560). (Stain: Elastic/Van Gicson) Fro. 8 (bottom, right).--Transverse section of a muscular puhnonary artery from a girl, aged 12 years, with idiopathic pulnmnary hypertension. The healing stage of arterial necrosis is present. Tim arcs of media destroyed by acatte necrotizing arteritis have been replaced by fibrous tissue which also forms masses in the adventitia and the lumen of the vessel9 (Stain: Elastic/Van Gieson)
tifiable to acquired. trunk and point. Ground
assume tliat all forms of idiopathic pulmonary hypertension are A study of the configuration of elastic tissue in the pulmonary aorta from a large series of cases is clearly desirable to settle this subslance.~Ground substance, which stains metaehromatically
392
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with tolnidine blue and which is considered to be acid mucopolysaeeharide related to chondroitins B and C, is found in the normal aorta and pulmonary trunk in young and aged persons. While it is found universally in the pulmonary trunk in diseases associated with pulmonary arterial hypertension, it is also present in the pulmonary trunk of cases of Fallot's tetralogy and pulmonary stenosis. Hence the presence of this metachromic material in the media of the elastic pulmonary artery in idiopathic pulmonary hyperteosion is of doubtful significance. It is however, well known that areas of media filled with this mucopolysaccharide tend to become cystic by the very nature of the mucoid material. While such a cystic change is found to a minimal degree in normal elastic arteries, it appears to become much accentuated in the presence of pulmonary hypertension.G,19 Hence the presence of "cystic medial necrosis" in tlle pulmonary trunk is of importance, first, because it is suggestive of increased pulmonary artery blood pressure and, secondly, because its existence in the media weakens this structure at tile very time that it is exposed to increased intravascular tension, and it is not surprising that rupture of the pulmonary trunk occurs under such circumstances, as Intimal reaction.~Iu .idiopathic pulmonary hypertension the intima of the elastic pulmonary arteries becomes the site for the development of atheromatous plaques. -0,27,-0s This is not specific for this disease since pulmonary athcroma is characteristic of all conditions associated with pulmonary arterial hypertension, even including young children with Fallot's tetralogy associated with a raised pulmonary artery blood pressure. -"9 Atheroma in the lesser circulation is not even specific for pulmonary hypertension since it is commonly found in the middle-aged and elderly who die from diseases unassociated with hemodynamie abnormalities in the lesser circulation. Intimal fibrosis in tile large elastic arteries is uncommon in idiopathic pulmonary hypertension, as in other forms of h)q~ertensive puhnonary vascular disease.
Mzlscular P,Imonary Arteries and Arterioles Medial hyperlrolJhy.--In idiopathic pu!monary hypertension many of tile muscular pulmonary arteries,6,2s (arterial vessels defined as exceeding 100 t~. in diameter) and pulmonary arterioles (arterial vessels less than 100 /~. in diameter) have a thick muscular media bounded by internal and external elastic laminae which may be equivalent in thickness to 30 per cent of the external diameter of the vesseF. (fig. 5). This represents a severe increase in medial thickness in these vessels, for tile normal muscular pulmonary artery under 300 It. in external diameter has a medial thickness less than 5 per cent of the external diameter of the vessel and tlle normal arteriole has no recognizable muscular media at all. 5 Available evidence suggests that both constriction and tile medial hypertrophy, including tile development of longitudinal and spiral smooth muscle,6 are concerned in bringing about this increase in medial thickness. Whatever the etiology of tile increase in the thickness of the media, the presence of vessels less than 100 ~.
393
IDIOPATIIIC PUL.~,IONARY tIYPERTENSION
in diameter with a thick muscular media between well defined internal and external elastic laminae is pathognomonic of severe pulmonary hypertension, though not necessarily, of course, of the idiopathic variety (fig. 7). Generalized vasCtdar dilatation.win all forms of hypertensive pulmonary vascular_disease, and especially in the case of idiopathic pulmonary hypertension where the rise in pulmonary arteriolar resistance is rapid, generalized dilatation occurs throughout the pulmonary vascular bed s (fig. 6). This is usually subsequent to the development of the thick media and since at first only some of the arterial vessels show dilatation, one sees hypertrophied and widely dilated muscular pulmonary arteries and pulmonary arterioles existing side by side in the same section of lung. For this reason it is clear that in idiopathic pulmonary hypertension as in all diseases associated with severely raised pulmonary artery blood pressure, the measurement of lumen-to-wall ratios, a technic widely used by many authors, is valueless and misleading. Intimal changes.--Intimal reaction is very commonly found in the small arteries and arterioles of the lung in idiopatlfic pulmonary hypertension. It is usually fibrous in nature (fig. 7), 2,r'8 either cellular or acellular, and very severe so that total occlusion of many small arteries throughout the lung occurs. This fibrous occlusion appears to be the cause for the very high total pulmonary and pulmonary arteriolar resistance in this disease. Tim fibrotic occlusion is clmracteristically focaF so that pulmonary arteries in lung biopsies may show only hypertrophy, or only dilatation, and this proves a trap for the unwary in the assessment of vascular changes in such material. Muscular intimal proliferation in arteries 100 ft. or less in diameter has been reported. 6 Localized "dilatation leslons."---As well as generalized arterial dilatation seen in this disease, localized, highly complex forms of dilatation may occur, giving rise to bizarre "dilatation lesions. These are essentially excessive dilatation of a segment of the pulmonary arterial tree usually at the site of origin of a small pulmonary arterial branch; They are found either proximal in the pulmonary vascular bed as a side branch of a medium-sized muscular pulmonary artery or distally as a terminal branch of a small muscular artery. Inside these distended sacs, endothelial cellular proliferation occurs. Four main types of "dilatation lesion" occur. They are (a) the plexiform lesion, so called because of the plexiform pattern of the proliferated endothelium in the distended sac, (b) the vein-like branch of an occluded muscular artery arising proximal to a focus of fibrotic occlusion and passing to the lung substance to form a collateral pulmonary blood flow, (c) the cavernous lesion and (d) the angiomatoid lesion. In the latter forms the designations are descriptive of the form of the dilated sacs in the lung substance. " Physiologic associations.--The association of medial hypertrophy in some pulmonary arteries with generalized and localized forms of dilatation in others, and the existence of widespread focal occlusio~ of muscular pulmonary arteries and arterioles forms a distinctive histologic picture that characterizes tile more severe forms of hypertensive pulmonary vascular disease. The association of 9
"
"30
394
WILLIA~Xt WtlITAKEH AND DONALD IIEA'I"}|
these features is of special importance in idiopathic pulmonary hypertension, for examples of this disease coming to autopsy rarely show earlier forms of structural change as is common in congenital heart disease. This combination of medial hypertrophy, vascular dilatation and widespreadocclusion of arteries by fibrous tissue has been known to have a precise physiologic connotation, always being associated with a very high total pulmonary and pulmonary arteriolar resistance, a high pulmonary artery blood pressure, a diminished pulmonary blood flow, usually 31 less than 2.5 L./M 2. Corresponding vascular changes found in association with congenital septal defects in the heart have been demonstrated to be associated with puhnonary hypertension which is either irreversible or only partially reversible, with a residual elevation of pulmonary artery blood pressure after surgical closure of the defect. 3z To summarize our description so far, tile structural changes in the pulmonary arteries in a case of idiopathic pulmonary hypertension are those of severe hypertensive pulmonary vascular disease of an aquired type such as might be found in a case of atrial septal defect with severe pulmonary hypertension. They are merely the structural changes brought about by the effects of acquired pulmonary hypertension and are in no sense specific for idiopathic pulmonary-hypertension. Necrolizing arterilis.--The high incidence of neerotizing arteritis in idiopathic pulmonary hypertension 6,2s tends to single this condition out from other forms of hypertensive pulmonary vascular disease, although again it must be stated,that medial necrosis is also found in the pulmonary arteries in pulmonary hypertension complicating congenital defects. In short, necrotizing arteritis is characteristic but not pathognomonic of idiopathic pulmonary hypertension (figs. 6 and 8). The reason for the relative frequency of necrosis of the muscle of the media in this disease appears to be that the pulmonary hypertension is of sudden onset and is rapidly exaggerated to extreme heights. This appears t o be the real significance of medial necrosis and since this hemodynamic situation is most commonly found in idiopathic pulmonary laypertension, so is the corresponding structural change in the pulmonary arteries. Both the acute stage, characterized by fibrinoid necrosis of tile medial muscle with a surrounding inflammatory response of polymorphonuclears, eosinophils and giant cells, and a subacute stateare found r (figs. 6 and 8). The latter is typified by masses of young basophilie granulation tissue in the media, forming dumb-bell shaped masses in the intima and adventitia.r,s Thrombi and emboli.mThrombi commonly, if not always, form over necrotic areas of media, and many of these are carried in the blood stream from the site of formation to plug the arterioles and smallest muscular arteries in the lung. 7 These thrombi then become organized 6 and form foci of fibrous tissue indistinguishable from those apparently formed directly as an effect of the pulmonary arterial hypertension on t h e intima of tile smallest pulmonary arteries. Thrombi- not formed near necrotic muscle also occur in idiopathic pulmonary.]~ypertension.-o,9,'-'T It is conceivable that emboli may initiate the vicious Circle of hypertension and fibrous occlusion in the pulmonary arteries, but it will be appreciated that it is impossible to differentiate cause from
IDIOPATIIIC PUL.X.fONAllYIIYPEHTENSION
effect by histologic means. in offering suggestions as histologic changes which with being the effect of arteries.
395
Herein lies the extreme difficulty for the pathologist to the etiology of pulmonary hypertension, for all have been described in this article are compatible severe pulmonary hypertension on the pulmonary ETIOLOGIC FACTORS
Numerous etiologic factors lmve been suggested. The predominance of the disease in the female. 7-9 has led some authors r to postulate nonfatal amniotic pulmonary embolism as a cause. The same authors r believe that in some cases the basis for the disease lies in the conditions set up by the menstrual cycle stimulating thrombosis in the puhnonary arteries or in the uterine vessels, which in turn leads to small and recurring pulmonary emboli. Recurring pulmonary thrombi or emboli, not related to the menstrual cycle, are commonly held to be an important etiological factor, r,33,3~ Increased tonus of the small pulmonary arteries with contraction of the terminal arterial segments is an important possibility. -~ Other factors which have been suggested are multiple loci of medial aplasia w i t h reactive intimal fibrosis over them, ~ syphilitic arteritis, and the excessive entry of blood-into the lesser circulation from the bronchial arteriesY It m a y well be, as suggested by Wade and Ball, G that this disease is not homogeneous clinically or pathologically. They favor the coexistence of functional contraction of muscular pulmonary arteries and abnormal bronchopulmonary anastomotie channels to bring about the pulmonary hypertension, but believe pulmonary arteritis may characterize a third group. From an examination of the configuration of the elastic tissue of the pulmonary trunk it should be possible to say at least whether cases of idiopathic pulmonary hypertension are all presen t from birth, all acquired or a heterogeneous group. REFERENCES 1. Romberg, E.: Ucber Sklerose der Lungenarterie. Deutsches Arch.klin.Med. 48:197, 1891. 2. Dresdale, D. T., Schultz, M. and Michtom, R. J.: Primary pulmonary hypertcnsion. Am.J.Med. 11:686, 1951. 3. Heath, D. and Whitaker, W.: tlypertensive pulmonary vascular disease. Circulation.14:323, 1956. 4. Wood, P.: Diseases of the Heart and Circulation. London, Eyre and Spottiswoode, 1956. 5. Brenner, O.: Pathology of the vessels of tile pulmonary circulation. Arch. Int.Med. 56:211, 1935. 6. Wade, G. and Ball, J.: Unexplained pulmonary hypertension. QuartJ.Med. 26:83, 1957. 7. Shepherd, J. T., Edwards, J. E., Bur-
8. 9. 10.
11.
chell, H. B., Swan, tt. J. C. and Wood, E. tI.: Clinical, physiological and pathological considerations in patients with idiopathic puhnonary hypertension. Brit. Heart J. 19:70, 1957. Heath, D., Whitaker, W. and Brown, J. W.: Idiopathic pulmonary hypertension. Brit. Heart J. 19:83, 1957. Evans, W., Short, D. S. and Bedford, D. E.: Solitary puhnonary hypertension. Brit. Heart J. 19:93, 1957. Berthrong, M. and Cochran, T. H.: Pathological findings in nine children with "primary" pulmonary hypertension. Johns Hopkins Ilosp.Bull. 97:69, 1955. WerkS, L. and Eliasch, H.: Circulatory studies in a case of primary pulmonary hypertension. Cardiologica
39~
21:403, 1952. 12. Edwards, J. E., In Gould, S. G., Ed.: Pathology of the Heart. Springfield, I11., C. C Thomas, 1953. 13. Gilmour, J. R. and Evans, W.: Primary pulmonary hypertension. J.Path.et. Bact. 58:687, 1946. 14. Branwood, A. W.: Primary pulmonary hypertension. Edinburgh MJ. 61:332, 1954. 15. Viar, W. N. and Harrison, T. R.: Chest pain in association with puhnonary hypertension. Circulation 5:1, 1952. 16. Stuckcy, D.: Cardiac pain in association with mitral stenosis and congenital heart disease. Brit. Heart J. 17:397, 1955. 17. Howarth, S. and Lowe, J. B.: The mechanism of effort syncope in primary pulmonary hypertension and cyanotic congenital heart disease. Brit. Heart J. 15.-47, 1953. 18. Brinton, W. D.: Primary'puhnonary hypertension. Brit. I/cart J. 12:305, 1950. 19. Whitakcr, W., Iteath, D. and Brown, J. W.: Patent ductus arteriosus with pulmonary hypertension. Brit. Heart J. 17:121, 1955. 20. Brown, J. W., Iteath, D. and Whitaker, W.: Eisenmenger's complex. Brit. Heart J. 17:273, 1955. 21. Heath, D., Brown, J. W. and Whitaker, W.: Mnscular defects in the ventricular septum. Brit. Heart J. 18:1, 1956. 22. Whitakcr, W., and Lodge, T.: Radiological~ manifestations of puhnonary hypertension in patients with mitral stenosis. J.Fac.Radiologists. 5:182, 1954. 23: Howarth, S., McMichael, J. and SharpeySchafcr, E. P.: Cardiac catheterization in cases of patent interauricular septmn, primary pulmonary hypertension, Fallot's tetralogy and pulmonary stenosis. Brit. Heart J. 9:292, 1947. 24. Platts, M. and Whitaker, W.: The diagnostic importance of the blood carbon dioxide content of patients with central cyanosis. Am. Ileart J. 48:77, 1954. 25. Inklcy, S. R., Gillespie, L. and Funkhouser, R. K.: Two cases of primary
WILLIA.~t ~VtIITAKER AND DONALD tIEATII pulmonary hypertension with sudden death associated with the administration of barbiturates. Ann.Int. Med. 43:396, 1955. 26. Heath, D., Wood, E. H. Dnshane, J. W. and Edwards, J. E.: The structure of the pulmonary trunk at different ages and in cases of pulmonary hypertension and pulmonary stenosis. J. Path.Bact. 77, April, 1959. 27. Brinton, W. D.: Primary pulmonary hypertension. Brit. Heart J. 12:305, 1950. 28. Aitchison, J. D. and Richmond, H. G.: Pulmonary hypertension associated with necrotizing pulmonary arteritis. Brit. Heart J. 17:312, 1955. 29.. tteath, D., Wood, E. H., Dushane, J. W. and Edwards, J. E.: The relation of age and blood pressure to atheroma in the pulmonary arteries and thoracic aorta in congenital heart disease. Lab.Invest. In press. 30. - and Edwards, J. E.: The pathology of hypertensive pulmonary vascular disease; a description of six grades of structural changes in the pulmonary arteries with special reference to congenital cardiac septal defects. Circulation 18:533, 1958. 31.--, Helmholz, H. F., Jr., Burchell, H. B., Dushane, J. W. and Edwards, J. E.: Graded pulmonary vascular changes and haemodynamie findings in atrial and vcntricular septal defect and patent ductus arteriosus. Circulation 18:1155, 1958. 32.--, Hohnolz, H. F., Jr., Burchell, It. B., Dushane, J. '~V., Kirklin, J. W. and Edwards, J. E.: Relation between structural changes in the small pulmonary arteries and the immediate reversibility of pulmonary hypertension following closure of ventricular and atrial septal defects. Circulation 18:1167, 1958. 33. Barnard, P. J.: Thrombo-embolie primary pulmonary arteriosclerosis. Brit. tteart J. 16:93, 1954. 34. Castleman, B. and Bland, E. T.: Organised emboli of the tertiary pulmonary arteries. An unusual cause of cor pulmonale. Arch.Path. 42:581, 1946.